WO2018233526A1 - Csf1r inhibitor, and manufacturing method therefor and application thereof - Google Patents

Abstract

A CSF1R inhibitor having a structure represented by formula (I), in particular, a compound represented by formula (I), and a stereoisomer or a pharmaceutically acceptable salt thereof, for treating cancers, autoimmune diseases, metabolic diseases, or metastatic diseases.

Description

CSF1R inhibitor and preparation method and application thereof Technical field

The invention belongs to the field of drug synthesis, and in particular relates to a CSF1R inhibitor and a preparation method and application thereof.

technical background

The full name of CSF1R (cFMS) is a cell colony stimulating factor receptor. CSF1R shares the same three types of growth hormone receptor family as cKIT, FLT3, and PDGFR-a&b. The receptor is a membrane protein expressed on the surface of macrophages and monocytes, and its extracellular domain is capable of binding to macrophage colony-stimulating factor, and intracellular tyrosine kinase activates macrophages and downstream of monocytes. Cell growth and reproduction signaling pathways, including MAPK, PI3K and the like. Therefore, the CSF1R signaling pathway has an important influence on the development and differentiation of macrophages, monocytes, and the physiological functions of Tumor-Associated Macrophage (TAM).

Tumor immunological checkpoint inhibitors are popular in the field of cancer treatment in recent years. These drugs can significantly inhibit tumor growth in clinical practice, and even some solid tumors completely disappear after treatment. However, clinical trials have shown that only about 30% of patients are able to respond to immunological checkpoint inhibitors such as PD-1/PD-L1. Due to the lack of relevant biomarkers, how to select a population of patients who may respond is also an unresolved issue. In addition, immunological checkpoint inhibitors produce immune system-related side effects in clinical practice, requiring experienced clinicians and medical institutions to successfully carry out treatment. Therefore, how to use immunological checkpoint inhibitors in combination with small molecule inhibitors to reduce toxic and side effects and improve the response rate of cancer patients is an urgent problem to be solved in the development of anti-tumor drugs.

With the advancement of tumor immunotherapy in recent years, tumor-associated macrophages (TAM) and bone marrow-derived suppressor cells (MDSC) are thought to be directly related to the formation of an immunosuppressive microenvironment within the tumor and angiogenesis supporting tumor growth. At the same time, clinical studies have shown that the content of TAM is negatively correlated with the prognosis of cancer patients. The pharmacodynamic experiments in mice have shown that inhibition of the CSF1R signaling pathway can significantly reduce the number of macrophages that inhibit the immune system within the tumor and increase the content of CD8-positive T cells. These experimental results indicate that CSF1R small molecule inhibitors may reverse the immunosuppressive environment inside the tumor, promote the activation of the immune system, and prolong the life of tumor patients.

Small molecule kinase inhibitors are ubiquitous in selectivity issues, especially for other members of the same kinase family. Since the small molecule drugs in this patent may be used in combination with other immunological checkpoint inhibitors in future clinical trials, the inventors tried to improve the molecular structure to enhance the inhibition of CSF1R targets and other The selectivity of the kinase receptor increases the therapeutic window and reduces the likelihood of clinical side effects. Therefore, how to find a CSF1R small molecule inhibitor with higher selectivity to meet domestic lung cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, melanoma, pancreatic cancer, head and neck cancer, glioma and tendon sheath giant cells The need for tumor-targeted therapies such as tumors has become an important part of current research by scientists.

Summary of the invention

The inventors of the present application have extensively and intensively studied to develop a CSF1R inhibitor having the structure of the formula (I) and a preparation method and application thereof for the first time. The compound of the invention has strong inhibitory effect on CSF1R kinase activity and can be widely applied to the preparation of drugs for treating cancer, tumor, autoimmune disease, metabolic disease or metastatic disease, especially for treating ovarian cancer, pancreatic cancer and prostate. Drugs for cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic diseases, neurodegenerative diseases, metastatic tumor sites or bone metastatic cancer are expected to be developed into a new generation of CSF1R inhibition. Drugs. On the basis of this, the present invention has been completed.

A first aspect of the invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

Wherein X is selected from -N(R ₂ )- or -C(R ₃ R ₄ )-;

Y is selected from a bond, -O-, -S(O) _r -, -CH=CH-, -C(R ₅ R ₆ )- or -N(R ₇ )-;

Z ₁ , Z ₂ , Z ₃ are each independently selected from C(R ₈ ) or N;

Z ₄ , Z ₅ , Z ₆ , Z ₇ are each independently selected from C(R ₉ ) or N;

R _{1 is} selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5- a 10-membered heteroaryloxy group or -NR ₁₀ R ₁₁ , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-8 alkyl, C _{2− 8} -alkenyl, C _2-8 alkynyl, halo-substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered Aryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R Substituted by a substituent of ₁₆ )-C(O)R ₁₅ ;

R _{2 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-10 cycloalkyl C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 ring Alkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ ,- C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ ,- C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

or,

R ₁ and R ₂ together with a group directly attached thereto form a 3-10 membered heterocyclic group, which is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano and nitro , azido, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 member Cyclic group, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O )OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O Substituting a substituent of NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen Substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R _{1 7} , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ , or,

R ₃ and R ₄ together with the carbon atom to which they are directly bonded form a C _3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the C _3-10 cycloalkane or 3-10 membered heterocyclic ring is optionally further One or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen substituted C _1-8 alkane , C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _{0 -8} -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 Substituted by a substituent of -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen Substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R _{1 7} , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ , or,

R ₅ , R ₆ and the carbon atom to which they are directly bonded together form a carbonyl group, a C _3-10 cycloalkyl group or a 3-10 membered heterocyclic group, optionally a C _3-10 cycloalkane or a 3-10 membered heterocyclic ring. further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl group, a halogen substituted C _{1- 8-} alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ ,- C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C ₀ Substituted by a substituent of _-8- NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

R _{7 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-10 cycloalkyl C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 ring Alkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ ,- C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ ,- C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

Each R ₈ and R _{9 are} independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _{3 -10} cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O)(=NR ₁₂ )R ₁₃ , -C _{0 -8} -B(OR ₁₄ ) ₂ , -C _0-8 -P(O)(R ₁₅ ) ₂ , -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ ,- C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ ,- C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ , wherein the above group is further further selected from one or more selected from the group consisting of hydrazine, halogen, =O, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halo substituted C _1-8 alkyl, C _3-10 ring Alkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ ,- C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ ,- Substituted by a substituent of C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

Each of R ₁₀ and R _{11 is} independently selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-10 cycloalkyl C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

Each R _{12 is} independently selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-10 cycloalkyl C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _{3- 10} cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

Each R _{13 is} independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, halo-substituted C _1-8 alkyl, halo-substituted C _1-8 alkoxy, C _2-8 Alkenyl, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 aryl An oxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group or -NR ₁₆ R ₁₇ , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, carbonyl, C _{1- 8-} alkyl, C _1-8 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 Substituted with an aryl group, a C _5-10 aryloxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group or a substituent of —NR ₁₆ R ₁₇ ;

Each R _{14 is} independently selected from the group consisting of hydrogen, deuterium, C _1-8 alkyl, C _2-8 alkenyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl or 5- a 10-membered heteroaryl group, the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, carbonyl, cyano, C _1-8 alkyl, C _1-8 alkoxy, C _3-10 ring Alkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl Substituted by a 5- to 10-membered heteroaryloxy group or a substituent of -NR ₁₆ R ₁₇ ;

Each R _{15 is} independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl a C _3-10 cycloalkoxy group, a 3-10 membered heterocyclic group, a 3-10 membered heterocyclic oxy group, a C _5-10 aryl group, a C _5-10 aryloxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group or -NR ₁₆ R ₁₇ , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, cyano, C _1-8 alkyl, C _1-8 alkoxy , C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 aryloxy Substituted by a 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or a substituent of -NR ₁₆ R ₁₇ ;

Each R ₁₆ and each R _{17 are} independently selected from the group consisting of hydrogen, hydrazine, hydroxy, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, 3-10 a heterocyclic group, a C _5-10 aryl group, a 5-10 membered heteroaryl group, a sulfonyl group, a methylsulfonyl group, an isopropylsulfonyl group, a cyclopropylsulfonyl group, a p-toluenesulfonyl group, an amino group, a monoalkylamino group, a dialkylamino group or a C _1-8 alkanoyl group, the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, C _3-10 Cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered Substituted with a substituent of an aryl group, a 5-10 membered heteroaryloxy group, an amino group, a monoalkylamino group, a dialkylamino group or a C _1-8 alkanoyl group;

Alternatively, R ₁₆ , R ₁₇ and the directly attached nitrogen atom thereof together form a 5-10 membered heterocyclyl group, said group optionally further comprising one or more selected from the group consisting of hydrazine, halogen, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 aryl, C Substituted with a substituent of _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or _C1-8 alkanoyl;

Each r is independently 0, 1, or 2.

And a preferred embodiment, wherein the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from -C(R ₅ R ₆ )-;

R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halo Substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _{0 - 4} -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ , or,

R ₅ , R ₆ and the carbon atom to which they are directly bonded together form a carbonyl group, a C _3-8 cycloalkyl group or a 3-8 membered heterocyclic group, optionally a C _3-10 cycloalkane or a 3-10 membered heterocyclic ring. further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl group, a halogen substituted C _{1- 4-} alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ ,- C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _{0 -4} -NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ is substituted with a substituent.

And a further preferred embodiment, wherein the compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from -C(R ₅ R ₆ )-;

R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, allyl, trifluoromethyl, cyclopropyl, cyclobutyl, 3- Oxetanyl, methoxy, trifluoromethoxy, methoxymethyl, methoxycarbonyl, acetoxy, amino, dimethylamino or acetylamino, or R ₅ and R ₆ directly attached thereto The carbon atoms together form a carbonyl group, a cyclopropyl group or a cyclobutyl group, and the cyclopropyl or cyclobutyl group is optionally further further selected from one or more selected from the group consisting of hydrazine, fluorine, chlorine, methyl, ethyl, isopropyl, Allyl, trifluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, methoxy, trifluoromethoxy, methoxymethyl, methoxycarbonyl, acetoxy, amino, Substituted by a substituent of dimethylamino or acetylamino.

As a further preferred embodiment, each of R ₈ in the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 Heteroaryl, -C _0-4 -S(O)(=NR ₁₂ )R ₁₃ , -C _0-4 -B(OR ₁₄ ) ₂ , -C _0-4 -P(O)(R ₁₅ ) ₂ , -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ ) —C(O)R ₁₅ , wherein the above group is further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halo-substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _{0 -4} -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C( O) Substituted by a substituent of R ₁₅ .

In a still further preferred embodiment, each of R ₈ in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, methyl, and B. Base, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, isopropoxy, methoxymethyl, trifluoromethyl, trifluoromethoxy , triterpene methyl or amino.

