WO2014079364A1 - Imidazolone derivatives, pharmaceutical compositions and uses thereof - Google Patents

Abstract

Imidazolone compounds, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof are disclosed. Pharmaceutical compositions comprising above substances and uses for preventing and treating protein kinases related diseases, such as cancers, metabolic diseases, cardiovascular diseases and the like, are also disclosed.

Description

 Imidazoxanide derivatives, pharmaceutical compositions thereof and uses thereof

Technical field

 The present application belongs to the field of medicine and relates to a series of imidazolone compounds, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, pharmaceutical compositions comprising the same, and for the treatment of protein kinase-related diseases such as cancer, Uses for metabolic diseases, cardiovascular diseases, etc.

Background technique

 The mammalian target of rapamycin (mTOR) is an atypical serine/threonine protein kinase belonging to the phosphatidylinositol 3-kinase phosphoinositide3- kinase, PI3K)-associated kinase family member, which is synthesized and decomposed intracellularly. The main signaling molecule for cellular functions such as metabolism. The mTOR signaling pathway is closely related to nutrition, energy status and growth factors. It regulates multiple cellular processes including autophagy, proteins, lipids, lysosomal synthesis and energy metabolism, cytoskeletal organization, cell survival, and the like. Under the changing nutrient conditions of mammalian cells, mTOR regulates the conversion of synthesis and degradation metabolism, allowing cells to grow and survive under different nutritional conditions. Due to the important role of mTOR in cells, abnormal or dysregulated mTOR signaling can lead to human disease (eg diseases such as cancer). Therefore, the mTOR signaling pathway has gradually become an important target for the design of anticancer drugs.

 Activation of PBK/Akt/mTOR signaling pathway is closely related to multiple tumorigenesis. In glioma, breast cancer and ovarian cancer, mTOR can accelerate cell cycle, reduce apoptosis and promote tumor cell migration. Activation of mTOR begins with growth factor receptors on the surface of some ligand-activated cells, such as the epidermal growth factor receptor and insulin-like growth factors 1 and -2 (IGF-1 and -2). Activation of the receptor results in activation of PBK kinase, which leads to activation of the downstream effector Akt protein. Akt is a regulator that regulates cell survival at multiple levels. Phosphorylation of Akt inhibits the downstream TSC1/2 complex, resulting in mTOR being activated by Rheb. Downstream of the PBK/Akt and PEN/Akt and Ras/Erkl/2 signaling pathways, the TSC1/2 complex plays a key role in regulating mTOR activation.

It has been found that there are two different mTOR protein complexes in the cell, mTORCl and B mTORC2. These two protein complexes contain unique proteins that interact with mTOR and are each regulated by a different mechanism. Significant progress has been made in the development of mTOR inhibitor drugs. Rapamycin was the first mTOR inhibitor to be discovered and showed good anti-cancer effects in various cancer models. Although rapamycin analogues with better pharmacological properties have been developed, clinically applicable rapamycin analogues are limited to only a few cancers. Akt is an important kinase for cancer cell survival, and mTORC2 directly phosphorylates Akt. This important finding is that mTORC2 is anti-cancer. The research provides new ideas and also promotes the development of second-generation anticancer drugs that act on both mTORCl and mTORC2 targets. Simultaneous inhibition of the activity of two mTOR complexes (mTORCl and B mTORC2) in cancer cells has a broader and more effective anticancer effect.

 mTORCl has six subunits and mTORC2 has seven subunits. The mTOR, mLST8, DEPTOR and Ttil/Tel2 catalytic subunits are present in the mTORCl and mTORC2 complexes. The two complexes have different regulatory proteins, Raptor and PRAS40 are present in mTORCl and rictor, mSin and rotorl/2 are present in mTORC2. The upstream signal of mTORCl is mainly derived from intracellular and extracellular pathways, including growth factors, cellular response, energy status, oxygen and amino acids. These signals control many major processes in the cell, including protein, mR A, lipid synthesis, and autophagy. The heterodimer (TSC1/TSC2) is a key upstream regulator of mTORCl and its function is the activation protein of the Rheb GTPase. Rheb, which binds to GTP, acts directly with mTORCl and activates its enzymatic activity. As a GTPase activating protein of Rheb, TSC1/2 converts Rheb into a state of being inactive and binding to GDP by negative regulation. mTORCl activates its downstream factors 4E-BP1 and S6K1 by phosphorylation to promote protein expression and increase mR A production. In addition, mTORCl also controls cell metabolism and ATP production by interacting with SREBP1/2 transcription factor and HIF1-alpha. In addition to its role in anabolism, mTORCl also regulates autophagy to promote cell growth with negative regulation. In mammals, mTORCl directly phosphorylates the ULK1/Atgl3/FIP20 kinase complex and inhibits the initiation of autophagy. mTORCl can also influence autophagy by other mechanisms, such as regulation of autophagy, DAP1, and promotion of column disintegration.

 Compared to mTORCl, little is known about the signaling pathway of mTORC2. mTORC2 signaling is insensitive to nutrient conditions but responds to some growth factors. mTORC2 regulates several subfamily members of AGC kinases, such as Akt, SGK1 and PKC-c Akt, which activate downstream signaling proteins to regulate cellular metabolism, survival, and apoptosis. , growth and proliferation. mTORC2 activates its function by directly phosphorylating the Akt ( Ser473 ) site. However, in the absence of mTORC2, phosphorylation of TSC2 and GSK3-P was not affected. mTORC2 also directly activates SGK1 kinase to regulate ion transfer and cell growth. However, compared with Akt, the function of SGK1 is completely suppressed without mTORC2. mTORC2 activation PKC-ct can affect actin skeleton formation.

Many studies have shown that the mTOR signaling pathway is involved in the development of cancer. There are many components in the cancer that are downstream of PBK and upstream of mTORC, including Tscl/2, Lkbl, Pten and B Nfl. Oncogene activation of mTOR can induce growth, survival and proliferation of several cancer cells. A growing body of research points to uncontrolled protein expression associated with mTORCl. Because 4E-BPl/eIF4 downstream of mTORCl plays a key role in tumor formation. 4E-BPl/eIF4 delivers oncogenic signals from Akt for mRNA expression, which leads to the expression of several specific oncogenic proteins, which in turn regulate cell survival, cell cycle, neovascularization, energy metabolism, and tumor metastasis. Also, with mTOR Activation-related ribosome synthesis may be associated with high levels of cell growth. Increased lipid synthesis is an important marker of tumor cell proliferation. This is because new cells need to produce fatty acids to synthesize cell membranes. The PBK signaling pathway activates the lipophilic synthesis factor (SREBP1), which is a signaling factor for PBK activation of SREBP1. At the same time, SREBP1 also drives the expression of some pentose phosphate oxidative components, and the pentose phosphate oxidation pathway controls lipid synthesis and nucleic acid synthesis.

 Continuous activation of PBK/mTORCl signaling can strongly inhibit autophagy. The side effect of inhibiting autophagy on tumor cells is to influence tumor formation by reducing the viability of tumor cells in the absence of nutrients and energy.

 mTORC2 has been shown to control vascular system formation and immune chemotaxis. This suggests that inhibition of mTORC2 can attenuate tumor formation and sustained growth by preventing neovascularization or reducing the invasion of immune cells. In some tumors, high expression of mTORC2 is associated with high expression of its subunit rictor. In mice, the absence of the tumor suppressor gene PTEN leads to an increase in TORC2 function. These results support that mTORC2 plays an important role in tumor formation, and also suggests that reducing mTORC2 activity is likely to be important in anticancer therapy.

Overview

 The present application provides a series of imidazolidone derivatives useful in the preparation of a medicament for the treatment of a protein kinase-associated disease. According to one aspect of the present application, the present application provides a compound represented by Formula I, a pharmaceutically acceptable salt thereof, solvating

其中，

among them,

 A is a monocyclic or bicyclic aryl or heteroaryl group;

 B is a monocyclic aryl or heteroaryl group;

Is 1-5 substituents selected from H; d- ₆ alkyl, d- ₆ alkoxy optionally substituted by one or more groups selected from the group consisting of halogen, cyano, amino, hydroxy and trifluoromethyl a C _{2 -6} alkenyl group or a C _{2 -6} block group; or an optionally substituted saturated or unsaturated monocyclic or bicyclic heterocyclic group containing one or more hetero atoms, the substituent being one or more One selected from R6CO, a group of R6SO ₂ and R^SO, wherein C _1-6 alkyl, monocyclic or bicyclic cycloalkyl optionally substituted with at least one of a hydroxy group, a thiol group, an amino group and a halogen, one or more a heterocyclic monocyclic or bicyclic heterocyclic group, a monocyclic or bicyclic heteroaryl group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms;

R _{2 is} selected from the group consisting of H, C^alkyl, C alkoxy, C^alkenyl or C^ block;

R _{3 is} selected from the group consisting of H, Cw alkyl, Cw alkoxy, Cw alkylamino, and at least one of R ₇ CONR ₈ -, R ₇ S0 ₂ NR ₈ - and R ₆ SON R ₈ -, wherein, and independently selected From 11, d ₆ alkyl, C _{2 -6} alkenyl or C _{2 -6} block;

R4 is at least one group selected from the group consisting of: H; halogen; hydroxy; amino; cyano; d- ₆ alkyl optionally substituted by halogen, d- ₆ alkoxy, C _{2 -6} alkenyl, C ₂ _ ₆ Block base; and a monocyclic or bicyclic aryl or heteroaryl group optionally substituted by halogen.

 X is selected from CH or N

 According to some embodiments of the present application, A in the above formula I is selected from a phenyl group, a pyridyl group, an imidazolyl group or a quinolyl group;

B is selected from pyridyl or imidazolyl.

According to some embodiments of the present disclosure, the above formula I is selected from H; or optionally substituted with one or more groups selected from halo, cyano, amino, hydroxy and trifluoromethyl radicals substituted d_ ₆ alkyl; R ₂ is selected from H, d_ ₆ alkyl group; R ₃ is selected from at least one of H and d_ ₆ alkyl; R4 is at least one selected from the group: H, halo, hydroxy, amino, cyano, optionally a d- ₆ alkyl group substituted by halogen and a monocyclic or bicyclic aryl or heteroaryl group optionally substituted by halogen.

