WO2024217587A1 - Substituted pyrazine compound having axl inhibitory activity - Google Patents

Abstract

The present invention relates to a substituted pyrazine compound having AXL inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and the use thereof. The compound can be used for treating conditions caused by, associated with and/or accompanied by AXL kinase hyperfunction.

Description

Substituted pyrazine compounds with AXL inhibitory activity Technical Field

The present invention belongs to the field of medicine, and in particular, relates to a substituted pyrazine compound having AXL inhibitory activity, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof. The present invention also relates to using the compound and the composition to treat diseases and disease states associated with AXL activity.

Background Art

AXL (also known as UFO, ARK and Tyro7 or JTK11), is a member of the TAM family of receptor tyrosine kinases (RTKs). AXL was originally identified as a transforming gene expressed in cells from patients with chronic myeloid leukemia or chronic myeloproliferative disorders. AXL overexpression has been reported to be associated with a variety of cancers, including non-small cell lung cancer (NSCLC), breast cancer, prostate cancer, gastric cancer, renal cell carcinoma, and glioblastoma. Activation of AXL provides a powerful signal for cell proliferation, survival, migration, invasion, and angiogenesis. In addition, AXL has been increasingly recognized as a key mediator of resistance to many approved tyrosine kinase inhibitor therapies. Therefore, AXL may serve as a potential target for cancer treatment.

In order to meet the current clinical demand for drugs to treat cancer, immune system diseases and circulatory system diseases and achieve better therapeutic effects, designing and researching and developing AXL kinase inhibitors and finding highly effective, low-toxic compounds with clinical application prospects are of great significance to the medical field.

Summary of the invention

The AXL inhibitors reported so far include: compounds with a pyrrolopyrimidine structure disclosed in U.S. Patent Application Publication No. 20100204221 and International Publication No. WO2010/090764; compounds with pyridine and pyrazine structures disclosed in International Publication No. WO2009/053737; compounds with a pyrazinylbenzimidazole structure disclosed in International Publication No. WO2009/024825; compounds with a triazole structure disclosed in International Publication No. WO2008/083367 and International Publication No. WO2008/083353; and compounds with a pyrimidinediamine structure disclosed in International Publication No. WO2008/045978.

The present disclosure provides a compound with novel structure and AXL inhibitory activity.

In one aspect, the present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof:

in,

X, Y ¹ , Y ² or Y ³ are each independently selected from N or CH;

is a double bond or a single bond, and the bond formed by the atoms at positions 5 and 6 and the bond formed by the atoms at positions 4 and 5 are not both double bonds;

When the atoms at positions 4 and 5 form a double bond, and the atoms at positions 5 and 6 form a single bond, ^Y4 is selected from N or CH, and ^Y5 is CH;

When the atoms at positions 4 and 5 form a single bond, and the atoms at positions 5 and 6 form a double bond, ^Y4 is C, ^Y5 is NR ^P , and ^RP is selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkyl substituted with C _6-10 aryl, or C _1-6 alkyl substituted with 3-10 heterocyclic groups;

R ¹ is selected from 5-10 membered heteroaryl, 3-18 membered heterocyclyl or C _2-6 alkynyl, the C _2-6 alkynyl is optionally substituted with halogen, amino, cyano, nitro or hydroxyl, the 5-10 membered heteroaryl or 3-18 membered heterocyclyl is optionally substituted with one or more halogen, carbonyl, amino, cyano, nitro, hydroxyl, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , halogenated C _1-6 alkyl, C _6-10 aryl, C _3-6 cycloalkyl, 5-7 membered heteroaryl, 3-10 membered heterocyclyl, C(O)OR ^1A , C(O)NR ^1B R ^1C , C(O)R ^1D , C(═NR ^1E )R ^1D , C(═NR ^1E )NR ^1B R ^1C , C(═NCN)NR ^1B R ^1C , C(═NOR ^1A )NR ^1B , S(O) ₂ R ^1D , S(O)(═NR ^1E )R ^1C or S(O) ₂ NR ^1B R ^1C , wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or halogenated C _1-6 alkyl is optionally substituted by one or more R ⁸ , and the C _6-10 aryl, C _3-6 cycloalkyl, 5-7 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted by one or more R ⁹ ;

^R8 is selected from _C1-6 alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, ^amino , cyano, nitro, ^OR1AA , C(O) ^R1DD , C(O ^{)NR1BBR1CC ,} OC( ^{O ) NR1BBR1CC} , NR1BBR1CC, ^{NR1BBNR1BBR1CC} , NR1BBC(O) ^R1DD , ^NR1BBC (O) ^OR1F , ^NR1BBC (O ^{) NR1BBR1CC} or hydroxy ^- substituted or unsubstituted ^C3-6 _cycloalkyl ^;

R ⁹ is selected from C _1-6 alkyl, C _1-6 alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, amino, cyano, nitro, OR ^1F , C(O)R ^1DD , C(O)NR ^1BB R ^1CC , OC(O)NR ^1BB R ^1CC , NR ^1BB R ^1CC , NR ^1BB NR ^1BB R ^1CC , NR ^1BB C(O)R ^1DD , NR ^1BB C(O)OR ^1F , NR ^1BB C(O)NR ^1BB R ^1CC or NR ^1BB R ^1CC ;

R ^1A , R ^1B , R ^1C or R ^1D are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or halogenated C _1-6 alkyl;

R ^1E or R ^1F are each independently selected from hydrogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, halogenated C _1-6 alkoxy or halogenated C _1-6 alkyl;

R ^1AA , R ^1BB , R ^1CC and R ^1DD are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or halogenated C _1-6 alkyl;

^R2 is selected from hydrogen, halogen, amino, cyano, nitro, hydroxyl, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl or halogenated _C1-6 alkyl;

R ³ , R ⁴ or R ⁵ are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl;

R ⁶ is selected from C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl, wherein the C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted with halogen, amino, cyano, nitro, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy;

R ^6a is selected from hydrogen, amide, C _1-6 alkyl, halogenated C _1-6 alkyl, halogen, nitro, cyano, amino, hydroxyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy;

R ⁷ is selected from hydrogen, halogen, amino, cyano, nitro, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl or C _1-6 alkanoyl.

In one aspect, the present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof:

in,

X, Y ¹ , Y ² or Y ³ are each independently selected from N or CH;

is a double bond or a single bond, and the bond formed by the atoms at positions 5 and 6 and the bond formed by the atoms at positions 4 and 5 are not both double bonds;

When the atoms at positions 4 and 5 form a double bond, and the atoms at positions 5 and 6 form a single bond, ^Y4 is selected from N or CH, and ^Y5 is CH;

When the atoms at positions 4 and 5 form a single bond, and the atoms at positions 5 and 6 form a double bond, ^Y4 is C, ^Y5 is NR ^P , and ^RP is selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkyl substituted with C _6-10 aryl, or C _1-6 alkyl substituted with 3-10 heterocyclic groups;

R ¹ is selected from 5-10 membered heteroaryl, 3-18 membered heterocyclyl or C _2-6 alkynyl, the C _2-6 alkynyl is optionally substituted by amino, cyano, nitro or hydroxyl, the 5-10 membered heteroaryl or 3-18 membered heterocyclyl is optionally substituted by one or more carbonyl, amino, cyano, nitro, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halogenated C _1-6 alkyl, C _6-10 aryl, C _3-6 cycloalkyl, 5-7 membered heteroaryl, 3-10 membered heterocyclyl, C(O)OR ^1A , C(O)NR ^1B R ^1C , C(O)R ^1D , C(═NR ^1E )R ^1D , C(═NR ^1E )NR ^1B R ^1C , C(═NCN)NR ^1B R ^1C , C(═NOR ^1A )NR ^1B , S(O) ₂ R ^1D , S(O)(═NR ^1E )R ^1C or S(O) ₂ NR ^1B R ^1C , wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or halogenated C _1-6 alkyl is optionally substituted by one or more R ⁸ , and the C _6-10 aryl, C _3-6 cycloalkyl, 5-7 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted by one or more R ⁹ ;

^R8 is selected from _C1-6 alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, ^amino , cyano, nitro, ^OR1AA , C(O) ^R1DD , C(O ^{)NR1BBR1CC ,} OC( ^{O ) NR1BBR1CC} , NR1BBR1CC, ^{NR1BBNR1BBR1CC} , NR1BBC(O) ^R1DD , ^NR1BBC (O) ^OR1F , ^NR1BBC (O ^{) NR1BBR1CC} or hydroxy ^- substituted or unsubstituted ^C3-6 _cycloalkyl ^;

R ⁹ is selected from C _1-6 alkyl, C _1-6 alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, amino, cyano, nitro, OR ^1F , C(O)R ^1DD , C(O)NR ^1BB R ^1CC , OC(O)NR ^1BB R ^1CC , NR ^1BB R ^1CC , NR ^1BB NR ^1BB R ^1CC , NR ^1BB C(O)R ^1DD , NR ^1BB C(O)OR ^1F , NR ^1BB C(O)NR ^1BB R ^1CC or NR ^1BB R ^1CC ;

R ^1A , R ^1B , R ^1C or R ^1D are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or halogenated C _1-6 alkyl;

R ^1E or R ^1F are each independently selected from hydrogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, halogenated C _1-6 alkoxy or halogenated C _1-6 alkyl;

R ^1AA , R ^1BB , R ^1CC and R ^1DD are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or halogenated C _1-6 alkyl;

^R2 is selected from hydrogen, halogen, amino, cyano, nitro, hydroxyl, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl or halogenated _C1-6 alkyl;

R ³ , R ⁴ or R ⁵ are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl;

R ⁶ is selected from C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl, wherein the C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted with halogen, amino, cyano, nitro, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy;

R ^6a is selected from amido, C _1-6 alkyl, halogenated C _1-6 alkyl, halogen, nitro, cyano, amino, hydroxyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy;

R ⁷ is selected from hydrogen, halogen, amino, cyano, nitro, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl or C _1-6 alkanoyl.

In one embodiment, X is N or CH.

In some embodiments, X is N.

In some embodiments, Y ¹ , Y ² or Y ³ is N.

In some embodiments, the atoms at positions 4 and 5 form a double bond, the atoms at positions 5 and 6 form a single bond, and ^Y4 is N and ^Y5 is CH.

In some embodiments, when the atoms at positions 4 and 5 form a single bond and the atoms at positions 5 and 6 form a double bond, ^Y4 is C, ^Y5 is NR ^P , and ^RP is selected from _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkyl substituted with _C6-10 aryl, or _C1-6 alkyl substituted with 3-10 heterocyclyl.

Preferably, ^RP is selected from isopropyl, cyclopentyl, benzyl or

In some embodiments, R ¹ is selected from 5-10 membered heteroaryl, 3-18 membered heterocyclyl or C _2-6 alkynyl, the C _2-6 alkynyl is optionally substituted with hydroxy, the 5-10 membered heteroaryl or 3-18 membered heterocyclyl is optionally substituted with one or more carbonyl, C _1-6 alkyl, 3-10 membered heterocyclyl, C _3-6 cycloalkyl, C(O)OR ^1A or C(O)NR ^1B R ^1C , wherein the C _1-6 alkyl is optionally substituted with one or more R ⁸ , the C _3-6 cycloalkyl or 3-10 membered heterocyclyl is optionally substituted with one or more R ⁹ , and R ^1A , R ^1B , R ^1C , R ⁸ and R ⁹ are as described above.

In some typical embodiments, R ¹ is selected from 5-10 membered heteroaryl or 3-18 membered heterocyclyl, wherein the 5-10 membered heteroaryl or 3-18 membered heterocyclyl is optionally substituted by one or more carbonyl, C _1-6 alkyl, 3-10 membered heterocyclyl, C _3-6 cycloalkyl, C(O)OR ^1A or C(O)NR ^1B R ^1C , wherein the C _1-6 alkyl is optionally substituted by one or more R ⁸ , the C _3-6 cycloalkyl or 3-10 membered heterocyclyl is optionally substituted by one or more R ⁹ ,

R ^1A , R ^1B and R ^1C are each independently selected from hydrogen or C _1-6 alkyl;

R ⁸ is selected from C _1-6 alkoxy, 4-7 membered heterocyclyl, cyano, OR ^1AA , NR ^1BB R ^1CC or C _3-6 cycloalkyl substituted by hydroxy;

R ⁹ is C _1-6 alkyl, 4-7 membered heterocyclic group, cyano, OR ^1F , C(O)R ^1DD or NR ^1BB R ^1CC ;

R ^1F is selected from hydrogen or C _1-6 alkyl;

R ^1AA , R ^1BB , R ^1CC or R ^1DD are each independently selected from hydrogen or C _1-6 alkyl.

In some more typical embodiments, R ¹ is selected from 5-10 membered heteroaryl or 3-18 membered heterocyclyl, wherein the 5-10 membered heteroaryl or 3-18 membered heterocyclyl is optionally substituted by one or more carbonyl, C _1-6 alkyl, 3-10 membered heterocyclyl, C _3-6 cycloalkyl, C(O)OR ^1A or C(O)NR ^1B R ^1C , wherein the C _1-6 alkyl is optionally substituted by one or more R ⁸ , the C _3-6 cycloalkyl or 3-10 membered heterocyclyl is optionally substituted by one or more R ⁹ ,

R ^1A , R ^1B and R ^1C are each independently selected from hydrogen or C _1-6 alkyl;

R ⁸ is selected from C _1-6 alkoxy, 4-7 membered heterocyclyl, cyano, OR ^1AA , NR ^1BB R ^1CC or C _3-6 cycloalkyl substituted by hydroxy;

R ⁹ is C _1-6 alkyl, 4-7 membered heterocyclic group, cyano or OR ^1F ;

R ^1F is selected from hydrogen or C _1-6 alkyl;

R ^1AA , R ^1BB or R ^1CC are each independently selected from hydrogen or C _1-6 alkyl.

In some embodiments, R is selected ^from and R ¹ is optionally substituted by one or more carbonyl, hydroxyl, C _1-6 alkyl, 3-10 membered heterocyclyl, C _3-6 cycloalkyl, C(O)OR ^1A or C(O)NR ^1B R ^1C , wherein the C _1-6 alkyl is optionally substituted by one or more R ⁸ , the C _3-6 cycloalkyl or 3-10 membered heterocyclyl is optionally substituted by one or more R ⁹ ,

R ^1A , R ^1B and R ^1C are each independently selected from hydrogen or C _1-6 alkyl;

R ⁸ is selected from C _1-6 alkoxy, 4-7 membered heterocyclyl, cyano, OR ^1AA , NR ^1BB R ^1CC or C _3-6 cycloalkyl substituted by hydroxy;

R ⁹ is C _1-6 alkyl, 4-7 membered heterocyclic group, cyano, OR ^1F , C(O)R ^1DD or NR ^1BB R ^1CC ;

R ^1F is selected from hydrogen or C _1-6 alkyl;

R ^1AA , R ^1BB , R ^1CC or R ^1DD are each independently selected from hydrogen or C _1-6 alkyl.

In some typical embodiments, R ¹ is selected from and R ¹ is optionally substituted by one or more carbonyl, hydroxyl, C _1-6 alkyl, 3-10 membered heterocyclyl, C _3-6 cycloalkyl, C(O)OR ^1A or C(O)NR ^1B R ^1C , wherein the C _1-6 alkyl is optionally substituted by one or more R ⁸ , the C _3-6 cycloalkyl or 3-10 membered heterocyclyl is optionally substituted by one or more R ⁹ ,

R ^1A , R ^1B and R ^1C are each independently selected from hydrogen or C _1-6 alkyl;

R ⁸ is selected from C _1-6 alkoxy, 4-7 membered heterocyclyl, cyano, OR ^1AA , NR ^1BB R ^1CC or C _3-6 cycloalkyl substituted by hydroxy;

R ⁹ is C _1-6 alkyl, 4-7 membered heterocyclic group, cyano or OR ^1F ;

R ^1F is selected from hydrogen or C _1-6 alkyl;

R ^1AA , R ^1BB or R ^1CC is selected from hydrogen or C _1-6 alkyl.

In some embodiments, R is selected ^from and R ¹ is optionally substituted by one or more carbonyl, hydroxyl, methyl, replace.

In some typical embodiments, R ¹ is selected from

In some more typical embodiments, ^R1 is selected from

Preferably, ^R1 is selected from

More preferably, R ¹ is selected from

More preferably, R ¹ is selected from

More preferably, R ¹ is selected from

In some embodiments, R ² is selected from hydrogen.

In some embodiments, ^R3 , ^R4 , and ^R5 are selected from hydrogen.

In some embodiments, R ³ , R ⁴ are hydrogen.

In some embodiments, R ⁵ is hydrogen.

In some embodiments, R ⁶ is selected from C _6-10 aryl or 5-10 membered heteroaryl, which is optionally substituted with _one or more halogen or C _1-3 alkyl.

In some embodiments, ^R is selected from C _6-10 aryl or 5 or 6 membered heteroaryl, and the C _6-10 aryl or 5 or 6 membered heteroaryl is optionally substituted by one or more halogen or C _1-3 alkyl. In some typical embodiments, ^R is selected from phenyl or pyridyl, and the phenyl or pyridyl is optionally substituted by one or more halogen or C _1-3 alkyl.

In some more typical embodiments, R ⁶ is selected from phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionally substituted with one or more fluoro or methyl groups.

In some more typical embodiments, ^R is selected from Preferably, ^R6 is selected from More preferably, ^R6 is selected from

In some embodiments, R ^6a is selected from hydrogen or C _1-6 alkyl;

In some embodiments, R ^6a is selected from C _1-6 alkyl; preferably, R ^6a is methyl.

In some embodiments, for in, Representation and Connected, Indicates that it is connected to Y ² .

In some embodiments, R ⁷ is halogen; preferably, R ⁷ is fluoro.

In some embodiments, the compound of the aforementioned formula I has a structure as shown in formula II,

wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined in the compound of formula I;

In some embodiments, the compound of the aforementioned formula I has a structure as shown in formula III,

wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ and X are as defined in the compound of formula I, and Y is selected from CH or N.

In some embodiments, the compound of the aforementioned formula I has a structure as shown in formula IV,

wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined in the compound of formula I;

In some embodiments, the compound of the aforementioned formula I has a structure as shown in formula V,

wherein R ¹ , R ⁶ and R ⁷ are as defined in the compound of formula I;

In some embodiments, the compound of the aforementioned formula I has a structure as shown in formula VI,

wherein R ¹ , R ⁵ , R ⁶ , R ⁷ and R ^p are as defined in the compound of formula I;

Preferably, ^RP is selected from isopropyl, cyclopentyl, benzyl or

In another aspect, the present invention provides the following compounds or pharmaceutically acceptable salts thereof:

In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In some embodiments, the present invention provides the use of a compound of Formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and/or preventing a disorder induced by AXL receptor tyrosine kinase.

In some embodiments, the present invention provides a method for treating and/or preventing AXL receptor tyrosine kinase-induced disorders, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention to a subject in need thereof.

In some embodiments, the AXL receptor tyrosine kinase-induced disorder is a disorder caused by, associated with, and/or accompanied by AXL kinase hyperfunction.

In some embodiments, the AXL receptor tyrosine kinase-induced disorder is cancer. The cancer is preferably a solid tumor or a hematological cancer.

In some typical embodiments, the AXL receptor tyrosine kinase-induced disorder is a solid tumor cancer.

In another aspect, the present invention provides compounds:

In another aspect, the present invention provides a method for preparing a compound of formula V, including but not limited to the following synthesis scheme:

Synthesis Scheme 1:

wherein R ¹ , R ⁶ and R ⁷ are as defined in the compound of formula I;

Or, Synthesis Scheme 2:

Wherein, R ¹ , R ⁶ and R ⁷ are defined as in the compound of formula I; further, the synthesis route of the compound VM is as follows:

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IH column, 20×250 mm, particle size 5 μm;

Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ETOH: DCM = 1:1;

Flow rate: 20 mL/min; Gradient: 30% B;

Detection wavelength: 254/220nm;

Isomer retention time: 12.663min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IH column, 20×250 mm, particle size 5 μm;

Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ETOH: DCM = 1:1;

Flow rate: 20 mL/min; Gradient: 30% B;

Detection wavelength: 254/220nm;

Isomer retention time: 17.55min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK IG column, 20×250 mm, particle size 5 μm;

Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ETOH: DCM = 1:1;

Flow rate: 20 mL/min; Gradient: 80% B;

Detection wavelength: 254/220nm;

Isomer retention time: 9.273min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK IG column, 20×250 mm, particle size 5 μm;

Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ETOH: DCM = 1:1;

Flow rate: 20 mL/min; Gradient: 80% B;

Detection wavelength: 254/220nm;

Isomer retention time: 12.713min min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK IG column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: acetonitrile; flow rate: 20 mL/min;

Gradient: 50% B;

Detection wavelength: 254/220nm;

Isomer retention time: 6.823min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK IG column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: acetonitrile; flow rate: 20 mL/min;

Gradient: 50% B;

Detection wavelength: 254/220nm;

Isomer retention time: 9.36min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-ID column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine); Mobile phase B: acetonitrile; Flow rate: 20 mL/min;

Gradient: 50% B; Detection wavelength: 254/220 nm;

Isomer retention time: 6.57min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-ID column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine); Mobile phase B: acetonitrile; Flow rate: 20 mL/min;

Gradient: 50% B; Detection wavelength: 254/220 nm;

Isomer retention time: 8.81min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IE column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: MeOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 60% B; Detection wavelength: 254/220 nm;

Isomer retention time: 7.6min.