As a further preferred embodiment, the compound of formula (I) has the structure of the compound of formula (II):

Wherein X is selected from -N(R ₂ )- or -C(R ₃ R ₄ )-; Y is selected from -C(R ₅ R ₆ )-;

R _{1 is} selected from the group consisting of hydrogen, hydrazine, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, 3-8 membered heterocyclic, 3-8 membered heterocyclooxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5- An 8-membered heteroaryloxy group or -NR ₁₀ R ₁₁ , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-4 alkyl, C _{2− 4} -alkenyl, C _2-4 alkynyl, halogen-substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered Aryl, -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R Substituted by a substituent of ₁₆ )-C(O)R ₁₅ ;

R _{2 is} selected from the group consisting of hydrogen, hydrazine, C _1-4 alkyl, C _3-8 cycloalkyl C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 ring Alkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ ,- C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ;

or,

R ₁ and R ₂ together with a group directly attached thereto form a 3-8 membered heterocyclic group, which is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano and nitro , azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered Cyclic group, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O )OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O Substituting a substituent of NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ;

R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halo Substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _{0 - 4} -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ , or, R ₃ Together with R ₄ and the carbon atom to which it is directly bonded, a C _3-8 cycloalkyl group or a 3-8 membered heterocyclic group is formed, and the C _3-8 cycloalkane or the 3-8 membered heterocyclic ring is optionally further subjected to one or a plurality of selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR Substituted by a substituent of ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ;

R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, methyl, methoxy, trifluoromethoxy or methoxymethyl, or R ₅ and R ₆ together with the carbon atom to which they are directly attached Carbonyl, cyclopropyl or cyclobutyl;

R _{8 is} selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, methyl, ethyl or methoxy;

Z ₄ , Z ₆ , R ₉ , R ₁₀ , R ₁₁ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , r are as defined for the compound of formula (I).

And a further preferred embodiment, wherein the compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of -N(R ₂ )- or -C(R ₃ R ₄ )-; Y is selected from -C(R ₅ R ₆ )-; Z _{4 is} selected from CH or N; Z _{6 is} selected from C(R ₉ ) or N;

R _{1 is} selected from C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl or 5-8 membered heteroaryl, and the above group is optionally further Or a plurality selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl , C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ , -C _{0- 4} -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 - Substituted by a substituent of NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ;

R _{2 is} selected from the group consisting of hydrogen, hydrazine, C _1-4 alkyl, C _3-8 cycloalkyl C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aromatic Base or 5-8 membered heteroaryl;

or,

R ₁ and R ₂ together with a group directly attached thereto form a 3-6 membered heterocyclic group, which is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano and nitro , azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered Cyclic group, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O )OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O Substituting a substituent of NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ;

R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, hydrazine, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic, C _5-6 aryl or 5-6 membered heteroaryl. Or, R ₃ and R ₄ together with the carbon atom to which they are directly bonded form a C _3-6 cycloalkyl group or a 3-6 membered heterocyclic group;

R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, methyl, methoxy, trifluoromethoxy or methoxymethyl, or R ₅ and R ₆ together with the carbon atom to which they are directly attached Carbonyl, cyclopropyl or cyclobutyl;

R _{8 is} independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, methyl, ethyl or methoxy;

R _{9 is} selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl 3-8 membered heterocyclic group, C _5-8 aryl group, 5-8 membered heteroaryl group, -C _0-4 -S(O)(=NR ₁₂ )R ₁₃ , -C _0-4 -B( OR ₁₄ ) ₂ , -C _0-4 -P(O)(R ₁₅ ) ₂ , -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 - C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 - C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ , the above group optionally further one or more selected from the group consisting of ruthenium, halogen, =0, cyano , nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halo substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3- 8-membered heterocyclic group, C _5-8 aryl group, 5-8 membered heteroaryl group, -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 - C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 - Substituted by a substituent of C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ .

And a further preferred embodiment, wherein the compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of -N(R ₂ )- or -C(R ₃ R ₄ )-; Y is selected from -C(R ₅ R ₆ )-; Z _{4 is} selected from CH or N; Z _{6 is} selected from C(R ₉ ) or N;

R _{1 is} selected from C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl or 5-8 membered heteroaryl, and the above group is optionally further Or a plurality selected from the group consisting of hydrazine, fluorine, chlorine, cyano, nitro, azide, hydroxy, methyl, ethyl, isopropyl, allyl, trifluoromethyl, cyclopropyl, cyclobutyl, Substitution of 3-oxetanyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methoxymethyl, methoxycarbonyl, acetoxy, amino, dimethylamino or acetylamino Substituted by

R _{2 is} selected from the group consisting of hydrogen, hydrazine, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic or cyclopropylmethyl;

or,

R ₁ and R ₂ together with a group directly attached thereto form a 4-6 membered heterocyclic group, which is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano and nitro Substituted with a substituent of an azide group, a C _1-4 alkyl group, a vinyl group, an allyl group, an ethynyl group, a trifluoromethyl group, a cyclopropyl group or a methoxy group;

R ₃ and R ₄ are each independently selected from hydrogen, hydrazine or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon atom to which they are directly bonded form a cyclopropyl or cyclobutyl group;

R ₅ and R ₆ are each independently selected from hydrogen, hydrazine, fluoro or methyl, or R ₅ and R ₆ together with the carbon atom to which they are directly bonded form a carbonyl group, a cyclopropyl group or a cyclobutyl group;

R _{8 is} independently selected from the group consisting of hydrogen, deuterium, methyl or ethyl;

R _{9 is} selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl 3-6 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group, -OR ₁₄ , -OC(O)R ₁₅ , -NR ₁₆ R ₁₇ , -C(O)NR ₁₆ R ₁₇ or -N (R ₁₆ )-C(O)R ₁₅ , wherein the above group is further further selected from one or more selected from the group consisting of hydrazine, fluorine, chlorine, =0, cyano, nitro, azide, hydroxy, methyl, and Base, isopropyl, allyl, trifluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, Substituted by a substituent of methoxymethyl, methoxycarbonyl, acetoxy, amino, dimethylamino or acetylamino.

As a most preferred embodiment, the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:

A second aspect of the present invention provides a process for the preparation of a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of: a compound of the formula (Ia) or an acid salt thereof and the formula (Ib) The compound is reacted to form a compound of formula (I) having the following reaction formula:

Wherein, when X is selected from -N(R ₂ )-, R is selected from the group consisting of isocyanato or acid chloride, and when X is selected from -C(R ₃ R ₄ )-, R is selected from a carboxyl group or an alkyl carboxylate. base;

X, Y, Z ₁ , Z ₂ , Z ₃ , Z ₄ , Z ₅ , Z ₆ , Z ₇ , R ₁ , R ₂ , R ₃ , R ₄ , 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 are as defined for the compound of formula (I).

Preferably, when X is selected from -N(R ₂ )-,

Prepared by:

A third aspect of the invention provides a pharmaceutical composition comprising the compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

According to a fourth aspect, the present invention provides a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for the preparation of a cancer, tumor, autoimmune disease, metabolic disease or metastasis Application in sexually transmitted diseases.

According to a fifth aspect of the present invention, there is provided a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for the preparation of ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, Kidney cancer, liver cancer, cervical cancer, metastatic cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumor, solid tumor, melanoma, mesothelioma, glioblastoma, flesh Tumor, multiple myeloma, hyperproliferative disease, metabolic disease, neurodegenerative disease, metastasis of primary tumor site, myeloproliferative disease, leukemia, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, Use in multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome, mastocytosis or mast cell leukemia drugs.

As a further preferred embodiment, a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, is prepared for the treatment of ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervix Use in cancer, glioblastoma, multiple myeloma, metabolic disease, neurodegenerative disease, metastasis of primary tumor sites, or bone metastatic cancer drugs.

A sixth aspect of the invention provides a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use in the treatment of cancer, tumor, autoimmune disease, metabolic disease Or a drug for metastatic disease.

A seventh aspect of the invention provides a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use in the treatment of ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast Cancer, kidney cancer, liver cancer, cervical cancer, bone metastatic cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumor, solid tumor, melanoma, mesothelioma, glioblastoma , osteosarcoma, multiple myeloma, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, myeloproliferative diseases, leukemia, rheumatoid arthritis, rheumatoid arthritis, bone and joint Inflammation, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome, mastocytosis or mast cell leukemia.

As a further preferred embodiment, there is provided a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use in the treatment of ovarian cancer, pancreatic cancer, prostate cancer, breast cancer , cervical cancer, glioblastoma, multiple myeloma, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites or drugs for bone metastatic cancer.

An eighth aspect of the invention provides a method of treating a cancer, a tumor, an autoimmune disease, a metabolic disease or a metastatic disease, comprising administering to a patient a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable substance thereof Salt, or the aforementioned pharmaceutical composition.

A ninth aspect of the present invention provides a method for treating ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastatic cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, stomach Intestinal stromal tumors, solid tumors, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, primary tumor sites Metastasis, myeloproliferative diseases, leukemia, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis Or a method for the treatment of hypereosinophilic syndrome, mastocytosis or mastocytoma, comprising administering to a patient a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above .

Detailed ways

DETAILED DESCRIPTION: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

"Alkyl" means a straight-chain or branched-chain saturated aliphatic hydrocarbon group, for example, "C _1-8 alkyl" means a straight-chain alkyl group having from 1 to 8 carbon atoms and a branched alkyl group, including but Not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropane 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methyl Hexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-Dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2, 5- Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethyl Hexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branches thereof Isomers, etc.

Alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from deuterium, halogen, cyano, nitro, azido group, C _{1 -8} alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _5-10 Aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _{0 -8} -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or- Substituents of C _0-8 -N(R ₁₆ )-C(O)R ₁₅ are substituted.

"Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, for example, "C _3-10 cycloalkyl" refers to a cycloalkyl group of 3 to 10 carbon atoms, which is divided into a single ring. a cycloalkyl, polycyclic cycloalkyl group, wherein:

Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl and the like.

Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spirocycloalkyl group is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of common spiro atoms between the ring and the ring, and the spirocycloalkyl group includes, but is not limited to:

"Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated π-electron system. Depending on the number of constituent rings, it may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and fused cycloalkyl groups include, but are not limited to:

"Bridge cycloalkyl" refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, and bridged cycloalkyl groups include but are not limited to:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group including, but not limited to, indanyl, tetrahydronaphthyl , benzocycloheptyl and the like.

The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C. _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _{5 - 10} aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or Substituted by a substituent of -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ .

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) _r (where r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. For example, "5-10 membered heterocyclic group" means a cyclic group containing 5 to 10 ring atoms, and "3-10 membered heterocyclic group" means a cyclic group containing 3 to 10 ring atoms.

Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.

Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) _r (where r is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of shared spiro atoms between the ring and the ring. Spiroheterocyclyl includes, but is not limited to:

"Fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none The ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) _r (wherein r is an integer of 0, 1, 2) heteroatoms, the remaining ring atoms being carbon. The bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group may be classified according to the number of constituent rings, and the fused heterocyclic group includes but is not limited to:

"Bridge heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) _r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. The bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group may be classified according to the number of constituent rings, and the bridged heterocyclic group includes but is not limited to:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group including, but not limited to:

The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C. _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _{5 - 10} aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or Substituted by a substituent of -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ .

"Aryl" means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated π-electron system (ie, having a ring adjacent to a carbon atom) a group, for example, "C _5-10 aryl" means an all-carbon aryl group having 5 to 10 carbons, and "5-10 membered aryl group" means an all-carbon aryl group having 5 to 10 carbons, including It is not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, including but not limited to:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-8. Alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halo substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C ₀ Substituted by a substituent of _-8- N(R ₁₆ )-C(O)R ₁₅ .

"Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O)r (wherein r is an integer of 0, 1, 2), for example, 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, and 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl, thiophene. Base, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring including, but not limited to:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C. _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _{5 - 10} aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or Substituted by a substituent of -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ .

"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, C _2-8 alkenyl refers to a straight or branched chain containing from 2 to 8 carbons. Alkenyl. These include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-8. Alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halo substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C ₀ Substituted by a substituent of _-8- N(R ₁₆ )-C(O)R ₁₅ .

"Alkynyl" means an alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example, _C2-8 alkynyl refers to a straight or branched chain containing from 2 to 8 carbons. Alkynyl. These include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-8. Alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halo substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C ₀ Substituted by a substituent of _-8- N(R ₁₆ )-C(O)R ₁₅ .

"Alkoxy" means -O-(alkyl) wherein alkyl is as defined above, for example, "C _1-8 alkoxy" refers to an alkyloxy group containing from 1 to 8 carbons, including but not It is limited to methoxy, ethoxy, propoxy, butoxy and the like.

The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _{5 -10} aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ ,- C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ Or a substituent of -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ is substituted.

"Cycloalkoxy" refers to and -O-(unsubstituted cycloalkyl), wherein cycloalkyl is as defined above, for example, "C _3-10 cycloalkoxy" refers to 3-10 carbons. Cycloalkyloxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.

The cycloalkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _{5 -10} aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ ,- C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ Or a substituent of -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ is substituted.

"3-10 membered heterocyclic oxy" refers to -O-(unsubstituted 3-10 membered heterocyclic group) wherein 3-10 membered heterocyclic group is as defined above, 3-10 membered heterocyclic oxy group. It may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-8 Alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halo substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C ₀ Substituted by a substituent of _-8- N(R ₁₆ )-C(O)R ₁₅ .

"C _5-10 aryloxy" means both -O-(unsubstituted C _5-10 aryl) wherein the C _5-10 aryl group is as defined above, and the C _5-10 aryloxy group may be optionally Substituted or unsubstituted, when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 Heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N Substituted by a substituent of (R ₁₆ )-C(O)R ₁₅ .

"5-10 membered heteroaryloxy" means -O-(unsubstituted 5-10 membered heteroaryl) wherein 5-10 membered heteroaryl is as defined above, 5-10 membered heteroaryloxy It may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-8 Alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halo substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C ₀ Substituted by a substituent of _-8- N(R ₁₆ )-C(O)R ₁₅ .

"C _1-8 alkanoyl" refers to a monovalent atomic group remaining after the C _1-8 alkyl acid has been removed from the hydroxy group, and is also generally referred to as "C _0-7 -C(O)-", for example, "C ₁ -C"(O)-" means acetyl; "C ₂ -C(O)-" means propionyl; "C ₃ -C(O)-" means butyryl or isobutyryl.

"C _3-10 cycloalkyl C _1-8 alkyl" refers to a C _3-10 cycloalkyl substituted C _1-8 alkyl group, wherein C _3-8 cycloalkyl, C _1-8 alkyl is as defined above Said.

"-C _0-8 -S(O)(=NR ₁₂ )R ₁₃ "" means that the sulfur atom in -S(O)(=NR ₁₂ )R ₁₃ is attached to a C _0-8 alkyl group, wherein C ₀ alkane The base refers to a bond, and the definition of a C _1-8 alkyl group is as described above.

"-C _0-8 -B(OR ₁₄ ) ₂ " means that the boron atom in -B(OR ₁₄ ) ₂ is attached to a C _0-8 alkyl group, wherein a C ₀ alkyl group means a bond, a C _1-8 alkane The definition of the base is as described above.

"-C _0-8 -P(O)(R ₁₅ ) ₂ "" means that the phosphorus atom in -P(O)(R ₁₅ ) ₂ is attached to a C _0-8 alkyl group, wherein C ₀ alkyl means a bond The definition of C _1-8 alkyl is as described above.

"-C _0-8 -S(O) _r R ₁₃ "" means that the sulfur atom in -S(O) _r R ₁₃ is attached to a C _0-8 alkyl group, wherein C ₀ alkyl refers to a bond, C _{1- 8} alkyl group defined as described above.

"-C _0-8 -OR ₁₄ " means that the oxygen atom in -OR ₁₄ is attached to a C _0-8 alkyl group, wherein the C ₀ alkyl group means a bond, and the C _1-8 alkyl group is as defined above.

"-C _0-8 -C(O)OR ₁₄ "" means that the carbonyl group of -C(O)OR ₁₄ is attached to a C _0-8 alkyl group, wherein C ₀ alkyl refers to a bond, C _1-8 alkyl The definition is as described above.

"-C _0-8 -C(O)R ₁₅ "" means that the carbonyl group of -C(O)R ₁₅ is attached to a C _0-8 alkyl group, wherein C ₀ alkyl refers to a bond, C _1-8 alkyl The definition is as described above.

"-C _0-8 -OC(O)R ₁₅ " means that the oxygen atom in -OC(O)R ₁₅ is attached to a C _0-8 alkyl group, wherein C ₀ alkyl refers to a bond, C _1-8 alkane The definition of the base is as described above.

"-C _0-8 -NR ₁₆ R ₁₇ " means that the nitrogen atom in -NR ₁₆ R ₁₇ is bonded to a C _0-8 alkyl group, wherein the C ₀ alkyl group means a bond, and the C _1-8 alkyl group is as defined above. Said.

"-C _0-8 -C(O)NR ₁₆ R ₁₇ "" means that the carbonyl group of -C(O)NR ₁₆ R ₁₇ is attached to a C _0-8 alkyl group, wherein C ₀ alkyl refers to a bond, C ₁ The definition of _-8 alkyl is as described above.

"-C _0-8 -N(R ₁₆ )-C(O)R ₁₅ "" means that the nitrogen atom of -N(R ₁₆ )-C(O)R ₁₅ is attached to a C _0-8 alkyl group, wherein C ₀ alkyl means a bond, and C _1-8 alkyl is as defined above.

"Halo-substituted C _1-8 alkyl" refers to a hydrogen on the alkyl group optionally substituted with a fluorine, chlorine, bromine or iodine atom, including 1 to 8 carbon alkyl groups, including but not limited to difluoromethyl, Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

The hydrogen on the "halo-substituted C _1-8 alkoxy" alkyl group is optionally a 1-8 carbon alkoxy group substituted with a fluorine, chlorine, bromine or iodine atom. These include, but are not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

"Halogen" means fluoro, chloro, bromo or iodo. "NaH" means sodium hydride. "MeOH" means methanol. "DCM" means dichloromethane. "DMF" means N,N-dimethylformamide. "DEAD" means diethyl azodicarboxylate. "X-phos" means 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl. "Dess-Martin oxidizing agent" means (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodo-3(1H)-one.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .

"Substituted" means that one or more hydrogen atoms in the group are each independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond such as an olefin.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

The present invention will be further described in detail with reference to the accompanying drawings, but by no way of limitation of the invention.

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ). The internal standard was four. Methyl silane (TMS).

LC-MS was determined by LC-MS using an Agilent 6120 mass spectrometer. The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification for TLC is 0.15mm~0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

Starting materials in the examples of the invention are known and commercially available or can be synthesized or synthesized according to methods known in the art.

Unless otherwise stated, all reactions of the present invention are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent being a dry solvent, and the reaction temperature in degrees Celsius (° C.).

First, the preparation of intermediates

1. Preparation of tert-butyl(5-formylpyridin-2-yl)carbamate (intermediate 1)

First step: Preparation of 6-tert-butoxycarbonylaminonicotinate methyl ester

Add 6-aminonicotinate (2.65 g, 17.4 mmol), 4-dimethylaminopyridine (109 mg, 0.86 mmol) and dichloromethane (50 mL) to a round bottom flask and slowly add di-tert- at room temperature. Butyl dicarbonate (5.0 g, 23 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with methylene chloride (50 mL), and the organic phase was washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. Methyl butoxycarbonylaminonicotinate (3.1 g, yield 70.5%). MS m/z (ESI): 254 [M+H] ⁺ .

Second step: preparation of tert-butyl (5-(hydroxymethyl)pyridin-2-yl)carbamate

Methyl 6-tert-butoxycarbonylaminonicotinate (3 g, 8.2 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). Lithium aluminum hydride (576 mg, 15.2 mmol) was slowly added under ice bath. After the reaction mixture was further stirred under an ice bath for 6 hours, the reaction was quenched by careful addition of sodium sulfate decahydrate. The reaction mixture was filtered through celite, and then filtered and evaporated. The crude product was purified by column chromatography eluting elut elut elut elut elut elut MS m/z (ESI): 224 [M+H] ⁺ .

Step 3: Preparation of tert-butyl(5-formylpyridin-2-yl)carbamate

tert-Butyl(5-(hydroxymethyl)pyridin-2-yl)carbamate (2 g, 8.9 mmol) was dissolved in dichloromethane (50 mL). Under ice bath, Dess-Martin oxidant (5.6 g, 13.4 mmol) was slowly added. After the addition, the reaction mixture was returned to room temperature and stirring was continued for 1 hour. The reaction mixture was diluted with methylene chloride (50 mL). EtOAc was evaporated. (5-Formylpyridin-2-yl)carbamate (1.35 g, yield 69%). MS m/z (ESI): 222 [M+H] ⁺ .

2. Preparation of tert-butyl (5-formyl-6-methylpyridin-2-yl)carbamate (intermediate 2)

First step: Preparation of 6-chloro-2-methylnicotin

5-bromo-2-chloro-6-methylpyridine (1.03 g, 5.0 mmol) and dry tetrahydrofuran (30 mL) were placed in a three-neck round bottom flask under nitrogen atmosphere. The solution was cooled to -78 ° C, and n-butyllithium (4.7 mL, 7.5 mmol) was slowly added dropwise. After the addition was completed, the solution was stirred at -78 ° C for 15 minutes. N,N-dimethylformamide (730 mg, 10.0 mmol) was added dropwise to the reaction mixture. After the dropwise addition, the reaction mixture was slowly warmed to room temperature and stirred overnight. The system was quenched by the addition of water (30 mL), ethyl acetate (30 mL×2), and the organic phase was combined, dried and concentrated to give 6-chloro-2-methylnicotaldehyde (358 mg, yield 46%). MS m/z (ESI): 162 [M+H] ⁺ .

Second step: Preparation of tert-butyl (5-formyl-6-methylpyridin-2-yl)carbamate

Add 6-chloro-2-methylnicotin (358 mg, 2.3 mmol), tert-butyl carbamate (593 mg, 5.1 mmol) and dry 1,4-dioxane (15 mL) in a 50 mL round bottom flask. After dissolution, cesium carbonate (1.5 g, 4.6 mmol), tris(dibenzylideneacetone)dipalladium (190 mg, 0.2 mmol) and 2-dicyclohexylphosphorus-2,4,6-triiso were sequentially added to the solution. Propylbiphenyl (191 mg, 0.4 mmol). After the mixture was purged with nitrogen, it was reacted at 85 ° C for 2 hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate (15 mL) and filtered. The filtrate was concentrated and purified by flash column chromatography toield (t-butyl-(s)-6-methyl-6-methylpyridin-2-yl)carbamate (540 mg, yield 95%). MS m/z (ESI): 437 [M+H] ⁺ .

