WO2021218755A1

WO2021218755A1 - Shp2 inhibitor, and composition and use thereof

Info

Publication number: WO2021218755A1
Application number: PCT/CN2021/088871
Authority: WO
Inventors: 吴颢; 吴文茂; 李玲; 张展; 王丰; 袁丁; 吴云飞; 陈强; 韩晗; 郭晶; 兰宏; 丁列明; 王家炳
Original assignee: 贝达药业股份有限公司
Priority date: 2020-04-30
Filing date: 2021-04-22
Publication date: 2021-11-04
Also published as: CN115279749A; CN115279749B

Abstract

The present invention relates to a compound (as represented by formula I) serving as an Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) inhibitor, a pharmaceutical composition thereof, a preparation method therefor, and the use thereof in the treatment of SHP2-mediated diseases. The compound has an effect by means of participating in the regulation of multiple processes, such as cell proliferation, apoptosis, migration and angiogenesis.

Description

SHP2 inhibitor and its composition and application

Technical field

The present invention relates to a series of compounds as inhibitors of Src homology region 2 (Src homology region 2-containing protein tyrosine phosphatase 2, SHP2), and preparation methods and pharmaceutical compositions thereof. The present invention also relates to the use of the above-mentioned compound or its pharmaceutical composition in the treatment of SHP2-mediated diseases.

Background technique

Src homology region 2 protein tyrosine phosphatase 2 (Src homology region 2-containing protein tyrosine phosphatase 2, SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, and PTPN11 is the first The discovered proto-oncogene encoding tyrosine kinase (Chan R J et al.PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase.Blood, 2007,109:862-867), and the encoded SHP2 protein contains N-terminal SHP2 domain (N-SHP2), C-terminal SHP2 domain (C-SHP2), protein phosphatase catalytic domain (PTP), two C-terminal tyrosine residues (Y542 and Y580) and a rich Proline (Pro) motif.

In recent years, research mainly believes that the Ras/ERK pathway is the most important signal transduction pathway for SHP2, and its mechanism (Dance M et al. The molecular functions of Shp2 in the RAS/mitogen-activated protein kinase (ERK1/2) pathway. Cell Signal, 2008, 20:453-459) roughly: After the growth factor receptor is activated, its tyrosine residues undergo autophosphorylation, which is the combination of Grb2 and SHP2 (adapter protein containing SH2 domain) phosphotyrosine Area SH2 provides stop points. The binding of Grb2 to phosphorylated growth factor receptors results in the accumulation of SOS protein in the cell membrane. As a guanine nucleotide exchange factor (GEF), SOS can catalyze the conversion of the membrane-bound protein Ras from inactive Ras-GDP to active Ras-GTP. Ras-GTP further connects with downstream signaling systems to activate Ser/Thr kinase Raf1, etc., and then activate ERK under the action of the regulatory kinase MEK. After activation, ERK directly acts on target molecules in the cytoplasm or transfers to the nucleus to regulate genes. Transcription to make cells proliferate or differentiate. This process may also be affected by SHP2 binding protein and substrate (SHP substrate-1, SHPS-1), Ras-GTPase activating protein (Ras-GAP) and other Src members.

SHP2 protein not only regulates the Ras/ERK signaling pathway, it is also reported to regulate multiple signaling pathways such as JAK-STAT3, NF-κB, PI3K/Akt, RHO, and NFAT, thereby regulating cell proliferation, differentiation, migration, apoptosis and other physiology Function.

SHP2 has been proved to be related to many diseases. Tartaglia et al. (Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syne drome. Nat Genet, 2001, 29: 465-468) found about 50 % Of patients with Noonan syndrome have missense mutations of PTPN11. In addition, studies have found that PTPN11 mutation is an important cause of JMML and a variety of leukemias (Tartaglia M et al. Nat Genet, 2003, 34: 148-150; Loh ML et al. Blood, 2004, 103: 2325-2331; Tartaglia M et al. Br J Haematol, 2005, 129: 333-339; Xu R et al. Blood, 2005, 106: 3142-3149.). With the deepening of research on PTPN11/SHP2, it has been found that it is related to the occurrence of lung cancer, gastric cancer, colon cancer, melanoma, thyroid cancer and other cancers (Tang Chunlan et al. Chinese Journal of Lung Cancer, 2010, 13: 98- 101; Higuchi M et al. Cancer Sci, 2004, 95: 442-447; Bentiers-Al j M et al. Cancer Res, 2004, 64: 8816-8820; Martinelli S et al. Cancer Genet Cytogenet, 2006, 166: 124-129.).

Therefore, SHP2 inhibitors have received more and more attention as potential treatments. There are a variety of SHP2 inhibitors currently under development. Novartis's TNO155 entered phase I clinical trials for the treatment of solid tumors in 2017. JAB-3068, designed and developed by Jacos, was officially approved by the US FDA for clinical trials of new drugs in January 2018. The RMC-4630 developed by Revolution undergoes its first human clinical trial in the second half of 2018. At present, there is no marketed product for this target at home and abroad.

Compound 243 was disclosed in the WO2019183367 patent published on September 26, 2019, and it was recorded that the IC ₅₀ measurement data in the SHP2 allosteric inhibition test was greater than 50 nM and less than or equal to 1 uM.

Therefore, the development of small molecule drugs that can target to inhibit SHP2 activity and provide patients with safer and more effective SHP2 inhibitors has important research significance.

Summary of the invention

The present invention relates to a compound as an inhibitor of Src homologous region 2 protein tyrosine phosphatase 2 (SHP2), or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, and solvate thereof , Chelate, non-covalent complex or prodrug, the compound is shown in formula I:

in,

Single bond or double bond;

Ring A is selected from a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; wherein the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains one or more O, N or S heteroatom; the 5-10 membered heterocyclic group contains at least one double bond;

Ring C is selected from C _3-10 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aryl group or 5-10 membered heteroaryl group;

Each R ^{c is} independently selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -SR ⁶ , -NR ⁷ R ⁸ , -(C=O)R ⁹ , -C (=O)OR ¹⁰ , -C(=O)NR ¹¹ R ¹² , -S(=O) ₂ R ¹³ , -S(=O) ₂ OR ¹⁴ , -S(=O) ₂ NR ¹⁵ R ¹⁶ , -O(CH ₂ ) _s OR ¹⁷ , -O(CH ₂ ) _s NR ¹⁸ R ¹⁹ , -NR ²⁰ (CH ₂ ) _t NR ²¹ R ²² , -NR ²³ (CH ₂ ) _t OR ²⁴ ; wherein, the C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-4 alkyl, C _2-4 alkenyl, C _{2- 4} alkynyl, C _3-10 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aryl, 5-10 membered heteroaryl, -OR ⁵ , -SR ⁶ , -NR ⁷ R ⁸ ,- (C=O)R ⁹ , -C(=O)OR ¹⁰ , -C(=O)NR ¹¹ R ¹² , -S(=O) ₂ R ¹³ , -S(=O) ₂ OR ¹⁴ , -S (=O) ₂ NR ¹⁵ R ¹⁶ , -O(CH ₂ ) _s OR ¹⁷ , -O(CH ₂ ) _s NR ¹⁸ R ¹⁹ , -NR ²⁰ (CH ₂ ) _t NR ²¹ R ²² , -NR ²³ (CH ₂ ) _t OR ²⁴ ;

R ^c1 and R ^c2 are each independently selected from hydrogen, halogen, C _1-4 alkyl or -OR ⁵ ;

Or R ^c1 and R ^c2 together with the atoms to which they are connected form a C _3-6 carbocyclic group or a 3-6 membered heterocyclic group;

Each R ^{1 is} independently selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 carbocyclic ring Group, 3-6 membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -NR ⁷ R ⁸ , -O(CH ₂ ) _s OR ¹⁷ , -O(CH ₂ ) _s NR ¹⁸ R ¹⁹ , -NR ²⁰ (CH ₂ ) _t NR ²¹ R ²² , -NR ²³ (CH ₂ ) _t OR ²⁴ ; wherein the C _1-4 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl, C _3-6 carbocyclic group, 3-6 membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; Substituents are selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 carbocyclic group, 3-6 Membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -SR ⁶ , -NR ⁷ R ⁸ , -(C=O)R ⁹ , -C(=O)OR ¹⁰ or -C(=O)NR ¹¹ R ¹² ;

M is selected from -O-, -NR ^1a -or -CR ^1b R ^1c -;

R ^{1a is} selected from hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

R ^1b and R ^1c are each independently selected from hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, -OR ^1d , -NR ^1e R ^1f or not present;

R ^1d , R ^1e , and R ^1f are each independently selected from hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocyclic group;

Y _{1 is} selected from -NR ^3a -or -CR ^3b R ^3c -;

R ^{3a is} selected from hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

R ^3b and R ^3c are each independently selected from hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

Y _{2 is} selected from -NR ^4a -or -CR ^4b R ^4c -;

R ^{4a is} selected from hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

R ^4b and R ^4c are each independently selected from hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

The ring D is a C _6-10 aryl group, a 5-10 membered heteroaryl group, a C _3-8 carbocyclic group, a 3-8 membered heterocyclic group or not present; wherein, the C _3-8 carbocyclic group Or a 3-8 membered heterocyclic group optionally contains a double bond;

Each R ^{4 is} independently selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -SR ⁶ , -NR ⁷ R ⁸ , -(C=O)R ⁹ , -C (=O)OR ¹⁰ , -C(=O)NR ¹¹ R ¹² , -S(=O) ₂ R ¹³ , -S(=O) ₂ OR ¹⁴ , -S(=O) ₂ NR ¹⁵ R ¹⁶ , -O(CH ₂ ) _s OR ¹⁷ , -O(CH ₂ ) _s NR ¹⁸ R ¹⁹ , -NR ²⁰ (CH ₂ ) _t NR ²¹ R ²² , -NR ²³ (CH ₂ ) _t OR ²⁴ ; wherein, the C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-4 alkyl, C _2-4 alkenyl, C _{2- 4} alkynyl, C _3-10 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aryl, 5-10 membered heteroaryl, -OR ⁵ , -SR ⁶ , -NR ⁷ R ⁸ ,- (C=O)R ⁹ , -C(=O)OR ¹⁰ , -C(=O)NR ¹¹ R ¹² , -S(=O) ₂ R ¹³ , -S(=O) ₂ OR ¹⁴ , -S (=O) ₂ NR ¹⁵ R ¹⁶ , -O(CH ₂ ) _s OR ¹⁷ , -O(CH ₂ ) _s NR ¹⁸ R ¹⁹ , -NR ²⁰ (CH ₂ ) _t NR ²¹ R ²² , -NR ²³ (CH ₂ ) _t OR ²⁴ ;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , -NR ²³ and R ²⁴ are each independently selected from hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 carbocyclic group, 3-10 member Heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

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

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

s is 1, 2, 3 or 4;

t is 1, 2, 3 or 4;

When n=0, the ring A is

And when ring C is phenyl, r is not equal to 0, and Rc is not hydrogen.

In some embodiments, in the formula I, ring A is selected from a 6-10 membered heteroaryl group or a 6-10 membered heterocyclic group; the 6-10 membered heterocyclic group contains at least one double bond.

In some embodiments, in the formula I, ring A is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl or pyrimidinonyl.

In some embodiments, in the formula I, ring A is selected from

Wherein, X ₁ and X ₂ are each independently selected from -NR ¹ -or -CR ¹ R ¹ -.

In some embodiments, in the formula I, ring A is selected from

In some embodiments, in the formula I, the ring C is selected from a C _3-10 carbocyclic group or a 3-10 membered heterocyclic group.

In some embodiments, in the formula I, the ring C is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl or piperidinyl.

In some embodiments, in the formula I, the ring C is selected from a C _6-10 aryl group or a 5-10 membered heteroaryl group.

In some embodiments, in the formula I, the ring C is selected from the group consisting of pyrazolyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, indolinyl, isoindolinyl, indolyl Azolyl, benzimidazolyl, purinyl, benzisoxazolyl, or indolazinyl.

In some embodiments, in the formula I, the ring C is selected from phenyl,

In some embodiments, in the formula I, n is 0 or 1.

In some embodiments, in the formula I, n is zero.

In some embodiments, in the formula I, n is 1.

In some embodiments, in the formula I, n is 2.

In some embodiments, in the formula I, each R ^{c is} independently selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aryl, 5-10 membered heteroaryl, -OR ⁵ , -SR ⁶ , -NR ⁷ R ⁸ , -(C=O)R ⁹ , -C(=O)OR ¹⁰ , -C(=O)NR ¹¹ R ¹² , -S(=O) ₂ R ¹³ , -S(=O) ₂ OR ¹⁴ , -S(=O) ₂ NR ¹⁵ R ¹⁶ , -O(CH ₂ ) _s OR ¹⁷ , -O(CH ₂ ) _s NR ¹⁸ R ¹⁹ , -NR ²⁰ (CH ₂ ) _t NR ²¹ R ²² , -NR ²³ (CH ₂ ) _t OR ²⁴ ; wherein the C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aryl and 5-10 membered heteroaryl are optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-4 alkane Group, C _2-4 alkenyl group, C _2-4 alkynyl group, C _3-10 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -SR ⁶ , -NR ⁷ R ⁸ , -(C=O)R ⁹ , -C(=O)OR ¹⁰ , -C(=O)NR ¹¹ R ¹² , -S(=O) ₂ R ¹³ , -S(=O) ₂ OR ¹⁴ , -S(=O) ₂ NR ¹⁵ R ¹⁶ , -O(CH ₂ ) _s OR ¹⁷ , -O(CH ₂ ) _s NR ¹⁸ R ¹⁹ , -NR ²⁰ (CH ₂ ) _t NR ²¹ R ²² or -NR ²³ (CH ₂ ) _t OR ²⁴ .

In some embodiments, in the formula I, each R ^{c is} independently selected from hydrogen, oxo, -NO ₂ , -CH ₃ , -OCH ₃ , -OH, -CN, -F,- Cl, -CF ₃ , -NH ₂ , -NHCH ₃ , -NHC(=O)CH ₃ , -C(=O)NH ₂ , -CH ₂ OH, -COOH, -COOEt, -S(=O) ₂ CH ₃ , -S(=O) ₂ NH ₂ , -CH ₂ OCH ₃ ,

In some embodiments, in the formula I, R ^c1 and R ^c2 are each independently selected from hydrogen, halogen, C _1-4 alkyl or -OR ⁵ .

In some embodiments, in the formula I, R ^c1 and R ^c2 are each independently selected from hydrogen, -CH ₃ , -F, and -OH.

In some embodiments, in the formula I, R ^c1 and R ^c2 are each independently selected from hydrogen.

In some embodiments, in the formula I, R ^c1 and R ^c2 together with the atoms to which they are attached form a cyclopropyl group.

In some embodiments, in the formula I, each R ^{1 is} independently selected from hydrogen, halogen, oxo, C _1-4 alkyl, -NR ⁷ R ⁸ ; wherein, the C _1-4 alkane The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-4 alkyl, C _2-4 alkenyl, C _{2- 4} alkynyl group, C _3-6 carbocyclic group, 3-6 membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -SR ⁶ , -NR ⁷ R ⁸ ,- (C=O)R ⁹ , -C(=O)OR ¹⁰ or -C(=O)NR ¹¹ R ¹² .

In some embodiments, in the formula I, each R ^{1 is} independently selected from hydrogen, oxo, -CH ₃ , -NH ₂ , and -CH ₂ OH.

In some embodiments, in the formula I, M is selected from -O- or -CR ^1b R ^1c -.

In some embodiments, in the formula I, R ^1b and R ^1c are each independently selected from hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR ^1d Or -NR ^1e R ^1f .

In some embodiments, in the formula I, Y _{1 is} selected from -NR ^3a -, and Y _{2 is} selected from -CR ^4b R ^4c -.

In some embodiments, in the formula I, Y _{1 is} selected from -CR ^3b R ^3c -, and Y _{2 is} selected from -NR ^4a -.

In some embodiments, in the formula I, Y _{1 is} selected from -CR ^3b R ^3c -, and Y _{2 is} selected from -CR ^4b R ^4c -.

In some embodiments, in the formula I, the ring D is a C _6-10 aryl group or a 5-10 membered heteroaryl group.

In some embodiments, in the formula I, the ring D is

In some embodiments, in the formula I, the ring D is a C _3-8 carbocyclic group or a 3-8 membered heterocyclic group.

In some embodiments, in the formula I, the ring D is

In some embodiments, in the formula I, each R ^{4 is} independently selected from hydrogen, halogen, oxo, C _1-8 alkyl, or -OR ⁵ .

In some embodiments, in the formula I, each R ^{4 is} independently selected from hydrogen, oxo, -CH ₃ or -OCH ₃ .

In some embodiments, in the formula I, p is 1, 2, or 3.

In some embodiments, in the formula I, q is 0, 1, or 2.

In some embodiments, in the formula I, r is 0, 1, 2 or 3.

In some embodiments, in the formula I, s is 1 or 2.

In some embodiments, in the formula I, t is 1 or 2.

In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, is selected Self-style II:

in,

Single bond or double bond;

M is selected from -O-, -NR ^1a -or -CR ^1b R ^1c -;

Y _{1 is} selected from -NR ^3a -or -CR ^3b R ^3c -;

Y _{2 is} selected from -NR ^4a -or -CR ^4b R ^4c -;

The ring D is a C _6-10 aryl group, a 5-10 membered heteroaryl group, a C _3-8 carbocyclic group or a 3-8 membered heterocyclic group; wherein, the C _3-8 carbocyclic group or a 3- The 8-membered heterocyclic group optionally contains a double bond;

p is 0, 1, 2 or 3;

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

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

s is 1, 2, 3 or 4;

t is 1, 2, 3, or 4.

In some embodiments, in the formula II, ring A is selected from a 6-10 membered heteroaryl group or a 6-10 membered heterocyclic group; the 6-10 membered heterocyclic group contains at least one double bond.

In some embodiments, in the formula II, ring A is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl or pyrimidinonyl.

In some embodiments, in the formula II, ring A is selected from

Wherein, X1 and X2 are each independently selected from -NR ¹ -or -CR ¹ R ¹ -.

In some embodiments, in the formula II, ring A is selected from

In some embodiments, in the formula I, ring A is selected from

In some embodiments, in the formula I, ring A is selected from

In some embodiments, in the formula II, the ring C is selected from 3-10 membered heterocyclic groups.

In some embodiments, in the formula II, the ring C is selected from morpholinyl, piperazinyl or piperidinyl.

In some embodiments, in the formula II, the ring C is selected from a C6-10 aryl group or a 5-10 membered heteroaryl group.

In some embodiments, in the formula II, the ring C is selected from the group consisting of pyrazolyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, indolinyl, isoindolinyl, indolyl Azolyl, benzimidazolyl, purinyl, benzisoxazolyl, or indolazinyl.

In some embodiments, in the formula II, the ring C is selected from phenyl,

In some embodiments, in the formula II, the ring C is selected from phenyl.

In some embodiments, in the formula II, each R ^{c is} independently selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aryl, 5-10 membered heteroaryl, -OR ⁵ , -SR ⁶ , -NR ⁷ R ⁸ , -(C=O)R ⁹ , -C(=O)OR ¹⁰ , -C(=O)NR ¹¹ R ¹² , -S(=O) ₂ R ¹³ , -S(=O) ₂ OR ¹⁴ , -S(=O) ₂ NR ¹⁵ R ¹⁶ , -O(CH ₂ ) _s OR ¹⁷ , -O(CH ₂ ) _s NR ¹⁸ R ¹⁹ , -NR ²⁰ (CH ₂ ) _t NR ²¹ R ²² , -NR ²³ (CH ₂ ) _t OR ²⁴ ; wherein the C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aryl and 5-10 membered heteroaryl are optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-4 alkane Group, C _2-4 alkenyl group, C _2-4 alkynyl group, C _3-10 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -SR ⁶ , -NR ⁷ R ⁸ , -(C=O)R ⁹ , -C(=O)OR ¹⁰ , -C(=O)NR ¹¹ R ¹² , -S(=O) ₂ R ¹³ , -S(=O) ₂ OR ¹⁴ , -S(=O) ₂ NR ¹⁵ R ¹⁶ , -O(CH ₂ ) _s OR ¹⁷ , -O(CH ₂ ) _s NR ¹⁸ R ¹⁹ , -NR ²⁰ (CH ₂ ) _t NR ²¹ R ²² or -NR ²³ (CH ₂ ) _t OR ²⁴ .