In some embodiments, the compound The isomers of The conditions are:

Column: CHIRALPAK-IE column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: MeOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 60% B; Detection wavelength: 254/220 nm;

Isomer retention time: 10.363min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-ID column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: EtOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 45% B; Detection wavelength: 254/220 nm;

Isomer retention time: 7.567min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-ID column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: EtOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 45% B; Detection wavelength: 254/220 nm;

Isomer retention time: 10.973min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IE column, 20×250 mm, particle size 5 μm;

Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: EtOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 50% B; Detection wavelength: 254/220 nm;

Isomer retention time: 11.07min.

In some embodiments, the compound The isomeric mixture was prepared by chiral separation The specific conditions are:

Column: CHIRALPAK-IE column, 20×250 mm, particle size 5 μm;

Mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: EtOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 50% B; Detection wavelength: 254/220 nm;

Retention time of isomer mixture: 15.53min.

In some typical embodiments, the above isomer mixture is prepared by chiral resolution, and the specific conditions are:

Column: CHIRAL ART Cellulose-SB, 30×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: EtOH; flow rate: 40 mL/min;

Gradient: 20% B; Detection wavelength: 254/220 nm;

Isomer retention time: 9.4min.

In some typical embodiments, the above isomer mixture is prepared by chiral resolution, and the specific conditions are:

Column: CHIRAL ART Cellulose-SB, 30×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: EtOH; flow rate: 40 mL/min;

Gradient: 20% B; Detection wavelength: 254/220 nm;

Isomer retention time: 10.8min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IE column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: MeOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 35% B; Detection wavelength: 254/220 nm;

Isomer retention time: 11.222min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IE column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: MeOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 35% B; Detection wavelength: 254/220 nm;

Isomer retention time: 12.781min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IE column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: MeOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 35% B; Detection wavelength: 254/220 nm;

Isomer retention time: 14.057min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IE column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: MeOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 35% B; Detection wavelength: 254/220 nm;

Isomer retention time: 19.041min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IF column, 20×250 mm, particle size 5 μm;

Mobile phase A: n-hexane (0.5% isopropylamine), mobile phase B: EtOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 60% B; Detection wavelength: 254/220 nm;

Isomer retention time: 12.484min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IF column, 20×250 mm, particle size 5 μm;

Mobile phase A: n-hexane (0.5% isopropylamine), mobile phase B: EtOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 60% B; Detection wavelength: 254/220 nm;

Isomer retention time: 17.042min.

In some embodiments, the compound The isomers of for:

Column: CHIRALPAK-IF column, 20×250 mm, particle size 5 μm;

Mobile phase A: n-hexane (0.5% isopropylamine), mobile phase B: MeOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 50% B; Detection wavelength: 254/220 nm;

Isomer retention time: 30.938min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IF column, 20×250 mm, particle size 5 μm;

Mobile phase A: n-hexane (0.5% isopropylamine), mobile phase B: MeOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 50% B; Detection wavelength: 254/220 nm;

Isomer retention time: 33.881min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IA column, 20×250 mm, particle size 5 μm;

Mobile phase A: n-hexane (0.5% diethylamine), mobile phase B: EtOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 40% B; Detection wavelength: 254/220 nm;

Isomer retention time: 12.594min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IA column, 20×250 mm, particle size 5 μm;

Mobile phase A: n-hexane (0.5% diethylamine), mobile phase B: EtOH: DCM = 1:1; flow rate: 20 mL/min;

Gradient: 40% B; Detection wavelength: 254/220 nm;

Isomer retention time: 18.266min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IF column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: EtOH: DCM = 1:1; flow rate: 20 mL/min; gradient: 50% B; detection wave Length: 254/220nm;

Isomer retention time: 11.636min.

In some embodiments, the compound The isomers of are prepared by chiral resolution, the specific conditions are:

Column: CHIRALPAK-IF column, 20×250 mm, particle size 5 μm;

Mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: EtOH: DCM = 1:1; flow rate: 20 mL/min; gradient: 50% B; detection wavelength: 254/220 nm;

Isomer retention time: 27.934min.

Related definitions

Unless otherwise indicated, the following terms used in this specification and the appended claims have the indicated meanings:

As used herein and unless otherwise specified, the terms "comprising", "including", "having", "containing", including grammatical equivalents thereof, should generally be understood as open and non-limiting, for example, not excluding other unlisted elements or steps.

The "compounds" of the present invention may be asymmetric, for example, having one or more chiral centers. Unless otherwise indicated, the "compounds" of the present invention may be any one isomer or a mixture of two or more isomers. The "compounds" of the present invention include isomers (such as stereoisomers), enantiomers, diastereomers, racemates or mixtures of two or more isomers of the compound.

The term "isomers" refers to different compounds with the same molecular formula but different arrangements and configurations of the atoms. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to refer to a racemic mixture where appropriate. "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-lngold-Prelog R-S system. When a compound is enantiomerically pure, the stereochemistry at each chiral carbon can be specified as R or S. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-) according to the direction in which they rotate plane polarized light (dextrorotatory- or levorotatory-) at the wavelength of the sodium D line or by their retention time when separated by chiral chromatography. Some of the compounds described herein contain one or more asymmetric centers or axes and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined in absolute stereochemistry as (R)- or (S)- or represented by (+) or (-) symbols. The present invention includes all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents may have a cis- or trans-configuration. That is, the compounds of the present invention include, but are not limited to, cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof. The compounds containing asymmetric carbon atoms of the present invention can be isolated in an optically pure form or in the form of a mixture of two or more isomers. The optically pure form can be separated from a mixture of two or more isomers, or synthesized by using chiral starting materials or chiral reagents.

The "compounds" of the present invention also include tautomeric forms. Tautomeric forms are derived from the exchange of a single bond with an adjacent double bond and the migration of a proton. The term "tautomer" or "tautomeric form" means that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert to each other.

The isomer mixtures obtainable according to the invention can be separated into the individual isomers in a known manner by a person skilled in the art; diastereomers can be separated, for example, by partitioning between multiphase solvent mixtures, recrystallization and/or chromatography, for example chromatography on silica gel or by medium pressure liquid chromatography, for example using reverse phase columns, racemates can be separated, for example, by salt formation with optically pure salt-forming agents and separation (for example by fractional crystallization) of the thus obtainable diastereomer mixtures or by chromatography on optically active column materials. Intermediates and end products can be worked up and/or purified according to standard methods, for example using chromatography, distribution methods, (re) crystallization, etc. At all stages of the reaction, the isomer mixtures formed can be separated into the individual isomers, for example diastereomers or enantiomers, or into any desired isomer mixtures, for example racemates or diastereomer mixtures.

Absolute stereochemistry and/or optical rotation are provided as appropriate for embodiments of the present invention. The present invention contemplates all stereochemical forms of the compounds provided herein. In some cases, the compounds contain two or more chiral centers. The relative stereochemistry of these compounds is identified by NMR studies and/or X-ray diffraction. In some cases, the relative stereochemistry of the diastereomeric pairs is not determined, so when only one isomer is separated and/or available, the enantiomers are labeled/distinguished according to the retention time under the given HPLC conditions. The same sample usually has the same retention time, but there may be certain operating errors. When samples obtained by the corresponding method are detected by the same instrument and detection method by a person of ordinary skill in the art, the retention time error The difference is usually within ±0.2min, preferably within ±0.1min; different technicians using different instruments may occasionally have a few retention time errors outside this range, such as errors within ±0.5min; or within ±0.3min; or within ±0.2min should all be considered to belong to the same substance, so retention time errors within ±0.5min, ±0.3min, ±0.2min or ±0.1min can be interpreted as within the scope of protection of the present invention.

In the present invention, Indicates the absolute configuration of a stereocenter.

The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art, such as single crystal X-ray diffraction (SARD).

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence of said event or circumstance and the non-occurrence of said event or circumstance.

Numeric ranges herein refer to each integer in the given range. For example, "C _1-3 " means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms; "C _1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

The term "substituted by..." means that any one or more hydrogen atoms on a specific group are replaced by a substituent, as long as the valence state of the specific group is normal and the substituted compound is stable. For example, "substituted by halogen" means that any one or more hydrogen atoms on a specific group are replaced by halogen, as long as the valence state of the specific group is normal and the substituted compound is stable. As used herein, optionally substituted by one or more A, B, C, D, E or F means that the group is optionally substituted by one or more substituents selected from A, B, C, D, E or F, and the one or more substituents may be the same or different.

the term In Refers to the chemical bond connection. When the connection position is uncertain, it means that the connection site can be Any atom in the monocyclic ring, as long as the valence permits.

The term "cyano" refers to a -CN group; the term "nitro" refers to a _-NO2 group; the term "amino" refers to a _-NH2 group; the term "hydroxy" refers to an -OH group; the term "halogen" refers to fluorine, chlorine, bromine and iodine, and the term "halo" refers to fluoro, chloro, bromo and iodo.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including a linear or branched saturated hydrocarbon group, having the indicated number of carbon atoms. For example, the term "C _1-3 alkyl" includes C 1 alkyl, C 2 alkyl, C 3 alkyl, and examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl; for example, the term "C _1-6 alkyl" includes C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl, and examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, and 3-hexyl, etc.

The term "alkoxy" refers to a group having an alkyl-O-structure, wherein the alkyl group is an alkyl group as defined above. For example, the term "C _1-3 alkoxy" includes C 1 alkoxy, C 2 alkoxy, C 3 alkoxy, and examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy; for example, the term "C _1-6 alkoxy" includes C 1 alkoxy, C 2 alkoxy, C 3 alkoxy, C 4 alkoxy, C 5 alkoxy, C 6 alkoxy, and examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy, 2-pentyloxy, 3-pentyloxy, n-hexyloxy, 2-hexyloxy, and 3-hexyloxy, etc.

The term "alkanoyl" refers to a group having a RC(=O)- structure, where R is a saturated aliphatic hydrocarbon group, including a linear or branched saturated hydrocarbon group. Examples of the term "C _1-6 alkanoyl" include, but are not limited to, formyl, acetyl, 2-methylacetyl, propionyl, and the like.

The term "hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyl (-OH) groups. For example, examples of the term "hydroxyC _1-6 alkyl" include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl, etc.

The term " _C2-6 alkenyl" refers to a group formed by an olefin having 2 to 6 carbon atoms losing one or two hydrogen atoms, and the olefin may be a monoolefin, a diolefin or a _triolefin , such _as -CH= _CH2 , _-C2H4 = _CH2 , -CH= _C2H4 , or the like.

The term "C _2-6 alkynyl" refers to a straight or branched hydrocarbon chain group consisting only of 2 to 6 carbon atoms and hydrogen atoms, which contains at least one triple bond, optionally at least one double bond, and which is connected to the rest of the molecule via a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, wait.

The term "haloalkyl" refers to an alkyl group as defined above substituted by one or more halogen atoms. For example, examples of the term "haloC _1-6 alkyl" include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl and the like.

The term "haloalkoxy" refers to an alkoxy group as defined above substituted by one or more halogen atoms. For example, examples of the term "haloC _1-6 alkoxy" include, but are not limited to, trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy and the like.

The term "aryl" refers to an all-carbon monocyclic group having a conjugated π-electron system or a bicyclic group having an all-carbon monocyclic ring having a conjugated π-electron system fused to an aromatic _carbocyclic ring, which is obtained by removing a hydrogen atom from a single carbon atom of the parent aromatic ring system. Examples include, but are not limited to, phenyl, naphthyl.

The term "cycloalkyl" refers to a stable saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which may include a spirocyclic or bridged ring system, having three to fifteen carbon atoms. For example, the term "C _3-6 cycloalkyl" refers to a cyclic alkyl group having 3 to 6 carbon atoms, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. For example, examples of "5-10 membered heteroaryl" of the present invention include, but are not limited to, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, The heteroaryl group also includes the above-mentioned heteroaryl group fused to an aryl group, a heterocyclic group or a cycloalkyl ring, and its non-limiting examples include: wait.

The term "heterocyclyl" refers to a non-aromatic saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, wherein two or more rings exist in the form of spiro, cyclic or bridged rings. The heterocyclyl of the present invention is preferably 3-18 members, wherein non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, (R ^a is C _1-6 alkyl, including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl and 3-hexyl) etc. Polycyclic heterocyclic groups include spirocyclic, condensed ring and bridged heterocyclic groups, non-limiting examples of which include:

The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acids and bases of a particular compound without adverse biological effects, such as acid (including organic acids and inorganic acids) addition salts or base addition salts (including organic bases and inorganic bases).

Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

The term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or pharmaceutical agent to achieve the desired effect.

The term "pharmaceutically acceptable carrier" refers to carriers that have no significant irritation to the body and do not impair the biological activity and performance of the active compound. It includes but is not limited to any diluent, disintegrant, binder, glidant, wetting agent approved by the State Food and Drug Administration for use in humans or animals.

The abbreviations used in the claims and the specification have the following meanings:

Pd(dppf)Cl ₂ ·DCM:(1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium-dichloromethane (1:1);

PdAMPHOS: dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II);

DIAD: diisopropyl azodicarboxylate;

PPh ₃ :triphenylphosphine;

t-BuONO::tert-butyl nitrite;

DMAP: 4-dimethylaminopyridine;

(Bpin) ₂ or B ₂ pin ₂ : Bis-pinacol borate;

TFA: trifluoroacetic acid;

TEA: triethylamine;

THF: tetrahydrofuran;

DMF-DMA: dimethylformamide dimethyl acetal;

DMF: N,N-dimethylformamide;

DME: N,N-dimethylacetamide

DCM: dichloromethane;

NMP: N-methylpyrrolidone;

MeOH: methanol;

EA: ethyl acetate;

PE: petroleum ether;

POCl ₃ : phosphorus oxychloride;

PhMe ₂ SI-Bpin: (dimethylphenylsilyl)boronic acid pinacol ester

In addition, the abbreviations “min” refer to minutes, “mL” to milliliters, and “V/V” to volume ratio;

N or M: represents concentration, mol/L. For example, “6M HCl” means the concentration of hydrochloric acid is 6 mol/L.

DETAILED DESCRIPTION

Preparation Example

Preparation Example 1:

a) Preparation of intermediate compound M1-1

Dissolve 2-cyano-N-(4-fluorophenyl)acetamide (1.88 g) in anhydrous ethanol (50 mL), add piperidine (0.5 mL) and acetylacetone (1 g) in sequence, stir at 90°C for 3 h, cool to room temperature, and filter to obtain 1.98 g of the title product.

b) Preparation of intermediate compound M1-2

M1-1 (1.98 g) was dissolved in DMF (30 mL), and DMF-DMA (1.07 g) was added, and the mixture was stirred at 90° C. for 2 h under nitrogen protection. The mixture was cooled to room temperature and directly desolventized to obtain 2.40 g of the title product.

c) Preparation of intermediate compound M1-3

M1-2 (2.40 g) was dissolved in concentrated sulfuric acid (10 mL), and stirred at 90°C for 2 h under nitrogen protection. The reaction solution was cooled to room temperature, slowly added into ice water, and the pH was adjusted to 8 with saturated potassium carbonate. The aqueous phase was extracted with n-butanol, and the organic phase was separated and dried with anhydrous sodium sulfate. The solvent was removed to obtain 2.10 g of the title product.

d) Preparation of intermediate compound M1

M1-3 (2.20 g) was dissolved in phosphorus oxychloride (20 mL), and stirred at 110°C for 2 h under nitrogen protection. The reaction solution was cooled to room temperature, concentrated, diluted with dichloromethane (100 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The organic phase was separated, dried over anhydrous sodium sulfate, desolventized, sanded, and column chromatography (DCM/MeOH=50/1) was performed to obtain 1.3 g of the title product.

MS(ESI+):289.1(M+H).

Preparation Example 2:

a) Preparation of intermediate compound M2-1

Under nitrogen protection, 3-bromo-5-chloropyrazin-2-amine (500 mg), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (853 mg), Pd(dppf)Cl ₂ ·DCM (195 mg), potassium phosphate (1.01 g, 4.80 mmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL), and the reaction solution was stirred at 80° C. for 3 h. The reaction solution was desolvated and purified by column chromatography (dichloromethane/methanol=50/1 (V/V)) to obtain 400 mg of the title product.

MS:[M+1],239.1

b) Preparation of intermediate compound M2

M2-1 (200 mg) and M1 (254 mg) were dissolved in n-butanol (5 mL), and then trifluoroacetic acid (0.5 mL) was added dropwise, and stirred at 120°C for 1 h under nitrogen protection. The reaction solution was concentrated and purified by column chromatography (dichloromethane/methanol = 20/1 (V/V)) to obtain 240 mg of the title product.

MS:[M+1],491.1

Preparation Examples 3 and 4

a) Preparation of intermediate compounds M3 and M4

Under nitrogen protection, NaH (937.83 mg) was added to DMF (70.0 mL) at -10 ° C in batches and stirred for 10 minutes. At -10 ° C in the reaction system, a DMF (10 mL) solution of 6-bromo-1H-indazole (3.5 g) was added dropwise to the reaction solution, and the reaction solution was stirred for 30 minutes, and then 1-iodo-2-methoxyethane (3.96 g) was slowly added dropwise to the reaction solution. After the dropwise addition, the reaction solution was reacted at room temperature for 2 h. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with EA (3x20 mL). The combined organic layer was washed with water (1×10 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was desolvated to dryness. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain the target intermediates M3 2.97 g and M4 1.79 g.

M3: ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ8.10 (d, J＝1.0Hz, 1H), 8.01 (dd, J＝1.6, 0.9Hz, 1H), 7.71 (dd, J＝8.6 ,0.7Hz,1H),7.25(dd,J＝8.5,1.6Hz,1H),4.57(t,J＝5.3Hz,2H),3.74(t,J＝5.2Hz,2H),3.18(s,3H ).

MS(ESI+):255(M+H).

M4: ¹ H NMR (400MHz, DMSO-d ₆ ,ppm) δ8.42 (d, J＝1.0Hz, 1H), 7.99-7.83 (m, 1H), 7.70 (dd, J＝8.8, 0.7Hz, 1H ),7.13(dd,J＝8.8,1.7Hz,1H),4.58(t,J＝5.2Hz,2H),3.82(dd,J＝5.6,4.8Hz,2H),3.22(s,3H).

MS(ESI+):255(M+H).

Preparation Examples 5 and 6

a) Preparation of intermediate compounds M5 and M6

Under nitrogen protection, NaH (2.27 g) was added in batches to DMF (45.0 mL) at -10°C and stirred for 10 minutes. At -10°C in the reaction system, a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (4.5 g) in DMF (10 mL) was added dropwise to the reaction solution, the reaction solution was stirred for 30 minutes, and then 2-bromoethanol (3.41 g) was slowly added dropwise to the reaction solution. After the dropwise addition, the reaction solution was reacted at room temperature for 2 h. The reaction was quenched with saturated aqueous ammonium chloride solution. The resulting mixture was extracted with EA (3x30 mL). The combined organic layers were washed with water (1×10 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was desolventized to dryness. The residue Purify by silica gel column chromatography with PE/EA (1:1) to obtain 900 mg of the target intermediates M5 and 540 mg of M6.

M5: ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ8.57 (d, J = 2.0 Hz, 1H), 8.53 (dd, J = 2.0, 1.0 Hz, 1H), 8.33 (d, J = 1.0 Hz, 1H), 4.87 (t, J = 5.4Hz, 1H), 4.48 (t, J = 5.3Hz, 2H), 3.79 (q, J = 5.4Hz, 2H).

MS(ESI+):242(M+H).

M6: δ8.81-8.67(m,1H),8.54(d,J＝2.1Hz,1H),8.44(dd,J＝2.0,1.0Hz,1H),5.02(t,J＝5.4Hz,1H) ,4.51(t,J＝5.4Hz,2H),3.90(q,J＝5.4Hz,2H).

MS(ESI+):242(M+H).

Preparation Examples 7 and 8:

a) Preparation of intermediate compounds M7 and M8

Under nitrogen protection, oxetane-2-ylmethanol (5.37 g) was added dropwise to a THF (20 mL) solution of 6-bromo-1H-indazole (10 g) and PPh ₃ (19.97 g), and then DIAD (20.53 g) was added dropwise to the reaction solution at 0°C. After the addition, the reaction solution was stirred at 0°C for 2 hours. The reaction solution was desolvated, and the obtained crude product was purified by reverse phase flash chromatography: column, C18; mobile phase, phase A: water (10 mmol/L NH ₄ HCO ₃ ), phase B: MeCN, gradient from 5% B to 95% B in 20 minutes; detector, UV 254 nm. 5 g of M7 and 450 mg of M8 were obtained.

M7: ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ8.12 (s, 1H), 8.05 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.26 (dd, J = 8.5 ,1.6Hz,1H),5.13-5.00(m,1H),4.76-4.57(m,2H),4.43(ddd,J＝8.6,7.0,5.6Hz,1H),4.21(dt,J＝9.1,6.0 Hz,1H),2.66(dtd,J＝11.2,8.1,6.2Hz,1H),2.48-2.37(m,1H).

MS(ESI+):267.0(M+H).

