WO2021027503A1

WO2021027503A1 - Tricyclic compound, preparation method therefor, and intermediate and use thereof

Info

Publication number: WO2021027503A1
Application number: PCT/CN2020/103225
Authority: WO
Inventors: 冯加权; 董加强; 王铁林
Original assignee: 罗欣药业(上海)有限公司; 山东罗欣药业集团股份有限公司
Priority date: 2019-08-12
Filing date: 2020-07-21
Publication date: 2021-02-18

Abstract

Disclosed are a tricyclic compound, a preparation method therefor, and an intermediate and use thereof. Such compounds have the activity of inhibiting tropomyosin receptor kinase and can be used to treat cancers, pain, neurological diseases, autoimmune diseases, inflammation and other diseases.

Description

Tricyclic compounds, their preparation methods, intermediates and applications

This application claims the priority of Chinese patent application 2019107415997 with the filing date of 2019/08/12 and the priority of Chinese patent application 2019113407818 with the filing date of 2019/12/23. This application quotes the full text of the aforementioned Chinese patent application.

Technical field

The invention relates to a tricyclic compound, its preparation method, intermediates and applications.

Background technique

Tropomyosin receptor kinase (Trk), also known as neurotrophic tyrosine kinase receptor (NTRK), belongs to the receptor tyrosine kinase family. The Trk family mainly includes 3 members, NTRK1/TrkA, NTRK2/TrkB and NTRK3/TrkC. The complete Trk kinase includes three parts: extracellular domain, transmembrane domain and intracellular domain. After the extracellular domain of Trk kinase is combined with the corresponding ligand, it can cause the kinase configuration to change and form a dimer. Autophosphorylation of the intracellular region of Trk kinase activates its own kinase activity, which further activates downstream signal transduction pathways such as MAPK, AKT, PKC, etc., to produce corresponding biological functions; among them, NGF (nerve growth factor) binds TrkA , BDNF (derived neurotrophic factor) binds TrkB, and NT3 (neurotrophic factor 3) binds TrkC.

Trk kinase plays important physiological functions in the development of nerves, including the growth and function maintenance of neuronal axons, the occurrence and development of memory, and the protection of neurons from damage. At the same time, a large number of studies have shown that the activation of the Trk signal transduction pathway is also strongly related to the occurrence and development of tumors. Activated Trk signaling proteins have been found in neurocytoma, prostate cancer, and breast cancer. The discovery of a variety of Trk fusion proteins in recent years has shown its biological function of promoting tumorigenesis. The earliest TPM3-TrkA fusion protein was found in colon cancer cells, with an incidence of about 1.5% in clinical patients tested. Later, different types of Trk fusion proteins, such as CD74-NTRK1, MPRIP-NTRK1, QKI-NTRK2, ETV6, were found in different types of clinical tumor patient samples such as lung cancer, head and neck cancer, breast cancer, thyroid cancer, glioma, etc. -NTRK3, BTB1-NTRK3, etc. These different NTRK fusion proteins are in a highly activated kinase activity state without ligand binding, so they can continuously phosphorylate downstream signal pathways, induce cell proliferation, and promote tumor occurrence and development. Therefore, in recent years, Trk fusion protein has become an effective anti-cancer target and research hotspot. In addition, cases of NTRK mutations have recently appeared clinically, such as NTRK1G595R and G667C mutations (Russo M. et al., Cancer Discovery, 2016, 6(1), 36-44), NTRK3G623R mutations (Drilon A. etc., Annals) of Oncology 2016,27(5),920-926).

Summary of the invention

The technical problem to be solved by the present invention is to provide a tricyclic compound with a new core structure, its preparation method, intermediates and applications. Such compounds have the activity of inhibiting tropomyosin receptor kinase and can be used to treat cancer and other diseases.

The present invention provides a compound represented by formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate:

Among them, Z ¹ is C or N; when Z ¹ is C, Z ² is N; when Z ¹ is N, Z ² is C;

M is C (R ^4a ) or N;

M ¹ is C(R ^4b ) or N;

R ² , R ^4a , R ^4b , R ⁵ and R ⁶ are each independently hydrogen, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O-(C _1-4 Alkyl), -(C _1-4 alkyl)-OH, -NH ₂ , -NH-(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 Alkyl) -NH ₂ , C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

R ⁴ is hydrogen, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O-(C _1-4 alkyl), -(C _1-4 alkyl)-OH , -NH ₂ , -NH-(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH ₂ , C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl or -C(O)N(R ^25a )(R ^25b );

R ^25a and R ^25b are each independently hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5-12 membered hetero Aryl group, wherein the C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group, 3-8 membered heterocycloalkyl group, C ₆ -C ₁₀ aryl group and 5-12 membered heteroaryl group are each independently Optionally by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl),-(C _1-4 alkane _{yl) -OH, -NH 2, -NH (} C 1-4 alkyl), - N (C _1-4 alkyl) _2, - (C _1- ₄ alkyl) -NH _2, C _3-6 cycloalkyl Substituents of alkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl;

Alternatively, R ^25a and R ^25b together with the nitrogen atom to which they are attached form a 3-8 membered heterocycloalkyl group, the 3-8 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), -(C _1-4 alkyl) -OH, -NH ₂ , -NH(C _{1- 4} alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH ₂ , C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6- Substituents of ₁₀ aryl and 5-12 membered heteroaryl;

R ^1a and R ^1b are each independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)OR ^a, or -C(O)NR ^a R ^b , wherein the C _1-6 alkyl group, C _3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally selected by one or more independently selected from halogen, -CN, and C _1-4 alkyl group , C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl),-(C _1-4 alkyl) -OH, -NH ₂ , -NH (C _1-4 alkyl),- N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH ₂ , C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5- Substituent substitution of 12-membered heteroaryl;

Alternatively, R ^1a and R ^1b and the carbon atoms to which they are attached together form a C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl Each independently is optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), -(C _{1 -4} _{alkyl) -OH, -NH 2, -NH (} C 1-4 alkyl), - N (C _1- ₄ alkyl) _2, - (C _1-4 alkyl) -NH _2, -CO ₂ H, -C(O)O(C _1-4 alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _{1 -4} alkyl) ₂ , -NHC(O)(C _1-4 alkyl), -N(C _1-4 alkyl)C(O)(C _1-4 alkyl), -OC(O)( C _1-4 alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3- Substituents of ₆ cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl;

X ¹ is a single bond, S, S(O), S(O) ₂ , O, N(R ⁷ ) or C(R ^24a )(R ^24b );

R ⁷ , R ^24a and R ^24b are each independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein the C _1-6 alkyl and C _3-6 cycloalkyl are each independently Selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), -(C _1-4 alkyl) ) -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ ,-(C _1-4 alkyl) -NH ₂ , -CO ₂ H,- C(O)O(C _1-4 alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) _{) 2, -NHC (O) (} C 1- 4 alkyl), - N (C _1-4 alkyl) C (O) (C _1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl And 3-6 membered heterocycloalkyl substituents;

Alternatively, R ⁷ and R ^1a and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1- ₄ alkyl), - (C _1-4 _{alkyl) -OH, -NH 2, -NH (} C 1- ₄ alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH ₂ , -CO ₂ H, -C(O)O(C _1-4 alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ , -NHC(O)(C _1-4 alkyl Group), -N(C _1-4 alkyl) C(O)(C _1-4 alkyl), -OC(O)(C _1-4 alkyl), -NHC(O)NH ₂ , -NHC (O) N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl substituent substituted;

Alternatively, R ⁷ and R ⁵ and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocycloalkyl group and the 5-6 membered heteroaryl group The group is optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), -(C _1-4 _{alkyl) -OH, -NH 2, -NH (} C 1-4 alkyl), - N (C _1- ₄ alkyl) _2, and - (C _1-4 alkyl) -NH ₂ substituents; The heteroatom in the 5-6 membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2 or 3;

p is 0 or 1;

X ⁸ is O or S;

X ⁶ is N(R ¹³ );

R ¹³ is hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein the C _1-6 alkyl or C _3-6 cycloalkyl is each independently optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), - (C _1- ₄ alkyl) -OH, -NH _2, - NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH ₂ , C _3-6 cycloalkyl and 3-6 membered heterocycloalkane Substituent substitution of the group;

X ⁵ is C(R ¹⁶ ) or N; and, when p is 0, X ⁵ is N;

R ³ , R ¹¹ and R ¹⁶ are each independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein the C _1-6 alkyl and C _3-6 cycloalkyl are each independently any Selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), -(C _1-4 alkyl) ) -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ ,-(C _1-4 alkyl) -NH ₂ , -CO ₂ H,- C(O)O(C _1-4 alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) _{) 2, -NHC (O) (} C 1- 4 alkyl), - N (C _1-4 alkyl) C (O) (C _1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl substituents;

Alternatively, R ³ , R ¹¹ and X ⁵ together form a C _3-8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C _3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each Independently optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), -(C _{1- 4} alkyl) -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ , -CO ₂ H, -C(O)O(C _1-4 alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1- ₄ alkyl) ₂ , -NHC(O)(C _1-4 alkyl), -N(C _1-4 alkyl)C(O)(C _1-4 alkyl), -OC(O)(C _1-4 alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 Substituent substitution of cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl;

Or, R ³ and R ^{4 are} connected together to form

The wavy line a is connected to X ⁵ , and the wavy line b is connected to the position where R ^{4 is} connected;

Or, R ³ and R ⁴ are connected to each other so that

And R ⁴ replaced with

The g end of the wave line is connected to X ³ , and the end of the wave line f is connected to the carbon atom connected to M;

X ⁷ is S, S(O), S(O) ₂ , O, N(R ¹² ) or C(R ¹⁴ )(R ¹⁵ );

k is 0, 1 or 2;

n is 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;

X ⁴ is S, S(O), S(O) ₂ , O, N(R ¹² ) or C(R ¹⁴ )(R ¹⁵ );

Each R ¹² is hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl, wherein the C _1-6 alkyl or C _3-6 cycloalkyl is each independently optionally by one or more independent Selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl),-(C _1-4 alkyl) -OH, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH ₂ , -CO ₂ H, -C(O)O(C _{_1-4-alkyl),} - C (O) NH 2, -C (O) NH (C 1-4 alkyl), - C (O) N (C 1-4 alkyl) _2, -NHC (O ) (C _1-4 alkyl), - N (C _1- ₄ alkyl) C (O) (C _1-4 alkyl), - OC (O) ( C 1-4 alkyl), - NHC ( O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl, 3-6 membered heterocycle Substituents of alkyl, C _6-10 aryl and 5-12 membered heteroaryl;

Each of R ^10a , R ^10b , R ¹⁴ and R ^{15 is} independently hydrogen, halogen, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR ^a , -SR ^a , -NR ^b R ^c , -OC(O)R ^a , -NR ^a C(O)R ^b , -C(O)OR ^a or -C(O)NR ^b R ^c , where Said C _1-6 alkyl, C _3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), - (C _1-4 _{alkyl) -OH, -NH 2, -NH (} C 1- 4 alkyl), - N ( C _1-4 alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ , -CO ₂ H, -C(O)O(C _1-4 alkyl), -C(O)NH ₂ , _{-C (O) NH (C 1-} 4 alkyl), - C (O) N (C 1-4 _{alkyl) 2, -NHC (O) (} C 1-4 alkyl), - N (C _{1 -4} alkyl) C (O) (C _1-4 alkyl), - OC (O) ( C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1- ₄ alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered hetero Substitution of aryl group;

Alternatively, R ^10a and R ^10b and the carbon atoms to which they are attached together form a C _3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group, wherein the C _3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl),- (C _1-4 _{alkyl) -OH, -NH 2, -NH (} C 1- 4 alkyl), - N (C _1-4 alkyl) _2, - (C _1-4 alkyl) -NH ₂ _{, -CO 2 H, -C (O} ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C _1-4 alkyl) ₂ , -NHC(O)(C _1-4 alkyl), -N(C _1-4 alkyl)C(O)(C _1-4 alkyl), -OC( O) (C _1- ₄ alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 _{alkyl) 2, -NHC (O) NH} (C 1-4 alkyl), Substituents of C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl;

Or, R ^10a and R ¹³ and the atoms to which they are attached together form

R ^9a and R ^9b are each independently hydrogen, halogen, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR ^a , -SR ^a , -NR ^b R ^c , -OC(O)R ^a , -NR ^a C(O)R ^b , -C(O)OR ^a or -C(O)NR ^b R ^c , wherein the C _1-6 alkyl group, C _3-6 cycloalkyl, and 4-7 membered heterocycloalkyl are each independently optionally substituted with one or more substituents independently selected from halogen, -CN, C _1- ₄ alkyl, C _1-4 haloalkyl, -OH , -O (C _1-4 alkyl), - (C _1-4 _{alkyl) -OH, -NH 2, -NH (} C 1-4 alkyl), - N (C _1- ₄ alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ , -CO ₂ H, -C(O)O(C _1-4 alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ , -NHC(O)(C _1-4 alkyl), -N(C _1-4 alkyl)C(O )(C _1-4 alkyl), -OC(O)(C _1-4 alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC (O) NH(C _1-4 alkyl), C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl substituents;

Alternatively, R ^9a and R ^10a and the carbon atoms to which they are attached together form a C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C _3-6 cycloalkyl and 3-6 membered hetero The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl),- (C _1-4 alkyl) -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ _{, -CO 2 H, -C (O} ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C _1-4 alkyl) ₂ , -NHC(O)(C _1-4 alkyl), -N(C _1-4 alkyl)C(O)(C _1-4 alkyl), -OC( O) (C _1- ₄ alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 _{alkyl) 2, -NHC (O) NH} (C 1-4 alkyl), Substituents of C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl

Alternatively, R ^9a and R ^9b and the carbon atoms to which they are attached together form a C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C _3-6 cycloalkyl or 3-6 membered hetero The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl),- (C _1-4 alkyl) -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ _{, -CO 2 H, -C (O} ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C _1-4 alkyl) ₂ , -NHC(O)(C _1-4 alkyl), -N(C _1-4 alkyl)C(O)(C _1-4 alkyl), -OC( O) (C _1- ₄ alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 _{alkyl) 2, -NHC (O) NH} (C 1-4 alkyl), Substituents of C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl;

m is 0 or 1;

And, the premise is that condition (i) or (ii) is satisfied:

(i) When m is 1, X ³ is C, and X ³ and R ⁶ and the carbon atoms to which they are connected together form a phenyl group or a 6-membered heteroaryl group; wherein the heteroaryl group in the 6-membered heteroaryl group The atom is nitrogen, and the number of heteroatoms is 1 or 2;

(ii) When m is 0, X ¹ is N(R ⁷ ), and R ⁷ and R ⁵ and their connected atoms together form

Wherein, X ² is S, S(O), S(O) ₂ , O, N(R ^2a ) or C(R ^3a )(R ^3b );

t is 0 or 1;

Y is

The d end of the wavy line is connected to the X ² end, and the c end of the wavy line is connected to the N atom; and, when X ² is O and t is 1, Y is not

Y ¹ is C(R ^6a ) or N;

Y ² is C(R ^6b ) or N;

R ^2a is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or 4-7 membered heterocycloalkyl, wherein said C _1-6 alkyl, C _3-6 cycloalkyl and 4-7 The membered heterocycloalkyl group is independently optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), -(C _1-4 alkyl)-OH, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH _2. -CO ₂ H, -C(O)O(C _1-4 alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O) N(C _1-4 alkyl) ₂ , -NHC(O)(C _1-4 alkyl), -N(C _1-4 alkyl)C(O)(C _1-4 alkyl), -OC (O)(C _1-4 alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl) , C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl substituents;

Each R ^3a , R ^3b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b are each independently hydrogen, halogen, -CN, -OR ^a , -SR ^a , -NR ^b R ^c , -OC(O)R ^a , -NR ^b C(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , C _1-6 alkyl, C _3-6 cycloalkyl Or 4-7 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen , -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl),-(C _1-4 alkyl) -OH, -NH ₂ , -NH (C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH ₂ , -CO ₂ H, -C(O)O(C _1-4 Alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ , -NHC(O)(C _1-4 alkyl), -N(C _1-4 alkyl)C(O)(C _1-4 alkyl), -OC(O)(C _1-4 alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl substituents are substituted;

Each R ^a, R ^b and R ^{c are} each independently hydrogen, C _1-4 alkyl or C _3-6 cycloalkyl;

The heteroatoms in the heterocycloalkyl and heteroaryl groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.

In some embodiments, in the compound represented by Formula I, X ⁸ is O.

In some embodiments, in the compound represented by Formula I, X ⁸ is S.

In some embodiments, the structure of the compound represented by Formula I is as follows:

M is C (R ^4a ) or N;

M ¹ is C(R ^4b ) or N;

R ^1a and R ^1b are each independently hydrogen, C _1-6 alkyl (e.g. methyl), C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C (O) OR ^a or -C (O)NR ^a R ^b , wherein the C _1-6 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O(C _1-4 alkyl), -(C _1-4 alkyl) -OH, -NH ₂ , -NH(C _1-4 Alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH ₂ , C _3-6 cycloalkyl (e.g. cyclopropyl), 3-6 membered heterocycloalkane Substituents of aryl groups, C _6-10 aryl groups and 5-12 membered heteroaryl groups;

X ¹ is a single bond, S, S(O), S(O) ₂ , O, N(R ⁷ ) or C(R ^24a )(R ^24b );

p is 0 or 1;

X ⁶ is N(R ¹³ );

X ⁵ is C(R ¹⁶ ) or N; and, when p is 0, X ⁵ is N;

Or, R ³ and R ^{4 are} connected together to form

Or, R ³ and R ⁴ are connected to each other so that

And R ⁴ replaced with

X ⁷ is S, S(O), S(O) ₂ , O, N(R ¹² ) or C(R ¹⁴ )(R ¹⁵ );

k is 0, 1 or 2;

n is 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;

X ⁴ is S, S(O), S(O) ₂ , O, N(R ¹² ) or C(R ¹⁴ )(R ¹⁵ );

Each R ^10a, R ^10b, R ¹⁴ and R ¹⁵ are each independently hydrogen, halogen, -CN, C _1-6 alkyl (e.g. methyl), C _3- ₆ cycloalkyl, 4-7 membered heterocyclic ring Alkyl, -OR ^a , -SR ^a , -NR ^b R ^c , -OC(O)R ^a , -NR ^a C(O)R ^b , -C(O)OR ^a, or -C(O)NR ^b R ^c , wherein the C _1-6 alkyl, C _3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C _{1- 4} alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl),-(C _1-4 alkyl) -OH, -NH ₂ , -NH (C _1-4 alkyl) ), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH ₂ , -CO ₂ H, -C(O)O(C _1-4 alkyl), -C( O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ , -NHC(O)(C _1-4 alkyl), -N(C _1-4 alkyl)C(O)(C _1-4 alkyl), -OC(O)(C _1-4 alkyl), -NHC(O)NH ₂ , -NHC(O) N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and Substituent substitution of 5-12 membered heteroaryl;

Or, R ^10a and R ¹³ and the atoms to which they are attached together form

R ^9a and R ^9b are each independently hydrogen, halogen, -CN, C _1-6 alkyl (e.g. methyl), C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR ^a ,- SR ^a , -NR ^b R ^c , -OC(O)R ^a , -NR ^a C(O)R ^b , -C(O)OR ^a or -C(O)NR ^b R ^c , wherein the C _{1 -6} alkyl, C _3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), - (C _1-4 _{alkyl) -OH, -NH 2, -NH (} C 1- 4 alkyl), - N (C _{1- 4} alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ , -CO ₂ H, -C(O)O(C _1-4 alkyl), -C(O)NH ₂ , -C( O) NH (C _1- ₄ alkyl), - C (O) N (C 1-4 _{alkyl) 2, -NHC (O) (} C 1-4 alkyl), - N (C _1-4 alkyl yl) C (O) (C _1-4 alkyl), - OC (O) ( C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl ) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl Substituent substitution;

Alternatively, R ^9a and R ^10a and the carbon atoms to which they are attached together form a C _3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group (for example

), wherein the C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 Halogenated alkyl, -OH, -O (C _1-4 alkyl),-(C _1-4 alkyl) -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _{1- 4} alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ , -CO ₂ H, -C(O)O(C _1-4 alkyl), -C(O)NH ₂ , -C( O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ , -NHC(O)(C _1-4 alkyl), -N(C _1-4 alkyl) Base) C(O)(C _1-4 alkyl), -OC(O)(C _1-4 alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl Substituent substitution

m is 0 or 1;

And, the premise is that condition (i) or (ii) is satisfied:

Wherein, X ² is S, S(O), S(O) ₂ , O, N(R ^2a ) or C(R ^3a )(R ^3b );

t is 0 or 1;

Y is

Y ¹ is C(R ^6a ) or N;

Y ² is C(R ^6b ) or N;

M is C (R ^4a ) or N;

M ¹ is C(R ^4b ) or N;

R ² , R ^4a , R ^4b and R ⁶ are each independently hydrogen, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O-(C _1-4 alkyl) , -(C _1-4 alkyl)-OH, -NH ₂ , -NH-(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ , C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

p is 0 or 1;

X ⁶ is N(R ¹³ );

X ⁵ is C(R ¹⁶ ) or N; and, when p is 0, X ⁵ is N;

R ¹¹ and R ¹⁶ are each independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein the C _1-6 alkyl and C _3-6 cycloalkyl are each independently optionally substituted by one Or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl),-(C _1-4 alkyl) -OH , -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH ₂ , -CO ₂ H, -C(O )O(C _1-4 alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ , -NHC (O) (C _1- ₄ alkyl), - N (C _1-4 alkyl) C (O) (C _1-4 alkyl), - OC (O) ( C 1-4 alkyl) , -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl, 3- Substituents of 6-membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl;

n is 0, 1, or 2, provided that the result of adding n and p is 1 or 2;

X ⁴ is S, S(O), S(O) ₂ , O, N(R ¹² ) or C(R ¹⁴ )(R ¹⁵ );

R ¹² is hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein the C _1-6 alkyl or C _3-6 cycloalkyl are each independently optionally selected from one or more halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), - (C _1- ₄ alkyl) -OH, -NH _2, - NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH ₂ , -CO ₂ H, -C(O)O(C _1- ₄ alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ , -NHC(O)( C _1-4 alkyl), - N (C _1- ₄ alkyl) C (O) (C _1-4 alkyl), - OC (O) ( C 1-4 alkyl), - NHC (O) NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl , C _6-10 aryl and 5-12 membered heteroaryl substituents;

R ^10a , R ^10b , R ¹⁴ and R ¹⁵ are each independently hydrogen, halogen, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR ^a , -SR ^a , -NR ^b R ^c , -OC(O)R ^a , -NR ^a C(O)R ^b , -C(O)OR ^a or -C(O)NR ^b R ^c , wherein the C _1-6 alkyl, C _3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _{1- 4} haloalkyl, -OH, -O (C _1-4 alkyl), - (C _1-4 _{alkyl) -OH, -NH 2, -NH (} C 1- 4 alkyl), - N (C _{1 -4} alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ , -CO ₂ H, -C(O)O(C _1-4 alkyl), -C(O)NH ₂ , -C (O) NH (C _1- ₄ alkyl), - C (O) N (C 1-4 _{alkyl) 2, -NHC (O) (} C 1-4 alkyl), - N (C _1-4 alkyl) C (O) (C _1-4 alkyl), - OC (O) ( C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl Group) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl Substituent substitution;

Or, R ^10a and R ¹³ and the atoms to which they are attached together form

X ² is S, S(O), S(O) ₂ , O, N(R ^2a ) or C(R ^3a )(R ^3b );

t is 0 or 1;

Y is

Y ¹ is C(R ^6a ) or N;

Y ² is C(R ^6b ) or N;

R ^2a is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or 4-7 membered heterocycloalkyl, wherein said C _1-6 alkyl, C _3-6 cycloalkyl and 4-7 Each membered heterocycloalkyl group is independently optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl) , -(C _1-4 alkyl)-OH, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)- NH ₂ , -CO ₂ H, -C(O)O(C _1-4 alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O ) N (C _1- ₄ _{alkyl) 2, -NHC (O) (} C 1-4 alkyl), - N (C _1-4 alkyl) C (O) (C _1-4 alkyl), - OC(O)(C _1-4 alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl) ), C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl substituents;

M is C (R ^4a ) or N;

M ¹ is C(R ^4b ) or N;

p is 0 or 1;

X ⁶ is N(R ¹³ );

X ⁵ is C(R ¹⁶ ) or N; and, when p is 0, X ⁵ is N;

n is 0, 1, or 2, provided that the result of adding n and p is 1 or 2;

X ⁴ is S, S(O), S(O) ₂ , O, N(R ¹² ) or C(R ¹⁴ )(R ¹⁵ );

Or, R ^10a and R ¹³ and the atoms to which they are attached together form

X ² is S, S(O), S(O) ₂ , O, N(R ^2a ) or C(R ^3a )(R ^3b );

t is 0 or 1;

Y is

Y ¹ is C(R ^6a ) or N;

Y ² is C(R ^6b ) or N;

M is C (R ^4a ) or N;

M ¹ is C(R ^4b ) or N;

R ² , R ^4a , R ^4b and R ⁵ are each independently hydrogen, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O-(C _1-4 alkyl) , -(C _1-4 alkyl)-OH, -NH ₂ , -NH-(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ , C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

X ¹ is a single bond, S, S(O), S(O) ₂ , O, N(R ⁷ ) or C(R ^24a )(R ^24b );

p is 0;

X ⁵ is N;

R ¹¹ is hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein the C _1-6 alkyl and C _3-6 cycloalkyl are each independently optionally selected from one or more halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), - (C _1- ₄ alkyl) -OH, -NH _2, - NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH ₂ , -CO ₂ H, -C(O)O(C _1- ₄ alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ , -NHC(O)( C _1-4 alkyl), - N (C _1- ₄ alkyl) C (O) (C _1-4 alkyl), - OC (O) ( C 1-4 alkyl), - NHC (O) NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl , C _6-10 aryl and 5-12 membered heteroaryl substituents;

n is 0 or 1;

X ⁴ is S, S(O), S(O) ₂ , O, N(R ¹² ) or C(R ¹⁴ )(R ¹⁵ );

Alternatively, R ^9a and R ^10a and the carbon atoms to which they are attached together form a C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C _3-6 cycloalkyl and 3-6 membered hetero The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl),- (C _1-4 alkyl) -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ _{, -CO 2 H, -C (O} ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C _1-4 alkyl) ₂ , -NHC(O)(C _1-4 alkyl), -N(C _1-4 alkyl)C(O)(C _1-4 alkyl), -OC( O) (C _1- ₄ alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 _{alkyl) 2, -NHC (O) NH} (C 1-4 alkyl), Substituents of C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl;

M is C (R ^4a ) or N;

M ¹ is C(R ^4b ) or N;

X ¹ is a single bond, S, S(O), S(O) ₂ , O, N(R ⁷ ) or C(R ^24a )(R ^24b );

p is 0 or 1;

X ⁶ is N(R ¹³ );

X ⁵ is C(R ¹⁶ ) or N; and, when p is 0, X ⁵ is N;

M is C (R ^4a ) or N;

M ¹ is C(R ^4b ) or N;

R ^1a and R ^1b are each independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)OR ^a, or -C(O)NR ^a R ^b , wherein the C _1-6 alkyl group, C _3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally selected by one or more independently selected from halogen, -CN, and C _1-4 alkyl group , C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl),-(C _1-4 alkyl) -OH, -NH ₂ , -NH (C _1-4 alkyl),- N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl)-NH ₂ , C _3-6 cycloalkyl (e.g. cyclopropyl), 3-6 membered heterocycloalkyl, C _6- Substituents of ₁₀ aryl and 5-12 membered heteroaryl;

X ⁵ is C(R ¹⁶ ) or N;

X ⁷ is S, S(O), S(O) ₂ , O, N(R ¹² ) or C(R ¹⁴ )(R ¹⁵ );

k is 0, 1 or 2;

X ¹ is N(R ⁷ );

R ⁷ forms together with R ⁵ and the atoms they are connected to

Wherein, X ² is S, S(O), S(O) ₂ , O, N(R ^2a ) or C(R ^3a )(R ^3b );

t is 0 or 1;

Y is

Y ¹ is C(R ^6a ) or N;

Y ² is C(R ^6b ) or N;

In some embodiments, in the compound represented by formula I as described in any one of the preceding embodiments, the halogen and the halogen in the C _1-4 haloalkyl group may each independently be fluorine, chlorine, or bromine. Or iodine.

In some embodiments, in the compound represented by formula I as described in any one of the preceding embodiments, the C _1-4 alkyl group, the C _1-4 alkyl group in the C _1-4 haloalkyl group , the -O (C _1-4 alkyl) is C _1-4 alkyl, said - (C _1- ₄ alkyl) -OH is C _1-4 alkyl, said - The C _1-4 alkyl in NH (C _1-4 alkyl), the C _1-4 alkyl in the -N (C _1-4 alkyl) ₂ , the C _1-4 alkyl in the -(C _1-4 alkyl) is -NH ₂ C _1-4 alkyl, the -C (O) O (C _1-4 alkyl) is C _1-4 alkyl, said -C (O) NH (C _1-4 alkyl) in C _1-4 alkyl, said -C (O)N (C _1-4 alkyl) ₂ in C _1-4 alkyl, said -NHC( O) (C _1-4 alkyl) is C _1-4 alkyl, said -N (C _1-4 alkyl) C (O) (C _1-4 alkyl) is C _1-4 alkyl group, said -OC (O) (C _1-4 alkyl) is C _1-4 alkyl, said -NHC (O) N (C _1-4 alkyl) ₂ C ₁ of _-4 alkyl, said -NHC (O) NH (C _1-4 alkyl) are each independently C _1-4 alkyl may be methyl, ethyl, n-propyl, isopropyl, n Butyl, isobutyl, sec-butyl or tert-butyl.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, the C _1-6 alkyl group may each independently be methyl, ethyl, n-propyl, isopropyl , N-butyl, isobutyl, sec-butyl or tert-butyl.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, the C _3-6 cycloalkyl group may independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclo Hexyl.