According to some embodiments of the present disclosure, the above formula I is selected from H; or optionally substituted with one or more groups selected from cyano and hydroxy group substituted d_ ₄ alkyl; or optionally substituted saturated or a saturated monocyclic heterocyclic group containing one or more hetero atoms, the substituent being one or more groups selected from the group consisting of R6C0, R6S0 ₂ and R^SO, wherein, selected from a hydroxyl group, a thiol group, a d- ₄ alkyl group substituted with at least one of an amino group and a halogen, a monocyclic heteroaryl group containing one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms.

According to some embodiments of the present application, R _{2 in} formula I is selected from the group consisting of H, CM alkyl, d- ₄ alkoxy, d- ₄ alkylamino, and R ₇ CONR ₈ -, R ₇ S0 ₂ NR ₈ - and R^SONRs At least one of, wherein, 1 ₇ and independently selected from the group consisting of H, C _l ;

According to some embodiments of the present application, in Formula I, R4 is at least one group selected from the group consisting of H, halogen, hydroxy, amino, cyano, d- ₄ alkyl optionally substituted by halogen, and optionally substituted by halogen Monocyclic or bicyclic aryl or heteroaryl.

According to some embodiments of the present application, the above formula I is selected from the group consisting of halogen, cyano, amino, hydroxy, trifluoromethyl substituted CM alkyl; R _{2 is} selected from H, CM alkyl; R _{3 is} selected from H ; a phenyl group selected from H, halogen, d- ₄ alkyl optionally substituted by halogen, phenyl optionally substituted by halogen, pyridyl or imidazolyl.

According to some embodiments of the present application, when selected from a heterocyclic group and the hetero atom is N, the substituent thereon is attached On the nitrogen hetero atom.

According to some embodiments of the present application, in Formula I, selected from the group consisting of d- _3- alkyl substituted by a cyano group.

According to some embodiments of the present application, in Formula I, the alkyl groups in R ₂ , and are independently selected from the group consisting of d- ₃ alkyl, wherein H of the alkyl group is optionally substituted with D.

According to some embodiments of the present application, in Formula I, selected from H _; R4 is at least one group selected from the group consisting of H, halogen, d- ₄ alkyl, phenyl optionally substituted by halogen, pyridyl or imidazolyl .

According to some embodiments of the present application, the above formula I is selected from the group consisting of cyano substituted d- ₃ alkyl; R _{2 is} selected from d- ₃ alkyl; R _{3 is} selected from H; and R4 is at least one group selected from the group consisting of : H, halo, d_ ₃ alkyl, phenyl optionally substituted with halogen, pyridyl or imidazolyl.

 According to another aspect of the present application, the present application provides a compound represented by the formula, a pharmaceutically acceptable salt thereof, a solvate, and more:

C is selected from a monocyclic or bicyclic aromatic or heteroaryl group having from 1 to 3 nitrogen atoms in the ring of the heteroaryl group; preferably selected from a quinolyl group, a pyridyl group or an imidazolyl group;

 D is selected from a saturated or unsaturated mono- or bi-heterocyclic ring containing one or two nitrogen heteroatoms;

R _{2 is} selected from the group consisting of H, C^alkyl, C alkoxy, C^alkenyl or C^ block;

R _{5 is} selected from the group consisting of R ₆ CO, R ₆ SO ₂ or R ^ SO, wherein, selected from the group consisting of a d ₆ alkyl group, a monocyclic or bicyclic cycloalkyl group optionally substituted with at least one of a hydroxy group, a decyl group, an amino group and a halogen, a saturated or unsaturated monocyclic or bicyclic heterocyclic group of a plurality of heteroatoms, a monocyclic or bicyclic heteroaryl group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms; Any of the following groups: H, d- ₆ alkyl (optionally substituted by hydroxy, d- ₆ alkoxy, decyl, amino or halogen), d- ₆ alkoxy, C _{2 -6} alkenyl, C ₂ _ ₆ a saturated or unsaturated monocyclic or bicyclic heterocyclic ring containing one or more heterocyclic atoms selected from nitrogen, oxygen and sulfur atoms, optionally substituted by hydroxy, decyl, amino or halogen. cycloalkyl (optionally substituted by d_ ₆ alkyl, substituted d_ ₆ alkoxy), containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms in the monocyclic or bicyclic heteroaryl (optionally substituted with d_ ₆ Alkyl or d- ₆ alkoxy substituted), d- ₆ alkyl-S0 ₂ NH- _; X is selected from CH or N.

 According to some embodiments of the present application, C in the above formula is selected from the group consisting of quinolyl; D is selected from the following structures

根据本申请的一些实施方式，式 Π中， R₂选自 d_₄烷基；或者， R₅选自 R6CO-、R6S0₂- 或 R^SO-, 其中， 选自任选被羟基、 巯基、 氨基和卤素中至少之一取代的 CM烷基、 含 一个或多个杂原子的饱和单环杂环基或含一个或多个杂原子的单环或双环杂芳基， 所述杂 原子选自氮、 氧或硫原子。

According to some embodiments of the present application, in the formula, R _{2 is} selected from d- ₄ alkyl; or R _{5 is} selected from R6CO-, R6S0 ₂ - or R^SO-, wherein, selected from a hydroxyl group, a thiol group, a CM alkyl group substituted with at least one of an amino group and a halogen, a saturated monocyclic heterocyclic group containing one or more hetero atoms or a monocyclic or bicyclic heteroaryl group having one or more hetero atoms selected from the group consisting of A nitrogen, oxygen or sulfur atom.

According to some embodiments of the present application, in the formula, R _{2 is} selected from d- ₄ alkyl; and R _{5 is} selected from R^CC R^SC^ or R^SO, wherein, selected from hydroxy, decyl, amino and at least one halogen-substituted d_ ₄ alkyl containing one or more hetero atoms or monocyclic or bicyclic heteroaryl, said heteroatoms selected from nitrogen, oxygen and sulfur atoms.

In some embodiments, in Formula II, R ₅ is attached to the N atom on the D ring. According to some embodiments of the present application, R ₂ in the above formula is selected from a methyl group; and R _{5 is} selected from the group consisting of an acetyl group, a hydroxy-substituted acetyl group, a hydroxy-substituted propionyl group, a methylsulfonyl group, and a triazolyl formyl group.

 According to some embodiments of the present application, the C is a quinolinyl group, and it is attached to the parent core in the formula II in the 2- or 3-position.

 According to some embodiments of the present application, the present application provides the following compounds:

2-methyl-2-{4-[3-methyl-2-oxo-8-(6-phenylpyridin-3-yl)-1Η-2,3-dihydroimidazo[4,5- c] quinoline small group] phenyl}propionitrile;

 2-methyl-2-{4-[3-methyl-2-oxo-8-(1-phenyl-1H-pyrazol-4-yl)-1Η-2,3-dihydroimidazo[ 4,5-c]quinolin-1-yl]phenyl}propionitrile;

 2-methyl-2-{4-{3-methyl-2-oxo-8-[6-(3-fluorophenyl)pyridin-3-yl]-1Η-2,3-dihydroimidazolium [4,5-c]quinolin-1-yl]phenyl}propionitrile;

 2-methyl-2-{4-{3-methyl-2-oxo-8-[6-(4-fluorophenyl) B-pyridin-3-yl]-1Η-2,3-dihydro Imidazo[4,5-c]quinolin-1-yl]phenyl}propionitrile;

2-methyl-2-{4-{3-methyl-2-oxo-8-[6-(pyridin-3-yl)pyridin-3-yl]-1Η-2,3-dihydroimidazolium [4,5-c] Quinoline-1-yl}phenyl}propionitrile;

 2-methyl-2-{4-{3-methyl-2-oxo-8-[6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]-1Η- 2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;

 2-methyl-2-{4-{3-methyl-2-oxo-8-[6-(quinolin-3-yl)pyridin-3-yl]-1Η-2,3-dihydroimidazole And [4,5-c]quinolin-1-yl}phenyl}propionitrile;

2-methyl- ₂ -{4-{3-methyl-2-oxo-8-[6-(6-phenylpyridin-3-yl)pyridin-3-yl]-1Η-2,3- Dihydroimidazo[4,5-c]quinolin-1-yl}phenyl)propanenitrile;

 2-methyl-2-{4-{3-methyl-2-oxo-8-[6-(1-phenyl-1-H-pyrazol-4-yl)pyridin-3-yl]- 1Η-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;

 2-methyl-2-{4-{3-methyl-2-oxo-8-{6-[6-(3-fluorophenyl)pyridin-3-yl]pyridin-3-yl}-111 -2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;

 2-methyl-2-{4-{3-methyl-2-oxo-8-{6-[6-(4-fluorophenyl)pyridin-3-yl]pyridin-3-yl}-111 -2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;

 2-methyl-2-{4-{3-methyl-2-oxo-8-{6-[6-(pyridin-3-yl)pyridin-3-yl]pyridin-3-yl}-1 2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;

 2-methyl-2-{4-{3-methyl-2-oxo-8-{6-[6-(pyridin-4-yl)pyridin-3-yl]pyridin-3-yl}-1 2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;

 2-methyl-2-{4-{3-methyl-2-oxo-8-{6-[6-(1-methyl-1-H-pyrazol-4-yl)pyridin-3-yl Pyridin-3-yl}-1Η-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;

 3-methyl-1-[4-(1-acetylpiperidin-4-yl)phenyl]-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline -2 ( 3H)

Ketone

 1-(4-(1-(4Η-1,2,4-triazol-3-carbonyl)piperidin-4-yl)phenyl)-3-methyl-8-(quinolin-3-yl) -1H-imidazo[4,5-c quinolin-2(3H)-one;

 3-methyl-1-{4-[1-(2-hydroxyacetyl)piperidin-4-yl]phenyl}-8-(quinolin-3-yl)-1H-imidazo[4, 5 -c] quinoline-2 (3H)-one;

 3-Methyl small {4-[1-(2-hydroxypropionyl)piperidin-4-yl])-phenyl}-8-(quinolin-3-yl)-1H-imidazo[4, 5 -c] quinoline-2 (3H)-one;

 3-methyl-1-[4-(1-methanesulfonylpiperidin-4-yl)-phenyl]-8-(quinolin-3-yl)-1H-imidazo[4, 5-c] Quinoline-2 (3H)-one;