M8: ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ8.44 (d, J = 1.0 Hz, 1H), 7.87 (p, J = 0.8 Hz, 1H), 7.72 (dd, J = 8.9, 0.7 Hz,1H),7.14(dd,J＝8.8,1.7Hz,1H),5.13(dtd,J＝7.8,6.3,4.3Hz,1H),4.68(qd,J＝14.0,5.3Hz,2H),4.49 (ddd,J＝8.6,7.2,5.7Hz,1H),4.29(dt,J＝9.0,6.0Hz,1H),2.74-2.61(m,1H),2.42(ddt,J＝11.1,9.0,6.9Hz ,1H).

MS(ESI+):267.0(M+H).

Preparation Example 9:

Preparation Example 9 Synthesis:

Referring to Preparation Example 1, replace 2-cyano-N-(4-fluorophenyl)acetamide in a) with 2-cyano-N-(5-fluoropyridin-2-yl)acetamide, and then follow b), c) and d) to obtain 500 mg of the target compound.

MS(ESI+):290.1(M+H).

Preparation Example 10:

Referring to Preparation Example 1, replace 2-cyano-N-(4-fluorophenyl)acetamide in step a) with 2-cyano-N-(5-methylpyridin-2-yl)acetamide, and then prepare according to steps b), c) and d) of Preparation Example 1 to obtain 1.1 g of the target compound.

MS(ESI+):286.1(M+H).

Preparation Example 11:

Referring to Preparation Example 1, replace 2-cyano-N-(4-fluorophenyl)acetamide in step a) with 2-cyano-N-(6-methylpyridin-3-yl)acetamide, and then prepare according to steps b), c) and d) of Preparation Example 1 to obtain 720 g of the target compound.

MS(ESI+):286.1(M+H).

Preparation Example 12:

Referring to Preparation Example 1, replace 2-cyano-N-(4-fluorophenyl)acetamide in step a) with 2-cyano-N-(pyridin-4-yl)acetamide, and then prepare according to steps b), c) and d) of Preparation Example 1 to obtain 200 mg of the target compound.

MS(ESI+):272.1(M+H).

Preparation Example 13:

a) Preparation of intermediate compound M13-1

Under nitrogen protection, 0.25M 4-fluorobenzylmagnesium chloride (104mL) was added dropwise to a solution of 4-amino-2-chloropyridine-3-carbonitrile (1g) in ether (15mL), and stirred at 30°C overnight. The reaction solution was cooled to zero degrees. A mixed solution of HCl/H ₂ O/EtOH (1:1:2) (30mL) was added dropwise to the reaction solution and stirred. The reaction solution was then heated to 80°C and reacted for two hours. After the reaction was complete, the reaction solution was cooled to room temperature and the pH was adjusted to 7 with a saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (50mL) for three times. The organic phases were combined and then washed with a saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate. Then filtered, the filtrate was desolventized to dryness, and purified by column chromatography (petroleum ether/ethyl acetate = 2/1 (V/V)) to obtain 580mg of the title product.

MS(ESI+):265.1(M+H).

b) Preparation of intermediate compound M13

Place triethyl orthoformate (324.7 mg) and intermediate compound M13-1 (580 mg) in a 100 mL single-mouth bottle and stir at 100°C for 1.5 hours. Then add 4-dimethylaminopyridine (26.7 mg) and continue the reaction overnight. When the reaction is complete, cool the reaction solution to room temperature, and a large amount of solid precipitates. Filter with suction, and wash the filter cake with isopropanol. Dry the filter cake to obtain 206 mg of the title product.

MS (ESI+): 275.1 (M+H)

Preparation Example 14:

a) Preparation of Compound 14-1

Under nitrogen protection, 3-bromo-5-chloropyrazin-2-amine (3 g), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4.1 g) were added. Pd(dppf)Cl ₂ (316 mg) and potassium phosphate (4.58 g) were placed in dioxane (30 mL)/H ₂ O (10 mL), and the reaction solution was stirred at 100° C. for 2 hours. The reaction solution was desolvated and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 2.72 g of the title product.

MS:[M+1],239.1

b) Preparation of Compound M14

Under nitrogen protection, M14-1 (1.2 g), (1-methyl-1H-pyrazol-4-yl)boronic acid (0.95 g), Pd(dppf)Cl ₂ (73 mg) and potassium carbonate (1.38 g) were placed in dioxane (15 mL)/H ₂ O (5 mL), and the reaction solution was stirred at 100° C. for 2 hours. The reaction solution was desolvated and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 1.32 g of the title product.

MS:[M+1],285.1

Example

Example 1

a) Preparation of Compound 1-1

Under nitrogen protection, a solution of 5-bromo-1H-indazole (4.5 g) and PPh ₃ (10.1 g) in THF (5 mL) was stirred at 0°C for 10 minutes. Then (2R)-1,4-dioxane-2-ylmethanol (3.2 g) and DIAD (7.8 g) were added at 0°C and stirred overnight. The reaction solution was concentrated under reduced pressure and purified by reverse phase flash chromatography (column, C18; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 30 mL/min; gradient: 5% B to 40% B, 60 min; detection wavelength: 256 nm; retention time of target compound: 30.00 min) to obtain 1.5 g of the title product.

b) Preparation of Compound 1-2

Under nitrogen protection, 1-1 (1.5 g), AcOK (1.48 g), (Bpin) ₂ (1.53 g) and Pd(dppf)Cl ₂ ·DCM (411.21 mg) were placed in dioxane (15 mL), and the reaction solution was reacted at 80° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 1.5 g of the title product.

c) Preparation of Compound 1-3

Under nitrogen protection, 1-2 (500 mg), 5-bromo-3-chloropyrazin-2-amine (583 mg), PdAMPHOS (76.21 mg) and cesium fluoride (980.94 mg) were placed in a n-butanol (5 mL)/H ₂ O (1 mL) solution, and the reaction solution was stirred at 60° C. for 2 hours. The reaction solution was desolvated and purified by column chromatography (PE/EA=5/1 (V/V)) to obtain 450 mg of the title product.

d) Preparation of Compound 1-4

Under nitrogen protection, 1-3 (450 mg), Pd(dppf)Cl ₂ ·DCM (106.01 mg) and cesium carbonate (1.27 g) were placed in dioxane (13.5 mL)/H ₂ O (2.7 mL), and the reaction solution was stirred at 100° C. for 2 hours. The reaction solution was desolvated and purified by column chromatography (PE/EA=10/1 (V/V)) to obtain 300 mg of the title product.

e) Preparation of Compound Example 1

1-4 (70 mg), M1 (72.1 mg), n-butanol (2 mL) and TFA (37.97 mg) were placed in a 25 mL single-mouth bottle, and the reaction solution was stirred at 50°C overnight. The reaction solution was cooled to room temperature and concentrated, and the crude product was purified by reverse phase high performance liquid chromatography (column: Ultimate μXB-C18, 30×150 mm, filler particle size 5 μm; mobile phase A: aqueous solution (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 100 mL/min; gradient: 43% B to 78% B, 20 min; detection wavelength: 254 nm; retention time of target compound: 20 min, column temperature: 25°C) to obtain 5.6 mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.05 (s, 1H), 8.61 (s, 1H), 8.35 (d, J = 5.4Hz, 1H), 8.33-8.22 (m, 2H), 8.11(d,J＝0.9Hz,1H),8.00(dd,J＝8.9,1.6Hz,1H),7.70(d,J＝8.9Hz,1H),7.61-7.46(m,4H),7.46-7.36 (m,2H),6.95(d,J＝5.5Hz,1H),6.73-6 .63(m,1H),6.18(s,2H),4.54-4.39(m,2H),3.95(dtd,J＝11.9,6.7,5.7,2.5Hz,1H),3.75(dd,J＝11.5, 2.6Hz,1H),3.68(d,J＝11.1Hz,1H),3.61(d,J＝10.5Hz,1H),3.48-3.37(m,2H),3.36-3.34(m,1H),2.06- 1.94(m,3H).

MS(ESI+):673.30(M+H).

Embodiment 2:

a) Preparation of Compound 2-1

Under nitrogen protection, a solution of 5-bromo-1H-indazole (2 g) and PPh ₃ (4.53 g) in THF (20 mL) was stirred at 0°C for 10 minutes. Then (2S)-1,4-dioxane-2-ylmethanol (1.44 g) and DIAD (3.49 g) were added at 0°C and stirred overnight. The reaction solution was concentrated under reduced pressure and purified by reverse phase flash chromatography (column, C18; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 30 mL/min; gradient: 5% B to 40% B, 60 min; detection wavelength: 256 nm; retention time of target compound: 30.00 min) to obtain 260 mg of the title product.

b) Preparation of Compound 2-2

Prepare by referring to the preparation method of Preparation Example 1, except replacing 1-1 in step b) with 2-1 to obtain 210 mg of the title product.

c) Preparation of Compound 2-3

Prepare by referring to the preparation method of Preparation Example 1, except replacing 1-2 in step c) with 2-2 to obtain 150 mg of the title product.

d) Preparation of Compound 2-4

Prepare by referring to the preparation method of Preparation Example 1, except that 1-3 in step d) is replaced by 2-3 to obtain 100 mg of the title product.

e) Preparation of Compound Example 2

Prepare with reference to the preparation method of Preparation Example 1, except that 1-4 in step e) is replaced by 2-4. Then the reaction solution is desolvated to dryness. The crude product is purified by reverse phase high performance liquid chromatography (column: Xselect CSH C18 OBD column, 30×150 mm, filler particle size 5 μm; mobile phase A: 0.05% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 52% B, 8 min; detection wavelength: 220 nm; retention time of target compound: 6.93 min) to obtain 10.1 mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.05 (s, 1H), 8.61 (s, 1H), 8.35 (d, J = 5.5Hz, 1H), 8.28 (d, J = 12.7Hz, 2H),8.11(s,1H),8.00(dd,J＝8.8,1.4Hz,1H),7.70(d,J＝8.9Hz,1H),7.54-7.48(m,4H),7.43(t,J =8.7Hz,2H),6.95(d,J ＝5.4Hz,1H),6.68(s,1H),6.18(s,2H),4.46(t,J＝6.3Hz,2H),3.95(s,1H),3.75(d,J＝10.6Hz,1H ),3.69(d,J＝11.1Hz,1H),3.61(d,J＝10.6Hz,1H),3.53-3.42(m,2H),3.41-3.38(m,1H),2.00(s,3H) .

MS(ESI+):673.30(M+H).

Embodiment 3:

a) Preparation of Compound Example 3:

Under nitrogen protection, M2 (200 mg), (1-methyl-1H-pyrazol-4-yl)boronic acid (76 mg), Pd(dppf)Cl ₂ ·DCM (40 mg), potassium carbonate (110 mg), 1,4-dioxane (7.5 mL) and water (2.5 mL) were placed in a 25 mL single-necked bottle, and the reaction solution was stirred at 100° C. for 2 h. The reaction solution was directly desolvated and purified by column chromatography (DCM/MeOH=10/1 (V/V)) to obtain 100 mg of the title product as a white solid.

¹ H NMR(400MHz, DMSO-d ₆ ,ppm)δ12.02(s,1H),8.38-8.21(m,3H),8.09(s,1H),7.84(s,1H),7.52-7.40(m ,6H),6.94(d,J=5.5Hz,1H),6.67(s,1H),5.95(s,2H),3.84(s,3H),1.99(s,3H).

MS(ESI+):537.2(M+H).

Embodiment 4:

a) Preparation of Compound 4-1

Under nitrogen protection, (2R)-1,4-dioxane-2-ylmethanol (1.74 g) was added dropwise to 6-nitroindazole (2 g) and PPh ₃ (4.82 g) dissolved in THF (20 mL). Then DIAD (4.96 g) was added dropwise to the reaction solution at 0°C. After the addition, the reaction solution was stirred at 0°C for 2 hours. The reaction solution was desolvated and purified by column chromatography (PE/EA=1/1 (V/V)) to obtain 700 mg of the title product.

b) Preparation of compound 4-2

4-1 (450 mg) and MeOH (15 mL) were added to a 50 mL single-mouth bottle, followed by 10% palladium carbon (45 mg). The reaction solution was reacted at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through a celite pad and concentrated under reduced pressure to obtain 370 mg of the target compound.

c) Preparation of Compound 4-3

At 0°C, t-BuONO (309.44 mg) was added dropwise to a solution of 4-2 (350 mg) and (Bpin) ₂ (1524.05 mg) in ACN (3.5 mL), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was desolvated and purified by column chromatography (PE/EA = 1/1 (V/V)) to obtain 80 mg of the title product.

d) Preparation of Compound Example 4

Under nitrogen protection, M2 (95 mg), 4-3 (80 mg), Pd(dppf)Cl ₂ ·DCM (15 mg), potassium carbonate (80 mg), 1,4-dioxane (7.5 mL) and water (2.5 mL) were placed in a 25 mL single-necked bottle, and the reaction solution was stirred at 100° C. for 2 h.

The reaction solution was then desolventized to dryness. The crude product was purified by reverse phase high performance liquid chromatography (column: Kinetex 5m EVO C18 column, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 40% B to 63% B, 10 min; detection wavelength: 220 nm; retention time of target compound: 9.02 min) to obtain 5.9 mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.06 (s, 1H), 8.65 (s, 1H), 8.35 (d, J = 5.4Hz, 1H), 8.32 (d, J = 1.0Hz, 1H),8.28(dd,J＝13.4,2.0Hz,1H),8.14(q,J＝1.1Hz,1H),7.72(qd,J＝8.8,1.2Hz,2H),7.65-7.45(m,4H ),7.43(t,J＝8.8Hz,2H),6.95(d,J＝5.5Hz,1H),6.7 0-6.64(m,1H),6.24(s,2H),4.53-4.40(m,2H),4.06-4.00(m,1H),3.80(dd,J＝11.5,2.6Hz,1H),3.74( d,J＝11.3Hz,1H),3.63(d,J＝11.2Hz,1H),3.55(dd,J＝10.7,2.4Hz,1H),3.49(dd,J＝13.7,2.3Hz,1H), 3.42(s,1H),2.00(s,3H).

MS(ESI+):673.30(M+H).

Embodiment 5:

a) Preparation of Compound 5-1

At room temperature, TsCl (6.78 g) was added dropwise to a solution of (2S)-1,4-dioxane-2-ylmethanol (2 g) and DMAP (5.58 g) in DCM (20.0 mL). After the addition was completed, the reaction solution was placed at 50 degrees for 4 hours. The reaction solution was desolvated and purified by column chromatography (PE/EA = 1/1 (V/V)) to obtain 1.7 g of the title product.

b) Preparation of compound 5-2

A mixture of 6-bromo-1H-indazole (1 g), 5-1 (2.35 g), potassium carbonate (2.10 g) and DMF (10 mL) was stirred at 80 degrees for 10 hours. The reaction solution was desolvated and purified by column chromatography (PE/EA = 1/1 (V/V)) to obtain 400 mg of the title product.

c) Preparation of Compound 5-3

Prepare by referring to the preparation method of Preparation Example 1, except replacing 1-1 in step b) with 5-2 to obtain 130 mg of the title product.

d) Preparation of Compound Example 5

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced by 5-3. Then the reaction solution is desolvated to dryness. The obtained crude product is purified by reverse phase high performance liquid chromatography (column: Kinetex 5m EVO C18 column, 30×150mm filler particle size 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 25%B～40%B, 10min; detection wavelength: 254/220nm; retention time of target compound: 7.68min) to obtain 14mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.06 (s, 1H), 8.71 (s, 1H), 8.35 (d, J = 5.4Hz, 1H), 8.31-8.24 (m, 1H), 8.20-8.15(m,1H),8.06(d,J＝0.9Hz,1H),7.77(d,J＝1.1Hz,2H),7.51(ddt,J＝6.5,5.4,3.5Hz,4H),7.43 (t,J＝8.8Hz,2H),6.95(d,J＝5.5Hz, 1H),6.68(d,J＝1.0Hz,1H),6.32(s,2H),4.53(dd,J＝14.6,7.0Hz,1H),4.44(dd,J＝14.6,4.8Hz,1H), 3.99(dd,J＝7.2,2.5Hz,1H),3.77-3.66(m,2H),3.60(d,J＝10.3Hz,1H),3.55-3.41(m,2H),3.39(s,1H) ,2.00(s,3H).

MS(ESI+):673.30(M+H).

Embodiment 6:

a) Preparation of Compound 6-1

Under nitrogen protection, M3 (2.85 g), AcOK (3.30 g), (Bpin) ₂ (3.40 g) and Pd(dppf)Cl ₂ ·DCM (817 mg) were placed in dioxane (40 mL), and the reaction solution was reacted at 80° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography (PE/EA=1/1 (V/V)) to obtain 3.2 g of the title product.

b) Preparation of Compound Example 6

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced by 6-1. Then the reaction solution is desolvated to dryness. The obtained crude product is purified by reverse phase high performance liquid chromatography (column: Kinetex 5m EVO C18 column, 30×150mm filler particle size 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 43%B～74%B, 8min; detection wavelength: 254/220nm; retention time of target compound: 7.28min) to obtain 19.6mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.06 (s, 1H), 8.70 (s, 1H), 8.35 (d, J = 5.5 Hz, 1H), 8.28 (dd, J = 13.7, 1.7 Hz,1H),8.18(d,J＝1.2Hz,1H),8.05(d,J＝1.0Hz,1H),7.77(d,J＝1.1Hz,2H),7.51(td, J＝4.9,2.6Hz,4H),7.47-7.36(m,2H),6.95(d,J＝5.5Hz,1H),6.71-6.63(m,1H),6.31(s,2H),4.60(t ,J＝5.4Hz,2H),3.77(t,J＝5.4Hz,2H),3.19(s,3H),2.00(s,3H).

MS(ESI+):631(M+H).

Embodiment 7:

a) Preparation of Compound 6-1

Under nitrogen protection, M4 (1.7 g), AcOK (1.96 g), (Bpin) ₂ (2.03 g) and Pd(dppf)Cl ₂ ·DCM (490 mg) were placed in dioxane (40 mL), and the reaction solution was reacted at 80° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography (PE/EA=1/1 (V/V)) to obtain 1.8 g of the title product.

b) Preparation of Compound Example 7

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with 7-1. Then the reaction solution is desolvated to dryness. The obtained crude product is purified by reverse phase high performance liquid chromatography (column: XBridge BEH C18 OBD column, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 43% B to 70% B, 8 min; detection wavelength: 254/220 nm; retention time of target compound: 7.58 min) to obtain 18.7 mg of the title product.

¹ H NMR (400 MHz, DMSO-d ₆ ,ppm)δ12.06(s,1H),8.65(s,1H),8.39-8.31(m,2H),8.28(dd,J＝13.4,2.0Hz,1H),8.14(q,J＝1.1Hz,1H),7.71(qd,J＝8.8,1.2Hz,2H),7.56-7.47(m,4 H),7.46-7.36(m,2H),6.95(d,J＝5.6Hz,1H),6.68(d,J＝1.1Hz,1H),6.24(s,2H),4.58(t,J＝5.2Hz,2H),3.83(t,J＝5.2Hz,2H),3.23(s,3H),2.05-1.9 3(m,3H).

MS(ESI+):631(M+H).

Embodiment 8:

a) Preparation of Compound 8-1

Under nitrogen protection, 5-bromo-1H-indazole-1-carboxylic acid isopropyl ester (240 mg), AcOK (249 mg), (Bpin) ₂ (258 mg) and Pd(dppf)Cl ₂ ·DCM (62 mg) were placed in dioxane (4 mL), and the reaction solution was reacted at 80° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography (PE/EA=1/1 (V/V)) to obtain 200 mg of the title product.

b) Preparation of Compound Example 8

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with 8-1. Then the reaction solution is desolvated to dryness. The crude product is purified by reverse phase high performance liquid chromatography (column: Kinetex 5m EVO C18 column, 30×150mm, filler particle size 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 50%B～75%B, 10min; detection wavelength: 254/220nm; retention time of target compound: 9.25min) to obtain 30.7mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.05 (s, 1H), 8.66 (s, 1H), 8.54-8.39 (m, 2H), 8.35 (d, J = 5.4Hz, 1H), 8.32-8.20(m,2H),8.16(d,J＝8.8Hz,1H),7.54-7.49(m,3H),7.44(td,J＝9.5,8.8,7.2Hz,3H),6.95(d, J＝5.5Hz,1H),6.68(s,1H),6.32(s,2H),5.24(p,J＝6.2Hz,1H),2.00(s,3H),1.44(d,J＝6.2Hz, 6H).

MS(ESI+):659.05(M+H).