In some embodiments, in the formula II, each R ^{c is} independently selected from hydrogen, oxo, -NO ₂ , -CH ₃ , -OCH ₃ , -OH, -CN, -F,- Cl, -CF ₃ , -NH ₂ , -NHCH ₃ , -NHC(=O)CH ₃ , -C(=O)NH ₂ , -CH ₂ OH, -COOH, -COOEt, -S(=O) ₂ CH ₃ , -S(=O) ₂ NH ₂ , -CH ₂ OCH ₃ ,

In some embodiments, in the formula II, R ^c1 and R ^c2 are each independently selected from hydrogen, halogen, C _1-4 alkyl, and -OR ⁵ .

In some embodiments, in the formula II, R ^c1 and R ^c2 are each independently selected from hydrogen, -CH ₃ , -F, and -OH.

In some embodiments, in the formula II, R ^c1 and R ^c2 are each independently selected from hydrogen.

In some embodiments, in the formula II, R ^c1 and R ^c2 together with the atoms to which they are attached form a cyclopropyl group.

In some embodiments, in the formula II, each R ^{1 is} independently selected from hydrogen, halogen, oxo, C _1-4 alkyl, -NR ⁷ R ⁸ ; wherein, the C _1-4 alkane The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-4 alkyl, C _2-4 alkenyl, C _{2- 4} alkynyl, C _3-6 carbocyclyl, 3-6-membered heterocyclyl, C _6- ₁₀ aryl, 5-10 membered ^{^{heteroaryl, -OR 5, -SR 6, -NR}} 7 R 8, - (C=O)R ⁹ , -C(=O)OR ¹⁰ or -C(=O)NR ¹¹ R ¹² .

In some embodiments, in the formula II, each R ^{1 is} independently selected from hydrogen, oxo, -CH ₃ , -NH ₂ , and -CH ₂ OH.

In some embodiments, in the formula II, M is selected from -O- or -CR ^1b R ^1c -.

In some embodiments, in the formula II, R ^1b and R ^1c are each independently selected from hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR ^1d Or -NR ^1e R ^1f .

In some embodiments, in the formula II, Y _{1 is} selected from -NR ^3a -, and Y _{2 is} selected from -CR ^4b R ^4c -.

In some embodiments, in the formula II, Y _{1 is} selected from -CR ^3b R ^3c -, and Y _{2 is} selected from -NR ^4a -.

In some embodiments, in the formula II, Y _{1 is} selected from -CR ^3b R ^3c -, and Y _{2 is} selected from -CR ^4b R ^4c -.

In some embodiments, in the formula II, the ring D is a C _6-10 aryl group or a 5-10 membered heteroaryl group.

In some embodiments, in the formula II, the ring D is

In some embodiments, in the formula II, each R ^{4 is} independently selected from hydrogen, halogen, oxo, C _1-8 alkyl, or -OR ⁵ .

In some embodiments, in the formula II, each R ^{4 is} independently selected from hydrogen, oxo, -CH ₃ or -OCH ₃ .

In some embodiments, in the formula I, q is 0, 1, or 2.

In some embodiments, in the formula I, r is 0, 1, 2 or 3.

In some embodiments, in the formula I, s is 1 or 2.

In some embodiments, in the formula I, t is 1 or 2.

In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, is selected Self-Form III:

in,

Single bond or double bond;

M is selected from -O-, -NR ^1a -or -CR ^1b R ^1c -;

Y _{1 is} selected from -NR ^3a -or -CR ^3b R ^3c -;

Y _{2 is} selected from -NR ^4a -or -CR ^4b R ^4c -;

p is 0, 1, 2 or 3;

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

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

s is 1, 2, 3 or 4;

t is 1, 2, 3 or 4;

When ring A is

And when ring C is phenyl, r is not equal to 0, and Rc is not hydrogen.

In some embodiments, in the formula III, ring A is selected from a 6-10 membered heteroaryl group or a 6-10 membered heterocyclic group; the 6-10 membered heterocyclic group contains at least one double bond.

In some embodiments, in the formula III, ring A is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl or pyrimidinonyl.

In some embodiments, in the formula III, ring A is selected from

In some embodiments, in the formula III, ring A is selected from

In some embodiments, in the formula III, ring A is selected from

In some embodiments, in the formula III, ring A is selected from

In some embodiments, in the formula III, the ring C is selected from a C _3-10 carbocyclic group or a 3-10 membered heterocyclic group.

In some embodiments, in the formula III, the ring C is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl or piperidinyl.

In some embodiments, in the formula III, each R ^{c is} independently selected from hydrogen, halogen, -CN, oxo, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkyne Group, C _3-8 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -SR ⁶ , -NR ⁷ R ⁸ , -(C ＝O)R ⁹ , -C(＝O)OR ¹⁰ , -C(＝O)NR ¹¹ R ¹² , -S(＝O) ₂ R ¹³ , -S(＝O) ₂ OR ¹⁴ , -S(＝ O) ₂ NR ¹⁵ R ¹⁶ , -O(CH ₂ ) _s OR ¹⁷ , -O(CH ₂ ) _s NR ¹⁸ R ¹⁹ , -NR ²⁰ (CH ₂ ) _t NR ²¹ R ²² , -NR ²³ (CH ₂ ) _t OR ²⁴ ; wherein, the C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-8 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aromatic group And 5-10 membered heteroaryl groups are optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-4 alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, C _3-10 carbocyclic group, 3-10 membered heterocyclic group, C _6-10 aryl, 5-10 membered heteroaryl, -OR ⁵ , -SR ⁶ , -NR ⁷ R ⁸ , -(C=O)R ⁹ , -C(=O)OR ¹⁰ , -C(=O)NR ¹¹ R ¹² , -S(=O) ₂ R ¹³ , -S(= O) ₂ OR ¹⁴ , -S(=O) ₂ NR ¹⁵ R ¹⁶ , -O(CH ₂ ) _s OR ¹⁷ , -O(CH ₂ ) _s NR ¹⁸ R ¹⁹ , -NR ²⁰ (CH ₂ ) _t NR ²¹ R ²² or -NR ²³ (CH ₂ ) _t OR ²⁴ .

In some embodiments, in the formula III, each R ^{c is} independently selected from hydrogen, oxo, -CH ₃ , -OCH ₃ , -OH, -CN, -F, -Cl, -CF ₃ , -NH ₂ , -NHCH ₃ , -CH ₂ OH, -COOH, -COOEt, -S(=O) ₂ CH ₃ , -S(=O) ₂ NH ₂ , -CH ₂ OCH ₃ ,

In some embodiments, in the formula III, each R ^{1 is} independently selected from hydrogen, halogen, oxo, C _1-4 alkyl, -NR ⁷ R ⁸ ; wherein, the C _1-4 alkane The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO ₂ , oxo, C _1-4 alkyl, C _2-4 alkenyl, C _{2- 4} alkynyl, C _3-6 carbocyclyl, 3-6-membered heterocyclyl, C _6- ₁₀ aryl, 5-10 membered ^{^{heteroaryl, -OR 5, -SR 6, -NR}} 7 R 8, - (C=O)R ⁹ , -C(=O)OR ¹⁰ or -C(=O)NR ¹¹ R ¹² .

In some embodiments, in the formula III, each R ^{1 is} independently selected from hydrogen, oxo, -CH ₃ , -NH ₂ , and -CH ₂ OH.

In some embodiments, in the formula III, M is selected from -O- or -CR ^1b R ^1c -.

In some embodiments, in the formula III, R ^1b and R ^1c are each independently selected from hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR ^1d Or -NR ^1e R ^1f .

In some embodiments, in the formula III, Y _{1 is} selected from -NR ^3a -, and Y _{2 is} selected from -CR ^4b R ^4c -.

In some embodiments, in the formula III, Y _{1 is} selected from -CR ^3b R ^3c -, and Y _{2 is} selected from -NR ^4a -.

In some embodiments, in the formula III, Y _{1 is} selected from -CR ^3b R ^3c -, and Y _{2 is} selected from -CR ^4b R ^4c -.

In some embodiments, in the formula III, the ring D is a C _6-10 aryl group or a 5-10 membered heteroaryl group.

In some embodiments, in the formula III, the ring D is

In some embodiments, in the formula III, the ring D is

In some embodiments, in the formula III, the ring D is

In some embodiments, in the formula III, the ring D is a C _3-8 carbocyclic group or a 3-8 membered heterocyclic group.

In some embodiments, in the formula III, the ring D is

In some embodiments, in the formula III, each R ^{4 is} independently selected from hydrogen, halogen, oxo, C _1-8 alkyl, or -OR ⁵ .

In some embodiments, in the formula III, each R ^{4 is} independently selected from hydrogen, oxo, -CH ₃ or -OCH ₃ .

In some embodiments, in the formula I, q is 0, 1, or 2.

In some embodiments, in the formula I, r is 0, 1, 2 or 3.

In some embodiments, in the formula I, s is 1 or 2.

In some embodiments, in the formula I, t is 1 or 2.

In some embodiments, the compound of formula I is selected from:

3-(5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine-2 -Base)-1-phenylprop-2-yn-1-ol;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-phenylprop-1-yne -1-yl)pyrazin-2-yl)methanol;

(S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl) Pyrazin-2-yl)prop-2-yn-1-yl)phenol;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-morpholinoprop-1-yne -1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4-methylpiperazine- 1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4-methoxybenzene (Yl)propyl-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(1-methyl-1H -Pyrazol-5-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-4-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl) Pyrazin-2-yl)prop-2-yn-1-yl)phenol;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-hydroxyphenyl)propane -1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-chloro-3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl)propane -1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3,4-dihydroxybenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-3-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)benzonitrile;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(2- (Trifluoromethyl)pyridin-3-yl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(trifluoro (Methyl)phenyl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-methoxyphenyl )Prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3,4-difluorobenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(R)-2-(1-Amino-8-azaspiro[4.5]dec-8-yl)-5-(3-(3-hydroxyphenyl)prop-1-yn-1-yl)-3 -Methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-3-methyl (Oxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2,3-dihydroxybenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3,5-dihydroxybenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(4- Morpholinophenyl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(6-methoxypyridine- 3-yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-4-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2-fluorobenzonitrile;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(6-hydroxypyridine-3- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(6-hydroxypyridine-2- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-hydroxypyridine-4- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-amino-3-chloro (Pyridin-4-yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-hydroxypyrimidine-4- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-aminopyrimidine-4- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-hydroxyl (Pyridin-4-yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-4-(3-(4-Amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl 6-oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2-fluorobenzonitrile;

(S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-amino -3-Chloropyridin-4-yl)prop-1-yn-1-yl)-3-methylpyrimidine-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(2- (Methylamino)pyridin-4-yl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-aminopyrimidine-5- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-5-(3-(4-(1H-pyrazol-1-yl)phenyl)prop-1-in-1-yl)-2-(1-amino-1,3-dihydrospiro Cyclo[indene-2,4'-piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;

4-(3-(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)-1-fluoropropene-2-p-1-yl)-2-hydroxybenzonitrile;

(S)-5-(3-(1H-indazol-6-yl)prop-1-yn-1-yl)-2-(1-amino-1,3-dihydrospiro[indene-2 ,4'-Piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxy-4-? (Pholinyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-6-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)indol-2-one;

(S)-5-(3-(1H-indol-6-yl)prop-1-yn-1-yl)-2-(1-amino-1,3-dihydrospiro[indene-2, 4'-Piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl)propane -1-yn-1-yl)pyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-amino-3-chloro (Pyridin-4-yl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;

(S)-5-(3-(2-Amino-3-chloropyridin-4-yl)prop-1-yn-1-yl)-2-(1-amino-6-methoxy-1,3 -Dihydrospirocyclo[indene-2,4'-piperidine]-1'-yl)pyrimidin-4(3H)-one;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-fluoro-3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-chloro-2,3 -Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-6-amino-2-(4-amino-4,6-dihydrospiro[d]thiazole-5,4'-piperidine]-1'-yl)-5-(3-(4 -Chloro-3-hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(4-Amino-4,6-dihydrospiro[d]thiazole-5,4'-piperidine]-1'-yl)-5-(3-(4-chloro-3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-2,3 -Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-3,5 -Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-6-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)propan-2-oct-1-yl)-2-hydroxy-3-methylbenzonitrile;

(S)-4-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2-hydroxybenzonitrile;

(S)-2-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-6-hydroxybenzonitrile;

(S)-4-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2,6-dihydroxybenzonitrile;

(S)-6-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-3-chloro-2-hydroxybenzonitrile;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl)- 3-methyl-1-yl)-3-methylpyrimidin-4(3H)-one;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-fluoro-3-(3-methyl (Oxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-hydroxy-3-(3-methyl (Oxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-hydroxy-3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(5-Amino-5,7-dihydrospiro[b]pyridine-6,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl) )Prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(7-Amino-5,7-dihydrospiro[d]pyrimidine-6,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl )Prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-((1-phenyl Cyclopropyl)ethynyl)pyrimidin-4(3H)-one;

(R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidine]-1'-yl)-5-(3-(4-chloro-3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(R)-2-(3'-Amino-3'H-spiro[piperidine-4,2'-thiophene[2,3-b]furan]-1-yl)-5-(3-(3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(R)-2-(6-Amino-6H-spiro[fluoro[3,2-d]thiazole-5,4'-piperidine]-1'-yl)-5-(3-(3-hydroxy (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(3-Amino-3H-spiro[furan[3,2-b]furan-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(6-Amino-6H-spiro[fluoro[2,3-d]oxazole-5,4'-piperidine]-1'-yl)-5-(3-(3- Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(R)-2-(6-Amino-2-methyl-6H-spiro[fluoro[3,2-d]thiazole-5,4'-piperidine]-1'-yl)-5-(3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2-(hydroxymethyl)cyclopropyl (Yl)ethynyl)-3-methylpyrimidin-4(3H)-one;

5-((2-(1,3,4-oxadiazol-2-yl)cyclopropyl)ethynyl)-2-((S)-1-amino-1,3-dihydrospiro[indene -2,4'-piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;

2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-yl)ethynyl)ethyl cyclopropane-1-carboxylate;

2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-yl)ethynyl)cyclopropane-1-carboxylic acid;

2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-yl)ethynyl)-N-cyclopropylcyclopropane-1-carboxamide;

2-((2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6-oxo -1,6-Dihydropyrimidin-5-yl)ethynyl)cyclopropane-1-carboxylic acid ethyl ester;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-((2-(methyl (Sulfonyl)cyclopropyl)ethynyl)pyrimidin-4(3H)-one;

2-((2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6-oxo -1,6-Dihydropyrimidin-5-yl)ethynyl)cyclopropane-1-sulfonamide;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-((2-(2 ,2,2-Trifluoro-1-hydroxyethyl)cyclopropyl)ethynyl)pyrimidin-4(3H)-one;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2-(methoxymethyl) Cyclopropyl)ethynyl)-3-methylpyrimidin-4(3H)-one;

(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'piperidine]-1'-yl)-5-(2-oxo-8-azaspiro[ 4.5] Dec-8-yl)3-hydroxy-3-(4-morpholinphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-2-yl)ethynyl)cyclopropaneamide;

2-((3S,4S)-4-amino-3-methyl-2-oxo-8-azo[4.5]dec-8-yl)-5-(3-(3-hydroxyphenyl)propan- 1-Alkyn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-3-carboxamide;

(S)-N-(3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)phenyl)acetamide;

(S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)benzamide;

(S)-4-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)benzamide;

(S)-4-(4-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)but-3-yn-1-yl)benzamide;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(4-phenylbut-1-yne- 1-yl)pyrazin-2-yl)methanol;

(S)-2-(3-(5-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)isoindoline-5-carboxamide;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-(3-(indol-1-yl) Prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-ol;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-amino-1H-indyl) Dol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-yl)acetamide;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6-amino-1H-indyl (Azol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4-amino-1H-indyl (Azol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indazole-5-carboxamide;

(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-4-yl)acetamide;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-benzo[d]imidazole-5-carboxamide;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-benzo[d]imidazole-6-carboxamide;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-methoxy-1H -Benzo[d]imidazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(6-(3-(1H-indol-1-yl)prop-1-yn-1-yl)-3-(1-amino-1,3-dihydrospiro[indene-2, 4'-Piperidine]-1'-yl)pyrazin-2-yl)methanol;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)indoline-5-carboxamide;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-nitroindole- 1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indole-5-carboxamide;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indazole-6-carboxamide;

(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-6-yl)acetamide;

(S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)benzo[d]isoxazole-6-carboxamide;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)indolazine-6-carboxamide;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-amino-1H-indyl) (Azol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-methoxy-1H -Indazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-nitro-1H- Indol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6-methoxy-1H -Benzo[d]imidazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6-amino-9H-purine -9-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol; or

4-(2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl) Pyrazin-2-yl)ethynyl)cyclopropyl)benzamide.

The present invention also provides a pharmaceutical composition characterized by comprising a therapeutically effective amount of at least one compound represented by formula I and at least one pharmaceutically acceptable excipient.

The present invention further provides a pharmaceutical composition, characterized in that the mass percentage of the therapeutically effective amount of at least one compound represented by formula I and pharmaceutically acceptable excipients is 0.0001:1-10.

The present invention provides the application of the compound or pharmaceutical composition represented by structural formula I in the preparation of medicines.

The present invention further provides a preferred technical solution for the application:

Preferably, the application is an application for preparing a medicine for treating, preventing, delaying or preventing cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or eye disease.

Preferably, the application is an application in preparing a medicine for treating diseases mediated by SHP2. Preferably, the disease is cancer.

Preferably, the cancer is selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumor , Lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer or a combination thereof.

Preferably, the application is an application for preparing an SHP2 inhibitor.

The present invention also provides a method for treating and/or preventing diseases mediated by SHP2, which comprises administering a therapeutically effective amount of at least any one compound or pharmaceutical composition represented by structural formula I to a subject.

Preferably, in the above method, the SHP2-mediated disease is cancer.

The present invention also provides a method for treating cancer, which comprises administering a therapeutically effective amount of at least any one compound or pharmaceutical composition represented by structural formula I to a subject.

Preferably, in the above method, the subject to be treated is a human.

Unless otherwise specified, the terms used in the present invention have the following meanings:

The term "alkyl" includes straight, branched or cyclic saturated alkyl groups. For example, alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3 -(2-Methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl and other similar groups group. Similar, "C _1-8 alkyl""C_1-8" means comprising 7 or 8 carbon atoms, a straight chain, branched chain or cyclic Formally arranged groups.

"Alkenyl" and "alkynyl" include linear, branched or cyclic alkenyl and alkynyl groups. Similarly, "C _2-8 alkenyl" and "C _2-8 alkynyl" refer to a linear, branched or cyclic arrangement containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms的alkenyl or alkynyl.

The term "alkoxy" refers to the oxyether form of the aforementioned linear, branched or cyclic alkyl group.

The term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic aromatic group including carbon atoms. It is preferably a 6 to 10 membered monocyclic or bicyclic aromatic group. Preferably, it is phenyl and naphthyl. Most preferred is phenyl.

The term "heteroaryl" refers to a monovalent heteroatom group formed by removing a hydrogen atom from a carbon atom of a parent heteroaromatic ring system. Heteroaryl groups include: 5- to 7-membered aromatic, monocyclic, including at least one heteroatom selected from N, O or S, for example, 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms, ring The other atoms on the above are carbon; the polyheteroaryl ring includes at least one heteroatom selected from N, O or S, for example, 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms, other atoms in the ring It is carbon, and at least one of the heteroatoms is on the aromatic ring; it also includes bicyclic or polycyclic rings, but at least one of the bicyclic or polycyclic rings is aromatic. Particularly preferred heteroaryl groups are C _3-10 heteroaryl groups, including, but not limited to, pyrrolyl, furyl, thienyl, pyridyl, pyranyl, pyrazolyl, pyrimidinyl, pyridazinyl, Pyrazinyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, indolyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzene And similar groups such as triazolyl, carbazolyl, quinolinyl, isoquinolinyl, purinyl and the like.

However, in any case, the heteroaryl group and the aryl group will not cross each other or contain each other. Therefore, according to the above definition, if at least one all-carbon aromatic ring is fused with a heterocyclic group, the result is a heteroaryl group instead of an aryl group.

"Carbocyclic group" refers to a saturated or unsaturated cyclic group that is not aromatic. According to its specific level of saturation, the terms "cycloalkyl", "cycloalkenyl" or "cycloalkynyl" are used respectively. Representative carbocyclic groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, or cyclohexene and similar groups.