3-methyl-1-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-8-(quinolin-3-yl)-1H- Imidazole And [4, 5-c]quinoline-2 (3H)-one and its hydrochloride;

 1-(4-(1-(1Η-1,2,4-triazol-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-methyl -8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one and its hydrochloride;

 3-methyl-1-(4-[1-(2-hydroxyacetyl)-1,2,3,6-tetrahydropyridin-4-yl]-phenyl}-8-(quinoline-3- -1H-imidazo[4,5-c]quinolin-2 (3H)-one and its hydrochloride;

 3-methyl-1-(4-[1-(2-hydroxypropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]-phenyl}-8-(quinoline-3- -1H-imidazo[4,5-c]quinolin-2 (3H)-one and its hydrochloride;

 3-methyl-1-(4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-phenyl}-8-(quinolin-3-yl) -1H-imidazo[4,5-c]quinolin-2(3H)-one and its hydrochloride;

 3-Methyl-[4-(8-acetyl-8-azabicyclo[3,2,1]-oct-3-en-3-yl)phenyl]-8-(quinolin-3-yl) -1H-imidazo[4,5-c]quinolin-2(3H)-one and its hydrochloride;

 1-(4-(8-(1Η-1,2,4-triazol-3-carbonyl)-8-azabicyclo[3.2.1]oct-3-en-3-yl)phenyl) - 3-methyl-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one and its hydrochloride;

 3-methyl small {4-[8-(2-hydroxyacetyl)-8-azabicyclo[3,2,1]-oct-3-en-3-yl]phenyl}-8- (quin Benz-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-one and its hydrochloride;

 3-methyl small {4-[8-(2-hydroxypropionyl)-8-azabicyclo[3,2,1]-oct-3-en-3-yl]phenyl}-8- (quin Benz-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-one and its hydrochloride;

 3-methyl-[4-(8-methylsulfonyl-8-azabicyclo[3,2,1]-oct-3-en-3-yl)phenyl]-8-(quinoline-3- -1H-imidazo[4,5-c]quinolin-2(3H)-one and its hydrochloride;

 3-methyl-1-[4-(1-methanesulfonylpiperazin-4-yl)-phenyl]-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quina Porphyrin-2

(3H)-ketone;

 3-methyl-1-[4-(1-methanesulfonylpiperidin-4-yl)-phenyl]-8-[6-(2-methoxyethoxy)pyridin-3-yl]- 1H-imidazo[4,5-c]quinolin-2(3H)-one;

 (^)-^4-0(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(quinolin-3-yl)-1H-imidazo[4,5 -c]quinoline-2(3H)-one

 3-methyl-8-(quinolin-3-yl)-1-(4-(1-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,6-tetrahydropyridine- 4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 1-(4-(1-(Cyclobutylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-methyl-8-(quinolin-3-yl) -1H-imidazo[4,5-c]quinoline-2(3H)-one

1-(4-(1-(3-hydroxy-3-methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-methyl-8- (quin啉-3-yl) -1H-mi Oxazo[4,5-c]quinoline-2(3H)-one

 3-methyl-l-(4-(l-(morpholin-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-8-(quinoline-3- -1H-imidazo[4,5-c]quinoline-2(3H)-one

 1-(4-(4-(4Η-1,2,4-triazol-3-carbonyl)piperazin-1-yl)phenyl)-3-methyl-8-(quinolin-3-yl) -1H-imidazo[4,5-c quinolin-2(3H)-one

 8-(6-(Ethylamino)pyridin-3-yl)-3-methyl-1-(4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)-1H-imidazole [4,5-c] quinoline-2(3H)-one

 1-(4-(1-(4Η-1,2,4-triazol-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-methyl 8-(6-phenylpyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 L-(4-(l-(4H-l,2,4-triazol-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-8-(6 -methoxy-5-methylpyridine

-3-yl)-3-methyl-1H-imidazo[4,5-c]quinoline-2(3H)-one

 (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-0phenyl-1H-pyrazol-4-yl) -1H-imidazo[4,5-c]quinoline-2(3H)-one

 (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-phenylpyridin-3-yl)-1H -imidazo[4,5-c]quinoline-2(3H)-one

 (S)-8-([2,3'-dipyridyl]-5-yl)-1-(4-(1-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3 -methyl-1H-imidazo[4,5-c]quinoline-2(3H)-one

 (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-8-(6-methoxy-5-methylpyridin-3-yl)- 3-methyl-1H-imidazo[4,5-c]quinoline-2(3H)-one

 (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazole) 4-yl)B-pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 1-(4-(1-(2-hydroxyacetyl)piperidin-3-yl)phenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazole-4- Pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl) B-pyridin-3-yl)-1-(4-(1-(methylsulfonyl)piperidine- 3-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 1-(4-(1-(4Η-1,2,4-triazol-3-carbonyl)piperidin-3-yl)phenyl-3-methyl-8-(6-(1-methyl) -1H-pyrazol-4-yl)oxidin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 L-(4-(l-((R)-2-hydroxypropanoyl)piperidin-3-yl)phenyl-3-methyl-8-(6-(1-methyl-1H-pyrazole- 4-yl)B-pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

L-(4-(l-((S)-2-hydroxypropanoyl)piperidin-3-yl)phenyl-3-methyl-8-(6-(1-methyl-1H-pyrazole- 4-base) B is pyridine-3- -1H-imidazo[4,5-c]quinoline-2(3H)-one

 L-(4-(l-ethylpiperidin-3-yl)phenyl-3-methyl-8-(6-(l-methyl-1H-pyrazol-4-yl) B-pyridin-3 -yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl) B-pyridin-3-yl)-1-(4-(1-(methylsulfonyl)piperidine- 4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 1-(4-(1-(2-hydroxyacetyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazole-4- Pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 1-(4-(1-(1Η-1,2,4-triazol-3-carbonyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-(1-A) -1H-pyrazol-4-yl)oxidin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 3-ethyl-1-(4-(1-(2-hydroxyacetyl)piperidin-4-yl)phenyl)-8-(6-(1-methyl-1H-pyrazol-4-yl) Pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 3-ethyl-8-(6-(1-methyl-1H-pyrazol-4-yl) B-pyridin-3-yl)-1-(4-(1-(methylsulfonyl)piperidine- 4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 1-(4-(1-(4Η-1,2,4-triazol-3-carbonyl)piperidin-4-yl)phenyl)-3-ethyl-8-(6-(1-A) -1H-pyrazol-4-yl)oxidin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(1Η-pyrrolo[3,2-b]pyridine -6-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

(S)-N-(5-(l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-2-oxo-2,3- dihydro -1H- imidazo ^[4, 5-c] quinolin-8-yl) - ² - methyl-pyridin-3-yl) methanesulfonamide

 3-deuterated methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1 -(4-(1-(methylsulfonyl))piperidine 4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 2-methyl-2-(4-(3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl) B-pyridin-3-yl)-2-oxo- 2,3-Dihydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)phenyl)-propanenitrile

 (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(4-methyl-6-(1Η-1, 2,4-triazol-3-yl)oxapyridin-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-one;

 (S)-8-(6-(2-hydroxypropan-2-yl) B-pyridin-3-yl)-1-(4-(1-(2-hydroxypropionyl)piperidin-4-yl) Phenyl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-one;

 (S)-l-(4-00hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-GH-pyrrolo[3,2-b]pyridine-6-yl) - 1H-imidazo[4,5-c]quinoline-2(3H)-one;

(S)-N-(5-(l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-2-oxo-2,3- Dihydro-1H-imidazo[4,5-c Quinoline-8-yl)-2-methylpyridin-3-yl)methanesulfonamide;

 (S)-l-(4-(l-(2-Hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(1-phenyl-1H-pyrazole-4- -1H-imidazo[4,5-c]quinoline-2(3H)-one;

 (S)-l-(4-(l-(2-Hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(1-(pyridin-3-yl)-1H- Pyrazol-4-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one;

 (S)-8-(l-(3-fluorophenyl)-1H-pyrazol-4-yl)-1-(4-(1-(2-hydroxypropionyl)piperidin-4-yl)benzene 3-methyl-1H-imidazo[4,5-c]quinoline-2(3H)-one;

 (S)-l-(4-(l-(2-Hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-phenylpyridin-3-yl)-1H -imidazo[4,5-c]quinoline-2(3H)-one;

 (S)-8-([2,3'-bipyridyl]-5-yl)-1-(4-(1-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3- Methyl-1H-imidazo[4,5-c]quinoline-2(3H)-one;

 (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazole) 4-yl)pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one;

 (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-8-(6-methoxy-5-methylpyridin-3-yl)- 3-methyl-1H-imidazo[4,5-c]quinoline-2(3H)-one;

 (S)- 1 -(4-(1-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-(tetrahydro-2H-pyran-4) -yl)pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one;

 (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-8-(6-(2-methoxyethoxy) B-pyridin-3 -yl)-3-methyl-1H-imidazo[4,5-c]quinoline-2(3H)-one;

 4-(4-(3-methyl-2-oxo-8-(1-phenyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-imidazo[4,5- c]quinolin-1-yl)phenyl)piperidine-1-carbaldehyde.

 According to some embodiments of the present application, the above compounds of the present application further include any one or more compounds in which H is substituted with the corresponding isotope D and / or T.

According to still another aspect of the present application, the present application provides a pharmaceutical composition comprising a compound described herein, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier . Such pharmaceutical compositions include, but are not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal administration dosage forms. In some embodiments, the pharmaceutical composition may be an oral tablet, a capsule, a pill, a powder, a sustained release preparation, a solution and a suspension, a sterile solution, suspension or emulsion for parenteral injection. A topical ointment or cream, or a suppository for rectal administration. In other embodiments, the pharmaceutical composition is in a unit dosage form suitable for single administration of precise dosages. In other embodiments, the amount of the compound ranges from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day. In other embodiments, the amount of the compound ranges from about 0.5 mg/kg body weight/day to about 50 mg/kg body weight/day. In some embodiments, the amount of the compound is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound is from about 0.005 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.01 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound is from about 0.1 g/day to about 1 g/day. In other embodiments, a dose level below the lower limit of the above range may already be sufficient. In other embodiments, dose levels above the upper limit of the above range may be required. In some embodiments, the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses more than once a day. In some embodiments, the compound is administered twice daily. In other embodiments, the compound is administered three times a day. In other embodiments, the compound is administered four times a day. In other embodiments, the compound is administered more than four times a day. In some embodiments, the individual to which the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human. In other embodiments, the pharmaceutical composition further comprises at least one therapeutic agent (ie, made into a dosage form). In some embodiments, the pharmaceutical composition and the at least one therapeutic agent are each combined into a combined product (separate dosage form) in separate dosage forms.