Embodiment 9:

a) Preparation of Compound 9-1

Under nitrogen protection, M5 (500 mg), AcOK (405 mg), (Bpin) ₂ (629 mg) and Pd(dppf)Cl ₂ ·DCM (168 mg) were placed in dioxane (4 mL), and the reaction solution was reacted at 80° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography (DCM/MeOH=10/1 (V/V)) to obtain 230 mg of the title product.

b) Preparation of Compound Example 9

Prepare according to the preparation method of Example 4, and replace 4-3 in step d) with 9-1. Then desolventize the reaction solution to dryness. The crude product was purified by reverse phase high performance liquid chromatography (column: Xselect CSHTM Prep C18 OBD column, 19×150mm filler particle size 5μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 20%B～55%B, 10min; detection wavelength: 254/220nm; retention time of target compound: 10.37min) to obtain 35.3mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.05 (s, 1H), 9.11 (d, J = 1.8 Hz, 1H), 8.75 (s, 1H), 8.55 (dd, J = 1.9, 1.0 Hz, 1H),8.35(d,J＝5.4Hz,1H),8.31-8.23(m,2H),7.59-7.47(m,4H),7.43(dd,J＝9.9,7.6Hz,2H),6.95(d ,J＝5.5Hz,1H),6.68(d,J＝1.1Hz,1H),6.43(s,2H),4.85(t,J＝5.5Hz,1H),4.51(t,J＝5.5Hz,2H ),3.81(q,J＝5.4Hz,2H),2.11-1.74(m,3H).

MS(ESI+):618.35(M+H).

Embodiment 10:

a) Preparation of Compound 10-1

Under nitrogen protection, M6 (600 mg), AcOK (730 mg), (Bpin) ₂ (755 mg) and Pd(dppf)Cl ₂ ·DCM (201 mg) were placed in dioxane (6 mL), and the reaction solution was reacted at 80° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography (DCM/MeOH=10/1 (V/V)) to obtain 260 mg of the title product.

b) Preparation of Compound Example 10

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with 10-1. Then the reaction solution is desolvated to dryness. The obtained crude product is purified by reverse phase high performance liquid chromatography (column: XBridge BEH Shield RP18 OBD column, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 30% B to 60% B, 10 min; detection wavelength: 254/220 nm; retention time of target compound: 8.82 min) to obtain 31.5 mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.06 (s, 1H), 9.13 (d, J = 2.0Hz, 1H), 8.73 (s, 1H), 8.62 (d, J = 1.0Hz, 1H),8.50(dd,J＝2.0,1.0Hz,1H),8.35(d,J＝5.4Hz,1H),8.28(dd,J＝13.5,2.0Hz,1H),7.59-7.47(m,4 H),7.43(dd,J＝9.9,7.6Hz,2H),6.95(d,J＝5.5Hz,1H),6.68(d,J＝1.0Hz,1H),6.37(s,2H),5.00( t,J＝5.4Hz,1H),4.50(t,J＝5.5Hz,2H),3.90(q,J＝5.5Hz,2H),2.08-1.86(m,3H).

MS(ESI+):618.10(M+H).

Embodiment 11:

a) Preparation of compound 11-1

Under nitrogen protection, NaH (91 mg) was added to DMF (5.0 mL) at 0 ° C and stirred for 10 minutes. At 0 ° C in the reaction system, a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (500 mg) in DMF (1 mL) was added dropwise to the reaction solution, and the reaction solution was stirred for 30 minutes, and then 1-iodo-2-methoxyethane (470 mg) was slowly added dropwise to the reaction solution. After the dropwise addition, the reaction solution was reacted at room temperature for 2 h. The reaction was quenched with saturated aqueous ammonium chloride. The resulting mixture was extracted with EA (3x20 mL). The combined organic layer was washed with water (1×10 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was desolvated to dryness. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain 200 mg of the target compound.

b) Preparation of compound 11-2

Under nitrogen protection, 11-1 (150 mg), AcOK (86 mg), (Bpin) ₂ (74 mg) and Pd(dppf)Cl ₂ ·DCM (21 mg) were placed in dioxane (2 mL), and the reaction solution was reacted at 80° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography (DCM/MeOH=10/1 (V/V)) to obtain 80 mg of the title product.

b) Preparation of Compound Example 11

Under nitrogen protection, M2 (95 mg), 11-2 (80 mg), Pd(dppf)Cl ₂ ·DCM (15 mg), potassium carbonate (80 mg), 1,4-dioxane (7.5 mL) and water (2.5 mL) were placed in a 25 mL single-necked bottle, and the reaction solution was stirred at 100° C. for 2 h.

The reaction solution was then desolventized to dryness. The crude product was purified by reverse phase high performance liquid chromatography (column: Kinetex 5m EVO C18 column, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 38% B to 63% B, 8 min; detection wavelength: 254/220 nm; retention time of target compound: 7.68 min) to obtain 25.2 mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.06 (s, 1H), 9.13 (d, J = 1.8 Hz, 1H), 8.76 (s, 1H), 8.58 (dd, J = 1.9, 1.0 Hz,1H),8.35(d,J＝5.5Hz,1H),8.32-8.26(m,2H),7.56-7.49(m,4H),7.47-7.41(m,2H),6.95(d,J＝ 5.5Hz,1H),6.70-6.66(m,1H),6.47(s,2H),4.64(t,J＝5.2Hz,2H),3.77(t,J＝5.2Hz,2H),3.18(s, 3H),2.01-1.98(s,3H).

MS(ESI+):632.05(M+H).

Examples 12 and 13:

a) Preparation of compound 12-1

Under nitrogen protection, M7 (5 g), AcOK (5.51 g), (Bpin) ₂ (4.75 g) and Pd(dppf)Cl ₂ ·DCM (1.52 g) were placed in dioxane (30 mL), and the reaction solution was reacted at 80° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography (PE/EA=1/1 (V/V)) to obtain 2.2 g of the title product.

b) Preparation of Compound Example 12 and Compound Example 13

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with 12-2. Then the reaction solution is desolvated to dryness. The obtained crude product is purified by reverse phase high performance liquid chromatography (column: Kinetex EVO C18 column, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 47% B to 66% B, 10 min; detection wavelength: 254/220 nm; retention time of target compound: 7.68 min) to obtain 30 mg of a racemic mixture. The product was then separated by a chiral column (column: CHIRALPAK-IH column, 20×250 mm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ETOH:DCM=1:1; flow rate: 20 mL/min; gradient: 30% B; detection wavelength: 254/220 nm; target compound 13: 12.663 min, target compound 12: 17.55 min; injection volume: 0.6 mL) to obtain target compound 12: 6.4 mg, target compound 13: 15.3 mg.

Compound Example 12: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.05 (s, 1H), 8.69 (s, 1H), 8.35 (d, J=5.4 Hz, 1H), 8.32-8.25 (m, 1H), 8.23 (q, J=1.2 Hz, 1H), 8.07 (d, J=0.9 Hz, 1H), 7.77 (d, J=1.0 Hz, 2H), 7.61-7.47 (m, 4H), 7.43 (dd, J=9.6, 7.9 Hz, 2H), 6.95 (d, J=5.5 Hz, 1H), 6.68 (d, J＝1.0Hz,1H),6.28(s,2H),5.11(p,J＝6.1Hz,1H),4.74(dd,J＝14.7,5.8Hz,1H),4.66(dd,J＝14.6,4.5Hz,1H),4.43(ddd,J＝8.6,7.1,5.6Hz,1H),4.25(dt,J ＝8.9,5.9Hz,1H),2.71-2.62(m,1H),2.58-2.51(m,1H),2.00(s,3H).

MS(ESI+):643.30(M+H).

Compound Example 13: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.05 (s, 1H), 8.69 (s, 1H), 8.35 (d, J=5.4 Hz, 1H), 8.32-8.25 (m, 1H), 8.23 (q, J=1.2 Hz, 1H), 8.07 (d, J=0.9 Hz, 1H), 7.77 (d, J=1.0 Hz, 2H), 7.61-7.47 (m, 4H), 7.43 (dd, J=9.6, 7.9 Hz, 2H), 6.95 (d, J=5.5 Hz, 1H), 6.68 (d, J＝1.0Hz,1H),6.28(s,2H),5.11(p,J＝6.1Hz,1H),4.74(dd,J＝14.7,5.8Hz,1H),4.66(dd,J＝14.6,4.5Hz,1H),4.43(ddd,J＝8.6,7.1,5.6Hz,1H),4.25(dt,J ＝8.9,5.9Hz,1H),2.71-2.62(m,1H),2.58-2.51(m,1H),2.00(s,3H).

MS(ESI+):643.30(M+H).

Examples 14 and 15:

a) Preparation of Compound 14-1

Under nitrogen protection, M8 (450 mg), AcOK (496 mg), (Bpin) ₂ (428 mg) and Pd(dppf)Cl ₂ ·DCM (510 mg) were placed in dioxane (30 mL), and the reaction solution was reacted at 80° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography (PE/EA=1/1 (V/V)) to obtain 280 mg of the title product.

b) Preparation of Compound Examples 14 and 15

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with 14-1. Then the reaction solution is desolvated to dryness. The obtained crude product is purified by reverse phase high performance liquid chromatography (column: Kinetex EVO C18 column, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 47% B to 66% B, 10 min; detection wavelength: 254/220 nm; retention time of target compound: 8.02 min) to obtain 20 mg of a racemic mixture. The product was then separated by a chiral column (column: CHIRALPAK IG column, 20×250 mm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ETOH:DCM=1:1; flow rate: 20 mL/min; gradient: 80% B; detection wavelength: 254/220 nm; target compound 15: 9.273 min, target compound 14: 12.713 min; injection volume: 1 mL) to obtain target compound 14: 3.8 mg, target compound 15: 3.8 mg.

Compound Example 14: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.05 (s, 1H), 8.65 (s, 1H), 8.38-8.31 (m, 2H), 8.28 (dd, J＝13.5,1.9 Hz, 1H), 8.15 (t, J＝1.2 Hz, 1H), 7.78-7.66 (m, 2H), 7.58-7.45 (m, 4H), 7.42 (d, J＝8.8 Hz, 2H), 6.95 (d, J＝5.5 Hz, 1H), 6.68 (d ,J＝1.0Hz,1H),6.23(s,2H),5.14(p,J＝6.2Hz,1H),4.73-4.62(m,2H),4.50(ddd,J＝8.6,7.1,5.6Hz,1H),4.31(dt,J＝9.1,6.0Hz,1H),2.91(d,J＝7.3Hz, 1H), 2.67 (d, J = 8.4Hz, 1H), 2.03-1.95 (s, 3H).

MS(ESI+):643.30(M+H).

Compound Example 15: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.05 (s, 1H), 8.65 (s, 1H), 8.38-8.31 (m, 2H), 8.28 (dd, J＝13.4, 1.9 Hz, 1H), 8.15 (d, J＝1.3 Hz, 1H), 7.78-7.68 (m, 2H), 7.58-7.47 (m, 4H), 7.45-7.38 (m, 2H), 6.95 (d, J＝5.5 Hz, 1H), 6.6 8(d,J＝1.0Hz,1H),6.23(s,2H),5.14(dd,J＝7.2,5.2Hz,1H),4.73-4.62(m,2H),4.52-4.47(m,1H),4.33-4.29(m,1H),2.68(dd,J＝10.5,7.3Hz,1H),2. 42(d,J＝6.9Hz,1H),2.03-1.97(s,3H).

MS(ESI+):643.30(M+H).

Examples 16 and 17

a) Preparation of Compound 16-1

Under nitrogen protection, 2-(iodomethyl)oxetane (703.6 mg) was added to a DMF (5 mL) solution of 6-bromo-5-methyl-1H-indazole (500 mg) and potassium carbonate (654.81 mg), and the reaction solution was stirred at 50°C for 12 hours. Water (30 mL) was added to the reaction solution, and extracted with EA (30 mL x 3). The combined organic phase was washed with brine (50 mL x 3) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase flash chromatography: column, C18; mobile phase, phase A: water (10 mmol/L NH ₄ HCO ₃ ), phase B: MeCN, gradient from 10% to 50% in 10 minutes; detector, UV 254 nm. The target compound 100 mg was obtained.

b) Preparation of compound 16-2

Under nitrogen protection, 16-1 (100 mg), AcOK (70 mg), (Bpin) ₂ (108 mg) and Pd(dppf)Cl ₂ ·DCM (29 mg) were placed in dioxane (5 mL), and the reaction solution was reacted at 80 degrees for 2 hours. The reaction solution was concentrated and purified by column chromatography (PE/EA=1/1 (V/V)) to obtain 60 mg of the title product.

c) Preparation of Compound Examples 16 and 17

Prepared with reference to the preparation method of Example 4, replacing 4-3 in step d) with 16-2. Then the reaction solution was desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 65 mg of a racemic mixture. Then separated by chiral column (column: CHIRALPAK IG column, 20×250 mm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: acetonitrile; flow rate: 20 mL/min; gradient: 50% B; detection wavelength: 254/220 nm; target compound 16: 6.823 min, target compound 17: 9.36 min; injection volume: 0.75 mL), to obtain target compound 16: 26.4 mg, target compound 17: 25.7 mg.

Compound Example 16: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.26 (dd, J=13.3, 1.6 Hz, 1H), 8.17 (s, 1H), 8.01 (d, J=0.9 Hz, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.54-7.34 (m, 6H), 6.94 (d, J=5.5 Hz, 1H), 6.67 (d, J=1.0 Hz, 1H), 6.24 (s, 2H ),5.14-4.96(m,1H),4.66(qd,J＝14.7,5.1Hz,2H),4.41(ddd,J＝8.5,7.0,5.6Hz,1H),4.22(dt,J＝9.0,6.0Hz,1H),2.64(ddt,J＝16.2,7.9,1.9Hz,1H),2. 44(dt,J＝8.9,2.3Hz,1H),2.40(s,3H),2.03-1.93(m,3H).

MS(ESI+):657.00(M+H).

Compound Example 17: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.30-8.22 (m, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.55-7.37 (m, 6H), 6.94 (d, J=5.5 Hz, 1H), 6.67 (s, 1H), 6.24 (s, 2H), 5.16 -5.00(m,1H),4.66(qd,J＝14.7,5.2Hz,2H),4.41(ddd,J＝8.5,7.1,5.6Hz,1H),4.22(dt,J＝8.9,5.9Hz,1H),2.63(dtd,J＝11.0,8.2,6.2Hz,1H),2.49-2. 42(m,1H),2.40(s,3H),1.99(s,3H).

MS(ESI+):657.05(M+H).

Examples 18 and 19

a) Preparation of Compound 18-1

Under nitrogen protection, oxetane-2-ylmethanol (1.2 g) was added dropwise to a solution of 6-bromo-5-methyl-1H-indazole (2 g) and PPh ₃ (4.2 g) in THF (20 mL), and then DIAD (3.2 g) was added dropwise to the reaction solution at 0°C. After the addition, the reaction solution was stirred at 0°C for 2 hours. The reaction solution was desolvated and purified by column chromatography (PE/EA=5/1 (V/V)) to obtain 1.7 g of the title product.

b) Preparation of compound 18-2

Under nitrogen protection, 18-1 (1.7 g), AcOK (1.3 g), (Bpin) ₂ (1.8 g) and Pd(dppf)Cl ₂ ·DCM (490 mg) were placed in dioxane (20 mL), and the reaction solution was reacted at 80° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography (PE/EA=3/1 (V/V)) to obtain 1.0 g of the title product.

c) Preparation of Compounds Example 18 and Example 19

Prepared with reference to the preparation method of Example 4, 4-3 in step d) was replaced with 18-2. Then the reaction solution was desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 30 mg of a racemic mixture. Then separated by chiral column (column: CHIRALPAK-ID column, 20×250 mm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: acetonitrile; flow rate: 20 mL/min; gradient: 50% B; detection wavelength: 254/220 nm; target compound 18: 6.57 min, target compound 19: 8.81 min; injection volume: 1.0 mL), to obtain target compound 18: 2.9 mg, target compound 19: 3.6 mg.

Compound Example 18: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.33 (d, J=5.4 Hz, 1H), 8.25 (d, J=13.4 Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.52-7.48 (m, 2H), 7.47-7.43 (m, 2H), 7.42-7.38 (m, 2 H),6.94(d,J＝5.5Hz,1H),6.67(s,1H),6.23(s,2H),5.13-4.99(m,1H),4.72-4.59(m,2H),4.45-4.38(m,1H),4.26-4.18(m,1H),2.64-2.57(m,2H), 2.40(s,3H),1.99(s,3H)..

MS(ESI+):657.00(M+H).

Compound Example 19: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.33 (d, J=5.4 Hz, 1H), 8.25 (d, J=13.4 Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.52-7.48 (m, 2H), 7.47-7.43 (m, 2H), 7.42-7.38 (m, 2 H),6.94(d,J＝5.5Hz,1H),6.67(s,1H),6.23(s,2H),5.13-4.99(m,1H),4.72-4.59(m,2H),4.45-4.38(m,1H),4.26-4.18(m,1H),2.64-2.57(m,2H), 2.40(s,3H),1.99(s,3H).

MS(ESI+):657.00(M+H).

Embodiment 20:

a) Preparation of Compound 20-1

The preparation method was referred to Example 1, except that 1-2 in step c) was replaced with 1-(2-methoxyethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-indazole. The reaction solution was then desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 100 mg of the target compound.

b) Preparation of Compound 20-2

The preparation method was referred to Example 1, except that 1-3 in step d) was replaced by 20-1. The reaction solution was then desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 120 mg of the target compound.

c) Preparation of Compound Example 20

Prepared by referring to the preparation method of Example 1, replacing 1-4 in step e) with 20-2, and replacing M1 with M9. Then the reaction solution was desolventized to dryness. The obtained crude product was purified by reverse phase high performance liquid chromatography (column: Kinetex 5m EVO C18, 30×150mm filler particle size 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 35%B～70%B, 8min; detection wavelength: 254/220nm; retention time of target compound: 7.32min) to obtain 19.8mg of the title product.

Compound Example 20: ¹ H NMR (400 MHz, DMSO-d ₆ )δ11.90(s,1H),8.79-8.58(m,2H),8.37(d,J＝5.4Hz,1H),8.27(dd,J＝13.4,1.9Hz,1H),8.19(d,J＝1.2Hz,1H),8.13-7.98(m,2H),7.88-7.64(m,3H),7 .58-7.42(m,2H),6.97(d,J＝5.5Hz,1H),6.79-6.60(m,1H),6.31(s,2H),4.60(t,J＝5.4Hz,2H),3.78(t,J＝5.4Hz,2H),3.19(s,3H),2.08-1.80(m,3H ).

MS(ESI+):632.2(M+H).

Embodiment 21

Preparation of Compound Example 21

Prepared by referring to the preparation method of Example 1, replacing 1-4 in step e) with 20-2, and replacing M1 with M11. Then the reaction solution was desolvated to dryness. The obtained crude product was purified by reverse phase high performance liquid chromatography (column: YMC Triart C18 ExRs 5m, 30×150mm filler particle size 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 46%B～70%B, 8min; detection wavelength: 254/220nm; retention time of target compound: 7.32min) to obtain 27.8mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.99 (s, 1H), 8.71 (s, 1H), 8.51 (d, J = 2.5Hz, 1H), 8.36 (d, J = 5.5Hz, 1H) ,8.28(dd,J＝13.3,1.8Hz,1H),8.19(d,J＝1.1Hz,1H),8.05(d,J＝0.9Hz,1H),7.82(dd,J＝8.2,2.6Hz, 1H),7.77( d,J＝1.1Hz,2H),7.60-7.38(m,3H),6.96(d,J＝5.5Hz,1H),6.71(d,J＝1.0Hz,1H),6.32(s,2H), 4.60(t,J＝5.4Hz,2H),3.77(t,J＝5.4Hz,2H),3.19(s,3H),2.59(s,3H),2.08-1.93(m,3H).

MS(ESI+):628.2(M+H).

Embodiment 22

Preparation of Compound Example 22

Prepared by referring to the preparation method of Example 1, 1-4 in step e) was replaced by 20-2, and M1 was replaced by M10. Then the reaction solution was desolventized to dryness. The obtained crude product was purified by reverse phase high performance liquid chromatography (column: XBridge BEH C18 OBD, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 43% B to 67% B, 8 min; detection wavelength: 254/220 nm; retention time of target compound: 7.32 min) to obtain 25.2 mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.97 (s, 1H), 8.70 (s, 1H), 8.52 (d, J = 2.3Hz, 1H), 8.36 (d, J = 5.4Hz, 1H) ,8.27(dd,J＝13.4,1.9Hz,1H),8.18(d,J＝1.2Hz,1H),8.05(d,J＝0.9Hz,1H),7.92(dd,J＝8.3,2.4Hz, 1H),7.77( d,J＝1.0Hz,2H),7.63-7.40(m,3H),6.96(d,J＝5.5Hz,1H),6.67(d,J＝1.1Hz,1H),6.30(s,2H), 4.60(t,J＝5.4Hz,2H),3.77(t,J＝5.4Hz,2H),3.19(s,3H),2.43(s,3H),2.02-1.87(m,3H).

MS(ESI+):628.2(M+H).

Embodiment 23:

a) Preparation of Compound Example 23

Prepared by referring to the preparation method of Example 4, except that 4-3 in step d) was replaced with 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Then the reaction solution was desolventized to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 22 mg of the target compound.

Example 23: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 12.03 (s, 1H), 8.40-8.29 (m, 2H), 8.25 (d, J=13.2 Hz, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.58-7.35 (m, 6H), 6.93 (d, J=5.4 Hz, 1H), 6.66 (s, 1H), 5.97 (s, 2H), 4.26 (t, J=5.3 Hz, 2H), 3.69 (t, J=5.4 Hz, 2H), 3.23 (s, 3H), 1.99 (s, 3H).

MS(ESI+):581.2(M+H).