"Heterocyclic group" refers to a saturated or unsaturated but not aromatic cyclic group, and one or more of the carbon atoms (and the attached hydrogen atom) can be respectively the same or different hetero Atom and the corresponding attached hydrogen atom are replaced. Representative heteroatoms that replace carbon atoms include, but are not limited to, N, P, O, S, and Si. When a specific degree of saturation needs to be described, the terms "heterocycloalkyl" or "heterocycloalkenyl" are used respectively. Representative heterocyclic groups include but are not limited to epoxy compounds, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran or tetrahydropyran and similar groups . Substituent heterocyclic groups also include ring systems substituted by at least one oxygen-containing (=O) or oxide (-O-) substituent, such as: piperidine-nitrogen-oxide, morpholinyl-nitrogen- Oxide, 1-oxo-1-thiomorpholinyl and 1-dioxo-1-thiomorpholinyl.

However, in any case, the heterocycloalkyl group and the carbocyclic group will not cross each other or contain each other. Therefore, according to the above definition, if at least one all-carbocyclic ring is fused with a heterocycloalkyl group to form a di-, poly- or spiro-ring, it will still be defined as a heterocycloalkyl group.

In addition, if a heteroaryl group is fused with a heterocyclic group to form a di-, poly- or spiro-ring, it will be defined as a heterocyclic group instead of a heteroaryl group.

"Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferred halogen refers to fluorine, chlorine and bromine.

"Halo" refers to a fluoro, chloro, bromo or iodo group. The preferred halo groups refer to fluoro and chloro.

"Substitution" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Representative substituents include, but are not limited to, halogen, amino, hydroxyl, oxo, carbonyl, cyano, -C(O)NH ₂ , alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl , Heteroaryl. In some embodiments, the substituent includes, but is not limited to, halogen, amino, hydroxyl, cyano, methyl, -CH ₂ OH, -C(O)NH ₂ , -OCH ₃ , trifluoromethyl.

Whenever the term "alkyl" or "aryl" or its prefixes appear in the name of a substituent (such as aralkyl, or dialkylamino), it shall be as described above for "alkyl" and "aryl". The definition provides a limited interpretation of the substituents. The specified number of carbon atoms (such as C _1-6 ) will independently represent the number of carbon atoms in an alkyl moiety or in an alkyl moiety (where the alkyl group is the prefix stem) in a larger substituent.

The "compound" of the present invention includes the compound of formula I, and all pharmaceutically acceptable forms thereof. These pharmaceutically acceptable forms include salts, solvates, non-covalent complexes, chelates, stereoisomers (including diastereomers, enantiomers and racemates), cis-trans Isomers, isotope-labeled compounds, tautomers, prodrugs, or any mixture of all the above forms.

The "cis-trans isomer" is a stereoisomerism that exists in certain double bond compounds or cyclic compounds. Due to the presence of double bonds or rings, the free rotation of these molecules is hindered, resulting in two isomers with different physical or chemical properties, called cis and trans isomers, respectively.

The "pharmaceutically acceptable" refers to those that are well-known for use in animals, especially those that can be used in humans.

The term "composition" in the present invention includes a product containing a specific amount of a specific component, and also includes any product obtained directly or indirectly from a specific amount of a specific component. Therefore, a pharmaceutical composition including the compound of the present invention as an active ingredient and a method for preparing the compound are the content of the present invention.

"Therapeutically effective amount" means that when a compound is administered to a subject to treat and prevent and/or inhibit at least one clinical symptom of a disease, condition, symptom, indication, and/or discomfort, it is sufficient for the disease, condition, A dose that produces a certain effect for the treatment of symptoms, indications or discomfort. The specific "effective therapeutic dose" may vary according to the compound, the route of administration, the age of the patient, the weight of the patient, the type of disease or discomfort to be treated, the symptoms and severity, etc. Whenever possible, an appropriate dose may be obvious to those skilled in the art, or it may be determined by conventional experimental methods.

The compounds provided by the present invention may exist in the form of "pharmaceutically acceptable salts". In terms of pharmaceutical applications, the salts of the compounds provided by the present invention refer to non-toxic pharmaceutically acceptable salts. The form of a pharmaceutically acceptable salt includes a pharmaceutically acceptable acid/anion or base/cation salt. Pharmaceutically acceptable acid/anionic salts generally exist in the form of protonation of basic nitrogen with inorganic or organic acids. Typical organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid , Tartaric acid, citric acid, α-ketoglutaric acid, hippuric acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid Acid, cyclohexylamine sulfonic acid, salicylic acid, saccharinic acid or trifluoroacetic acid. Pharmaceutically acceptable base/cation salts, including, but not limited to, aluminum salt, calcium salt, chloroprocaine salt, choline, diethanolamine salt, ethylenediamine salt, lithium salt, magnesium salt, potassium salt, sodium Salt and zinc salt.

The prodrug of the compound of the present invention is included in the protection scope of the present invention. Generally, the prodrug is a functional derivative that is easily converted into the desired compound in the body. Therefore, the term "administration" involved in the treatment method provided by the present invention includes the administration of the compound disclosed in the present invention, or although it is not clearly disclosed but can be converted into the compound disclosed in the present invention in vivo after administration to the subject. disease. The conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as "Design of Prodrugs" (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).

Obviously, the definition of any substituent or variable at a specific position in one molecule is irrelevant to the definition of any substituent or variable at a specific position in other molecules. It is easy to understand that the compound of the present invention can be selected according to the prior art of the subject to select suitable substituents or substitution forms to provide chemically stable and easy preparation and synthesis using the prior art of the subject or the method described in the present invention.

When the compound represented by formula I and its pharmaceutically acceptable salt are in the form of a solvate or polymorph, the present invention includes any possible solvate and polymorph. The type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, its corresponding salt can be prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), iron, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like. In particular, salts of ammonium, calcium, magnesium, potassium, and sodium are preferred. The non-toxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

When the compound provided by the present invention is a base, the corresponding salt can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, isethionic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, Hydrochloric acid, lactic acid, maleic acid, malic acid, mandelic acid, α-ketoglutaric acid, hippuric acid, methanesulfonic acid, mucic acid, nitric acid, hexanoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonate Sour etc. Preferably, malic acid, citric acid, hydrobromic acid, hydrochloric acid, methanesulfonic acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, phosphoric acid, hydrochloric acid and malic acid. Since the compound of formula I will be used as a pharmaceutical, it is preferred to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, particularly suitably at least 98% purity (% is a weight ratio).

The pharmaceutical composition provided by the present invention includes the compound represented by formula I (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient, and other optional therapeutic components or adjuvants. Although in any given case, the most suitable way of administering the active ingredient depends on the particular subject to be administered, the nature of the subject and the severity of the disease, the pharmaceutical composition of the present invention includes oral, rectal, topical and Pharmaceutical compositions for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration). The pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.

In fact, according to conventional drug mixing technology, the compound represented by formula I of the present invention, or prodrug, or metabolite, or pharmaceutically acceptable salt, can be used in combination as an active component and mixed with a drug carrier to form a drug combination Things. The pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may take the form of a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition, in addition to the common dosage forms mentioned above, the compound represented by Formula I or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with the carrier constituting one or more necessary ingredients. In general, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two. In addition, the product can be easily prepared into the desired appearance.

Therefore, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula I, or a pharmaceutically acceptable salt thereof. The compound represented by formula I, or a pharmaceutically acceptable salt thereof, and one or more other compounds having therapeutic activity in combination are also included in the pharmaceutical composition of the present invention.

The drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier. Examples of solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, mannitol, sorbitol, microcrystalline cellulose, inorganic salts , Starch, pregelatinized starch, powdered sugar, dextrin, etc. Examples of liquid carriers include syrup, peanut oil, olive oil and water. Examples of gas carriers include carbon dioxide and nitrogen. When preparing oral pharmaceutical preparations, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc. can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used in oral solid preparations such as powders, capsules and tablets. In view of ease of administration, tablets and capsules are preferred for oral preparations. Alternatively, standard aqueous or non-aqueous formulation techniques can be used for tablet coating.

Tablets containing the compound or pharmaceutical composition of the present invention can be prepared by, optionally, mixing, compression or molding with one or more auxiliary components or adjuvants. The active ingredient is in a free-flowing form such as powder or granules, mixed with lubricants, inert diluents, surface active or dispersing agents, and compressed in a suitable machine to produce compressed tablets. The powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to form a molded tablet. Preferably, each tablet contains about 0.01 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.1 mg to 0.5 g of active ingredient. For example, a dosage form intended for oral administration to humans contains about 0.1 mg to about 0.5 g of active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 99.99% of the total pharmaceutical composition. . The unit dosage form generally contains about 0.1mg to about 0.5g of effective ingredients, typically 0.1mg, 0.2mg, 0.5mg, 1mg, 2mg, 2.5mg, 5mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg Or 500mg.

The pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding active components into water. Suitable surfactants such as sodium lauryl sulfate, polysorbate-80 (Tween-80), polyoxyethylene hydrogenated castor oil, and poloxamer may be included. In glycerol, liquid polyethylene glycol, and their mixture in oil, dispersion systems can also be prepared. Furthermore, a preservative may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.

The present invention provides pharmaceutical compositions suitable for injection use, including sterile aqueous solutions or dispersion systems. Further, the above-mentioned pharmaceutical composition can be prepared in the form of a sterile powder that can be used for immediate preparation of sterile injections. In any case, the final injection form must be sterile, and for easy injection, it must be easy to flow. In addition, the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

The pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting, or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device. These preparations can be prepared by using the compound represented by formula I of the present invention, or a pharmaceutically acceptable salt thereof, through conventional processing methods. As an example, an emulsion or ointment is prepared by adding a hydrophilic material and water (the total amount of the two is about 5% to 50% by weight of the compound) to prepare a cream or ointment with the expected consistency.

The pharmaceutical composition provided by the present invention can be made into a form suitable for rectal administration with a solid as a carrier. Suppositories in which the mixture forms a unit dose are the most preferred dosage form. Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared. First, the pharmaceutical composition is mixed with softened or melted excipients, and then cooled and molded.

In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and additives. Thickeners, lubricants, preservatives (including antioxidants), etc. Further, other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood. The pharmaceutical composition containing the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, can also be prepared in the form of a powder or a concentrated solution.

Detailed ways

In order to make the above content clearer and clearer, the present invention will use the following embodiments to further illustrate the technical solution of the present invention. The following examples are only used to illustrate specific implementations of the present invention, so that those skilled in the art can understand the present invention, but are not used to limit the protection scope of the present invention. In the specific embodiments of the present invention, technical means or methods that are not specifically described are conventional technical means or methods in the art.

Unless otherwise specified, all parts and percentages in the present invention are calculated by weight, and all temperatures refer to degrees Celsius.

The following abbreviations are used in the examples:

DCM: dichloromethane;

DIEA: N,N-diisopropylethylamine;

DIBAL-H: diisobutyl aluminum hydride;

DME: Ethylene Glycol Dimethyl Ether

DMF: N,N-dimethylformamide;

DMSO: dimethyl sulfoxide;

EtOAc: ethyl acetate;

h, hr or hrs: hour;

LC-MS or LCMS: liquid chromatography-mass spectrometry;

MeCN: Acetonitrile;

MeOH: methanol;

min or mins: minutes;

NEt ₃ : Triethylamine;

Prep-HPLC: Preparative high performance liquid chromatography;

PdCl ₂ (PPh ₃ ) ₂ : Bistriphenylphosphorus palladium dichloride;

Pd(PPh ₃ ) ₄ : Tetrakis (triphenylphosphine) palladium;

PE: petroleum ether;

rt, r.t. or RT: room temperature;

TFA: trifluoroacetic acid;

THF: Tetrahydrofuran;

Ti(OEt) ₄ : tetraethyl titanate; and

TLC: Thin layer chromatography.

Preparation of intermediate compound M1:

Step 1: Preparation of compound M1-3

Under nitrogen protection, dissolve 25.00g of compound M1-1 in 200mL of DMF, cool to 0°C, add 22.70g NaH in batches, keep at 0°C for 1hr, and then slowly add 54.96g of compound M6-2 dropwise to the reaction solution After dropping, react at 0°C for 1 hr, and then heat to 60°C to continue the reaction for 1 hr. The reaction solution was cooled to 0°C, quenched with 500 mL ice water, extracted with EtOAc (500 mL×3), combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was passed through the column Analyze and purify to obtain 29.00g of brown oil M1-3.

Step 2: Preparation of compound M1-5

29.00 g of compound M1-3 was dissolved in 50 mL of Ti(OEt) ₄ , 34.99 g of compound M1-4 was added, and then heated to 90° C. for reaction for 12 hrs. TCL detected that the reaction was complete. Pour the reaction solution into 500 mL ice water, add 300 mL EtOAc and stir for 1 hr, extract with EtOAc (300 mL×3), combine the organic phases, and wash the organic phase with saturated brine (100 mL×4), anhydrous sulfuric acid It was dried with sodium and concentrated under reduced pressure to obtain 39.00 g of crude compound M1-5 as a brown oil.

Step 3: Preparation of compound M1-6

Under the protection of nitrogen, 48.00 g of compound M1-5 was dissolved in 500 mL of anhydrous THF, the temperature was lowered to -20°C, and 6.73 g of NaHB ₄ was slowly added, and then the temperature was raised to RT and stirred for 2 hrs. After the reaction was completed, the reaction solution was cooled to 0°C, quenched with 300 mL of water, extracted with EtOAc (300 mL×3), combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was passed through a column Chromatographic purification yielded 25.40 g of compound M1-6 as a brown oil.

Step 4: Preparation of compound M1-7

10.00 g of compound M1-6 was dissolved in 100 mL of DCM solution, 28.04 g of TFA solution was added dropwise, and then reacted at RT for 1 hr. The reaction solution was cooled to 0°C, _{quenched with 100 mL saturated aqueous NaHCO 3} solution, extracted with EtOAc:THF=3:1 (100 mL×3), combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, and reduced pressure It was concentrated to obtain 7.64 g of a brown solid, the crude compound M1-7, which was directly used in the next reaction.

¹ H NMR(500MHz,DMSO-d ₆ )δ7.26-7.21(m,4H), 5.80(d,J=10.5Hz,1H), 4.43(d,J=10.5Hz,1H), 3.17-3.15( m, 2H), 3.08 (d, J = 15.5 Hz, 1H), 2.98-2.88 (m, 2H), 2.69 (d, J = 15.5 Hz, 1H), 2.04-1.99 (m, 1H), 1.80-1.75 (m, 1H), 1.62-1.59 (m, 1H), 1.35 (m, 1H), 1.22 (s, 9H).

Step 5: Preparation of compound M1-8

1.29g methyl 3,6-dibromopyrazine-2-carboxylate and 1.60g compound M1-7 were dissolved in 20mL tetrahydrofuran, 1.12g DIEA was added dropwise, and the reaction was stirred at 60°C for 12 hours. TLC detected the completion of the reaction, concentrated under reduced pressure, added 50 mL of water, and extracted with EtOAc (50 mL×3), combined the organic layers, dried over sodium sulfate and desolventized, purified by column chromatography to obtain 1.60 g of compound M1-8.

Step 6: Preparation of compounds M1 and M2

Under nitrogen protection, 1.00 g of compound M1-8 was dissolved in 30 mL of anhydrous dichloromethane, the temperature was reduced to -78°C, and DIBAL-H (1M, 9.6 mL) in n-hexane was added dropwise. The reaction was stirred at -78°C for 1 hour. Then slowly increase the temperature to -40°C, and continue the reaction for 2 hours. TLC detected that the reaction of the raw materials was complete. At 0°C, 0.4 mL of water was slowly added dropwise, and then sodium hydroxide aqueous solution (15%, 0.4 mL) was added dropwise, and then 1 mL of water was added. Warm to room temperature and stir for 15 minutes. Add sodium sulfate to dry, stir for ten minutes and filter. The filtrate was concentrated and purified by column chromatography to obtain 0.40 g of compound M1 and 0.11 g of compound M2.

The intermediate M11 listed in Table 1 was prepared by using different reaction starting materials and appropriate reagents (the raw materials and reagents are commercially available), using a method similar to the foregoing intermediate M1-7.

Table 1

Preparation of intermediate compound M14:

Step 1: Preparation of compound M14-2

Dissolve 2.00 g of compound M14-1 in 40 mL THF, add NaOH (30 mL, 1N), and then react with RT for 2 hrs. TLC detects the completion of the reaction. Pour the reaction solution into 100mL water, adjust the pH to 4-5 with 6N HCl, add EtOAc to extract (100mL×4), combine the organic phases, wash with 50mL saturated NaCl, and dry with anhydrous sodium sulfate. It was concentrated under pressure, and the residue was slurried with n-hexane to obtain 1.67 g of light yellow solid M14-2.

Step 2: Preparation of compound M14-3

Dissolve 1.28g of compound M14-2 in 13mL DMF, lower the temperature to 0°C, add 3.26g of Cs ₂ CO ₃ _{, and then add 2.13g of CH 3} I dropwise, and then heat up to 10°C to react for 1 hr. TLC detected the completion of the reaction, the reaction solution was cooled to 0°C, 20 mL EtOAc and 20 mL water were added, the organic phase was separated, the aqueous phase was extracted with 20 mL EtOAc, the organic phases were combined, washed with saturated NaCl (5×4 mL), and dried over anhydrous sodium sulfate After concentration under reduced pressure, the residue was purified by column chromatography to obtain 635 mg of compound M14-3.

Step 3: Preparation of compound M14-5

Dissolve 359 mg of compound M14-3 and 448 mg of compound M1-7 in 6 mL of DMAc, add 860 mg of DIPEA, replace with nitrogen three times, and react in a microwave at 120°C for 1 hr. The reaction was completed by TLC detection, the reaction solution was cooled to room temperature, 20 mL of water was added, and EtOAc (20 mL×3) was added for extraction. The organic phases were combined, washed with saturated NaCl (5 mL×4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue Purified by column chromatography, 290 mg of compound M14-5 was obtained.

Preparation of intermediate compound M15:

Step 1: Preparation of compound M15-2

0.50g of compound M15-1 and 1.19g of compound M1-7 were dissolved in 15ML of anhydrous N,N-dimethylformamide, and 3.13g of benzotriazol-1-yloxy three were sequentially added in an ice bath. (Dimethylamino)phosphonium hexafluorophosphate, 3.78g DBU, stirred and reacted at room temperature for 18 hours. LCMS detected that the reaction was complete, added 25 mL of water, and then extracted with DCM (20 mL×3), combined the organic layers, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate and desolventized, purified by column chromatography (DCM :MeOH=95%-92%) to obtain 0.59 g of compound M15-2.

Step 2: Preparation of compound M15-3

Under the protection of nitrogen, 0.59 g of compound M15-2 was dissolved in 10 mL of anhydrous N,N-dimethylformamide, and 0.39 g of N-iodosuccinimide was added to the above reaction solution under an ice bath. TLC detected that the reaction was complete, 15 mL of water was added, and then extracted with DCM (20 mL×3). The organic layers were combined, washed with saturated brine (10 mL×3), dried with anhydrous sodium sulfate, and the solution was removed and purified by column chromatography (DCM :MeOH=95%-92%) to obtain 0.42g of compound M15.

Preparation of intermediate compound M30:

Step 1: Preparation of compound M30-3

10.00 g of compound M30-1 and 7.59 g of compound M30-2 were dissolved in 170 mL of chloroform, 350 mg of iodine was added, and the reaction was stirred at room temperature for 24 hours. TLC detects that the reaction is complete. Pour the compound into an aqueous sodium thiosulfate solution (100 mL, 0.4 mol/L), add an aqueous sodium hydroxide solution (70 mL, 40%), and extract with chloroform (150 mL×2). Combine the organic layers. After drying with sodium sulfate, it was desolventized, and recrystallized with dichloromethane/n-hexane to obtain 8.77 g of compound M30-3.

Step 2: Preparation of compound M30-5

8.77 g of compound M30-3 was dissolved in 300 mL of anhydrous tetrahydrofuran, the temperature was lowered to -30°C, a n-hexane solution of n-butyllithium (2.5M, 16 mL) was added dropwise, and the mixture was kept warm and stirred for 1 hour. Subsequently, 8.15 g of compound M30-4 was dissolved in 30 mL of tetrahydrofuran and slowly added dropwise to the reaction solution. After the addition, the temperature was raised to -10° C. and the reaction was continued for 2.5 hours. The reaction solution was quenched with 200 mL saturated brine, extracted with EtOAc (300 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 11.06 g of compound M30-5.

Step 3: Preparation of compound M30-7

11.06 g of compound M30-5 was dissolved in a mixed solution of water (40 mL) and dichloromethane (200 mL), followed by 3.17 g of pyridine, 12.83 g of compound M30-6, and 0.86 g of tetrabutylammonium bromide. Stir at room temperature for 24 hours. The reaction solution was quenched with 100 mL saturated brine, extracted with DCM (100 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 5.46 g of compound M30-7.