 According to another aspect of the present application, the present application is also directed to a compound, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof thereof, which includes any one or more Hs by a corresponding isotope D, The T-substituted compound) is used in the preparation of a medicament for inhibiting one, two or more of mTOR, PBK kinase, S6 protein kinase and Akt protein kinase.

 According to a further aspect of the present application, the present application also relates to the preparation of a compound, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof for the prophylaxis and treatment of mTOR, PBK kinase, S6 protein kinase and Akt protein The use of a drug in one, two or more related diseases of a kinase.

According to still another aspect of the present application, the compound of the present application, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, is for use in inhibiting one, two of mTOR, PBK kinase, S6 protein kinase and Akt protein kinase Kind or more. It can be used to treat tumors; to treat metabolic diseases; or to treat cardiovascular diseases. According to another aspect of the present application, the present application provides a method of modulating protein kinase activity (eg, inhibiting protein kinase activity), comprising the protein kinase and the above compound or a pharmaceutically acceptable salt, solvate thereof, polymorph thereof Contact with the drug or prodrug. This method can be used in vivo as well as in vitro. Preferably, the protein kinase is selected from at least one of mTOR, PBK, S6 and Akt. According to another aspect of the present application, the present application provides a method of treating a disease associated with protein kinase activity, the method comprising administering the above compound or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof Apply to individuals with this need. According to still another aspect of the present application, the present application provides a method of treating a disease associated with protein kinase activity, the method comprising administering the above compound or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof At least one therapeutic agent is administered in combination to an individual in need thereof.

 According to some embodiments of the present application, the disease associated with protein kinase activity described in the present application may be a tumor, such as leukemia, malignant lymphoma, multiple myeloma, gastrointestinal stromal tumor, colon cancer, rectal cancer, Breast cancer, liver cancer, gastric cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, choriocarcinoma, lung cancer, kidney cancer, prostate cancer, bladder cancer, pancreatic cancer, glioma, mast cell tumor, brain tumor, Germ cell tumors, melanoma, sarcoma, including dermatofibrosarcoma, osteosarcoma. The diseases associated with protein kinase activity described in the present application may also be metabolic diseases (e.g., diabetes and obesity) and cardiovascular diseases (e.g., atherosclerosis). Detailed

 The claims of the present application particularly set forth the novel features of the present application. Exemplary embodiments utilizing the principles of the present application are set forth in the detailed description which follows. The features and advantages of the present application will be better understood by reference to the following.

 Although preferred embodiments of the present application are described herein, these embodiments are provided by way of example only. It will be appreciated that variations of the embodiments of the invention described herein may also be used in the practice of the application. It will be appreciated by those skilled in the art that various modifications, changes and substitutions may be made without departing from the scope of the application. It is to be understood that the scope of the present invention is defined by the scope of the claims, and the scope of the claims and the equivalents thereof.

 The section headings used herein are for the purpose of organizing articles only and are not to be construed as limiting the subject matter. All documents or parts of the literature cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are hereby incorporated by reference in their entirety. Certain chemical terms

 Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety herein in their entirety herein

The above description and the following detailed description are to be considered as illustrative and not restrictive. In the present application, the use of the singular includes the plural unless otherwise specified. Also note that unless otherwise Description, otherwise use "or", "or" to mean "and / or". In addition, the terms "comprising" and "including", "include", "include", and "include" are used as a non-limiting description.

The definition of standard chemical terms can be found in references such as Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 ^th ED." Vols. A (2000) and B (2001), Plenum Press, New York. Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy and pharmacological methods, are employed unless otherwise indicated. Unless specifically defined, the terms used herein in relation to analytical chemistry, organic synthetic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or the reaction and purification can be carried out in a manner well known in the art or as described in the present application. The above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification. In the present specification, a group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, CH ₂ 0 is equivalent to OCH ₂ .

 Unless otherwise indicated, the general chemical terms used, such as but not limited to, "alkyl", "amine", "aryl", etc., are used in the form of their optional substitution. For example, "mercapto" as used herein includes an optionally substituted alkyl group.

As used herein, "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes. The compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present application containing asymmetrically substituted carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by the use of chiral starting materials or chiral reagents. The compounds of the present application also include tautomeric forms. The tautomeric form is derived from the exchange of a single bond with an adjacent double bond and accompanied by a proton transfer. The compounds of the present application also include atoms of all isotopes, whether in the intermediate or the final compound. The atoms of an isotope include the same number of atoms, but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium. That is, the compound of the present application includes a compound in which part or all of hydrogen (H) is replaced by ruthenium (T) and/or ruthenium (D); and some or all of ¹² C is replaced by ¹³ C and/or ¹⁴ C Compounds; and alternative compounds between other isotopes (such as N, 0, P, S), such as ¹⁴ N and ¹⁵ N; ¹⁸ 0 and ¹⁷ 0; ³¹ P and ³² P; ³⁵ S and ³⁶ S, and the like. The compounds described herein may have one or more stereoisomeric centers, and each isomeric center may exist in the R or S configuration or a combination thereof. Similarly, the compounds described herein can have one or more double bonds, and each double bond can exist in an E (trans) or Z (cis) configuration, or a combination thereof. a specific stereoisomer, regioisomer, diastereomer, enantiomer or epimer It is to be understood to include all possible isomers such as stereoisomers, structural isomers, diastereomers, enantiomers or epimers, and mixtures thereof. Thus, the compounds described herein include all stereoisomers, structural isomers, diastereomers, enantiomers or epimeric forms, and corresponding mixtures thereof, which are different in configuration. Techniques for transforming a particular stereoisomer or retaining a particular stereoisomer, as well as techniques for resolving a mixture of stereoisomers, are well known in the art, and those skilled in the art will be able to select a suitable method for the particular situation. See, for example, Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; and Heller, Acc. Chem. Res. 1990, 23, 128. The term "optional/arbitrary" or "optionally/arbitrarily" means that the subsequently described event or circumstance may or may not occur, the description including the occurrence of the event or circumstance and the occurrence of the event or circumstance. For example, according to the definition below, "optionally substituted alkyl" means "unsubstituted alkyl" (alkyl substituted without a substituent) or "substituted alkyl" (alkyl substituted with a substituent) .

dC _n as used herein includes dC ₂ , dC ₃ , . . . . . . dC _n . For example, the "dC^ group means that the moiety has from 1 to 4 carbon atoms, that is, the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Therefore, By way of example, "dC ₄ alkyl" refers to an alkyl group having from 1 to 4 carbon atoms, ie, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl , sec-butyl and tert-butyl. The numerical ranges herein, such as "1-10", refer to each integer in a given range, for example "1-10 carbon atoms" means that the group can have 1 carbon Atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched aliphatic hydrocarbon. The "mercapto" herein may preferably have from 1 to about 20 carbon atoms, for example from 1 to about 10 carbon atoms, from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms, or from 1 to about 4. One carbon atom or from 1 to about 3 carbon atoms. Examples of alkyl groups herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1 -butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethylpropyl, 2-methyl-amyl, 3-methyl-1- Pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl -1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso Pentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups such as heptyl and octyl. A group as defined herein, such as "alkyl" when a numerical range is present, such as "dC ₆ alkyl" or "d- ₆ alkyl" means 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 An alkyl group consisting of 5 carbon atoms or 6 carbon atoms. The alkyl group herein also contains an unspecified number. The scope of the word range. As used herein, "alkyl" includes alkyl groups bonded to other groups, such as alkyl groups in alkoxy groups, alkyl groups in alkylthio groups, hydroxyalkyl groups, haloalkyl groups, cyanoalkyl groups, alkylamino groups ( Such as "monoalkylamino", "dialkylamino" in the "fluorenyl" and the like. The term "alkylamino" as used herein, alone or in combination, means alkylamino (-HN-alkyl (δΡ, monoalkylamino) or -N-(alkyl) ₂ (ie, dialkylamino). The definition of alkyl is as described above.

 The term "decyloxy" as used herein, alone or in combination, refers to an alkyl ether group (0-alkyl), and non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropyl Oxyl, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched monovalent hydrocarbon radical having one or more C=C double bonds. The alkenyl group has, but is not limited to, from 2 to about 18 carbon atoms, for example, from 2 to about 10 carbon atoms, or from 2 to about 8 carbon atoms, from 2 to about 6 carbon atoms, from 2 to 4 carbon atom. The double bond in these groups may be in the cis or trans conformation and should be understood to include both isomers. Examples include, but are not limited to, vinyl (CH=CH ₂ ), 1-propenyl (CH ₂ CH=CH ₂ ), isopropenyl (C(CH ₃ )=CH ₂ ), butenyl, and 1,3- Butadienyl and the like. When an alkenyl group as defined herein appears in the numerical range, for example "C ₂ -C ₆ alkenyl" or "C ₂ - ₆ alkenyl" means 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbons An alkenyl group consisting of an atom or 6 carbon atoms, and the alkenyl group herein also covers the case where the numerical range is not specified.