Embodiment 24:

Preparation of Compound Example 24

Prepared by referring to the preparation method of Example 4, 4-3 in step d) was replaced with 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propionitrile. Then the reaction solution was desolventized to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 12 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.04(s,1H),8.38-8.30(m,2H),8.30-8.20(m,2H),7.97(s,1H),7.56-7.39(m ,6H),6.95(d,J＝5.5Hz,1H),6.68(s,1H),6.02(s,2H),4.40(t,J＝6.4Hz,2H),3.09(t,J＝6.4Hz ,2H),2.00(s,3H).

MS(ESI+):576.2(M+H).

Embodiment 25:

Preparation of Compound Example 25

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with 1-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. Then, the reaction solution is desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 20 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.03 (s, 1H), 8.35 (s, 1H), 8.34 (d, J = 5.4Hz, 1H), 8.31 (s, 1H), 8.25 (dd, J＝13.4,1.9Hz,1H),7.99(s,1H),7.55-7.38(m,6H),6.94(d,J＝5.5Hz,1H),6.68(s,1H),6.04(s,2H ),5.38(s,2H),3.24(s,3H),1.99(s,3H).

MS(ESI+):567.2(M+H).

Embodiment 26:

Preparation of Compound Example 26

The preparation method of Example 4 was used to prepare the product, except that 4-3 in step d) was replaced with 1-(oxetane-3-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The reaction solution was then desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 24.1 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.03 (s, 1H), 8.39-8.11 (m, 4H), 7.88 (s, 1H), 7.45 (dd, J = 21.9, 13.1Hz, 7H), 6.98-6.88(m,1H),6.66(s,1H),5.98(s,2H),4.63(t,J＝7.2Hz,2H),4.41(d,J＝7.2Hz,4H),1.99(s ,3H).

MS(ESI+):593.2(M+H).

Embodiment 27:

Preparation of Compound Example 27

Prepared by referring to the preparation method of Example 4, except that 4-3 in step d) was replaced with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. Then the reaction solution was desolventized to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 19 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.03 (s, 1H), 8.41 (s, 1H), 8.33 (d, J = 5.4Hz, 1H), 8.25 (d, J = 14.4Hz, 1H) ,8.01(dd,J＝9.5,2.6Hz,1H),7.50(dd,J＝8.6,5.0Hz,3H),7.48-7.44(m,3H),7.43(s,1H),6.94(d,J ＝5.5Hz,1H),6.67(s,1H),6.46(d,J＝9.4Hz,1H),6.15(s,2H),3.50(s,3H),1.99(s,3H).

MS(ESI+):564.2(M+H).

Embodiment 28:

Preparation of Compound Example 28

The preparation method of Example 4 was used to prepare the product, except that 4-3 in step d) was replaced with N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineamide. The reaction solution was then desolventized to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 19 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.06 (s, 1H), 9.17 (d, J = 2.3Hz, 1H), 8.74 (d, J = 7.9Hz, 2H), 8.46 (dd, J = 8.2,2.3Hz,1H),8.37-8.24(m,2H),8.05(d,J＝8.3Hz,1H),7.53-7.40(m,6H),6.95(d,J＝5.5Hz,1H), 6.68(s,1H),6.55(s,2H),2.83(d,J＝4.8Hz,3H),2.00(s,3H).

MS(ESI+):591.2(M+H).

Embodiment 29:

a) Preparation of Compound 29-1

Prepared by referring to the preparation method of Example 4, except that 4-3 in step d) was replaced with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate. Then the reaction solution was desolventized to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 70 mg of the target compound.

b) Preparation of Compound Example 29

29-1 (70 mg) and DCM (5 mL) were placed in a 25 mL single-mouth bottle and stirred at room temperature. TFA (2 mL) was added to the reaction solution, and then the reaction solution was reacted at room temperature overnight. The reaction solution was desolvated to dryness and then dissolved with DCM (20 mL). The organic phase was washed three times with 1N sodium hydroxide solution (10 mL). The organic phase was desolvated to dryness and purified by column chromatography (DCM/MeOH=10/1 (V/V)) to obtain 5.5 mg of the target compound.

MS(ESI+):606.3(M+H).

Embodiment 30:

a) Preparation of Compound 30-1

Under nitrogen protection, a mixture of 3-bromo-4H,5H,6H-pyrrolo[1,2-b]pyrazole (100 mg), PhMe2SI-BPin (210.3 mg), KOMe (44.8 mg) and DME (5.0 mL) was stirred at 30°C for 2 h. The reaction solution was concentrated to dryness and purified by column chromatography (PE/EA=4/1 (V/V)) to obtain 45 mg of the target compound.

b) Preparation of Compound Example 30

Prepared by referring to the preparation method of Example 4, 4-3 in step d) was replaced with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole. Then the reaction solution was desolventized to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 5 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.02 (s, 1H), 8.34 (d, J = 5.4Hz, 1H), 8.21 (d, J = 1.9Hz, 1H), 8.19 (s, 1H) ,7.85(s,1H),7.58-7.35(m,6H),6.94(d,J＝5.5Hz,1H),6.74-6.61(m,1H),5.92(s,2H),4.07(t,J ＝7.3Hz,2H),3.02(t,J＝7.3Hz,2H),2.57(p,J＝7.4Hz,2H),2.04-1.93(m,3H).

MS(ESI+):563.2(M+H).

Embodiment 31:

a) Preparation of compound 31-1

Prepared by referring to the preparation method of Example 4, replacing 4-3 in step d) with tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate. Then the reaction solution was desolventized to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 70 mg of the target compound.

b) Preparation of Compound Example 31

A mixture of 31-1 (70 mg) and 4M hydrochloric acid (dioxane solution) (2 mL) was stirred at room temperature for 1 h. The reaction solution was concentrated to dryness. The crude product was purified by reverse phase HPLC (column: YMC Triart C18 ExRs column, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 40% B to 62% B, 8 min; detection wavelength: 254/220 nm; retention time of target compound: 6.32 min), and 18.2 mg of the title product was obtained.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.01 (s, 1H), 8.34 (d, J = 5.4Hz, 1H), 8.29-8.09 (m, 2H), 7.90 (s, 1H), 7.63-7.22(m,6H),6.94(d,J＝5.5Hz,1H),6.72-6.62(m,1H),5.95(s,2H),4.14(s,2H),4.02(t,J＝ 5.5Hz,2H),3.12(t,J＝5.6Hz,2H),2.04-1.90(m,3H).

MS(ESI+):578.2(M+H).

Embodiment 32:

a) Preparation of compound 32-1

Under nitrogen protection, a mixture of 3-bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (100 mg), PhMe ₂ SI-BPin (210.3 mg), KOMe (44.8 mg) and DME (5.0 mL) was stirred at 30°C for 2 h. The reaction solution was concentrated to dryness and purified by column chromatography (PE/EA=4/1 (V/V)) to obtain 35 mg of the target compound.

b) Preparation of Compound Example 32

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with (6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)boronic acid. Then the reaction solution is desolvated to dryness. The obtained crude product is purified by reverse phase high performance liquid chromatography (column: XBridge BEH C18 OBD, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 40% B to 67% B, 8 min; detection wavelength: 254/220 nm; retention time of target compound: 7.02 min) to obtain 11.6 mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.02 (s, 1H), 8.34 (d, J = 5.4Hz, 1H), 8.31 (s, 1H), 8.26-8.18 (m, 1H), 7.98 ( s,1H),7.53-7.47(m,4H),7.43(t,J＝8.8Hz,2H),6.94(d,J＝5.5Hz,1H),6.72-6.61(m,1H),6.01(s ,2H),4.99(s,2H),4.13(t,J＝5.2Hz,2H),4.04(dd,J＝6.0,4.3Hz,2H),2.05-1.91(m,3H).

MS(ESI+):579.2(M+H).

Embodiment 33:

a) Preparation of compound 33-1

Under nitrogen protection, a mixture of 3-bromopyrazolo[1,5-a]pyrazine (100 mg), PhMe ₂ SI-BPin (210.3 mg), KOMe (44.8 mg) and DME (5.0 mL) was stirred at 30° C. for 2 h. The reaction solution was concentrated to dryness and purified by column chromatography (PE/EA=4/1 (V/V)) to obtain 120 mg of the target compound.

b) Preparation of Compound Example 33

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with 33-1. Then the reaction solution is desolvated to dryness. The obtained crude product is purified by reverse phase high performance liquid chromatography (column: XBridge BEH Shield RP18, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 45% B to 70% B, 10 min; detection wavelength: 254/220 nm; retention time of target compound: 8.33 min) to obtain 3.7 mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.06 (s, 1H), 9.64 (d, J = 1.4Hz, 1H), 8.82-8.71 (m, 2H), 8.65 (s, 1H), 8.36 ( d,J＝5.4Hz,1H),8.29(dd,J＝13.6,2.0Hz,1H),7.92(d,J＝4.8Hz,1H),7.59(t,J＝8.4Hz,1H),7.56- 7.48(m,3H),7.48-7.38(m,2H),6.95(d,J＝5.5Hz,1H),6.73-6.62(m,1H),6.28(s,2H),2.07-1.92(m, 3H).

MS(ESI+):574.2(M+H).

Embodiment 34:

Preparation of compound 34:

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)acetonitrile. Then, the reaction solution is desolventized to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 7 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.05 (s, 1H), 8.35 (d, J = 5.5Hz, 2H), 8.27 (d, J = 13.2Hz, 2H), 8.05 (s, 1H) ,7.48(dq,J＝33.2,9.9,7.5Hz,6H),6.95(d,J＝5.5Hz,1H),6.68(s,1H),6.11(s,2H),5.50(s,2H), 2.00(s,3H).

MS(ESI+):562.2(M+H).

Example 35 and Example 36:

Preparation of Compound Example 35 and Compound Example 36:

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with 1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. Then, the reaction solution is desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 43 mg of a racemate. The product was then separated by chiral column (column: CHIRALPAK-IE column, 20×250 mm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: MeOH:DCM=1:1; flow rate: 20 mL/min; gradient: 60% B; detection wavelength: 254/220 nm; target compound 35: 7.6 min, target compound 36: 10.363 min; injection volume: 0.93 mL) to obtain target compound 35: 15.6 mg, target compound 36: 15.3 mg.

Compound Example 35: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.02 (s, 1H), 8.33 (s, 1H), 8.32 (s, 1H), 8.24 (dd, J=13.4, 2.0 Hz, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7.50 (ddd, J=8.0, 6.3, 3.6 Hz, 2H), 7.42 (td, J=8.6, 6.3 Hz, 4H), 6.94 (d, J=5.5 Hz, 1H), 6.76-6.55 (m, 1H), 6.06-5.89(m,2H),5.03(ddt,J＝7.9,6.1,3.9Hz,1H),4.02-3.94(m,2H),3.90(dd,J＝9.4,3.8Hz,1H),3.81(td,J＝8.2,5.5Hz,1H),2.43-2.33(m,1H),2 .29(dddd,J＝18.5,9.4,4.5,3.0Hz,1H),2.08-1.90(m,3H).

MS(ESI+):593.2(M+H).

Compound Example 36: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.02 (s, 1H), 8.33 (s, 1H), 8.32 (s, 1H), 8.24 (dd, J=13.4, 2.0 Hz, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7.50 (ddd, J=8.0, 6.3, 3.6 Hz, 2H), 7.42 (td, J=8.6, 6.3 Hz, 4H), 6.94 (d, J=5.5 Hz, 1H), 6.76-6.55 (m, 1H), 6.06-5.89(m,2H),5.03(ddt,J＝7.9,6.1,3.9Hz,1H),4.02-3.94(m,2H),3.90(dd,J＝9.4,3.8Hz,1H),3.81(td,J＝8.2,5.5Hz,1H),2.43-2.33(m,1H),2 .29(dddd,J＝18.5,9.4,4.5,3.0Hz,1H),2.08-1.90(m,3H).

MS(ESI+):593.2(M+H).

Embodiment 37:

a) Preparation of Compound Example 37

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. Then, the reaction solution is desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 10 mg of the target compound.

Example 37: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.04 (s, 1H), 8.36-8.31 (m, 2H), 8.28-8.19 (m, 2H), 7.89 (s, 1H), 7.54-7.39 (m, 6H), 6.95 (d, J=5.5 Hz, 1H), 6.68 (s, 1H), 5.99 (s, 2H), 4.46-4.36 (m, 1H), 3.99-3.92 (m, 2H), 3.51-3.44 (m, 2H), 2.05-1.89 (m, 7H).

MS(ESI+):607.2(M+H).

Embodiment 38:

a) Preparation of Compound 38-1

Under ice bath, p-toluenesulfonyl chloride (1.28 g) was added to a DCM (30 mL) solution of 3-(benzyloxy)cyclobutane-1-ol (1 g,) and TEA (1.14 g) in portions. The reaction solution was reacted at room temperature overnight. The resulting mixture was washed with water (3×50 mL), saturated sodium chloride (50 mL) and dried over Na ₂ SO ₄ in sequence. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using (PE/EA＝2/1 (V/V)) as eluent to obtain 1.4 g of the target compound.

b) Preparation of compound 38-2

38-1 (550 mg), Cs2CO ₃ (333.24 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (424.68 mg) and NMP (16 mL) were placed in a 30 mL microwave tube and subjected to microwave reaction at 80°C for 2 hours. The reaction solution was poured into 100 mL of water, and the resulting mixture was extracted with EA (3×100 mL). The combined organic layer was washed with brine (3×100 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with (PE/EA＝2/1 (V/V)) to obtain 400 mg of the target compound.

c) Preparation of Compound 38-3

Under nitrogen protection, 38-2 (400 mg), Pd/C (40 mg), concentrated hydrochloric acid (0.5 mL) and MeOH (5 mL) were placed in a 25 mL two-necked bottle. The mixture was hydrogenated at room temperature for 16 hours using a hydrogen balloon, filtered through a celite pad and concentrated under reduced pressure to obtain 200 mg of the target compound.

d) Preparation of Compound Example 38

The preparation method was referred to that of Example 4, except that 4-3 in step d) was replaced by 38-3. The reaction solution was then desolventized to dryness, and the crude product was purified by reverse phase high performance liquid chromatography (column: XBridge BEH C18 OBD, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 33% B to 57% B, 8 min; detection wavelength: 254/220 nm; retention time of target compound: 7.63 min) to obtain 12.4 mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.03 (s, 1H), 8.40-8.30 (m, 2H), 8.27-8.17 (m, 2H), 7.89 (d, J = 0.7Hz, 1H), 7.56-7.32(m,6H),6.94(d,J＝5.5Hz,1H),6.68(d,J＝1.1Hz,1H),5.98(s,2H),5.20(d ,J＝5.2Hz,1H),4.94(tt,J＝8.4,5.4Hz,1H),4.44(td,J＝7.1,4.8Hz,1H),2.64(dddd,J＝13.0,6.8,4.4,2.5 Hz,2H),2.34(tt,J=9.5,3.9Hz,2H),2.02-1.95(m,3H).

MS(ESI+):593.2(M+H).

Embodiment 39:

Preparation of Compound Example 39

Prepared by referring to the preparation method of Example 4, except that 4-3 in step d) was replaced with 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine. Then the reaction solution was desolventized to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 7.8 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.03 (s, 1H), 8.34 (d, J = 5.4Hz, 1H), 8.30 (s, 1H), 8.24 (dd, J = 13.4, 2.0Hz, 1H),8.15(s,1H),7.86(s,1H),7.55-7.37(m,6H),6.94(d,J＝5.5Hz,1H),6.67(s,1H),5.96(s,2H ),4.23(t,J＝6.6Hz,2H),3.53(t,J＝4.6Hz,4H),2.72(t,J＝6.6Hz,2H),2.40(t,J＝4.7Hz,4H), 1.99(s,3H).

MS(ESI+):636.3(M+H).

Embodiment 40:

Preparation of Compound Example 40

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. Then, the reaction solution is desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 25 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.03 (s, 1H), 8.34 (d, J = 5.5Hz, 1H), 8.22 (s, 1H), 7.75 (s, 1H), 7.57-7.41 ( m,6H),7.01-6.86(m,2H),6.68(s,1H),5.97(s,2H),3.75(s,3H),2.47(s,3H),2.00(s,3H).

MS(ESI+):551.2(M+H).

Embodiment 41:

a) Preparation of Compound Example 41

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. Then, the reaction solution is desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 20 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.02 (s, 1H), 8.34 (d, J = 5.4Hz, 1H), 8.23 (dd, J = 13.5, 1.9Hz, 1H), 7.98 (s, 1H),7.55-7.38(m,6H),6.94(d,J＝5.5Hz,1H),6.68(s,1H),5.99(s,2H),3.68(s,3H),2.31(d,J =1.7Hz,3H),2.21(s,3H),2.00(s,3H).

MS(ESI+):565.2(M+H).

Embodiment 42:

a) Preparation of Compound Example 42

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. Then, the reaction solution is desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 18 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.04(s,1H),8.39-8.32(m,2H),8.31-8.21(m,1H),7.54-7.41(m,7H),6.95(d ,J＝5.5Hz,1H),6.66(dd,J＝12.1,1.5Hz,2H),6.43(s,2H),4.01(s,3H),2.00(s,3H).

MS(ESI+):537.2(M+H).

Embodiment 43:

a) Preparation of Compound Example 43

The preparation method of Example 4 was used to prepare the product, except that 4-3 in step d) was replaced with 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. The reaction solution was then desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 16 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.04 (s, 1H), 8.46 (s, 1H), 8.34 (d, J = 5.4Hz, 1H), 8.26 (dd, J = 13.4, 2.0Hz, 1H),7.69(d,J＝2.2Hz,1H),7.55-7.41(m,5H),7.44-7.38(m,1H),6.94(d,J＝5.5Hz,1H),6.67(s,1H ), 6.56 (d, J = 2.2Hz, 1H), 6.13 (s, 2H), 3.88 (s, 3H), 1.99 (s, 3H).

MS(ESI+):537.2(M+H).

Embodiment 44:

Preparation of Compound Example 44

Prepared by referring to the preparation method of Example 4, except that 4-3 in step d) was replaced with N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)ethan-1-amine. Then the reaction solution was desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 9 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.03 (s, 1H), 8.34 (d, J = 5.5Hz, 1H), 8.30 (s, 1H), 8.24 (dd, J = 13.3, 2.0Hz, 1H),8.12(s,1H),7.86(s,1H),7.53-7.39(m,6H),6.94(d,J＝5.5Hz,1H),6.67(s,1H),5.95(s,2H ),4.19(t,J＝6.5Hz,2H),2.64(t,J＝6.5Hz,2H),2.15(s,6H),1.99(s,3H).

MS(ESI+):594.3(M+H).

Embodiment 45:

Preparation of Compound Example 45

Prepared by referring to the preparation method of Example 4, 4-3 in step d) was replaced with 1-(oxetane-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Then the reaction solution was desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 6 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.03(s,1H),8.38-8.22(m,4H),8.02(s,1H),7.54-7.42(m,6H),6.94(d,J ＝5.5Hz,1H),6.68(s,1H),6.03(s,2H),5.76(s,1H),4.91(d,J＝7.0Hz,4H),1.99(s,3H).

MS(ESI+):579.2(M+H).

Embodiment 46:

a) Preparation of compound 46-1:

7-Bromo-[1,2,4]triazolo[1,5-a]pyridine (200 mg), bis-pinacol borate (385 mg), Pd(dppf)Cl ₂ -DCM (82 mg), KOAc (198 mg) were dissolved in dioxane (5 mL). Under nitrogen protection, the reaction solution was stirred at 100°C for 2 h. The reaction solution was concentrated and purified by column chromatography (DCM/MeOH=50/1 (V/V)) to obtain 249 mg of the target compound.

b) Preparation of Compound Example 46

The preparation method was referred to Example 4, except that 4-3 in step d) was replaced with [1,2,4]triazolo[1,5-a]pyridin-7-ylboronic acid. The reaction solution was then desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 6 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.06 (s, 1H), 8.94 (d, J = 7.1Hz, 1H), 8.86 (s, 1H), 8.48 (s, 1H), 8.40-8.26 ( m,3H),7.83(dd,J＝7.2,1.9Hz,1H),7.61-7.37(m,6H),6.95(d,J＝5.5Hz,1H),6.65(d,J＝24.0Hz,3H ),2.00(s,3H).

MS(ESI+):574.2(M+H).

Embodiment 47:

a) Preparation of Compound Example 47

Prepare with reference to the preparation method of Example 4, except that 4-3 in step d) is replaced with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole-1-carboxylate. Then, the reaction solution is desolventized to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 6 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.92 (s, 1H), 12.03 (s, 1H), 8.37-8.28 (m, 2H), 8.24 (dd, J = 13.3, 2.0Hz, 1H), 8.14(s,1H),7.90(s,1H),7.50(ddd,J＝6.8,5.8,3.5Hz,2H),7.47-7.35(m,4H),6.94(d,J＝5.5Hz,1H) ,6.67(d,J＝1.0Hz,1H),5.94(s,2H),2.04-1.93(m,3H).

MS(ESI+):523.2(M+H).