In some embodiments, in the compound of Formula I as described in any one of the preceding embodiments, the 3-8 membered heterocycloalkyl group may independently be 3, 4, 5, 6, 7 or 8 membered Heterocycloalkyl.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, the 4-7 membered heterocycloalkyl group may independently be a 4, 5, 6 or 7 membered heterocycloalkyl group .

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, the C _6-10 aryl group may independently be a phenyl group.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, the 5-12 membered heteroaryl group may independently be a 5-6 membered heteroaryl group.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, the 3-6 membered heterocycloalkyl group may independently be a 3, 4, 5, or 6 membered heterocycloalkyl group .

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, Z ¹ is C and Z ² is N.

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, Z ¹ is N and Z ² is C.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, R ² is halogen.

In some embodiments, in the compound of formula I as described in any one of the preceding embodiments, R ² is fluorine.

In some embodiments, in the compound represented by Formula I as described in any of the preceding embodiments, when R ^{4 is} present and not connected to other variables, R ⁴ is halogen.

In some embodiments, in the compound of Formula I as described in any one of the preceding embodiments, when R ^{4 is} present and not connected to other variables, R ⁴ is fluorine.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, R ^4a is hydrogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, M is CH or N.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, M is CH.

In some embodiments, M is N in the compound of formula I as described in any of the preceding embodiments.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, R ^4b is hydrogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, M ¹ is CH or N.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, M ¹ is CH.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ^{4 is} present and is not connected to other variables,

for

for

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ³ and R ^{4 are} connected together to form

Time,

for

E position wherein the wavy line is connected to the M1 terminal connection, the wavy line connected to the terminal f connected to the R ⁴ position.

Time,

for

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{5 is} present and not connected to other variables, R ⁵ is hydrogen.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ^{6 is} present and not connected to other variables, R ⁶ is hydrogen, -NH ₂ , -NH-(C _1-4 alkyl) or -N(C _1-4 alkyl) ₂ .

In some embodiments, in the compound represented by Formula I as described in any of the preceding embodiments, when R ^{6 is} present and not connected to other variables, R ⁶ is hydrogen or -NH ₂ .

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{6 is} present and not connected to other variables, R ⁶ is hydrogen.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when X ^{2 is} present, X ² is C(R ^3a )(R ^3b ).

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ⁷ and R ⁵ and the atoms to which they are connected together form

And when t is 0, the

for

And when t is 1, the

for

When the said

for

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when R ^{3a is} present, R ^3a is hydrogen or halogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{3a is} present, R ^3a is hydrogen or fluorine.

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when R ^{3b is} present, R ^3b is hydrogen or halogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{3b is} present, R ^3b is hydrogen or fluorine.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^3a and R ^3b are present, R ^3a and R ^3b are each independently hydrogen or halogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^3a and R ^3b are present, R ^3a and R ^3b are hydrogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^3a and R ^3b are present, R ^3a and R ^3b are fluorine.

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when R ^{5a is} present, R ^5a is hydrogen or C _1-6 alkyl (e.g. methyl), wherein said C _1-6 alkyl is optionally selected by one or more independently selected from halogen (e.g. fluorine), -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl ), -(C _1-4 alkyl) -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ , -CO ₂ H, -C(O)O(C _1-4 alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C( O) N (C _1-4 alkyl) ₂ , -NHC (O) (C _1-4 alkyl), -N (C _1-4 alkyl) C (O) (C _1-4 alkyl), -OC(O)(C _1-4 alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkane Group), C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-10 aryl and 5-12 membered heteroaryl substituents.

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when R ^{5a is} present, R ^5a is hydrogen or C _1-6 alkyl (e.g. methyl), wherein said C _{The 1-6} alkyl group is optionally substituted with one or more halogens (e.g., fluorine).

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when R ^{5a is} present, R ^5a is hydrogen or C _1-6 alkyl (eg, methyl).

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{5a is} present, R ^5a is hydrogen.

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when R ^{5b is} present, R ^5b is hydrogen.

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when R ^{6a is} present, R ^6a is hydrogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{6b is} present, R ^6b is hydrogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{7a is} present, R ^7a is hydrogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{7b is} present, R ^7b is hydrogen.

When the said

for

(E.g

Preferred

Further preferred

), wherein the definition of R ^5a is as described in any aspect of the present invention. In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ⁷ and R ⁵ and the atoms to which they are connected together form

When the said

for

When the said

for

(E.g

E.g

), wherein the definitions of R ^3a , R ^3b and R ^5a are as described in any aspect of the present invention.

When the said

for

When the said

for

When the said

for

When the said

for

When the said

for

or

In some embodiments, in the compound of formula I as described in any one of the preceding embodiments, R ^1b is hydrogen or a C _1-6 alkyl group, and the C _1-6 alkyl group is optionally substituted by one or more Independently selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), -(C _1-4 alkyl) -OH and C _3-6 ring Alkyl substituents are substituted.

In some embodiments, in the compound of formula I as described in any one of the preceding embodiments, R ^1b is hydrogen or a C _1-6 alkyl group, and the C _1-6 alkyl group is optionally substituted by a C _{3- 6} Cycloalkyl substituted.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, R ^1b is hydrogen.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ^{1a is} not connected to other variables, R ^1a is hydrogen or C _1-6 alkyl, and the C _{1 -6} alkyl optionally substituted with one or more substituents independently selected from halogen, C _1- ₄ alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), - (C _1-4 Alkyl) -OH and C _3-6 cycloalkyl substituent substituted;

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ^{1a is} not connected to other variables, R ^1a is hydrogen or C _1-6 alkyl, and the C _{1 The -6} alkyl group is optionally substituted with a C _3-6 cycloalkyl group.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ^{1a is} not connected to other variables, R ^1a is C _1-6 alkyl, and the C _1-6 The alkyl group is optionally substituted with a C _3-6 cycloalkyl group.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ^{1a is} not connected to other variables, R ^1a is methyl or

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, X ¹ is N(R ⁷ ).

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ^{7 is} present and not connected to other variables, R ⁷ is hydrogen or C _1-6 alkyl.

In some embodiments, in the compound of Formula I as described in any one of the preceding embodiments, when R ^{7 is} present and not connected to other variables, R ⁷ is hydrogen.

In some embodiments, in the compound represented by Formula I as described in any of the preceding embodiments, when R ⁷ and R ^1a and the atoms to which they are attached together form a 4-7 membered heterocycloalkyl group, R ⁷ and R ^1a and the atoms they are connected to form together

Wherein, each R ^{21 is} independently halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), -(C _1-4 alkyl) ) -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ ,-(C _1-4 alkyl) -NH ₂ , -CO ₂ H,- _{C (O) O (C 1-} 4 alkyl), - C (O) NH 2, -C (O) NH (C 1-4 alkyl), - C (O) N (C 1-4 alkyl _{) 2, -NHC (O) (} C 1-4 alkyl), - N (C _1- ₄ alkyl) C (O) (C _1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl And 3-6 membered heterocycloalkyl;

Each u is independently 0, 1, or 2;

R ²⁰ is hydrogen, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), -(C _1-4 alkyl) -OH, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ , -CO ₂ H, -C(O) O(C _1-4 alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ ,- NHC(O)(C _1-4 alkyl), -N(C _1-4 alkyl)C(O)(C _1-4 alkyl), -OC(O)(C _1-4 alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl or 3-6 Member heterocycloalkyl.

Wherein, R ²⁰ is hydrogen, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O(C _1-4 alkyl), -(C _1-4 alkyl)- OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ ,-(C _1-4 alkyl) -NH ₂ , -CO ₂ H, -C( O) O (C _1- ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1-4 alkyl), - C (O) N (C 1-4 alkyl) ₂ , -NHC (O) (C _1-4 alkyl), - N (C _1- ₄ alkyl) C (O) (C _1-4 alkyl), - OC (O) ( C 1-4 alkyl ), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl or 3 -6 membered heterocycloalkyl.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{20 is} present, R ²⁰ is hydrogen or halogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{20 is} present, R ²⁰ is hydrogen or fluorine.

In some embodiments, in the compound represented by formula I as described in any of the foregoing embodiments, when the carbon atom to which R ^1a and R ^{1b are} connected has chirality, it may be in the R configuration or the S configuration.

In some embodiments, in the compound represented by Formula I as described in any of the foregoing embodiments, when the carbon atom to which R ^1a and R ^{1b are} connected has chirality, it may be in the R configuration.

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when R ^1b is hydrogen,

for

In some embodiments, in the compound represented by Formula I as described in any of the preceding embodiments, when R ⁷ and R ^1a and the atoms to which they are attached together form a 4-7 membered heterocycloalkyl group, R ⁷ and R ¹ and the atoms they are connected to form together

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ⁷ and R ¹ and the atoms to which they are connected together form

When the said

for

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ⁷ and R ^1a and the atoms to which they are connected together form

When the said

for

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{13 is} present and not connected to other variables, R ¹³ is hydrogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{16 is} present, R ¹⁶ is hydrogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, X ⁵ is N.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ^{3 is} not connected to other variables, R ³ is hydrogen, C _1-6 alkyl or C _3-6 Cycloalkyl.

In some embodiments, in the compound represented by Formula I as described in any of the preceding embodiments, when R ^{3 is} not connected to other variables, R ³ is hydrogen or C _1-6 alkyl.

In some embodiments, in the compound represented by Formula I as described in any of the preceding embodiments, when R ^{11 is} not connected to other variables, R ¹¹ is hydrogen.

In some embodiments, in the compound represented by Formula I as described in any of the preceding embodiments, when R ³ and R ^{4 are} not connected to each other, p is 1.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ³ , R ¹¹ and X ⁵ together form a 3-8 membered heterocycloalkyl group,

for

Wherein, each R ^{23 is} independently halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), -(C _1-4 alkyl) ) -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ ,-(C _1-4 alkyl) -NH ₂ , -CO ₂ H,- _{C (O) O (C 1-} 4 alkyl), - C (O) NH 2, -C (O) NH (C 1-4 alkyl), - C (O) N (C 1-4 alkyl _{) 2, -NHC (O) (} C 1-4 alkyl), - N (C _1- ₄ alkyl) C (O) (C _1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C _6-10 aryl or 5-12 membered heteroaryl;

v is 0, 1, 2 or 3;

R ²² is hydrogen, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -O (C _1-4 alkyl), -(C _1-4 alkyl) -OH, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -(C _1-4 alkyl) -NH ₂ , -CO ₂ H, -C(O) O(C _1-4 alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ ,- NHC(O)(C _1-4 alkyl), -N(C _1-4 alkyl)C(O)(C _1-4 alkyl), -OC(O)(C _1-4 alkyl), -NHC(O)NH ₂ , -NHC(O)N(C _1-4 alkyl) ₂ , -NHC(O)NH(C _1-4 alkyl), C _3-6 cycloalkyl, 3-6 Member heterocycloalkyl, C _6-10 aryl or 5-12 membered heteroaryl.

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when R ^{23 is} present, R ²³ is C _1-4 alkyl, -OH, -O(C _1-4 alkane Group) or -(C _1-4 alkyl)-OH.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{23 is} present, R ²³ is -OH.

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when v is present, v is zero.

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when R ^{22 is} present, R ²² is hydrogen, C _1-4 alkyl, -OH, -O(C _{1- 4} alkyl) or -(C _1-4 alkyl)-OH.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{22 is} present, R ²² is -OH.

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when

for

Time,

for

for

Time,

for

In some embodiments, in the compound represented by Formula I as described in any of the foregoing embodiments, when R ^{3 is} not connected to R ⁴ , X ⁵ , R ³ and R ¹¹ are defined as follows:

X ⁵ is N;

R ³ and R ¹¹ are each independently hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, wherein the C _1-6 alkyl and C _3-6 cycloalkyl are each independently optionally substituted by one Or multiple substituents independently selected from C _1-4 alkyl, -OH, -O(C _1-4 alkyl) and -(C _1-4 alkyl)-OH;

Alternatively, R ³ , R ¹¹ and X ⁵ together form a 3-8 membered heterocycloalkyl group, wherein the C _3-8 cycloalkyl group and the 3-8 membered heterocycloalkyl group are each independently optionally substituted by one or more One substituent independently selected from C _1-4 alkyl, -OH, -O(C _1-4 alkyl) and -(C _1-4 alkyl)-OH.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ³ and R ^{4 are} not connected to each other,

for

The definition of each variable is as described above.

for

Time,

for

Time,

for

E.g

Time,

for

for

Time,

for

for

Time,

for

for

Time,

for

for

Time,

for

for

Time,

for

Time,

for

Time,

for

In some embodiments, in the compound represented by Formula I as described in any of the preceding embodiments, when X ^{4 is} present, X ⁴ is C(R ¹⁴ )(R ¹⁵ ) or O.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{14 is} present, R ¹⁴ is hydrogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{15 is} present, R ¹⁵ is hydrogen.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ¹⁴ and R ¹⁵ are present, R ¹⁴ and R ¹⁵ are both hydrogen.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when X ^{4 is} present, X ⁴ is CH ₂ or O.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when X ^{4 is} present, X ⁴ is CH ₂ .

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when X ^{4 is} present, X ⁴ is O.

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{9b is} present, R ^9b is hydrogen.

In some embodiments, in the compound represented by Formula I as described in any of the preceding embodiments, when R ^{9a is} present and not connected to other variables, R ^9a is hydrogen or C _1-6 alkyl.

In some embodiments, in the compound of Formula I as described in any one of the preceding embodiments, when R ^{9a is} present and not connected to other variables, R ^9a is hydrogen or methyl.

In some embodiments, in the compound represented by Formula I as described in any of the foregoing embodiments, when the carbon atom to which R ^9a and R ^{9b are} connected has chirality, it may be in the R configuration or the S configuration.

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when R ^9b is hydrogen,

for

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ^{10a is} present and not connected to other variables, R ^10a is hydrogen or C _1-6 alkyl, and The C _1-6 alkyl group is optionally substituted with one or more hydroxy groups.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ^{10a is} present and not connected to other variables, R ^10a is hydrogen, methyl, or

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ^{10b is} present and is not connected to other variables, R ^10b is hydrogen or C _1-6 alkyl, and The C _1-6 alkyl group is optionally substituted with one or more hydroxy groups.

In some embodiments, in the compound represented by formula I as described in any of the preceding embodiments, when R ^{10b is} present and not connected to other variables, R ^10b is hydrogen, methyl, or

In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, when R ^{10b is} present and not connected to other variables, R ^10b is hydrogen.

for

Time,

for

E.g

for

Time,

for

E.g

E.g

for

Time,

for

E.g

E.g

for

Time,

for

E.g

E.g

for

Time,

for

E.g

E.g

for

Time,

for

or

E.g

E.g

E.g

for

Time,

for

or

E.g

E.g

for

Time,

for

or

E.g

E.g

for

Time,

for

E.g

E.g

for

Time,

for

E.g

E.g

Time,

for

Time,

for

Time,

for

Time,

for

When, p is 1.

When, p is 0.

In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when m is 1, X ³ is C, X ³ and R ⁶ and the carbon atoms to which they are attached together form benzene base.

In some embodiments, in the compound represented by formula I as described in any of the preceding schemes, the definitions of each variable are as follows:

Z ¹ is C or N; when Z ¹ is C, Z ² is N; when Z ¹ is N, Z ² is C;

M is CH or N;

M ¹ is N;

R ² and R ⁴ are each independently hydrogen or halogen;

R ⁵ and R ⁶ are hydrogen;

R ^1b is hydrogen;

R ^1a is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally substituted by a C _3-6 cycloalkyl group;

X ¹ is N(R ⁷ );

R ⁷ is hydrogen or C _1-6 alkyl;

Alternatively, R ⁷ and R ^1a and the atoms to which they are attached together form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally substituted by one or more halogens;

p is 0 or 1;

X ⁶ is N(R ¹³ );

R ¹³ is hydrogen;

X ⁵ is N; and, when p is 0, X ⁵ is N;

R ¹¹ is hydrogen;

R ³ is hydrogen, C _1-6 alkyl or C _3-6 alkyl;

Alternatively, R ³ , R ¹¹ and X ⁵ together form a 3-8 membered heterocycloalkyl group, wherein each of the 3-8 membered heterocycloalkyl group is independently optionally selected by one or more independently selected from C _1-4 Alkyl, -OH, -O (C _1-4 alkyl) and -(C _1-4 alkyl) -OH substituents;

Or, R ³ and R ^{4 are} connected together to form

n is 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;

X ⁴ is O or CH ₂ ;

R ^10a and R ^10b are each independently hydrogen or C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted with one or more -OH;

Alternatively, R ^10a and R ^10b and the carbon atoms to which they are attached together form a C _3-6 cycloalkyl group;

Or, R ^10a and R ¹³ and the atoms to which they are attached together form

R ^9a and R ^9b are each independently hydrogen or C _1-6 alkyl;

Alternatively, R ^9a and R ^10a and the carbon atoms to which they are attached together form a C _3-6 cycloalkyl group;

m is 0 or 1;

And, the premise is that condition (i) or (ii) is satisfied:

(i) When m is 1, X ³ is C, and X ³ and R ⁶ and the carbon atoms to which they are attached together form a phenyl group;

(ii) When m is 0, R ⁷ and R ⁵ and their connected atoms together form

Said

for

R ^3a and R ^3b are each independently hydrogen or halogen;

R ^5a is hydrogen or C _1-6 alkyl;

The heteroatoms in the heterocycloalkyl group are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.

Z ¹ is C or N; when Z ¹ is C, Z ² is N; when Z ¹ is N, Z ² is C;

M is CH or N;

M ¹ is N;

R ² and R ⁴ are each independently hydrogen or halogen;

R ⁵ and R ⁶ are hydrogen;

R ^1b is hydrogen;

X ¹ is N(R ⁷ );

R ⁷ is hydrogen or C _1-6 alkyl;

p is 0 or 1;

X ⁶ is N(R ¹³ );

R ¹³ is hydrogen;

X ⁵ is N; and, when p is 0, X ⁵ is N;

R ¹¹ is hydrogen;

R ³ is hydrogen, C _1-6 alkyl or C _3-6 alkyl;

Or, R ³ and R ^{4 are} connected together to form

n is 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;

X ⁴ is O or CH ₂ ;

Or, R ^10a and R ¹³ and the atoms to which they are attached together form

R ^9a and R ^9b are each independently hydrogen or C _1-6 alkyl;

m is 0 or 1;

And, the premise is that condition (i) or (ii) is satisfied:

(ii) When m is 0, R ⁷ and R ⁵ and their connected atoms together form

Said

for

R ^3a and R ^3b are each independently hydrogen or halogen;

Z ¹ is C or N; when Z ¹ is C, Z ² is N; when Z ¹ is N, Z ² is C;

M is CH or N;

M ¹ is N;

R ² and R ⁴ are each independently hydrogen or halogen;

R ⁵ and R ⁶ are hydrogen;

R ^1b is hydrogen;

X ¹ is N(R ⁷ );

R ⁷ is hydrogen or C _1-6 alkyl;

p is 0 or 1;

X ⁶ is N(R ¹³ );

R ¹³ is hydrogen;

X ⁵ is N; and, when p is 0, X ⁵ is N;

R ¹¹ is hydrogen;

R ³ is hydrogen, C _1-6 alkyl or C _3-6 alkyl;

Or, R ³ and R ^{4 are} connected together to form

n is 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;

X ⁴ is O or CH ₂ ;

Or, R ^10a and R ¹³ and the atoms to which they are attached together form

m is 0 or 1;

And, the premise is that condition (i) or (ii) is satisfied:

(ii) When m is 0, R ⁷ and R ⁵ and their connected atoms together form

Said

for

The heteroatoms in the heterocycloalkyl group are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3. In some embodiments, the compound represented by Formula I has any of the following structures:

In some embodiments, the compound represented by Formula I has any of the following structures:

Wherein, the definition of each variable is as described in any aspect of the present invention.

The definition of each variable is as described in the compound represented by formula I as described in any of the foregoing schemes.

The present invention also provides a method for preparing the compound represented by formula I as described above, which is selected from any of the following schemes:

Scheme 1 includes the following steps: in a solvent, the compound represented by formula II and the compound

Carry out the condensation reaction as shown below in the presence of carbonyl diimidazole to obtain the compound shown in formula I; wherein p is 1, X ⁵ is N, R ^{3 is} not connected to R ⁴ , and other variables are defined as above The compound described in any one of the schemes is described in the compound represented by formula I;

Scheme 2 includes the following steps: in a solvent, the compound represented by formula III and the compound

Carry out the condensation reaction shown below to obtain the compound shown in formula I; wherein p is 1, X ⁵ is N, R ^{3 is} not connected to R ⁴ , and the definitions of other variables are as described in any of the foregoing schemes. As described in the compound represented by formula I;

Scheme 3 includes the following steps: in a solvent, the compound represented by formula IV and the compound

In the presence of a condensing agent (such as EDCI or pentafluorophenyl diphenyl phosphonate) and a base, the condensation reaction shown below can be carried out to obtain the compound shown in formula I; wherein p is 0 and X ⁵ is N, R ^{3 is} not connected to R ⁴ , and the definitions of other variables are as described in any of the foregoing schemes as described in the compound represented by formula I;

Scheme 4 includes the following steps: in a solvent, the compound represented by formula V is subjected to the condensation reaction shown below in the presence of a base to obtain the compound represented by formula I; where p is 1, X ⁵ Is N, R ³ and R ^{4 are} connected together to form

The definitions of other variables are as described in the compound represented by formula I as described in any of the foregoing schemes;

Scheme 5 includes the following steps: in a solvent, the compound represented by formula VI is subjected to the condensation reaction shown below in the presence of a condensing agent (such as EDCI, pentafluorophenyl diphenyl phosphonate) and a base to obtain The compound shown in formula I is sufficient; wherein p is 0, X ⁵ is N, and R ³ and R ^{4 are} connected together to form

The method for preparing the compound represented by formula VI may include the following steps; in a solvent, the compound represented by formula VI-1 is subjected to the oxidation reaction shown below in the presence of an oxidizing agent (such as NaClO ₂ ) , It is sufficient to obtain the compound represented by formula VI; the definition of each variable is as described in the compound represented by formula VI described in any of the foregoing schemes;

The method for preparing the compound represented by formula III may include the following steps; in a solvent, the compound represented by formula II as described above is combined with

Carry out the substitution reaction as shown below in the presence of a base to obtain the compound represented by formula III; the definition of each variable is as described in the compound represented by formula III as described in any of the foregoing schemes ；

The method for preparing the compound represented by formula V may include the following steps: in a solvent, the compound represented by formula V-1 is subjected to the de-Boc reaction shown below in the presence of an acid, It suffices to obtain the compound represented by formula VI; the definition of each variable is as described in the compound represented by formula V as described in any of the foregoing schemes;

The compound represented by formula V-1 may include the following steps: in a solvent, the compound represented by formula V-2 and

Carry out the substitution reaction as shown below in the presence of a base to obtain the compound shown in formula V-1; the definition of each variable is as shown in any one of the preceding schemes as shown in formula V-1 Described in the compound;

The compound represented by formula V-2 may include the following steps: in a solvent, the compound represented by formula V-3 is subjected to the following reduction reaction in the presence of Fe and NH ₄ Cl to obtain The compound represented by formula V-2 is sufficient; wherein X ⁶ is NH; the definition of other variables is as described in the compound represented by formula V-2 as described in any of the foregoing schemes;

The present invention also provides a compound of any of the following structures:

The present invention also provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula I, its stereoisomers, its tautomers, its isotopic derivatives, and its pharmaceutically acceptable salts Or its solvates, and pharmaceutical excipients.

The present invention also provides a compound as shown in formula I, its stereoisomers, its tautomers, its isotopic derivatives, its pharmaceutically acceptable salts or solvates thereof, or The application of the above-mentioned pharmaceutical composition in the preparation of a medicine for treating cancer, pain, neurological disease, autoimmune disease or inflammation.

The present invention also provides a method for the treatment of cancer, pain, neurological disease, autoimmune disease or inflammation, which comprises administering to a patient in need of such treatment a therapeutically effective amount of the compound represented by formula I as described above, and its three-dimensional Isomers, tautomers, isotopic derivatives thereof, pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions as described above.

The cancer can be non-small cell lung cancer, papillary thyroid cancer, glioblastoma multiforme, acute myeloid leukemia, colorectal cancer, large cell neuroendocrine cancer, prostate cancer, colon cancer, acute myeloid cell Leukemia, sarcoma, pediatric glioma, intrahepatic cholangiocarcinoma, pilocytic astrocytoma, low-grade glioma, lung adenocarcinoma, salivary gland cancer, secretory breast cancer, fibrosarcoma, nephroma, or breast.

The cancer may be the following cancers related to Trk: non-small cell lung cancer, papillary thyroid cancer, glioblastoma multiforme, acute myeloid leukemia, colorectal cancer, large cell neuroendocrine cancer, prostate cancer , Colon cancer, acute myeloid leukemia, sarcoma, pediatric glioma, intrahepatic cholangiocarcinoma, pilocytic astrocytoma, low-grade glioma, lung adenocarcinoma, salivary gland cancer, secretory breast cancer, fiber Sarcoma, kidney tumor, breast.

The present invention also provides a method for inhibiting the activity of Trk kinase, which comprises combining cells containing Trk kinase with an effective amount of the compound represented by formula I, its stereoisomers, and its tautomers as described above. , Its isotope derivative, its pharmaceutically acceptable salt or its solvate contact, said contact is carried out in vivo or in vitro.

The present invention also provides a compound represented by formula I, its stereoisomers, its tautomers, its isotope derivatives, its pharmaceutically acceptable salts or solvates as described above. Application of Trk kinase inhibitors.

The Trk kinase may be TrkA kinase, such as one or more of wild-type TrkA kinase, G595R mutant TrkA kinase, and G667C mutant TrkA kinase.

The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients.

The term "patient" refers to any animal that is about to or has received administration of a compound or composition, mammals are preferred, and humans are preferred. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, it can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. A salt. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, diethanolamine salt. When the compound of the present invention contains a relatively basic functional group, the acid addition can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. A salt. The pharmaceutically acceptable acids include inorganic acids, and the inorganic acids include, but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , Tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (ie 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid)), amino acids (for example, glutamic acid, arginine), and the like. When the compound of the present invention contains relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt. For details, please refer to Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

The term "plurality" refers to 2, 3, 4, or 5.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to a saturated linear or branched hydrocarbon group. C _1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as C ₁ alkyl (ie methyl), C ₂ alkyl (ie ethyl), C ₃ Alkyl, C ₄ alkyl, C ₅ alkyl or C ₆ alkyl. C _1-4 alkyl refers to an alkyl group having 1, 2, 3 or 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl.

The term "haloalkyl" means that one or more hydrogen atoms in the alkyl group are replaced by halogen, and the number of halogens can be one or more; when the number of halogens is more than one, the halogens are the same or different. Examples of haloalkyl include, but are not limited to, 2-chloro-1,1,2-trifluoroethyl, trifluoromethyl, and difluoromethyl.

The term "cycloalkyl" refers to a non-aromatic saturated or partially unsaturated cyclic hydrocarbon group. Cycloalkyl groups can be monocyclic or polycyclic (for example, bicyclic and tricyclic), and can be fused, spiro, and bridged ring structures. The cycloalkyl group optionally contains one or more double bonds or triple bonds. The C _3-6 cycloalkyl group refers to a cycloalkyl group having 3, 4, 5, or 6 carbon atoms in the ring. For example, a C ₅ cycloalkyl group refers to a cycloalkyl group having 5 carbon atoms in the ring. C _3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "heterocycloalkyl" refers to a group formed by replacing at least one carbon atom on the cycloalkyl ring with a heteroatom (for example, N, O, or S). A 3-6 membered heterocycloalkyl group refers to a heterocycloalkyl group in which the number of atoms in the ring is 3, 4, 5, or 6, and at least one of the atoms is a heteroatom. Examples of 3-6 membered heterocycloalkyl include, but are not limited to, aziridinyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl and the like.

The term "aryl" refers to any stable monocyclic or polycyclic (eg, bicyclic or tricyclic) carbocyclic ring with up to 7 atoms in each ring, in which at least one ring is aromatic. Examples of aryl groups include but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthracenyl, or acenaphthyl. It is understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is made through the aromatic ring.

The term "heteroaryl" refers to a stable monocyclic or polycyclic (for example, bicyclic or tricyclic) carbocyclic ring with up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and contains at least one selected from O, N and S heteroatom. Heteroaryl groups can be connected to other parts of the molecule through heteroatoms or carbon atoms. Examples of heteroaryl groups include, but are not limited to, acridinyl, carbazolyl, cinolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, benzothienyl , Benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl (e.g., pyrrol-1 -Based

Pyrrol-2-yl

), Tetrahydroquinolinyl. It is understood that in the case where the heteroaryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is made through the aromatic ring. A 5-6 membered heteroaryl group refers to a heteroaryl group in which the number of atoms in the ring is 5 or 6, in which at least one ring atom is a heteroatom, and the remaining ring atoms are carbon atoms. Examples of 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, pyridyl, pyrazolyl and the like.