The term "block group" as used herein, alone or in combination, refers to an optionally substituted straight or branched chain monovalent hydrocarbon group having one or more C≡C triple bonds. The block group has, but is not limited to, 2 to about 18 carbon atoms, for example, it has 2 to about 10 carbon atoms, or has 2 to about 8 carbon atoms, or 2 to about 6 carbon atoms, or 2 to about 4 carbon atoms. Block-based embodiments herein include, but are not limited to, an E-block group, a 2-propyl block group, a 2-butyl block group, a 1,3-butane block group, and the like. When a block number as defined herein appears in the numerical range, for example "C ₂ -C ₆ block group" or "C ₂ - ₆ block group" means 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbons A block group consisting of an atom or 6 carbon atoms, the block base of this article also covers the case of an unspecified number range. The term "halo" or "halogen-substituted" as used herein, alone or in combination, means that one or more hydrogen atoms of an optionally substituted group (eg, alkyl, alkenyl, and block) are replaced with fluorine, chlorine. , bromine, iodine atoms or a combination thereof. In some embodiments, two or more hydrogen atoms (eg, difluoromethyl, trifluoromethyl) are replaced with the same halogen atom as each other; in other embodiments, two are replaced with halogen atoms that are not identical to each other. Or a plurality of hydrogen atoms (for example, 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examples of haloalkyl groups are fluoromethyl and bromoethyl. A non-limiting example of a haloalkenyl group is a bromovinyl group. A non-limiting example of a halo block is a chloroethyl block. The term "aryl/aryl" as used herein, alone or in combination, refers to an optionally substituted aromatic hydrocarbon radical having from 6 to about 20, such as from 6 to 12 or from 6 to 10 ring-forming carbon atoms. It may be a fused aromatic ring or a non-fused aromatic ring. The fused aromatic ring contains 2-4 aromatic ring fused rings, and the other independent ring may be an alicyclic ring, a heterocyclic ring, an aromatic ring, an aromatic heterocyclic ring or any combination thereof. The aryl group herein includes a monocyclic, bicyclic, tricyclic or more cyclic aryl group. Non-limiting examples of monocyclic aryl groups include from 6 to about 12, from 6 to about 10 or from 6 to about 8 monocyclic aryl groups of a ring-forming carbon atom, such as phenyl; fused ring aryl groups include bicyclic rings, A tricyclic or more cyclic aryl group such as a naphthyl group, a phenanthryl group, an anthracenyl group, an oxa group; a non-fused bisaryl group including a biphenyl group. The term "heteroaryl" as used herein, alone or in combination, refers to an optionally substituted monovalent heteroaryl group containing from about 5 to about 20, such as from 5 to 12 or from 5 to 10 backbones, wherein one or one a plurality of (eg, 1-4, 1-3, 1-2) ring-forming atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. Atom, but not limited to this. The ring of the group does not contain two adjacent 0 or S atoms. Heteroaryl groups include monocyclic heteroaryl or polycyclic heteroaryl (e.g., bicyclic heteroaryl, tricyclic heteroaryl, etc.). In embodiments in which two or more heteroatoms are present in the ring, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other. The term heteroaryl includes an optionally substituted monovalent fused or non-fused heteroaryl having at least one hetero atom. Furthermore, the term heteroaryl also includes fused and non-fused heteroaryl groups containing from 5 to about 12 backbone-forming ring atoms, and fused and non-fused, containing from 5 to about 10 backbone-forming ring atoms. Heteroaryl. It can be bonded to a heteroaryl group through a carbon atom or a hetero atom. Thus, for example, an imidazole may be passed through any of its carbon atoms (; imidazol-2-yl, imidazol-4-yl or imidazol-5-yl) or its nitrogen atom (imidazolyl- or imidazol-3-yl) The parent molecules are connected. Similarly, a heteroaryl group can be further substituted by any or all of its carbon atoms and/or any or all of the heteroatoms. The fused heteroaryl group may contain 2-4 aromatic heterocyclic fused fused rings, and the other independent ring may be an alicyclic ring, a heterocyclic ring, an aromatic ring, an aromatic heterocyclic ring or any combination thereof. Non-limiting examples of monocyclic heteroaryl groups include from 5 to about 12, from 5 to about 10, from 5 to about 7 or 6 monocyclic heteroaryl groups which are backbone-ringed, for example, non-limiting examples thereof include pyridyl; fused ring heteroaryl groups include benzimidazolyl (benzimida _Z olyl), quinolyl (quinolinyl), acridinyl (acridinyl), non-fused heteroaryl groups include bis-dipyridyl (bipyridinyl) . Other examples of heteroaryl groups include, but are not limited to: pyridine, pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, imidazole, triazole, tetrazole, thiazole, isothiazole, 1,2,4-thiadiene Azole, pyrrole, pyrazole, oxazole, isoxazole, oxadiazole, benzofuran, benzothiophene, benzothiazole, hydrazine, carbazole, quinoline, isoquinoline, hydrazine, carbazole, benzo Imidazole, pyrrolopyridine, pyrrolopyrimidine, pyrazolopyridine, pyrazolopyrimidine and the like. Acridinyl, phenazinyl, benzoxazolyl, benzothiadiazolyl, benzoxazodiazolyl, benzotriazolyl, isoquinolyl, indolizinyl, isothiazolyl ( Isothiazolyl), isoindolyl, oxadiazolyl, purinyl, phthalazinyl, pteridinyl quinazolinyl, quinoxaline Quinoxalinyl, triazinyl, and thiadiazolyl (thiadiazolyl) and the like, and oxides thereof, such as pyridyl-N-oxide. The term "heterocycle" or "heterocyclyl" as used herein, alone or in combination, refers to a non-aromatic heterocycle, including heterocycloalkyl (saturated heterocyclyl) and heterocycloalkenyl (unsaturated heterocyclyl). One or more (e.g., 1-4, 1-3, 1-2) ring-forming atoms are heteroatoms such as oxygen, nitrogen or sulfur atoms. The heterocyclic group may include a monocyclic heterocyclic group (heterocyclic group having one ring) or a polycyclic heterocyclic group (for example, a bicyclic heterocyclic group (heterocyclic group having two rings), a tricyclic heterocyclic group, etc.). The bicyclic heterocyclic group may be a spiro ring or a bridged ring. Heterocyclyl groups can have from 3 to about 20, such as from 3 to about 10, from 3 to about 8, from 5 to about 8, or from 5 to about 6 ring atoms. Non-limiting examples of heterocyclic groups include a _Z inyl, azetidinyl oxetanyl, thietanyl, homopiperidinyl. (homopiperidinyl), oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl (1,2,3,6-tetrahydropyridinyl), 2-pyrrolinyl , 3-pyrrolinyl, indolinyl 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl ), dihydrothienyl, dihydrofuranyl pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl (3-azabicyclo[3.1.0]hexyl), 3-azabicyclo[4.1.0]heptyl (3-azabicyclo[4.1.0]heptyl) 3H-indolyl and quinolinyl ( Quinolizinyl) . The term also encompasses all cyclic forms of saccharides including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Examples include, but are not limited to, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, isoxazolidine, isothiazolidine, pyrazolidine, morpholine, thio Porphyrin, piperazine, piperidinyl and the like. Heterocyclyl also includes heterocycles having one or more aromatic rings fused (ie, having a common bond), such as 2,3-dihydrobenzofuran, 1,3-benzodioxolane, benzo -1,4-dioxane, phthalimide, naphthalimide. The heterocyclic group having one or more aromatic condensations may be bonded to other groups through an aromatic ring or a non-aromatic ring moiety. Other groups may be bonded to the heterocycle via a heteroatom or a carbon atom (ie, the heterocycle is attached or further substituted with the parent molecule).

The term "cycloalkyl" as used herein, alone or in combination, refers to a non-aromatic carbocyclic ring, including cycloalkyl and cycloalkenyl. The cycloalkyl group may be a monocyclic cycloalkyl group or a polycyclic cycloalkyl group (for example, having 2, 3 or 4 rings; such as a bicyclic cycloalkyl group), which may be a spiro ring or a bridged ring. The cycloalkyl group may have 3 to 20 carbon atoms, for example, having 3 to about 15 ring-forming carbon atoms or 3 to about 10 ring-forming carbon atoms or 3 to 6 ring-forming carbon atoms, and may have 0, 1, 2 Or 3 double keys and / or 0, 1 or 2 triple keys. For example, a cycloalkyl group having 3-8 or 3-6 ring-forming carbon atoms (e.g., a saturated monocyclic cycloalkyl group). The cycloalkyl group also includes a ring having one or more aromatic rings fused (i.e., having a common bond), for example, a benzo derivative substituted pentane, pentene, hexane, or the like. One or more aromatic fused cycloalkyl groups may be attached to the other groups through an aromatic ring or a moiety other than the aromatic ring. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclopentenyl group, a cyclohexadienyl group, a cycloheptatrienyl group, an adamantyl group and the like.

"Halogen" means fluorine, chlorine, bromine, and iodine. The preferred choices are fluorine, chlorine and bromine. Cyano refers to "-CN"; hydroxy means "-OH"; thiol means "-SH"; amino means "-NH ₂ ".

 The term "substituted" means that one or more hydrogens are replaced by a specified group on a particular atom. If the normal valence of the specified atom is not exceeded in the existing case, the result of the substitution is one. A stable compound.

 Certain pharmacy terms

 Certain pharmacy terms as used herein with respect to the terms "subject," "patient," or "individual" refers to an individual, including a mammal, and a non-mammal, having a disease, disorder, condition, or the like. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; Animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

 The term "treatment" and other similar synonyms as used herein includes alleviating, alleviating or ameliorating the symptoms of a disease or condition, inhibiting a disease or condition, such as preventing the progression of a disease or condition, alleviating a disease or condition, improving the disease or condition, and alleviating the disease. Or the symptoms caused by the condition, or the symptoms of the disease or condition are stopped, other symptoms are prevented, and the potential metabolic causes of the symptoms are improved or prevented. In addition, the term includes the purpose of prevention. The term also includes obtaining a therapeutic effect and/or a preventive effect. The therapeutic effect refers to curing or ameliorating the underlying disease to be treated. In addition, the healing or amelioration of one or more physiological symptoms associated with a underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, an improvement in the patient's condition is observed. In terms of prophylactic effect, the composition can be administered to a patient at risk for a particular disease, or even if a diagnosis of the disease has not been made, the composition is administered to a patient having one or more physiological symptoms of the disease.

 The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount," as used herein, refers to at least one active substance that is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent after administration ( The amount of the compound as in the present application). The result can be a reduction and/or relief of signs, symptoms or causes, or any other desired change in the biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic. An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.

The terms "administering,""administering,""administering," and the like, as used herein, refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including Intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. The techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa.

 The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that there is no long-term detrimental effect on the general health of the subject being treated.

 The term "pharmaceutically acceptable" as used herein, refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable biological reactions. Or interacting with any of the components contained in the composition in a poor manner.

 The term "pharmaceutical composition" as used herein refers to a mixture of a compound of the present application and at least one pharmaceutically acceptable substance. The pharmaceutically acceptable substances include, but are not limited to, carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.

 The term "carrier" as used herein refers to a relatively non-toxic material that facilitates the introduction of a compound of the present application into a cell or tissue.