Embodiment 48:

a) Preparation of Compound 48-1

A mixture of 4-bromopyrazole (10 g), K ₂ CO ₃ (18.81 g) and ethyl chloroacetate (31.25 mL) was stirred at 80°C for 15 hours. EA (500 mL) was added to the mixture, followed by washing with water (3×250 mL). The organic layer was dried over anhydrous Na 2 SO 4 . The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (PE/EA=4/1 (V/V)) to obtain 13.6 g of the target compound.

b) Preparation of Compound 48-2

Under nitrogen protection, a mixture of 48-1 (12 g), Ti(O ⁱ Pr) ₄ (7.32 g,) and THF (120 mL) was stirred at 60°C. Ethylmagnesium bromide (20.59 g) was slowly added dropwise to the reaction solution, and the resulting mixture was stirred at 60°C for another 2 hours. When the reaction solution was cooled to room temperature, a saturated NH 4 Cl solution (300 mL) was added thereto. The resulting mixture was extracted with EtOAc (3x400 mL). The combined organic layer was washed with brine (3×200 mL) and dried over anhydrous Na 2 SO 4. The filtrate was then desolventized to dryness and purified by column chromatography (PE/EA＝3/1 (V/V)) to obtain 1.7 g of the target compound.

c) Preparation of Compound 48-3

Under nitrogen protection, n-BuLi (6.450 mmol) was added dropwise to a solution of 48-2 (700 mg) and THF (7 mL) at -78°C, and then triisopropyl borate (1819.5 mg) was added in batches. The resulting mixture was stirred at -78°C for another 2 hours. Water/ice (300 mL) was added to the reaction solution to quench the reaction. The mixture was concentrated under reduced pressure, and the crude product was purified by reverse phase flash chromatography: column, C18; mobile phase, phase A: water (0.1% HCl), phase B: MeCN, gradient from 10% B to 50% B in 10 minutes; detector, UV 254 nm. 80 mg of the target compound was obtained.

d) Preparation of Compound Example 48

The preparation method was referred to Example 4, except that 4-3 in step d) was replaced by 48-3. The reaction solution was then desolventized to dryness, and the crude product was purified by reverse phase high performance liquid chromatography (column: YMC Triart C18 ExRs, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 45% B to 62% B, 10 min; detection wavelength: 254/220 nm; retention time of target compound: 9.2 min) to obtain 3.4 mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.03 (s, 1H), 8.34 (d, J = 5.5 Hz, 1H), 8.25 (dd, J = 13.5, 2.0 Hz, 1H), 7.86 (s, 1H),7.56(d,J＝2.2Hz,1H),7.50(ddt,J＝8.2,5.4,2.7Hz,2H),7.45-7.36(m,5H),6.94(d ,J＝5.5Hz,1H),6.67(d,J＝1.1Hz,1H),6.25(t,J＝2.1Hz,1H),5.87(s,2H),5.12(s,2H),2.83(dd ,J＝8.1,4.5Hz,2H),2.77(dd,J＝8.1,4.5Hz,2H),1.99(d,J＝1.0Hz,3H).

MS(ESI+):593.2(M+H).

Embodiment 49:

Preparation of Compound Example 49

Prepared by referring to the preparation method of Example 4, 4-3 in step d) was replaced with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)propan-2-ol. Then the reaction solution was desolventized to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 28 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) 1H NMR (400MHz, DMSO-d6) δ12.03 (s, 1H), 8.37-8.29 (m, 2H), 8.25 (dd, J＝13.3, 1.9Hz, 1H ),8.05(s,1H),7.87(s,1H),7.54-7.38(m,6H),6.93(d,J＝5.5Hz,1H),6.67(s,1H),5.97(s,2H) ,4.71(s,1H),4.02(s,2H),1.99(s,3H),1.07(s,6H).

MS(ESI+):595.2(M+H).

Example 50 and Example 51:

a) Preparation of compound 50-1:

TsCl (2.36 g) was added in batches to 3-hydroxycyclobutane-1-carbonitrile (1 g) and TEA (3.13 g) in DCM (30 mL), and stirred at room temperature for 16 hours. Water (200 mL) was added to the reaction solution, followed by extraction with DCM (3 x 200 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Purification by column chromatography (PE/EA = 3/1 (V/V)) gave 2 g of the target compound.

b) Preparation of Compound Example 50 and Compound Example 51:

Under nitrogen protection, 50-1 (14.43 mg), 47 (30 mg), cesium carbonate (13.11 mg) and NMP (2 mL) were placed in a microwave tube and microwaved at 80 degrees for 2 hours. Water (20 mL) was added to the reaction solution, followed by extraction with EA (3x20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase high performance liquid chromatography (column: Xselect CSHTM Prep C18 OBD, 19×150 mm, filler particle size 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 35% B to 63% B, 10 min; detection wavelength: 254/220 nm; racemic retention time: 8.57 min) to obtain 8 mg of the title mixture. Then, the product was separated by chiral column (column: CHIRALPAK-ID column, 20×250 mm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: EtOH:DCM=1:1; flow rate: 20 mL/min; gradient: 45% B; detection wavelength: 254/220 nm; target compound 50: 7.567 min, target compound 51: 10.973 min; injection volume: 1.0 mL). The target compound 50 was obtained at 5.4 mg and the target compound 51 was obtained at 1.1 mg.

Compound Example 50: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 12.02 (s, 1H), 8.37-8.29 (m, 2H), 8.28-8.20 (m, 2H), 7.96 (s, 1H), 7.54-7.46 (m, 2H), 7.50-7.36 (m, 4H), 6.94 (d, J=5.5 Hz, 1H), 6.67 (s, 1H), 5.99 (s, 2H), 5.17 (m, J=7.9 Hz, 1H), 3.53-3.43 (m, 1H), 2.95-2.83 (m, 2H), 2.83-2.72 (m, 2H), 2.00 (s, 3H).

MS(ESI+):602.2(M+H).

Compound Example 51: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 12.02 (s, 1H), 8.43-8.28 (m, 3H), 8.24 (dd, J=13.3, 2.0 Hz, 1H), 7.96 (s, 1H), 7.54-7.47 (m, 2H), 7.46-7.36 (m, 4H), 6.94 (d, J=5.5 Hz, 1H), 6.67 (s, 1H), 5.99 (s, 2H), 4.87 (m, J=8.3 Hz, 1H), 3.26-3.17 (m, 1H), 2.82 (m, J=7.8 Hz, 4H), 2.00 (s, 3H).

MS(ESI+):602.2(M+H).

Embodiment 52:

Preparation of Compound Example 52

Under nitrogen protection, 47 (50 mg), 4-bromo-1-methylpiperidine (25.6 mg), cesium carbonate (187 mg) and NMP (2 mL) were placed in a microwave tube and subjected to microwave reaction at 80°C for 2 hours. Water (20 mL) was added to the reaction solution, followed by extraction with EA (3x20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (column: Ultimate μXB-C18; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 100 mL/min; gradient: 40% B to 80% B, 20 min; detection wavelength: 254/220 nm; retention time of the target compound: 24 min) to obtain 6.5 mg of the title compound.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.36-8.29 (m, 2H), 8.24 (dd, J = 13.3, 2.0Hz, 1H), 8.17 (s, 1H) ),7.86(s,1H),7.50(qd,J＝6.4,5.8,2.1Hz,2H),7.46-7.38(m,4H),6.94(d,J＝5.5Hz,1H),6.67(s, 1H), 5.96 (s, 2H), 4.12 (s, 1H), 2.87 (s, 2H), 2.22 (s, 3H), 1.99 (d, J = 7.4Hz, 9H).

MS(ESI+):620.2(M+H).

Embodiment 53:

a) Preparation of compound 53-1:

TsCl (503.2 mg) was added portionwise to tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg) and DMAP (537 mg) in DCM. (30mL) and stirred at room temperature for 16 hours. Water (200mL) was added to the reaction solution, followed by extraction with DCM (3x200mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (PE/EA=3/1 (V/V)) to obtain 600 mg of the target compound.

b) Preparation of compound 53-2:

Under nitrogen protection, 53-1 (30 mg), 47 (45 mg), cesium carbonate (153 mg) and NMP (2 mL) were placed in a microwave tube and microwaved at 80 degrees for 2 hours. Water (20 mL) was added to the reaction solution, followed by extraction with EA (3x20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (DMC/MeOH=20/1 (V/V)) to obtain 10 mg of the target compound.

c) Preparation of Compound Example 53:

A mixture of 53-2 (10 mg) and dioxane hydrochloride solution (4 M, 1 mL) was stirred at room temperature for 1 h. The filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (column: Xselect CSHTM Prep C18 19×150 mm, filler particle size 5 μm; mobile phase A: water (0.1% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5% B to 38% B, 10 min; detection wavelength: 254/220 nm; retention time of target compound: 8.93 min) to obtain 2.2 mg of the title mixture.

¹ H NMR (400 MHz, DMSO-d ₆ ,ppm)δ12.02(s,1H),8.34(d,J＝5.4Hz,1H),8.30(s,1H),8.24(dd,J＝13.4,2.0Hz,1H),8.15(s,1H),7.87(s,1H),7.49(ddd,J＝8.9,6.8,3.6Hz,2H),7.4 6-7.37(m,4H),6.94(d,J＝5.5Hz,1H),6.67(s,1H),5.96(s,2H),4.60(t,J＝5.8Hz,1H),3.71(s,2H),2.06(t,J＝12.3Hz,2H),2.00(s,3H),1.97(s,2H) ,1.81(s,4H).

MS(ESI+):632.2(M+H).

Embodiment 54:

a) Preparation of compound 54-1:

Referring to the preparation method of Example 53, the tert-butyl ester of 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate in step a was replaced with tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate to obtain 1.2 g of the target compound.

b) Preparation of compound 54-2:

Referring to the preparation method of Example 53, 53-1 in step b was replaced by 54-1 to obtain 40 mg of the target compound.

c) Preparation of Compound Example 54:

Refer to the preparation method of Example 53, and replace 53-2 in step c with 54-2. The crude product was purified by reverse phase high performance liquid chromatography (column: Kinetex 5m EVO C18 30×150mm, filler particle size 5μm; mobile phase A: water (10mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 25%B～51%B, 8min; detection wavelength: 254/220nm; retention time of target compound: 6.95min) to obtain 6.3mg of the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ,ppm)δ12.02(s,1H),8.33(d,J＝5.4Hz,1H),8.30(s,1H),8.23(dd,J＝13.5,2.0Hz,1H),8.17(s,1H),7.87(s,1H),7.53-7.47(m,2H),7.46-7.36(m,4H ),6.94(d,J＝5.5Hz,1H),6.67(d,J＝1.2Hz,1H),5.95(s,2H),4.71(h,J＝8.2Hz,1H),3.82(s,1H),3.59(s,1H),3.49(s,1H),3.10(s,1H),2.71-2.53(m ,4H),1.99(s,3H).

MS(ESI+):618.2(M+H).

Embodiment 55:

a) Preparation of compound 55-1:

Referring to the preparation method of Example 53, tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate was used to replace tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate in step a to obtain 400 mg of the target compound.

b) Preparation of compound 55-2:

Referring to the preparation method of Example 53, 53-1 in step b was replaced by 55-1 to obtain 43 mg of the target compound.

c) Preparation of Compound 55:

Refer to the preparation method of Example 53, and replace 53-2 in step c with 55-2. The crude product was purified by reverse phase high performance liquid chromatography (column: Sunfire C18 30×150 mm, filler particle size 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5% B to 36% B, 10 min; detection wavelength: 254/220 nm; retention time of target compound: 9.87 min) to obtain 8.7 mg of the title mixture.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.02 (s, 1H), 8.40 (s, 1H), 8.33 (d, J = 5.5Hz, 1H), 8.30 (s, 1H), 8.23 ( dd,J＝13.3,2.0Hz,1H),7.85(d,J＝0.7Hz,1H),7.49(ddd,J＝6.7,5.6,3.5Hz,2H),7.47-7.36(m,4H),6.94 (d,J＝5.5Hz,1H) ,6.67(d,J＝1.1Hz,1H),5.94(s,2H),4.12(q,J＝9.5,7.8Hz,1H),3.60(s,2H),3.50(s,2H),2.07( d,J＝12.9Hz,2H),2.00(s,3H),1.94(d,J＝12.8Hz,2H),1.75(q,J＝12.2Hz,2H),1.56(t,J＝12.6Hz, 2H).

MS(ESI+):646.2(M+H).

Embodiment 56:

a) Preparation of compound 56-1:

Referring to the preparation method of Example 53, tert-butyl 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate was used to replace tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate in step a to obtain 560 mg of the target compound.

b) Preparation of compound 56-2:

Referring to the preparation method of Example 53, 53-1 in step b was replaced by 56-1 to obtain 40 mg of the target compound.

c) Preparation of Compound Example 56:

Refer to the preparation method of Example 53, and replace 53-2 in step c with 56-2. The crude product was purified by reverse phase high performance liquid chromatography (column: Sunfire C18 30×150 mm, filler particle size 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 20% B to 50% B, 8 min; detection wavelength: 254/220 nm; retention time of target compound: 7.37 min) to obtain 6.0 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.02 (s, 1H), 8.37-8.29 (m, 2H), 8.28-8.19 (m, 2H), 7.90 (d, J = 1.9Hz, 1H ),7.55-7.36(m,6H),6.94(d,J＝5.5Hz,1H),6.68(s,1H),5.97(s,2H),4.99-4.76(m,1H),3.31(s, 1H),3.06(d,J＝6.3Hz,3H),2.96(d,J＝7.7Hz,1H),2.38(m,2H),1.98(d,J＝8.9Hz,5H),1.91(d, J＝7.4Hz,1H).

MS(ESI+):632.2(M+H).

Example 57, Example 58 and Example 59:

a) Preparation of compound 57-1:

Refer to the preparation method of Example 53, and replace tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate with tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate to obtain 1.5 g of the target compound.

b) Preparation of compound 57-2:

Referring to the preparation method of Example 53, 53-1 in step b was replaced by 57-1 to obtain 45 mg of the target compound.

c) Preparation of compounds 57, 58, and 59:

Refer to the preparation method of Example 53, and replace 53-2 in step c with 57-2. The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge BEH C18 OBD Prep Column 130, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 32% B to 55% B, 8 min; detection wavelength: 254/220 nm; retention time of target compound: 6.27 min) to obtain 23 mg of a mixture. The product was then separated by a chiral column (column: CHIRALPAK-IE column, 20×250 mm, filler particle size 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: EtOH:DCM=1:1; flow rate: 20 mL/min; gradient: 50% B; detection wavelength: 254/220 nm; target compound 57: 11.07 min, mixture of 58 and 59: 15.53 min; injection volume: 1.16 mL) to obtain target compound 57: 2.5 mg, mixture of 58 and 59: 10 mg. The mixture of 58 and 59 was separated by chiral column (column: CHIRAL ART Cellulose-SB, 30×250 mm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: EtOH; flow rate: 40 mL/min; gradient: 20% B; detection wavelength: 254/220 nm; target compound 58: 9.4 min, target compound 59: 10.8 min; to obtain target compound 58: 2.6 mg, target compound 59: 2.7 mg.

Compound Example 57: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 8.32 (s, 1H), 8.24 (dd, J=13.4, 2.0 Hz, 1H), 8.14 (s, 1H), 7.86 (s, 1H), 7.54-7.36 (m, 6H), 6.94 (d, J=5.5 Hz, 1H), 6.68 (s, 1H), 5.96(s,2H),4.32-4.19(m,1H),3.10(d,J＝12.4Hz,1H),2.77(s,1H),2.72(d,J＝12.5Hz,1H),2.00(s,5H),1.76(m,1H),1.52(m,1H),1.19(m,1H),1 .07(d,J＝6.3Hz,3H).

MS(ESI+):620.2(M+H).

Compound Example 58: ¹ H NMR (400 MHz, DMSO-d ₆ ,ppm)δ12.03(s,1H),8.34(d,J＝5.4Hz,1H),8.32(s,1H),8.24(d,J＝13.3Hz,1H),8.15(s,1H),7.88(s,1H),7.50(dt,J＝9.1,4.7Hz,2H),7.47-7.38(m ,4H),6.94(d,J=5.5Hz,1H),6.68(s,1H),5.97(s,2H),4.33(s,1H),2.89(s,1H),2.82(s,1H),2.06(m,2H),2.00(s,3H),1.83(s,1H),1.63(s,1H), 1.30(s,1H),1.24(s,3H).

MS(ESI+):620.2(M+H).

Compound Example 59: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 12.03 (s, 1H), 8.34 (m, 2H), 8.27-8.21 (m, 2H), 7.91 (s, 1H), 7.54-7.47 (m, 2H), 7.47-7.35 (m, 4H), 6.94 (d, J=5.5 Hz, 1H), 6.68 (d, J=1.0 Hz, 1H), 5.98 (s, 2H), 4.57 (s, 1H), 2.97 (m, 2H), 2.28 (m, 1H), 2.18 (s, 1H), 2.08-1.93 (m, 4H), 1.76 (s, 1H), 1.25 (s, 1H), 1.14 (d, J=6.6 Hz, 3H).

MS(ESI+):620.2(M+H).

Example 60, Example 61, Example 62 and Example 63:

a) Preparation of compound 60-1:

Referring to the preparation method of Example 53, the tert-butyl ester of 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate in step a was replaced with tert-butyl 4-hydroxy-2,6-dimethylpiperidine-1-carboxylate to obtain 0.7 g of the target compound.

b) Preparation of compound 60-2:

Referring to the preparation method of Example 53, 53-1 in step b was replaced by 60-1 to obtain 115 mg of the target compound.

c) Preparation of Compound Example 60, Compound Example 61, Compound Example 62 and Compound Example 63:

Refer to the preparation method of Example 53, and replace 53-2 in step c with 60-2. The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge BEH C18 OBD Prep Column 130, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 30% B to 53% B, 10 min; detection wavelength: 254/220 nm; retention time of target compound: 8.62 min) to obtain 40 mg of a mixture. Then, the mixture was separated by chiral column (column: CHIRALPAK-IE column, 20×250 mm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: MeOH:DCM=1:1; flow rate: 20 mL/min; gradient: 35% B; detection wavelength: 254/220 nm; injection volume: 1.56 mL), target compound 60: 11.222 min; target compound 61: 12.781 min; target compound 62: 14.057 min; target compound 63: 19.041 min; to obtain target compound 60: 2.9 mg, target compound 61: 1.2 mg, target compound 62: 11.2 mg, target compound 63: 8.6 mg,

Compound Example 60: ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.34 (d, J = 5.5 Hz, 1H), 8.31 (s, 1H), 8.25 (dd, J ＝13.3,2.0Hz,1H),8.14(d,J＝0.8Hz,1H),7.85(s,1H),7.57-7.34(m,6H),6.94(d,J＝5.5Hz,1H),6.68 (d,J＝1.0Hz,1H),5.97(s,2H),4.26(s,1H),2.80(s,2H),1.99(d,J＝0.9Hz,6H),1.43(d,J＝ 12.9Hz,2H),1.23(s,2H),1.06(d, J = 6.2 Hz, 3H).

MS(ESI+):634.2(M+H).

Compound Example 61: ¹ H NMR (400 MHz, DMSO-d ₆ ,ppm)δ12.03(s,1H),8.34(d,J＝5.5Hz,1H),8.31(s,1H),8.25(dd,J＝13.3,2.0Hz,1H),8.14(d,J＝0.8Hz,1H),7.85(s,1H),7.57-7.34(m,6H),6.94(d, J＝5.5Hz,1H),6.68(d,J＝1.0Hz,1H),5.97(s,2H),4.26(s,1H),2.80(s,2H),1.99(d,J＝0.9Hz,6H),1.43(d,J＝12.9Hz,2H),1.23(s,2H),1.06(d,J＝6.2 Hz,3H).

MS(ESI+):634.2(M+H).

Compound Example 62: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 8.31 (s, 1H), 8.25 (dd, J=13.3, 2.0 Hz, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.62-7.30 (m, 6H), 6.94 (d, J=5.5 Hz, 1H), 6.68 (s, 1H),5.97(s,2H),4.55(t,J＝12.4Hz,1H),3.48(s,1H),3.14(s,1H),1.99(s,5H),1.85(s,1H),1.52(q,J＝11.9Hz,1H),1.23(d,J＝6.8Hz,3H),1.05(d ,J＝6.2Hz,3H).

MS(ESI+):634.2(M+H).

Compound Example 63: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 8.31 (s, 1H), 8.25 (dd, J=13.3, 2.0 Hz, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.61-7.27 (m, 6H), 6.94 (d, J=5.5 Hz, 1H), 6.68 (s, 1H ),5.97(s,2H),4.52(d,J＝12.2Hz,1H),3.45(s,1H),3.11(s,1H),1.99(s,5H),1.85(d,J＝13.1Hz,1H),1.55-1.40(m,1H),1.22(d,J＝7.5Hz,3H),1.04( d,J＝6.2Hz,3H).

MS(ESI+):634.2(M+H).