When the number of a linking group is 0, such as -(X) ₀ -, it means that the linking group is a single bond. When one of the variables is selected from a single bond, it means that the two groups connected are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ. For example, in -M ₁ -(M ₂ ) _y -M ₃ -, when y is 0, -M ₁ -(M ₂ ) _m -M ₃ -is actually -M ₁ -M ₃ -.

The term "optional" or "optionally" refers to the event or condition described later that may but not necessarily occur, and the description includes the situation in which the event or condition occurs and the situation in which the event or condition does not occur . For example, the term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.

The term "substituted" or "substituent" means that one or more hydrogen atoms are replaced by a specified group. When the substitution position is not specified, the substitution can be at any position, but only the formation of a stable or chemically feasible chemical is allowed.

When any variable (such as R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, and R has independent options in each case. In addition, combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.

The "compounds" and "pharmaceutically acceptable salts" described herein may exist in the form of solvates. The term "solvate" refers to a substance formed by combining a compound with a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate can exist in an ordered or non-ordered arrangement. The solvent includes, but is not limited to: water, methanol, ethanol and the like.

The "compounds", "pharmaceutically acceptable salts" and "solvates" described herein may exist in crystalline or amorphous forms. The term "crystal form" means that the ions or molecules are arranged strictly and periodically in a three-dimensional space in a certain way, and have the regularity of periodic recurrence at intervals; due to the above-mentioned periodic arrangement, there may be many Crystal form, that is, polymorphism. The term "amorphous" means that the ions or molecules present in a disorderly distribution state, that is, there is no periodic arrangement between the ions and molecules.

The "compound", "pharmaceutically acceptable salt" and "solvate" described herein may be used as a single stereoisomer or a mixture (for example, racemate) if there are stereoisomers. Form exists. The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotation chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or salting (physical bonding, etc.). The term "single stereoisomer" means that the mass content of one stereoisomer of a compound relative to all stereoisomers of the compound is not less than 95%.

The "compounds", "pharmaceutically acceptable salts" and "solvates" described herein may exist in the form of single tautomers or their mixtures if there are tautomers. Among them, the enol-keto interconversion is a typical tautomeric form.

The atoms in the "compounds", "pharmaceutically acceptable salts" and "solvates" described herein may exist in the form of their natural abundance or non-natural abundance (ie isotopic derivatives). For example, with the structure of the present invention, in addition to using "deuterium" or "tritium" instead of hydrogen, or using ¹⁸ F-fluorine label ( ¹⁸ F isotope) instead of fluorine, or using ¹¹ C-, ¹³ C-, or ¹⁴ C-rich Compounds in which collective carbons ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) replace carbon atoms are within the scope of the present invention. In some embodiments, the isotopic derivative is deuterated. In some embodiments, the isotopic derivative is a derivative obtained by replacing the hydrogen at the R ^9a and/or R ^9b position with deuterium.

The term "pharmaceutical excipients" refers to excipients and additives used in the production of drugs and formulating prescriptions, and are all substances contained in pharmaceutical preparations except for the active ingredients. See also Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

The term "treatment" refers to therapeutic therapy. When it comes to a specific disease, treatment refers to: (1) alleviating one or more biological manifestations of the disease or disease, (2) interfering with (a) one or more points in the biological cascade causing or causing the disease, or (b) ) One or more biological manifestations of the disease, (3) Improve one or more symptoms, effects or side effects related to the disease, or one or more symptoms, effects or side effects related to the disease or its treatment, Or (4) to slow down the development of the disease or one or more biological manifestations of the disease.

The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat the diseases or conditions described herein when administered to a patient. The "therapeutically effective amount" will vary according to the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted by those skilled in the art as needed.

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive progress effect of the present invention is to provide a tricyclic compound with a new core structure, its preparation method, intermediates and applications. Such compounds have the activity of inhibiting tropomyosin receptor kinase and can be used to treat cancer and other diseases.

detailed description

The present invention will be further explained by way of examples below, but the present invention is not limited to the scope of the described examples. In the following examples, the experimental methods without specific conditions are selected according to conventional methods and conditions, or according to the product specification.

Preparation of intermediates

Intermediate 1: 5-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine

Step A: Synthesis of diethyl 2-(2-((tert-butyldimethylsilyl)oxo)ethyl)malonate

Dissolve diethyl malonate (100.0 g, 418 mmol) in ethanol (1500 ml), add sodium ethoxide (29.0 g, 426 mmol), heat to 95 degrees Celsius to react for 1 hour, cool to room temperature, add (2 -Bromoethoxy)-tert-butyldimethylsilane (67.0 g, 418 mmol), stirred overnight at 95 degrees Celsius, the reaction was stopped, the solvent was evaporated under reduced pressure, ethyl acetate (1.0 liter) was added, and saturated Washed with sodium chloride solution (500 ml×2 times), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 120.0 g of light yellow oily product diethyl 2-(2-((tert-butyl Dimethylsilyl)oxo)ethyl)malonate. It is directly used in the next reaction without further purification.

Step B: Synthesis of 7-hydroxy-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one

Diethyl 2-(2-((tert-butyldimethylsilyl)oxo)ethyl)malonate (110.0 g, 347 mmol) and 1H-pyrazol-5-amine ( 27.5 g, 330 mmol) was dissolved in ethanol (1000 ml), sodium ethoxide (45.0 g, 662 mmol) was added, heated to 90 degrees Celsius and stirred overnight, the reaction was stopped, the solvent was evaporated under reduced pressure, and water (1000 ml) was added. Adjust the pH to 5 with 1 mole per liter of hydrochloric acid, and more white solids will precipitate out, filter, wash the filter cake with a small amount of water, put the filter cake into the reaction flask, add water (300 ml) and stir, add 5.0 ml of concentrated hydrochloric acid dropwise , Stirred at room temperature for 10 hours, filtered, and the filter cake was dried to obtain 30.0 grams of white solid product 7-hydroxy-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one .

MS (ESI) M/Z: 196 [M+H ⁺ ].

Step C: Synthesis of 5,7-dichloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine

Dissolve 7-hydroxy-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidine-5(4H)-one (25.0g, 128mmol) in phosphorus oxychloride (200ml) , Add triethylamine (25 ml), heat to 120 degrees Celsius to react for 3 hours, stop the reaction, cool to room temperature, pour into ice water (1000 ml) and stir. After quenching is complete, use dichloromethane (1000 ml×3 After extraction, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: dichloromethane). After concentration, 8.0 g of 5,7-dichloro-6-( 2-Chloroethyl)pyrazolo[1,5-a]pyrimidine.

MS (ESI) M/Z: 250 [M+H ⁺ ].

Step D: Synthesis of 5-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine

Dissolve 5,7-dichloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine (8.0 g, 32.0 mmol) in tetrahydrofuran (80 mL) and add acetic acid (1.0 mL) Then add zinc-copper reagent (1.4g), heat to 50 degrees Celsius and react for 3 hours, stop the reaction, filter, concentrate the filtrate under reduced pressure, and separate with silica gel column chromatography (eluent: dichloromethane). After concentration, 3.5 G 5-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine.

MS (ESI) M/Z: 216 [M+H ⁺ ].

Intermediate 2: 5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine

Step A: Synthesis of diethyl 2-(3-((tert-butyldimethylsilyl)oxo)propyl)malonate

Dissolve diethyl malonate (15.9 g, 99.2 mmol) in ethanol (120 mL), add sodium ethoxide (6.6 g, 99.2 mmol), heat to 76 degrees Celsius and react for 1 hour, cool to room temperature, add (3 -Bromopropoxy)(tert-butyl)dimethylsilane (25.0g, 99.2mmol), stirred overnight at 76°C to stop the reaction, the solvent was evaporated under reduced pressure, ethyl acetate (200ml) was added, Washed with saturated sodium chloride solution (100 ml×3 times), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 31.0 g of diethyl 2-(3-((tert- Butyldimethylsilyl)oxo)propyl)malonate. It is directly used in the next reaction without further purification.

Step B: Synthesis of 7-hydroxy-6-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one

Combine 2-(3-((tert-butyldimethylsilyl)oxo)propyl)malonate (18.0 g, 54.2 mmol) and 1H-pyrazole-5-amine (4.1 g, 49.3 mmol) was dissolved in ethanol (150 ml), sodium ethoxide (6.7 g, 98.6 mmol) was added, heated to 90 degrees Celsius and stirred overnight, the reaction was stopped, the solvent was evaporated under reduced pressure, water (200 ml) was added, and 1 mole Adjust the pH to 5 per liter of hydrochloric acid, and more white solids will precipitate out, filter, wash the filter cake with a small amount of water, put the filter cake into the reaction flask, add 100 ml of water and stir, add 0.5 ml of concentrated hydrochloric acid dropwise, and stir at room temperature for 10 After hours, it was filtered and the filter cake was dried to obtain 7.8 grams of white solid product 7-hydroxy-6-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one.

MS(ESI)M/Z:210[M+1].

Step C: Synthesis of 5,7-dichloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine

Dissolve 7-hydroxy-6-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidine-5(4H)-one (5.8 g, 27.8 mmol) in phosphorus oxychloride (40 mL) , Add triethylamine (5 ml), heat to 120 degrees Celsius to react for 3 hours, stop the reaction, cool to room temperature, pour the vessel into ice water (100 ml) and stir. After quenching is complete, use dichloromethane (100 ml) × 3 times) extraction, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column chromatography (eluent: dichloromethane), after concentration, 2.5 g of 5,7-dichloro-6 -(3-Chloropropyl)pyrazolo[1,5-a]pyrimidine.

MS(ESI)M/Z:265[M+1].

Step D: Synthesis of 5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine

Dissolve 5,7-dichloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine (2.4 g, 9.1 mmol) in tetrahydrofuran (30 mL), and add acetic acid (1.0 mL) Then add zinc-copper reagent (1.5 g), heat to 50 degrees Celsius and react for 3 hours, stop the reaction, filter, concentrate the filtrate under reduced pressure, and separate by silica gel column chromatography (eluent: dichloromethane), and concentrate to obtain 1.0 G 5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine.

MS(ESI)M/Z:230[M+1].

Intermediate 3: tert-Butyl((S)-2-(2-((R)-1-aminoethyl)-4-fluorophenoxy)propyl)carbamate

Step A: Synthesis of (R,E)-N-(5-fluoro-2-hydroxybenzylidene)-2-methylpropane-2-sulfinamide

Take a 1 liter three-necked flask, and mix 5-fluoro-2-hydroxybenzaldehyde (30.00 g, 214.2 mmol), cesium carbonate (111.60 g, 342.8 mmol), (R)-(+)-tert-butylsulfinamide (26.20 g, 214.2 mmol) was dissolved in dichloromethane (500 mL) and stirred at room temperature overnight.

Post-treatment: After the reaction was cooled to 0 degrees Celsius, water (400 mL) was added to quench the reaction. It was extracted with dichloromethane (400 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The filtrate obtained by filtration was concentrated under reduced pressure to obtain 48.50 g of yellow solid (R,E)-N-(5-fluoro-2-hydroxybenzylidene)-2-methylpropane-2-sulfenamide, No purification is required and it is used directly in the next step.

MS (ESI) M/Z: 244 [M+H ⁺ ].

Step B: Synthesis of (R)-N-((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)-2-methylpropane-2-sulfinamide

Take a 1 liter three-necked flask and dissolve (R,E)-N-(5-fluoro-2-hydroxybenzylidene)-2-methylpropane-2-sulfenamide (48.50 g, 199.6 mmol) In dry tetrahydrofuran (400 ml), nitrogen was replaced three times. After stirring for 10 minutes at -78 degrees Celsius, methylmagnesium bromide (3 mol/L, 303 mL, 909 mmol) was added thereto. The reaction was then carried out at -78 degrees Celsius for 2 hours, then the reaction was gradually warmed to room temperature and stirred overnight.

Post-treatment: the reaction was quenched by adding ice water (500 mL) under vigorous stirring. It was extracted with ethyl acetate (500 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The filtrate obtained by filtration was concentrated under reduced pressure. The remaining solid residue was separated by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1:3), and after concentration, 20.50 g of light yellow solid (R)-N-((R)-1-( 5-fluoro-2-hydroxyphenyl)ethyl)-2-methylpropane-2-sulfinamide.

MS (ESI) M/Z: 260 [M+H ⁺ ].

Step C: Synthesis of tert-butyl((S)-2-(2-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy (Base) propyl) carbamate

(R)-N-((R)-1-(5-Fluoro-2-hydroxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (5.00 g, 19.3 mmol), ( R)-1-Boc-aminopropan-2-ol (4.39 g, 25.1 mmol) triphenylphosphine (7.59 g, 29.0 mmol) dissolved in dichloromethane (50 mL), replaced with nitrogen three times, at 0 degrees Celsius , Diethyl azodicarboxylate (5.00 g, 29.0 mmol) was slowly added dropwise to the reaction system. Warm up naturally and stir overnight.

Post-treatment: add saturated brine (100 mL) to quench the reaction. It was extracted with ethyl acetate (50 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the solid residue obtained was separated by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1:3). After concentration, 6.10 g of colorless oily tert-butyl ((S )-2-(2-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)propyl)carbamate.

MS (ESI) M/Z: 417 [M+H ⁺ ].

Step D: Synthesis of tert-butyl((S)-2-(2-((R)-1-aminoethyl)-4-fluorophenoxy)propyl)carbamate

Add tert-butyl((S)-2-(2-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)propane Di) carbamate (6.00 g, 14.42 mmol) and iodine (0.75 g, 2.88 mmol) were dissolved in tetrahydrofuran (60 mL) and water (12 mL). Stir at 65 degrees Celsius for 6 hours.

Post-treatment: add saturated brine (100 mL) to quench the reaction. It was extracted with ethyl acetate (50 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain 4.0 g of oily tert-butyl((S)-2-(2-((R)-1-aminoethyl)-4-fluorophenoxy)propyl)aminomethyl Acid ester.

MS (ESI) M/Z: 312 [M+H ⁺ ].

Intermediate 4: tert-butyl((2R)-4-(3-(1-aminoethyl)-5-fluoropyrimidin-2-yl)butyl-2-yl)carbamate

Step A: Synthesis of 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-ol

5-Fluoro-2-methoxy-3-pyridinecarbaldehyde (20.00 g, 129.0 mmol) was dissolved in dry tetrahydrofuran (200 mL) and replaced with nitrogen three times. After stirring for 10 minutes at -78°C, methylmagnesium bromide (3 mol/L, 129 ml, 387.0 mmol) was added thereto. The reaction was then carried out at -78 degrees Celsius for 2 hours, then the reaction was gradually warmed to room temperature and stirred overnight. The reaction was stopped, and the reactant was added to ice water (200 ml) under vigorous stirring to quench the reaction. It was extracted with ethyl acetate (200 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The filtrate obtained by filtration was concentrated under reduced pressure. 20.00 g of 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-ol was obtained as a colorless oil.

MS (ESI) M/Z: 172 [M+H ⁺ ].

Step B: Synthesis of 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-one

Dissolve 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-ol (20.00 g, 117.0 mmol) and activated manganese dioxide (101.75 g, 1.17 mol) in chloroform (150 Ml), stirring at 95 degrees Celsius for 24 hours. The reaction was filtered while hot. It was washed with chloroform (200 ml), and the obtained organic phases were combined and concentrated under reduced pressure. 18.50 g of light yellow oily 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-one was obtained.

MS (ESI) M/Z: 170 [M+H ⁺ ].

Step C: Synthesis of 1-(5-fluoro-2-hydroxypyridin-3-yl)ethane-1-one

Dissolve 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-one (18.00 g, 106.5 mmol) in a 1,4-dioxane solution (4 mol/ Liter, 200 ml, 800.0 mmol), stirred at 70 degrees Celsius for 7 hours. The reaction was stopped, and after the reaction solution was cooled to room temperature, the reaction was concentrated under reduced pressure. 16.20 g of black solid 1-(5-fluoro-2-hydroxypyridin-3-yl)ethane-1-one hydrochloride was obtained.

MS (ESI) M/Z: 156 [M+H ⁺ ].

Step D: Synthesis of 3-acetyl-5-fluoropyridin-2-yl trifluoromethanesulfonate

Combine 1-(5-fluoro-2-hydroxypyridin-3-yl)ethane-1-one (16.00 g, 103.2 mmol), N-phenyl bis(trifluoromethanesulfonyl)imide (44.21 g, 123.8 mmol), 4-dimethylaminopyridine (1.26 g, 10.3 mmol) and N,N-diisopropylethylamine (39.94 g, 309.6 mol) dissolved in N,N-dimethylformamide (150 Ml), stirred at 25 degrees Celsius for 2 hours. The reaction was stopped, and saturated brine (150 mL) was added to quench the reaction. It was extracted with ethyl acetate (200 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the remaining solid residue was separated by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1:10). After concentration, 12.30 g of yellow oily 3-acetyl-5- Fluoropyridin-2-yl triflate.

MS (ESI) M/Z: 288 [M+H ⁺ ].

Step E: Synthesis of (E)-3-(1-((tert-butylsulfinyl<sulfinyl>)imino)ethyl)-5-fluoropyridin-2-yl trifluoromethanesulfonate

Dissolve 5-fluoro-2-methoxy-3-pyridinecarbaldehyde (20.00 g, 69.7 mmol) and tert-butylsulfinamide (10.12 g, 83.6 mmol) in tetrahydrofuran (100 mL), and replace with nitrogen three times . Tetraisopropyl titanate (39.58 g, 139.4 mmol) was slowly added thereto, and stirred at 75 degrees Celsius for 2 hours. The reaction was stopped, after cooling to room temperature, saturated brine (100ml) was added and stirred vigorously for 20 minutes, then filtered, the filter cake was washed with ethyl acetate (100ml), and then extracted with ethyl acetate (100ml×3 times) and combined The obtained organic phase was dried with anhydrous sodium sulfate. The filtrate obtained by filtration was concentrated under reduced pressure. 22 g of colorless oily 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-ol was obtained, which was used directly in the next step without purification.

MS (ESI) M/Z: 391 [M+H ⁺ ].

Step F: Synthesis of 3-(1-((tert-butylsulfinyl<sulfinyl>)amino)ethyl)-5-fluoropyridin-2-yl trifluoromethanesulfonate

(E)-3-(1-((tert-butylsulfinyl<sulfinyl>)imino)ethyl)-5-fluoropyridin-2-yl trifluoromethanesulfonate (20.00 g, 51.3 mmol) was dissolved in dry tetrahydrofuran (200 mL), and after stirring at -78°C for 10 minutes, sodium borohydride (5.85 g, 153.9 mmol) was slowly added thereto in portions. Then react at -78 degrees Celsius for 1 hour. The reaction was stopped, and the reactant was added to ice water (150 mL) under vigorous stirring to quench the reaction. It was extracted with ethyl acetate (150 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The filtrate obtained by filtration was concentrated under reduced pressure. The remaining solid residue was separated by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1:1), and after concentration, 18 g of colorless oily 3-(1-((tert-butylsulfite) was obtained. Acyl<sulfinyl>)amino)ethyl)-5-fluoropyridin-2-yl trifluoromethanesulfonate.

MS (ESI) M/Z: 393 [M+H ⁺ ].

Step G: Synthesis of tert-butyl((2R)-4-(3-(1-((tert-butylsulfinyl)amino)ethyl)-5-fluoropyridin-2-yl)butyl- 3-yn-2-yl) carbamate

Add 3-(1-((tert-butylsulfinyl<sulfinyl>)amino)ethyl)-5-fluoropyridin-2-yl trifluoromethanesulfonate (2.00 g, 5.1 mmol), (R)-tert-butylbut-3-yn-2-yl carbamate (1.72 g, 10.2 mmol), cuprous iodide (0.19 g, 1.0 mmol), bistriphenylphosphine dichloride Palladium (0.70 g, 1.0 mmol) and N,N-diisopropylethylamine (2.59 g, 15.3 mol) were dissolved in dry N,N-dimethylformamide (10 mL). At 90 degrees Celsius, microwave reaction for 2 hours. After cooling to room temperature, saturated brine (50 mL) was added. It was extracted with ethyl acetate (50 ml×3 times), the obtained organic phases were combined and washed with saturated brine (50 ml×2 times), and then the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the solid residue obtained was separated by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1:1). After concentration, 1.80 g of black oily tert-butyl ((2R) -4-(3-(1-((tert-butylsulfinyl)amino)ethyl)-5-fluoropyridin-2-yl)butyl-3-yn-2-yl)carbamate .

MS (ESI) M/Z: 312 [M+H ⁺ -100].

Step H: Synthesis of tert-butyl((2R)-4-(3-(1-((tert-butylsulfinyl)amino)ethyl)-5-fluoropyrimidin-2-yl)butyl- 2-yl) carbamate

Add tert-butyl((2R)-4-(3-(1-((tert-butylsulfinyl)amino)ethyl)-5-fluoropyridin-2-yl)butyl-3-yne -2-yl) carbamate (1.80 g, 4.38 mmol) was dissolved in ethanol (30 ml), 20% palladium hydroxide on carbon (1.5 g) was added, and hydrogen was replaced three times. The reaction system was stirred at 35 degrees Celsius and 3 atmospheres of hydrogen for 30 hours. The reaction was stopped, the reactant was filtered, then washed with methanol (50 mL), and the resulting organic phases were combined and concentrated under reduced pressure. 1.70 g of light yellow oily tert-butyl ((2R)-4-(3-(1-((tert-butylsulfinyl)amino)ethyl)-5-fluoropyrimidin-2-yl) Butyl-2-yl) carbamate.

MS (ESI) M/Z: 416 [M+H ⁺ ].

Step I: Synthesis of tert-butyl((2R)-4-(3-(1-aminoethyl)-5-fluoropyrimidin-2-yl)butyl-2-yl)carbamate

The tert-butyl ((2R)-4-(3-(1-((tert-butylsulfinyl)amino)ethyl)-5-fluoropyrimidin-2-yl)butyl-2-yl ) Carbamate (1.70 g, 4.10 mmol) and iodine (0.21 g, 0.82 mmol) were dissolved in tetrahydrofuran (20 mL) and water (4 mL). The reaction system was stirred at 65 degrees Celsius for 6 hours. The reaction was quenched by adding saturated brine (30 mL), extracted with ethyl acetate (30 mL×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain 1.50 g of oily tert-butyl((2R)-4-(3-(1-aminoethyl)-5-fluoropyrimidin-2-yl)butyl-2-yl ) Carbamate.

MS (ESI) M/Z: 312 [M+H ⁺ ].

Intermediate 5: 1-(5-fluoro-2-methoxypyridin-3-yl)ethyl-1-amine

Step A: Synthesis of 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-ol

5-Fluoro-2-methoxy-3-pyridinecarbaldehyde (20.00 g, 129.0 mmol) was dissolved in dry tetrahydrofuran (200 mL) and replaced with nitrogen three times. After stirring for 10 minutes at -78 degrees Celsius, methylmagnesium bromide (3 mol/L, 129 mL, 387.0 mmol) was added thereto. The reaction was then carried out at -78 degrees Celsius for 2 hours, then the reaction was gradually warmed to room temperature and stirred overnight. The reaction was quenched by adding ice water (200 mL) with vigorous stirring. It was extracted with ethyl acetate (200 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The filtrate obtained by filtration was concentrated under reduced pressure. 20.00 g of 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-ol was obtained as a colorless oil, which was used directly in the next step without purification.

MS (ESI) M/Z: 172 [M+H ⁺ ].

Step B: Synthesis of 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-one

Dissolve 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-ol (20.00 g, 117.0 mmol) and activated manganese dioxide (101.75 g, 1.17 mol) in chloroform (150 Ml), stirring at 95 degrees Celsius for 24 hours. The reaction was filtered while hot. It was washed with chloroform (200 ml), and the obtained organic phases were combined and concentrated under reduced pressure. 18.50 g of light yellow oily 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-one was obtained, which was used directly in the next step without purification.

MS (ESI) M/Z: 170 [M+H ⁺ ].

Step C: Synthesis of 1-(5-fluoro-2-methoxypyridin-3-yl)ethyl-1-amine

Dissolve 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-one (18.00 g, 106.5 mmol) and ammonium acetate (81 g, 49.3 mmol) in methanol (180 ml ), stirring at 70 degrees Celsius for 2 hours, then cooling to room temperature, adding sodium cyanoborohydride (25.20 g, 426.0 mmol), and stirring at 70 degrees Celsius for 8 hours. After the reaction solution was cooled to room temperature, the reaction was concentrated under reduced pressure. Add to 200ml water, extract with ethyl acetate (200ml×3 times), then adjust the pH of the aqueous phase to 10 with sodium hydroxide solid, then extract with ethyl acetate (200ml×3 times), combine the second The extracted organic phase was dried and concentrated to obtain 11 grams of target product.

MS (ESI) M/Z: 171 [M+H ⁺ ].

Intermediate 6: (5-Fluoro-2-methoxypyridin-3-yl)methylamine

Synthesis scheme

Step A: Synthesis of (5-fluoro-2-methoxypyridin-3-yl)methanol

Take a 500 ml clean three-necked flask and add NaBH ₄ (6.02 g, 157 mmol) and tetrahydrofuran (150 ml) into the 500 ml three-necked flask. Dissolve 5-fluoro-2-methoxynicotinaldehyde (16.00 g, 103 mmol) in tetrahydrofuran (70 mL) and slowly drop it into the reaction solution with a constant pressure dropping funnel. After the addition is complete, react at room temperature for 2 hours. Add 1N hydrochloric acid to quench the reaction, and adjust the pH to about 5. Then add saturated saline (50 ml) and let stand for phase separation. The organic phase was washed with saturated brine (100 ml×2 times), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain 16.02 g of white solid (5-fluoro-2-methoxypyridin-3-yl)methanol .

MS (ESI) M/Z: 158 [M+H ⁺ ].

Step B: Synthesis of 3-(chloromethyl)-5-fluoro-2-methoxypyridine

Take a 250 ml single-neck bottle, dissolve (5-fluoro-2-methoxypyridin-3-yl)methanol (16.02 g, 102 mmol) in dichloromethane (100 ml), and slowly add dichloromethane dropwise at room temperature Sulfoxide (25 mL), stir overnight after the addition is complete. The reaction solution was concentrated to dryness to obtain the crude solid-liquid mixture 3-(chloromethyl)-5-fluoro-2-methoxypyridine (20.18 g).

MS (ESI) M/Z: 176 [M+H ⁺ ].

Step C: Synthesis of (5-fluoro-2-methoxypyridin-3-yl)methylamine

Take 1000 ml mono vial, 3- (chloromethyl) -5-fluoro-2-methoxypyridine (20.18 g) of crude product was dissolved in 500 ml of methanol at room temperature was slowly added dropwise 7mol / L of NH ₃ / MeOH Solution (200 mL). After the addition is complete, react for 3d. The reaction solution was concentrated to dryness, and the solid obtained was separated by silica gel column chromatography (eluent dichloromethane/methanol=9:1). After concentration, 10.00 g of brown solid (5-fluoro-2-methoxypyridine-3-基)methylamine.

MS (ESI) M/Z: 157 [M+H ⁺ ].

Example 1: (1 ³ E,1 ⁴ E,2R,5S)-3 ⁵ -fluoro-2,5-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-4-oxa-7 -Aza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclosinfan-8-one

Step A: Synthesis of 5-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde

Dissolve 5-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine (700 mg, 3.3 mmol) in N,N-dimethylformamide (5 mL), add Phosphorus oxychloride (1.0 ml), stirred overnight at room temperature, stop the reaction, add saturated sodium carbonate solution (30 ml), extract with ethyl acetate (100 ml), and use saturated sodium chloride solution (100 ml×3 Times) washing, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 500 mg of crude product 5-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde .

MS (ESI) M/Z: 245 [M+H ⁺ ].

Step B: Synthesis of tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-formyl-6,7-dihydro-5H-pyrazolo[1, 5-a]pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)phenoxy)propyl)carbamate

Combine 5-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (600 mg, 2.5 mmol) and tert-butyl((S)-2-( 2-((R)-1-aminoethyl)-4-fluorophenoxy)propyl)carbamate (925 mg, 3.0 mmol) dissolved in N,N-dimethylformamide (15 mL ), add potassium carbonate (682 mg, 5.0 mmol), heat to 110 degrees Celsius to react for 1 hour, stop the reaction, add ethyl acetate (80 ml) to dilute, wash with saturated sodium chloride solution (50 ml x 3 times), organic The phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated with a silica gel preparation plate (developing solvent: dichloromethane: methanol = 10:1, eluent: ethyl acetate), and concentrated to obtain 100 mg of tert-butyl Base ((S)-2-(4-fluoro-2-((R)-1-(3-formyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[ 2,3-d]pyrimidin-5-yl)ethyl)phenoxy)propyl)carbamate.

MS(ESI) M/Z: 484[M+1].

Step C: Synthesis of 5-((R)-1-(2-(((S)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxo)-5-fluorophenyl )Ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid

The tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-formyl-6,7-dihydro-5H-pyrazolo[1,5-a ]Pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)phenoxy)propyl)carbamate (100mg, 0.2mmol) dissolved in dimethylsulfoxide (6ml), Add dropwise an aqueous solution (1 ml) of sodium dihydrogen phosphate (300 mg, 2.1 mmol) at room temperature, and then add dropwise an aqueous solution (1 ml) of sodium chlorite (380 mg, 4.2 mmol), heat to 35 degrees Celsius and stir. Stop the reaction overnight, add ethyl acetate (50 ml) to dilute, wash with saturated sodium chloride solution (50 ml x 3 times), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 110 mg of crude product 5 -((R)-1-(2-(((S)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxo)-5-fluorophenyl)ethyl)- 6,7-Dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid.