Preparation of 3-, 5-methoxy-1H-pyrrolo[2,3-b]pyridine (Intermediate 3)

Under a nitrogen atmosphere, 5-bromo-7-azaindole (1.0 g, 5.1 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (32 mL) and methanol (20 mL). Sodium methoxide (14.5 g, 268.7 mmol), cuprous bromide (1.45 g, 10.1 mmol). After nitrogen exchange, the reaction mixture was heated to reflux and stirred for 3 hours. After cooling, the solvent was evaporated under reduced pressure, and the residue was evaporated, evaporated, evaporated, evaporated, evaporated [2,3-b]pyridine (795 mg, yield 91.4%). MS m/z (ESI): 149 [M+H] ⁺ .

4. Preparation of 5-isopropyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 4)

First step: Preparation of 1H-pyrrolo[2,3-b]pyridine-5-ol

Boron tribromide (17% dichloromethane solution, 37 mL, 25 mmol) was slowly added dropwise to 5-methoxy-1H-pyrrole[2,3-b]pyridine (1.4 g, 10 mmol) at -30 °C. In a solution of dichloromethane (30 mL). The addition mixture was slowly returned to room temperature and stirred overnight. The mixture was carefully added to ice water to quench the reaction and the pH was adjusted to 6. The organic phase is separated, the aqueous phase is extracted with dichloromethane, and the organic phase is combined, washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure, and the crude product is purified by flash column chromatography to obtain 1H-pyrrole [ 2,3-b]pyridine-5-ol (1.1 g, yield 87%). MS m/z (ESI): 135 [M+H] ⁺ .

Second step: Preparation of 5-isopropyl-1H-pyrrolo[2,3-b]pyridine

1H-pyrrole[2,3-b]pyridine-5-ol (134 mg, 1 mmol), triphenylphosphine (315 mg, 1.2 mmol), isopropanol (73 mg, 1.2 mmol) and diethyl azodicarboxylate (209 mg, 1.2 mmol) was taken in anhydrous tetrahydrofuran (5 mL). The mixture was stirred at room temperature overnight, diluted with ethyl acetate. EtOAc (EtOAc m. Pyridine (85 mg, yield 49%). MS m/z (ESI): 177 [M+H] ⁺ .

Intermediates 5 to 7 were prepared by the synthesis of Intermediate 4:

8. Preparation of N,N-dimethyl-1H-pyrrolo[2,3-b]pyridine-5-amine (Intermediate 8)

First step: Preparation of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

5-Bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5.08 mmol) was added to N,N-dimethylformamide (20 mL), and sodium hydride (60%) , 345 mg, 8.6 mmol). After the addition, (2-(chloromethoxy)ethyl)trimethylsilane (1.16 mL, 8.13 mmol) was added. The reaction mixture was returned to room temperature and stirred overnight. The mixture was poured into ice water, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and then purified to silica gel column chromatography to give 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine. (1.32 g, yield 79%). MS m/z (ESI): 327 [M+H] ⁺ .

Second step: N,N-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-amine preparation

Add 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (330 mg, 1.0 mmol) to a 50 mL sealed tube. A solution of dimethylamine in tetrahydrofuran (2.5 mL, 5.0 mmol) and dry 1,4-dioxane (15 mL) was dissolved. Then, cesium carbonate (980 mg, 3.0 mmol) was added to the solution, tris(benzylidene). Acetone) dipalladium (92 mg, 0.1 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (98 mg, 0.2 mmol). After the mixture was replaced with nitrogen, the mixture was sealed at 110 ° C for 4 hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate (15 mL) and filtered. The filtrate was concentrated and separated by flash column chromatography to give N,N-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b] Pyridine-5-amine (270 mg, yield 92%). MS m/z (ESI): 292 [M+H] ⁺ .

The third step: preparation of N,N-dimethyl-1H-pyrrolo[2,3-b]pyridine-5-amine

Add N,N-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5 to a 50 mL round bottom flask -Amine (270 mg, 0.93 mmol) and dichloromethane (6 mL). Trifluoroacetic acid (6 mL) was added during the stirring. The mixture was stirred at room temperature for 1 hour and then concentrated. EtOAc (EtOAc) After the dissolution, aqueous ammonia (7 mL) was added, and the reaction liquid was heated to 50 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature, extracted twice with dichloromethane (20 mL), and the organic phase was combined, dried and concentrated and then purified by flash column chromatography to give N,N-dimethyl-1H-pyrrolo[2,3-b] Pyridine-5-amine (119 mg, yield 80%). MS m/z (ESI): 162 [M+H] ⁺ .

Intermediate 9 was prepared by the synthesis of Intermediate 8:

Preparation of (4-methylpiperazin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (Intermediate 10)

1H-Pyro[2,3-b]pyridine-5-carboxylic acid (162 mg, 1 mmol) was dissolved in DMF (3 mL), triethylamine (152 mg, 1.5 mmol), HATU (420 mg, 1.1 mmol) and N Methylpiperazine (110 mg, 1.1 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. (1H-Pyrolo[2,3-b]pyridin-5-yl)methanone (147 mg, yield 60%). MS m/z (ESI): 245 [M+H] ⁺ .

Preparation of 5-(5H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-amine (Intermediate 11)

First step: tert-butyl (5-(hydroxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamate with tert-butyl ( Preparation of 5-(methoxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamate

1H-pyrrolo[2,3-b]pyridine (118 mg, 1 mmol), tert-butyl(5-formylpyridin-2-yl)carbamate (222 mg, 1 mmol), potassium hydroxide (168 mg, 3 mmol) was dissolved in anhydrous methanol (5 mL) and stirred at room temperature for 24 hours. The methanol was evaporated under reduced pressure, and the residue was evaporated. mjjjjjjjjjjjjjjj -(Hydroxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamate with tert-butyl (5-(methoxy (1H-pyrrole) A mixture of [2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamate (275 mg, yield 80%). MS m/z (ESI): 341; 355 [M+H] ⁺ .

Second step: Preparation of 5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-amine

tert-Butyl (5-(hydroxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamate with tert-butyl (5-( A mixture of methoxy (1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamate (170 mg, 0.5 mmol) was dissolved in EtOAc (10 mL) Trifluoroacetic acid (570 mg, 5 mmol) and triethylsilane (585 mg, 5 mmol) were added. The reaction mixture was heated to 80 ° C for 8 hours. The mixture was depressurized to remove acetonitrile, and dichloromethane was added to dissolve. The organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to afford 5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-amine (95 mg, yield: 85%). MS m/z (ESI): 225 [M+H] ⁺ .

12. 2-Methyl-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Intermediate 12) preparation

First step: Preparation of 3-bromo-2-methyl-6-nitropyridine

Concentrated sulfuric acid (50 mL) was cooled to 0 ° C, then 30% H ₂ O ₂ (35 mL) was slowly added dropwise to concentrated sulfuric acid, and stirring was continued at 0 ° C for 1 hour. 5-Bromo-6-methylpyridin-2-amine (10 g, 53.5 mmol) was dissolved in concentrated sulfuric acid (50 mL) and slowly added dropwise to the above solution at 0 ° C, and the reaction mixture was stirred at 0 ° C for 1 hour, then The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into an ice-water mixture (2 L), and the product was precipitated. The product was collected by filtration, and the product was washed with a large amount of water and concentrated to give crude 3-bromo-2-methyl-6-nit. Pyridine (7.2 g, crude yield 62%).

Second step: 2-methyl-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

3-Bromo-2-methyl-6-nitropyridine (5 g, 23 mmol) was dissolved in 1,4-dioxane (30 mL), and then the mixture of bis-di-boric acid (7 g, 27.6 mmol). 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.88 g, 2.3 mmol) and potassium acetate (4.5 g, 46.1 mmol) and then evacuated at room temperature for nitrogen After 3 times, the mixture was heated to 90 ° C and stirred for 12 hours. Then, the mixture was cooled to room temperature with ethyl acetate and a water layer. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography [eluent: petroleum ether / acetic acid Ester (20:1) - petroleum ether / ethyl acetate (5:1)] gave the compound 2-methyl-6-nitro-3-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)pyridine (4.1 g, yield 67.4%). MS m/z (ESI): 183 [M+H] ⁺ .

13-14,5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-methylpyridin-2-amine (Intermediate 13) and tert-butyl 3- Preparation of ((6-Amino-2-methylpyridin-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate 14)

First step: Preparation of tert-butyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

1H-Pyrolo[2,3-b]pyridine-3-carbaldehyde (5.0 g, 34.2 mmol) was dissolved in dichloromethane (30 mL), and di-tert-butyl dicarbonate (8.96 g, 41.1 mmol) was added at 0 °C. And 4-dimethylaminopyridine (418 mg, 3.42 mmol) were then warmed to room temperature and the reaction was stirred at room temperature for 2 hours. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography [eluent: petroleum ether / ethyl acetate (10: 1) ~ petroleum ether / ethyl acetate (5:1)] to give tert-butyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (7.6 g, yield 90 %). MS m/z (ESI): 247 [M+H] ⁺ .

Second step: Preparation of tert-butyl 3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

tert-Butyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (5.0 g, 20.3 mmol) was dissolved in methanol (30 mL) and sodium borohydride (1.0 g, 24.4 mmol). The reaction was stirred at room temperature for 4 hours. The organic layer is then washed with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and then purified. (5:1) to dichloromethane/methanol (3:1)] to give tert-butyl 3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (4.8 g, yield 95%). MS m/z (ESI): 495 [M+H] ⁺ .

Step 3: Preparation of tert-butyl 3-(bromomethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

tert-Butyl 3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (4.0 g, 16.1 mmol) was dissolved in dichloromethane (30 mL) at 0 ° C Phosphorus tribromide (10.8 g, 40.3 mmol) was added. The reaction was warmed to room temperature and stirred for 4 hours. The aqueous solution of sodium hydrogencarbonate was adjusted to make the pH of the reaction mixture to be basic. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous sodium sulfate. Eluent: petroleum ether / ethyl acetate (5:1) - petroleum ether / ethyl acetate (5:2)] to give tert-butyl 3-(bromomethyl)-1H-pyrrolo[2,3- b] Pyridine-1-carboxylate (1.7 g, yield 34%). MS m/z (ESI): 311 [M+H] ⁺ .

Fourth step: tert-butyl 3-((2-methyl-6-nitropyridin-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate preparation

tert-Butyl 3-(bromomethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.7 g, 5.5 mmol) was dissolved in toluene/water (10 mL/10 mL) and added 2-methyl-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.74 g, 6.6 mmol), Tetra-triphenylphosphine palladium (634 mg, 0.55 mmol), and sodium carbonate (1.74 g, 16.5 mmol). The mixture was purged with nitrogen three times at normal temperature, and the reaction was heated to 90 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature, and the organic layer was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography [eluent: petroleum ether / acetic acid Ester (5:1) - petroleum ether / ethyl acetate (5:2)] to give tert-butyl 3-((2-methyl-6-nitropyridin-3-yl)methyl)-1H-pyrrole And [2,3-b]pyridine-1-carboxylate (1.3 g, yield 65%). MS m/z (ESI): 369 [M+H] ⁺ .