Example 64 and Example 65:

a) Preparation of compound 64-1:

Referring to the preparation method of Example 53, tert-butyl 6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate was used to replace tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate in step a to obtain 280 mg of the target compound.

b) Preparation of compound 64-2:

Referring to the preparation method of Example 53, 53-1 in step b was replaced by 64-1 to obtain 50 mg of the target compound.

c) Preparation of Compound Example 64 and Compound Example 65:

Refer to the preparation method of Example 53, and replace 53-2 in step c with 64-2. The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge BEH Shield RP18, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 31% B to 48% B, 10 min; detection wavelength: 254/220 nm; retention time of target compound: 8.13 min) to obtain 15 mg of a mixture. The product was then separated by a chiral column (column: CHIRALPAK-IF column, 20×250 mm, filler particle size 5 μm; mobile phase A: n-hexane (0.5% isopropylamine), mobile phase B: EtOH:DCM=1:1; flow rate: 20 mL/min; gradient: 60% B; detection wavelength: 254/220 nm; target compound 64: 12.484 min, target compound 65: 17.042 min; injection volume: 1.3 mL) to obtain target compound 64: 3.8 mg, target compound 65: 5.4 mg.

Compound Example 64: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.30 (s, 1H), 8.24 (dd, J=13.3, 2.1 Hz, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.54-7.46 (m, 2H), 7.46-7.36 (m, 4H), 6.94 (d, J=5 .5Hz,1H),6.68(s,1H),5.97(s,2H),4.78-4.65(m,1H),3.69-3.44(m,4H),2.41-2.35(m,1H),2.34-2.29(m,1H),2.26-2.15(m,2H),1.99(s,3H), 1.96-1.84(m,2H).

MS(ESI+):632.2(M+H).

Compound Example 65: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.29 (d, J=8.6 Hz, 1H), 8.24 (d, J=13.4 Hz, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.57-7.47 (m, 2H), 7.46-7.24 (m, 4H), 6.98 (s, 1H), 6. 68(s,1H),5.97(s,2H),4.83-4.57(m,1H),3.88-3.55(m,2H),3.24-3.00(m,2H),2.43-2.35(m,1H),2.27-2.18(m,1H),2.14-2.03(m,2H),1.99( s,3H),1.95-1.89(m,2H).

Example 66 and Example 67:

a) Preparation of compound 66-1:

Under nitrogen protection, tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyrazol-1-yl]pyrrolidine-1-carboxylate (100 mg), 47 (135 mg), Pd(dppf)Cl ₂ ·DCM (24 mg) and cesium carbonate (179 mg) were placed in dioxane (10 mL)/H ₂ O (2 mL), and the reaction solution was stirred at 100° C. for 2 hours. The reaction solution was desolvated and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 100 mg of the title product.

b) Preparation of Compound Example 66 and Compound Example 67:

A mixture of 66-1 (100 mg) and dioxane hydrochloride solution (4M, 5 mL) was stirred at room temperature for 1 h. The filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase high performance liquid chromatography (column: XBridge BEH Shield RP18 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 28% B to 58% B, 10 min; detection wavelength: 254/220 nm; retention time of target compound: 7.93 min) to obtain 50 mg of the mixture. Then, the target compound 66 was separated by chiral column (column: CHIRALPAK-IF column, 20×250 mm, filler particle size 5 μm; mobile phase A: n-hexane (0.5% isopropylamine), mobile phase B: MeOH:DCM=1:1; flow rate: 20 mL/min; gradient: 50% B; detection wavelength: 254/220 nm; target compound 66: 30.938 min, target compound 67: 33.881 min); to obtain target compound 66: 14.1 mg, target compound 67:10.7mg.

Compound Example 66: ¹ H NMR (400 MHz, DMSO-d ₆ ,ppm)δ12.03(s,1H),8.35-8.31(m,2H),8.24(d,J＝14.6Hz,2H),7.91(s,1H),7.53-7.38(m,6H),6.94(d,J＝5.4Hz,1H),6.68(s,1H),5.98(s,2H),4.9 5(d,J＝7.7Hz,1H),3.29(s,1H),3.16(dt,J＝12.3,6.6Hz,2H),3.01(q,J＝9.6,8.3Hz,1H),2.26(dq,J＝15.1,7.7Hz,1H),2.17-2.05(m,1H),1.99(s,3H) .

MS(ESI+):592.2(M+H).

Compound Example 67: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.36-8.30 (m, 2H), 8.24 (d, J=12.4 Hz, 2H), 7.92 (s, 1H), 7.50 (ddd, J=7.3, 5.9, 3.5 Hz, 2H), 7.47-7.37 (m, 4H), 6.94 (d, J=5.5 Hz, 1H), 6.68 (s, 1H ),5.99(s,2H),5.03-4.82(m,1H),3.22(d,J＝2.4Hz,1H),3.20-3.11(m,2H),3.04(q,J＝9.5,8.3Hz,1H),2.31-2.20(m,1H),2.14(dd,J＝11.9,6.2Hz,1H ),2.00(s,3H).

MS(ESI+):592.2(M+H).

Example 68 and Example 69:

Preparation of Compound Example 68 and Compound Example 69:

Under nitrogen protection, 1-bromo-3-methoxycyclobutane (22 mg), 47 (70 mg), cesium carbonate (261 mg) and NMP (2 mL) were placed in a microwave tube and subjected to microwave reaction at 80 degrees for 2 hours. Water (20 mL) was added to the reaction solution, followed by extraction with EA (3x20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (column: XBridge BEH C18 OBD 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 40% B to 67% B, 8 min; detection wavelength: 254/220 nm; retention time of the target compound: 7.52 min) to obtain 20 mg of a mixture. The product was then separated by chiral column (column: CHIRALPAK-IA column, 20×250 mm, filler particle size 5 μm; mobile phase A: n-hexane (0.5% diethylamine), mobile phase B: EtOH:DCM=1:1; flow rate: 20 mL/min; gradient: 40% B; detection wavelength: 254/220 nm; target compound 68: 12.594 min, target compound 69: 18.266 min;) to obtain target compound 68: 1.4 mg, target compound 69: 9.4 mg.

Compound Example 68: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 8.31 (s, 1H), 8.24 (dd, J=13.2, 2.0 Hz, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.49 (td, J=7.7, 6.4, 3.7 Hz, 2H), 7.46-7.37 (m, 4H), 6.94 (d, J= 5.4Hz,1H),6.67(s,1H),5.98(s,2H),4.94(ddd,J＝14.4,8.4,5.9Hz,1H),4.14(dt,J＝6.8,3.2Hz,1H),3.19(s,3H),2.68-2.58(m,2H),2.43(td,J＝8. 6,4.1Hz,2H),1.99(s,3H).

MS(ESI+):607.2(M+H).

Compound Example 69: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.03 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.25 (dd, J=13.4, 2.0 Hz, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 7.49 (td, J=8.4, 7.8, 3.6 Hz, 2H), 7.46-7.39 (m, 4H), 6. 94(d,J＝5.5Hz,1H),6.67(s,1H),5.98(s,2H),4.54-4.43(m,1H),3.73(p,J＝7.1Hz,1H),3.18(s,3H),2.75(dtd,J＝9.3,6.9,3.0Hz,2H),2.40-2.30( m,2H),1.99(s,3H).

MS(ESI+):607.2(M+H).

Embodiment 70:

a) Preparation of compound 70-1:

Prepare by referring to the preparation method of Preparation Example 1, except that 1-2 in step c) is replaced by (1-methyl-1H-pyrazol-4-yl)boric acid, and 5-bromo-3-chloropyrazine-2-amine is replaced by 3-bromo-5-iodopyridin-2-amine to obtain 1.64 g of the title product.

d) Preparation of Compound 70-2

Prepared by referring to the preparation method of Preparation Example 1, except that 1-3 in step d) was replaced by 70-1 to obtain 278 mg of the title product.

e) Preparation of Compound Example 70

Prepare by referring to the preparation method of Preparation Example 1, except that 1-4 in step e) is replaced by 70-2. Then the reaction solution is desolventized to dryness. The obtained crude product is purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 37 mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.97 (s, 1H), 8.32 (d, J = 5.4 Hz, 1H), 8.22 (d, J ＝2.3Hz,1H),8.18(d,J＝2.1Hz,1H),8.03(s,1H),7.77(s,1H),7.49(qd,J＝7.1,6.4,2.1Hz,4H),7.45 -7.40(m,2H),7.31(t,J＝8.5Hz,1H),6.92(d,J＝5.5Hz,1H),6.66(s,1H),5.49(s,2H),3.82(s, 3H),1.99(s,3H).

MS(ESI+):536.2(M+H).

Embodiment 71:

Synthesis of Compound Example 71:

Under nitrogen protection, a mixture of M2 (49 mg), 2-methyl-3-butyn-2-ol (270 mg), TEA (2.3 mL), cuprous iodide (19 mg), bis(triphenylphosphine)palladium dichloride (7 mg) and acetonitrile (7 mL) was reacted at 90°C for 4 hours. The reaction solution was then desolventized to dryness. The crude product was purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 26 mg of the title product.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.05 (s, 1H), 8.34 (d, J = 5.4 Hz, 1H), 8.24 (dd, J ＝13.4,2.1Hz,1H),8.02(s,1H),7.53-7.40(m,6H),6.94(d,J＝5.5Hz,1H),6.67(s,1H),6.49(s,2H) ,5.47(s, 1H),1.99(s,3H),1.45(s,6H).

MS(ESI+):539.2(M+H).

Embodiment 72

a) Synthesis of Example 72

A mixture of 29 (120 mg), 3-oxetanone (15.7 mg) and DCM (1 mL) was reacted at room temperature for 1 hour. Sodium triacetoxyborohydride (46.19 mg) was added to the reaction solution in batches, and then the reaction solution was stirred at room temperature overnight. The reaction solution was desolventized to dryness. The crude product was purified by reverse phase HPLC (column: Kinetex 5m EVO C18, 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 35% B to 53% B, 8 min; detection wavelength: 254/220 nm; retention time of the target compound: 7.37 min) to obtain 4.7 mg of the title product.

¹ H NMR(400MHz, DMSO-d ₆ ,ppm) ¹ H NMR(400MHz, DMSO-d ₆ )δ12.03(s,1H),8.34(d,J＝5.4Hz,1H),8.31(s,1H ),8.24(dd,J＝13.4,2.0Hz,1H),8.19(s,1H),7.87(s,1H),7.50(ddd,J＝9.0,6.8,3.6Hz,2H),7.46-7.37( m,4H),6.94(d,J＝ 5.5Hz,1H),6.68(s,1H),5.97(s,2H),4.54(t,J＝6.5Hz,2H),4.43(t,J＝6.1Hz,2H),4.16(m,1H) ,3.43(p,J＝6.4Hz,1H),2.78(d,J＝7.1Hz,2H),2.06-1.98(m,5H),1.95(m,4H).

MS(ESI+):662.2(M+H).

Example 73 and Example 74

a) Preparation of compound 73-1:

Referring to the preparation method of Example 53, 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in step a was replaced with cyclopentane-1,3-diol to obtain 1.2 g of the target compound.

b) Preparation of Example 73 and Example 74:

Refer to the preparation method of Example 53, and replace 53-1 in step b with 73-1. The crude product was purified by reverse phase high performance liquid chromatography (column: YMC Triart C18 ExRs 30×150 mm, filler particle size 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 42% B to 72% B, 8 min; detection wavelength: 254/220 nm; retention time of target compound: 7 min) to obtain 32 mg of a mixture. The product was then separated by chiral column (column: CHIRALPAK-IF column, 20×250 mm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: EtOH:DCM=1:1; flow rate: 20 mL/min; gradient: 50% B; detection wavelength: 254/220 nm; target compound 73: 11.636 min, target compound 74: 27.934 min;) to obtain target compound 73: 11.2 mg, target compound 74: 9.1 mg.

Compound Example 73: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.02 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 8.31 (s, 1H), 8.24 (dd, J=13.3, 2.0 Hz, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.50 (ddd, J=8.3, 6.5, 3.6 Hz, 2H), 7.46-7.29 (m, 4H), 6.94 (d, J=5.5 Hz, 1H), 6. 67(s,1H),5.95(s,2H),4.86(d,J＝4.7Hz,1H),4.69(p,J＝7.8Hz,1H),4.17(h,J＝5.1Hz,1H),2.38-2.31(m,1H),2.12-2.05(m,2H),1.99(s,3H),1.85 (dt,J＝12.4,5.8Hz,1H),1.79-1.64(m,2H).

MS(ESI+):607.2(M+H).

Compound Example 74: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ12.02 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 8.31 (s, 1H), 8.24 (dd, J=13.3, 2.1 Hz, 1H), 8.18 (d, J=0.8 Hz, 1H), 7.87 (d, J=0.8 Hz, 1H), 7.50 (ddd, J=8.7, 6.7, 3.6 Hz, 2H), 7.46-7.23 (m, 4H), 6.94 (d, J=5.6 Hz, 1H), 6.67 (d,J＝1.0Hz,1H),5.96(s,2H),4.87(d,J＝4.7Hz,1H),4.69(p,J＝7.7Hz,1H),4.17(h,J＝5.5,5.0Hz,1H),2.40-2.28(m,1H),2.19-2.02(m,2H),1.99(d, J＝1.0Hz,3H),1.87-1.78(m,1H),1.71(dt,J＝13.0,8.3Hz,2H).

MS(ESI+):607.2(M+H).

Embodiment 75:

a) Preparation of Compound Example 75

M12 (32 mg), M14 (33 mg), n-butanol (2 mL) and TFA (0.1 mL) were placed in a 10 mL single-mouth bottle. Under nitrogen protection, the reaction solution was reacted at 100°C for 2 h. The reaction solution was then desolventized to dryness and purified by column chromatography (DCM/MeOH = 20/1 (V/V)) to obtain 5.11 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.89 (s, 1H), 8.88-8.80 (m, 2H), 8.36 (d, J＝5.5Hz ,1H),8.29(s,1H),8.24(dd,J＝13.3,2.0Hz,1H),8.09(s,1H),7.84(s,1H),7.61-7.55(m,2H),7.56- 7.38(m,2H),6.96(d,J＝5.5Hz,1H),6.71(s,1H),5.96(s,2H),3.84(s,3H),2.01(s,3H).

MS(ESI+):520.2(M+H).

Embodiment 76:

a) Preparation of Compound Example 76

M2 (70 mg) and 1,2,4-1H-triazole (200 mg) were placed in a 10 mL microwave tube and subjected to microwave reaction at 270° C. for 1 hour. The reaction solution was then desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 3 mg of the target compound.

MS(ESI+):524.2(M+H).

Embodiment 77:

a) Preparation of Compound 77-1

Imidazole (299 mg), 3-chloro-5-iodopyrazine-2-amine (1.02 g), cuprous iodide (76 mg), and cesium carbonate (2.6 g) were dissolved in DMF (15 mL), and stirred in a microwave at 130° C. for 1 h under nitrogen protection. The reaction solution was desolventized, sanded, and subjected to column chromatography (DCM/MeOH=20/1) to obtain 81 mg of the target compound.

MS:[M+1],196.2

b) Preparation of Compound 77-2

The preparation method was referred to Example 1, except that 1-3 in step d) was replaced by 77-1. The reaction solution was then desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 120 mg of the target compound.

MS:[M+1],271.1

c) Preparation of Compound Example 77

The preparation method was referred to Example 1, except that 1-4 in step e) was replaced by 77-2. The reaction solution was then desolvated to dryness and purified by column chromatography (DCM/MeOH=20/1 (V/V)) to obtain 9 mg of the target compound.

Compound Example 77: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.05 (s, 1H), 8.44 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.32-8.23 (m, 2H), 7.80-7.69 (m, 1H), 7.52-7.40 (m, 6H), 7.08 (d, J=1.2 Hz, 1H), 6.95 (d, J=5.6 Hz, 1H), 6.68 (d, J=1.1 Hz, 1H), 6.34 (s, 2H), 1.99 (s, 3H).

MS(ESI+):523.2(M+H).

Embodiment 78:

a) Preparation of Compound 78

Piperidin-4-ol (16 mg), 3-chloro-5-iodopyrazin-2-amine (20 mg), Pd ₂ (dba) ₃ (5 mg), Ruphos (15 mg), cesium carbonate (11 mg) were dissolved in dioxane (5 mL) and protected with nitrogen. The reaction solution was reacted at 100°C for 6 h. The reaction solution was desolventized, sanded, and column chromatographed (DCM/MeOH=20/1) to obtain 9 mg of the target compound.

Compound Example 78: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.99 (s, 1H), 8.32 (d, J=5.5 Hz, 1H), 8.20 (dd, J=13.5, 1.9 Hz, 1H), 7.77 (s, 1H), 7.54-7.37 (m, 6H), 6.93 (d, J=5.5 Hz, 1H), 6.67 (d, J=1.1 Hz, 1H), 5.11 (s, 2H), 4. 65(d,J＝4.3Hz,1H),3.77(d,J＝12.8Hz,2H),3.62(dd,J＝8.7,4.5Hz,1H),2.96-2.83(m,2H),2.02-1.96(m,3H),1.78(d,J＝12.5Hz,2H),1.40(q,J＝10.8 ,8.9Hz,2H).

MS(ESI+):556.2(M+H).

Embodiment 79:

a) Preparation of Compound 79-1

2-Iodopropane (170 mg) and cesium carbonate (326 mg) were added to a solution of M13 (137 mg) in THF (3 ml), and the mixture was reacted at 64°C for 8 h. After the reaction solution was cooled to room temperature, it was filtered. The filtrate was concentrated and purified by column chromatography (DCM/MeOH=20/1) to obtain 35 mg of the target compound.

MS(ESI+):317.1(M+H).

b) Preparation of Compound 79

79-1 (35 mg), M14 (35 mg), and TFA (25 mg) were dissolved in n-butanol (3 mL), and stirred at 90° C. for 2 h under nitrogen protection. The reaction solution was directly desolventized, sanded, and subjected to column chromatography (DCM/MeOH=20/1) to obtain 22 mg of the target compound.

MS(ESI+):565.2(M+H).

Embodiment 80:

a) Preparation of Compound 80-1

To a solution of M13 (137 mg) in DMF (3 ml), cyclopentyl bromide (148 mg) and cesium carbonate (326 mg) were added, and the mixture was reacted at 100°C for 8 h. After the reaction solution was cooled to room temperature, it was filtered. The filtrate was concentrated and purified by column chromatography (DCM/MeOH=20/1) to obtain 39 mg of the target compound.

MS(ESI+):543.1(M+H).

b) Preparation of Compound 80

80-1 (35 mg), M14 (35 mg), and TFA (25 mg) were dissolved in n-butanol (3 mL), and stirred at 90° C. for 2 h under nitrogen protection. The reaction solution was directly desolventized, sanded, and subjected to column chromatography (DCM/MeOH=20/1) to obtain 24 mg of the target compound.

MS(ESI+):591.2(M+H).

Embodiment 81:

a) Preparation of Compound 81-1

M13 (40 mg), M14 (31 mg), and TFA (25 mg) were dissolved in n-butanol (2 mL), and stirred at 90° C. for 2 h under nitrogen protection. The reaction solution was cooled to room temperature and filtered to obtain 88 mg of compound 81-1.

MS(ESI+):523.2(M+H).

b) Preparation of Compound 81

81-1 (20 mg), benzyl bromide (6 mg), potassium carbonate (11 mg) were dissolved in DMF (3 mL), and the mixture was stirred at 20°C for 2 h under nitrogen protection. The reaction solution was directly desolventized, sanded, and subjected to column chromatography (DCM/MeOH=20/1) to obtain 8.5 mg of the target compound.

Compound Example 81: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.49 (s, 1H), 8.60 (s, 1H), 8.34-8.19 (m, 3H), 8.10 (s, 1H), 7.85 (s, 1H), 7.82-7.74 (m, 2H), 7.49-7.27 (m, 9H), 6.90 (d, J=6.3 Hz, 1H), 5.97 (s, 2H), 5.59 (s, 2H), 3.85 (s, 3H).

MS(ESI+):613.2(M+H).

Embodiment 82:

a) Preparation of Compound 82

4-(Bromomethyl)tetrahydro-2H-pyran (7 mg), 81-1 (20 mg), potassium carbonate (11 mg) were dissolved in DMF (3 mL), and the mixture was protected with nitrogen and stirred at 100° C. for 16 h. The reaction solution was directly desolventized, sanded, and subjected to column chromatography (DCM/MeOH=20/1) to obtain 8.1 mg of the target compound.

¹ H NMR (400MHz, DMSO-d ₆ ) δ13.56(s,1H),8.37-8.23(m,4H),8.10(s,1H),7.85(s,1H),7.78-7.67(m,2H ),7.46(d,J＝7.6Hz,2H),7.29(t,J＝8.9Hz,2H),7.14(d,J＝6.3Hz,1H),5.96(s,2H),4.22(d,J ＝7.5Hz,2H),3.85(s,5H),3.22(d,J＝11.9Hz,2H),2.01(t,J＝7.6Hz,1H),1.51(d,J＝12.7Hz,2H), 1.44-1.36(m,2H).

MS(ESI+):621.3(M+H).

Biological activity test

The BGB-324 used in the activity test was purchased from Hubei Kele Fine Chemical Co., Ltd.