MS(ESI)M/Z:500[M+1].

Step D: Synthesis of 5-((R)-1-(2-(((S)-1-aminopropan-2-yl)oxo)-5-fluorophenyl)ethyl)-6,7-di Hydrogen-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid

Put 5-((R)-1-(2-(((S)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxo)-5-fluorophenyl)ethyl )-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid (110 mg, 0.2 mmol) dissolved in dichloromethane ( 6 ml), 4 moles per liter of hydrochloric acid/1,4-dioxane solution (2 ml) was added, and the mixture was stirred at room temperature for 2 hours. LCMS detected that the reaction was complete and evaporated to dryness under reduced pressure to obtain 120 mg of crude product 5-( (R)-1-(2-(((S)-1-Aminopropan-2-yl)oxo)-5-fluorophenyl)ethyl)-6,7-dihydro-5H-pyrazolo [1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid.

MS(ESI)M/Z:400[M+1].

Step E: Synthesis of (1 ³ E,1 ⁴ E,2R,5S)-3 ⁵ -fluoro-2,5-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-4-oxa-7 -Aza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclosinfan-8-one

Add 5-((R)-1-(2-(((S)-1-aminopropan-2-yl)oxo)-5-fluorophenyl)ethyl)-6,7-dihydro-5H -Pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid (120mg, 0.3mmol) dissolved in N,N-dimethylformamide (3ml)/ Dichloromethane (4 mL), ethyl diisopropylamine (0.3 mL) was added, followed by pentafluorophenyl diphenyl phosphonate (150 mg, 0.4 mmol), stirred at room temperature for 2 hours, and acetic acid was added Ethyl acetate (50 mL) was diluted, washed with saturated sodium chloride solution (50 mL x 1 time), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated with a silica gel preparation plate (developer: dichloromethane: Methanol=20:1, eluent: ethyl acetate), after concentration, 35.0 mg of product (1 ³ E,1 ⁴ E,2R,5S)-3 ⁵ -fluoro-2,5-dimethyl-1 ⁶ ,1 ⁷ -Dihydro-1 ⁵ H-4-oxa-7-aza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3 (1,2)-Benzocyclosimphan-8-one.

MS (ESI) M/Z: 382 [M+1].

¹ H NMR (400MHz, DMSO-d ₆ , ppm): δ10.36 (dd, J ₁ =6.8Hz, J ₂ =2.8Hz, 1H), 8.33(t, J = 1.6Hz, 1H), 7.92(s ,1H),7.38(dd,J ₁ =9.6Hz,J ₂ =2.8Hz,1H),7.05-7.00(m,2H),5.53(dd,J ₁ =7.2Hz,J ₂ =1.6Hz,1H) ,4.62(dd,J ₁ ＝10.8Hz,J ₂ ＝6.8Hz,1H), 4.30(dd,J ₁ ＝16.8Hz,J ₂ ＝7.2Hz,1H),4.06(dd,J ₁ ＝17.2Hz,J ₂ =7.6Hz,1H), 3.88–3.82(m,1H), 3.21–3.11(m,3H), 1.58(d,J=7.2Hz,3H), 1.44(d,J=6.0Hz,3H).

Example 2: (1 ³ E,1 ⁴ E,2R,5S)-3 ⁵ -fluoro-2,5-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -tetrahydro-4-oxa -7-Aza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(1,2)-benzocyclosinfan-8-one

Step A: Synthesis of 5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde

Dissolve 5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine (420 mg, 1.8 mmol) in N,N-dimethylformamide (5 mL), add Phosphorus oxychloride (0.8 ml), stirred overnight at room temperature, stop the reaction, add saturated sodium carbonate solution (30 ml), extract with ethyl acetate (100 ml), and use saturated sodium chloride solution (100 ml x 3 times) for the organic phase ) Wash, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 500 mg of crude product 5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde.

MS (ESI) M/Z: 259 [M+1].

Step B: Synthesis of tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-formyl-7,8-dihydropyrazolo[1,5-a ]Pyrido[2,3-d]pyrimidine-5(6H)-yl)ethyl)phenoxy)propyl)carbamate

Combine 5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (500 mg, 1.9 mmol) and tert-butyl((S)-2-( 2-((R)-1-Aminoethyl)-4-fluorophenoxy)propyl)carbamate (560mg, 1.8mmol) dissolved in N,N-dimethylformamide (10ml ), add potassium carbonate (535 mg, 3.9 mmol), heat to 110 degrees Celsius to react for 1 hour, stop the reaction, add ethyl acetate (60 ml) to dilute, wash with saturated sodium chloride solution (50 ml x 3 times), organic The phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated with a silica gel preparation plate (developing solvent: dichloromethane: methanol = 10:1, eluent: ethyl acetate), and concentrated to obtain 100 mg of tert-butyl Base ((S)-2-(4-fluoro-2-((R)-1-(3-formyl-7,8-dihydropyrazolo[1,5-a]pyrido[2,3 -d] Pyrimidine-5(6H)-yl)ethyl)phenoxy)propyl)carbamate.

MS (ESI) M/Z: 498 [M+1].

Step C: Synthesis of 5-((R)-1-(2-(((S)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxo)-5-fluorophenyl )Ethyl)-5,6,7,8-tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-carboxylic acid

The tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-formyl-7,8-dihydropyrazolo[1,5-a]pyrido [2,3-d]pyrimidine-5(6H)-yl)ethyl)phenoxy)propyl)carbamate (100mg, 0.2mmol) dissolved in dimethyl sulfoxide (8ml) at room temperature Add dropwise an aqueous solution (1 ml) of sodium dihydrogen phosphate (460 mg, 3.2 mmol), then dropwise add an aqueous solution (1 ml) of sodium chlorite (580 mg, 6.4 mmol), heat to 35 degrees Celsius and stir overnight , The reaction was stopped, diluted with ethyl acetate (60 ml), washed with saturated sodium chloride solution (50 ml x 3 times), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 120 mg of crude product 5- ((R)-1-(2-(((S)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxo)-5-fluorophenyl)ethyl)-5 ,6,7,8-Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-carboxylic acid.

MS(ESI)M/Z:514[M+1].

Step D: Synthesis of 5-((R)-1-(2-(((S)-1-aminopropan-2-yl)oxo)-5-fluorophenyl)ethyl)-5,6,7 ,8-Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-carboxylic acid

Put 5-((R)-1-(2-(((S)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxo)-5-fluorophenyl)ethyl )-5,6,7,8-tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-carboxylic acid (120 mg, 0.2 mmol) dissolved in dichloromethane (3 ml), add 4 moles per liter of hydrochloric acid/1,4-dioxane solution (1 ml), stir at room temperature for 2 hours, LCMS detects that the reaction is complete, and evaporate to dryness under reduced pressure to obtain 110 mg of crude product 5- ((R)-1-(2-(((S)-1-Aminopropan-2-yl)oxo)-5-fluorophenyl)ethyl)-5,6,7,8-tetrahydropyridine Azolo[1,5-a]pyrido[2,3-d]pyrimidine-3-carboxylic acid.

MS(ESI) M/Z: 414[M+1].

Step E: Synthesis of (1 ³ E,1 ⁴ E,2R,5S)-3 ⁵ -fluoro-2,5-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -tetrahydro-4-oxa -7-Aza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(1,2)-benzocyclosinfan-8-one

Add 5-((R)-1-(2-(((S)-1-aminopropan-2-yl)oxo)-5-fluorophenyl)ethyl)-5,6,7,8- Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-carboxylic acid (110 mg, 0.2 mmol) dissolved in N,N-dimethylformamide (2 mL) /Dichloromethane (3ml), add ethyldiisopropylamine (0.5ml), then add pentafluorophenyl diphenylphosphonate (135mg, 0.3mmol), stir overnight at room temperature, add acetic acid Ethyl acetate (80 mL) was diluted, washed with saturated sodium chloride solution (60 mL x 1 time), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated with silica gel preparation plate (developing solvent: petroleum ether: acetic acid Ethyl ester=2:3, eluent: ethyl acetate), after concentration, 32.0 mg of product (1 ³ E,1 ⁴ E,2R,5S)-3 ⁵ -fluoro-2,5-dimethyl-1 is obtained ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -Tetrahydro-4-oxa-7-aza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d] Pyrimidine-3(1,2)-benzocyclosimphan-8-one.

MS (ESI) M/Z: 396 [M+1].

¹ H NMR (400MHz, DMSO-d ₆ , ppm): δ9.51 (dd, J ₁ ＝7.2Hz, J ₂ ＝2.8Hz, 1H), 8.50(s, 1H), 7.99(s, 1H), 7.14 (dd,J ₁ =9.2Hz,J ₂ =2.8Hz,1H),7.05(q,J=4.8Hz,1H),6.99(dd,J ₁ =8.4Hz,J ₂ =2.8Hz,1H),6.02 (dd, J ₁ =14.0Hz, J ₂ ＝6.8Hz, 1H), 4.56 (dd, J ₁ =10.8Hz, J ₂ ＝6.8Hz, 1H), 4.14(dd, J ₁ ＝8.0Hz, J ₂ ＝ 4.8Hz, 1H), 3.90--3.84(m,1H), 3.80--3.73(m,1H), 3.20--3.14(m,1H), 2.85--2.68(m,2H), 2.07--1.90(m,2H) ,1.51(d,J=7.2Hz,3H),1.46(d,J=6.0Hz,3H).

Example 3: (1 ³ E,1 ⁴ E,2R,5S)-35-fluoro-2,5-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-4-oxa-7, 9-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclononan-8-one

Step A: Synthesis of 5-chloro-6-(2-chloroethyl)-3-nitropyrazolo[1,5-a]pyrimidine

Dissolve 5-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine (700 mg, 3.3 mmol) in concentrated sulfuric acid (4 mL), cool to zero degrees Celsius, and add nitric acid dropwise (2ml), after the addition is complete, remove the ice bath, stir at room temperature for 3 hours, stop the reaction, pour into ice water (50ml) and stir, more yellow solids precipitate out, filter, and dry the filter cake to obtain 700 Milligrams of product 5-chloro-6-(2-chloroethyl)-3-nitropyrazolo[1,5-a]pyrimidine.

MS(ESI)M/Z:261[M+1].

Step B: Synthesis of tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-nitro-6,7-dihydro-5H-pyrazolo[1, 5-a]pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)phenoxy)propyl)carbamate

Combine 5-chloro-6-(2-chloroethyl)-3-nitropyrazolo[1,5-a]pyrimidine (700 mg, 2.7 mmol) and tert-butyl ((S)-2- (2-((R)-1-aminoethyl)-4-fluorophenoxy)propyl)carbamate (837 mg, 2.7 mmol) dissolved in N,N-dimethylformamide (15 Ml), potassium carbonate (740 mg, 5.4 mmol) was added, heated to 110 degrees Celsius and reacted for 1 hour, the reaction was stopped, diluted with ethyl acetate (100 ml), washed with saturated sodium chloride solution (80 ml x 3 times), The organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated with a silica gel preparation plate (developing solvent: petroleum ether: ethyl acetate=1:1, eluent: ethyl acetate), and after concentration, 160 mg of tertiary -Butyl((S)-2-(4-fluoro-2-((R)-1-(3-nitro-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrole And [2,3-d]pyrimidin-5-yl)ethyl)phenoxy)propyl)carbamate.

MS(ESI)M/Z:501[M+1].

Step C: Synthesis of tert-butyl((S)-2-(2-((R)-1-(3-amino-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrole And [2,3-d]pyrimidin-5-yl)ethyl)-4-fluorophenoxy)propyl)carbamate

The tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-nitro-6,7-dihydro-5H-pyrazolo[1,5-a ]Pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)phenoxy)propyl)carbamate (125 mg, 0.2 mmol) dissolved in tetrahydrofuran (8 mL)/ethanol (4 mL) , Add reduced iron powder (480 mg, 8.6 mmol) and ammonium chloride (480 mg, 9.0 mmol) in water (3 ml), heat to 80 degrees Celsius and react for 2 hours. LCMS detects that the reaction of the raw materials is complete, and the reaction is stopped. The solvent was removed under pressure, diluted with ethyl acetate (80 ml), washed with saturated sodium chloride solution (50 ml x 2 times), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 98 mg of crude product tert- Butyl((S)-2-(2-((R)-1-(3-amino-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3- d]Pyrimidine-5-yl)ethyl)-4-fluorophenoxy)propyl)carbamate.

MS (ESI) M/Z: 471 [M+1].

Step D: Synthesis of tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-((phenoxycarbonyl)amino)-6,7-dihydro-5H- Pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)phenoxy)propyl)carbamate

The tert-butyl ((S)-2-(2-((R)-1-(3-amino-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2 ,3-d]pyrimidin-5-yl)ethyl)-4-fluorophenoxy)propyl)carbamate phenyl chloroformate (40 mg, 0.26 mmol) was dissolved in dichloromethane (1 ml), Add ethyl diisopropylamine (0.2 ml) dropwise, and react for 30 minutes in an ice bath. LCMS detects that the raw material has reacted completely. The reaction is stopped. It is diluted with ethyl acetate (60 ml) and diluted with saturated hydrogen carbonate. Washed with sodium solution (50 ml x 2 times) saturated sodium chloride solution (50 ml x 1 time), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 100 mg of crude product tert-butyl ((S)- 2-(4-Fluoro-2-((R)-1-(3-((phenoxycarbonyl)amino)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[ 2,3-d]pyrimidin-5-yl)ethyl)phenoxy)propyl)carbamate.

MS (ESI) M/Z: 591 [M+1].

Step E: Synthesis of phenyl(5-((R)-1-(2-(((S)-1-aminopropyl-2-yl)oxy)-5-fluorophenyl)ethyl)-6, 7-Dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-3-yl)carbamate

The tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-((phenoxycarbonyl)amino)-6,7-dihydro-5H-pyrazolo [1,5-a]pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)phenoxy)propyl)carbamate (100 mg, 0.17 mmol) dissolved in dichloromethane (5 Ml), 4 moles per liter of hydrochloric acid/1,4-dioxane solution (1.5 ml) was added, stirred at room temperature for 2 hours, LCMS detected that the reaction was complete, and evaporated to dryness under reduced pressure to obtain 90 mg of crude product (5-( (R)-1-(2-(((S)-1-Aminopropyl-2-yl)oxy)-5-fluorophenyl)ethyl)-6,7-dihydro-5H-pyrazolo [1,5-a]pyrrolo[2,3-d]pyrimidin-3-yl)carbamate.

MS (ESI) M/Z: 491 [M+1].

Step F: Synthesis of (1 ³ E, 1 ⁴ E, 2R, 5S)-35-fluoro-2,5-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-4-oxa-7, 9-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclononan-8-one

Add (5-((R)-1-(2-(((S)-1-aminopropyl-2-yl)oxy)-5-fluorophenyl)ethyl)-6,7-dihydro- 5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-3-yl)carbamate (90 mg, 0.18 mmol) was dissolved in acetonitrile (20 mL), and ethyl Diisopropylamine (0.3 mL), heated to 45 degrees Celsius and stirred overnight, LCMS detected the complete reaction of the raw materials, concentrated under reduced pressure, diluted with ethyl acetate (60 mL), washed with saturated sodium chloride solution (60 mL x 1 time) , The organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated with a silica gel preparation plate (developing solvent: ethyl acetate: methanol = 20:1, eluent: ethyl acetate), and concentrated to obtain 6.0 mg of product (1 ³ E,1 ⁴ E,2R,5S)-35-fluoro-2,5-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-4-oxa-7,9-diaza Hetero-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclononane-8-one.

MS (ESI) M/Z: 397 [M+1].

¹ H NMR (400MHz, CDCl ₃ , ppm): δ8.67 (bs, 1H), 7.80 (s, 1H), 7.46 (s, 1H), 7.32 (dd, J ₁ ＝8.8Hz, J ₂ ＝2.8Hz ,1H),6.94–6.89(m,1H),6.83(dd,J ₁ =9.2Hz,J ₂ =4.4Hz,1H),6.41(bs,1H),6.00(dd,J ₁ =14.0Hz,J ₂ = 7.2Hz, 1H), 4.53-4.50 (m, 1H), 4.02–3.90 (m, 2H), 3.76 (dd, J ₁ =14.0Hz, J ₂ = 2.0Hz, 1H), 3.47 (dd, J ₁ = 14.0Hz, J ₂ = 6.8Hz, 1H), 3.11-3.03 (m, 2H), 1.58 (d, J = 7.2Hz, 3H), 1.44 (d, J = 6.4Hz, 3H).

Example 4: (1 ³ E,1 ⁴ E,2R,5S)-3 ⁵ -fluoro-2,5-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -tetrahydro-4-oxa -7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(1,2)-benzocyclononfan- 8-ketone

Step A: Synthesis of 5-chloro-6-(3-chloropropyl)-3-nitropyrazolo[1,5-a]pyrimidine

Dissolve 5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine (700 mg, 3.1 mmol) in concentrated sulfuric acid (5 mL), cool to zero degrees Celsius, and add nitric acid dropwise (1.5 ml). After the addition is complete, remove the ice bath, stir at room temperature for 3 hours, stop the reaction, pour into ice water (50 ml) and stir. More light yellow solids precipitate out, filter, and dry the filter cake to obtain 700 mg of product 5-chloro-6-(3-chloropropyl)-3-nitropyrazolo[1,5-a]pyrimidine.

MS(ESI) M/Z: 275[M+1].

Step B: Synthesis of tert-butyl((S)-2-(4-fluoro-2-((R)-1-(3-nitro-7,8-dihydropyrazolo[1,5-a ]Pyrido[2,3-d]pyrimidine-5(6H)-yl)ethyl)phenoxy)propyl)carbamate

Combine 5-chloro-6-(3-chloropropyl)-3-nitropyrazolo[1,5-a]pyrimidine (600 mg, 2.2 mmol) and tert-butyl ((S)-2- (2-((R)-1-aminoethyl)-4-fluorophenoxy)propyl)carbamate (680 mg, 2.2 mmol) dissolved in N,N-dimethylformamide (16 Ml), potassium carbonate (602 mg, 4.4 mmol) was added, heated to 110 degrees Celsius and reacted for 1 hour, the reaction was stopped, diluted with ethyl acetate (100 ml), washed with saturated sodium chloride solution (100 ml x 3 times), The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1). After concentration, 600 mg of tert-butyl((S)-2-( 4-Fluoro-2-((R)-1-(3-nitro-7,8-dihydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-5(6H) -Base) ethyl) phenoxy) propyl) carbamate.

MS(ESI) M/Z: 515[M+1].

Step C: Synthesis of tert-butyl((S)-2-(2-((R)-1-(3-amino-7,8-dihydropyrazolo[1,5-a]pyrido[2 ,3-d)pyrimidine-5(6H)-yl)ethyl)-4-fluorophenoxy)propyl)carbamate

The tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-nitro-7,8-dihydropyrazolo[1,5-a]pyrido [2,3-d]pyrimidine-5(6H)-yl)ethyl)phenoxy)propyl)carbamate (300mg, 0.6mmol) dissolved in tetrahydrofuran (8ml)/ethanol (4ml) , Add reduced iron powder (1.0 g, 17.9 mmol) and an aqueous solution (3 ml) of ammonium chloride (1.0 g, 18.7 mmol), heat to 80 degrees Celsius and react for 2 hours. LCMS detects that the reaction of the raw materials is complete and stops the reaction. The solvent was removed by pressure, diluted with ethyl acetate (60 ml), washed with saturated sodium chloride solution (50 ml x 2 times), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 250 mg of crude product tert- Butyl((S)-2-(2-((R)-1-(3-amino-7,8-dihydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine -5(6H)-yl)ethyl)-4-fluorophenoxy)propyl)carbamate.

MS(ESI)M/Z:485[M+1].

Step D: Synthesis of tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-((phenoxycarbonyl)amino)-7,8-dihydropyrazolo) [1,5-a]pyrido[2,3-d]pyrimidino-5(6H)-yl)ethyl)phenoxy)propyl)carbamate

The tert-butyl ((S)-2-(2-((R)-1-(3-amino-7,8-dihydropyrazolo[1,5-a]pyrido[2,3- d]Pyrimidine-5(6H)-yl)ethyl)-4-fluorophenoxy)propyl)carbamate (250 mg, 0.52 mmol) was dissolved in dichloromethane (5 ml), and cooled to At 0 degrees Celsius, dissolve phenyl chloroformate (106 mg, 0.68 mmol) in dichloromethane (1 mL), add dropwise to the above solution, then add ethyl diisopropylamine (0.3 mL), and react under ice bath. After 30 minutes, LCMS detected that the reaction of the raw materials was complete. The reaction was stopped, and ethyl acetate (50 ml) was added to dilute, washed with saturated sodium bicarbonate solution (50 ml x 2 times) and saturated sodium chloride solution (50 ml x 1 time), and the organic phase was used Dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 280 mg of crude product tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-((phenoxycarbonyl) )Amino)-7,8-dihydropyrazolo[1,5-a]pyrido[2,3-d]pyrimido-5(6H)-yl)ethyl)phenoxy)propyl)aminomethyl Acid ester.

MS(ESI)M/Z:605[M+1].

Step E: Synthesis of phenyl(5-((R)-1-(2-(((S)-1-aminopropyl-2-yl)oxy)-5-fluorophenyl)ethyl)-5, 6,7,8-Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3-yl)carbamate

The tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-((phenoxycarbonyl)amino)-7,8-dihydropyrazolo[1, 5-a]pyrido[2,3-d]pyrimido-5(6H)-yl)ethyl)phenoxy)propyl)carbamate (280 mg, 0.46 mmol) dissolved in dichloromethane ( 5 ml), add 4 moles per liter of hydrochloric acid/1,4-dioxane solution (1.0 ml), stir at room temperature for 2 hours, LCMS detects that the reaction is complete, and evaporate to dryness under reduced pressure to obtain 260 mg of crude product phenyl ( 5-((R)-1-(2-(((S)-1-aminopropyl-2-yl)oxy)-5-fluorophenyl)ethyl)-5,6,7,8-tetra Hydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3-yl)carbamate.

MS(ESI)M/Z:505[M+1].

Step F: Synthesis of (1 ³ E,1 ⁴ E,2R,5S)-3 ⁵ -fluoro-2,5-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -tetrahydro-4-oxa -7,9-Diaza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(1,2)-benzocyclononfan- 8-ketone

Phenyl (5-((R)-1-(2-(((S)-1-aminopropyl-2-yl)oxy)-5-fluorophenyl)ethyl)-5,6,7 ,8-Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3-yl)carbamate (260 mg, 0.52 mmol) was dissolved in acetonitrile (20 mL), Add ethyl diisopropylamine (0.3 mL), heat to 45 degrees Celsius and stir overnight. LCMS detects the complete reaction of the raw materials, concentrates under reduced pressure, adds ethyl acetate (60 mL) and dilutes with saturated sodium chloride solution (60 mL x 1 The organic phase was washed with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated with a silica gel preparation plate (developing solvent: ethyl acetate: methanol = 10:1), and concentrated to obtain 12.0 mg of product (1 ³ E, ^{1 4 E, 2R, 5S)} -3 5 - ^{fluoro-2,5-dimethyl--15,} ^16, ^17, 1 ⁸ - tetrahydro-4-oxa-7,9-diaza - 1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(1,2)-benzocyclononane-8-one.

MS (ESI) M/Z: 411 [M+1].

¹ H NMR (400MHz, CDCl ₃ , ppm): δ7.91 (s, 1H), 7.61 (t, J = 5.6 Hz, 1H), 7.52 (s, 1H), 6.94-6.89 (m, 3H), 6.48 (dd,J ₁ = 14.4Hz, J ₂ = 7.2Hz, 1H), 6.01(s,1H), 4.52-4.48(m,1H), 3.66–3.50(m,4H), 2.75(t,J=6.0 Hz, 2H), 2.09-1.94 (m, 2H), 1.51 (d, J = 7.6 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H).

Example 5: (1 ³ E,1 ⁴ E,2R,6R)-3 ⁵ -fluoro-6-(hydroxymethyl)-2-methyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-4 -Oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzo ring Renfan-8-one

Step A: Synthesis of tert-butyl(1-(2-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)-3- Hydroxypropyl-2-yl) carbamate

Add (R)-N-((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)-2-methylpropane-2-sulfenamide (1.50 g, 5.7 mmol), N -BOC-serinol (3.30 g, 17.1 mmol) and triphenylphosphorus (4.60 g, 17.1 mmol) were dissolved in anhydrous methylene chloride (50 mL) solution, replaced with nitrogen three times, and cooled to 0 degrees Celsius. Subsequently, diisopropyl azodicarboxylate (3.60 g, 17.1 mmol) was added, stirred at 0 degrees Celsius for 5 minutes, and then reacted at room temperature overnight. Add dichloromethane (500 ml) to dilute, and wash with saturated sodium chloride solution (100 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4.0 g of crude product synthetic tert-butyl (1 -(2-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)-3-hydroxypropyl-2-yl)aminomethyl Acid ester.

MS (ESI) M/Z: 333 [M+H ⁺ ].

Step B: Synthesis of tert-butyl (1-(2-((R)-1-aminoethyl)-4-fluorophenoxy)-3-hydroxypropyl-2-yl)carbamate

Will synthesize tert-butyl (1-(2-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)-3-hydroxypropyl 2-yl) carbamate (3.30 g, 7.6 mmol) was dissolved in tetrahydrofuran (60 mL) and water (12 mL), and elemental iodine (0.39 g, 1.50 mmol) was slowly added in batches. After the addition is complete, react at 50 degrees Celsius for 4 hours. Add ethyl acetate to dilute (200), and wash with saturated brine (30 ml×3 times) for signs, and the organic phase is dried over anhydrous sodium sulfate. The filtrate obtained by filtration was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1:1). After concentration, 4.00 g of brown solid tert-butyl (1-( 2-((R)-1-aminoethyl)-4-fluorophenoxy)-3-hydroxypropyl-2-yl)carbamate.

MS (ESI) M/Z: 329 [M+H ⁺ ].

Step C: Synthesis of tert-butyl (1-(4-fluoro-2-((R)-1-(3-nitro-6,7-dihydro-5H-pyrazolo[1,5-a] Pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)phenoxy)-3-hydroxypropyl-2-yl)carbamate

The tert-butyl (1-(2-((R)-1-aminoethyl)-4-fluorophenoxy)-3-hydroxypropyl-2-yl) carbamate (2.0 g, 7.0 milli Mol) was dissolved in N,N-dimethylformamide (40 ml), potassium carbonate (4.80 g, 35.0 mmol) and 5-chloro-6-(2-chloroethyl)-3-nitropyrazole And [1,5-a]pyrimidine (1.83 g, 7.0 mmol) was added to the reaction system, and the reaction was stirred at 110 degrees Celsius for 1 hour. The reaction solution was diluted by adding ethyl acetate (100 mL). The organic phase was washed with saturated brine (20 ml×3 times), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the solid residue obtained was separated by silica gel column chromatography (eluent: ethyl acetate/ethanol/petroleum ether=3:1:3). After concentration, 1.50 g of black solid tert-butyl ( 1-(4-Fluoro-2-((R)-1-(3-nitro-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d] Pyrimidine-5-yl)ethyl)phenoxy)-3-hydroxypropyl-2-yl)carbamate carbamate.

MS (ESI) M/Z: 517 [M+H ⁺ ].

Step D: Synthesis of tert-butyl(1-(2-((R)-1-(3-amino-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2, 3-d)pyrimidin-5-yl)ethyl)-4-fluorophenoxy)-3-hydroxypropyl-2-yl)carbamate

The tert-butyl(1-(4-fluoro-2-((R)-1-(3-nitro-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[ 2,3-d]pyrimidin-5-yl)ethyl)phenoxy)-3-hydroxypropyl-2-yl)carbamate (1.50 g, 2.9 mmol), iron powder (910 mg, 16.3 mmol) Mol) and ammonium chloride (93 mg, 1.7 mmol) were dissolved in ethanol (40 mL) and water (48 mL), replaced with nitrogen three times, and stirred at 100 degrees Celsius for 1.5 hours. After the reaction solution was cooled to room temperature, the filter residue was removed by filtration, and the solvent was removed by concentration under reduced pressure. The remaining solid residue was separated by silica gel column chromatography (eluent: methanol/dichloromethane=1:10). After concentration, 0.70 g of black solid tert-butyl (1-(2-((R)-1-(3-amino-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo [2,3-d]pyrimidin-5-yl)ethyl)-4-fluorophenoxy)-3-hydroxypropyl-2-yl)carbamate.

MS (ESI) M/Z: 487 [M+H ⁺ ].

Step E: Synthesis of tert-butyl (1-(4-fluoro-2-((R)-1-(3-((phenoxycarbonyl)amino)-6,7-dihydro-5H-pyrazolo[ 1,5-a]pyrrolo[2,3-d]pyrimidine-5-yl)ethyl)phenoxy)-3-hydroxypropyl-2-yl)carbamate

The tert-butyl(1-(2-((R)-1-(3-amino-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d ]Pyrimidin-5-yl)ethyl)-4-fluorophenoxy)-3-hydroxypropyl-2-yl)carbamate (600 mg, 1.23 mmol) and triethylamine (630 mg, 6.20 mmol) Mol) was dissolved in dry dichloromethane (10 ml), and after stirring for 1 minute at 0°C, phenyl chloroformate (155 mg, 1.00 mmol) was added thereto. The reaction was then carried out at room temperature for 1.5 hours. To the reaction mixture, dichloromethane (100 mL) was added, followed by saturated brine (20 mL×2 times). The organic phase was dried with anhydrous sodium sulfate. The organic phase obtained by filtration was concentrated under reduced pressure to obtain 745 mg of colorless liquid tert-butyl (1-(4-fluoro-2-((R)-1-(3-((phenoxycarbonyl)amino)- 6,7-Dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-5-yl)ethyl)phenoxy)-3-hydroxypropyl-2-yl ) Carbamate.