Step 4: Preparation of compound M30-8

Dissolve 5.46 g of compound M30-7 and 2.84 g of potassium tert-butoxide in 85 mL of anhydrous tetrahydrofuran, replace with nitrogen three times, and react in a microwave at 70° C. for 5 minutes. The solvent was removed under reduced pressure, 100 mL of saturated brine was added, and then extracted with EtOAc (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2.91 g of compound M30-8.

Step 5: Preparation of compound M30-9

Dissolve 1.30g of compound M30-8, 1.56g of (R)-(+)-tert-butylsulfinamide in a mixed solution of tetraethyl titanate (10mL) and anhydrous tetrahydrofuran (2mL), and replace with nitrogen 3 times Then, the reaction was carried out at 90°C for 8 hours. The heating was stopped, the reaction solution was poured into 200 mL of ice water, 150 mL of ethyl acetate was added, and the mixture was stirred for 1 hour. Filter to remove the filter residue. The filtrate was extracted with ethyl acetate (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.90 g of compound M30-9.

Step 6: Preparation of compound M30-10

Dissolve 1.30 g of compound M30-9 in 25 mL of anhydrous tetrahydrofuran, add 344 mg of sodium borohydride in batches at -20°C, slowly warm to room temperature, and then stir at room temperature for 3 hours. At 0°C, 100 mL of water was added, and then extracted with EtOAc (80 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 0.94 g of compound M30-10.

Step 7: Preparation of compound M30

0.94 g of compound M30-10 was dissolved in 10 mL of dichloromethane, and then 2.62 g of trifluoroacetic acid was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was reduced to 0°C, and then saturated aqueous sodium bicarbonate solution was added to adjust the pH to weakly alkaline. It was extracted with a mixed solution of EtOAc:THF=1:1 (60 mL×4), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 692 mg of compound M30 was obtained.

Through different reaction starting materials and appropriate reagents (the raw materials and reagents are commercially available), the intermediates listed in Table 2 were prepared by a method similar to the foregoing intermediate M30.

Table 2

Example 1 Compound A01 (3-(5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Pyrazine-2-yl)-1-phenylprop-2-yn-1-ol) preparation:

Step 1: Preparation of compound A01-1

100mg of the A01-SM, 30mg M1,7.11mg Pd ( dppf) Cl 2, 1.93mg CuI, 41mg Et 3 N was added in tetrahydrofuran (2mL), a nitrogen thrice, 70 deg.] C The reaction was stirred for 3hrs under nitrogen. LCMS and TLC detected that the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 66 mg of yellow solid compound A01-1.

Step 2: Preparation of compound A01

66 mg of compound A01-1 was dissolved in 2.0 mL of tetrahydrofuran, 2N HCl (0.2 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hrs. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The residue was _{dissolved by adding H 2} O (1.0 mL), the _{solution was adjusted to pH=8 with saturated NaHCO 3} , extracted with dichloromethane (3×3 mL), the organic phase was dried and concentrated in vacuo, and purified by a preparation plate to obtain 6.4 mg of yellow solid compound A01.

[M+H ⁺ ]=441.33.

Example 3 Compound A03((S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6 -(Hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)phenol) preparation:

Step 1: Preparation of compound A03-1

400 mg of compound M1, 159 mg of trimethylsilyl acetylene, 28 mg of PdCl ₂ (PPh ₃ ) ₂ and 7.7 mg of CuI were dissolved in THF (7 mL) and Et ₃ N (0.7 mL). After nitrogen replacement, the reaction was stirred at room temperature for 1 h. LC-MS and TLC detected that the reaction was complete, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 370 mg of yellow solid compound A03-1.

Step 2: Preparation of compound A03-2

370 mg of compound A03-1 was dissolved in MeOH (5 mL), 200 mg of K ₂ CO ₃ was added, and after nitrogen replacement, the reaction was stirred at room temperature for 1 h. LC-MS and TLC detected that the reaction was complete, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 310 mg of light yellow solid compound A03-2.

Step 3: Preparation of compound A03-3

200mg compound A03-2, 16mg PdCl ₂ (PPh ₃ ) ₂ , 4.3mg CuI, 100mg Et ₃ N were dissolved in DMF (4mL), after nitrogen replacement, the reaction was stirred at room temperature for 10 minutes, and then 138mg 3-methoxy The benzyl bromide was added to the above reaction solution, and the mixture was stirred at 100°C for 4 hours under nitrogen protection. LC-MS and TLC detect the completion of the reaction, add 10 mL of water to quench, extract with ethyl acetate (3x10 mL), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by column chromatography to obtain 70 mg of yellow solid compound A03- 3.

Step 4: Preparation of compound A03

70 mg of compound A03-3 was dissolved in 10 mL of anhydrous dichloromethane, cooled to -60°C, and then BBr ₃ (0.1 mL) was slowly added to the above solution, and the temperature was slowly raised to -20°C and the reaction was stirred. LC-MS and TLC check that the reaction is complete, add saturated sodium bicarbonate aqueous solution to quench the reaction, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, spin-dry the filtrate, and spin-dry the product. The plate was purified to obtain 11.6 mg of compound A03.

[M+H ⁺ ]=441.39.

¹ H NMR(500MHz,DMSO-d ₆ )δ9.42(s,1H), 8.21(s,1H), 7.31(d,J=6.5Hz,1H), 7.21-7.10(m,4H), 6.85– 6.77 (m, 2H), 6.65 (d, J = 8.0 Hz, 1H), 5.40 (t, J = 6.0 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.85 (s, 1H), 3.83(s,2H),3.73-3.69(m,2H),3.13-3.06(m,2H),3.03(d,J=15.5Hz,1H), 2.60(d,J=15.5Hz,1H),1.90 --1.87 (m, 1H), 1.80 - 1.74 (m, 1H), 1.53-1.50 (m, 1H), 1.13-1.10 (m, 1H).

Example 4 Compound A04 ((S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-morpholine (Prop-1-yn-1-yl)pyrazin-2-yl)methanol) preparation:

Step 1: Preparation of compound A04-1

Dissolve 50 mg of compound M1 and 25 mg of compound SM1 in 1 mL of THF, add 3.5 mg of PdCl ₂ (PPh ₃ ) ₂ , 0.9 mg of CuI, and 0.1 mL of TEA. After nitrogen replacement, react at room temperature for 1 hr. LCMS detected that the reaction was complete, the reaction solution was filtered, concentrated under reduced pressure, and the residue was purified with a preparation plate to obtain 36.8 mg of compound A04-1 as a white solid.

Step 2: Preparation of compound A04

36.8 mg of compound A04-1 was dissolved in 0.8 mL of THF, 0.2 mL of EtOH was added, 0.12 mL of HCl in EA solution (2M) was added dropwise with stirring, and the mixture was stirred at room temperature for 20 mins. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 1 mL of water, 1 mL of saturated sodium bicarbonate solution was added dropwise, the precipitated solid was collected, and purified with a preparation plate to obtain 9.0 mg of yellow solid compound A04. [M+H ⁺ ]=434.47.

Example 91 Compound A67(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( Preparation of (hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-3-carboxamide:

Step 1: Preparation of compound A67-1

Dissolve 200mg pyrazole-3-carboxamide in DMF (10.0mL), add 270mg K ₂ CO _{3 and} stir for 10 min at room temperature. Add 0.15 mL of bromopropyne dropwise. After nitrogen replacement, the reaction is stirred at room temperature for 1 h. LC-MS and TLC detected that the reaction was complete, added 20 mL of water, extracted with ethyl acetate (3×20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 150 mg of white solid compound A67-1.

Step 2: Preparation of compound A67-2

200 mg of compound M1, 28 mg of PdCl ₂ (PPh ₃ ) ₂ , 4 mg of CuI, and 91 mg of compound A67-1 were dissolved in DMF (6.0 mL) and Et ₃ N (1.1 mL), and after nitrogen replacement, the reaction was carried out at 60° C. for 2.5 hours. LC-MS and TLC check that the reaction is complete, add 20 mL of water, 10 mL of ethyl acetate for extraction, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by a preparation plate to obtain 100 mg of light yellow solid, which is compound A67- 2.

Step 2: Preparation of compound A67

Dissolve 100 mg of compound A67-2 in 6.0 mL of dioxane, then add 1.5 mL of MeOH, add 0.26 mL of HCl EA solution (2M) dropwise with stirring, and stir for 30 min at room temperature. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 10 mL of water, saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8-9, the precipitated solid was collected, and purified with a preparation plate to obtain 35 mg of yellow solid compound A67.

[M+H ⁺ ]=458.38.

¹ H NMR (500MHz, DMSO) δ 8.23 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.52 (s, 1H), 7.30 (d, J = 7.0 Hz, 1H), 7.25 ( s, 1H), 7.20-7.10 (m, 3H), 6.69 (d, J = 2.3 Hz, 1H), 5.44 (t, J = 6.0 Hz, 1H), 5.39 (s, 2H), 4.46 (d, J =5.8Hz,2H),3.83(s,1H),3.82-3.74(m,2H),3.18-3.06(m,2H),3.03(d,J=15.6Hz,1H),2.60(d,J= 15.6Hz, 1H), 1.90-1.82 (m, 1H), 1.80-1.72 (m, 1H), 1.55-1.48 (m, 1H), 1.14-1.07 (m, 1H).

Through different reaction starting materials, suitable reagents (starting materials and reagents are all commercially available), and the intermediate M1 prepared in the present invention, the use is similar to the foregoing Example 1, Example 3, Example 4, and Example 88 The method to prepare the compounds in Table 3.

table 3

Compound A08 ¹ H NMR (500MHz, DMSO) δ 9.31 (s, 1H), 8.20 (s, 1H), 7.31 (d, J = 6.6 Hz, 1H), 7.21-7.11 (m, 5H), 6.74 (d ,J=8.4Hz,2H),5.39(t,J=6.0Hz,1H),4.47(d,J=6.0Hz,2H),3.86(s,1H),3.78(s,2H),3.75-3.67 (m,2H),3.12–3.01(m,3H),2.61(d,J=15.8Hz,1H),1.90–1.87(m,1H),1.79–1.76(m,1H),1.51–(m, 1H), 1.14-1.11 (m, 1H).

Example 95 Compound A71(S)-4-(4-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( Preparation of (hydroxymethyl)pyrazin-2-yl)but-3-yn-1-yl)benzamide:

Step 1: Preparation of compound A71-1

Add 1.49g of LDA and 0.889g of n-BuLi to THF (20.0mL), under N ₂ protection, cool to -78℃, add 3.56g of DMU, add 2.95g of 4-methylbenzonitrile to the reaction system , Stir the reaction for 0.5h, add 1.50g 2-bromopropyne to the reaction system, keep stirring at -78℃ for 1.5h, LC-MS and TLC check the reaction is complete, add 20mL water, extract with ethyl acetate (3×20mL), Wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by column chromatography to obtain 800 mg of white solid, namely compound A71-1.

Step 2: Preparation of compound A71-2

Under nitrogen protection, 0.4 g of compound A71-1, 0.41 g of sodium hydroxide and 0.23 g of potassium carbonate were dissolved in dioxane (4 mL) and H ₂ O (2 mL), and reacted at 60° C. for 16 h. TLC detected that the reaction was complete, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography to obtain 0.10 g of yellow solid, namely compound A71-2.

Step 3: Preparation of compound A71-3

150 mg of compound M1, 6.4 mg of PdCl ₂ (PPh ₃ ) ₂ , 3.5 mg of CuI and 100 mg of compound A71-2 were dissolved in DMF (4.0 mL) and Et ₃ N (1.0 mL), and after nitrogen replacement, the reaction was carried out at 60° C. for 15 h. LC-MS and TLC check that the reaction is complete, add 10mL ethyl acetate, filter out the insolubles, 20mL water dispersion filtrate, saturated brine washing the organic phase, dry with anhydrous sodium sulfate, vacuum concentration, the crude product is purified by the preparation plate to obtain 83mg light yellow Solid, compound A71-3.

Step 4: Preparation of compound A71

Dissolve 83 mg of compound A71-3 in 6 mL of dioxane, add 2 mL of MeOH, add 0.28 mL of HCl EA solution (2M) dropwise with stirring, and stir for 30 min at room temperature. LCMS detected the completion of the reaction, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 10 mL of water, saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8-9, the precipitated solid was collected, and purified with a preparation plate to obtain 41.5 mg of yellow solid, which is the compound A71.

[M+H ⁺ ]=482.38.

¹ H NMR(500MHz,DMSO)δ8.11(s,1H),7.91(s,1H),7.84-7.80(m,2H),7.39(d,J=8.3Hz,2H),7.30(d,J =5.5Hz, 2H), 7.19-7.11 (m, 3H), 5.37 (t, J = 6.0Hz, 1H), 4.46 (d, J = 5.9 Hz, 2H), 3.84 (s, 1H), 3.77-3.65 (m,2H),3.12-3.00(m,3H),2.92(t,J=7.3Hz,2H), 2.78(t,J=7.3Hz,2H), 2.59(d,J=15.6Hz,1H) ,1.90-1.84(m,1H), 1.78-1.73(m,1H), 1.52-1.50(m,1H), 1.07-1.04(m,1H).

Using different reaction starting materials, suitable reagents (both starting materials and reagents are commercially available), and the intermediate M1 prepared in the present invention, the compounds in Table 3 were prepared by a method similar to that in Example 95.

table 3

Example 97 Compound A73(S)-2-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( Preparation of (hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)isoindoline-5-carboxamide:

Step 1: Preparation of compound A73-1

Dissolve 4.000g 5-bromoisoindoline-2-carboxylic acid tert-butyl ester, 3.150g zinc cyanide, 3.100g tetrakistriphenylphosphine palladium in DMF (80mL), _{replace with N 2} and heat at 80°C to react overnight . TLC detected the complete reaction of the raw materials, the reaction solution was cooled to room temperature, filtered, the filtrate was diluted with EA, washed with water, dried over anhydrous sodium sulfate, and spin-dried. The crude product was purified by column chromatography to obtain 3.260 g of white solid, namely compound A73-1.

Step 2: Preparation of compound A73-2

3.260g of compound A73-1 and 35mg Parkin’s reagent were dissolved in EtOH (30mL) and water (30mL), and reacted at 80°C overnight. LC-MS and TLC detected the complete reaction of the raw materials, extracted with ethyl acetate (20mL×3), combined the organic phases, washed with saturated brine (10mL×4), dried over anhydrous sodium sulfate, concentrated in vacuo, and purified the crude product by column chromatography 1.320 g of white solid was obtained, namely compound A73-2.

Step 3: Preparation of compound A73-3

1.320 g of compound A73-2 was dissolved in DCM (15 mL) and TFA (15 mL), and the reaction was stirred at RT for 1 hour. LCMS and TLC detected that the reaction was complete, the reaction solution was _{adjusted to pH=8 with saturated NaHCO 3} , filtered, the filter cake was washed with water, and dried to obtain a crude product, 0.816 g of off-white solid, namely compound A73-3.

Step 4: Preparation of compound A73-4

Suspend 0.162g A73-3 in DMF (10mL), add 0.171g trifluoroacetic acid, the reaction solution becomes clear, add 0.690g potassium carbonate and stir for 5 minutes, then add 0.123g bromopropyne, and react at room temperature overnight. TLC detects that the raw material has reacted completely, add 10 mL of water, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (10 mL×4), dry with anhydrous sodium sulfate, concentrate in vacuo, and purify the crude product by column chromatography The yield is 0.030 g, which is compound A73-4.

Step 5: Preparation of compound A73-5

29 mg of compound A73-4, 65 mg of compound M1, 4.6 mg of PdCl ₂ (PPh ₃ ) ₂ and 1.3 mg of CuI were dissolved in DMF (2 mL) and triethylamine (0.7 mL), replaced with nitrogen, and reacted at 60° C. overnight. LC-MS and TLC detected the complete reaction of the raw materials, added 10 mL of water to precipitate a solid, filtered, and the filter cake was dissolved with DCM, dried over sodium sulfate, and spin-dried. The crude product was purified by a preparative plate to obtain a solid 12 mg, namely compound A73-5.

Step 6: Preparation of compound A73

12 mg of compound A73-5 was dissolved in dioxane (1.5 mL) and methanol (1.0 mL), 2N HCl (0.05 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hour. LCMS and TLC detected that the reaction was complete, the reaction solution was _{adjusted to pH=8 with saturated NaHCO 3} and the reaction solution was spin-dried to obtain a crude product. The crude product was purified by a preparation plate to obtain 7.5 mg of a pale yellow solid, namely compound A73.

[M+H ⁺ ]=509.41.

¹ H NMR(500MHz,DMSO-d ₆ )δ8.20(s,1H),7.91(s,1H),7.76(d,J=1.7Hz,1H),7.73(dd,J=7.8,1.7Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.30-7.29 (m, 2H), 7.20-7.10 (m, 3H), 5.40 (t, J = 5.9 Hz, 1H), 4.46 (d, J =5.8Hz,2H),4.04(s,4H),3.89(s,2H),3.83(s,1H),3.78-3.69(m,2H),3.14-3.05(m,2H),3.02(d, J=15.4Hz, 1H), 2.59(d, J=15.6Hz, 1H), 1.90-1.84(m, 1H), 1.78-1.71(m, 1H), 1.52-1.47(m, 1H), 1.11-1.08 (m,1H).

Example 98 Compound A74(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(indole Preparation of -1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol:

Step 1: Preparation of compound A74-1

1.00 g of indoline, 1.74 g of potassium carbonate and 1.49 g of bromopropyne were dissolved in DMF (10 mL) and reacted at room temperature for 2 hours. TLC detected that the reaction was complete, added 20 mL of ethyl acetate, 20 mL of water layer, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 1.02 g of red solid, namely compound A74-1.

Step 2: Preparation of compound A74-2

100 mg of compound M1, 48 mg of compound A74-1, 7.1 mg of PdCl ₂ (PPh ₃ ) ₂ and 1.9 mg of CuI were dissolved in tetrahydrofuran (2.5 mL) and triethylamine (0.2 mL). After nitrogen replacement, the mixture was reacted at 60°C for 12 hours . LC-MS and TLC check that the reaction is complete, add 20 mL of water, 10 mL of dichloromethane for extraction, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by a preparation plate to obtain 99 mg of yellow solid, which is compound A74-2 .

Step 3: Preparation of compound A74

99 mg of compound A74-2 was dissolved in dioxane (3 mL) and ethanol (1 mL), 2N HCl (0.13 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hour. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. Add H ₂ O (1.0 mL) to dissolve the _{residue, adjust the solution to pH=8 with saturated NaHCO 3} , extract with dichloromethane (3×3 mL), dry the organic phase and concentrate in vacuo. Purify on a preparation plate to obtain 33.2 mg of light yellow solid Namely compound A74.

[M+H ⁺ ]=466.3.

¹ H NMR(500MHz, DMSO-d ₆ )δ8.13(s,1H), 7.32-7.26(m,1H), 7.19-7.12(m,3H), 7.09-7.02(m,2H), 6.71(d ,J=7.8Hz,1H),6.66(t,J=7.3Hz,1H), 5.40(t,J=6.0Hz,1H), 4.43(d,J=6.0Hz,2H), 4.28(s,2H ), 3.82(s,1H),3.79-3.69(m,2H),3.41(t,J=8.2Hz,2H),3.13-3.04(m,2H),3.02(d,J=15.4Hz,1H) ,2.92(t,J=8.2Hz,2H),2.58(d,J=15.6Hz,1H),1.90-1.82(m,1H),1.79-1.71(m,1H),1.53-1.47(m,1H) ), 1.12-1.06 (m, 1H).

Example 99 Compound A75(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( Preparation of (hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-ol:

Step 1: Preparation of compound A75-1

Under the protection of nitrogen, 1.00g 5-methoxy-1H-indazole, 0.96g bromopropyne and 1.40g potassium carbonate were dissolved in DMF (20 mL) and reacted at 60°C for 15h. TLC detected that the reaction was complete, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography to obtain 0.64 g of yellow solid, namely compound A75-1.

Step 2: Preparation of compound A75-2

0.200 g of compound A75-2 was dissolved in 5 mL of dichloromethane, and after nitrogen replacement, 3.6 mL of BBr ₃ was slowly added dropwise at -78° C., and the temperature was slowly warmed to room temperature to react for 5 hours. LC-MS and TLC check that the reaction is complete, add saturated sodium bicarbonate solution to quench the reaction, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, and purify the crude product by column chromatography. 140 mg pale yellow solid, compound A75-2.