Step 5: 5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-methylpyridin-2-amine (26) and tert-butyl 3-(( Preparation of 6-amino-2-methylpyridin-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (27)

tert-Butyl 3-((2-methyl-6-nitropyridin-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.2 g, 3.3 mmol) was dissolved in ethanol/water (10 mL/10 mL), iron powder (912 mg, 16.3 mmol), and ammonium chloride (1.76 g, 32.6 mmol) were added. The reaction mixture was warmed to 90 ° C and stirred for 2 hours, cooled to After the reaction at room temperature, the organic layer was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate 1) to dichloromethane/methanol (10:1)] to give 5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-methylpyridin-2-amine ( 550 mg, yield 70.8%). ESI-MS 239 [M+H] ⁺ . At the same time, tert-butyl 3-((6-amino-2-methylpyridin-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (150 mg, produced) The rate is 13.6%). MS m/z (ESI): 339 [M+H] ⁺ .

15. Tert-Butyl 3-((6-amino-2-methylpyridin-3-yl)methyl)-5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2,3 -b]Preparation of Pyridine-1-carboxylate (Intermediate 15)

First step: Preparation of 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

5-Bromo-6-methylpyridin-2-amine (1.0 g, 5.37 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2' -(1,3,2-dioxaborolan) (2.0 g, 8.06 mmol), potassium acetate (1.6 g, 16.11 mmol) and 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (438 mg, 0.537 mmol) was dissolved in 1,4-dioxane (10 mL). After completion of the reaction, water (20 mL) was added, and ethyl acetate was evaporated. EtOAc was evaporated. 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (700 mg, yield 56%). MS m/z (ESI): 266 [M+H] ⁺ .

Second step: Preparation of 5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2,3-b]pyridine

1H-pyrrolo[2,3-b]pyridin-5-phenol (1 g, 7.46 mmol) and tetrahydrofuran-3-ol (0.788 g, 8.95 mmol), triphenylphosphine (2.34 g, 8.95 mmol) were dissolved. Diisopropyl azodicarboxylate (1.56 g, 8.95 mmol) was added dropwise to tetrahydrofuran (30 mL) at 0 ° C, and allowed to react at room temperature for 16 hours. The reaction solution was poured into water (20 mL) The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography [eluent: PE/EA (3:1)] to give 5-((tetrahydrofuran-3-yl)oxy)-1H-pyrrolo[2,3- b] pyridine (1.4 g, yield 92%). MS m/z (ESI): 205 [M+H] ⁺ .

The third step: preparation of 5-((tetrahydrofuran-2-yl)oxy)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

5-((Tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2,3-b]pyridine (1.4 g, 6.86 mmol) was dissolved in acetic acid (10 mL) and water (10 mL). The product (1.44 g, 10.29 mmol) was reacted at 120 ° C for 16 hours. After completion of the reaction, water (20 mL) was added, and ethyl acetate was evaporated, and the organic layer was washed with water, brine, and dried over anhydrous sodium sulfate and evaporated to give 5-((tetrahydrofuran-2-yl)oxy)-1H-pyrrolo[2, 3-b]pyridine-3-carbaldehyde (670 mg, yield 42%). MS m/z (ESI): 242 [M+H] ⁺ .

Step 4: Preparation of tert-butyl 3-formyl-5-((tetrahydrofuran-3-yl)oxy)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

5-((Tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (670 mg, 2.89 mmol), 4-dimethylaminopyridine (35 mg, 0.289 mmol) N,N-diisopropylethylamine (373 mg, 2.89 mmol) was dissolved in dichloromethane (10 mL), and di-tert-butyl dicarbonate (944 mg, 4.33 mmol) was added and reacted at room temperature for 16 hours. After concentration, column chromatography separation [eluent: PE/EA (3:1)] afforded tert-butyl 3-formyl-5-((tetrahydrofuran-3-yl)oxy)-1H-pyrrolo[2 , 3-b]pyridine-1-carboxylate (450 mg, yield 47%). MS m/z (ESI): 333 [M+H] ⁺ .

Step 5: Preparation of tert-butyl 3-(hydroxymethyl)-5-((tetrahydrofuran-3-yl)oxy)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

Dissolve tert-butyl 3-formyl-5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (450 mg, 1.35 mmol) In methanol (10 mL), the mixture was cooled to 0 ° C, and sodium borohydride (77 mg, 2.03 mmol) was added portionwise and then reacted at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture to quench the reaction, then extracted with ethyl acetate (15 mL×2), dried over anhydrous sodium sulfate and evaporated. )] tert-butyl 3-(hydroxymethyl)-5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (360 mg, Yield 80%). MS m/z (ESI): 335 [M+H] ⁺ .

Step 6: Preparation of tert-butyl 3-(bromomethyl)-5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

tert-Butyl 3-(hydroxymethyl)-5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (360 mg, 1.08 mmol) Dissolved in dichloromethane (10 mL), cooled to 0 ° C, and then triphenylphosphine (426 mg, 1.62 mmol) and carbon tetrabromide (535 mg, 1.62 mmol) were added dropwise, and allowed to react at room temperature for 1 hour. After concentration, column chromatography separation [eluent: PE/EA (4:1)] afforded tert-butyl 3-(bromomethyl)-5-((tetrahydrofuran-3-yl)oxy)-1H-pyrrole And [2,3-b]pyridine-1-carboxylate (70 mg, yield 17%).

Step 7: tert-Butyl 3-((6-amino-2-methylpyridin-3-yl)methyl)-5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2 , 3-b]pyridine-1-carboxylate preparation

tert-Butyl 3-(bromomethyl)-5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (400 mg, 1.01 mmol) ,6-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (284 mg, 1.21 mmol), Sodium carbonate (320 mg, 3.03 mmol) and tetra-triphenylphosphine palladium (117 mg, 0.101 mmol) were dissolved in toluene (10 mL) and water (10 mL). Then it was diluted with ethyl acetate (5 mL), washed with water (5 mL×3) and brine (5 mL), and dried over anhydrous sodium sulfate. 1)] Obtained tert-butyl 3-((6-amino-2-methylpyridin-3-yl)methyl)-5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2 , 3-b]pyridine-1-carboxylate (270 mg, yield 63%). MS m/z (ESI): 425 [M+H] ⁺ .

Intermediates 16-29 are prepared by the synthesis of intermediate 11 or 13 or 14 or 15:

Preparation of (6-aminopyridin-3-yl)(1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (Intermediate 30)

First step: Preparation of 3-iodo-1H-pyrazolo[3,4-b]pyridine

1H-pyrazolo[3,4-b]pyridine (1 g, 8.4 mmol) was dissolved in 1,4-dioxane (50 mL) and 4M aqueous sodium hydroxide (50 mL). 2.13 g, 8.40 mmol) was reacted at 55 ° C for 16 hours. Acetic acid was adjusted to pH 6 and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, and then concentrated and then purified by column chromatography (eluent: DCM/MeOH (20:1)) to give 3-iodo-1H-pyrazolo[3,4-b]pyridine (1.3 g, Yield 65%). MS m/z (ESI): 246 [M+H] ⁺ .

Second step: Preparation of tert-butyl (5-(hydroxy(1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamate

3-iodo-1H-pyrazolo[3,4-b]pyridine (700 mg, 2.86 mmol) was dissolved in tetrahydrofuran (5 mL), the reaction solution was cooled to ° C, and after nitrogen was applied, 2 M isopropyl magnesium chloride (5.72) was added. mL, 5.72 mmol). After stirring at 0 ° C for 30 minutes, tert-butyl (5-formylpyridin-2-yl)carbamate (630 mg, 2.86 mmol) was dissolved in tetrahydrofuran (5 mL) and the mixture was added dropwise to the mixture and the mixture was stirred at 0 ° C for 1 hour. . After the completion of the reaction, water (10 mL) was added, and ethyl acetate was evaporated, and the organic layer was concentrated, and then, then, then, then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Pyrazolo[3,4-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamate (150 mg, 15% yield). MS m/z (ESI): 342 [M+H] ⁺ .

Third step: preparation of tert-butyl (5-(1H-pyrazolo[3,4-b]pyridine-3-carbonyl)pyridin-2-yl)carbamate

Dissolving tert-butyl (5-(hydroxy(1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamate (200 mg, 0.59 mmol) In a dichloromethane (5 mL), Dess-Martin periodinane (370 mg, 0.88 mmol) was added at 0 ° C and reacted at room temperature for 2 hours. Then, it was diluted with ethyl acetate (10 mL), washed with water (5 mL×3) and brine (5 mL), and dried over anhydrous sodium sulfate. :1)]: tert-Butyl (5-(1H-pyrazolo[3,4-b]pyridine-3-carbonyl)pyridin-2-yl)carbamate (190 mg, yield 99%) was obtained. MS m/z (ESI): 340 [M+H] ⁺ .

Step 4: Preparation of (6-aminopyridin-3-yl)(1H-pyrazolo[3,4-b]pyridin-3-yl)methanone

tert-Butyl (5-(1H-pyrazolo[3,4-b]pyridine-3-carbonyl)pyridin-2-yl)carbamate (190 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL) In the middle, trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 16 hours. The aqueous sodium hydrogencarbonate solution was adjusted to pH 8 and then diluted with methylene chloride (5 mL), washed successively (5 mL×2) and brine (5 mL) and dried over anhydrous sodium sulfate. Aminopyridin-3-yl)(1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (130 mg, yield 95%). MS m/z (ESI): 240 [M+H] ⁺ .

31. Preparation of tert-amyl isocyanate (intermediate 31)

Trimethylacetamide (101 mg, 1 mmol) was dissolved in 1,2-dichloroethane (5 mL) and oxalyl chloride (121 mg, 0.95 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 1 hour, then warmed to 75 ° C and stirring was continued for 1 hour. After the reaction solution was cooled, it was used in the next reaction without post-treatment.

Intermediates 31 to 33 were prepared by the synthesis of Intermediate 30:

Preparation of 34,2,2,4,4-tetramethyl-3-oxopentanoic acid (Intermediate 34)

Methyl 4,4-dimethyl-3-oxopentanoate (800 mg, 5.06 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). NaH (607 mg, 15.2 mmol) was slowly added and stirred at 0 ° C. After a minute, iodomethane (0.9 mL, 15.2 mmol) was added to the mixture and stirred at room temperature overnight. After completion of the reaction, it was quenched with a saturated aqueous solution of ammonium chloride (50 mL), and the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (20 mL × 3). The organic phase was combined and concentrated to about 20 mL When the solution is stopped, the concentration is stopped. Tetrahydrofuran (30 mL), water (40 mL) and lithium hydroxide monohydrate (1.0 g, 25.3 mmol) were added to the obtained mixture, and stirred at room temperature overnight. The tetrahydrofuran was removed under reduced pressure and the residual aqueous solution was extracted with methyl t-butyl ether (20mL). The aqueous phase was adjusted to pH 5-6, and then extracted with dichloromethane (20 mL×3). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered and concentrated to give crude 2,2,4,4-tetramethyl-3- Oxyvaleric acid (500 mg, yield 57%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.43 (s, 6H), 1.25 (s, 9H).