MS (ESI) M/Z: 607 [M+H ⁺ ].

Step F: Synthesis of phenyl(5-((1R)-1-(2-(2-amino-3-hydroxypropoxy)-5-fluorophenyl)ethyl)-6,7-dihydro-5H -Pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-3-yl)carbamate

The tert-butyl (1-(4-fluoro-2-((R)-1-(3-((phenoxycarbonyl)amino)-6,7-dihydro-5H-pyrazolo[1,5 -a]pyrrolo[2,3-d]pyrimidine-5-yl)ethyl)phenoxy)-3-hydroxypropyl-2-yl)carbamate (745 mg, 1.23 mmol) dissolved in two To methyl chloride (10 mL), 4 mol/L hydrogen chloride/1,4-dioxane solution (3 mL, 12 mmol) was added at room temperature, and the mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain 622 mg of colorless liquid phenyl (5-((1R)-1-(2-(2-amino-3-hydroxypropoxy)-5-fluorophenyl)ethyl)- 6,7-Dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-3-yl)carbamate.

MS (ESI) M/Z: 607 [M+H ⁺ ].

Step G: Synthesis of (1 ³ E,1 ⁴ E,2R,6R)-3 ⁵ -fluoro-6-(hydroxymethyl)-2-methyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-4 -Oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzo ring Renfan-8-one

Phenyl (5-((1R)-1-(2-(2-amino-3-hydroxypropoxy)-5-fluorophenyl)ethyl)-6,7-dihydro-5H-pyrazole And [1,5-a]pyrrolo[2,3-d]pyrimidin-3-yl)carbamate (622 mg, 1.23 mmol) was dissolved in acetonitrile (10 mL), and triethylamine was added at room temperature (1.0 g, 9.9 mmol), the reaction was heated at 45 degrees Celsius overnight. The reaction solution was concentrated under reduced pressure, and the remaining solid residue was separated by silica gel column chromatography (eluent: methanol/dichloromethane=1:10). After concentration, 200 mg of black solid was obtained, and 50 mg of solid was taken with acetonitrile ( 3ml) was dissolved until clear, and then purified by preparative high performance liquid chromatography (column: Welch Xtimate C18 30mm*150mm, 5um; mobile phase: water (containing 0.05% ammonia) and acetonitrile; flow rate: 30 ml/min; gradient : Within 9 minutes, acetonitrile increased from 40% to 95%; detection wavelength: 254nm) The product was collected and lyophilized to obtain 2.0 mg of white solid (1 ³ E, 1 ⁴ E, 2R, 6R)-3 ⁵ -fluoro- 6-(Hydroxymethyl)-2-methyl-1 ⁶ ,1 ⁷ -Dihydro-1 ⁵ H-4-oxa-7,9-diaza-1(5,3)-pyrazolo[ 1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclononane-8-one.

MS (ESI) M/Z: 413 [M+H ⁺ ].

¹ H NMR (400MHz, CD ₃ OD, ppm): δ 9.16 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.20 (dd, J ₁ ＝9.2, J ₂ ＝2.8Hz, 1H), 6.94-6.84(m, 1H), 6.27(q, J＝7.2Hz, 1H), 4.38(d, J＝8.0Hz, 1H), 3.91-3.84 (m, 3H), 3.66-3.61 (m, 1H), 3.49-3.43 (m, 1H), 2.94-2.82 (m, 3H), 1.52 (d, J=7.2 Hz, 3H).

Example 6: (2 ³ E,2 ⁴ E,3R)-4 ⁵ -fluoro-3-methyl-2 ⁶ ,2 ⁷ -dihydro-2 ⁵ H-5-oxa-2(3,5) -Pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-1(1,4)-imidazopentidine-4(1,2)-benzocyclohexane-12-one

Step A: Synthesis of (1 ⁴ R,2 ³ E,2 ⁴ E,3R)-4 ⁵ -fluoro-3-methyl-2 ⁶ ,2 ⁷ -dihydro-2 ⁵ H-5-oxa-2( 3,5)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-1(1,4)-imidazopentidine-4(1,2)-benzocyclohexane -12-ketone

Dissolve triphenylphosphorus (480 mg, 1.8 mmol) in anhydrous dichloromethane (5 mL) solution, replace with nitrogen three times, cool to 0 degrees Celsius, and then add diethyl azodicarboxylate (317 mg, 1.8 Millimoles), stirred at 0 degrees Celsius for 5 minutes, and then slowly added (1 ³ E,1 ⁴ E,2R,6R)-3 ⁵ -fluoro-6-(hydroxymethyl)-2-methyl-1 ⁶ ,1 ⁷ -Dihydro-1 ⁵ H-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine- 3(1,2)-benzocyclononane-8-one (150 mg, 0.36 mmol). After the addition is complete, react at room temperature overnight. Dichloromethane (50 mL) was added for dilution, and washed with saturated sodium chloride solution (50 mL), and the organic phase was dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the remaining solid residue was separated by silica gel column chromatography (eluent: methanol/dichloromethane=1:10). After concentration, the solid was dissolved in acetonitrile (3 ml) until it became clear, and then passed through a preparative high-performance liquid Purification by phase chromatography (Welch Xtimate C18 30mm*150mm, 5um; mobile phase: water (containing 0.05% ammonia) and acetonitrile; flow rate: 30 ml/min; gradient: within 10 minutes, acetonitrile rises from 35% to 95%; detection Wavelength: 254nm), the product was collected and lyophilized to obtain 3.0 mg of white solid (1 ⁴ R, 2 ³ E, 2 ⁴ E, 3R)-4 ⁵ -fluoro-3-methyl-2 ⁶ ,2 ⁷ -dihydro -2 ⁵ H-5-oxa-2(3,5)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-1(1,4)-imidazopentidine- 4(1,2)-Benzocyclohexane-12-one.

MS (ESI) M/Z: 395 [M+H ⁺ ].

¹ H NMR (400MHz, CD ₃ OD, ppm): δ 7.87 (s, 1H), 7.42 (s, 1H), 7.22-7.19 (m, 1H), 6.96-6.94 (m, 2H), 5.70 (q ,J=7.6Hz,1H),4.52(q,J=7.2Hz,1H),4.54–4.41(m,1H),4.29–4.21(m,3H),4.19–4.11(m,2H),3.80( d, J=9.2 Hz, 2H), 1.62 (d, J=7.2 Hz, 3H).

Example 7: (1 ³ E,1 ⁴ E,2R,5S)-2-(cyclopropylmethyl)-3 ⁵ -fluoro-5-methyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H -4-oxa-7-aza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclooctane Fan-8-one

Step A: Synthesis of 2-cyclopropyl-N-methoxy-N-methylacetamide

Dissolve 2-cyclopropylacetic acid (5.00 g, 50 mmol) in anhydrous dichloromethane solution (30 mL), and then react with N,N'-carbonyldiimidazole (8.91 g, 55 mmol) at room temperature After 1.5 hours, N,O-dimethylhydroxylamine hydrochloric acid (5.36 g, 55 mmol) was added, and after the addition was completed, it was replaced with nitrogen three times and reacted at room temperature overnight. Dichloromethane (150 ml) was added for dilution, and washed with dilute hydrochloric acid solution (1 mol/L, 50 ml), the aqueous phase was added with dichloromethane (50 ml×2 times), and the organic phase was dried over anhydrous sodium sulfate. Concentrated under reduced pressure to obtain 7.0 g of colorless liquid crude product 2-cyclopropyl-N-methoxy-N-methylacetamide. It is directly used in the next reaction without purification.

MS (ESI) M/Z: 144 [M+H ⁺ ].

Step B: Synthesis of 2-cyclopropyl-1-(5-fluoro-2-methoxyphenyl)ethane-1-one

Dissolve 2-bromo-4-fluoro-1-methoxybenzene (6.00 g, 29 mmol) in anhydrous tetrahydrofuran solution (50 mL), replace with nitrogen three times, and cool to -75 degrees Celsius, then add n-butyl Lithium (2.5 mol/L, 14 mL, 35 mmol), react at -75 degrees Celsius for 0.5 hours, then add 2-cyclopropyl-N-methoxy-N-methylacetamide (5.00 g, 35 mmol) Anhydrous tetrahydrofuran solution (10 ml) of tetrahydrofuran, after the addition, react at room temperature for 1 hour. Saturated ammonium chloride solution (30 mL) was added to quench the reaction, and ethyl acetate (150 mL × 2 times) was added for extraction, and the organic phase was dried with anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure. The remaining solid residue was separated by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1:10). After concentration, 3.30 g of black, colorless liquid 2-cyclopropyl-1-(5-fluoro-2-methoxyphenyl)ethane-1-one was obtained. It is directly used in the next reaction without purification.

MS (ESI) M/Z: 209 [M+H ⁺ ].

Step C: Synthesis of 2-cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethane-1-one

Dissolve 2-cyclopropyl-1-(5-fluoro-2-methoxyphenyl)ethane-1-one (3.30 g, 16 mmol) in anhydrous dichloromethane solution (50 mL), and nitrogen After three replacements, it was cooled to -75 degrees Celsius, and then boron trichloride (1 mol/L, 20 ml, 20 mmol) was added and reacted at -75 degrees Celsius for 2 hours. The reaction solution was slowly added to ice water (100 ml), and ethyl acetate (150 ml×2 times) was added for extraction, and the organic phase was dried with anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure. The remaining solid residue was separated by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1:10). After concentration, 2.50 g of white solid 2-cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethane-1-one was obtained.

MS (ESI) M/Z: 195 [M+H ⁺ ].

Step D: Synthesis of tert-butyl(S)-(2-(2-(2-cyclopropylacetyl)-4-fluorophenoxy)propyl)carbamate

Combine 2-cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethane-1-one (2.10 g, 11 mmol), tert-butyl(R)-(2-hydroxypropyl) Carbamate (3.80 g, 11 mmol) and triphenylphosphorus (10.0 g, 38 mmol) were dissolved in anhydrous dichloromethane solution (50 mL), replaced with nitrogen three times and cooled to 0 degrees Celsius, and then Diethyl azodicarboxylate (5.70 g, 32 mmol), after the addition, react at room temperature overnight. Dichloromethane (100 mL) was added to dilute and washed with saturated sodium chloride solution (50 mL), and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure. The remaining solid residue was separated by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1:5). After concentration, 1.60 g of white solid tert-butyl(S)-(2-(2-(2-cyclopropylacetyl)-4-fluorophenoxy)propyl)carbamate was obtained.

MS (ESI) M/Z: 252 [M+H ⁺ -Boc].

Step E: Synthesis of tert-butyl((2S)-2-(2-(1-amino-2-cyclopropylethyll)-4-fluorophenoxy)propyl)carbamate

Combine tert-butyl(S)-(2-(2-(2-cyclopropylacetyl)-4-fluorophenoxy)propyl)carbamate (1.60 g, 4.5 mmol) and ammonium acetate (3.50 g, 45 mmol) was dissolved in anhydrous methanol solution (30 ml) and added 1 drop of acetic acid as catalyst. After nitrogen replacement three times, the temperature was raised to 50 degrees Celsius, stirred for 3 hours, and then sodium cyanoborohydride (0.90 g) , 13.5 mmol), after the addition, react at 50 degrees Celsius for 3 hours. The reaction was concentrated by hydraulic pressure to remove the solvent, dissolved in water (30 mL), and extracted with ethyl acetate (100 mL×2 times), and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure. The remaining solid residue was separated by silica gel column chromatography (eluent: methanol/dichloromethane=1:10). After concentration, 1.60 g of white solid tert-butyl((2S)-2-(2-(1-amino-2-cyclopropylethyll)-4-fluorophenoxy)propyl)carbamate was obtained.

MS (ESI) M/Z: 353 [M+H ⁺ ].

Step F: Synthesis of tert-butyl ((2S)-2-(2-(2-cyclopropyl-1-(3-formyl-6,7-dihydro-5H-pyrazolo[1,5- a]pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)-4-fluorophenoxy)propyl)carbamate

Add tert-butyl((2S)-2-(2-(1-amino-2-cyclopropylethyll)-4-fluorophenoxy)propyl)carbamate (500mg, 1.4mmol ), 5-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (350 mg, 1.4 mmol) and potassium carbonate (600 mg, 4.2 mmol) In an anhydrous N,N-dimethylformamide solution (10 mL), after the addition is complete, replace with nitrogen three times and then raise the temperature to 120 degrees Celsius, and react for 1.5 hours. The reaction solution was diluted with ethyl acetate (50 mL), washed with saturated sodium chloride solution (50 mL×3 times), and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure. The remaining solid residue was separated by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1:1). After concentration, 400 mg of black solid tert-butyl((2S)-2-(2-(2-cyclopropyl-1-(3-formyl-6,7-dihydro-5H-pyrazolo[ 1,5-a]pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)-4-fluorophenoxy)propyl)carbamate.

MS (ESI) M/Z: 524 [M+H ⁺ ].

Step G: Synthesis of 5-(1-(2-(((S)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxo)-5-fluorophenyl)-2- Cyclopropylethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid

The tert-butyl((2S)-2-(2-(2-cyclopropyl-1-(3-formyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrole And [2,3-d]pyrimidin-5-yl)ethyl)-4-fluorophenoxy)propyl)carbamate (150 mg, 0.3 mmol) and sodium dihydrogen phosphate (343 mg, 2.9 mmol) Mol) was dissolved in anhydrous dimethyl sulfoxide (8 mL) and water (2 mL), replaced with nitrogen three times and cooled to 0 degrees Celsius, then sodium chlorite (520 mg, 5.8 mmol) was added in batches, and After the completion, the temperature was raised to 30 degrees Celsius after nitrogen replacement three times, and the reaction was carried out overnight. The reaction solution was diluted with ethyl acetate (50 mL), washed with saturated sodium chloride solution (20 mL×3 times), and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure. After concentration, 150 mg of yellow solid 5-(1-(2-(((S)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxo)-5-fluorophenyl was obtained )-2-Cyclopropylethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid. It is directly used in the next reaction without purification.

MS (ESI) M/Z: 540 [M+H ⁺ ].

Step H: Synthesis of 5-(1-(2-(((S)-1-aminopropan-2-yl)oxo)-5-fluorophenyl)-2-cyclopropylethyl)-6,7 -Dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid

Add 5-(1-(2-(((S)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxo)-5-fluorophenyl)-2-cyclopropyl Ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid (150 mg, 0.28 mmol) dissolved in anhydrous To the dichloromethane solution (6 mL), a dioxane solution of hydrogen chloride (4.0 mol/L, 1.5 mL, 6 mmol) was then added. After the addition, the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent. After concentration, 100 mg of yellow solid 5-(1-(2-(((S)-1-aminopropan-2-yl)oxo)-5-fluorophenyl)-2-cyclopropylethyl) was obtained. -6,7-Dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid. It is directly used in the next reaction without purification.

MS (ESI) M/Z: 440 [M+H ⁺ ].

Step I: Synthesis of (1 ³ E,1 ⁴ E,2R,5S)-2-(cyclopropylmethyl)-3 ⁵ -fluoro-5-methyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H -4-oxa-7-aza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclooctane Fan-8-one

Add 5-(1-(2-(((S)-1-aminopropan-2-yl)oxo)-5-fluorophenyl)-2-cyclopropylethyl)-6,7-dihydro -5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid (100 mg, 0.22 mmol) dissolved in anhydrous N,N-dimethylformamide ( 4ml) and dichloromethane solution (4ml), then pentafluorophenyl diphenyl phosphate (130mg, 0.34mmol) was added, after the addition, the reaction was carried out at room temperature overnight. The reaction solution was diluted with ethyl acetate (50 mL), washed with saturated sodium chloride solution (20 mL×3 times), and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure. The reaction solution was concentrated under reduced pressure to remove the solvent. The remaining solid residue was separated by silica gel column chromatography (eluent: methanol/dichloromethane=1:1). After concentration, the solid was dissolved in acetonitrile (3 ml) until it became clear, and then purified by preparative high performance liquid chromatography (column: Welch Xtimate C18 30mm*150mm, 5um; mobile phase: water (containing 0.05% ammonia) and acetonitrile; flow rate: 30 ml/min; gradient: within 8 minutes, acetonitrile rose from 30% to 70%; detection wavelength: 254nm), the product was collected and lyophilized to obtain 2.1 mg of white solid (1 ³ E, 1 ⁴ E, 2R, 5S) )-2-(Cyclopropylmethyl)-3 ⁵ -fluoro-5-methyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-4-oxa-7-aza-1(5,3 )-Pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclosinphen-8-one.

MS (ESI) M/Z: 422 [M+H ⁺ ].

¹ H NMR (400MHz, CD ₃ OD, ppm): δ8.07 (s, 1H), 7.97 (s, 1H), 7.19 (dd, J ₁ =9.2, J ₂ = 3.2Hz, 1H), 7.00 (dd ,J ₁ =9.2,J ₂ =4.8Hz,1H),7.01-6.91(m,1H),5.72(d,J=7.2Hz,1H), 4.66(q,J=6.4Hz,1H), 4.28- 4.15(m,2H),4.02-3.95(m,1H), 3.34(d,J=2.8Hz,1H),3.21(d,J=6.4Hz,2H),2.11-1.84(m,2H),1.51 (d,J=7.2Hz,3H),1.31-1.23(m,1H),0.62-0.54(m,1H),0.50-0.43(m,1H),0.40-0.34(m,1H),0.22-0.15 (m,1H).

Example 8: (1 ³ E,1 ⁴ E,6R)-3 ⁵ -fluoro-2,6-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-7-aza-1 (5 ,3)-Pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(3,2)-pyridocyclosinfan-8-one

Step A: Synthesis of tert-butyl((2R)-4-(5-fluoro-3-(1-(3-formyl-6,7-dihydro-5H-pyrazolo[1,5-a] Pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)pyrimidin-2-yl)butyl-2-yl)carbamate

The tert-butyl ((2R)-4-(3-(1-aminoethyl)-5-fluoropyridine-2-yl)butyl-2-yl)carbamate (700 mg, 2.250 mg Mol), 5-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (549 mg, 2.250 mmol) and potassium carbonate (1.55 g, 11.250 mmol) Dissolved in dry N,N-dimethylformamide (10 mL), the reaction system was reacted at 120 degrees Celsius for 2 hours. The reaction was stopped, and after cooling to room temperature, saturated brine (50 mL) was added. It was extracted with ethyl acetate (50 ml×3 times), the obtained organic phases were combined and washed with saturated brine (50 ml×2 times), and then the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the solid residue obtained was separated by silica gel column chromatography (eluent: methanol/dichloromethane=1:20). After concentration, 70 mg of yellow oily tert-butyl ((2R)- 4-(5-Fluoro-3-(1-(3-formyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-5- (Yl)ethyl)pyrimidin-2-yl)butyl-2-yl)carbamate.

MS (ESI) M/Z: 483 [M+H ⁺ ].

Step B: Synthesis of 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl)ethyl)-6,7 -Dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid

The tert-butyl ((2R)-4-(5-fluoro-3-(1-(3-formyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[ 2,3-d]pyrimidin-5-yl)ethyl)pyrimidin-2-yl)butyl-2-yl)carbamate (70 mg, 0.145 mmol) dissolved in dimethyl sulfoxide (5.00 ml ) And water (1.50 ml), after stirring for 10 minutes at 0°C. A solution of sodium dihydrogen phosphate (348 mg, 2.900 mmol) in water (1 ml) was slowly added dropwise thereto. Then sodium chlorite (522 mg, 5.800 mmol) in water (2 mL) was slowly added dropwise thereto. The reaction system was reacted at 0 degrees Celsius for 30 minutes, and then the reactants were gradually heated to 30 degrees Celsius and stirred overnight. The reaction was quenched by adding saturated brine (10 mL). It was extracted with ethyl acetate (20 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain 70 mg of oily 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl )Ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid.

MS (ESI) M/Z: 499 [M+H ⁺ ].

Step C: Synthesis of 5-(1-(2-((R)-3-aminobutyl)-5-fluoropyridin-3-yl)ethyl)-6,7-dihydro-5H-pyrazolo[ 1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid

The 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl)ethyl)-6,7-dihydro -5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid (70 mg, 0.141 mmol) was dissolved in dichloromethane (5.00 mL). A 1,4-dioxane solution (4 mol/L, 2.00 mL, 8.000 mmol) of hydrochloric acid was slowly dropped into the reaction system. The reaction system was reacted at 25 degrees Celsius for 2 hours. The reaction was stopped and concentrated under reduced pressure to obtain 60 mg of yellow solid 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl )Ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid.

MS (ESI) M/Z: 399 [M+H ⁺ ].

Step D: Synthesis of (1 ³ E,1 ⁴ E,6R)-3 ⁵ -fluoro-2,6-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-7-aza-1(5 ,3)-Pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(3,2)-pyridocyclosinfan-8-one

The 5-(1-(2-((R)-3-aminobutyl)-5-fluoropyridin-3-yl)ethyl)-6,7-dihydro-5H-pyrazolo[1,5 -a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid (50 mg, 0.125 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (48 mg, 0.250 mmol), 4-dimethylaminopyridine (31 mg, 0.250 mmol) and N,N-diisopropylethylamine (81 mg, 0.625 mmol) dissolved in dichloromethane (10 mL ). Stir at 25 degrees Celsius for 16 hours. The reaction was quenched by adding saturated brine (10 mL). It was extracted with ethyl acetate (20 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the solid residue obtained was separated by a high-performance thin-layer chromatography preparation plate (eluent: methanol/dichloromethane=1:20), and after concentration, water (5 ml) was added to freeze-dried under reduced pressure at low temperature. Obtain 8.7 mg of white solid (1 ³ E, 1 ⁴ E, 6R)-3 ⁵ -fluoro-2,6-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-7-aza-1 ( 5,3)-Pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-3(3,2)-pyridocyclosinfan-8-one.

MS (ESI) M/Z: 381 [M+H ⁺ ].

¹ H NMR (400MHz, CDCl ₃ , ppm): δ 8.32-8.30 (m, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.28-7.23 (m, 1H), 5.42-5.17 ( m, 1H), 4.28-4.02 (m, 3H), 3.60-3.54 (m, 1H), 3.20-2.78 (m, 3H), 2.34-1.94 (m, 2H), 1.55-1.53 (d, J = 8Hz) , 3H), 1.32-1.30 (d, J=8Hz, 3H).

Example 9: (1 ³ E,1 ⁴ E,2R,6R)-3 ⁵ -fluoro-2,6-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -tetrahydro-7-aza -1(5,3)-Pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3(3,2)-pyridocyclosimphan-8-one

Example 10: (1 ³ E,1 ⁴ E,2S,6R)-3 ⁵ -fluoro-2,6-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -tetrahydro-7-aza -1(5,3)-Pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3(3,2)-pyridocyclosimphan-8-one

Step A: Synthesis of tert-butyl((2R)-4-(5-fluoro-3-(1-(3-formyl-7,8-dihydropyrazolo[1,5-a]pyrido[ 2,3-d)pyrimidine-5(6H)-yl)ethyl)pyridin-2-yl)butyl-2-yl)carbamate

Add tert-butyl ((2R)-4-(3-(1-aminoethyl)-5-fluoropyridin-2-yl)butyl-2-yl)carbamate (1.20 g, 4.67 milli Mol), 5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (1.45 g, 4.67 mmol) and potassium carbonate (3.22 g, 23.35 mmol) Dissolved in dry N,N-dimethylformamide (15 mL), the reaction system was reacted at 120 degrees Celsius for 2 hours. The reaction was stopped, after cooling to room temperature, saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3 times). The obtained organic phases were combined and washed with saturated brine (50 mL × 2 times), and then The organic phase was dried with anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the obtained crude solid product was separated by silica gel column chromatography (eluent: methanol/dichloromethane=1:20). After concentration, 200 mg of tert-butyl((2R)-4-( 5-fluoro-3-(1-(3-formyl-7,8-dihydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-5(6H)-yl)ethyl Yl)pyridin-2-yl)butyl-2-yl)carbamate.

MS (ESI) M/Z: 497 [M+H ⁺ ].

Step B: Synthesis of tert-butyl((2R)-4-(5-fluoro-3-(1-(3-formyl-7,8-dihydropyrrolo[1,5-a]pyrido[2 ,3-d)pyrimidine-5(6H)-yl)ethyl)pyridin-2-yl)butyl-2-yl)carbamate

The tert-butyl ((2R)-4-(5-fluoro-3-(1-(3-formyl-7,8-dihydropyrazolo[1,5-a]pyrido[2,3 -d]pyrimidine-5(6H)-yl)ethyl)pyridin-2-yl)butyl-2-yl)carbamate (200 mg, 0.40 mmol) dissolved in dimethyl sulfoxide (12.0 ml) ), after stirring for 10 minutes at 0 degrees Celsius. A solution of sodium dihydrogen phosphate (1.0 g, 7.04 mmol) in water (3 mL) was slowly added dropwise thereto. Then sodium chlorite (1.0 g, 11.11 mmol) in water (3 mL) was slowly added dropwise thereto. The reaction system was reacted at 0 degrees Celsius for 30 minutes, and then the reactants were gradually heated to 35 degrees Celsius and stirred overnight. The reaction was stopped, and saturated brine (50 mL) was added. It was extracted with ethyl acetate (50 ml×3 times), the obtained organic phases were combined and washed with saturated brine (50 ml×2 times), then the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 190 mg The crude product tert-butyl((2R)-4-(5-fluoro-3-(1-(3-formyl-7,8-dihydropyrrolo[1,5-a]pyrido[2,3 -d] Pyrimidine-5(6H)-yl)ethyl)pyridin-2-yl)butyl-2-yl)carbamate.

MS (ESI) M/Z: 513 [M+H ⁺ ].

Step C: Synthesis of 5-(1-(2-((R)-3-aminobutyl)-5-fluoropyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrazolo [1,5-a]pyrido[2,3-d]pyrimidine-3-carboxylic acid

The tert-butyl ((2R)-4-(5-fluoro-3-(1-(3-formyl-7,8-dihydropyrrolo[1,5-a]pyrido[2,3- d] Pyrimidine-5(6H)-yl)ethyl)pyridin-2-yl)butyl-2-yl)carbamate (190 mg, 0.37 mmol) was dissolved in dichloromethane (12.0 mL). A 1,4-dioxane solution (4 mol/L, 4.0 mL, 16.0 mmol) of hydrochloric acid was slowly added dropwise to the reaction system. The reaction system was reacted at room temperature for 2 hours. LCMS detected that the reaction was complete, the reaction was stopped, and concentrated under reduced pressure to obtain 155 mg of yellow solid 5-(1-(2-((R)-3-aminobutyl)-5-fluoropyridin-3-yl)ethyl) -5,6,7,8-Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-carboxylic acid.

MS (ESI) M/Z: 413 [M+H ⁺ ].

Step D: Synthesis of (1 ³ E,1 ⁴ E,2R,6R)-3 ⁵ -fluoro-2,6-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -tetrahydro-7-aza -1(5,3)-Pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3(3,2)-pyridocyclosimphan-8-one

The 5-(1-(2-((R)-3-aminobutyl)-5-fluoropyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrazolo[1, 5-a]pyrido[2,3-d]pyrimidine-3-carboxylic acid (155 mg, 0.37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride The salt (141 mg, 0.74 mmol), 4-dimethylaminopyridine (90 mg, 0.74 mmol) and N,N-diisopropylethylamine (0.1 mL) were dissolved in dichloromethane (10 mL). Stir at room temperature for 16 hours. The reaction was stopped, and saturated brine (50 mL) was added to quench the reaction. It was extracted with ethyl acetate (50 ml×2 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the obtained crude solid product was separated by a high-performance thin-layer chromatography preparation plate (eluent: methanol/dichloromethane=1:20) to obtain 12.5 mg of white solid (1 ³ E, 1 ⁴ E, 2R,6R)-3 ⁵ -fluoro-2,6-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -tetrahydro-7-aza-1(5,3)-pyrazolo[1 ,5-a]pyrido[2,3-d]pyrimidine-3(3,2)-pyridocyclosimphan-8-one and 10 mg of white solid (1 ³ E, 1 ⁴ E, 2S, 6R) -3 ⁵ -Fluoro-2,6-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -Tetrahydro-7-aza-1(5,3)-pyrazolo[1,5-a ]Pyrido[2,3-d]pyrimidin-3(3,2)-pyridocyclosinphen-8-one.

Example 9 (1 ³ E,1 ⁴ E,2R,6R)-3 ⁵ -fluoro-2,6-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -tetrahydro-7-aza- 1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3(3,2)-pyridocyclosimphan-8-one data:

MS (ESI) M/Z: 395 [M+H ⁺ ].

¹ H NMR (400MHz, CDCl ₃ , ppm): δ8.41(d,J=7.6Hz,1H), 8.33(d,J=2.4Hz,1H), 8.19(s,1H), 8.05(s,1H) ), 7.08(d,J=8.4Hz,1H), 5.92(d,J=6.0Hz,1H), 4.41(d,J=4.8Hz,1H), 4.00–3.97(m,1H), 3.89–3.84 (m,1H), 3.28(dd, J ₁ =16.0Hz, J ₂ ＝4.0Hz, 1H), 2.90–2.77(m,4H), 2.25–2.15(m,3H), 1.60(d,J=7.2 Hz, 3H), 1.34 (d, J=6.4 Hz, 3H).

Example 10 (1 ³ E,1 ⁴ E,2S,6R)-3 ⁵ -fluoro-2,6-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -tetrahydro-7-aza- 1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3(3,2)-pyridocyclosimphan-8-one data:

MS (ESI) M/Z: 395 [M+H ⁺ ].