Step 3: Preparation of compound A75-3

150 mg of compound M1, 78.5 mg of compound A75-2, 6.4 mg of PdCl ₂ (PPh ₃ ) ₂ and 3.5 mg of CuI were dissolved in DMF (4 mL) and NEt ₃ (1 mL). After nitrogen replacement, the reaction was carried out at 60° C. for 15 hours. LC-MS and TLC check that the reaction is complete, add 10 mL of ethyl acetate, filter out the insolubles, add 20 mL of water, extract with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. It was purified to obtain 160 mg of light yellow solid, namely compound A75-3.

Step 4: Preparation of compound A75

160 mg of compound A75-3 was dissolved in 6.0 mL of dioxane and 2.0 mL of MeOH, 2N HCl (0.27 mL, ethyl acetate solution) was added, and the reaction was stirred at room temperature for 0.5 h. The reaction was completed by LCMS and TLC, the reaction solution was concentrated under reduced pressure, the residue was _{dissolved by adding H 2} O (1.0 mL), the _{solution was adjusted to pH=8 with saturated NaHCO 3} , extracted with EA (3×3 mL), the organic phase was dried and concentrated in vacuo , Purified by preparation plate to obtain 83.5 mg of light yellow solid, namely compound A75.

[M+H ⁺ ]=481.34.

¹ H NMR(500MHz,DMSO)δ9.24(s,1H), 8.17(s,1H),7.91(s,1H), 7.60(d,J=8.9Hz,1H), 7.29(d,J=6.7 Hz,1H),7.19-7.11(m,3H),7.03-6.97(m,2H),5.55(s,2H), 5.40(t,J=6.0Hz,1H), 4.43(d,J=5.8Hz ,2H),3.85-3.72(m,3H),3.15-3.05(m,2H),3.02(d,J=15.6Hz,1H),2.58(d,J=15.6Hz,1H),1.89-1.83( m, 1H), 1.77-1.69 (m, 1H), 1.51-1.49 (m, 1H), 1.14-1.07 (m, 1H).

Example 100 Compound A76(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5- Preparation of amino-1H-indol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol:

Step 1: Preparation of compound A76-1

Dissolve 1g 5-nitroindole in DMF (10.0mL), add 1.30g K ₂ CO _{3 and} stir at room temperature for 10 min, drop 0.80 mL bromopropyne, and after nitrogen replacement, stir at room temperature for 1 h, LC-MS and TLC detected that the reaction was complete, 60 mL of water was added, and after the precipitation was complete, the crude product was obtained by filtration, which was a brown-yellow solid, and 1.22 g of compound A76-1 was obtained, and proceeded directly to the next step.

Step 2: Preparation of compound A76-2

0.50 g of compound A76-1 was dissolved in 20 mL of mixed solution (EtOH:H ₂ O=3:1), 0.56 g of reduced iron powder and 0.80 g of NH ₄ Cl were added, and the temperature was raised to 90° C. under reflux and stirring for 3 hours. LC-MS and TLC detected that the reaction was complete, filtered through a pad of diatomaceous earth while hot, and the filtrate was concentrated in vacuo and purified by column chromatography to obtain 0.20 g of dark brown solid, namely compound A76-2.

Step 3: Preparation of compound A76-3

300 mg of compound M1, 43 mg of PdCl ₂ (PPh ₃ ) ₂ , 6 mg of CuI and 155 mg of compound A76-2 were dissolved in DMF (10.0 mL) and Et ₃ N (1.5 mL), and after nitrogen replacement, the reaction was carried out at 60° C. for 3 hours. LC-MS and TLC check that the reaction is complete, add 10mL ethyl acetate, filter out the insoluble matter, 20mL water dispersion filtrate, saturated brine washing the organic phase, anhydrous sodium sulfate drying, vacuum concentration, the crude product is purified by the preparation plate to 0.30g depth Brown solid, compound A76-3.

Step 4: Preparation of compound A76

Dissolve 300 mg of compound A76-3 in 15.0 mL of dioxane, then add 3.0 mL of MeOH, add 1.0 mL of HCl EA solution (2M) dropwise with stirring, and stir for 30 min at room temperature. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 10 mL of water, saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8-9, the precipitated solid was collected, and purified with a preparation plate to obtain 195 mg of brown solid, namely compound A76 .

[M+H ⁺ ]=479.38.

¹ H NMR (500MHz, DMSO) δ 8.18 (s, 1H), 7.29 (d, J = 6.9 Hz, 1H), 7.26 (d, J = 6.2 Hz, 1H), 7.25 (s, 1H), 7.16 ( t,J=6.2Hz,2H), 7.13(d,J=3.5Hz,1H), 6.70(d,J=1.8Hz,1H), 6.57 (dd,J=8.6,1.9Hz,1H), 6.19( d, J = 3.0Hz, 1H), 5.42 (t, J = 6.0 Hz, 1H), 5.24 (s, 2H), 4.54 (s, 2H), 4.43 (d, J = 5.9 Hz, 2H), 4.10 ( d,J=5.2Hz,1H),3.83(s,1H),3.82-3.74(m,2H),3.19-3.06(m,2H),3.03(d,J=15.6Hz,1H),2.60(d ,J=15.6Hz,1H), 1.89-1.82(m,1H), 1.79-1.72(m,1H), 1.54-1.48(m,1H), 1.13-1.07(m,1H).

Example 101 Compound A77(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)- Preparation of 6-(hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-yl)acetamide:

Step 1: Preparation of compound A77-1

Under nitrogen protection, 1.00 g of 5-nitro-1H-indazole, 0.80 g of bromopropyne and 1.27 g of potassium carbonate were added to DMF (30 mL) and reacted at room temperature for 2 hours. TLC detected that the reaction was complete, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography to obtain 1.00 g of gray solid A77-1.

Step 2: Preparation of compound A77-2

1.00 g of compound A77-1, 1.11 g of Fe powder, and 1.60 g of ammonium chloride were dissolved in 4 mL of water and 16 mL of ethanol, and the reaction was refluxed for 2 hours. LC-MS and TLC check that the reaction is complete, cool to room temperature, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by column chromatography to obtain 600 mg of light yellow solid compound A77- 2.

Step 3: Preparation of compound A77-3

100 mg of compound M1, 52.0 mg of compound A77-2, 4.3 mg of PdCl ₂ (PPh ₃ ) ₂ , 2.4 mg of CuI were dissolved in DMF (4 mL) and NEt ₃ (1 mL), and after nitrogen replacement, the reaction was carried out at 60° C. for 15 h. LC-MS and TLC detect the completion of the reaction, add 20 mL of water, extract with 10 mL of ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by a preparation plate to obtain 70 mg of light yellow solid, namely compound A77- 3.

Step 4: Preparation of compound A77-4

70 mg of compound A77-3 was dissolved in 3 mL of DCM, and 14 mg of acetic anhydride was added to react at room temperature for 0.5 h under the condition of an ice-water bath protected by _{N 2.} LC-MS and TLC check that the reaction is complete, cool to room temperature, add saturated sodium bicarbonate solution to adjust the pH to 8-9, extract with ethyl acetate (3×10 mL), wash the combined organic phase with saturated brine, and dry with anhydrous sodium sulfate , Concentrated in vacuo, and the crude product was purified by column chromatography to obtain 68 mg of light yellow solid compound A77-4.

Step 5: Preparation of compound A77

68 mg of compound A77-4 was dissolved in 4.0 mL of dioxane and 1.0 mL of MeOH, 2N HCl (0.12 mL, ethyl acetate solution) was added, and the reaction was stirred at room temperature for 0.5 h. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. Add H ₂ O (1.0 mL) to the _{residue to dissolve, adjust the solution to pH=8 with saturated NaHCO 3} , extract with EA (3×3 mL), dry the organic phase and concentrate in vacuo. Purify on a preparation plate to obtain 37.1 mg of a light yellow solid that is the compound A77.

[M+H ⁺ ]=522.34.

¹ H NMR (500MHz, DMSO) δ9.99 (s, 1H), 8.18 (s, 1H), 8.15 (d, J = 1.3 Hz, 1H), 8.09 (d, J = 0.8 Hz, 1H), 7.72 ( d,J=9.0Hz,1H),7.48(dd,J=9.0,1.9Hz,1H),7.30(d,J=6.8Hz,1H),7.19-7.12(m,3H),5.60(s,2H) ), 5.41 (t, J = 6.0 Hz, 1H), 4.43 (d, J = 5.8 Hz, 2H), 3.85 (s, 1H), 3.80-3.74 (m, 2H), 3.18-3.08 (m, 2H) ,3.02(d,J=15.7Hz,1H),2.60(d,J=15.6Hz,1H),2.06(s,3H),1.88-1.82(m,1H),1.77-1.72(m,1H), 1.51-1.48 (m, 1H), 1.12-1.09 (m, 1H).

Example 102 Compound A78(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6- Preparation of amino-1H-indazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol:

Step 1: Preparation of compound A78-1

1.00 g of 6-nitro-2H-indazole, 0.85 g of potassium carbonate and 0.73 g of bromopropyne were dissolved in DMF (10 mL) and reacted at room temperature for 1 hour. TLC detected that the reaction was complete, added 50 mL of water layer, extracted with 50 mL of ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 0.6 g of a yellow solid, namely compound A78- 1.

Step 2: Preparation of compound A78-2

Disperse 0.6g A78-1, 0.66g iron powder and 0.95g ammonium chloride in 6mL ethanol and 2mL water, react at 80℃ for 3 hours, LC-MS and TLC detection reaction no longer proceed, diatomite filter, filter cake is added Wash with 10 mL methanol, concentrate the filtrate; add 20 mL water, 20 mL dichloromethane extraction, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by column chromatography to obtain 0.45 g of white solid, which is compound A78-2 .

Step 3: Preparation of compound A78-3

150 mg of compound M1, 78 mg of compound A78-2, 10.7 mg of PdCl ₂ (PPh ₃ ) ₂ and 2.9 mg of CuI were dissolved in DMF (3 mL) and triethylamine (1 mL). After nitrogen replacement, the reaction was carried out at 60° C. for 12 hours. LC-MS and TLC detect that the reaction is no longer proceeding, add 20 mL of water, 20 mL of dichloromethane for extraction, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by a preparation plate to obtain 98 mg of yellow solid, which is compound A78 -3.

Step 3: Preparation of compound A78

98 mg of compound A78-2 was dissolved in dioxane (3 mL) and ethanol (1 mL), 2N HCl (0.5 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hour. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. Add H ₂ O (1.0 mL) to dissolve the _{residue, adjust the solution to pH=8 with saturated NaHCO 3} , extract with dichloromethane (3×3 mL), dry the organic phase and concentrate in vacuo. Purify on a preparation plate to obtain 47.2 mg of light yellow solid Namely compound A78.

[M+H ⁺ ]=480.38.

¹ H NMR(500MHz,DMSO-d ₆ )δ8.18(s,1H),7.77(s,1H),7.40(d,J=8.6Hz,1H), 7.29(d,J=7.0Hz,1H) ,7.18-7.11(m,3H),6.61(s,1H),6.54(dd,J=8.6,2.0Hz,1H), 5.44(s,2H), 5.42(t,J=6.1Hz,1H), 5.37(s,2H),4.43(d,J=6.0Hz,2H),3.82(s,1H),3.80-3.75(m,3H),3.15-3.05(m,2H),3.02(d,J= 15.5Hz,1H),2.58(d,J=15.5Hz,1H),1.86-1.82(m,1H),1.77-1.72(m,1H),1.51-1.49(m,1H),1.10-1.08(m ,1H).

Example 103 Compound A79(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4- Preparation of amino-1H-indazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol:

Step 1: Preparation of compound A79-00

The M1 1g material was dissolved in 1,4-dioxane and 20 mL of methanol 5mL, N ₂ substitutions, ethyl acetate was added dropwise 1.52mL of hydrochloric acid solution (2M), room temperature for 1h. TLC (DCM:MeOH=10:1) monitoring showed that the reaction of the raw materials was complete. It was concentrated under reduced pressure, dissolved in 10 mL of water, and saturated sodium bicarbonate solution was added dropwise to pH 8-9. Precipitation was precipitated, filtered, and the crude product was subjected to column chromatography ( DCM:MeOH=15:1) purified to obtain 540mg of A79-00 white powder.

Step 2: Preparation of compound A79-1

Dissolve 1 g of raw material A79-0 and 1.27 g of K ₂ CO ₃ in 10 mL of DMF, then add 948 mg of 3-bromo-1-propyne, and react at room temperature for 2 hours. TLC (PE:EA=3:1) test showed that the reaction of the raw materials was complete, the reaction system was added dropwise to 150mL of stirring water, there is solid precipitation, filtered, drained, the filter cake was slurried with PE, filtered and drained to obtain 1.07g Black powder compound A79-1.

Step 3: Preparation of compound A79-2

Add 10 mL of water and 10 mL of ethanol to a reaction flask containing 1.07 g of compound A79-1, 1.19 g of iron powder and 1.14 g of ammonium chloride, _{replace with N 2} and react at 80° C. for 3 hours. After TLC (PE:EA=3:1) detection showed that the raw material reaction was complete, it was filtered, the filtrate was concentrated under reduced pressure, and separated and purified by column chromatography (PE:EA=3:1) to obtain 360 mg of yellow solid compound A79-2.

Step 4: Preparation of compound A79

53 mg of compound A79-2, 80 mg of A79-00, 4.3 mg of Pd(PPh ₃ ) ₂ Cl ₂ and 2.3 mg of CuI were dissolved in 2 mL DMF and 0.5 mL triethylamine, _{replaced with N 2} and reacted at 45° C. for 12 h. After TLC (DCM:MeOH=10:1) detection showed that the reaction of the raw materials was complete, 10mL ethyl acetate and 10mL water were added for extraction, the organic phase was separated, and the organic phase was washed with 3×10mL saturated sodium chloride solution, separated and dried, and passed through the column. Analysis (DCM:MeOH=15:1) was separated and purified to obtain 81.4 mg of light yellow solid A79.

[M+H ⁺ ]=480.37

¹ H NMR(500MHz,DMSO-d ₆ )δ8.20(s,1H), 8.14(d,J=0.9Hz,1H), 7.53(d,J=7.4Hz,1H), 7.38-7.24(m, 3H), 7.08 (t, J = 7.9 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.20 (d, J = 7.4 Hz, 1H), 5.86 (s, 2H), 5.47 (s, 2H), 4.44 (d, J = 6.1 Hz, 2H), 4.34 (s, 1H), 3.86 (d, J = 13.6 Hz, 1H), 3.78 (d, J = 13.6 Hz, 1H), 3.16-3.11 ( m, 2H), 3.07-3.04 (m, 1H), 2.97-2.93 (m, 1H), 1.86-1.78 (m, 2H), 1.56-1.46 (m, 2H).

Example 104 Compound A80(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( Preparation of (hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazole-5-carboxamide:

Step 1: Preparation of compound A80-1

Dissolve 2.00 g methyl indazole-5-carboxylate and 1.82 g NaOH solid in 15 mL water and 15 mL tetrahydrofuran, and react under reflux at 80°C for 3 hours. After TLC (PE:EA=1:1) monitoring showed that the reaction of the raw materials was complete, concentrate under reduced pressure, spin off the solvent, add 20 mL of water to dissolve the solids, add dropwise 2M hydrochloric acid until the pH is neutral, the solids precipitate, filter, and repeat the operation for the filtrate Two times, the solids were combined and dried to obtain 1.77 g of white solid powder, namely compound A80-1.

Step 2: Preparation of compound A80-2

1.00 g of compound A80-1, 2.64 mL of NH ₃ in methanol, 1.77 g of EDCI, 1.25 g of HOBt and 1.78 mL of triethylamine were dissolved in 15 mL of DMF and reacted at room temperature for 2 hours. TLC (PE:EA=1:1) detection showed that the reaction was complete, add 20mL water, extract with EA/THF (1:1) (20mL×6), wash the organic phase with 3×20mL saturated sodium chloride solution, separate the organic Phase, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 886 mg of off-white powder, namely compound A80-2.

Step 3: Preparation of compound A80-3

Dissolve 886 mg of compound A80-2, 654 mg of 3-bromo-1-propyne and 1.14 g of potassium carbonate in 10 mL of DMF, and react at room temperature for 2 hours. After TLC (PE:EA=1:2) monitoring showed that the reaction was complete, 20 mL of water was added and extracted with EA/THF (1:1) (20 mL×6). The organic phase was washed with 3×20 mL saturated sodium chloride solution and separated. The organic phase was taken out, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (DCM:MeOH=15:1) to obtain 290 mg of off-white powder, namely compound A80-3.

Step 4: Preparation of compound A80-4

242 mg of compound A80-3, 400 mg of M1, 17 mg of Pd(PPh ₃ ) ₂ Cl ₂ and 9.3 mg of CuI were dissolved in 6 mL DMF and 1.5 mL triethylamine, _{replaced with N 2} and reacted at 60° C. for 12 h. After TLC (DCM:MeOH=10:1) detection showed that the reaction of the raw materials was complete, 10mL ethyl acetate and 10mL water were added for extraction, the organic phase was washed with saturated sodium chloride solution (10mL×3), dried with anhydrous sodium sulfate, and passed through a column. Chromatography (DCM:MeOH=19:1) was separated and purified to obtain 279 mg of light yellow solid, namely compound A80-4.

Step 5: Preparation of compound A80

Dissolve 279 mg of compound A80-4 in 8 mL of dioxane and 2 mL of methanol solution, replace with nitrogen, add 0.34 mL of HCl EA solution (2M) dropwise with stirring, and stir for 30 minutes at room temperature. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 5 mL of water, saturated sodium bicarbonate solution was added dropwise to pH 8-9, the precipitated solid was collected, and then subjected to column chromatography (DCM:MeOH=19:1 ) Purification to obtain 136.8 mg of light yellow powder, namely compound A80.

[M+H ⁺ ]=508.38

¹ H NMR(500MHz,DMSO-d ₆ )δ8.38(s,1H), 8.28(s,1H), 8.19(s,1H), 8.07-7.93(m,2H), 7.84(d,J=8.9 Hz, 1H), 7.37-7.25 (m, 2H), 7.21-7.09 (m, 3H), 5.68 (s, 2H), 5.40 (t, J = 6.0 Hz, 1H), 4.43 (d, J = 5.9 Hz ,2H),3.83(s,1H),3.80-3.72(m,2H),3.15-3.03(m,2H),3.13-3.04(m,2H),3.03(d,J=15.4Hz,1H), 2.59(d,J=15.4Hz,1H),1.90-1.80(m,1H),1.80-1.70(m,1H),1.55-1.45(m,1H),1.25-1.15(m,1H).

Example 105 Compound A81(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)- 6-(Hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-4-yl)acetamide and preparation:

Step 1: Preparation of compound A81-1

Dissolve 150 mg of raw material A79-2 in 2 mL of dichloromethane, add 0.1 mL of acetic anhydride, stir at room temperature for 20 min, TLC (PE:EA=1:1) monitoring shows that the reaction is complete, concentrate under reduced pressure, and then use 10 mL of DCM and 10 mL of saturated sodium bicarbonate solution was extracted, and the organic phase was washed with 3×10 mL of saturated sodium chloride, separated and dried, and concentrated under reduced pressure to obtain 166 mg of product A81-1 as a yellow powder.

Step 2: Preparation of compound A81

541 mg of compound A81-1, 50 mg of A79-00, 2.7 mg of Pd(PPh ₃ ) ₂ Cl ₂ , and 1.5 mg of CuI were dissolved in 2 mL DMF and 0.4 mL triethylamine, _{replaced with N 2} and reacted at 45° C. for 12 h. After TLC (DCM:MeOH=10:1) detection showed that the raw material reaction was complete, 10mL ethyl acetate and 10mL water were added for extraction, the organic phase was separated, and the organic phase was washed with 3×10mL saturated sodium chloride solution, filtered and dried. (DCM:MeOH=10:1) was separated and purified to obtain 38.9 mg of light yellow solid A81.

[M+H ⁺ ]=522.40

¹ H NMR(500MHz,DMSO-d ₆ )δ10.05(s,1H), 8.35(s,1H), 8.18(s,1H), 7.72(d,J=7.6Hz,1H), 7.47(d, J = 8.3Hz, 1H), 7.37 (t, J = 8.0Hz, 1H), 7.30 (d, J = 6.7Hz, 1H), 7.20-7.11 (m, 3H), 5.61 (s, 2H), 4.43 ( d,J=5.6Hz,2H),3.85(s,1H),3.80-3.74(m,2H),3.15-3.08(m,2H),3.02(d,J=15.5Hz,1H),2.60(d ,J = 15.5Hz, 1H), 2.17 (s, 3H), 1.89-1.81 (m, 1H), 1.80-1.69 (m, 1H), 1.52-1.46 (m, 1H), 1.14-1.08 (m, 1H) ).