2. Preparation of specific examples of compounds

Example 1. N-((5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamoyl)pivaloyl quinone dione amide preparation

5-((1H-Pyrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-amine (45 mg, 0.2 mmol), triethylamine (40 mg, 0.4 mmol) was dissolved in dichloro In a methane (5 mL), a 1,2-dichloromethane solution of di-pivalyl isocyanate (about 0.2 mmol) was slowly added dropwise, and the reaction was continued at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride. The organic layer was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. [2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamoyl)pivaloyl quinone dione amide (42 mg, yield 62%). MS m/z (ESI): 352 [M+H] ⁺ . ^{1 H NMR (400MHz, DMSO-} d 6) δ11.43 (s, 1H), 11.05 (s, 1H), 10.34 (s, 1H), 8.29 (d, J = 2.3Hz, 1H), 8.23-8.05 ( m,1H), 8.01–7.77 (m, 2H), 7.75–7.60 (m, 1H), 7.31 (d, J=2.3 Hz, 1H), 7.05–6.91 (m, 1H), 4.02 (s, 2H) , 1.21 (s, 9H).

Examples 2 to 16 were prepared by referring to the synthesis method of Example 1:

Among them, the nuclear magnetic data prepared by the above compounds 2 to 16 are listed as follows:

Example 17. N-(5-((5-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)-4,4-dimethyl Preparation of keto-3-carbonyl pentamide

5-((5-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-amine (22 mg, 0.1 mmol), 4,4-dimethyl Methyl 3-oxopentanoate (16 mg, 0.1 mmol) was dissolved in toluene (2 mL) and warmed to 120 ° C for 2 hr. The toluene was distilled off under reduced pressure, and the residue was subjected to chromatography to afford N-(5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl -4,4-Dimethyl-3-carbonylpentanamide (27 mg, yield 77%, containing about 25% enol). MS m/z (ESI): 381 [M+H] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ13.95 (s, 0.2H), 11.30 (s, 1H), 10.48-10.43 (m, 1H), 8.28 (s, 1H), 8.00-7.94 (m, 2H), 7.70-7.68 (m, 1H), 7.45 (s, 1H), 7.26 (s, 1H), 5.51 (s 0.2H), 3.99 (s, 2H), 3.78 (s, 3H), 3.74 (s , 1.6H), 1.10 (s, 9H).

Example 18, N-(5-((5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)-2,2,4, Preparation of 4-tetramethyl-3-carbonylpentanamide

2,2,4,4-Tetramethyl-3-oxopentanoic acid (100 mg, 0.59 mmol), 5-((5-methoxy-1H-pyrrolo[2,3-b]pyridine-3 -yl)methyl)pyridin-2-amine (50 mg, 0.19 mmol), 2-chloro-1,3-dimethylimidazolium (100 mg, 0.59 mmol) dissolved in pyridine (3 mL) After stirring at room temperature for 16 hours, LCMS showed that the material was evaporated, and the mixture was concentrated. The residue was partitioned with methylene chloride (10 mL), water (10 mL). Drying over magnesium sulfate, filtration, EtOAc (EtOAc m. -1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)-2,2,4,4-tetramethyl-3-carbonylpentanamide (0.5 mg, produced Rate 1%). MS m/z (ESI): 409 [M+H] ⁺ .

^{1 H NMR (400MHz, MeOH-} d 4) δ8.26 (s, 1H), 7.92 (d, J = 5.4Hz, 2H), 7.72 (s, 1H), 7.39 (d, J = 2.6Hz, 1H) , 7.17 (s, 1H), 4.08 (s, 2H), 3.81 (s, 3H), 1.48 (s, 6H), 1.22 (s, 9H).

Example 19, N-(5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-methylpyridin-2-yl)-3,3-dimethyl Preparation of 2-carbonylpyrrolidine-1-carboxamide

First step: tert-butyl 3-((6-(3,3-dimethyl-2-carbonylpyrrolidin-1-carbamoylamino)-2-methylpyridin-3-yl)-

Of -1H-pyrrolo[2,3-b]pyridine-1-carboxylate

Triphosgene (94 mg, 0.316 mmol) was dissolved in dichloromethane (2 mL), and 3,3-dimethylpyrrolidin-2-one (53 mg, 0.472 mmol) and pyridine (112 mg, 1.4 mmol) Methyl chloride (2 mL) solution was stirred in an ice-bath for 30 min and then applied to t-butyl 3-((6-amino-2-methylpyridin-3-yl)methyl)- A solution of 1H-pyrrolo[2,3-b]pyridine-1-carboxylate (80 mg, 0.236 mmol) and pyridine (19 mg, 0.236 mmol) in dichloromethane (1 mL) The reaction mixture was poured into water (30 mL), EtOAc (EtOAc) (EtOAc) To give tert-butyl 3-((6-(3,3-dimethyl-2-carbonylpyrrolidin-1-carbamoylamino)-2-methylpyridin-3-yl)methyl)- 1H-pyrrolo[2,3-b]pyridine-1-carboxylate (10 mg, yield 8.9%). MS m/z (ESI): 478 [M+H] ⁺ .

Second step: N-(5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-methylpyridin-2-yl)-3,3-dimethyl Preparation of 2-carbonylpyrrolidine-1-carboxamide

tert-Butyl 3-((6-(3,3-dimethyl-2-carbonylpyrrolidin-1-carbamoylamino)-2-methylpyridin-3-yl)methyl)-1H- Pyrrolo[2,3-b]pyridine-1-carboxylate (10 mg, 0.021 mmol) was added to a 4M aqueous solution of dioxane (2 mL), and the mixture was stirred at room temperature overnight. Then, concentrated-phase column chromatography was carried out to separate [eluent: 0.5% aqueous solution of ammonium hydrogencarbonate - 0.5% aqueous solution of ammonium hydrogencarbonate / acetonitrile (40:60)] to obtain N-(5-((1H-pyrrolo[2] ,3-b]pyridin-3-yl)methyl)-6-methylpyridin-2-yl)-3,3-dimethyl-2-carbonylpyrrolidin-1-carboxamide (3.7 mg, yield 46.7%). MS m/z (ESI): 378 [M+H] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ11.44 (s, 1H), 10.83 (s, 1H), 8.18 (dd, J = 4.7,1.6Hz, 1H), 7.81 (dd, J = 7.9,1.6 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.00 (dd, J = 7.8, 4.7 Hz, 1H), 4.01 (s, 2H), 3.78 - 3.70 (m, 2H), 2.41 (s, 3H), 1.88 (t, J = 7.0 Hz, 2H), 1.17 (s, 6H).

Examples 20 to 24 were prepared by referring to the synthesis method of Example 19:

Among them, the nuclear magnetic data prepared by the above compounds 20 to 24 are listed as follows:

Biological test evaluation

I. CSF1R in vitro biochemical kinase assay

The present invention employs the CSF1R ADP-Glo assay to determine the properties of a compound against CSF1R inhibitory activity. Compound-mediated inhibition was evaluated by inhibiting the production of ADP (produced by consumption of ATP) using the ADP-Glo kit (Promega, cat. No. V9101). The specific experimental process is as follows:

1. The kinase reaction carried out in the present invention was carried out in a 384-well plate (Perkinelmer, cat. No. 6007290), and 3.95 nM of CSF1R, 500 μM of ATP and 0.2 mg/ml of polypeptide (Poly(Glu4, Try1), respectively. , Sigma, cat. No. P0275);

2. A series of gradient-diluted compounds were tested in a reaction system containing 40 mM Tris, pH 7.5, 20 mM MgCl ₂ , 0.01% Triton X-100, 0.1 mg/ml BSA, 2.5 mM DTT, 0.1% DMSO;

3. React at 30 ° C for 60 minutes;

4. Add a stop solution ADP-Glo of the same volume as the enzyme reaction;

5. Incubate at 25 ° C for 60 minutes to stop the enzyme reaction;

6. Adding a detection reagent for 2 times the enzyme reaction volume;

7. Incubate at 25 ° C for 30 minutes;

8, using a plate reader (Tecan, M1000), and Compound IC ₅₀ values were determined using Graphpad Prism the four parameter curve. The enzymatic activities of the specific examples of the compounds are shown in Table 1.

2. KIT/PDGFRA in vitro biochemical kinase assay

1. Prepare 1 time of kinase buffer and stop solution

1.1 1X kinase buffer: 50 mM HEPES, pH 7.5, 0.0015% Brij-35.

1.2 Stop solution: 100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3 50 mM EDTA

2, compound preparation

2.1 compound dilution

1) The final concentration of the compound was determined to be 40 μM, and was set to a concentration of 50 times, that is, 2 mM.

2) 80 μL of 100% DMSO was added to the second well of a 96-well plate, and 20 μL of a 10 mM compound solution was added to prepare a 2 mM compound solution. The other wells were added to 60 μL of 100% DMSO. 20 μL of the compound was taken from the second well and added to the third well, and then serially diluted 4 times, and a total of 10 concentrations were diluted.

2.2 Transfer 5 times compound to the reaction plate

1) 10 μL from each well of the above 96-well plate to another 96-well plate, and 90 μL of kinase buffer was added.

2) Remove 5 μl from the above 96-well plate to a 384-well reaction plate.

2.3 Kinase reaction

1) KIT/PDGFRA kinase was added to 1X kinase buffer to form a 2.5-fold enzyme solution.

2) The FAM-labeled polypeptide and ATP were added to 1X kinase buffer to form a 2.5-fold substrate solution.

3) Add 10 μL of a 2.5-fold enzyme solution to a 384-well reaction plate and incubate for 10 minutes at room temperature. (5 μL of 5 times DMSO dissolved 5 times compound in the 384-well reaction plate.)

4) 10 μL of a 2.5-fold substrate solution was added to the 384-well reaction plate.

5) Kinase reaction and termination: Incubate at 28 ° C for a certain period of time, and add 25 μL of stop solution to stop the reaction.

2.4 Caliper EZ Reader II Read Data

2.5 inhibition rate, IC ₅₀ calculation

1) Copy conversion rate data from Caliper EZ Reader II.

2) Convert the conversion rate into inhibition rate data. Where max is the conversion of the DMSO control and min is the conversion of the enzyme-free control.

Percent inhibition = (max-conversion) / (max-min) * 100.

3) Fit the IC ₅₀ value with XLFit excel add-in version 5.4.0.8: Fit formula:

Y=Bottom+(Top-Bottom)/(1+(IC ₅₀ /X)^HillSlope).

The cell viability of the specific examples of the compounds is shown in Table 1.