¹ H NMR (400MHz, CDCl ₃ , ppm): δ8.35(s,1H), 8.19(s,1H), 8.05(s,1H), 7.61(d,J=6.4Hz,1H), 7.18(d ,J=8.4Hz,1H), 5.84(d,J=6.0Hz,1H), 4.41(d,J=4.8Hz,1H), 4.00–3.98(m,1H), 3.89–3.84(m,1H) ,3.65–3.58(m,1H),2.90–2.66(m,4H),2.37–2.00(m,3H),1.54(d,J=7.2Hz,3H),1.23(d,J=6.4Hz,3H ).

Example 11: (3S)-N-(5-(1-(2,5-difluorophenyl)ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrole And [2,3-d]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide

Step A: Synthesis of 1-(2,5-difluorophenyl)ethane-1-amine

Dissolve 1-(2,5-difluorophenyl)ethane-1-one (10.0 g, 64 mmol) and ammonium acetate (50.0 g, 640 mmol) in anhydrous methanol (200 mL), and react at room temperature After 3 hours, sodium cyanoborohydride (4.0 g, 64 mmol) was added, heated to 50 degrees Celsius and reacted for 3 hours, the reaction was stopped, cooled to room temperature, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: methanol /Dichloromethane=1:10), after concentration, 6.0 g of 1-(2,5-difluorophenyl)ethane-1-amine is obtained.

MS (ESI) M/Z: 158 [M+H ⁺ ].

Step B: Synthesis of 5-(1-(2,5-difluorophenyl)ethyl)-3-nitro-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[ 2,3-d]pyrimidine

Combine 5-chloro-6-(2-chloroethyl)-3-nitropyrazolo[1,5-a]pyrimidine (300 mg, 1.15 mmol), 1-(2,5-difluorophenyl) ) Ethane-1-amine (360 mg, 2.30 mmol) and potassium carbonate (317 mg, 2.30 mmol) were dissolved in dry N,N-dimethylformamide (15 mL), and the reaction system was at 110 degrees Celsius React for 2 hours. The reaction was stopped, and after cooling to room temperature, saturated brine (50 mL) was added. Extract with ethyl acetate (50 ml×3 times), combine the obtained organic phases and wash with saturated brine (50 ml×2 times), then dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain The crude solid product was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:1), and after concentration, 150 mg of 5-(1-(2,5-difluorophenyl)ethyl)- 3-Nitro-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine.

MS (ESI) M/Z: 346 [M+H ⁺ ].

Step C: Synthesis of 5-(1-(2,5-difluorophenyl)ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d ]Pyrimidine-3-amine

The 5-(1-(2,5-difluorophenyl)ethyl)-3-nitro-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3 -d] Pyrimidine (150 mg, 0.43 mmol) was dissolved in methanol (20 ml), added 10% palladium on carbon (0.3 g), covered with a hydrogen balloon, replaced the hydrogen, and reacted at room temperature for 2 hours. LCMS detected the complete reaction of the raw materials. The reaction was stopped, filtered, and concentrated under reduced pressure to obtain 135 mg of 5-(1-(2,5-difluorophenyl)ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a] Pyrrolo[2,3-d]pyrimidin-3-amine.

MS(ESI) M/Z: 316[M+1].

Step D: Synthesis of phenyl(5-(1-(2,5-difluorophenyl)ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2, 3-d)pyrimidin-3-yl)carbamate

The 5-(1-(2,5-difluorophenyl)ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine- 3-amine (135 mg, 0.42 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 degrees Celsius in an ice bath, and phenyl chloroformate (84 mg, 0.54 mmol) was dissolved in dichloromethane (1 mL) , Added dropwise to the above solution, then added ethyldiisopropylamine (0.3ml), reacted under ice bath for 30 minutes, LCMS detected the complete reaction of the raw materials, stopped the reaction, added ethyl acetate (50ml) to dilute, with saturated carbonic acid Washed with sodium hydrogen solution (50 ml x 2 times) saturated sodium chloride solution (50 ml x 1 time), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 160 mg of crude product phenyl (5-(1- (2,5-Difluorophenyl)ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-3-yl)aminomethyl Acid ester.

MS(ESI) M/Z:436[M+1].

Step E: Synthesis of (3S)-N-(5-(1-(2,5-difluorophenyl)ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrole And [2,3-d]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide

The phenyl(5-(1-(2,5-difluorophenyl)ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d ]Pyrimidin-3-yl) carbamate (160 mg, 0.37 mmol) was dissolved in acetonitrile (20 mL), (S)-pyrrolidin-3-ol (225 mg, 2.6 mmol) was added, and the mixture was stirred at room temperature Overnight, LCMS detected that the reaction was complete, diluted with ethyl acetate (50 ml), washed with saturated sodium chloride solution (50 ml x 1 time), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and prepared by reversed phase Chromatographic separation and purification (column: Welch Xtimate C18 30mm*150mm, 5um; mobile phase: water (containing 0.05% ammonia) and acetonitrile; flow rate: 30 ml/min; gradient: within 8 minutes, acetonitrile rises from 30% to 70 %; detection wavelength: 254nm), the product was collected and lyophilized to obtain 25.0 mg (3S)-N-(5-(1-(2,5-difluorophenyl)ethyl)-6,7-dihydro- 5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide.

MS (ESI) M/Z: 429 [M+1].

¹ H NMR (400MHz, DMSO-d ₆ , ppm): δ 8.21 (s, 1H), 7.65 (s, 1H), 7.41-7.37 (m, 1H), 7.29-7.18 (m, 3H), 5.56 ( dd,J ₁ ＝14.0Hz,J ₂ ＝7.2Hz,1H), 4.96(d,J＝3.6Hz,1H), 4.28(s,1H), 3.73(dd,J ₁ ＝17.2Hz, J ₂ ＝8.0 Hz, 1H), 3.43–3.34(m, 4H), 3.33–3.24(m, 1H), 2.99(t, J=7.2Hz, 2H), 1.94–1.88(m, 1H), 1.80–1.77(m, 1H), 1.56(d, J=7.2Hz, 3H).

Example 12: (S)-N-(2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2- b]Indazol-10-yl)-3-hydroxypyrrolidine-1-carboxamide

Step A: Synthesis of 2-chloro-10-nitropyrimido[1,2-b]indazole

Dissolve 10-nitropyrimido[1,2-b]indazole-2(1H)-one (100 mg, 0.43 mmol) in acetonitrile (10 mL), and add phosphorus oxychloride ( 132 mg, 0.86 mmol), after the dropping, the temperature was raised to 90 degrees Celsius and refluxed for 2 hours. The reaction solution was cooled to room temperature and poured into ice water at 0 degrees Celsius. It was extracted with ethyl acetate (20 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The filtrate obtained by filtration was concentrated under reduced pressure to obtain 100 mg of yellow solid 2-chloro-10-nitropyrimido[1,2-b]indazole, which was used directly in the next step without purification.

MS (ESI) M/Z: 249 [M+H ⁺ ].

Step B: Synthesis of 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-10-nitropyrimido[1,2-b] Indazole

Dissolve 2-chloro-10-nitropyrimido[1,2-b]indazole (100 mg, 0.4 mmol) in n-butanol (5 mL) and add (2R,4S)-2-(2 ,5-Difluorophenyl)-4-fluoropyrrolidine (81 mg, 0.4 mmol) and N,N-diisopropylethylamine (0.5 mL) were heated to 160 degrees Celsius and stirred for 20 hours. The reaction solution was cooled to room temperature, and then water (20 mL) was added. It was extracted with ethyl acetate (30 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The filtrate obtained by filtration was concentrated under reduced pressure. Obtain 90 mg of yellow solid 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-10-nitropyrimido[1,2-b ] Indazole, without purification, used directly in the next step.

MS (ESI) M/Z: 414 [M+H ⁺ ].

Step C: Synthesis of 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2-b]indazole-10- amine

The 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-10-nitropyrimido[1,2-b]indazole ( 90 mg, 0.22 mmol) was dissolved in methanol (10 mL), added to 10% palladium on carbon (60 mg), replaced with hydrogen three times, and stirred at room temperature for 6 hours. The reaction was stopped, and the reaction solution was directly filtered and concentrated under reduced pressure to obtain 80 mg of 2-((2R,4S)- 2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimidine [1,2-b]Indazole-10-amine.

MS (ESI) M/Z: 384 [M+H ⁺ ].

Step D: Synthesis of (S)-N-(2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2- b]Indazol-10-yl)-3-hydroxypyrrolidine-1-carboxamide

The 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimidino[1,2-b]indazole-10-amine (80 Mg, 0.21 mmol) was dissolved in anhydrous dichloromethane (10 mL), then added N,N'-carbonyldiimidazole (176 mg, 1.05 mmol), stirred at room temperature for half an hour, and then added (S) -Pyrrolidin-3-ol (55 mg, 0.63 mmol), continue stirring at room temperature for 5 hours. The reaction was quenched by adding saturated brine (10 mL). It was extracted with dichloromethane (15 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, separated by silica gel column chromatography (eluent: dichloromethane: methanol), and concentrated to obtain 24.0 mg of (S)-N-(2-((2R,4S)-2-(2,5- Difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2-b]indazol-10-yl)-3-hydroxypyrrolidine-1-carboxamide.

MS(ESI)M/Z: 497[M+H ⁺ ]

¹ H NMR (400MHz, CDCl ₃ , ppm): δ 8.90 (d, J = 8 Hz, 1H), 8.69 (s, 1H), 7.71 (d, J = 4 Hz, 1H), 7.37-7.28 (m, 3H) ), 7.24-7.19 (m, 1H), 7.04 (d, J = 8Hz, 1H), 6.43 (s, 1H), 5.50-5.46 (m, 1H), 5.10 (s, 1H), 4.47-4.34 (m ,2H),4.23--4.12(m,1H) 3.75-3.50(m,2H), 3.50-3.49(m,1H) 3.25-2.75(m,2H), 2.50-2.25(m,1H),2.25-1.75 (m, 3H).

Example 13: 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-N-ethylpyrimidino[1,2-b] Indazole-10-carboxamide

Step A: Synthesis of methyl 3-amino-2-cyanobenzoate

Dissolve methyl 2-cyano-3-nitrobenzoate (5 g, 24 mmol) in ethanol (100 ml), then add iron powder (13.5 g, 240 mmol), add dropwise under ice Concentrated hydrochloric acid (20 ml), after the addition was completed, the temperature was raised to 80 degrees Celsius and stirred for 2 hours. LCMS detected that the reaction was complete, the reaction was stopped, the reaction solution was filtered, the filter residue was washed with ethanol (20 ml×3 times), the filtrates were combined and concentrated under reduced pressure. After concentration, the solid was dissolved in ethyl acetate (100 ml), water (50 ml) was added, the layers were separated, the organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4 g of methyl 3-amino-2-cyano Benzoate.

MS(ESI)M/Z: 177[M+H ⁺ ]

Step B: Synthesis of methyl 3-amino-1H-indazole-4-carboxylate

Methyl 3-amino-2-cyanobenzoate (4 g, 23 mmol) was dissolved in concentrated hydrochloric acid (30 ml), cooled to 0 degrees Celsius, and sodium nitrite (1.88 g)/water (30 ml) was added dropwise. Ml), stir for 1 hour and 30 minutes under ice bath, then add stannous chloride dihydrate (42.5 g)/concentrated hydrochloric acid (30 ml) dropwise, and continue stirring under ice bath for 1 hour. The reaction was stopped, the reaction solution was filtered, the filter residue was washed with water (10 ml), and after drying, 3.5 g of methyl 3-amino-1H-indazole-4-carboxylate was obtained.

MS(ESI)M/Z: 192[M+H ⁺ ]

Step C: Synthesis of methyl 2-hydroxypyrimido[1,2-b]indazole-10-carboxylate

Methyl 3-amino-1H-indazole-4-carboxylate (3.5 g, 18 mmol) was dissolved in nitrogen, nitrogen-dimethylformamide (100 ml), and cesium carbonate (12 g, 36 Millimoles) and ethyl ethoxyacrylate (3.2 g, 9.6 millimoles), heated to 110 degrees Celsius and stirred overnight. Stop the reaction, adjust the pH of the reaction solution to 5-6 with 1 mole per liter of dilute hydrochloric acid, add ethyl acetate (300 ml), and then repeatedly wash the organic phase with saturated sodium chloride solution (100 ml × 3 times) The organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.5 g of crude product methyl 2-hydroxypyrimido[1,2-b]indazole-10-carboxylate.

MS(ESI)M/Z: 244[M+H ⁺ ]

Step D: Synthesis of methyl 2-chloropyrimido[1,2-b]indazole-10-carboxylate

Methyl 2-hydroxypyrimido[1,2-b]indazole-10-carboxylate (1.5 g) was dissolved in 30 ml of acetonitrile, and phosphorus oxychloride (5.7 ml) was added dropwise under ice. After the addition is complete, the temperature is raised to 100 degrees Celsius and stirred overnight. The reaction solution was cooled, poured slowly into ice water, extracted with ethyl acetate (100 mL), the organic phase was dried, and concentrated under reduced pressure. The obtained solid was slurried by adding acetonitrile (5 ml), cooled, and filtered to obtain 300 mg of methyl 2-chloropyrimido[1,2-b]indazole-10-carboxylate.

MS(ESI)M/Z: 262[M+H ⁺ ]

Step E: Synthesis of methyl 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2-b]indazole- 10-carboxylate

Dissolve methyl 2-chloropyrimido[1,2-b]indazole-10-carboxylate (300 mg, 1.2 mmol) in n-butanol (10 mL) and add (2R,4S)-2 -(2,5-Difluorophenyl)-4-fluoropyrrolidine (230 mg, 1.2 mmol) and N,N-diisopropylethylamine (0.5 mL), heated to 160 degrees Celsius, and stirred for 20 hours. The reaction solution was cooled to room temperature, and then water (10 mL) was added. It was extracted with ethyl acetate (15 ml×3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The filtrate obtained by filtration was concentrated under reduced pressure. Obtained 110 mg of yellow solid methyl 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2-b]indazole -10-carboxylate.

MS(ESI)M/Z: 427[M+H ⁺ ]

Step F: Synthesis of 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2-b]indazole-10- carboxylic acid

Methyl 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimidino[1,2-b]indazole-10-carboxy The ester (110 mg, 0.26 mmol) was dissolved in a methanol (5 mL)/tetrahydrofuran (5 mL) mixed solvent, and 2 mol of lithium hydroxide (5 mL) was added, and the temperature was raised to 50 degrees Celsius and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, and the layers were separated. The pH of the aqueous phase was adjusted to between 5-6 with 1 molar dilute hydrochloric acid solution, and then extracted with ethyl acetate (20 ml×3 times). The organic phases were combined, dried, and concentrated under reduced pressure to obtain 80 mg of 2-((2R, 4S)-2-(2,5-Difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2-b]indazole-10-carboxylic acid.

MS(ESI)M/Z: 413[M+H ⁺ ]

Step G: Synthesis of 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-N-ethylpyrimido[1,2-b] Indazole-10-carboxamide

The 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimidino[1,2-b]indazole-10-carboxylic acid ( 80 mg, 0.19 mmol) was dissolved in dichloromethane (20 ml), and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluoro Phosphate (110 mg, 0.29 mmol) and triethylamine (0.5 mL). Stir at room temperature for 4 hours. Saturated brine (10 ml) was added to the reaction system, the liquids were separated, and the organic phase was dried with anhydrous sodium sulfate. Concentrated under reduced pressure, separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate), and concentrated to obtain 4.0 mg (S)-N-(2-((2R,4S)-2-(2,5) -Difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2-b]indazol-10-yl)-3-hydroxypyrrolidine-1-carboxamide.

MS(ESI)M/Z: 440[M+H ⁺ ]

¹ H NMR (400MHz, CDCl ₃ , ppm): δ10.49 (s, 1H), 8.65-8.60 (m, 1H), 8.20-8.15 (m, 1H), 7.79 (d, J = 6Hz, 1H), 7.60-7.55 (m, 1H), 7.15-7.10 (m, 1H), 7.05-7.00 (m, 1H), 6.97-6.92 (m, 1H), 6.45-6.5 (m, 1H), 5.59-5.46 (m ,2H),4.58-4.50(m,1H),4.25-4.18(m,1H),3.80-3.60(m,1H),3.20-3.05(m,1H),2.36-2.29(m,2H),1.40 -1.36(m,3H).

Example 14: (S)-N-(2-((R)-2-(2,5-difluorophenyl)pyrrol-1-yl)pyrimidino[1,2-b]indazole-10- Yl)-3-hydroxypyrrolidine-1-carboxamide

Step A: Synthesis of 4-nitro-2H-indazol-3-amine

Take a 100 ml round bottom flask, dissolve 2-fluoro-6-nitrobenzonitrile (500 mg, 3.0 mmol) in ethanol (30 ml), and slowly add hydrazine hydrate (1 ml, 15 ml) at 80 degrees Celsius. Millimoles), and then the reaction solution was heated to 100 degrees Celsius for 4 hours. After the reactant was cooled to room temperature, it was concentrated under reduced pressure to remove ethanol. The obtained solid residue was separated by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1:3), and after concentration, 300 mg of yellow solid 4-nitro-2H-indazol-3-amine was obtained.

MS (ESI) M/Z: 179 [M+H ⁺ ].

Step B: Synthesis of 10-nitropyrimidino[1,2-b]indazole-2(1H)-one

4-Nitro-2H-indazol-3-amine (300 mg, 1.68 mmol) was dissolved in DMF (5 mL), and ethyl 3-ethoxyacrylate (480 mg, 3.37 mmol) and Cesium carbonate (800 mg, 2.52 mmol). After the addition is complete, react at 100 degrees Celsius for 2 hours. Pour the reaction liquid into ice water (50 ml), adjust the pH to about 5 with dilute hydrochloric acid (1M), and solids will precipitate out. The solids are filtered and dried to obtain 400 mg of brown solid crude 10-nitropyrimidine [1 ,2-b]Indazol-2(1H)-one, directly used in the next reaction without purification.

MS (ESI) M/Z: 231 [M+H ⁺ ].

Step C: Synthesis of 2-chloro-10-nitropyrimido[1,2-b]indazole

Dissolve 10-nitropyrimido[1,2-b]indazole-2(1H)-one (300 mg, 1.3 mmol) in acetonitrile (6 mL), and then add phosphorus oxychloride (2 mL) Into the reaction system. After the addition is complete, react at 100 degrees Celsius for 3 hours. The reaction solution was concentrated to obtain 400 mg of yellow solid 2-chloro-10-nitropyrimido[1,2-b]indazole.

MS (ESI) M/Z: 249 [M+H ⁺ ].

Step D: Synthesis of (R)-2-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-10-nitropyrimido[1,2-b]indazole

Combine 2-chloro-10-nitropyrimido[1,2-b]indazole (400 mg, 1.6 mmol), (R)-2-(2,5-difluorophenyl)pyrrolidine (300 mg , 1.6 mmol) and diisopropylethylamine (600 mg, 4.8 mmol) were dissolved in n-butanol (1 mL). Stir overnight at 120°C. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to remove the solvent. The remaining solid residue was separated by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). After concentration, 200 mg of red solid (R)-2-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-10-nitropyrimido[1,2-b]indazole was obtained.

MS (ESI) M/Z: 396 [M+H ⁺ ].

Step E: Synthesis of (R)-2-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrimido[1,2-b]indazole-10-amine

The (R)-2-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-10-nitropyrimidino[1,2-b]indazole (100 mg, 0.31 mmol ) Was dissolved in methanol (5.00 ml), 10% palladium on carbon (100 mg) was added for hydrogen replacement three times, and the hydrogen atmosphere was kept at room temperature to react for 4 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain 100 mg of crude (R)-2-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrimido[1,2-b]indazole-10 -amine.

MS (ESI) M/Z: 366 [M+H ⁺ ].

Step F: Synthesis of (S)-N-(2-((R)-2-(2,5-difluorophenyl)pyrrol-1-yl)pyrimido[1,2-b]indazole-10- Yl)-3-hydroxypyrrolidine-1-carboxamide

(R)-2-(2-(2,5-Difluorophenyl)pyrrolidin-1-yl)pyrimid[1,2-b]indazole-10-amine (90 mg, 0.3 mmol) Dissolved in dichloromethane (3.0 mL), carbonyldiimidazole (53 mg, 0.33 mmol) was added to it. React at room temperature for 1 hour, and then add (S)-pyrrolidin-3-ol (29 mg, 0.33 mmol) to the reaction solution. After the dropwise addition is complete, the reaction mixture is continuously stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting solid residue was separated by silica gel column chromatography (eluent: ethyl acetate/n-hexane=3:1). After concentration, 58 mg of white solid (S)-N-(2-( (R)-2-(2,5-Difluorophenyl)pyrrol-1-yl)pyrimido[1,2-b]indazol-10-yl)-3-hydroxypyrrolidine-1-carboxamide.

MS (ESI) M/Z: 479 [M+H+].

1H NMR(400MHz,DMSO-d ₆ )δ8.83-8.81(m,2H), 7.73(d,J=8.0Hz,1H), 7.38-7.28(m,2H), 7.22-7.17(m,1H) ,7.03(d,J=8.0Hz,1H),6.97–6.93(m,1H),6.34(br,s,1H),5.39(br,s,1H),4.39(s,1H),4.09(t ,J=8.0Hz,1H),3.79–3.48(m,5H),2.56-2.51(m,1H),2.05–1.92(m,5H).

Example 15: ((1 ³ E,1 ⁴ E,2R,6R)-3 ⁵ -fluoro-2,6-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -tetrahydro-4-oxy 7-Aza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(3,2)-pyridinecyclosimphan-8-one

Step A: Synthesis of 5-(1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrazolo[1,5-a]pyridine And [2,3-d]pyrimidine-3-carbaldehyde

The 1-(5-fluoro-2-hydroxypyridin-3-yl)ethane-1-amine (5.00 g, 29.5 mmol), 5-chloro-6-(3-chloropropyl)pyrazolo [1 ,5-a] pyrimidine-3-carbaldehyde (10.00 g, 39.0 mmol) and anhydrous potassium carbonate (10.00 g, 72.5 mmol) were dissolved in N,N-dimethylformamide (100 mL) and dissolved in 150 Stir for 4 hours at °C. The reaction was quenched by adding saturated brine (200 mL). It was extracted with ethyl acetate (200 ml × 3 times), the obtained organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The remaining solid residue was separated by silica gel column chromatography (eluent: ethyl acetate Ester/petroleum ether = 1:1), after concentration, 3.30 g of the target product is obtained as a yellow solid.

MS (ESI) M/Z: 356 [M+H ⁺ ].

Step B: Synthesis of 5-(1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrazolo[1,5-a]pyridine And [2,3-d]pyrimidine-3-carboxylic acid

The 5-(1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrazolo[1,5-a]pyrido[2 ,3-d] pyrimidine-3-carbaldehyde (3.00 g, 8.4 mmol) and sodium dihydrogen phosphate (10.20 g, 84.0 mmol) were dissolved in dimethyl sulfoxide/water (50/20 ml) and dissolved in 0 In degrees Celsius, a solution of sodium chlorite (15.20 g, 168.0 mmol) in water (10 ml) was slowly added dropwise, and after the addition, the temperature was slowly raised to 35 degrees Celsius and stirred for 12 hours. The reaction was quenched by adding saturated brine (200 mL). It was extracted with ethyl acetate (200 ml×3 times), the obtained organic phases were combined, washed with water, dried, and concentrated to obtain 3.00 g of yellow solid. No purification is required and it is used directly in the next step.

MS (ESI) M/Z: 372 [M+H ⁺ ].

Step C: Synthesis of 5-(1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-N-((R)-1-hydroxypropyl-2-yl)-5,6 ,7,8-Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-carboxamide

The 5-(1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrazolo[1,5-a]pyrido[2 ,3-d]pyrimidine-3-carboxylic acid (200 mg, 1.08 mmol), (R)-2-aminopropyl-1-ol (97 mg, 1.29 mmol), 1-(3-dimethylaminopropyl) Yl)-3-ethylcarbodiimide hydrochloride (248 mg, 1.29 mmol), 1-hydroxybenzotriazole (175 mg, 1.29 mmol) and N,N-diisopropylethylamine ( 348 mg, 2.70 mmol) was dissolved in N,N-dimethylformamide (5 mL), and stirred at room temperature for 12 hours. The reaction was quenched by adding saturated brine (20 mL). It was extracted with ethyl acetate (20 ml×3 times), the obtained organic phases were combined, washed with water, dried, and concentrated. The solid residue obtained was separated by silica gel column chromatography (eluent: dichloromethane/methanol=20:1 ), after concentration, 120 mg of yellow oily target product is obtained.

MS (ESI) M/Z: 429 [M+H ⁺ ].

Step D: Synthesis of 5-(1-(5-fluoro-2-hydroxypyridin-3-yl)ethyl)-N-((R)-1-hydroxypropyl-2-yl)-5,6,7 ,8-Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-amide

Put 5-(1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-N-((R)-1-hydroxypropyl-2-yl)-5,6,7, 8-Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-carboxamide (120 mg, 0.28 mmol) dissolved in 4N hydrochloric acid/1-4 dioxane Solution (5 mL). React at 60 degrees Celsius for 4 hours. After the reaction solution was cooled to room temperature, it was directly concentrated to obtain 110 mg of yellow oil.

MS (ESI) M/Z: 415 [M+H ⁺ ].

Step E: Synthesis of ((1 ³ E,1 ⁴ E,2R,6R)-3 ⁵ -fluoro-2,6-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -tetrahydro-4-oxy 7-Aza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(3,2)-pyridinecyclosimphan-8-one

The 5-(1-(5-fluoro-2-hydroxypyridin-3-yl)ethyl)-N-((R)-1-hydroxypropyl-2-yl)-5,6,7,8- Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-amide (110 mg, 0.27 mmol) and triphenylphosphine (141 mg, 0.54 mmol) are dissolved in tetrahydrofuran (5 mL), replaced with nitrogen three times. At 0 degrees Celsius, di-tert-butyl azodicarboxylate (124 mg, 0.54 mmol) in tetrahydrofuran (2 mL) was slowly added dropwise to the above mixed solution, and reacted at 60 degrees Celsius for 3 hours. The reaction was quenched by adding saturated brine (20 mL). It was extracted with ethyl acetate (20 ml×3 times), the obtained organic phases were combined, washed with water, dried, and concentrated. The solid residue obtained was separated by a high-performance thin-layer chromatography preparation plate (eluent: dichloromethane/methanol= 20:1), add water (5 ml) and freeze-dry under low temperature and reduced pressure after concentration to obtain 8.5 mg of white solid ((1 ³ E,1 ⁴ E,2R,6R)-3 ⁵ -fluoro-2,6-dimethyl Group-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -Tetrahydro-4-oxo7-aza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d ]Pyrimidine-3(3,2)-pyridinecyclosimphan-8-one.

MS (ESI) M/Z: 397 [M+H ⁺ ].

¹ H NMR (400MHz, CD ₃ OD, ppm): δ8.22 (t, J = 1.2Hz, 1H), 8.06 (s, 1H), 7.69 (dd, J ₁ ＝8.8, J ₁ ＝2.8Hz, 1H ), 6.22-6.17(m,1H),4.57(s,1H),4.40-4.35(m,1H), 4.20(dd,J=1.6,10.8Hz,1H),4.12-4.06(m,1H), 3.94-3.88(m,1H),2.86-2.82(m,2H),2.09-2.00(m,2H), 1.65(d,J=7.2Hz,3H), 1.47(d,J=7.2Hz,3H) .

Example 16: (1 ³ E,1 ⁴ E,2R,5S)-3 ⁵ -fluoro-2,5-dimethyl-1 ⁵ ,1 ⁶ ,1 ⁷ ,1 ⁸ -tetrahydro-4-oxy- 7-Aza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(3,2)-pyridinecyclosimphan-8-one

The synthesis method is the same as in Example 15. In step C, (S)-1-aminopropyl-2-ol is substituted for (R)-2-aminopropyl-1-ol.

MS (ESI) M/Z: 397 [M+H ⁺ ].

¹ H NMR (400MHz, DMSO-d ₆ , ppm): δ9.40(d,J=7.2Hz,1H), 8.50(d,J=4.4Hz,1H), 8.03–7.90(m,2H), 7.78 (dd,J ₁ =8.8Hz,J ₂ =3.2Hz,1H), 6.04–5.99(m,1H), 5.13–5.08(m,1H), 4.02-3.90(m,1H), 3.81–3.72(m ,2H),3.63–3.58(m,1H),2.84-2.68(m,2H),2.06–1.88(m,2H),1.57(d,J=7.2Hz,3H),1.47(d,J=6.4 Hz, 3H).

With reference to the synthesis method of Example 15, the following compounds were also synthesized:

Example 24: (1 ³ E,1 ⁴ E,1 ⁶ R,6R)-3 ⁵ -fluoro-1 ⁶ ,6-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-4-oxy -7-Nitro-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(3,2)-pyridinecyclononane-8-one

Synthesis scheme

Step A: Synthesis of 7-hydroxypyrazolo[1,5-a]pyrimidin-5(4H)-one

Dissolve 1H-pyrazole-5-amine (20.0 g, 241 mmol), diethyl malonate (42.4 g, 265 mmol) in absolute ethanol (300 mL), and add sodium ethoxide (49.0 g, 723 Millimoles), heated to 115 degrees Celsius and reacted for 16 hours. LCMS detected that the reaction was complete. The reaction was stopped. The solvent was evaporated under reduced pressure. Water (60 ml) was added. Under ice bath conditions, the pH was adjusted to 5 with 6N hydrochloric acid, and the product precipitated. It was filtered and dried to obtain 18.0 g of 7-hydroxypyrazolo[1,5-a]pyrimidin-5(4H)-one.