Example 106 Compound A82(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( (Hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-benzo[d]imidazole-5-carboxamide and compound A83(S)-1-(3-(5- (1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)prop-2-yne- Preparation of 1-yl)-1H-benzo[d]imidazole-6-carboxamide:

Preparation of compounds A82 and A83:

Step 1: Preparation of compound A82-1

1.00 g of the raw material 1H-benzimidazole-5-carbonitrile and 30 mg of Parkin’s reagent were dissolved in 9 mL of ethanol and 3 mL of water, and reacted at 80°C for 72 hours. After TLC (PE:EA=1:1) monitoring showed that the reaction was complete, it was concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=20:1) to obtain 266 mg of solid powder A82-1.

Step 2: Preparation of compounds A82-2 and A83-1

Dissolve 266 mg of compound A82-1, 216 mg of 3-bromo-1-propyne and 296 mg of potassium carbonate in 5 mL DMF, and react at room temperature for 2 hours. After TLC (PE:EA=1:1) monitoring showed that the reaction was complete, add 10mL water, extract with 10mL EA, wash the organic phase with 3×10mL saturated sodium chloride solution, separate the organic phase, dry with anhydrous sodium sulfate, and reduce pressure Concentrate to obtain a total of 301 mg of solid powder of the mixture of compound A82-2 and A83-1.

Step 3: Preparation of compounds A82-3 and A83-2

The mixture of 181mg of the compound A82-2 and _{A83-1, 150mg M1,6.4mg Pd (PPh 3)} 2 Cl 2 and 3.5mg CuI were dissolved in 5mL DMF, 60 ℃ reacted with 1.5mL triethylamine, N ₂ substitution 12h . After TLC (DCM:MeOH=10:1) detection showed that the reaction of the raw materials was complete, 10mL ethyl acetate and 10mL water were added for extraction, the organic phase was separated, and the organic phase was washed with 3×10mL saturated sodium chloride solution, separated and dried, and passed through the column. Analysis (DCM:MeOH=12:1) was separated and purified to obtain 294 mg of a mixture of compound A82-3 and A83-2.

Step 4: Preparation of compounds A82 and A83

A mixture of 294 mg of compound A82-3 and A83-2 was dissolved in 8 mL of dioxane and 3 mL of methanol solution, replaced with nitrogen, 0.36 mL of HCl EA solution (2M) was added dropwise with stirring, and stirred at room temperature for 30 min. LCMS detected the completion of the reaction, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 5 mL of water, saturated sodium bicarbonate solution was added dropwise to pH 8-9, the precipitated solid was collected, and then separated and purified by RP-HPLC to obtain 47.9 mg of pale yellow powder compound The formate salt of A82 and 38.6 mg of the formate salt of compound A83 as a pale yellow powder.

A82: [M+H ⁺ ]=508.31

¹ H NMR(500MHz,DMSO-d ₆ )δ8.45(s,1H), 8.28(s,1H), 8.23(s,1H), 8.00(s,1H), 7.90(d,J=8.4Hz, 1H), 7.76 (d, J = 8.5Hz, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 7.24-7.16 (m, 3H), 5.55 (s, 2H), 4.44 (s, 2H) ), 3.85-3.75 (m, 3H), 3.18-3.05 (m, 3H), 2.72 (d, J = 15.6Hz, 1H), 1.92-1.71 (m, 2H), 1.54-1.48 (m, 1H), 1.29-1.22(m,1H).

A83: [M+H ⁺ ]=508.32

¹ H NMR(500MHz,DMSO-d ₆ )δ8.48(s,1H), 8.32(s,1H), 8.23(s,1H), 8.03(s,1H), 7.83(d,J=8.4Hz, 1H), 7.73 (d, J = 8.5Hz, 1H), 7.39 (s, 1H), 7.29 (s, 1H), 7.24-7.16 (m, 3H), 5.55 (s, 2H), 4.44 (s, 2H) ), 3.85-3.75 (m, 3H), 3.18-3.05 (m, 3H), 2.72 (d, J = 15.6Hz, 1H), 1.92-1.71 (m, 2H), 1.54-1.48 (m, 1H), 1.29-1.22(m,1H).

Example 107 Compound A84(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5- Preparation of methoxy-1H-benzo[d]imidazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol:

Step 1: Preparation of compound A84-1

0.8g of 5-methoxybenzimidazole, 0.707g of 3-bromopropyne, and 1.49g of potassium carbonate were dissolved in DMF (8mL) and reacted at room temperature for 16 hours. The reaction was completed by TLC detection, cooled to room temperature, quenched by adding 20 mL of water, extracted with DCM (3×10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was subjected to column chromatography (PE:EA=3:1 ) Purified to obtain 200 mg of light yellow solid, which is compound A84-1.

Step 2: Preparation of compound A84-2

200 mg of compound A84-1, 530 mg of M1, 45 mg of PdCl ₂ (PPh ₃ ) ₂ and 12.3 mg of CuI were dissolved in DMF (2.0 mL) and Et ₃ N (0.5 mL). After nitrogen replacement, the reaction was carried out at 60°C for 16 hours. MS and TLC detected that the reaction was complete, cooled to room temperature, quenched by adding 20 mL of water, extracted with ethyl acetate (3×20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography to obtain 300 mg of light. Yellow solid, compound A84-2.

Step 3: Preparation of compound A84

Dissolve 180 mg of compound A84-2 in 2.0 mL of dioxane, then add 4 mL of MeOH, add 0.3 mL of HCl EA solution (2M) dropwise with stirring, and stir at room temperature for 1 hour. LCMS detects that the reaction is complete, add saturated sodium bicarbonate solution to adjust the pH to 8-9, add 20 mL of water to quench, extract with dichloromethane (3×10 mL), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The preparation plate was purified to obtain 23 mg of yellow solid, namely compound A84.

[M+H ⁺ ]=495.29.

¹ H NMR (500MHz, DMSO) δ 8.25 (s, 1H), 8.21 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.32-7.29 (m, 1H), 7.22 (d, J =2.3Hz,1H),7.20-7.13(m,3H),6.96(dd,J＝8.8,2.3Hz,1H), 5.47(s,2H),5.44-5.33(m,1H), 4.44(s, 2H), 3.86(s, 1H), 3.83-3.73(m, 2H), 3.79(s, 3H), 3.16-3.06(m, 2H), 3.03(d, J=15.6Hz, 1H), 2.61(d ,J=15.6Hz,1H),1.89-1.80(m,1H),1.79-1.70(m,1H),1.54-1.46(m,1H),1.16-1.11(m,1H).

Through different reaction starting materials, suitable reagents (starting materials and reagents are all commercially available), and the intermediate M1 prepared by the present invention, the compounds in Table 4 were prepared using methods similar to the foregoing Example 97-Example 107 .

Table 4

A97: ¹ H NMR (500MHz, DMSO-d ₆ ) δ 8.28 (s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.20- 7.10 (m, 3H), 5.43 (s, 1H), 5.33 (s, 2H), 4.45 (s, 2H), 3.83 (s, 1H), 3.83-3.73 (m, 2H), 3.18-3.06 (m, 2H), 3.02(d,J=15.6Hz,1H), 2.59(d,J=15.6Hz,1H), 1.89-1.82(m,1H), 1.78-1.72(m,1H), 1.54-1.47(m ,1H),1.13-1.08(m,1H).

Example 12 Compound A12((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3 ,4-Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidine-4(3H)-one):

Step 1: Preparation of compound A12-1

2.5 g of compound M14, 681 mg of trimethylsilyl acetylene, 162 mg of PdCl ₂ (PPh ₃ ) ₂ , and 44 mg of CuI were dissolved in THF (20 mL) and Et ₃ N (2 mL). After nitrogen replacement, the reaction was stirred at room temperature for 1 h. LC-MS and TLC detected that the reaction was complete, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 1.88 g of yellow solid compound A12-1.

Step 2: Preparation of compound A12-2

1.5 g of compound A12-1 was dissolved in MeOH (10 mL), and then 812 mg of K ₂ CO ₃ was added. After nitrogen replacement, the reaction was stirred at room temperature for 1 h. LC-MS and TLC detected that the reaction was complete, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 1.2 g of yellow solid compound A12-2.

Step 3: Preparation of compound A12-3

Dissolve A12-2 (158mg) in THF (5mL), add 56mg of isopropylmagnesium chloride (2M) dropwise under ice bath and replace with nitrogen, stir on ice bath for 1h, add 50mg 3,4-dimethoxybenzaldehyde , Return to room temperature and stir for 2h. LC-MS and TLC detect that the reaction is complete, add saturated ammonium chloride solution to quench, add 5ml EA for extraction, separate the organic phase, wash the organic phase with 2×5ml saturated sodium chloride solution, separate and dry, concentrate in vacuo, and pass the crude product to column chromatography 30 mg of white solid compound A12-3 was obtained by purification.

Step 4: Preparation of compound A12-4

30 mg of compound A12-3 was dissolved in DCM (5 mL), and 12 mg of triethylsilyl was added first, and then 51 mg of trifluoroacetic acid was added, followed by nitrogen replacement, and reaction at room temperature for 1 h. LC-MS and TLC detect that the reaction is complete, add saturated sodium bicarbonate to quench, add 3×2ml DCM for extraction, dry the organic phase, concentrate the crude product and purify it by preparation plate to obtain 11mg of white solid compound A12-3.

Step 5: Preparation of compound A12

11 mg of compound A12-3 was dissolved in 3 mL of anhydrous dichloromethane, cooled to -60°C, and then BBr ₃ (70 mg) was slowly added to the above solution, and the mixture was slowly raised to room temperature and stirred for reaction. LC-MS and TLC check that the reaction is complete, add saturated sodium bicarbonate aqueous solution to quench the reaction, extract with dichloromethane, the combined organic phases are washed with saturated brine, dried with anhydrous sodium sulfate, filtered, the filtrate is spin-dried, and the crude product is purified by a preparation plate 1.9 mg of compound A12 was obtained.

[M+H] ⁺ =457.27.

Example 10 Compound A10((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4 -Preparation of chloro-3-hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidine-4(3H)-one):

Step 1: Preparation of compound A10-1

250mg compound A12-1, 10.4mg PdCl ₂ (PPh ₃ ) ₂ , 5.6mg CuI, 7.7mg PPh ₃ , dissolved in DMF (9.0mL) and Et ₃ N (2.5mL), after nitrogen replacement, add 192.0mg TBAF, stirred at room temperature for 10 minutes, then added 230.5mg of 4-(bromomethyl)-1-chloro-2-methoxybenzene into the above reaction solution, stirred for 0.5h at 80°C under nitrogen protection, and continued to add 230.5mg 4 -(Bromomethyl)-1-chloro-2-methoxybenzene was added to the above reaction solution and stirred at 80°C for 0.5h under nitrogen protection. LC-MS and TLC detect that the reaction is complete, add 10 mL of water to quench, extract with ethyl acetate (3x10 mL), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by column chromatography to obtain 180 mg of light yellow solid compound A10 -1.

Step 2: Preparation of compound A10

180 mg of compound A10-1 was dissolved in 10 mL of anhydrous DCM, cooled to -60°C, and then BBr ₃ (0.24 mL) was slowly added to the above solution, and the temperature was slowly warmed to room temperature and the reaction was stirred. LC-MS and TLC check that the reaction is complete, add saturated sodium bicarbonate aqueous solution to quench the reaction, extract with dichloromethane, the combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate is spin-dried, and the spin-dried product is passed through a preparation plate It was purified to obtain 17.0 mg of compound A10.

[M+H ⁺ ]=475.31.

¹ H NMR (500MHz, DMSO) δ 7.97 (s, 1H), 7.29 (dd, J = 18.8, 7.5 Hz, 2H), 7.23-7.11 (m, 3H), 7.01 (s, 1H), 6.82 (d ,J=8.1Hz,1H), 3.86(s,1H), 3.80(s,2H), 3.60–3.47(m,2H), 3.38(s,3H), 3.11–2.96(m,3H), 2.60( d, J=15.5Hz, 1H), 1.87–1.85(m,1H), 1.80–1.76(m,1H), 1.52–1.50(m,1H), 1.14–1.11(m,1H).

Example 19 Compound A19 ((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3 ,4-Difluorophenyl)prop-1-yn-1-yl)-3-methylpyrimidine-4(3H)-one):

Step 1: Preparation of compound A19-1

Dissolve 246 mg of compound A12-1, 200 mg of compound SM1 in 5 mL of DMF, add 17 mg of PdCl ₂ (PPh ₃ ) ₂ , 4.6 mg of CuI, 0.7 mL of TEA, replace with nitrogen, react at room temperature for 30 minutes, and add 50 mg of TBAF in THF ( 1M), stirring at 90°C for 30 min. LCMS detected that the reaction was complete, the reaction solution was poured into 30 mL of saturated brine, and extracted with dichloromethane (20 mL×4). The organic phases were combined, washed with saturated brine (30 mL×4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with a preparation plate to obtain 147 mg of compound A19-1 as a yellow solid.

Step 2: Preparation of compound A19

80 mg of compound A19-1 was dissolved in 2.5 mL of THF, 0.5 mL of EtOH was added, 0.25 mL of HCl EA solution (2M) was added dropwise with stirring, and the mixture was stirred at room temperature for 20 mins. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 1 mL of water, and 1 mL of saturated sodium bicarbonate solution was added dropwise. The precipitated solid was collected and purified with a preparation plate to obtain 40.7 mg of yellow solid compound A19.

[M+H ⁺ ]=461.37.

¹ H NMR(500MHz,DMSO-d6)δ7.97(s,1H), 7.50-7.38(m,2H), 7.32-7.30(m,1H), 7.28-7.24(m,1H), 7.19-7.13( m, 3H), 3.90 (s, 2H), 3.86 (s, 1H), 3.57-3.49 (m, 2H), 3.38 (s, 3H), 3.12-2.98 (m, 3H), 2.60 (d, J = 15.6Hz, 1H), 1.87 (m, 1H), 1.78 (m, 1H), 1.55-1.49 (m, 1H), 1.14-1.11 (m, 1H).

Example 23 Compound A23 ((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5- Preparation of (3-(4-morpholinophenyl)prop-1-yn-1-yl)pyrimidin-4(3H)-one):

Step 1: Preparation of compound A23-1

Dissolve trimethylsilyl acetylene (4.1g) in THF (19mL), add 75mL ethylmagnesium bromide (1M) dropwise under an ice bath and replace with nitrogen, stir and react in an ice bath for 1h, then add A24-SM (2g) , Return to room temperature and stir for 2h. LC-MS and TLC detect that the reaction is complete, add saturated ammonium chloride solution for quenching, add 20ml EA for extraction, separate the organic phase, wash the organic phase with 2×10ml saturated sodium chloride solution, separate and dry, concentrate in vacuo, and pass the crude product to column chromatography Purified to obtain 1.98 g of white solid compound A23-1.

Step 2: Preparation of compound A23-2

Dissolve 600 mg of compound M14, 418 mg of compound A23-1, 23 mg of PdCl ₂ (PPh ₃ ) ₂ , 13 mg of CuI, and 17 mg of PPh ₃ in THF (10 mL) and Et ₃ N (2 mL). After nitrogen replacement, the reaction was stirred at 70°C for 20 min. After that, 87mg TBAF was added, and stirring was continued for 3h. LC-MS and TLC detected that the reaction was complete, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 645 mg of yellow solid compound A23-2.

Step 3: Preparation of compound A23-3

300 mg of compound A23-2 was dissolved in DCM (8 mL) and replaced with nitrogen. First, 111 mg of triethylsilane and then 217 mg of trifluoroacetic acid were added, and the reaction was carried out at room temperature for 1 h. LC-MS and TLC detect that the reaction is complete, add saturated sodium bicarbonate to quench, add 3×10ml DCM for extraction, dry the organic phase, concentrate the crude product and purify it on a preparation plate to obtain 20mg of pale yellow solid compound A23-3.

Step 4: Preparation of compound A23

20 mg of compound A23-3 was dissolved in 2 mL of dioxane and 0.5 mL of methanol solution, replaced with nitrogen, 50 μL of HCl in EA solution (2M) was added dropwise with stirring, and stirred at room temperature for 20 min. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 1 mL of water, 1 mL of saturated sodium bicarbonate solution was added dropwise, the precipitated solid was collected, and purified with a preparation plate to obtain 3.6 mg of light yellow solid compound A23. [M+H] ⁺ =510.42.

Example 87 Compound A66(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'piperidine]-1'-yl)-5-(2-oxo-8 -Azaspiro[4.5]dec-8-yl)3-hydroxy-3-(4-morpholinphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one ) Preparation:

Step 1: Preparation of compound A66

60 mg of compound A23-2 was dissolved in 3 mL of dioxane and 0.5 mL of methanol solution, replaced with nitrogen, 167 μL of HCl in EA solution (2M) was added dropwise with stirring, and stirred at room temperature for 20 min. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 1 mL of water, 1 mL of saturated sodium bicarbonate solution was added dropwise, the precipitated solid was collected, and purified with a preparation plate to obtain 1.8 mg of pale yellow solid compound A66. [M-OH] ⁺ =508.39.

Example 45 Compound A45 ((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3 -Hydroxyphenyl)prop-1-yn-1-yl)pyrimidine-4(3H)-one) preparation:

Step 1: Preparation of compound A45-1

Dissolve 6.73g compound 3,4-dimethoxybenzyl alcohol in THF (300mL), after nitrogen replacement, add 3.85g sodium tert-butoxide, cool to -40℃, add M1-7, and then keep the reaction at -40℃ For 0.5h, slowly warm to room temperature and react for 2h. LC-MS and TLC check that the reaction is complete, add 200 _{mL of H 2} O, then 150 mL of EA, then extract with 150 mL * 3 EA, combine the organic phases, wash with 200 mL * 2 saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain a crude product. After adding 200 mL (PE:EA=10:1) for beating, then filtering and drying to obtain 10.2 g of light yellow solid compound A45-1.

Step 2: Preparation of compound A45-2

Dissolve 5.0 g of compound A45-1 and 4.19 g of compound M5 in 50 mL of dioxane, add 3.73 g of triethylamine, and heat at 75° C. to react for 2 hours. TLC detected that the reaction was complete, the reaction solution was spin-dried, and purified by column chromatography to obtain 3.9 g of compound A45-2.

Step 3: Preparation of compound A45-3

1.0g of compound A45-2, 290.3mg of trimethylsilylacetylene, 32mg of PdCl ₂ (PPh ₃ ) ₂ , and 17mg of CuI were dissolved in THF (15mL) and Et ₃ N (3.75mL). After nitrogen replacement, the reaction was stirred at room temperature. 3h. LC-MS and TLC detected that the reaction was complete, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 650 mg of gray solid compound A45-3.

Step 4: Preparation of compound A45-4

400mg compound A45-3, 13.0mg PdCl ₂ (PPh ₃ ) ₂ , 7.1mg CuI, 9.7mg PPh ₃ were dissolved in DMF (16.0mL) and Et ₃ N (4.0mL), after nitrogen replacement, 242.5mg was added TBAF, stirring at room temperature for 10 minutes, then adding 373.0mg of 3-methoxybenzyl bromide to the above reaction solution, stirring at 80°C under nitrogen protection for 0.5h, and then continuing to add 373.0mg of 3-methoxybenzyl bromide to the above reaction solution , Stir at 80°C for 0.5h under nitrogen protection. LC-MS and TLC check that the reaction is complete, add 10mL of water to quench, extract with ethyl acetate (3x10mL), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by column chromatography to obtain 256mg of light yellow solid compound A45. -4.

Step 5: Preparation of compound A45-5

Dissolve 100 mg of compound A45-3 in 3 mL of DCM, add 0.2 mL of trifluoroacetic acid, and react for 1 hour at RT. LCMS detected that the reaction was complete, and the reaction solution was spin-dried to obtain 90 mg of crude compound A45-5, which was directly used in the next step.

Step 6: Preparation of compound A45

90 mg of compound A45-5 was dissolved in 3 mL of anhydrous dichloromethane, cooled to -60°C, and then BBr ₃ (70 mg) was slowly added to the above solution, and the reaction was slowly raised to room temperature and stirred. LC-MS and TLC check that the reaction is complete, add saturated sodium bicarbonate aqueous solution to quench the reaction, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, spin-dry the filtrate, and purify the crude product on a preparation plate 10.2 mg of compound A45 was obtained.

[M+H] ⁺ =427.27.