The term "pharmaceutically acceptable salt" as used herein, refers to a salt which retains the biological effectiveness of the free acid and free base of the specified compound, and which has no adverse effects biologically or otherwise. The compounds of the present application also include pharmaceutically acceptable salts. A pharmaceutically acceptable salt refers to a form in which a base group in a parent compound is converted into a salt. Pharmaceutically acceptable salts include, but are not limited to, base or inorganic or organic acid salts of amine (amino) groups. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound, i.e., the basic group in the parent compound is reacted with from 1 to 4 equivalents of acid in a solvent system. Suitable salts bad lj held in ^{Remingtong's Pharmaceutical Scicences, 17 th ed} ., Mack Publishing Company, Easton, Pa., 1985, p. 1418 Hekou Journal of Pharmaceutical Science, 66, 2 (1977) in.

 The salt in the present application means an acid salt formed with an organic acid/inorganic acid, and a basic salt formed with an organic base/inorganic base, unless otherwise specified. In addition, when the basic functional group of the compound of the formula is pyridine or imidazole (but not limited to pyridine or imidazole), the acidic functional group is a carboxylic acid (but not limited to a carboxylic acid), and a zwitterion (internal salt) is formed, the inner salt Also included in the salt in this application.

The term "solvate" as used herein refers to a combination of a compound of the present application and a solvent molecule formed by solvation. In some cases, a solvate refers to a hydrate, i.e., the solvent molecule is a water molecule, and the combination of the compound of the present application and water forms a hydrate. One or more compounds in the present application may exist in the form of a solvate, as in the form of a solvate formed with a pharmaceutically acceptable solvent such as water or ethanol. Thus, the present application includes both solvates and unsolvates. Two forms. "Solvate" refers to a physical agglomerate of a compound of the present application formed with one or more solvent molecules comprising varying degrees of ionic and covalent bonds, such as hydrogen bonds. This solvate has been confirmed to be isolated, for example, when one or more solvent molecules are mixed in the crystal lattice of the crystal. "Solvate" includes both a solvent phase and a separable solvate. There are many examples of corresponding solvates, including ethanol solvates, methanol solvates, and the like. "Hydrate" is a solvate with a water (H ₂ 0) molecule as a solvent.

 One or more compounds of the present application can be prepared as solvates at will. The preparation of solvates is well known. The preparation of the solvate of the antifungal fluconazole, i.e., prepared with ethyl acetate and water, is described, for example, in M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004). EC van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); 卩 AL Bingham et al, Chem. Commun., 603-604 (2001) also describe similar solvates, hydrates Preparation. A typical, non-limiting preparation process is to dissolve the applied compound in a desired amount of an ideal solvent (organic solvent or water or a mixed solvent thereof) at a temperature higher than normal temperature, to cool down, to deposit crystallization, The crystals are then separated by standard methods. The presence of a solvent (water) which forms a solvate (hydrate) in the crystal can be confirmed by I.R. spectroscopy.

 The term "polymorph" or "polymorph" as used herein, refers to a compound of the present application that exists in a different lattice form. The term "pharmaceutically acceptable prodrug" as used herein, refers to any pharmaceutically acceptable salt, ester, ester salt or other derivative of a compound of the present application which is capable of providing the present application, either directly or indirectly, after administration to a recipient. a compound or a pharmaceutically active metabolite or residue thereof. Particularly preferred prodrugs are those compounds which, when administered to a patient, increase the bioavailability of the compounds of the present application (for example, may render the orally administered compound more readily absorbed into the blood), or promote the parent compound to the biological organ or site of action. Those compounds delivered (eg, brain or lymphatic system).

 Various prodrug forms are well known in the art. See, Pro-drugs as by T. Higuchi and V. Stella

Novel Delivery Systems (1987) Vol. 14 of the A.C.S. Symposium Series, Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and the Pergamon Press provide a discussion of prodrugs. Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al, Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, pages 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, the above references are incorporated herein by reference.

The terms "administered in combination,""administered in combination with," and the like, and the like, are intended to mean the administration of a selected therapeutic agent to the same patient, and are intended to encompass the same or different routes of administration or the same or different. The number of doses to administer the therapeutic strategy of the agent. In some embodiments, the compounds described herein are administered in combination with other agents. These terms cover Two or more agents are administered to the animal such that the agent and/or its metabolite are present simultaneously in the animal. These terms include the simultaneous administration of different compositions, the administration of different compositions at different times and/or the application of a composition containing different active ingredients. Thus, in some embodiments, a compound of the invention and other agents are administered in a single composition. It is worth noting that any of the carbon, and heteroatoms in the text, routes, examples, and tables in this patent that do not satisfy the valence principle are assumed to contain a sufficient number of hydrogen atoms to satisfy the valence principle. The compounds of formula I and formulae may exist in different tautomeric forms, and such forms are embraced within the scope of the present application. For example, compounds in the form of keto-enol and imine-enamine.

The present application also includes isotopically labeled compounds, but in fact, it is common for one or more atoms to be replaced by an atom of a different atomic mass or mass number in nature. The isotopes included in the compounds of the present application include H, C, N, 0, P, F, S, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ 0, ¹⁷ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ S.

detailed description

The LC-MS analysis conditions during the synthesis were as follows:

Instrument: Agilent LCMS 1260/MSD6120

Column: Agilent SB-C18, 2.1*50mm, 1.8 μm, SN: USWEY07289

Mobile phase: A : H20 (0.1%FA) 90%, B: ACN 10%, 0.400 mL/min, 45.00 ° C

Timetable

Time function parameter

 2.24 Change solvent composition Solvent component A: 0.0 % B: 100.0 %

 3.00 Change solvent composition Solvent component A: 0.0 % B: 100.0 %

3.01 Change Flow Flow: 0.5 mL/min

 3.01 Change solvent component Solvent component A: 90.0 % B: 10.0 %

 5.00 Change solvent component Solvent component A: 90.0 % B: 10.0 %

 5.01 Change Flow Rate: 0.4 mL/min

 5.01 Change solvent component Solvent component A: 90.0 % B: 10.0 %

Instrument parameters:

Ionization mode : API-ES

Polarity : Positive

Collision induced dissociation step: disabled

Cycle time percentage: 50.00 % synthetic route

(1) Route

Synthesis of intermediate 1:

 Mix 70 g of ice and 32 g of NaOH, slowly add 15.4 ml of nitromethane with stirring, and stir at 0 °C for 1 h. Then pour it into 70 g of ice and 72 ml of 37% HCl mixture for later use. Add 50 g of 2-amino-5-bromobenzoic acid to a 2000 ml single-necked flask, stir in 300 ml of water, 300 ml of acetone, add the stock solution, react at room temperature, and monitor by TLC. After the reaction is completed, the solution is filtered and drained. The yellow solid intermediate 1 50.25 g, yield 76%. Synthesis of intermediate 2:

50.25 g (0.175 mol) of intermediate 1 was placed in a 500 ml one-necked flask, 250 ml of acetic anhydride was added, the temperature was raised to 60 ° C, and 18.2 g (0.23 mol) of potassium acetate was added. The temperature was raised to 110 ° C and monitored by TLC. After 4 h, it was cooled to room temperature, filtered and washed with EtOAc EtOAc. Synthesis of Intermediate 3:

 26.8 g (99 mmol) of intermediate 2 was placed in a 500 ml single-necked flask, 200 ml of phosphorus oxychloride was added, and refluxed at 120 ° C for 1 h, and monitored by TLC. After the reaction is completed, it is poured into a large amount of ice water, and a precipitate is precipitated by stirring. After filtration, the filter cake was washed with ice water and dissolved in dichloromethane. The organic phase was washed three times with brine, dried over anhydrous magnesium sulfate Synthesis of intermediate 4:

20 g (0.12 mol) of 4-nitrophenylacetonitrile, 2.2 g (7.4 mmol) of TBAB, and mixed with 21 mL (0.396 mol) of methyl iodide and 174 ml of dichloromethane in a 500 mL one-necked flask. The solution was slowly added with 168 mL of sodium hydroxide ( 1.96 mol/L) solution. After stirring at room temperature for 4 h, the reaction mixture was evaporated. EtOAcjjjjjjjjjjjj , V: V) Intermediate 15.57 g, yield 66%. 1H NMR (400MHz, CDC1 ₃ ) δ: 1.77 (s, 6H, -CH3x2), 7.66-7.68 (d, 2H, J=8.9Hz, -ArHx2), 8.24-8.26 (d, 2H, J=8.9 Hz, -ArHx2); ¹³ CNMR (100 MHz, CDC1 ₃ ) δ: 28.6, 37.2, 123.1, 123.9, 126.2, 147.1, 148.2. Synthesis of intermediate 5:

22 g (0.115 mol) of intermediate 4 was dissolved in 300 ml of absolute ethanol, followed by 19.48 g (0.35 mol) of iron powder, 37.2 g of O.694 mol) ammonium chloride solution (37.2 g of ammonium chloride / 40 ml). Water), refluxing at 120 °C for 6 h, hot-cold filtration, hot ethanol washing, water, methylene chloride extraction, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. Deliquoring: ethyl acetate/petroleum ether = 1: 10, V: V), mp. 1H NMR (400 MHz, CDC1 ₃ ) δ: 1.67 (s, 6H, -CH3x2), 3.71 (s, 2H, -NH2), 6.67-6.68 (d, 2H, J = 6.8 Hz, -ArHx2), 7.23- 7.24 (d, 2H, J = 7.2 Hz, -ArHx2); ¹³ C NMR (100 MHz, CDC1 ₃ ) δ: 28.9, 36.0, 114.9, 124.9, 125.8, 130.7, 145.9. Synthesis of intermediate 6:

12 g (75 mmol) of intermediate 5 was dissolved in 300 ml of glacial acetic acid, and 13 g (45.2 mmol) of intermediate 3 was slowly added. The reaction was carried out for 2 h at room temperature. A large amount of water was added, and a yellow solid was precipitated, filtered and washed with water to obtain yellow. Solid intermediate 6 16.81 g, yield 90% 1H NMR (400 MHz, CDC1 ₃ ) δ: 1.76 (s, 6H, -CH3x2), 7.17-7.19 (d, 2H, J=8 Hz, -ArHx2),

7.52-7.54 (d, 2H, J=8 Hz, -ArHx2), 7.62 (s, 1H, -NH), 7.73-7.75 (d, 1H, J=8.8Hz, -ArH), 7.86-7.89 (d, 1H, J=8.8Hz, -ArH), 9.44 (s, 1H, -ArH), 10.52 (s, 1H, -ArH); ⁱ C NMR (100 MHz, CDC1 ₃ ) δ: 29.2, 37.0, 119.4, 120.0, 124.0, 126.8, 128.9, 129.6, 132.0, 135.7, 139.8, 140.4, 145.3, 146.9, 149.2. Synthesis of intermediate 7:

 Take 2.8 g (6.8 mmol) of intermediate 6 dissolved in 30 ml of absolute ethanol and add 1.20 g to 100 ml three-necked flasks.