MS (ESI) M/Z: 152 [M+H ⁺ ].

Step B: Synthesis of 5,7-dichloropyrazolo[1,5-a]pyrimidine

Dissolve 7-hydroxypyrazolo[1,5-a]pyrimidine-5(4H)-one (6.0 g, 39.7 mmol) in phosphorus oxychloride (60 mL), add triethylamine (6 mL), Heat to 120 degrees Celsius and react for 3 hours. LCMS detects that the reaction is complete. The reaction is stopped. Phosphorus oxychloride is evaporated under reduced pressure. Then the residue is poured into ice water (80 ml) and stirred for 5 minutes, and extracted with dichloromethane (100 ml×2) The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (dichloromethane) to obtain 4.0 g of 5,7-dichloropyrazolo[1,5-a]pyrimidine.

MS (ESI) M/Z: 188 [M+H ⁺ ].

Step C: Synthesis of tert-butyl(R)-(1-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate

Dissolve 5,7-dichloropyrazolo[1,5-a]pyrimidine (3.00 g, 16.04 mmol) in tetrahydrofuran (40 mL), add lithium diisopropylamide (10.0 mL, 20.00 at -78 degrees Celsius) Millimoles), react for 1 hour, add 2-methyl-2-propyl(4R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (4.18 g, 17.65 mmol), react for 2 hours, LCMS detects that the reaction is complete, stop the reaction, add citric acid (100 mL) and ethyl acetate (100 mL) to dilute, and use saturated sodium chloride solution (80 mL × 2 times ) Wash, the organic phase is dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1), yielding 5.0 g

Tert-butyl (R)-(1-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate.

MS (ESI) M/Z: 345 [M+H ⁺ ].

Step D: Synthesis of tert-butyl(R)-(1-(5-chloropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate

Add tert-butyl (R)-(1-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate (2.0 g, 5.8 MM) was dissolved in ethanol (30 mL) and water (10 mL), zinc powder (1.5 g, 23.2 mmol) and ammonium chloride solution (2 mL) were added, and stirred at 50 degrees Celsius for 4 hours. LCMS detected that the reaction was complete. It was concentrated under reduced pressure, diluted with dichloromethane (100 ml), washed with saturated sodium chloride solution (100 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.56 g of tert-butyl (R )-(1-(5-Chloropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate.

MS (ESI) M/Z: 311 [M+H ⁺ ].

Step E: Synthesis of (R)-1-(5-chloropyrazolo[1,5-a]pyrimidin-6-yl)propane-2-amine

Add tert-butyl(R)-(1-(5-chloropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate (1.56 g, 5.01 mmol) Dissolved in dichloromethane (10 mL), added trifluoroacetic acid (5 mL), stirred at room temperature overnight, LCMS detected that the reaction was complete, and concentrated to dryness under reduced pressure to obtain 1.05 g (R)-1-(5-chloropyrazolo [1,5-a]pyrimidin-6-yl)propane-2-amine.

MS (ESI) M/Z: 211 [M+H ⁺ ].

Step F Synthesis of (R)-6-methyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine

(R)-1-(5-Chloropyrazolo[1,5-a]pyrimidin-6-yl)propane-2-amine (1.05 g, 5.01 mmol) was dissolved in acetonitrile (10 mL), and three Ethylamine (2 ml), stirred at 80 degrees Celsius for 4 hours, LCMS detected that the reaction was complete, concentrated to dryness under reduced pressure, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 420 mg of (R) -6-Methyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine.

MS (ESI) M/Z: 175 [M+H ⁺ ].

Step G Synthesis of (R)-5-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-methyl-6,7-dihydro-5H-pyrazolo[1, 5-a]pyrrolo[2,3-d]pyrimidine

Dissolve sodium hydride (193 mg, 4.82 mmol) in N,N-dimethylformamide (3 mL), add (R)-6-methyl-6,7-dihydro-5H-pyridine at 0 degrees Celsius Azolo[1,5-a]pyrrolo[2,3-d]pyrimidine (420 mg, 2.41 mmol), react for 1 hour, add 3-(chloromethyl)-5-fluoro-2-methoxy Pyridine (675 mg, 3.86 mmol), reacted for 2 hours, LCMS detected that the reaction was complete, the reaction was stopped, water (30 mL) and ethyl acetate (100 mL) were added, and saturated sodium chloride solution (80 mL×2 times) After washing, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 640 mg of (R)-5-((5-fluoro -2-Methoxypyridin-3-yl)methyl)-6-methyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine .

MS (ESI) M/Z: 314 [M+H+].

Step H Synthesis of (R)-5-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-methyl-6,7-dihydro-5H-pyrazolo[1, 5-a]pyrrolo[2,3-d]pyrimidine-3-carbaldehyde

Add (R)-5-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-methyl-6,7-dihydro-5H-pyrazolo[1,5- a]Pyrrolo[2,3-d]pyrimidine (593 mg, 1.82 mmol) was dissolved in N,N-dimethylformamide (3 mL), and phosphorus oxychloride (0.8 mL) was added at 0 degrees Celsius to react 2 Hours, LCMS detected that the reaction was complete, the reaction was stopped, water (30 ml) and ethyl acetate (100 ml) were added, washed with saturated sodium chloride solution (80 ml × 2 times), the organic phase was dried with anhydrous sodium sulfate and filtered , Concentrated under reduced pressure to obtain 690 mg

(R)-5-((5-Fluoro-2-methoxypyridin-3-yl)methyl)-6-methyl-6,7-dihydro-5H-pyrazolo[1,5-a ]Pyrrolo[2,3-d]pyrimidine-3-carbaldehyde.

MS (ESI) M/Z: 342 [M+H ⁺ ].

Step I Synthesis of (R)-5-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-methyl-6,7-dihydro-5H-pyrazolo[1, 5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid

Add (R)-5-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-methyl-6,7-dihydro-5H-pyrazolo[1,5- a]Pyrrolo[2,3-d]pyrimidine-3-carbaldehyde (593 mg, 1.72 mmol) was dissolved in tert-butanol (20 mL), 2-methylbut-2-ene (2.5 mL) was added, and Sodium dihydrogen phosphate (2.08 g, 17.3 mmol) aqueous solution (10 mL), sodium chlorite (1.25 g, 13.87 mmol) aqueous solution (10 mL) was added, and the mixture was stirred overnight at room temperature. LCMS detected that the reaction was complete and stopped the reaction. Dilute with ethyl acetate (150 ml), wash with saturated sodium chloride solution (100 ml × 1 time), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 710 mg of (R)-5-(( 5-fluoro-2-methoxypyridin-3-yl)methyl)-6-methyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3- d] Pyrimidine-3-carboxylic acid.

MS (ESI) M/Z: 342 [M+H ⁺ ].

Step J Synthesis of (R)-5-((5-fluoro-2-methoxypyridin-3-yl)methyl)-N-((R)-1-hydroxypropan-2-yl)-6-methyl -6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxamide

Add (R)-5-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-methyl-6,7-dihydro-5H-pyrazolo[1,5- a]Pyrrolo[2,3-d]pyrimidine-3-carboxylic acid (200 mg, 0.56 mmol) and (R)-2-aminopropan-1-ol (84 mg, 1.12 mmol) are dissolved in N, N-dimethylformamide (5ml), add 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (320mg, 10.84ml) Mol) and triethylamine (1.0 ml), stirred overnight at room temperature, LCMS detected that the reaction was complete, the reaction was stopped, diluted with ethyl acetate (100 ml), washed with saturated sodium chloride solution (80 ml × 2 times), the organic phase Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to obtain 170 mg of (R)-5-((5-fluoro-2-methyl Oxypyridin-3-yl)methyl)-N-((R)-1-hydroxypropan-2-yl)-6-methyl-6,7-dihydro-5H-pyrazolo[1,5 -a]pyrrolo[2,3-d]pyrimidine-3-carboxamide.

MS (ESI) M/Z: 415 [M+H ⁺ ].

Step K Synthesis of (R)-5-((5-fluoro-2-hydroxypyridin-3-yl)methyl)-N-((R)-1-hydroxypropan-2-yl)-6-methyl- 6,7-Dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxamide

Add (R)-5-((5-fluoro-2-methoxypyridin-3-yl)methyl)-N-((R)-1-hydroxypropan-2-yl)-6-methyl- 6,7-Dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxamide (180mg, 0.436mmol) dissolved in 10ml of acetonitrile), add Sodium iodide (196 mg, 1.30 mmol) and trimethylchlorosilane (140 mg, 1.31 mmol) were stirred overnight at room temperature. LCMS detected that the reaction was complete. Dilute with dichloromethane (100 mL) and dilute with saturated sodium chloride The solution (100 mL) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (methanol: ethyl acetate = 1:10) to obtain 130 mg of (R)-5-( (5-Fluoro-2-hydroxypyridin-3-yl)methyl)-N-((R)-1-hydroxypropan-2-yl)-6-methyl-6,7-dihydro-5H-pyridine Azolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxamide.

MS (ESI) M/Z: 401 [M+H ⁺ ].

Step L Synthesis of (1 ³ E, 1 ⁴ E, 1 ⁶ R, 6R)-3 ⁵ -fluoro-1 ⁶ ,6-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-4-oxy- 7-Azo-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(3,2)-pyridinecyclononane-8-one

Add (R)-5-((5-fluoro-2-hydroxypyridin-3-yl)methyl)-N-((R)-1-hydroxypropan-2-yl)-6-methyl-6, 7-Dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxamide (130 mg, 0.325 mmol) was dissolved in tetrahydrofuran (10 mL), and three Phenylphosphine (170 mg, 0.65 mmol) and di-tert-butyl azodicarboxylate (224 mg, 0.975 mmol) were stirred at room temperature overnight. LCMS detected that the reaction was complete, added ethyl acetate (60 mL) to dilute, and saturated Washed with sodium chloride solution (30 ml x 3 times), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 75 mg ( ^{^{1 3 E, 1 4 E,}} 1 6 R, 6R) -3 5 - ^{^{-16-fluoro-2,6-dimethyl--16,}} ^17-- dihydro -1 ⁵ H-4- oxo-7-nitrogen - 1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(3,2)-pyridylcyclononane-8-one.

MS (ESI) M/Z: 383 [M+H ⁺ ].

¹ H NMR (400MHz, CDCl ₃ , ppm): δ10.35(d,J=8.0Hz,1H), 8.22(s,1H),7.96(s,1H),7.94(d,J=2.8Hz,1H ), 7.30 (dd, J = 8.0, 3.2 Hz, 1H), 5.19 (dd, J = 13.6, 1.6 Hz, 1H), 4.62 (dd, J = 10.4, 4.0 Hz, 1H), 4.53-4.43 (m, 2H), 4.17(dd,J=10.4,2.4Hz,1H), 4.09(d,J=14.8Hz,1H), 3.40-3.33(m,1H), 2.84-2.78(m,1H), 1.56(d , J=6.4Hz, 3H), 1.52 (d, J=6.8Hz, 3H).

Example 25: (1 ³ E,1 ⁴ E,16R,5S)-3 ⁵ -fluoro-1 ⁶ ,5-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ hydrogen-4-oxo-7 -Nitrogen-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(3,2)-pyridinecyclononane-8-one

Refer to Example 24 for the synthesis method.

MS (ESI) M/Z: 383 [M+H ⁺ ].

¹ H NMR(400MHz,CD ₃ OD)δ8.12(s,1H),8.02(s,1H),7.95(d,J=3.0Hz,1H),7.68(dd,J=8.4,3.0Hz,1H ), 5.35–5.30 (m, 1H), 4.97 (dd, J = 14.8, 1.6 Hz, 1H), 4.72–4.61 (m, 1H), 4.35 (d, J = 14.8 Hz, 1H), 4.05 (dd, J＝13.2,4.6Hz,1H), 3.46–3.39(m,1H), 2.87–2.82(m,1H), 1.53(d,J＝6.4Hz,3H), 1.52(d,J＝6.4Hz,3H ).

Example 26: (R,3'E,4'E)-5'-fluoro-6'-methylspiro[cyclopropane-1,6'-4-oxo-7-nitrogen-1(5,3) -Pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(3,2)-pyridylcyclononane-8'-one

Refer to Example 24 for the synthesis method.

MS (ESI) M/Z: 395 [M+H ⁺ ].

¹ H NMR (400MHz, CDCl ₃ ): δ9.95 (s, 1H), 8.16 (s, 1H), 7.97 (t, J = 1.6 Hz, 1H), 7.93 (d, J = 3.2 Hz, 1H), 7.28(dd,J＝8.0,2.8Hz,1H), 5.31(dd,J＝14.8,1.6Hz,1H), 4.86(dd,J＝10.8,1.6Hz,1H),4.44-4.40(m,1H) ,4.07(d,J=14.8Hz,1H), 3.68(d,J=10.8Hz,1H), 3.38-3.31(m,1H),2.83-2.77(m,1H),1.58(d,J=6.0 Hz, 3H), 1.53-1.46 (m, 1H), 1.11-1.08 (m, 1H), 1.01-0.95 (m, 1H), 0.79-0.74 (m, 1H).

Example 27: (1 ³ E,1 ⁴ E,1 ⁶ R,6R)-3 ⁵ -fluoro-1 ⁶ ,6-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-4-oxy -7-Nitro-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(3,2)-pyridinecyclononane-8-thione

The (1 ³ E, 1 ⁴ E, 1 ⁶ R, 6R)-3 ⁵ -fluoro-1 ⁶ ,6-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H- obtained in Example 24 4-oxo-7-nitrogen-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(3,2)-pyridine cyclononane-8- Ketone (30 mg, 0.078 mmol) was dissolved in toluene (2 mL), Lawson reagent (100 mg, 0.247 mmol) was added, microwaved at 80 degrees Celsius for 5 hours, diluted with ethyl acetate (60 mL), and saturated with chlorine Washed with sodium chloride solution (30 ml x 3 times), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: ethanol = 9: 3:1) to obtain 10 mg (1 ³ E, 1 ⁴ E, 1 ⁶ R, 6R) -3 ⁵ -fluoro-1 ⁶ ,6-dimethyl-1 ⁶ ,1 ⁷ -dihydro-1 ⁵ H-4-oxo-7 -Nitrogen-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(3,2)-pyridinecyclononane-8-thione.

MS (ESI) M/Z: 399 [M+H ⁺ ].

¹ H NMR (400MHz, CD ₃ OD) δ 12.52 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 8.10 (t, J = 2.0 Hz, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.67 (dd, J = 8.4, 2.8 Hz, 1H), 5.06 (dd, J = 15.2, 1.6 Hz, 1H), 4.72 (dd, J = 10.8, 4.0 Hz, 2H), 4.39–4.35 (m,1H), 4.29–4.27(m,1H), 3.40–3.56(m,1H), 2.86–2.80(m,2H), 1.55(d,J=6.8Hz,3H), 1.52(d,J =6.4Hz, 3H).

Biological activity experiment

1. Detection of NTRK kinase inhibitory activity

Homogeneous time-resolved fluorescence (HTRF) method was used to establish the kinase activity detection platform of TrkA, TrkB, and TrkC to determine the activity of the compound. Start the compound from 250μM, use 100% DMSO to carry out a 4-fold gradient dilution (2-10th concentration), the 11th concentration does not contain the compound (a total of 11 concentrations), each concentration 0.5μL is added to the 49.5μL reaction In the buffer (containing 5mM MgCl ₂ , 1mM DTT, 12.5nM SEB), mix well, and use as a 2.5* compound. Use reaction buffer to prepare 5*TrkA, 5*TrkB, 5*TrkC kinase (purchased in Thermo, final concentrations are 0.2ng/μL, 0.03ng/μL, 0.03ng/μL) and 2.5* substrate mixture (ATP+ TK peptide), (where the final concentration of ATP is 22μM, 7μM, 6.6μM; the final concentration of TK peptide is 1μM,

KinEASE ^TM -TK, purchased from Cisbio) ready for use. Add 4 μL of the compound to a 384-well plate (purchased in Thermo), add 4 μL of the substrate mixture, and then add 2 μL of kinase, centrifuge and mix, and start the reaction (the total reaction volume is 10 μL). Place the 384-well plate in an incubator at 30°C and incubate for 30 min, 40 min, and 45 min respectively, and then add 5 μL of Eu ³⁺ cryptate-labeled anti-phosphotyrosine antibody (cryptate-labled anti-phosphotyrosine antibody,

KinEASE ^TM -TK), 5μL XL-665 labeled streptavidin (Streptavidin-XL-665,

KinEASE ^TM -TK) stops the reaction. Then read the fluorescence value on a microplate reader (Tecan Spark) (320nm excitation, detection of 665nm and 620nm emission light, the ratio of the two is the enzyme activity). The enzyme activity was measured for each compound at 11 concentrations, and the data was calculated using Graphpad Prism7 to obtain the IC ₅₀ value of the compound.

2. TrkA ^G595R , TrkA ^G667C kinase inhibitory activity detection

The homogeneous time-resolved fluorescence (HTRF) method was used to establish the kinase activity detection platform of TrkA ^G595R and TrkA ^G667C to determine the activity of the compound. Start the compound from 250μM, use 100% DMSO to carry out a 4-fold gradient dilution (2-10th concentration), the 11th concentration does not contain the compound (a total of 11 concentrations), each concentration 0.5μL is added to the 49.5μL reaction In the buffer (containing 5mM MgCl ₂ , 1mM DTT, 12.5nM SEB), mix well, and use as a 2.5* compound. Use reaction buffer to prepare 5*TrkA ^G595R , 5*TrkA ^G667C kinase (purchased from SignalChem, the final concentration is 0.002ng/μL) and 2.5*substrate mixture (ATP+TK peptide) (the final concentration of ATP is 3.1μM, respectively) , 3.5μM; the final concentration of TK peptide is 1μM,

KinEASE ^TM -TK, purchased from Cisbio) ready for use. Take 4μL of the compound into a 384-well plate (purchased from Thermo), add 4μl of substrate mixture, and then add 2μL of kinase, centrifuge to mix, and start the reaction (total reaction volume is 10μl). Place the 384-well plate in an incubator at 30°C and incubate for 60 minutes, and then add 5 μL of Eu ³⁺ cryptate-labeled anti-phosphotyrosine antibody (cryptate-labled anti-phosphotyrosine antibody,

KinEASE ^TM -TK), 5μL XL-665 labeled streptavidin (Streptavidin-XL-665,

3. Cytological activity determination method

use

Luminescent Cell Viability Assay kit (purchased from Shanghai Promag Bioproducts Co., Ltd.) detects the inhibitory effect of compounds on cell proliferation activity. The cell line used was Ba/F3 cells stably transfected with TPM3-NTRKA. The cells are resuscitated and cultured for 3-5 days, after the cell viability reaches >95%, it can be used for cell proliferation experiments. Use Countstar (Shanghai Ruiyu Biological Co., Ltd.) to count the cell viability and concentration, and then inoculate the Costar 96-well white microtiter plate (purchased from Corning) at 4000 cells/100μL per well. During seeding, the cells are only seeded in the inner 60 microwells, and 100μL of phosphate buffered saline (PBS) is added to the peripheral wells to reduce edge effects. After the cells were seeded, they were placed in a 37°C CO ₂ incubator and cultured overnight. On the second day, the compound was diluted with 100% DMSO at a 3-fold gradient (9 concentrations in total) starting from 6mM, and the last well was a DMSO control without compound. Then add 1 μL of each concentration to 99 μL of cell culture medium and mix well to form a 6* compound solution. Use a multi-channel pipette to add 20 μL of the 6* compound solution to the cell well containing 100 μL of culture medium, shake gently to mix, and incubate in a 37°C CO ₂ incubator for 72 hours. After the compound treatment, the cell culture plate was taken out, placed on the laboratory table, and allowed to stand at room temperature for 30 minutes. Prepare according to the kit instructions provided by the manufacturer

Luminescent Cell Viability Assay (Luminescent Cell Viability Assay) related reagents, and then add 60μL to each well containing cells

Reagents. Place the culture plate on a horizontal shaker and shake for 30 minutes at a speed of 220 rpm; avoid light during incubation. Read the chemiluminescence value (Integration Time=0.25s) with a microplate reader (Tecan SPARK). The calculation formula for the inhibition rate (inh%) of each concentration is: inh%=(1-compound treatment well reading/DMSO control well reading)*100%. Is then calculated using Graphpad Prism7 data, the IC ₅₀ values obtained compound.

Acronym description:

In the above activity experiment, unless otherwise specified, the following terms have the following meanings:

(1) "*" means multiplication, which means multiple.

(2) "4-fold gradient dilution" means adding 3 volumes of diluted solution to 1 volume of original solution 1 to obtain original solution 2; then take 1 volume of original solution 2 and add 3 volumes of diluted solution to obtain original solution 3; By analogy, solutions of different concentrations are obtained.

(3) "3-fold gradient dilution" means adding 2 volumes of diluted solution to 1 volume of original solution 1 to obtain original solution 2; then take 1 volume of original solution 2 and add 2 volumes of diluted solution to obtain original solution 3; By analogy, solutions of different concentrations are obtained.

(4) "Final concentration" refers to the concentration in the starting reaction system, which is based on the total volume of the reaction.

(5) "DTT" means dithiothreitol, and "DMSO" means dimethyl sulfoxide.

The compounds prepared in the above examples were tested according to the biological methods described in this application, and the results are shown in Table 1:

Table 1 Inhibitory activity of compounds on wild-type and mutant TRKA kinases and Ba/F3-TMP3-NTRKA cells

Note:-means not tested.

Claims

A compound represented by formula I, its stereoisomers, its tautomers, its isotopic derivatives, its pharmaceutically acceptable salts or solvates:

Among them, Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;

M is C (R 4a ) or N;

M 1 is C(R 4b ) or N;

R 2 , R 4a , R 4b , R 5 and R 6 are each independently hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 Alkyl), -(C 1-4 alkyl)-OH, -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 Alkyl) -NH 2 , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

R 4 is hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-OH , -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or -C(O)N(R 25a )(R 25b );

R 25a and R 25b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-12 membered hetero Aryl group, wherein the C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 10 aryl group and 5-12 membered heteroaryl group are each independently Optionally by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkane yl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1-4 alkyl) 2, - (C 1- 4 alkyl) -NH 2, C 3-6 cycloalkyl Substituents of alkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

Alternatively, R 25a and R 25b together with the nitrogen atom to which they are attached form a 3-8 membered heterocycloalkyl group, the 3-8 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2 , -NH(C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6- Substituents of 10 aryl and 5-12 membered heteroaryl;

R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)OR a, or -C(O)NR a R b , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally selected by one or more independently selected from halogen, -CN, and C 1-4 alkyl group , C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl),- N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5- Substituent substitution of 12-membered heteroaryl;

Alternatively, R 1a and R 1b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl Each independently is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1 -4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2, - (C 1-4 alkyl) -NH 2, -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1 -4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)( C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3- Substituents of 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

X 1 is a single bond, S, S(O), S(O) 2 , O, N(R 7 ) or C(R 24a )(R 24b );

R 7 , R 24a and R 24b are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl And 3-6 membered heterocycloalkyl substituents;

Alternatively, R 7 and R 1a and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1- 4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl Group), -N(C 1-4 alkyl) C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC (O) N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl substituent substituted;

Alternatively, R 7 and R 5 and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocycloalkyl group and the 5-6 membered heteroaryl group The group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2, and - (C 1-4 alkyl) -NH 2 substituents; The heteroatom in the 5-6 membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2 or 3;

p is 0 or 1;

X 8 is O or S;

X 6 is N(R 13 );

R 13 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl and 3-6 membered heterocycloalkane Substituent substitution of the group;

X 5 is C(R 16 ) or N; and, when p is 0, X 5 is N;

R 3 , R 11 and R 16 are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently any Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl substituents;

Alternatively, R 3 , R 11 and X 5 together form a C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each Independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1- 4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1- 4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 Substituent substitution of cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

Or, R 3 and R 4 are connected together to form
The wavy line a is connected to X 5 , and the wavy line b is connected to the position where R 4 is connected;

Or, R 3 and R 4 are connected to each other so that
And R 4 replaced with
The g end of the wave line is connected to X 3 , and the end of the wave line f is connected to the carbon atom connected to M;

X 7 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );

k is 0, 1 or 2;

n is 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;

X 4 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );

Each R 12 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is each independently optionally by one or more independent Selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4-alkyl), - C (O) NH 2, -C (O) NH (C 1-4 alkyl), - C (O) N (C 1-4 alkyl) 2, -NHC (O ) (C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 alkyl), - NHC ( O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycle Substituents of alkyl, C 6-10 aryl and 5-12 membered heteroaryl;

Each of R 10a , R 10b , R 14 and R 15 is independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , where Said C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N ( C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2, -NHC (O) ( C 1-4 alkyl), - N (C 1 -4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1- 4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered hetero Substitution of aryl group;

Alternatively, R 10a and R 10b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group, wherein the C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1-4 alkyl) 2, - (C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC( O) (C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl) 2, -NHC (O) NH (C 1-4 alkyl), Substituents of C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

Or, R 10a and R 13 and the atoms to which they are attached together form

R 9a and R 9b are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl, and 4-7 membered heterocycloalkyl are each independently optionally substituted with one or more substituents independently selected from halogen, -CN, C 1- 4 alkyl, C 1-4 haloalkyl, -OH , -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O )(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC (O) NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl substituents;

Alternatively, R 9a and R 10a and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 3-6 membered hetero The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC( O) (C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl) 2, -NHC (O) NH (C 1-4 alkyl), Substituents of C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl

Alternatively, R 9a and R 9b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl or 3-6 membered hetero The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC( O) (C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl) 2, -NHC (O) NH (C 1-4 alkyl), Substituents of C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

m is 0 or 1;

And, the premise is that condition (i) or (ii) is satisfied:

(i) When m is 1, X 3 is C, and X 3 and R 6 and the carbon atoms to which they are connected together form a phenyl group or a 6-membered heteroaryl group; wherein the heteroaryl group in the 6-membered heteroaryl group The atom is nitrogen, and the number of heteroatoms is 1 or 2;

(ii) When m is 0, X 1 is N(R 7 ), and R 7 and R 5 and their connected atoms together form

Wherein, X 2 is S, S(O), S(O) 2 , O, N(R 2a ) or C(R 3a )(R 3b );

t is 0 or 1;

Y is
The d end of the wavy line is connected to the X 2 end, and the c end of the wavy line is connected to the N atom; and, when X 2 is O and t is 1, Y is not

Y 1 is C(R 6a ) or N;

Y 2 is C(R 6b ) or N;

R 2a is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 The membered heterocycloalkyl group is independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl)-OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2. -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O) N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC (O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl) , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl substituents;

Each R 3a , R 3b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, halogen, -CN, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR b C(O)R a , -C(O)OR a , -C(O)NR b R c , C 1-6 alkyl, C 3-6 cycloalkyl Or 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen , -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4 Alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl substituents are substituted;

Each R a, R b and R c are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;

The heteroatoms in the heterocycloalkyl and heteroaryl groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
The compound of formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate as claimed in claim 1, characterized in that: The structure of the compound represented by formula I is as follows:

Among them, Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;

M is C (R 4a ) or N;

M 1 is C(R 4b ) or N;

R 2 , R 4a , R 4b , R 5 and R 6 are each independently hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 Alkyl), -(C 1-4 alkyl)-OH, -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 Alkyl) -NH 2 , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

R 4 is hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-OH , -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or -C(O)N(R 25a )(R 25b );

R 25a and R 25b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-12 membered hetero Aryl group, wherein the C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 10 aryl group and 5-12 membered heteroaryl group are each independently Optionally by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkane yl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1-4 alkyl) 2, - (C 1- 4 alkyl) -NH 2, C 3-6 cycloalkyl Substituents of alkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

Alternatively, R 25a and R 25b together with the nitrogen atom to which they are attached form a 3-8 membered heterocycloalkyl group, the 3-8 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2 , -NH(C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6- Substituents of 10 aryl and 5-12 membered heteroaryl;

R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)OR a, or -C(O)NR a R b , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally selected by one or more independently selected from halogen, -CN, and C 1-4 alkyl group , C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl),- N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5- Substituent substitution of 12-membered heteroaryl;

Alternatively, R 1a and R 1b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl Each independently is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1 -4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2, - (C 1-4 alkyl) -NH 2, -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1 -4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)( C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3- Substituents of 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

X 1 is a single bond, S, S(O), S(O) 2 , O, N(R 7 ) or C(R 24a )(R 24b );

R 7 , R 24a and R 24b are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl And 3-6 membered heterocycloalkyl substituents;

Alternatively, R 7 and R 1a and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1- 4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl Group), -N(C 1-4 alkyl) C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC (O) N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl substituent substituted;

Alternatively, R 7 and R 5 and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocycloalkyl group and the 5-6 membered heteroaryl group The group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2, and - (C 1-4 alkyl) -NH 2 substituents; The heteroatom in the 5-6 membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2 or 3;

p is 0 or 1;

X 6 is N(R 13 );

R 13 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl and 3-6 membered heterocycloalkane Substituent substitution of the group;

X 5 is C(R 16 ) or N; and, when p is 0, X 5 is N;

R 3 , R 11 and R 16 are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently any Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl substituents;

Alternatively, R 3 , R 11 and X 5 together form a C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each Independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1- 4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1- 4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 Substituent substitution of cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