Third, CSF-1R cell proliferation experiment

The present invention employs (Cell Titer Glo (CTG) experiment) to evaluate the functional effects of compounds on cell proliferation. M-NFS-60 mouse myeloid leukemia lymphocytes (Catalog No. CCBJ078) from the China Food and Drug Administration Institute in RPMI 1640 (Gibco, cat. No. 11875-119), 10% fetal bovine serum (Gibco, 10099) -141), human 10 ng/ml M-CSF macrophage colony stimulating factor (R&D, cat. No. MVN0915101) and cultured in an incubator at 37 ° C, 5% CO ₂ . Since ATP is an indicator of living cell metabolism, the use of CTG (Promega, #G7573) reagent is a homogeneous detection method for detecting the number of viable cells in culture by quantitatively measuring ATP. Therefore, compound-mediated inhibition of cell proliferation/survival is evaluated by quantifying ATP content in cells, and the specific experimental procedure is as follows:

1. Inoculate the cells into tissue culture medium-treated 96-well plates (Costar #3904) at 5000 cells/well/80 μL of fresh medium;

2. After 24 hours, add 10 μL of medium containing a compound dilution of 10 times its final desired concentration;

3. Simultaneously add 10 μL of medium containing M-CSF macrophage colony-stimulating factor dilution at 10 times its final desired concentration;

4. The dose-effect effect was evaluated by 3-fold serial dilution of the test compound;

5. After the cells were incubated for 3 days at 37 ° C and 5% CO ₂ , the effect of the inhibitor on cell survival was quantified by adding 50 μL of CTG and luminescence assay;

6, using a plate reader (M1000, Tecan) using Graphpad Prism 7 in a four-parameter curve fitting to determine the concentration of compound resulting in half-maximal growth inhibition (IC ₅₀₎ and leads to compound concentration (Absolute IC ₅₀₎ half the absolute growth inhibition. The cell viability of the specific examples of the compounds is shown in Table 1.

Fourth, CSF-1R cell proliferation experiment

The present invention evaluates the functional effects of compounds on the proliferation of several cells by using the Cell Titer Glo (CTG) experiment, thereby observing the proliferative effect of the compounds on different cells to judge the selectivity of the cells. M07e human giant cell leukemia cells (Catalog No. CBP60791) from Nanjing Kezhen Biotechnology Co., Ltd. were used in RPMI1640 (Gibco, cat. No. 11875-119), 20% fetal bovine serum (Gibco, 10099-141). ), human 10 ng/ml GM-CSF granulocyte macrophage colony-stimulating factor (R&D, cat. No. 215-GM-010) and cultured in an incubator at 37 ° C, 5% CO ₂ ; kasumi- 1 human acute myeloid leukemia cell (Catalog No. CBP60524), under RPMI1640 (Gibco, cat. No. 11875-119), 20% fetal bovine serum (Gibco, 10099-141) and 37 ° C, 5% CO ₂ Cultured in an incubator; NCI-H1703 human non-small cell lung cancer squamous carcinoma (Catalog No. CBP60115), in RPMI 1640 (Gibco, cat. No. 11875-119), 10% fetal bovine serum (Gibco, 10099-141) and Cultured in an incubator at 37 ° C, 5% CO ₂ ; MV-4-11 human acute monocytic leukemia cells (Catalog No. CBP60522), in IMDM (Invitrogen, cat. No. 12440053), 20% fetal calf Serum (Gibco, 10099-141) and cultured in an incubator at 37 ° C, 5% CO ₂ ; since ATP is an indicator of living cell metabolism, the use of CTG (Promega, #G7573) reagent is through A A homogeneous assay for the quantitative determination of TP to detect the number of viable cells in culture. Therefore, compound-mediated inhibition of cell proliferation/survival is evaluated by quantifying the ATP content in the cells, and the specific experimental procedure is as follows. The cell viability of the specific examples of the compounds is shown in Table 1.

a), M07e human giant cell leukemia cells:

1. The cells were inoculated into a tissue culture medium 96-well plate (Costar #3904) at 3500 cells/well/80 μL of fresh medium for 24 hours;

2. Next day, add 10 μL of medium containing a compound dilution of 10 times its final desired concentration;

3. Simultaneously add 10 μL of medium containing a dilution of SCF recombinant human stem cell factor (R&D, cat. No. 7466-SC-010) at 10 times its final desired concentration;

4. The dose effect was evaluated by 4-fold serial dilution of the test compound, starting at 18 μM;

5. After the cells were incubated for 3 days at 37 ° C and 5% CO ₂ , the effect of the inhibitor on cell survival was quantified by adding 50 μL of CTG and luminescence assay;

6, using a plate reader (M1000, Tecan) using Graphpad Prism 7 in a four-parameter curve fitting to determine the concentration of compound resulting in half-maximal growth inhibition (IC ₅₀₎ and leads to compound concentration (Absolute IC ₅₀₎ half the absolute growth inhibition.

b) NCI-H1703 human non-small cell lung cancer squamous cell carcinoma:

1. The cells were inoculated into a tissue culture medium 96-well plate (Costar #3904) at 5000 cells/well/90 μL of fresh medium for 24 hours;

2. Next day, add 10 μL of medium containing a compound dilution of 10 times its final desired concentration;

3. The dose effect was evaluated by 3-fold serial dilution of the test compound, starting at 18 μM;

4. After the cells were incubated for 3 days at 37 ° C and 5% CO ₂ , the effect of the inhibitor on cell survival was quantified by adding 50 μL of CTG and luminescence assay;

5, using a plate reader (M1000, Tecan) using Graphpad Prism 7 in a four-parameter curve fitting to determine the concentration of compound resulting in half-maximal growth inhibition (IC ₅₀₎ and leads to compound concentration (Absolute IC ₅₀₎ half the absolute growth inhibition.

c), MV-4-11 human acute monocytic leukemia cells:

1. The cells were inoculated into a tissue culture medium 96-well plate (Costar #3904) at 5000 cells/well/90 μL of fresh medium for 24 hours;

2. Next day, add 10 μL of medium containing a compound dilution of 10 times its final desired concentration;

3. The dose effect was evaluated by 3-fold serial dilution of the test compound, starting at 18 μM;

4. After the cells were incubated for 3 days at 37 ° C and 5% CO ₂ , the effect of the inhibitor on cell survival was quantified by adding 50 μL of CTG and luminescence assay;

5, using a plate reader (M1000, Tecan) using Graphpad Prism 7 in a four-parameter curve fitting to determine the concentration of compound resulting in half-maximal growth inhibition (IC ₅₀₎ and leads to compound concentration (Absolute IC ₅₀₎ half the absolute growth inhibition.

Table 1 Enzymology and cell activity test results

From the enzymatic activity data of the specific examples, the compounds of the present invention have a strong inhibitory effect on CSF1R kinase activity. From the cell activity data of the specific example compounds, the series of compounds of the present invention have a strong inhibitory effect on the proliferation activity of M-NFS-60 mouse myeloid leukemia lymphocytes which are highly expressed by CSF1R. In addition, from the above experimental results, the series of compounds of the present invention have strong selectivity for KIT, FLT3, and PDGFRA, and are expected to be developed into a new generation of highly selective CSF1R inhibitors to meet clinical application requirements.

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the present invention.

Claims (15)

1. a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

   

   among them,

   X is selected from -N(R ₂ )- or -C(R ₃ R ₄ )-;

   Y is selected from a bond, -O-, -S(O) _r -, -CH=CH-, -C(R ₅ R ₆ )- or -N(R ₇ )-;

   Z ₁ , Z ₂ , Z ₃ are each independently selected from C(R ₈ ) or N;

   Z ₄ , Z ₅ , Z ₆ , Z ₇ are each independently selected from C(R ₉ ) or N;

   R _{1 is} selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5- 10 membered heteroaryloxy or -NR ₁₀ R ₁₁ ,

   The above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, Halogen substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R Substituent of ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ Replace

   R _{2 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-10 cycloalkyl C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 ring Alkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ ,- C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ ,- C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

   or,

   R ₁ and R ₂ together with a group directly attached thereto form a 3-10 membered heterocyclic group, which is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano and nitro , azido, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 member Cyclic group, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O )OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O Substituting a substituent of NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

   R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen Substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R _{1 7} , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ,

   or,

   R ₃ and R ₄ together with the carbon atom to which they are directly bonded form a C _3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the C _3-10 cycloalkane or 3-10 membered heterocyclic ring is optionally further One or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen substituted C _1-8 alkane , C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _{0 -8} -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 Substituted by a substituent of -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

   R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halogen Substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R _{1 7} , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ,

   or,

   R ₅ , R ₆ and the carbon atom to which they are directly bonded together form a carbonyl group, a C _3-10 cycloalkyl group or a 3-10 membered heterocyclic group, optionally a C _3-10 cycloalkane or a 3-10 membered heterocyclic ring. further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl group, a halogen substituted C _{1- 8-} alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ ,- C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C ₀ Substituted by a substituent of _-8- NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

   R _{7 is} selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-10 cycloalkyl C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 ring Alkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ ,- C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ ,- C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

   Each R ₈ and R _{9 are} independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _{3 -10} cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O)(=NR ₁₂ )R ₁₃ , -C _{0 -8} -B(OR ₁₄ ) ₂ , -C _0-8 -P(O)(R ₁₅ ) ₂ , -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ ,- C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ ,- C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ,

   The above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, =0, cyano, nitro, azide, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 chain Alkynyl, halo-substituted C _1-8 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S (O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC( O) R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ Substituted by a substituent;

   Each of R ₁₀ and R _{11 is} independently selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-10 cycloalkyl C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

   Each R _{12 is} independently selected from the group consisting of hydrogen, hydrazine, C _1-8 alkyl, C _3-10 cycloalkyl C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _{3- 10} cycloalkyl, 3-10 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₁₃ , -C _0-8 -OR ₁₄ , -C _0-8 -C(O)OR ₁₄ , -C _0-8 -C(O)R ₁₅ , -C _0-8 -OC(O)R ₁₅ , -C _0-8 -NR ₁₆ R ₁₇ , -C _0-8 -C(O)NR ₁₆ R ₁₇ or -C _0-8 -N(R ₁₆ )-C(O)R ₁₅ ;

   Each R _{13 is} independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, halo-substituted C _1-8 alkyl, halo-substituted C _1-8 alkoxy, C _2-8 Alkenyl, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 aryl An oxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group or -NR ₁₆ R ₁₇ , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, carbonyl, C _{1- 8-} alkyl, C _1-8 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 Substituted with an aryl group, a C _5-10 aryloxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group or a substituent of —NR ₁₆ R ₁₇ ;

   Each R _{14 is} independently selected from the group consisting of hydrogen, deuterium, C _1-8 alkyl, C _2-8 alkenyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl or 5- a 10-membered heteroaryl group, the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, carbonyl, cyano, C _1-8 alkyl, C _1-8 alkoxy, C _3-10 ring Alkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl Substituted by a 5- to 10-membered heteroaryloxy group or a substituent of -NR ₁₆ R ₁₇ ;

   Each R _{15 is} independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl a C _3-10 cycloalkoxy group, a 3-10 membered heterocyclic group, a 3-10 membered heterocyclic oxy group, a C _5-10 aryl group, a C _5-10 aryloxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group or -NR ₁₆ R ₁₇ , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, cyano, C _1-8 alkyl, C _1-8 alkoxy , C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 aryloxy Substituted by a 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or a substituent of -NR ₁₆ R ₁₇ ;

   Each R ₁₆ and each R _{17 are} independently selected from the group consisting of hydrogen, hydrazine, hydroxy, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, 3-10 a heterocyclic group, a C _5-10 aryl group, a 5-10 membered heteroaryl group, a sulfonyl group, a methylsulfonyl group, an isopropylsulfonyl group, a cyclopropylsulfonyl group, a p-toluenesulfonyl group, an amino group, a monoalkylamino group, a dialkylamino group or a C _1-8 alkanoyl group, the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, C _3-10 Cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered Substituted with a substituent of an aryl group, a 5-10 membered heteroaryloxy group, an amino group, a monoalkylamino group, a dialkylamino group or a C _1-8 alkanoyl group;