1. TAM family kinase (AXL, Mer, Tyro3) inhibitor screening experiment

1) Preparation and loading of AXL, Mer, and Tyro3 kinases (Carna, 08-107, 08-108, and 08-109): AXL was diluted to a working concentration of 0.027 ng/μL (1.67×, final concentration 0.016 ng/uL) using 1× enzyme buffer (5× enzyme buffer (Cisbio, 62EZBFDD), 5 mM MgCl ₂ , 1 mM DTT, 15.62 nM SEB, H ₂ O); Mer was diluted to 1.25 ng/μL (1.67×, final concentration 0.75 ng/uL); Tyro3 was diluted to 0.017 ng/μL (1.67×, final concentration 0.01 ng/uL), and the sample was added using BioTek (MultiFlo FX) automatic dispenser, added to a white 384-well plate (Greiner), 6 μL was added to each well, and an equal volume of 1× enzyme buffer was added to the blank control group;

2) Compound preparation and sample addition: The compound prepared in the example was diluted from 10 mM to 100 μM using DMSO, and titrated using a compound titrator (Tecan, D300e). The titrator automatically sprayed the required concentration into each well, with a starting concentration of 1 μM, 1/2 log gradient dilution, a total of 8 concentrations, centrifuged at 2500 rpm for 30 s, and incubated at room temperature for 15 min;

3) Preparation and loading of ATP and substrates: 1× enzyme buffer was used to prepare the ATP (Sigma, A7699) working solutions for AXL, Mer and Tyro3 kinase reactions in sequence: diluted from 10 mM to 75 μM (5×, final concentration 15 μM), 50 μM (5×, final concentration 10 μM), and 2 μM (5×, final concentration 0.4 μM) in sequence; 1× enzyme buffer was used to dilute the substrate TK Substrate-biotin (Cisbio, 61TK0BLC) from 500 μM to 5 μM (5×, final concentration 1 μM); ATP and substrate were mixed in equal volumes, and 4 μL was added to each well using a BioTek automatic dispenser; centrifuged at 2500 rpm for 30 s, and reacted at 25°C for 45 min (AXL kinase reaction time), 45 min (Mer kinase reaction time), and 30 min (Tyro3 kinase reaction time);

4) Preparation and loading of detection reagents: Use detection buffer (Cisbio, 62SDBRDF) to dilute Streptavidin-XL665 (Cisbio, 610SAXLG) from 16.67μM to 250nM (4×, final concentration is 62.5nM); Use detection buffer to dilute TK Antibody-Cryptate (Cisbio) from 100× to 1×; Mix equal volumes of Streptavidin-XL665 and TK Antibody-Cryptate, use BioTek automatic dispenser to add 10μL to each well, centrifuge at 2500rpm for 30s, and react at 25℃ for 1 hour. After the reaction, use the HTRF module of the multi-function plate reader (PerkinElmer, Envision) for detection;

5) Data calculation

Ratio＝(Signal 665nm/Signal 615nm)*10,000

Inhibition rate (%) = (Ratio negative control group - Ratio compound group) / (Ratio negative control group - Ratio blank control group) × 100%

GraphPad Prism 5 software was used to fit the dose-effect curve: log (compound concentration) vs. inhibition rate-Variable slope, and the IC ₅₀ value of the compound on enzyme inhibition was obtained.

6) Experimental results

The experimental results are shown in Table 1. BGB-324 AXL IC ₅₀ : 2.2 nM, Mer IC ₅₀ : 6.6 nM, Tyro3 IC ₅₀ : 93.4 nM.

Table 1 IC ₅₀ data of compounds inhibiting AXL, Mer and Tyro ₃ activities

2. Single-dose pharmacokinetic study in mice

Experimental purpose: To study the pharmacokinetic properties of the test substance in mice by measuring the plasma drug concentration after a single oral administration to ICR mice.

Experimental animals: Male ICR mice, 6-10 weeks old, 3 mice/group/test compound, purchased from Weitonglihua Experimental Animal Technology Co., Ltd.

Test method: The compound to be tested was prepared into a solution with a concentration of 1 mg/ml. The solvent was 25 mM citric acid-sodium citrate buffer (pH 3.0) containing 5% DMSO. The mice were fasted overnight the day before the experiment, and were allowed to drink water freely. They were fed 4 hours after administration. On the day of the experiment, each group of mice was gavaged with the test substance at 10 mg/kg.

Sample collection time points: 15min, 30min, 1h, 2h, 4h, 8h and 24h after administration.

Sampling: After administration, about 40 μL of blood was collected from the eye sockets of mice at various time points and placed in EDTA-K2 anticoagulant tubes. The whole blood samples were centrifuged at 1500-1600 g for 10 min, and the separated plasma was stored in a refrigerator at -40 to -20 °C, and the samples were quantitatively analyzed by LC-MS/MS.

The experimental results are shown in Table 2.

Table 2 Pharmacokinetic experimental results of the test compounds in mice

3. Liver microsome metabolic stability test

The incubation system with a total volume of 200 μL containing 1 μM of the test compound, the medium was 100 mM phosphate buffer (PBS, pH 7.4), including human or mouse liver microsomal protein with a final concentration of 0.5 mg/mL, 1 mM NADPH and 3 mM magnesium chloride, and was co-incubated in a 37°C water bath. At different time points (0, 5, 15, 30, 60 min), 20 μL of the incubation sample was taken out and transferred to acetonitrile containing the internal standard. After protein precipitation, the supernatant was taken by centrifugation. The test compound in the supernatant was analyzed by LC-MS/MS method. The in vitro intrinsic clearance rate was calculated based on the elimination half-life of the test compound in the incubation system, and midazolam was incubated in parallel as a positive control.

The experimental results are shown in Table 3.

Table 3 Metabolic stability data of test compounds in liver microsomes

The foregoing description of specific exemplary embodiments of the present invention is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present invention to the precise form disclosed, and it is clear that many changes and variations can be made based on the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present invention and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present invention and various different selections and changes. The scope of the present invention is intended to be limited by the claims and their equivalents.

Claims (14)

A compound as shown in Formula I or a pharmaceutically acceptable salt thereof:
in, X, Y ¹ , Y ² or Y ³ are each independently selected from N or CH; is a double bond or a single bond, and the bond formed by the atoms at positions 5 and 6 and the bond formed by the atoms at positions 4 and 5 are not both double bonds; When the atoms at positions 4 and 5 form a double bond, and the atoms at positions 5 and 6 form a single bond, ^Y4 is selected from N or CH, and ^Y5 is CH; When the atoms at positions 4 and 5 form a single bond, and the atoms at positions 5 and 6 form a double bond, ^Y4 is C, ^Y5 is NR ^P , and ^RP is selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkyl substituted with C _6-10 aryl, or C _1-6 alkyl substituted with 3-10 membered heterocyclyl; R ¹ is selected from 5-10 membered heteroaryl, 3-18 membered heterocyclyl or C _2-6 alkynyl, the C _2-6 alkynyl is optionally substituted with halogen, amino, cyano, nitro or hydroxyl, the 5-10 membered heteroaryl or 3-18 membered heterocyclyl is optionally substituted with one or more halogen, carbonyl, amino, cyano, nitro, hydroxyl, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , halogenated C _1-6 alkyl, C _6-10 aryl, C _3-6 cycloalkyl, 5-7 membered heteroaryl, 3-10 membered heterocyclyl, C(O)OR ^1A , C(O)NR ^1B R ^1C , C(O)R ^1D , C(═NR ^1E )R ^1D , C(═NR ^1E )NR ^1B R ^1C , C(═NCN)NR ^1B R ^1C , C(═NOR ^1A )NR ^1B , S(O) ₂ R ^1D , S(O)(═NR ^1E )R ^1C or S(O) ₂ NR ^1B R ^1C , wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or halogenated C _1-6 alkyl is optionally substituted by one or more R ⁸ , and the C _6-10 aryl, C _3-6 cycloalkyl, 5-7 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted by one or more R ⁹ ; ^R8 is selected from _C1-6 alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, ^amino , cyano, nitro, ^OR1AA , C(O) ^R1DD , C(O ^{)NR1BBR1CC ,} OC( ^{O ) NR1BBR1CC} , NR1BBR1CC, ^{NR1BBNR1BBR1CC} , NR1BBC(O) ^R1DD , ^NR1BBC (O) ^OR1F , ^NR1BBC (O ^{) NR1BBR1CC} or hydroxy ^- substituted or unsubstituted ^C3-6 _cycloalkyl ^; R ⁹ is selected from C _1-6 alkyl, C _1-6 alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, amino, cyano, nitro, OR ^1F , C(O)R ^1DD , C(O)NR ^1BB R ^1CC , OC(O)NR ^1BB R ^1CC , NR ^1BB R ^1CC , NR ^1BB NR ^1BB R ^1CC , NR ^1BB C(O)R ^1DD , NR ^1BB C(O)OR ^1F , NR ^1BB C(O)NR ^1BB R ^1CC or NR ^1BB R ^1CC ; R ^1A , R ^1B , R ^1C or R ^1D are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or halogenated C _1-6 alkyl; R ^1E or R ^1F are each independently selected from hydrogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, halogenated C _1-6 alkoxy or halogenated C _1-6 alkyl; R ^1AA , R ^1BB , R ^1CC and R ^1DD are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or halogenated C _1-6 alkyl; ^R2 is selected from hydrogen, halogen, amino, cyano, nitro, hydroxyl, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl or halogenated _C1-6 alkyl; R ³ , R ⁴ or R ⁵ are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl; R ⁶ is selected from C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl, wherein the C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted with halogen, amino, cyano, nitro, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy; R ^6a is selected from hydrogen, amide, C _1-6 alkyl, halogenated C _1-6 alkyl, halogen, nitro, cyano, amino, hydroxyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy; R ⁷ is selected from hydrogen, halogen, amino, cyano, nitro, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl or C _1-6 alkanoyl. The compound of formula I according to claim 1, wherein X, Y ¹ , Y ² or Y ³ are each independently selected from N or CH; is a double bond or a single bond, and the bond formed by the atoms at positions 5 and 6 and the bond formed by the atoms at positions 4 and 5 are not both double bonds; When the atoms at positions 4 and 5 form a double bond, and the atoms at positions 5 and 6 form a single bond, ^Y4 is selected from N or CH, and ^Y5 is CH; When the atoms at positions 4 and 5 form a single bond, and the atoms at positions 5 and 6 form a double bond, ^Y4 is C, ^Y5 is NR ^P , and ^RP is selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkyl substituted with C _6-10 aryl, or C _1-6 alkyl substituted with 3-10 membered heterocyclyl; R ¹ is selected from 5-10 membered heteroaryl, 3-18 membered heterocyclyl or C _2-6 alkynyl, the C _2-6 alkynyl is optionally substituted by amino, cyano, nitro or hydroxyl, the 5-10 membered heteroaryl or 3-18 membered heterocyclyl is optionally substituted by one or more carbonyl, amino, cyano, nitro, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halogenated C _1-6 alkyl, C _6-10 aryl, C _3-6 cycloalkyl, 5-7 membered heteroaryl, 3-10 membered heterocyclyl, C(O)OR ^1A , C(O)NR ^1B R ^1C , C(O)R ^1D , C(═NR ^1E )R ^1D , C(═NR ^1E )NR ^1B R ^1C , C(═NCN)NR ^1B R ^1C , C(═NOR ^1A )NR ^1B , S(O) ₂ R ^1D , S(O)(═NR ^1E )R ^1C or S(O) ₂ NR ^1B R ^1C , wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or halogenated C _1-6 alkyl is optionally substituted by one or more R ⁸ , and the C _6-10 aryl, C _3-6 cycloalkyl, 5-7 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted by one or more R ⁹ ; ^R8 is selected from _C1-6 alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, ^amino , cyano, nitro, ^OR1AA , C(O) ^R1DD , C(O ^{)NR1BBR1CC ,} OC( ^{O ) NR1BBR1CC} , NR1BBR1CC, ^{NR1BBNR1BBR1CC} , NR1BBC(O) ^R1DD , ^NR1BBC (O) ^OR1F , ^NR1BBC (O ^{) NR1BBR1CC} or hydroxy ^- substituted or unsubstituted ^C3-6 _cycloalkyl ^; R ⁹ is selected from C _1-6 alkyl, C _1-6 alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, amino, cyano, nitro, OR ^1F , C(O)R ^1DD , C(O)NR ^1BB R ^1CC , OC(O)NR ^1BB R ^1CC , NR ^1BB R ^1CC , NR ^1BB NR ^1BB R ^1CC , NR ^1BB C(O)R ^1DD , NR ^1BB C(O)OR ^1F , NR ^1BB C(O)NR ^1BB R ^1CC or NR ^1BB R ^1CC ; R ^1A , R ^1B , R ^1C or R ^1D are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or halogenated C _1-6 alkyl; R ^1E or R ^1F are each independently selected from hydrogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, halogenated C _1-6 alkoxy or halogenated C _1-6 alkyl; R ^1AA , R ^1BB , R ^1CC and R ^1DD are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or halogenated C _1-6 alkyl; ^R2 is selected from hydrogen, halogen, amino, cyano, nitro, hydroxyl, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl or halogenated _C1-6 alkyl; R ³ , R ⁴ or R ⁵ are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl; R ⁶ is selected from C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl, wherein the C _6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted with halogen, amino, cyano, nitro, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy; R ^6a is selected from amido, C _1-6 alkyl, halogenated C _1-6 alkyl, halogen, nitro, cyano, amino, hydroxyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy; R ⁷ is selected from hydrogen, halogen, amino, cyano, nitro, hydroxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl or C _1-6 alkanoyl; Preferably, the compound of formula I has a structure as shown in formula II, formula III, formula IV, formula V or formula VI below,
Wherein, R ⁵ , R ⁶ , R ⁷ and R ⁸ are respectively defined as in claim 1;
Wherein, Y is selected from CH or N; R ⁵ , R ⁶ , R ⁷ , and R ⁸ are as defined in claim 1;
Wherein, R ⁵ , R ⁶ , R ⁷ and R ⁸ are respectively defined as in claim 1;
Wherein, R ⁵ , R ⁶ , R ⁷ and R ⁸ are respectively defined as in claim 1;
Wherein, R ¹ , R ⁵ , R ⁶ , R ⁷ , and ^RP are respectively defined as in claim 1; Preferably, ^RP is selected from isopropyl, cyclopentyl, benzyl or The compound of formula I according to claim 1 or 2, wherein X is N. The compound of formula I according to any one of claims 1 to 3, wherein Y ¹ , Y ² or Y ³ is N. The compound of formula I according to any one of claims 1 to 4, wherein the atoms at positions 4 and 5 form a double bond, the atoms at positions 5 and 6 form a single bond, and Y ⁴ is N and Y ⁵ is CH. A compound of formula I according to any one of claims 1 to 5, wherein R ¹ is selected from a 5-10 membered heteroaryl, a 3-18 membered heterocyclyl or a C _2-6 alkynyl, the C _2-6 alkynyl is optionally substituted with a hydroxyl group, the 5-10 membered heteroaryl or the 3-18 membered heterocyclyl is optionally substituted with one or more carbonyl, C _1-6 alkyl, a 3-10 membered heterocyclyl, a C _3-6 cycloalkyl, C (O) OR ^1A or C (O) NR ^1B R ^1C , wherein the C _1-6 alkyl is optionally substituted with one or more R ⁸ , the C _3-6 cycloalkyl or the 3-10 membered heterocyclyl is optionally substituted with one or more R ⁹ ; R ^1A , R ^1B , R ^1C , R ⁸ , and R ⁹ are respectively as defined above; Preferably, R ¹ is selected from 5-10 membered heteroaryl or 3-18 membered heterocyclyl, wherein the 5-10 membered heteroaryl or 3-18 membered heterocyclyl is optionally substituted by one or more carbonyl, C _1-6 alkyl, 3-10 membered heterocyclyl, C _3-6 cycloalkyl, C(O)OR ^1A or C(O)NR ^1B R ^1C , wherein the C _1-6 alkyl is optionally substituted by one or more R ⁸ is substituted, the C _3-6 cycloalkyl or 3-10 membered heterocyclyl is optionally substituted by one or more R ⁹ , R ^1A , R ^1B and R ^1C are each independently selected from hydrogen or C _1-6 alkyl; R ⁸ is selected from C _1-6 alkoxy, 4-7 membered heterocyclyl, cyano, OR ^1AA , NR ^1BB R ^1CC or C _3-6 cycloalkyl substituted by hydroxy; R ⁹ is C _1-6 alkyl, 4-7 membered heterocyclic group, cyano, OR ^1F , C(O)R ^1DD or NR ^1BB R ^1CC ; R ^1F is selected from hydrogen or C _1-6 alkyl; R ^1AA , R ^1BB , R ^1CC or R ^1DD are each independently selected from hydrogen or C _1-6 alkyl; More preferably, R ¹ is selected from 5-10 membered heteroaryl or 3-18 membered heterocyclyl, wherein the 5-10 membered heteroaryl or 3-18 membered heterocyclyl is optionally substituted by one or more carbonyl, C _1-6 alkyl, 3-10 membered heterocyclyl, C _3-6 cycloalkyl, C(O)OR ^1A or C(O)NR ^1B R ^1C , wherein the C _1-6 alkyl is optionally substituted by one or more R ⁸ , the C _3-6 cycloalkyl or 3-10 membered heterocyclyl is optionally substituted by one or more R ⁹ , R ^1A , R ^1B and R ^1C are each independently selected from hydrogen or C _1-6 alkyl; R ⁸ is selected from C _1-6 alkoxy, 4-7 membered heterocyclyl, cyano, OR ^1AA , NR ^1BB R ^1CC or C _3-6 cycloalkyl substituted by hydroxy; R ⁹ is C _1-6 alkyl, 4-7 membered heterocyclic group, cyano or OR ^1F ; R ^1F is selected from hydrogen or C _1-6 alkyl; R ^1AA , R ^1BB or R ^1CC are each independently selected from hydrogen or C _1-6 alkyl. The compound of formula I according to any one of claims 1 to 5, wherein R ¹ is selected from and R ¹ is optionally substituted by one or more carbonyl, hydroxyl, C _1-6 alkyl, 3-10 membered heterocyclyl, C _3-6 cycloalkyl, C(O)OR ^1A or C(O)NR ^1B R ^1C , wherein the C _1-6 alkyl is optionally substituted by one or more R ⁸ , the C _3-6 cycloalkyl or 3-10 membered heterocyclyl is optionally substituted by one or more R ⁹ , R ^1A , R ^1B and R ^1C are each independently selected from hydrogen or C _1-6 alkyl; R ⁸ is selected from C _1-6 alkoxy, 4-7 membered heterocyclyl, cyano, OR ^1AA , NR ^1BB R ^1CC or C _3-6 cycloalkyl substituted by hydroxy; R ⁹ is C _1-6 alkyl, 4-7 membered heterocyclic group, cyano, OR ^1F , C(O)R ^1DD or NR ^1BB R ^1CC ; R ^1F is selected from hydrogen or C _1-6 alkyl; R ^1AA , R ^1BB , R ^1CC or R ^1DD are each independently selected from hydrogen or C _1-6 alkyl; Preferably, ^R1 is selected from and R ¹ is optionally substituted by one or more carbonyl, hydroxyl, C _1-6 alkyl, 3-10 membered heterocyclyl, C _3-6 cycloalkyl, C(O)OR ^1A or C(O)NR ^1B R ^1C , wherein the C _1-6 alkyl is optionally substituted by one or more R ⁸ , the C _3-6 cycloalkyl or 3-10 membered heterocyclyl is optionally substituted by one or more R ⁹ , R ^1A , R ^1B and R ^1C are each independently selected from hydrogen or C _1-6 alkyl; R ⁸ is selected from C _1-6 alkoxy, 4-7 membered heterocyclyl, cyano, OR ^1AA , NR ^1BB R ^1CC or C _3-6 cycloalkyl substituted by hydroxy; R ⁹ is C _1-6 alkyl, 4-7 membered heterocyclic group, cyano or OR ^1F ; R ^1F is selected from hydrogen or C _1-6 alkyl; R ^1AA , R ^1BB or R ^1CC are each independently selected from hydrogen or C _1-6 alkyl. The compound of formula I according to any one of claims 1 to 5, wherein R ¹ is selected from and R ¹ is optionally substituted by one or more carbonyl, hydroxyl, methyl, replace; Preferably, ^R1 is selected from More preferably, R ¹ is selected from A compound of formula I according to any one of claims 1 to 8, wherein R ⁶ is selected from C _6-10 aryl or 5 or 6 membered heteroaryl, wherein the C _6-10 aryl or 5 or 6 membered heteroaryl is optionally substituted with one or more halogen or C _1-3 alkyl; Preferably, ^R6 is selected from phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one or more halogen or _C1-3 alkyl; More preferably, R ⁶ is selected from The compound of formula I according to any one of claims 1 to 9, wherein R ^6a is selected from hydrogen or C _1-6 alkyl; preferably, R ^6a is selected from C _1-6 alkyl; Preferably, R ^6a is methyl. The compound of formula I according to any one of claims 1 to 10, wherein for in, Representation and Connected, It means connected to Y ² ; Preferably, R ⁷ is halogen; more preferably, R ⁷ is fluorine. The following compounds or pharmaceutically acceptable salts thereof:



A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Use of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating and/or preventing a disease induced by AXL receptor tyrosine kinase; Preferably, the AXL receptor tyrosine kinase-induced disorder is a disorder caused by AXL kinase hyperfunction, a disorder associated with AXL kinase hyperfunction and/or a disorder accompanied by AXL kinase hyperfunction; More preferably, the AXL receptor tyrosine kinase-induced disease is cancer, and the cancer is preferably a solid tumor or a blood cancer; more preferably, the AXL receptor tyrosine kinase-induced disease is a solid tumor cancer.