(20.4 mmol) iron powder, 2.20 g (40.8 mmol) ammonium chloride, 5 ml acetic acid, and reacted at 90 °C for 2 h. The mixture was filtered while hot, EtOAc (EtOAc)EtOAc. V: V) gave a yellow solid intermediate 7 2.24 g, yield 86.3%. 1H NMR (400 MHz, CDCI3) δ: 1.68 (s, 6H, -CH3x2), 4.12 (brs, 2H, -NH2), 5.78 (s, IH, -NH), 6.62-6.64 (d, 2H, J= 8.8 Hz, -ArHx2), 7.29-7.31 (d, 2H, J=8.4Hz, -ArHx2), 7.50-7.52 (dd,lH, J=8.8Hz, -ArH), 7.85-7.87 (d, IH, J = 8.8 Hz, -ArH), 7.90 (s, IH, -ArH), 8.59 (s, IH, -ArH); ¹³ C NMR (100 MHz, CDCI3) δ: 21.3, 29.0, 36.3, 114.6, 121.4, 123.2 , 124.8, 126.3, 127.9, 129.0, 130.7, 132.5, 136.1, 141.4, 142.7, 143.5. Synthesis of intermediate 8:

15.34 g (40.2 mmol) of intermediate 7 was dissolved in 200 ml of dichloromethane, and 6.73 ml (48.3 mmol) of triethylamine was added to 100 ml of dichloromethane and added to the reaction flask. 13.14 g (44.2 mmol) of triphosgene was dissolved in 200 ml of dichloromethane, placed in a dropping funnel, slowly added dropwise to the reaction flask at 0 ° C, and kept at 0 ° C for 4 h. Saturated sodium bicarbonate solution was added and the reaction was extracted and stirred for 5 min. CH ₂ C1 ₂ extraction, spin-drying, recrystallization from acetone to give intermediate 8 12.45 g, yield 76% 1H NMR (400 MHz, DMF) 5: 2.05 (s, 6H, -CH3x2), 7.29 (s, IH, quinolineH ), 7.84-7.86 (dd, lH, J=8.5Hz, quinolineC7-H), 7.97-7.99 (d, 2H, J=8.1Hz, ArHx2), 8.08-8.10 (d, 2H, j=8.1 Hz, ArHx2 ), 8.14 (s, IH, quinolineC5-H), 8.18 (d, IH, quinoline C8-H), 9.05 (s, IH, quinoline-H), 11.93 (s,lH, -NH); ¹³ C NMR ( 100 MHz, DMF) δ: 29.9, 38.8, 117.9, 120.54, 124.1, 124.4, 126.0, 128.5, 130.6, 131, 1, 131.2, 134.2, 136.5, 136.7, 144.8, 145.3, 155.3. Synthesis of Intermediate 9:

5 g (12.2 mmol) of intermediate 8, 0.24 g (0.7 mmol) of TBAB was dissolved in 100 ml of dichloromethane, 1.33 g (33.2 mmol) of sodium hydroxide was dissolved in 17 ml of water, and the reaction was stirred for 5 min. 2.1 mL (40.5 mmol) of methyl iodide was dissolved in 100 ml of dichloromethane and slowly added dropwise to the reaction system. After stirring overnight at room temperature, CH ₂ C1 ₂ was evaporated. EtOAcjjjjjjjjjjjj 9 4.3 g, yield 83% 1H NMR (400 MHz, CDC1 ₃ ) 5: 1.85 (s, 6H, -CH3x2), 3.68 (s, 3H, -NCH3) _: 7.16-7.17 (d, 1H, J=2.0 Hz, -ArH), 7.26 (s, 1H, -ArH), 7.53-7.54 (d, 1H, J=6.6 Hz, -ArH) _: 7.58-7.60 (dd, 1H, J=9.0Hz, -ArH), 7.77-7.78 (d, 2H, J=10Hz, -ArHx2), 7.96-7.98 (d, 1H _: J=9.0Hz, -ArH), 8.79 (s, 1H, -ArH); ¹³ C NMR (100MHz, CDC1 ₃ ) 5:27.9, 29.2, 37.3, 116.1, 120.3, 122.7, 123.4, 123.8, 126.9, 128.0, 128.9, 130.5, 132.3, 132.7, 134.3, 143.5, 143.7, 153.4. Example 1: 2-Methyl-2-ί4-"3-methyl-2-oxo-8-(6-phenylpyridin-3-yl)-1Η-2,3-dihydroimidazolium "4 , 5-c1

Under a N ₂ protection, add 0.5 g (1.2 mmol) of intermediate 9, 0.03 g (0.036 mmol) of bisdiphenylphosphonium dichlorochloride palladium palladium, 55 mmll DDMMFF in a 50 ml three-necked flask. The reaction at 110000 ° ° CC should be 22 hh. . Add to 33 mmLL 2211%% potassium carbonate potassium carbonate aqueous solution, 33 mmLL containing 00..3311 gg ((11..5566 mmmmooll)) 66--phenylphenylpyrrolidine--33 -- DDMMFF solution of boric acid, at 110000 ° °CC followed by continued reaction for 33 hh. . The reaction should be reduced to the room temperature at the end of the knot. Add 2255 mmll ice-cold water, stir and mix 3300 mmiinn, and filter through the filter to obtain a crude crude product through a silica gel column. Column chromatography ((washing eluent:: methyl alcohol: dichlorochloromethane ==11::6600,, VV::VV)), obtained white solid color solid Example 11 Example 1 Product target product 00..4466 gg, yield yield 7788%%. . MMSS ((MM++HH ⁺⁺ )):: Calculated value 449966..2211,, actual

1155 Value: 449966..11. . 1H1H NNMMRR ((440000MMHHzz,, CCDDCC11 ₃₃ )) δδ:: 11..8899 ((ss,, 66HH,, --CCHH33xx22)),, 33..7700 ((ss,, 33HH,, >>NNCCHH33)) ,, 77..2266--77..2277 ((dd,, JJ==44..44 HHzz,, 22HH,, --AArrHHxx22)),, 77..4433~~77..4488 ((dddd ,,JJ==66..88 HHzz,, 1122HHzz,, 33HH,, --AArrHH)),, 77..6622--77..6644 ((dd,, JJ==88HHzz,, 22HH,, - -AArrHHxx22)),, 77..6677 ((ss,, qquuiinnoolliinneeHH)),, 77..7744--77..7766 ((dd,, JJ==88HHzz,, 11HH,, ppyyrriiddiinneeHH)),, 77 ..8800--77..8822 ((dd,, JJ==88HHzz,, 11HH,, qquuiinnoolliinneeHH)),, 77..8844--77..8866 ((dd,, JJ==55..22HHzz ,,,,,,,,,,,,,,,,,,, 88..2233 ((dd,, JJ==88..44HHzz,, 11HH,, ppyyrriiddiinnee--HH)),, 88..6644 ((ss,, 11HH,, qquuiinnoolliinneeHH)),, 88..8811 ((ss,, 11HH,, ppyyrriiddiinneeHH));; ¹¹³³ CC

2200 NNMMRR ((110000 MMHHzz,, CCDDCC11 ₃₃ )) δδ:: 2277..99,, 2299..22,, 3377..33,, 111155..33,, 111188..22,, 112200..22, , 112233..33,, 112233..99,, 112255..77,, 112266..77,, 112277..00,, 112288..88,, 112299..22,, 112299..33,, 113311 ,,66,,113322..77,, 113333..55,, 113344..55,, 113355..00,, 113388..66,, 114433..77,, 114444..88,, 114477.. 77,, 115533..55,, 115566..55. . Example 22:: 22--Methylmethyl--22--ίί44--""33--Methylmethyl--22--oxooxo--88-- ((11- -Phenylphenyl--11ΗΗ-pyrazolazole--44--yl))-11ΗΗ--22,,33--dihydrohydroimidazolium and ""44,,55- -cc11

0.5 g (1.2 mmol) of intermediate 9, 0.03 g (0.036 mmol) of bisdiphenylphosphine palladium dichloride, 5 ml of DMF were added to a 50 ml three-necked flask under N ₂ protection, and heated to 100 ° C for 2 h. 3 mL of 21% potassium carbonate aqueous solution, 3 mL of a DMF solution containing 0.31 g (1.56 mm ₀ l) of 1-phenyl-1H-pyrazole-4-boronic acid was added, and the reaction was continued at 100 ° C for 3 h. After the temperature was lowered to room temperature, 25 ml of ice water was added, and the mixture was stirred for 30 min, and filtered to give a crude material (yield: 0.8 g, EtOAc (EtOAc:MeOH: Example 2 The target product was 0.47 g, yield 82.4%. MS (M+H ⁺ ): Calcd 485.20, found: 485.2 Intermediate 5-bromo-2- (3-fluoro

lOOmL三颈瓶中， 加入 1 g (3.53 mmol) 5-溴 -2-碘吡啶， 10 mL 1,4-二氧六环， N₂保护 下加入 0.12 g (0.1 mmol)四三苯基磷钯， 搅拌 10 min。 依次加入 9ml 21%碳酸钾溶液， 3 ml 含 0.59 g (4.2 mmol)3-氟苯硼酸的 1，4-二氧六环溶液， 100 °C反应 4 h。 反应结束后降至室 温， 将其投入冰水中， 有固体析出， 搅拌至固体析出完全， 抽滤， 得粗品经硅胶柱层析（洗 脱液： 乙酸乙酯 /石油醚 =1/50， V:V)得 5-溴 -2- (3-氟苯基)吡啶 0.7 g， 收率 80%。 'HNMR (400MHz, CDC1₃) δ: 7.09-7.13 (t, J=1.6Hz, 8Hz， 1H, -ArH), 7.39-7.44 (m， 1H, Pyridine-H), 7.57 (d, J=8.4Hz, 1H, Pyridine-H), 7.68-7.72 (t， 2H, -ArHx2), 7.85〜7.87 (dd， J=1.6Hz, 6.8Hz， 1H, Pyridine-H), 8.72 (s， 1H, Pyridine-H); ¹³CNMR (100MHz, CDC1₃) δ: 113.8, 119.8， 121.5, 122.2, 130.25, 139.4, 140.2, 150.6， 154.3, 162.0, 164.4。 实施例 3: 2-甲基 -2-ί4-ί3-甲基 -2-氧代 -8-「6-( -氟苯基)吡啶 -3-基 Ί-ΙΗ-2,3-二氢咪唑并「4,5-c1 喹啉 -1-基 1苯基 丙腈