Through different reaction starting materials, suitable reagents (starting materials and reagents are all commercially available), and intermediates prepared in the present invention, the same as those in the foregoing Example 10, Example 12, Example 19, and Example 23 are used. The compounds in Table 5 were prepared in a similar manner to Example 87.

table 5

Compound A11 ¹ H NMR (500MHz, DMSO) δ 8.21 (s, 1H), 7.96 (s, 1H), 7.41-7.39 (m, 1H), 7.25-7.22 (m, 3H), 7.13-7.10 (m, 1H), 6.81-7.79 (m, 2H), 6.64-6.61 (m, 1H), 4.09 (s, 1H), 3.78 (s, 2H), 3.55-3.52 (m, 2H), 3.38 (s, 3H) ,3.11–3.05(m,2H),2.76(d,J=15.8Hz,1H),2.54(d,J=15.8Hz,1H),1.90–1.78(m,2H),1.51–1.48(m,1H ), 1.31-1.28 (m, 1H).

Compound A17 ¹ H NMR (500MHz, DMSO) δ 7.96 (s, 1H), 7.44 (d, J = 6.7 Hz, 1H), 7.31-7.22 (m, 4H), 7.03-6.94 (m, 2H), 6.81 (d,J=8.2Hz,1H),4.21(s,1H),3.85(s,2H),3.76(s,3H),3.57-3.52(m,2H),3.39(s,3H),3.11– 3.06(m,2H), 2.84(d,J=15.8Hz,1H), 1.84-1.81(m,2H), 1.51-1.49(m,1H), 1.40-1.38(m,1H).

The following compounds can be synthesized by a similar method.

Table 6

Example 75 Compound D04 (2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( (Hydroxymethyl)pyrazin-2-yl)ethynyl)cyclopropane-1-carboxylic acid ethyl ester) preparation:

Step 1: Preparation of compound D04-1

5.07 g of compound D04-SM and 10 g of compound 3-bromo-1-trimethylsilyl-1-propyne were dissolved in acetone (50 mL), and after nitrogen replacement, the reaction was stirred at room temperature for 18 hours. TLC detected that the reaction was complete, the reaction solution was filtered, the filter cake was washed with acetone (20 ml*3), and the filter cake was spin-dried under vacuum to obtain 5.8 g of white solid compound D04-1.

Step 2: Preparation of compound D04-2

3.84g of compound D04-1 was dissolved in 27mL of anhydrous tetrahydrofuran, 1.25g of ethyl acrylate was added at room temperature, after nitrogen replacement, 848mg of sodium hydrogen (60%) was added to the above reaction solution in batches, and the reaction was stirred at room temperature for 8 hours. The reaction was completed by TLC detection. Under 200-300 mesh silica gel filter aid, the reaction solution was filtered, the filter cake was washed with THF (20ml*2), the filtrate was spin-dried, and the residue was purified by column chromatography to obtain 2.1 g of colorless liquid compound D04-2 .

Step 3: Preparation of compound D04-3

Add 320mg of D04-2, 500mgM1, 35.65mg Pd(dppf)Cl ₂ , 9.65mg CuI, 205mg Et ₃ N to tetrahydrofuran (5mL), replace with nitrogen three times, stir at room temperature for 5 minutes under nitrogen protection, and add 530mg of tetrabutyl Ammonium fluoride was added to the above reaction solution, and the reaction was stirred at 70°C for 18 hrs. LCMS and TLC detected that the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 500 mg of light yellow solid compound D04-3.

Step 4: Preparation of compound D04

50 mg of compound D04-3 was dissolved in 2.0 mL of tetrahydrofuran, 2N HCl (0.2 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hrs. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The residue was _{dissolved by adding H 2} O (1.0 mL), the _{solution was adjusted to pH=8 with saturated NaHCO 3} , extracted with dichloromethane (3×3 mL), the organic phase was dried and concentrated in vacuo, and purified by a preparation plate to obtain 9.4 mg of yellow solid compound D04. [M+H ⁺ ]=447.36.

Example 90 Compound D13(2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( (Hydroxymethyl)pyrazin-2-2-yl)ethynyl)cyclopropaneamide) preparation:

Step 1: Preparation of compound D13-1

500 mg of compound D04-3 was dissolved in tetrahydrofuran (6 mL), and 75 mg of lithium hydroxide monohydrate dissolved in water (2 mL) was added to the above solvent, and the reaction was stirred at room temperature for 5 hours. TLC detected that the reaction was complete, the tetrahydrofuran in the reaction solution was rotated off, extracted with ethyl acetate (5 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain 410 mg of light yellow solid compound D13-1.

Step 2: Preparation of compound D13-2

Dissolve 100 mg of compound D13-1, 73 mg of EDCI, and 39 mg of Hobt in anhydrous dichloromethane (2 mL), stir at room temperature for 15 min, add 10 mg of ammonia and 74 mg of DIEA to the above reaction solution, under nitrogen protection, stir at room temperature for 1 hour . TLC detects that the reaction is complete, add water (5mL) to the reaction solution, extract with dichloromethane (5mL*2), combine the organic phases, dry with anhydrous sodium sulfate, filter the filtrate and spin-dry, and spin the dried product on a preparation plate to obtain 71mg of light yellow Compound D13-2.

Step 3: Preparation of compound D13

71 mg of compound D13-2 was dissolved in 2.0 mL of tetrahydrofuran, 2N HCl (0.3 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 2 hrs. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The residue was dissolved by adding H2O (1.0 mL), adjusting the solution to pH=8 with saturated NaHCO3, extracting with dichloromethane (3×3 mL), drying the organic phase and then concentrating in vacuo. Purified by a preparation plate, 23 mg of yellow solid compound D13 was obtained. [M+H ⁺ ]=418.22

Example 78 Compound D07(2-((2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl Preparation of 6-oxo-1,6-dihydropyrimidin-5-yl)ethynyl)cyclopropane-1-carboxylic acid ethyl ester:

Step 1: Preparation of compound D07-1

Add 630mg of D04-3, 750mg M14, 48mg Pd(dppf)Cl ₂ , 13mg CuI and 205mg Et ₃ N to tetrahydrofuran (10mL), replace with nitrogen three times, stir at room temperature for 5 minutes under nitrogen protection, and fluoride 783mg of tetrabutyl Ammonium was added to the above reaction solution, and the reaction was stirred at 70°C for 3 hours. The reaction was completed by LCMS and TLC, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 660 mg of light yellow solid compound D07-1.

Step 2: Preparation of compound D07

60 mg of compound D07-1 was dissolved in 2.0 mL of tetrahydrofuran, 2N HCl (0.2 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hour. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The residue was _{dissolved by adding H 2} O (1.0 mL), the _{solution was adjusted to pH=8 with saturated NaHCO 3} , extracted with dichloromethane (3×3 mL), the organic phase was dried and concentrated in vacuo, and purified by a preparation plate to obtain 7.2 mg of yellow solid compound D07. [M+H ⁺ ]=447.35.

Example 72 Compound D01(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2-( Preparation of hydroxymethyl)cyclopropyl)ethynyl)-3-methylpyrimidine-4(3H)-one):

Step 1: Preparation of compound D01-1

100 mg of compound D07-1 was dissolved in anhydrous dichloromethane (5 mL), the temperature was lowered to -78°C, 0.7 mL of DIBAL (1 mol/L, DCM solution) was slowly added to the above solution, and the reaction was stirred at -78°C for 1.5 hours. TLC detects that the reaction is complete, add ether (10ml) to the reaction solution, warm to 0°C, slowly add 2 drops of H ₂ O, then add 2 drops of 15% sodium hydroxide aqueous solution, add 5 drops of H ₂ O, warm to room temperature and stir. After reacting for 15 minutes, adding anhydrous sodium sulfate, stirring the reaction for 30 minutes, filtering under the aid of diatomaceous earth, the filtrate was spin-dried, and the filtrate was spin-dried to obtain 32 mg of light yellow solid compound D01-1.

Step 2: Preparation of compound D01-2

32 mg of compound D01-1 and 4.5 mg of sodium borohydride were dissolved in 2 mL of anhydrous tetrahydrofuran, and the reaction was stirred at room temperature under nitrogen protection for 0.5 hours. TLC detects the completion of the reaction. Add saturated aqueous ammonium chloride solution (5mL) to the reaction solution, extract with ethyl acetate (5mL*2), combine the organic phases, dry with anhydrous sodium sulfate, filter the filtrate and spin-dry, and spin-dried to purify by a preparation plate 20 mg of light yellow solid compound D01-2 was obtained.

Step 3: Preparation of compound D01

20 mg of compound D01-2 was dissolved in 2.0 mL of tetrahydrofuran, 2N HCl (0.2 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1.5 hours. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. Add H ₂ O (1.0 mL) to dissolve the _{residue, adjust the solution to pH=8 with saturated NaHCO 3} , extract with dichloromethane (3x3 mL), dry the organic phase and concentrate in vacuo, and purify it on a preparation plate to obtain 3.5 mg of light yellow solid compound D01 . [M+H ⁺ ]=405.44.

Example 74 Compound D03 (5-((2-(1,3,4-oxadiazol-2-yl)cyclopropyl)ethynyl)-2-((S)-1-amino-1,3- Preparation of dihydrospirocyclo[indene-2,4'-piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one):

Step 1: Preparation of compound D03-1

200 mg of compound D03-1 was dissolved in tetrahydrofuran (6 mL), and 31 mg of lithium hydroxide monohydrate dissolved in water (2 mL) was added to the above solvent, and the reaction was stirred at room temperature for 3 hours. TLC detected that the reaction was complete, the tetrahydrofuran in the reaction solution was removed, extracted with ethyl acetate (5 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain 110 mg of light yellow solid compound D03-1.

Step 2: Preparation of compound D03-2

Dissolve 100mg of compound D07-1, 73mg EDCI and 39mg Hobt in anhydrous dichloromethane (2mL), stir at room temperature for 15min, add 19mg hydrazine monohydrate (80%) and 74mg DIEA to the above reaction solution, protect the room temperature with nitrogen The reaction was stirred for 0.5 hour. TLC detects that the reaction is complete, add water (5mL) to the reaction solution, extract with dichloromethane (5mL*2), combine the organic phases, dry with anhydrous sodium sulfate, filter the filtrate and spin-dry, and spin the dried product to obtain 63mg of light yellow with a preparation plate. Solid compound D03-2.

Step 3: Preparation of compound D03-3

60 mg of compound D03-2 and 10 mg of p-toluenesulfonic acid were dissolved in trimethyl orthoformate (2 mL), and the reaction was stirred at 85°C for 2 hours. TLC detects that the reaction is complete. Add water (5mL) to the reaction solution, extract with dichloromethane (6mL*3), combine the organic phases, dry with anhydrous sodium sulfate, filter, spin-dry the filtrate, and spin-dry the product through a preparation plate to obtain 36mg of light. Yellow solid compound A31-3.

Step 4: Preparation of compound D03

36 mg of compound D03-3 was dissolved in 2.0 mL of tetrahydrofuran, 2N HCl (0.2 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 2 hours. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The residue was _{dissolved by adding H 2} O (1.0 mL), the _{solution was adjusted to pH=8 with saturated NaHCO 3} , extracted with dichloromethane (3×3 mL), the organic phase was dried and concentrated in vacuo, and purified by a preparation plate to obtain 14.4 mg of white solid compound D03. [M+H ⁺ ]=443.30.

Through different reaction starting materials, suitable reagents (starting materials and reagents are commercially available) and intermediates prepared in the present invention, using the same as the foregoing embodiment 72, embodiment 74, embodiment 75, embodiment 78 or implementation The compounds in Table 7 were prepared in a similar manner to Example 90.

Table 7

The following compounds can be synthesized by a similar method.

Table 8

Example 108 Compound D14 4-(2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6 (Hydroxymethyl)pyrazin-2-yl)ethynyl)cyclopropyl)benzamide:

Step 1: Preparation of D14-1

Dissolve 7.00g 4-cyanobenzaldehyde, 369mg DBU and 13.41g potassium carbonate in triethyl phosphonoacetate (10.88g) and react at room temperature for 2 hours. TLC detected that the reaction was complete, filtered, the filter cake was washed with 20 mL of ethyl acetate, the filtrate was concentrated in vacuo, the crude product was dissolved in methyl tert-butyl ether, n-hexane was added to precipitate a solid, and 9.10 g of a white solid was obtained by filtration, namely D14-1.

Step 2: Preparation of D14-2

Dissolve 2.17g sodium hydride (60%) in anhydrous DMSO (100mL), after nitrogen replacement, add 11.94g trimethyl iodide mixed sulfoxide in batches, stir at room temperature until the reaction solution is clear, add 9.10g mixture D14-1 Dissolve in anhydrous DMSO (100 mL), slowly add dropwise to the reaction solution, and complete the reaction at room temperature for 12 hours. TLC detects the completion of the reaction, adds 200 mL of water with stirring in an ice bath, extracts with 500 mL of ethyl acetate, washes the organic phase with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 1.85 g of a colorless transparent oily liquid. Namely D14-2.

Step 3: Preparation of D14-3

Dissolve 0.50g mixture D14-2 in anhydrous THF (15mL), after nitrogen replacement, add 615mg sodium borohydride and 295mg lithium chloride in batches under ice bath, stir for 15 minutes and then move to room temperature, slowly add MeOH dropwise (5mL), after dropping, stirring at room temperature for 12 hours. TLC detection reaction is complete, add 5mL 0.1N HCl, 20mL ethyl acetate extraction under ice bath stirring, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, the crude product is purified by column chromatography to obtain 278mg colorless transparent oily liquid , Namely D14-3.

Step 4: Preparation of D14-4

278 mg of the mixture D14-3 was dissolved in DCM (10 mL), and 987 mg of Dess Martin oxygen mixture was added with stirring, and the mixture was stirred at room temperature for 1 hour. The reaction was completed by TLC detection. Saturated sodium thiosulfate solution (30mL) was added, extracted with DCM (30mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 235mg of a colorless transparent oily liquid , Which is D14-4.

Step 5: Preparation of D14-5

332 mg of the mixture D14-4 and 1.61 g of potassium carbonate were dissolved in MeOH (2 mL), 745 mg of (1-diazo-2-oxopropyl) dimethyl phosphonate was added with stirring, and the mixture was stirred at room temperature for 1 hour. TLC detected the completion of the reaction, filtered, the filter cake was washed with 20 mL of ethyl acetate, the filtrate was concentrated in vacuo, and the crude product was purified by column chromatography to obtain 197 mg of white solid, namely D14-5.

Step 6: Preparation of D14-6

200 mg of mixture M1, 102 mg of mixture D14-5, 14 mg of PdCl ₂ (PPh ₃ ) ₂ , and 3.9 mg of CuI were dissolved in tetrahydrofuran (6 mL) and triethylamine (1 mL). After nitrogen replacement, the mixture was reacted at 60° C. for 12 hours. LC-MS and TLC detect that the reaction is complete, add 20 mL of water, extract with 20 mL of dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by a preparation plate to obtain 106 mg of yellow solid, namely D14-6.

Step 7: Preparation of D14-7

106 mg of mixture D14-6 and 2 mg of Parkin’s reagent were dissolved in EtOH (3 mL) and water (3 mL), and reacted at 80°C for 12 hours. LCMS and TLC detected that the reaction was complete, concentrated in vacuo, added 20 mL of dichloromethane, dispersed in 20 mL of water, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by a preparation plate to obtain 86 mg of light yellow solid, namely D14- 7.

Step 8: Preparation of D14

86 mg of the mixture D14-7 was dissolved in dioxane (3 mL) and ethanol (1.5 mL), 2N HCl (143.9 μL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hour. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. Add H ₂ O (1.0 mL) to dissolve the _{residue, adjust the solution to pH=8 with saturated NaHCO 3} , extract with dichloromethane (3×3 mL), dry the organic phase and concentrate in vacuo. Purify on a preparation plate to obtain 40.2 mg of pale yellow solid Get D14.

[M+H ⁺ ]=494.2.

¹ H NMR(500MHz,DMSO--d ₆ )δ8.17(s,1H),7.92(s,1H),7.82-7.78(m,2H),7.33-7.23(m,4H),7.19-7.10( m, 3H), 5.39 (t, J = 5.9 Hz, 1H), 4.47 (d, J = 5.8 Hz, 2H), 3.84 (s, 1H), 3.79-3.65 (m, 2H), 3.21-2.99 (m ,3H), 2.59(d,J=15.6Hz,1H),2.03–1.94(m,2H),1.92–1.84(m,1H),1.81–1.72(m,1H),1.56–1.41(m,3H) ), 1.15-1.07 (m, 1H).

Pharmacological test

Example A: SHP2 allosteric inhibition enzyme activity assay

SHP2 is allosterically activated by the binding of a bis-tyrosyl-phosphorylated peptide to its Src homology 2 (SH2) domain. This subsequent activation step results in the release of the SHP2 auto-inhibitory interface, which in turn activates the SHP2 protein tyrosine phosphatase (PTP) and can be used for substrate recognition and reaction catalysis. The surrogate DiFMUP was used to monitor the catalytic activity of SHP2 in the rapid fluorescence assay format.

experiment procedure:

(1) Compound preparation:

The compound of the present invention (10mM stock solution) was diluted to an appropriate multiple with 100% DMSO. The final test concentration of the compound of the present invention was 10μM, 3.3333μM, 1.1111μM, 0.3704μM, 0.1235μM, 0.0412μM, 0.0137μM, 0.0046μM, 0.0015μM , 0.00μM;

(2) Prepare working solution for enzyme reaction:

In a 96-well black polystyrene plate (flat bottom, low flange, non-binding surface) (Perki Elmer, Cat#6005270) at room temperature, use a final reaction volume of 50μL and the following assay buffer conditions for SHP2 enzyme activity detection: 60mM HEPES, 75mM NaCl, 75mM KCl, 0.05% BRIJ-35, 1mM EDTA, 5mM DTT.

(3) Enzyme catalytic reaction and data monitoring:

Take the compound of the present invention and add it to the corresponding 96-well plate, and set the blank test well without adding the compound and enzyme and only adding buffer. Put SHP2Activating Peptide (IRS1_pY1172(dPEG8)pY1222) on ice to melt, add 25μM to each well, then add 0.2ng SHP2 protein sample to the corresponding well plate, and incubate at room temperature for 1 hour. The replacement substrate DiFMUP (Invitrogen, Cat#D6567) was added to the reaction, and the reaction was carried out at room temperature for 2 hours. The fluorescence signal was monitored by a microplate reader (Envision, Perki Elmer) with excitation wavelength and emission wavelength of 340nm and 450nm, respectively.

(4) Data analysis:

Calculation formula:

Inhibition rate%=[1-(Conversion_ _sample -Conversion_ _min )/(Conversion_ _max -Conversion_ _min )]×100%

Among them: Conversion_sample is the conversion rate reading of the sample; Conversion_min is the average value of the blank control well, representing the conversion rate reading of the wells without enzyme activity; Conversion_max is the average value of the positive control wells, representing the conversion rate reading of the wells without compound inhibition. The analysis software GraphPad Prism log (inhibitor) vs. response-Variable slope was used to fit the dose-effect curve, and the IC ₅₀ value of the compound to the enzyme activity was calculated.

_{The IC 50} data of some examples are shown in Table 9.

Table 9

The compound of the present invention has an allosteric inhibitory effect on the SHP2 protein.

Example B: Cell Proliferation Test

In vitro cell assays were used to evaluate the effects of the compounds of the present invention on the proliferation of leukemia cells MV-4-11 and lung cancer cells NCI-H358. The detection method used in the experiment is the CELL TITER-GLO (CTG) luminescence method, which can detect the number of living cells by quantitatively measuring ATP. Because ATP participates in a variety of enzymatic reactions in organisms and is an indicator of living cell metabolism, its content directly reflects the number and cell state of cells. During the experiment, CellTiter-Glo ^TM reagent was added to the cell culture medium to measure the luminescence value. The value is directly proportional to the amount of ATP, and ATP is positively related to the number of living cells, so cell viability can be inspected by detecting ATP content.

experiment procedure:

(1) Cell plating:

Take a bottle of MV-4-11 cells in logarithmic growth phase, collect the cells and resuspend them by centrifugation, count them, adjust the cell density and inoculate them into a 96-well plate, inoculate 4000 cells per well, and place the plate at 37°C, 5% After culturing in a CO ₂ incubator for 24 hrs, the compound of the present invention is added for treatment;

Take a bottle of NCI-H358 cells in the logarithmic growth phase, digest and resuspend the cells, count them, adjust the cell density and inoculate them into a 96-well transparent low-adsorption cell culture plate, inoculate 2000 cells per well, and place the plate at 37℃, After culturing in a 5% CO ₂ incubator for 24 hrs, the compound of the present invention is added for treatment;

(2) Cell compound treatment:

Prepare an appropriate amount of the compound of the present invention for cell treatment, and the final concentration of the compound from high to low is 1000nM, 333.3nM, 111.1nM, 37.04nM, 12.35nM, 4.115nM, 1.372nM, 0.4572nM, 0.1524nM, 0nM. Enter 37℃, 5% CO ₂ incubator for culture. Only adding culture medium without adding cell wells is set as the zero adjustment group; the compound concentration of 0 nM group is the blank group.