Or, R 3 and R 4 are connected together to form
The wavy line a is connected to X 5 , and the wavy line b is connected to the position where R 4 is connected;

Or, R 3 and R 4 are connected to each other so that
And R 4 replaced with
The g end of the wave line is connected to X 3 , and the end of the wave line f is connected to the carbon atom connected to M;

X 7 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );

k is 0, 1 or 2;

n is 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;

X 4 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );

Each R 12 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is each independently optionally by one or more independent Selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4-alkyl), - C (O) NH 2, -C (O) NH (C 1-4 alkyl), - C (O) N (C 1-4 alkyl) 2, -NHC (O ) (C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 alkyl), - NHC ( O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycle Substituents of alkyl, C 6-10 aryl and 5-12 membered heteroaryl;

Each of R 10a , R 10b , R 14 and R 15 is independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , where Said C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N ( C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2, -NHC (O) ( C 1-4 alkyl), - N (C 1 -4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1- 4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered hetero Substitution of aryl group;

Alternatively, R 10a and R 10b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group, wherein the C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1-4 alkyl) 2, - (C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC( O) (C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl) 2, -NHC (O) NH (C 1-4 alkyl), Substituents of C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

Or, R 10a and R 13 and the atoms to which they are attached together form

R 9a and R 9b are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl, and 4-7 membered heterocycloalkyl are each independently optionally substituted with one or more substituents independently selected from halogen, -CN, C 1- 4 alkyl, C 1-4 haloalkyl, -OH , -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O )(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC (O) NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl substituents;

Alternatively, R 9a and R 10a and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 3-6 membered hetero The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC( O) (C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl) 2, -NHC (O) NH (C 1-4 alkyl), Substituents of C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl

Alternatively, R 9a and R 9b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl or 3-6 membered hetero The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC( O) (C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl) 2, -NHC (O) NH (C 1-4 alkyl), Substituents of C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

m is 0 or 1;

And, the premise is that condition (i) or (ii) is satisfied:

(i) When m is 1, X 3 is C, and X 3 and R 6 and the carbon atoms to which they are connected together form a phenyl group or a 6-membered heteroaryl group; wherein the heteroaryl group in the 6-membered heteroaryl group The atom is nitrogen, and the number of heteroatoms is 1 or 2;

(ii) When m is 0, X 1 is N(R 7 ), and R 7 and R 5 and their connected atoms together form

Wherein, X 2 is S, S(O), S(O) 2 , O, N(R 2a ) or C(R 3a )(R 3b );

t is 0 or 1;

Y is
The d end of the wavy line is connected to the X 2 end, and the c end of the wavy line is connected to the N atom; and, when X 2 is O and t is 1, Y is not

Y 1 is C(R 6a ) or N;

Y 2 is C(R 6b ) or N;

R 2a is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 The membered heterocycloalkyl group is independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl)-OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2. -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O) N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC (O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl) , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl substituents;

Each R 3a , R 3b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, halogen, -CN, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR b C(O)R a , -C(O)OR a , -C(O)NR b R c , C 1-6 alkyl, C 3-6 cycloalkyl Or 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen , -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4 Alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl substituents are substituted;

Each R a, R b and R c are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;

The heteroatoms in the heterocycloalkyl and heteroaryl groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
The compound of formula I, its stereoisomer, its tautomer, its isotopic derivative, its pharmaceutically acceptable salt or its solvate according to claim 1 or 2, characterized in , The halogen and the halogen in the C 1-4 haloalkyl are each independently fluorine, chlorine, bromine or iodine;

And / or a C 1-4 alkyl, C 1-4 haloalkyl in the C 1-4 alkyl, the -O (C 1-4 alkyl) is C 1- 4 alkyl group, said - (C 1-4 alkyl) -OH is C 1-4 alkyl, said -NH (C 1-4 alkyl) is C 1-4 alkyl, the described -N (C 1-4 alkyl) 2 C 1-4 alkyl of said - (C 1-4 alkyl) -NH 2 C 1-4 in the alkyl group, the - C (O) O (C 1-4 alkyl) in C 1-4 alkyl, said -C (O) NH (C 1-4 alkyl) in C 1-4 alkyl, said is -C (O) N (C 1-4 alkyl) 2 in C 1-4 alkyl, said -NHC (O) (C 1-4 alkyl) is C 1-4 alkyl, said -N (C 1- 4 alkyl) C (O) (C 1-4 alkyl) is C 1-4 alkyl, said -OC (O) (C 1-4 alkyl) The C 1-4 alkyl in the -NHC(O)N(C 1-4 alkyl) 2 , the C 1-4 alkyl in the -NHC(O)NH(C 1-4 C 1-4 alkyl in alkyl) is each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or, the C 1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or, the C 3-6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

And/or, the 3-8 membered heterocycloalkyl is independently 3, 4, 5, 6, 7 or 8 membered heterocycloalkyl;

And/or, the 4-7 membered heterocycloalkyl is independently 4, 5, 6 or 7 membered heterocycloalkyl;

And/or, the 3-6 membered heterocycloalkyl is independently a 3, 4, 5 or 6 membered heterocycloalkyl;

And/or, the C 6-10 aryl group is independently phenyl;

And/or, the 5-12 membered heteroaryl group is independently a 5-6 membered heteroaryl group;

And/or, the heterocycloalkyl group is a saturated heterocycloalkyl group;

And/or, the cycloalkyl group is a saturated cycloalkyl group.
The compound of formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate according to any one of claims 1-3 , Characterized in that R 2 is halogen;

And/or, when R 4 is present and not connected to other variables, R 4 is halogen;

And/or, R 4a is hydrogen;

And/or, R 4b is hydrogen;

And/or, when R 5 is present and not connected to other variables, R 5 is hydrogen;

And / or, when R 6 is present and not connected to other variables, R 6 is hydrogen, -NH 2, -NH- (C 1-4 alkyl), or -N (C 1- 4 alkyl) 2;

And/or, when R 7 and R 5 and the atoms they are connected together form
When the said
for

And/or, when R 3a is present, R 3a is hydrogen or halogen;

And/or, when R 3b is present, R 3b is hydrogen or halogen;

And/or, R 1b is hydrogen or C 1-6 alkyl, and the C 1-6 alkyl is optionally selected by one or more independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O(C 1-4 alkyl), -(C 1-4 alkyl)-OH and C 3-6 cycloalkyl substituents;

And/or, when R 1a is not connected to other variables, R 1a is hydrogen or C 1-6 alkyl, and the C 1-6 alkyl is optionally selected by one or more independently selected from halogen, C 1- 4 Alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH and C 3-6 cycloalkyl substituents are substituted;

And/or, X 1 is N(R 7 );

And/or, when R 7 is present and not connected to other variables, R 7 is hydrogen or C 1-6 alkyl;

And/or, when R 7 and R 1a and their connected atoms together form a 4-7 membered heterocycloalkyl, R 7 and R 1a and their connected atoms together form
Wherein, each R 21 is independently halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)(C 1-4 Alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl And 3-6 membered heterocycloalkyl; each u is independently 0, 1 or 2; R 20 is hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH,- O(C 1-4 alkyl), -(C 1-4 alkyl)-OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 ,- (C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1- 4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)( C 1-4 alkyl), -OC(O) (C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O ) NH(C 1-4 alkyl), C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

And/or, when R 13 is present and not connected to other variables, R 13 is hydrogen;

And/or, when R 16 is present, R 16 is hydrogen;

And/or, X 5 is N;

And/or, when R 3 is not connected to other variables, R 3 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl;

And/or, when R 11 is not connected to other variables, R 11 is hydrogen;

And/or, when R 3 , R 11 and X 5 together form a 3-8 membered heterocycloalkyl group,
for
Wherein each R 23 is independently halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C (O) O (C 1- 4 alkyl), - C (O) NH 2, -C (O) NH (C 1-4 alkyl), - C (O) N (C 1-4 alkyl ) 2, -NHC (O) ( C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C 6-10 aryl or 5-12 membered heteroaryl; v is 0, 1, 2 or 3; R 22 is hydrogen, halogen, -CN, C 1-4 alkane group, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), -N (C 1-4 alkyl) 2, - (C 1-4 alkyl) -NH 2, -CO 2 H, -C (O) O (C 1- 4 alkyl), - C (O) NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 alkyl), - NHC (O) NH 2, -NHC (O) N ( C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl or 5- 12-membered heteroaryl;

And/or, when R 3 and R 4 are connected to each other, R 3 and R 4 are connected together to form

And/or, when R 3 and R 4 are joined together to form
Time,
for

And/or, when X 4 is present, X 4 is C(R 14 )(R 15 ) or O;

And/or, when R 14 is present, R 14 is hydrogen;

And/or, when R 15 is present, R 15 is hydrogen;

And/or, when the carbon atom to which R 1a and R 1b are connected has chirality, it is in R configuration or S configuration;

And/or, when the carbon atom to which R 9a and R 9b are connected has chirality, it is in R configuration or S configuration;

And/or, when m is 1, X 3 is C, X 3 and R 6 and the carbon atoms to which they are attached together form a phenyl group.
The compound of formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate according to any one of claims 1 to 4 , Characterized in that R 2 is fluorine;

And/or, when R 4 is present and not connected to other variables, R 4 is fluorine;

And/or, when R 6 is present and not connected to other variables, R 6 is hydrogen or -NH 2 ;

And/or, when R 7 is present and not connected to other variables, R 7 is hydrogen;

And/or, when R 7 and R 5 and the atoms they are connected together form
When the said
for

And/or, when R 3a is present, R 3a is hydrogen or fluorine;

And/or, when R 3b is present, R 3b is hydrogen or fluorine;

And/or, R 1b is hydrogen or C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by a C 3-6 cycloalkyl;

And/or, when R 1a is not connected to other variables, R 1a is hydrogen or C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by a C 3-6 cycloalkyl;

And/or, when R 5a is present, R 5a is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally selected by one or more independently selected from halogen, -CN, C 1-4 Alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl) , -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O )NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl),- N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N (C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5 -12-membered heteroaryl substituent substitution;

And/or, when R 5b is present, R 5b is hydrogen;

And/or, when R 6a is present, R 6a is hydrogen;

And/or, when R 6b is present, R 6b is hydrogen;

And/or, when R 7a is present, R 7a is hydrogen;

And/or, when R 7b is present, R 7b is hydrogen;

And/or, when R 7 and R 1a and their connected atoms together form a 4-7 membered heterocycloalkyl, R 7 and R 1a and their connected atoms together form
Wherein, R 20 is hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O(C 1-4 alkyl), -(C 1-4 alkyl)- OH, -NH 2, -NH (C 1-4 alkyl), - N (C 1- 4 alkyl) 2, - (C 1-4 alkyl) -NH 2, -CO 2 H, -C ( O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl) ), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl or 3 -6 membered heterocycloalkyl;

And/or, when R 3 is not connected to other variables, R 3 is hydrogen or C 1-6 alkyl;

And/or, when R 3 , R 11 and X 5 together form a 3-8 membered heterocycloalkyl group,
for
Wherein each R 23 is independently C 1-4 alkyl, -OH, -O (C 1-4 alkyl), or - (C 1-4 alkyl) -OH; v is 0 or 3; R 22 is hydrogen, C 1-4 alkyl, -OH, -O(C 1-4 alkyl) or -(C 1-4 alkyl)-OH;

And/or, when R 3 and R 4 are joined together,
Time,
for

And/or, when X 4 is present, X 4 is CH 2 or O;

And/or, when R 9b is present, R 9b is hydrogen;

And/or, when R 9a is present and not connected to other variables, R 9a is hydrogen or C 1-6 alkyl;

And/or, when R 10a is present and not connected to other variables, R 10a is hydrogen or C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by one or more hydroxyl groups;

And/or, when R 10b is present and not connected to other variables, R 10b is hydrogen or C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted with one or more hydroxy groups.
The compound of formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate according to any one of claims 1-5 , Characterized in that, when R 4 exists and is not connected to other variables,
for

And/or, when R 3 and R 4 are joined together to form
Time,
for
The e end of the wavy line is connected to the M1 connection position, and the wavy line f end is connected to the R 4 connection position;

And/or, when R 6 is present and not connected to other variables, R 6 is hydrogen;

And/or, when R 3a and R 3b are present, R 3a and R 3b are both hydrogen;

And/or, R 1b is hydrogen;

And/or, when R 1a is not connected to other variables, R 1a is methyl or

And/or, when R 5a is present, R 5a is hydrogen or C 1-6 alkyl;

And/or, when R 7 and R 1a and their connected atoms together form a 4-7 membered heterocycloalkyl, R 7 and R 1a and their connected atoms together form
Wherein, R 20 is hydrogen or halogen;

And/or, when R 3 , R 11 and X 5 together form a 3-8 membered heterocycloalkyl group,
for
Wherein, each R 23 is independently C 1-4 alkyl, -OH, -O(C 1-4 alkyl) or -(C 1-4 alkyl)-OH; v is 0, 1, 2 or 3; R 22 is -OH;

and / or,
for

And/or, when R 9a is present and not connected to other variables, R 9a is hydrogen or methyl;

And/or, when R 10a is present and not connected to other variables, R 10a is hydrogen, methyl or

And/or, when R 10b is present and not connected to other variables, R 10b is hydrogen;

And/or, when R 3 and R 4 are joined together to form
Time,
for
The compound of formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate according to any one of claims 1-6 , Characterized in that, when R 4 exists and is not connected to other variables,
for

And/or, when R 3 and R 4 are joined together to form
Time,
for
The e end of the wavy line is connected to the M1 connection position, and the wavy line f end is connected to the R 4 connection position;

And/or, when R 7 and R 5 and the atoms they are connected together form
When the said
for

And/or, when R 7 and R 1a and their connected atoms together form a 4-7 membered heterocycloalkyl, R 7 and R 1a and their connected atoms together form
Wherein, R 20 is hydrogen or fluorine;

And/or, when R 1b is hydrogen,
for

And/or, when R 3 and R 4 are not connected to each other, p is 1;

And/or, when R 3 , R 11 and X 5 together form a 3-8 membered heterocycloalkyl group,
for

And/or, when R 3 and R 4 are joined together to form
Time,
for
The compound of formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate as claimed in claim 1, characterized in that:

Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;

M is CH or N;

M 1 is N;

R 2 and R 4 are each independently hydrogen or halogen;

R 5 and R 6 are hydrogen;

R 1b is hydrogen;

R 1a is a C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally substituted by a C 3-6 cycloalkyl group;

X 1 is N(R 7 );

R 7 is hydrogen or C 1-6 alkyl;

Alternatively, R 7 and R 1a and the atoms to which they are attached together form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally substituted by one or more halogens;

p is 0 or 1;

X 6 is N(R 13 );

R 13 is hydrogen;

X 5 is N; and, when p is 0, X 5 is N;

R 11 is hydrogen;

R 3 is hydrogen, C 1-6 alkyl or C 3-6 alkyl;

Alternatively, R 3 , R 11 and X 5 together form a 3-8 membered heterocycloalkyl group, wherein each of the 3-8 membered heterocycloalkyl group is independently optionally selected by one or more independently selected from C 1-4 Alkyl, -OH, -O (C 1-4 alkyl) and -(C 1-4 alkyl) -OH substituents;

Or, R 3 and R 4 are connected together to form
The wavy line a is connected to X 5 , and the wavy line b is connected to the position where R 4 is connected;

n is 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;

X 4 is O or CH 2 ;

R 10a and R 10b are each independently hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more -OH;

Alternatively, R 10a and R 10b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl group;

Or, R 10a and R 13 and the atoms to which they are attached together form

R 9a and R 9b are each independently hydrogen or C 1-6 alkyl;

Alternatively, R 9a and R 10a and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl group;

m is 0 or 1;

And, the premise is that condition (i) or (ii) is satisfied:

(i) When m is 1, X 3 is C, and X 3 and R 6 and the carbon atoms to which they are attached together form a phenyl group;

(ii) When m is 0, R 7 and R 5 and their connected atoms together form
Said
for

R 3a and R 3b are each independently hydrogen or halogen;

The heteroatoms in the heterocycloalkyl group are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
The compound of formula I, its stereoisomers, its tautomers, its isotope derivatives, its pharmaceutically acceptable salts, or its solvates according to claim 1, characterized in that:

Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;

M is CH or N;

M 1 is N;

R 2 and R 4 are each independently hydrogen or halogen;

R 5 and R 6 are hydrogen;

R 1b is hydrogen;

R 1a is a C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally substituted by a C 3-6 cycloalkyl group;

X 1 is N(R 7 );

R 7 is hydrogen or C 1-6 alkyl;

p is 0 or 1;

X 6 is N(R 13 );

R 13 is hydrogen;

X 5 is N; and, when p is 0, X 5 is N;

R 11 is hydrogen;

R 3 is hydrogen, C 1-6 alkyl or C 3-6 alkyl;

Alternatively, R 3 , R 11 and X 5 together form a 3-8 membered heterocycloalkyl group, wherein each of the 3-8 membered heterocycloalkyl group is independently optionally selected by one or more independently selected from C 1-4 Alkyl, -OH, -O (C 1-4 alkyl) and -(C 1-4 alkyl) -OH substituents;

Or, R 3 and R 4 are connected together to form
The wavy line a is connected to X 5 , and the wavy line b is connected to the position where R 4 is connected;

n is 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;

X 4 is O or CH 2 ;

R 10a and R 10b are each independently hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more -OH;

Or, R 10a and R 13 and the atoms to which they are attached together form

m is 0 or 1;

And, the premise is that condition (i) or (ii) is satisfied:

(i) When m is 1, X 3 is C, and X 3 and R 6 and the carbon atoms to which they are attached together form a phenyl group;

(ii) When m is 0, R 7 and R 5 and their connected atoms together form
Said
for

The heteroatoms in the heterocycloalkyl group are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
The compound of formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate as claimed in claim 1, characterized in that: The structure of the compound represented by formula I is as follows:

Among them, Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;

M is C (R 4a ) or N;

M 1 is C(R 4b ) or N;

R 2 , R 4a , R 4b and R 6 are each independently hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 alkyl) , -(C 1-4 alkyl)-OH, -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)OR a, or -C(O)NR a R b , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally selected by one or more independently selected from halogen, -CN, and C 1-4 alkyl group , C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl),- N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5- Substituent substitution of 12-membered heteroaryl;

Alternatively, R 1a and R 1b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl Each independently is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1 -4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2, - (C 1-4 alkyl) -NH 2, -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1 -4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)( C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3- Substituents of 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

p is 0 or 1;

X 6 is N(R 13 );

R 13 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl and 3-6 membered heterocycloalkane Substituent substitution of the group;

X 5 is C(R 16 ) or N; and, when p is 0, X 5 is N;

R 11 and R 16 are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently optionally substituted by one Or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH , -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O )O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC (O) (C 1- 4 alkyl), - N (C 1-4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 alkyl) , -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3- Substituents of 6-membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

n is 0, 1, or 2, provided that the result of adding n and p is 1 or 2;

X 4 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );

R 12 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl are each independently optionally selected from one or more halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1- 4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)( C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 alkyl), - NHC (O) NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , C 6-10 aryl and 5-12 membered heteroaryl substituents;

R 10a , R 10b , R 14 and R 15 are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1- 4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1 -4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2, -NHC (O) ( C 1-4 alkyl), - N (C 1-4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl Group) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl Substituent substitution;

Alternatively, R 10a and R 10b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group, wherein the C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1-4 alkyl) 2, - (C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC( O) (C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl) 2, -NHC (O) NH (C 1-4 alkyl), Substituents of C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

Or, R 10a and R 13 and the atoms to which they are attached together form

R 9a and R 9b are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl, and 4-7 membered heterocycloalkyl are each independently optionally substituted with one or more substituents independently selected from halogen, -CN, C 1- 4 alkyl, C 1-4 haloalkyl, -OH , -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O )(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC (O) NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl substituents;

Alternatively, R 9a and R 10a and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 3-6 membered hetero The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC( O) (C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl) 2, -NHC (O) NH (C 1-4 alkyl), Substituents of C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl

Alternatively, R 9a and R 9b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl or 3-6 membered hetero The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC( O) (C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl) 2, -NHC (O) NH (C 1-4 alkyl), Substituents of C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

X 2 is S, S(O), S(O) 2 , O, N(R 2a ) or C(R 3a )(R 3b );

t is 0 or 1;

Y is
The d end of the wavy line is connected to the X 2 end, and the c end of the wavy line is connected to the N atom; and, when X 2 is O and t is 1, Y is not

Y 1 is C(R 6a ) or N;

Y 2 is C(R 6b ) or N;

R 2a is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 Each membered heterocycloalkyl group is independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl) , -(C 1-4 alkyl)-OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)- NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O ) N (C 1- 4 alkyl) 2, -NHC (O) ( C 1-4 alkyl), - N (C 1-4 alkyl) C (O) (C 1-4 alkyl), - OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl) ), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl substituents;

Each R 3a , R 3b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, halogen, -CN, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR b C(O)R a , -C(O)OR a , -C(O)NR b R c , C 1-6 alkyl, C 3-6 cycloalkyl Or 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen , -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4 Alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl substituents are substituted;

Each R a, R b and R c are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;

The heteroatoms in the heterocycloalkyl and heteroaryl groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
The compound of formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate as claimed in claim 1, characterized in that: The structure of the compound represented by formula I is as follows:

Among them, Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;

M is C (R 4a ) or N;

M 1 is C(R 4b ) or N;

R 2 , R 4a , R 4b and R 5 are each independently hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 alkyl) , -(C 1-4 alkyl)-OH, -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)OR a, or -C(O)NR a R b , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally selected by one or more independently selected from halogen, -CN, and C 1-4 alkyl group , C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl),- N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5- Substituent substitution of 12-membered heteroaryl;

Alternatively, R 1a and R 1b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl Each independently is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1 -4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2, - (C 1-4 alkyl) -NH 2, -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1 -4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)( C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3- Substituents of 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

X 1 is a single bond, S, S(O), S(O) 2 , O, N(R 7 ) or C(R 24a )(R 24b );

R 7 , R 24a and R 24b are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl And 3-6 membered heterocycloalkyl substituents;

Alternatively, R 7 and R 1a and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1- 4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl Group), -N(C 1-4 alkyl) C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC (O) N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl substituent substituted;

Alternatively, R 7 and R 5 and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocycloalkyl group and the 5-6 membered heteroaryl group The group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2, and - (C 1-4 alkyl) -NH 2 substituents; The heteroatom in the 5-6 membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2 or 3;

p is 0;

X 5 is N;

R 11 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently optionally selected from one or more halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1- 4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)( C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 alkyl), - NHC (O) NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , C 6-10 aryl and 5-12 membered heteroaryl substituents;

n is 0 or 1;

X 4 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );

R 12 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl are each independently optionally selected from one or more halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1- 4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)( C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 alkyl), - NHC (O) NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , C 6-10 aryl and 5-12 membered heteroaryl substituents;

R 10a , R 10b , R 14 and R 15 are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1- 4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1 -4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2, -NHC (O) ( C 1-4 alkyl), - N (C 1-4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl Group) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl Substituent substitution;

Alternatively, R 10a and R 10b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group, wherein the C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1-4 alkyl) 2, - (C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC( O) (C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl) 2, -NHC (O) NH (C 1-4 alkyl), Substituents of C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

R 9a and R 9b are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl, and 4-7 membered heterocycloalkyl are each independently optionally substituted with one or more substituents independently selected from halogen, -CN, C 1- 4 alkyl, C 1-4 haloalkyl, -OH , -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O )(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC (O) NH(C 1-4 alkyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl substituents;

Alternatively, R 9a and R 10a and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 3-6 membered hetero The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC( O) (C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl) 2, -NHC (O) NH (C 1-4 alkyl), Substituents of C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl

Alternatively, R 9a and R 9b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl or 3-6 membered hetero The cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC( O) (C 1- 4 alkyl), - NHC (O) NH 2, -NHC (O) N (C 1-4 alkyl) 2, -NHC (O) NH (C 1-4 alkyl), Substituents of C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

Each R a, R b and R c are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;

The heteroatoms in the heterocycloalkyl and heteroaryl groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
The compound of formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate as claimed in claim 1, characterized in that: The structure of the compound represented by formula I is as follows:

Among them, Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;

M is C (R 4a ) or N;

M 1 is C(R 4b ) or N;

R 2 , R 4a , R 4b and R 5 are each independently hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 alkyl) , -(C 1-4 alkyl)-OH, -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

R 4 is hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-OH , -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or -C(O)N(R 25a )(R 25b );

R 25a and R 25b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-12 membered hetero Aryl group, wherein the C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 10 aryl group and 5-12 membered heteroaryl group are each independently Optionally by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkane yl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1-4 alkyl) 2, - (C 1- 4 alkyl) -NH 2, C 3-6 cycloalkyl Substituents of alkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

Alternatively, R 25a and R 25b together with the nitrogen atom to which they are attached form a 3-8 membered heterocycloalkyl group, the 3-8 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2 , -NH(C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6- Substituents of 10 aryl and 5-12 membered heteroaryl;

R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)OR a, or -C(O)NR a R b , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally selected by one or more independently selected from halogen, -CN, and C 1-4 alkyl group , C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl),- N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5- Substituent substitution of 12-membered heteroaryl;

Alternatively, R 1a and R 1b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl Each independently is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1 -4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2, - (C 1-4 alkyl) -NH 2, -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1 -4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)( C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3- Substituents of 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

X 1 is a single bond, S, S(O), S(O) 2 , O, N(R 7 ) or C(R 24a )(R 24b );

R 7 , R 24a and R 24b are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl And 3-6 membered heterocycloalkyl substituents;

Alternatively, R 7 and R 1a and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1- 4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl Group), -N(C 1-4 alkyl) C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC (O) N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl substituent substituted;

Alternatively, R 7 and R 5 and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocycloalkyl group and the 5-6 membered heteroaryl group The group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2, and - (C 1-4 alkyl) -NH 2 substituents; The heteroatom in the 5-6 membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2 or 3;

p is 0 or 1;

X 6 is N(R 13 );

R 13 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl and 3-6 membered heterocycloalkane Substituent substitution of the group;

X 5 is C(R 16 ) or N; and, when p is 0, X 5 is N;

R 3 , R 11 and R 16 are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently any Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl substituents;

Alternatively, R 3 , R 11 and X 5 together form a C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each Independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1- 4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1- 4 alkyl) 2 , -NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NHC(O)NH(C 1-4 alkyl), C 3-6 Substituent substitution of cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-12 membered heteroaryl;

Each R a, R b and R c are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;

The heteroatoms in the heterocycloalkyl and heteroaryl groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
The compound of formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate as claimed in claim 1, characterized in that: The compound represented by formula I has any of the following structures:

Wherein, Z 1 , Z 2 , M, M 1 , R 1a , R 2 , R 3a , R 3b , R 5a , R 6 , R 7 , R 9a , R 9b , R 10a and R 10b are as defined in the claims As described in any one of 1-12.
The compound of formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate according to any one of claims 1-13 , Characterized in that Z 1 is C and Z 2 is N.
The compound of formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate according to any one of claims 1-13 , Characterized in that Z 1 is N and Z 2 is C.
The compound of formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate as claimed in claim 1, characterized in that: The compound represented by formula I has any of the following structures:
A method for preparing the compound of formula I according to claim 1, which is selected from any of the following schemes:

Scheme 1 includes the following steps: in a solvent, the compound represented by formula II and the compound
Carry out the condensation reaction shown below in the presence of carbonyl diimidazole to obtain the compound shown in formula I; wherein p is 1, X 5 is N, R 3 is not connected to R 4 , and other variables are as claimed in claim 1. -16;

Scheme 2 includes the following steps: in a solvent, the compound represented by formula III and the compound
Carry out the condensation reaction shown below to obtain the compound shown in formula I; wherein p is 1, X 5 is N, R 3 is not connected to R 4 , and other variables are as defined in any one of claims 1-16 Narrate

Scheme 3 includes the following steps: in a solvent, the compound represented by formula IV and the compound
Carry out the condensation reaction as shown below in the presence of a condensing agent and a base to obtain the compound shown in formula I; wherein p is 0, X 5 is N, R 3 is not connected to R 4 , and other variables are as claimed Any one of 1-16;

Scheme 4 includes the following steps: in a solvent, the compound represented by formula V is subjected to the condensation reaction shown below in the presence of a base to obtain the compound represented by formula I; where p is 1, X 5 Is N, R 3 and R 4 are connected together to form
Other variables are as described in any one of claims 1-16;

Scheme 5 includes the following steps: in a solvent, the compound represented by formula VI is subjected to the condensation reaction shown below in the presence of a condensing agent and a base to obtain a compound represented by formula I; where p is 0, X 5 is N, R 3 and R 4 are connected together to form
Other variables are as described in any one of claims 1-16;
A compound of any of the following structures:

The variables are as described in any one of claims 1-16.
A pharmaceutical composition comprising the compound represented by formula I, its stereoisomers, its tautomers, its isotopic derivatives, and its pharmaceutically Acceptable salts or solvates thereof, and pharmaceutical excipients.
A compound of formula I, its stereoisomers, its tautomers, its isotope derivatives, its pharmaceutically acceptable salts, or its pharmaceutically acceptable salt according to any one of claims 1-16 Use of a solvate or the pharmaceutical composition according to claim 19 in the preparation of a medicine for treating cancer, pain, neurological disease, autoimmune disease or inflammation.
A compound of formula I, its stereoisomers, its tautomers, its isotope derivatives, its pharmaceutically acceptable salts, or its pharmaceutically acceptable salt according to any one of claims 1-16 Application of solvates in the preparation of Trk kinase inhibitors.