   Alternatively, R ₁₆ , R ₁₇ and the directly attached nitrogen atom thereof together form a 5-10 membered heterocyclyl group, said group optionally further comprising one or more selected from the group consisting of hydrazine, halogen, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C _5-10 aryl, C Substituted with a substituent of _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or _C1-8 alkanoyl;

   r is 0, 1, or 2.
2. The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein Y is selected from -C(R ₅ R ₆ )-;

   R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halo Substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _{0 - 4} -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ,

   or,

   R ₅ , R ₆ and the carbon atom to which they are directly bonded together form a carbonyl group, a C _3-8 cycloalkyl group or a 3-8 membered heterocyclic group, optionally a C _3-10 cycloalkane or a 3-10 membered heterocyclic ring. further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl group, a halogen substituted C _{1- 4-} alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ ,- C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C ₀ Substituted by a substituent of _-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ;

   Preferably, R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, allyl, trifluoromethyl, cyclopropyl, cyclobutyl. , 3-oxetanyl, methoxy, trifluoromethoxy, methoxymethyl, methoxycarbonyl, acetoxy, amino, dimethylamino or acetylamino, or R ₅ and R ₆ and The directly linked carbon atoms together form a carbonyl group, a cyclopropyl group or a cyclobutyl group, and the cyclopropyl group or cyclobutyl group is optionally further selected from one or more selected from the group consisting of hydrazine, fluorine, chlorine, methyl, ethyl and iso Propyl, allyl, trifluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, methoxy, trifluoromethoxy, methoxymethyl, methoxycarbonyl, acetoxy Substituted by a substituent of an amino group, a dimethylamino group or an acetylamino group,

   R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ and r are as defined in claim 1.
3. The compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein each R _{8 is} independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide , C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5- 10-membered heteroaryl, -C _0-4 -S(O)(=NR ₁₂ )R ₁₃ , -C _0-4 -B(OR ₁₄ ) ₂ , -C _0-4 -P(O)(R _{15 2} , -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ,

   The above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, Halogen substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ substituent Replace

   Preferably, each R _{8 is} independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, methoxy, Ethoxy, isopropoxy, methoxymethyl, trifluoromethyl, trifluoromethoxy, trimethyl or amino

   R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ and r are as defined in claim 1.
4. A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, which is selected from the group consisting of the compound of the formula (II):

   

   Wherein X is selected from -N(R ₂ )- or -C(R ₃ R ₄ )-;

   Y is selected from -C(R ₅ R ₆ )-;

   R _{1 is} selected from the group consisting of hydrogen, hydrazine, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, 3-8 membered heterocyclic, 3-8 membered heterocyclooxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5- An 8-membered heteroaryloxy group or -NR ₁₀ R ₁₁ , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-4 alkyl, C _{2− 4} -alkenyl, C _2-4 alkynyl, halogen-substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered Aryl, -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R Substituted by a substituent of ₁₆ )-C(O)R ₁₅ ;

   R _{2 is} selected from the group consisting of hydrogen, hydrazine, C _1-4 alkyl, C _3-8 cycloalkyl C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 ring Alkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ ,- C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ;

   or,

   R ₁ and R ₂ together with a group directly attached thereto form a 3-8 membered heterocyclic group, which is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano and nitro , azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered Cyclic group, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O )OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O Substituting a substituent of NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ;

   R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halo Substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _{0 - 4} -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ , or, R ₃ Together with R ₄ and the carbon atom to which it is directly bonded, a C _3-8 cycloalkyl group or a 3-8 membered heterocyclic group is formed, and the C _3-8 cycloalkane or the 3-8 membered heterocyclic ring is optionally further subjected to one or a plurality of selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR Substituted by a substituent of ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ;

   R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, methyl, methoxy, trifluoromethoxy or methoxymethyl, or R ₅ and R ₆ together with the carbon atom to which they are directly attached Carbonyl, cyclopropyl or cyclobutyl;

   R _{8 is} independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, methyl, ethyl or methoxy;

   Z ₄ , Z ₆ , R ₉ , R ₁₀ , R ₁₁ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ and r are as defined in claim 1.
5. A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 4, wherein X is selected from -N(R ₂ )- or -C(R ₃ R ₄ )- Y is selected from -C(R ₅ R ₆ )-; Z _{4 is} selected from CH or N; Z _{6 is} selected from C(R ₉ ) or N;

   R _{1 is} selected from C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl or 5-8 membered heteroaryl, and the above group is optionally further Or a plurality selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl , C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ , -C _{0- 4} -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 - Substituted by a substituent of NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ;

   R _{2 is} selected from the group consisting of hydrogen, hydrazine, C _1-4 alkyl, C _3-8 cycloalkyl C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aromatic Base or 5-8 membered heteroaryl;

   or,

   R ₁ and R ₂ together with a group directly attached thereto form a 3-6 membered heterocyclic group, which is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano and nitro , azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered Cyclic group, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O )OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O Substituting a substituent of NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ;

   R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, hydrazine, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic, C _5-6 aryl or 5-6 membered heteroaryl. Or, R ₃ and R ₄ together with the carbon atom to which they are directly bonded form a C _3-6 cycloalkyl group or a 3-6 membered heterocyclic group;

   R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, methyl, methoxy, trifluoromethoxy or methoxymethyl, or R ₅ and R ₆ together with the carbon atom to which they are directly attached Carbonyl, cyclopropyl or cyclobutyl;

   R _{8 is} independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, methyl, ethyl or methoxy;

   R _{9 is} selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl 3-8 membered heterocyclic group, C _5-8 aryl group, 5-8 membered heteroaryl group, -C _0-4 -S(O)(=NR ₁₂ )R ₁₃ , -C _0-4 -B( OR ₁₄ ) ₂ , -C _0-4 -P(O)(R ₁₅ ) ₂ , -C _0-4 -S(O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 - C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC(O)R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 - C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ ,

   The above group is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, =0, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 chain Alkynyl, halo-substituted C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S (O) _r R ₁₃ , -C _0-4 -OR ₁₄ , -C _0-4 -C(O)OR ₁₄ , -C _0-4 -C(O)R ₁₅ , -C _0-4 -OC( O) R ₁₅ , -C _0-4 -NR ₁₆ R ₁₇ , -C _0-4 -C(O)NR ₁₆ R ₁₇ or -C _0-4 -N(R ₁₆ )-C(O)R ₁₅ Substituted by a substituent.
6. A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 5, wherein X is selected from -N(R ₂ )- or -C(R ₃ R ₄ )- Y is selected from -C(R ₅ R ₆ )-; Z _{4 is} selected from CH or N; Z _{6 is} selected from C(R ₉ ) or N;

   R _{1 is} selected from C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-8 aryl or 5-8 membered heteroaryl, and the above group is optionally further Or a plurality selected from the group consisting of hydrazine, fluorine, chlorine, cyano, nitro, azide, hydroxy, methyl, ethyl, isopropyl, allyl, trifluoromethyl, cyclopropyl, cyclobutyl, Substitution of 3-oxetanyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methoxymethyl, methoxycarbonyl, acetoxy, amino, dimethylamino or acetylamino Substituted by

   R _{2 is} selected from the group consisting of hydrogen, hydrazine, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic or cyclopropylmethyl;

   or,

   R ₁ and R ₂ together with a group directly attached thereto form a 4-6 membered heterocyclic group, which is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano and nitro Substituted with a substituent of an azide group, a C _1-4 alkyl group, a vinyl group, an allyl group, an ethynyl group, a trifluoromethyl group, a cyclopropyl group or a methoxy group;

   R ₃ and R ₄ are each independently selected from hydrogen, hydrazine or C _1-4 alkyl, or R ₃ and R ₄ together with the carbon atom to which they are directly bonded form a cyclopropyl or cyclobutyl group;

   R ₅ and R ₆ are each independently selected from hydrogen, hydrazine, fluoro or methyl, or R ₅ and R ₆ together with the carbon atom to which they are directly bonded form a carbonyl group, a cyclopropyl group or a cyclobutyl group;

   R _{8 is} selected from the group consisting of hydrogen, deuterium, methyl or ethyl;

   R _{9 is} selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl 3-6 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group, -OR ₁₄ , -OC(O)R ₁₅ , -NR ₁₆ R ₁₇ , -C(O)NR ₁₆ R ₁₇ or -N (R ₁₆ )-C(O)R ₁₅ , wherein the above group is further further selected from one or more selected from the group consisting of hydrazine, fluorine, chlorine, =0, cyano, nitro, azide, hydroxy, methyl, and Base, isopropyl, allyl, trifluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, Substituted by a substituent of methoxymethyl, methoxycarbonyl, acetoxy, amino, dimethylamino or acetylamino.
7. A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, which is selected from the group consisting of the following compounds:

   
8. A process for the preparation of a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, comprising the step of: a compound of the formula (Ia) or an acid salt thereof and a formula (Ib) The compound is reacted to form a compound of formula (I) having the following reaction formula:

   

   Wherein, when X is selected from -N(R ₂ )-, R is selected from the group consisting of isocyanato or acid chloride, and when X is selected from -C(R ₃ R ₄ )-, R is selected from a carboxyl group or an alkyl carboxylate. base;

   Preferably, when X is selected from -N(R ₂ )-,

   

   Prepared by the following reaction:

   

   X, Y, Z ₁ , Z ₂ , Z ₃ , Z ₄ , Z ₅ , Z ₆ , Z ₇ , R ₁ , R ₂ , R ₃ , R ₄ , 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 and r are as defined in claim 1.
9. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10. The compound of the formula (I) according to any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 for the preparation of a cancer, tumor, autoimmune disease , in the application of drugs for metabolic diseases or metastatic diseases.
11. The compound of the formula (I) according to any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 for the preparation of ovarian cancer, pancreatic cancer, prostate cancer , lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastatic cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumor, solid tumor, melanoma, mesothelioma, Glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, myeloproliferative diseases, leukemia, rheumatoid arthritis, rheumatoid joints Inflammation, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome, mastocytosis or mast cells Application in leukemia drugs;

    Preferably, in the preparation of treatment for ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic diseases, neurodegenerative diseases, metastatic tumor sites or bones Application in metastatic cancer drugs.
12. A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 9, for use in the treatment of cancer, tumor, A drug for an autoimmune disease, a metabolic disease, or a metastatic disease.
13. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 9, for use in the treatment of ovarian cancer, pancreas Cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastatic cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumor, solid tumor, melanoma, between Dermatoma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, myeloproliferative diseases, leukemia, rheumatoid arthritis, Rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome, mastocytosis Drugs for mastitis or mast cell leukemia;

    Preferably, for use in the treatment of ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites or bone A drug for metastatic cancer.
14. A method for treating cancer, a tumor, an autoimmune disease, a metabolic disease or a metastatic disease, which comprises administering to a patient a compound of the formula (I) according to any one of claims 1 to 7, which is stereoisomerized Or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9.
15. A treatment for ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastatic cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumor, Solid tumors, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, myeloproliferative diseases, Leukemia, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, high eosinophils A method of cell syndrome, mastocytosis or mast cell leukemia, comprising administering to a patient a compound of formula (I) according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable thereof Salt, or the pharmaceutical composition of claim 9.