(3) CTG detection:

After NCI-H358 cells were cultured for 96hrs, 50μL of

Luminescent Cell Viability Assay solution, gently shake for 2mins, and continue to incubate for 10mins at room temperature. The cell reaction system was transferred to a 96-well plate with a white background. Read the detection value of each well on the multi-function microplate reader.

After MV-4-11 cells are cultured for 120hrs, add 50μL to each well

Luminescent Cell Viability Assay solution, gently shake for 2mins, continue to incubate for 10mins at room temperature, and read the detection value of each well on the multifunctional microplate reader.

(4) Data analysis:

Calculate the inhibition rate based on the luminous value reading,

Inhibition rate%=(1-(administration group value-zero adjustment group value)/(blank group value-zero adjustment group value)*100

GraphPad Prism the log (inhibitor) vs.response-Variable slope fitting dose-response curve and calculate IC ₅₀ of compounds to inhibit cell proliferation.

The experimental data is shown in Table 10.

Table 10

Note: "/" means not detected.

The compound of the present invention has a good inhibitory effect on the proliferation of MV-4-11 cells and NCI-H358 cells.

Example C: In vivo drug efficacy experiment on subcutaneous xenograft tumor model of MIA-PaCa2 cells

BALB/c nude mice, female, 6-8 weeks old, weighing about 18-22 grams. Each mouse was subcutaneously inoculated with 0.2 mL (1×10 ⁷ cells) of MIA-PaCa2 cells (with Matrigel, volume ratio 1:1) on the right back. The administration was started when the average tumor volume reached approximately 113 cubic millimeters. The test compound was orally administered daily at a dose of 10 mpk QD. The tumor volume is measured twice a week, and the volume is measured in cubic millimeters, and calculated by the following formula: V=0.5a×b ² , where a and b are the long diameter and short diameter of the tumor, respectively.

The anti-tumor efficacy of the compound was evaluated by TGI (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI(%): TGI(%)=[(1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the beginning of the treatment group))/(Average tumor at the end of treatment in the solvent control group Volume-the average tumor volume at the start of treatment in the solvent control group)]×100%.

The compound of the present invention exhibits a significant anti-tumor effect in a subcutaneous xenograft tumor model of MIA-PaCa2 cells. The TGI and body weight changes of the solvent control group and compound A68 on day 24 are shown in Table 11.

Table 11

Grouping

TGI(%)

Weight change (%)

溶剂对照组Solvent control group	//	1313
化合物A68Compound A68	8787	1010

Although the present invention has been fully described through its embodiments, it is worth noting that various changes and modifications are obvious to those skilled in the art. Such changes and modifications should be included in the scope of the appended claims of the present invention.

Claims

A compound represented by formula I, or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, wherein the compound is As shown in formula I:

in,

Single bond or double bond;

Ring A is selected from a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; wherein the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains one or more O, N or S heteroatom; the 5-10 membered heterocyclic group contains at least one double bond;

Ring C is selected from C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;

Each R c is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;

R c1 and R c2 are each independently selected from hydrogen, halogen, C 1-4 alkyl or -OR 5 ;

Or R c1 and R c2 together with the atoms to which they are connected form a C 3-6 carbocyclic group or a 3-6 membered heterocyclic group;

Each R 1 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic ring Group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -NR 7 R 8 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; Substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 Membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 ;

M is selected from -O-, -NR 1a -or -CR 1b R 1c -;

R 1a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -OR 1d , -NR 1e R 1f or not present;

R 1d , R 1e , and R 1f are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;

Y 1 is selected from -NR 3a -or -CR 3b R 3c -;

R 3a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

R 3b and R 3c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

Y 2 is selected from -NR 4a -or -CR 4b R 4c -;

R 4a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

R 4b and R 4c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

The ring D is a C 6-10 aryl group, a 5-10 membered heteroaryl group, a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group; wherein, the C 3-8 carbocyclic group or a 3- The 8-membered heterocyclic group optionally contains a double bond;

Each R 4 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;

R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , -NR 23 and R 24 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 member Heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

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

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

s is 1, 2, 3 or 4;

t is 1, 2, 3 or 4;

When n=0, the ring A is
And when ring C is phenyl, r is not equal to 0, and R c is not hydrogen.
The compound of claim 1, wherein n is 0 or 1.
The compound according to claim 1 or 2, wherein the compound is selected from formula II:

in,

Single bond or double bond;

Ring A is selected from a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; wherein the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains one or more O, N or S heteroatom; the 5-10 membered heterocyclic group contains at least one double bond;

Ring C is selected from C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;

Each R c is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;

R c1 and R c2 are each independently selected from hydrogen, halogen, C 1-4 alkyl or -OR 5 ;

Or R c1 and R c2 together with the atoms to which they are connected form a C 3-6 carbocyclic group or a 3-6 membered heterocyclic group;

Each R 1 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic ring Group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -NR 7 R 8 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; Substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 Membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 ;

M is selected from -O-, -NR 1a -or -CR 1b R 1c -;

R 1a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -OR 1d , -NR 1e R 1f or not present;

R 1d , R 1e , and R 1f are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;

Y 1 is selected from -NR 3a -or -CR 3b R 3c -;

R 3a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

R 3b and R 3c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

Y 2 is selected from -NR 4a -or -CR 4b R 4c -;

R 4a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

R 4b and R 4c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

The ring D is a C 6-10 aryl group, a 5-10 membered heteroaryl group, a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group; wherein, the C 3-8 carbocyclic group or a 3- The 8-membered heterocyclic group optionally contains a double bond;

Each R 4 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;

R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , -NR 23 and R 24 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 member Heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;

p is 0, 1, 2 or 3;

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

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

s is 1, 2, 3 or 4;

t is 1, 2, 3, or 4.
The compound according to any one of claims 1-3, wherein R c1 and R c2 are each independently selected from hydrogen, -CH 3 , -F, and -OH.
The compound according to any one of claims 1 to 4, wherein R c1 and R c2 are each selected from hydrogen.
The compound according to any one of claims 1 to 3, wherein R c1 and R c2 together with the atoms to which they are attached form a cyclopropyl group.
The compound according to any one of claims 1-6, wherein the ring C is selected from morpholinyl, piperazinyl or piperidinyl.
The compound according to any one of claims 1-6, wherein the ring C is selected from a C 6-10 aryl group or a 5-10 membered heteroaryl group.
The compound according to any one of claims 1-6 or 8, wherein the ring C is selected from the group consisting of pyrazolyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, indolinyl , Isoindolinyl, indazolyl, benzimidazolyl, purinyl, benzisoxazolyl or indolazinyl.
The compound according to any one of claims 1-6 or 8-9, wherein the ring C is selected from phenyl,
The compound according to any one of claims 1-6 or 8-10, wherein the ring C is selected from phenyl.
The compound according to claim 1 or 2, wherein the compound is selected from formula III:

in,

Single bond or double bond;

Ring A is selected from a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; wherein the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains one or more O, N or S heteroatom; the 5-10 membered heterocyclic group contains at least one double bond;

Ring C is selected from C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;

Each R c is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;

Each R 1 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic ring Group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -NR 7 R 8 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; Substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 Membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 ;

M is selected from -O-, -NR 1a -or -CR 1b R 1c -;

R 1a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -OR 1d , -NR 1e R 1f or not present;

R 1d , R 1e , and R 1f are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;

Y 1 is selected from -NR 3a -or -CR 3b R 3c -;

R 3a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

R 3b and R 3c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

Y 2 is selected from -NR 4a -or -CR 4b R 4c -;

R 4a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

R 4b and R 4c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;

The ring D is a C 6-10 aryl group, a 5-10 membered heteroaryl group, a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group; wherein, the C 3-8 carbocyclic group or a 3- The 8-membered heterocyclic group optionally contains a double bond;

Each R 4 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;

R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , -NR 23 and R 24 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 member Heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;

p is 0, 1, 2 or 3;

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

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

s is 1, 2, 3 or 4;

t is 1, 2, 3 or 4;

When ring A is
And when ring C is phenyl, r is not equal to 0, and R c is not hydrogen.
The compound according to claim 12, wherein the ring C is selected from C 3-10 carbocyclic group or 3-10 membered heterocyclic group.
The compound according to claim 12 or 13, wherein the ring C is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl or piperidinyl.
The compound according to any one of claims 1-14, wherein ring A is selected from
Wherein, X 1 and X 2 are each independently selected from -NR 1 -or -CR 1 R 1 -.
The compound of claims 1-15, wherein ring A is selected from
The compound of claims 1-15, wherein ring A is selected from
The compound according to any one of claims 1-17, wherein the ring DD is a C 6-10 aryl group or a 5-10 membered heteroaryl group.
The compound of any one of claims 1-18, wherein the ring D is
The compound of any one of claims 1-19, wherein the ring D is
The compound according to any one of claims 1-20, wherein each R c is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2 -8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(= O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 ,-NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 carbocyclic group, 3-10 The membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered hetero Aryl, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(= O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 or -NR 23 (CH 2 ) t OR 24 .
The compound according to any one of claims 1-21, wherein each R c is independently selected from hydrogen, oxo, -NO 2 , -CH 3 , -OCH 3 , -OH,- CN, -F, -Cl, -CF 3 , -NH 2 , -NHCH 3 , -NHC(=O)CH 3 , -C(=O)NH 2 , -CH 2 OH, -COOH, -COOEt,- S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -CH 2 OCH 3 ,
The compound according to any one of claims 1-22, wherein each R 1 is independently selected from hydrogen, halogen, oxo, C 1-4 alkyl, -NR 7 R 8 ; wherein The C 1-4 alkyl is optionally substituted by one or more substituents; the substituent is selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 ,- NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 .
The compound according to any one of claims 1-23, wherein each R 1 is independently selected from hydrogen, oxo, -CH 3 , -NH 2 , and -CH 2 OH.
The compound according to any one of claims 1-24, wherein M is selected from -O- or -CR 1b R 1c -.
The compound according to any one of claims 1-25, wherein R 1b and R 1c are independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered hetero Cyclic group, -OR 1d or -NR 1e R 1f .
The compound according to any one of claims 1-26, wherein Y 1 is selected from -CR 3b R 3c -, and Y 2 is selected from -CR 4b R 4c -.
The compound according to any one of claims 1-27, wherein each R 4 is independently selected from hydrogen, halogen, oxo, C 1-8 alkyl, or -OR 5 .
The compound of any one of claims 1-28, wherein each R 4 is independently selected from hydrogen, oxo, -CH 3 or -OCH 3 .
The compound of any one of claims 1-29, wherein p is 1, 2, or 3.
The compound according to any one of claims 1-30, wherein q is 0, 1, or 2.
The compound of any one of claims 1-31, wherein r is 0, 1, 2, or 3.
The compound according to any one of claims 1-32, wherein s is 1 or 2.
The compound according to any one of claims 1-34, wherein t is 1 or 2.
The compound of claim 1, wherein the compound is selected from:

3-(5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine-2 -Base)-1-phenylprop-2-yn-1-ol;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-phenylprop-1-yne -1-yl)pyrazin-2-yl)methanol;

(S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl) Pyrazin-2-yl)prop-2-yn-1-yl)phenol;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-morpholinoprop-1-yne -1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4-methylpiperazine- 1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4-methoxybenzene (Yl)propyl-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(1-methyl-1H -Pyrazol-5-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-4-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl) Pyrazin-2-yl)prop-2-yn-1-yl)phenol;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-hydroxyphenyl)propane -1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-chloro-3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl)propane -1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3,4-dihydroxybenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-3-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)benzonitrile;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(2- (Trifluoromethyl)pyridin-3-yl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(trifluoro (Methyl)phenyl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-methoxyphenyl )Prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3,4-difluorobenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(R)-2-(1-Amino-8-azaspiro[4.5]dec-8-yl)-5-(3-(3-hydroxyphenyl)prop-1-yn-1-yl)-3 -Methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-3-methyl (Oxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2,3-dihydroxybenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3,5-dihydroxybenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(4- Morpholinophenyl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(6-methoxypyridine- 3-yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-4-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2-fluorobenzonitrile;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(6-hydroxypyridine-3- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(6-hydroxypyridine-2- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-hydroxypyridine-4- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-amino-3-chloro (Pyridin-4-yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-hydroxypyrimidine-4- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-aminopyrimidine-4- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-hydroxyl (Pyridin-4-yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-4-(3-(4-Amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl 6-oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2-fluorobenzonitrile;

(S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-amino -3-Chloropyridin-4-yl)prop-1-yn-1-yl)-3-methylpyrimidine-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(2- (Methylamino)pyridin-4-yl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-aminopyrimidine-5- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-5-(3-(4-(1H-pyrazol-1-yl)phenyl)prop-1-in-1-yl)-2-(1-amino-1,3-dihydrospiro Cyclo[indene-2,4'-piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;

4-(3-(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)-1-fluoropropene-2-p-1-yl)-2-hydroxybenzonitrile;

(S)-5-(3-(1H-indazol-6-yl)prop-1-yn-1-yl)-2-(1-amino-1,3-dihydrospiro[indene-2 ,4'-Piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxy-4-? (Pholinyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-6-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)indol-2-one;

(S)-5-(3-(1H-indol-6-yl)prop-1-yn-1-yl)-2-(1-amino-1,3-dihydrospiro[indene-2, 4'-Piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl)propane -1-yn-1-yl)pyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-amino-3-chloro (Pyridin-4-yl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;

(S)-5-(3-(2-Amino-3-chloropyridin-4-yl)prop-1-yn-1-yl)-2-(1-amino-6-methoxy-1,3 -Dihydrospirocyclo[indene-2,4'-piperidine]-1'-yl)pyrimidin-4(3H)-one;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-fluoro-3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-chloro-2,3 -Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-6-amino-2-(4-amino-4,6-dihydrospiro[d]thiazole-5,4'-piperidine]-1'-yl)-5-(3-(4 -Chloro-3-hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(4-Amino-4,6-dihydrospiro[d]thiazole-5,4'-piperidine]-1'-yl)-5-(3-(4-chloro-3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-2,3 -Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-3,5 -Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-6-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)propan-2-oct-1-yl)-2-hydroxy-3-methylbenzonitrile;

(S)-4-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2-hydroxybenzonitrile;

(S)-2-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-6-hydroxybenzonitrile;

(S)-4-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2,6-dihydroxybenzonitrile;

(S)-6-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-3-chloro-2-hydroxybenzonitrile;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl)- 3-methyl-1-yl)-3-methylpyrimidin-4(3H)-one;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-fluoro-3-(3-methyl (Oxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-hydroxy-3-(3-methyl (Oxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-hydroxy-3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(5-Amino-5,7-dihydrospiro[b]pyridine-6,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl) )Prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(7-Amino-5,7-dihydrospiro[d]pyrimidine-6,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl )Prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-((1-phenyl Cyclopropyl)ethynyl)pyrimidin-4(3H)-one;

(R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidine]-1'-yl)-5-(3-(4-chloro-3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(R)-2-(3'-Amino-3'H-spiro[piperidine-4,2'-thiophene[2,3-b]furan]-1-yl)-5-(3-(3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(R)-2-(6-Amino-6H-spiro[fluoro[3,2-d]thiazole-5,4'-piperidine]-1'-yl)-5-(3-(3-hydroxy (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(3-Amino-3H-spiro[furan[3,2-b]furan-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-2-(6-Amino-6H-spiro[fluoro[2,3-d]oxazole-5,4'-piperidine]-1'-yl)-5-(3-(3- Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

(R)-2-(6-Amino-2-methyl-6H-spiro[fluoro[3,2-d]thiazole-5,4'-piperidine]-1'-yl)-5-(3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2-(hydroxymethyl)cyclopropyl (Yl)ethynyl)-3-methylpyrimidin-4(3H)-one;

5-((2-(1,3,4-oxadiazol-2-yl)cyclopropyl)ethynyl)-2-((S)-1-amino-1,3-dihydrospiro[indene -2,4'-piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;

2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-yl)ethynyl)ethyl cyclopropane-1-carboxylate;

2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-yl)ethynyl)cyclopropane-1-carboxylic acid;

2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-yl)ethynyl)-N-cyclopropylcyclopropane-1-carboxamide;

2-((2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6-oxo -1,6-Dihydropyrimidin-5-yl)ethynyl)cyclopropane-1-carboxylic acid ethyl ester;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-((2-(methyl (Sulfonyl)cyclopropyl)ethynyl)pyrimidin-4(3H)-one;

2-((2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6-oxo -1,6-Dihydropyrimidin-5-yl)ethynyl)cyclopropane-1-sulfonamide;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-((2-(2 ,2,2-Trifluoro-1-hydroxyethyl)cyclopropyl)ethynyl)pyrimidin-4(3H)-one;

2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2-(methoxymethyl) Cyclopropyl)ethynyl)-3-methylpyrimidin-4(3H)-one;

(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'piperidine]-1'-yl)-5-(2-oxo-8-azaspiro[ 4.5] Dec-8-yl)3-hydroxy-3-(4-morpholinphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;

2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-2-yl)ethynyl)cyclopropaneamide;

2-((3S,4S)-4-amino-3-methyl-2-oxo-8-azo[4.5]dec-8-yl)-5-(3-(3-hydroxyphenyl)propan- 1-Alkyn-1-yl)-3-methylpyrimidin-4(3H)-one;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-3-carboxamide;

(S)-N-(3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)phenyl)acetamide;

(S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)benzamide;

(S)-4-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)benzamide;

(S)-4-(4-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)but-3-yn-1-yl)benzamide;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(4-phenylbut-1-yne- 1-yl)pyrazin-2-yl)methanol;

(S)-2-(3-(5-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)isoindoline-5-carboxamide;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-(3-(indol-1-yl) Prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-ol;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-amino-1H-indyl) Dol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-yl)acetamide;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6-amino-1H-indyl (Azol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4-amino-1H-indyl (Azol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indazole-5-carboxamide;

(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-4-yl)acetamide;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-benzo[d]imidazole-5-carboxamide;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-benzo[d]imidazole-6-carboxamide;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-methoxy-1H -Benzo[d]imidazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(6-(3-(1H-indol-1-yl)prop-1-yn-1-yl)-3-(1-amino-1,3-dihydrospiro[indene-2, 4'-Piperidine]-1'-yl)pyrazin-2-yl)methanol;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)indoline-5-carboxamide;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-nitroindole- 1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indole-5-carboxamide;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indazole-6-carboxamide;

(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-6-yl)acetamide;

(S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)benzo[d]isoxazole-6-carboxamide;

(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)indolazine-6-carboxamide;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-amino-1H-indyl) (Azol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-methoxy-1H -Indazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-nitro-1H- Indol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6-methoxy-1H -Benzo[d]imidazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;

(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6-amino-9H-purine -9-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol; or

4-(2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl) Pyrazin-2-yl)ethynyl)cyclopropyl)benzamide.
A pharmaceutical composition characterized by comprising a therapeutically effective amount of at least one compound according to any one of claims 1-35 and at least one pharmaceutically acceptable excipient.
The composition according to claim 36, wherein the mass percentage of the therapeutically effective amount of at least one compound according to any one of claims 1-35 and pharmaceutically acceptable excipients is 0.0001:1-10.
Use of the compound of any one of claims 1-35 or the pharmaceutical composition of claim 36 or 37 in the preparation of medicines.
The application according to claim 38, wherein the medicine is used to treat, prevent, delay or prevent cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or eye disease.
The use according to claim 38, wherein the medicine is used to treat diseases mediated by SHP2.
The use according to claim 40, wherein the disease is cancer.
The use according to claim 41, wherein the cancer is selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, Acute myeloid leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
The use according to claim 38, wherein the drug is used as an SHP2 inhibitor.
A method for treating and/or preventing diseases mediated by SHP2, comprising administering a therapeutically effective amount of at least any one of the compounds or pharmaceutical compositions of any one of claims 1-35 to a subject to be treated.
The method of claim 44, wherein the SHP2-mediated disease is cancer.
A method for treating cancer, comprising administering a therapeutically effective amount of at least any one of the compounds or pharmaceutical compositions of any one of claims 1-35 to a subject.
The method of claim 46, wherein the cancer is selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, Acute myeloid leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
The method according to claim 46 or 47, wherein the subject to be treated is a human.