In a 100 mL three-necked flask, add 1 g (3.53 mmol) of 5-bromo-2-iodopyridine, 10 mL of 1,4-dioxane, and add 0.12 g (0.1 mmol) of tetratriphenylphosphorus palladium under N ₂ protection. , stir for 10 min. 9 ml of a 21% potassium carbonate solution, 3 ml of a 1,4-dioxane solution containing 0.59 g (4.2 mmol) of 3-fluorophenylboronic acid were sequentially added, and reacted at 100 ° C for 4 h. After the completion of the reaction, the mixture was cooled to room temperature, and the mixture was poured into ice water, and a solid was precipitated, and the mixture was stirred until the solid was completely separated, and filtered to give a crude product which was subjected to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1/50, V :V) gave 5-bromo-2-(3-fluorophenyl)pyridine 0.7 g in a yield of 80%. 'HNMR (400MHz, CDC1 ₃ ) δ: 7.09-7.13 (t, J=1.6Hz, 8Hz, 1H, -ArH), 7.39-7.44 (m, 1H, Pyridine-H), 7.57 (d, J=8.4Hz , 1H, Pyridine-H), 7.68-7.72 (t, 2H, -ArHx2), 7.85~7.87 (dd, J=1.6Hz, 6.8Hz, 1H, Pyridine-H), 8.72 (s, 1H, Pyridine-H ¹³ CNMR (100 MHz, CDC1 ₃ ) δ: 113.8, 119.8, 121.5, 122.2, 130.25, 139.4, 140.2, 150.6, 154.3, 162.0, 164.4. Example 3: 2-Methyl-2-ί4-ί3-methyl-2-oxo-8-"6-(-fluorophenyl)pyridin-3-ylindole-indole-2,3-dihydroimidazole And "4,5-c1 quinolin-1-yl 1 phenylpropanenitrile

0.67 g (2.6 mmol) of diboronic acid pinacol ester was dissolved in 5 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.05 g (0.07 mmol), 0.39 was added under nitrogen. g (3.9 mmol) potassium acetate. After stirring for 5 min, a solution of 0.33 g (1.3 mmol) of 5-bromo-2-(3-fluorophenyl)pyridine in 1,4-dioxane was added and the reaction was carried out at 110 °C. 2 h. Down to room temperature, intermediate 9 0.3 g (0.7 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.05 g (0.07 mmol), cesium carbonate 1.29 g (3.9 mmol), 2M carbonic acid were added sequentially under N ₂ protection. 4 mL of sodium solution was refluxed at 90 °C for 4 h. The mixture was cooled, poured into ice water, and filtered to give a white-white crude product, which was obtained by silica gel column chromatography (eluent: methanol / methylene chloride = 1:30, V: V). . MS (M+H ⁺ ): Calcd. 514.21. 1H NMR (400MHz, MeOD) δ: 1.82 (s, 3H, -CH3), 1.86 (s, 3H, -CH3), 3.64 (d, 3H, >NCH3), 7.06-7.09 (t, J=6.4Hz, 8Hz, IH, -ArH), 7.12-7.14 (d, J=8.4Hz, IH, -ArH), 7.23-7.30 (m, IH, -ArH), 7.39-7.44 (m, IH, -ArH), 7.51 -7.53 (d, J=8.4Hz, 2H, -ArH), 7.60-7.62 (d, J=8.4Hz, IH, pyridineH), 7.65~7.68 (m, 1H, quinolineH), 7.70-7.73 (d, J =8.4Hz, 2H, -ArH), 7.80-7.82 (d, J=8.4Hz, IH, pyridineH), 8.03-8.06 (d, J=8.4Hz, IH, quinolineH), 8.14~8.16 (d, J= 8.8Hz, IH, quinolineH), 8.54 (s, IH, quinolineH), 8.74 (d, IH, pyridineH); ¹³ C NMR (100MHz, MeOD) δ: 27.4, 28.6, 36.9, 113.2, 114.8, 115.6, 118.0, 120.0, 122.5, 123.7, 125.7, 126.6, 126.8, 127.3, 128.6, 130.1, 130.4, 131.9, 132.4, 134.5, 140.4, 142.9, 143.6, 144.5, 147.2, 153.3, 153.5, 154.9, 161.7. Example 4: 2- Methyl-2-ί4-ί3-methyl-2-oxo-846- 4-fluorophenyl)pyridin-3-ylindole-indole-2,3-dihydroimidazo[4,5-c1

N₂保护下于 50 ml三颈瓶中加入 0.5 g (1.2 mmol)中间体 9， 0.03 g (0.036 mmol)双二苯 基磷二氯化钯， 5 ml DMF, 加热至 100 °C反应 2 h。加入 3 mL 21%碳酸钾水溶液， 3 mL含 0.34 g (1.57 mmol) 6-(4-氟苯基) B比啶 -3-硼酸的 DMF溶液， 100 °C继续反应 3 h。 降至室温 后， 加入 25 ml冰水， 搅拌 30分钟， 过滤得粗品， 经硅胶柱层析 （洗脱液： 甲醇： 二氯甲 烷 =1 :60， V:V)，得白色固体实施例 4目标产物 0.24 g，产率 41%。MS (M+H⁺): 计算值 514.21， 实际值： 514.1 中间体 5-溴 -2-3' -联吡啶 10b的合成

Under a N ₂ protection, add 0.5 g (1.2 mmol) of intermediate 9, 0.03 g (0.036 mmol) of bisdiphenylphosphine palladium dichloride, 5 ml of DMF in a 50 ml three-necked flask, and heat to 100 °C for 2 h. . 3 mL of 21% potassium carbonate aqueous solution, 3 mL of a DMF solution containing 0.34 g (1.57 mmol) of 6-(4-fluorophenyl) B-pyridin-3-boronic acid was added, and the reaction was continued at 100 ° C for 3 h. After the temperature was lowered to room temperature, 25 ml of ice water was added, and the mixture was stirred for 30 minutes, and filtered to give a white crystals. The target product was 0.24 g, yield 41%. MS (M+H ⁺ ): calcd. 514.21.,,,,,,,,,,,,

100 mL三颈瓶中， 加入 2 g (7.06 mmol) 2-碘 -5-溴吡啶， 10 mL 1,4-二氧六环溶解， 氮 气保护下加入 0.24 g (0.2 mmol)四三苯基磷钯， 搅拌 10 min。 依次加入 6 mL 21%碳酸钾水 溶液， 3 mL含 1.04 g (8.45 mmol)吡啶 -3-硼酸的 1,4-二氧六环溶液， 100 °C反应 4 h。降至室 温后， 将其投入冰水中， 有固体析出， 搅拌至固体析出完全， 抽滤， 得淡黄色粗品， 粗品 经硅胶柱层析 （洗脱液： 甲醇 /二氯甲烷 =1/60，V:V) 化合物 5-溴 -2-3' -联吡啶 1.35 g， 收率 81.6%。 1H NMR (400MHz， CDC1₃) δ:7.65 (d, J=8.4 Hz, 1H)， 7.83 (d， J=4.4 Hz, 2H), 7.89-7.91 (dd， J=1.6 Hz, 2 Hz, 1H), 8.69 (d, J=4.8 Hz, 2H), 8.75 (s， 1H); ¹³CNMR (100 MHz, CDC1₃) δ: 120.7, 121.2, 121.8, 139.5, 145.2, 150.3, 151.1， 152.8。 实施例 5: 2-甲基 -2-ί4-ί3-甲基 -2-氧代 -8-「6- (吡啶 -3-基） 吡啶 -3-基 Ί -ΙΗ-2,3-二氢咪唑并 f4,5-c1 喹 -1-基 苯基 丙腈

In a 100 mL three-necked flask, add 2 g (7.06 mmol) of 2-iodo-5-bromopyridine, 10 mL of 1,4-dioxane, and add 0.24 g (0.2 mmol) of tetratriphenylphosphine under nitrogen. Palladium, stirring for 10 min. 6 mL of 21% potassium carbonate aqueous solution, 3 mL of 1.04 g (8.45 mmol) of pyridine-3-boronic acid in 1,4-dioxane were added in sequence, and reacted at 100 ° C for 4 h. After the temperature was lowered to room temperature, it was poured into ice water, and a solid was precipitated, and the mixture was stirred until the solid was separated, and then filtered to give a pale-yellow crude product. The crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/60, V: V) Compound 5-bromo-2-3'-bipyridine 1.35 g, yield 81.6%. 1H NMR (400MHz, CDC1 ₃ ) δ: 7.65 (d, J=8.4 Hz, 1H), 7.83 (d, J=4.4 Hz, 2H), 7.89-7.91 (dd, J=1.6 Hz, 2 Hz, 1H) , 8.69 (d, J = 4.8 Hz, 2H), 8.75 (s, 1H); ¹³ CNMR (100 MHz, CDC1 ₃ ) δ: 120.7, 121.2, 121.8, 139.5, 145.2, 150.3, 151.1, 152.8. Example 5: 2-Methyl-2-ί4-ί3-methyl-2-oxo-8-"6-(pyridin-3-yl)pyridin-3-ylindole-indole-2,3-dihydro Imidazo-f4,5-c1 quin-1-ylphenylpropionitrile

将 1.1 g (4.33 mmol)联硼酸频哪醇酯溶于 10 mL 1，4-二氧六环中， 氮气保护下加入 Pd(dppf)Cl₂-CH₂Cl₂ 0.08 g (0.22 mmol), 0.59 g (6.02 mmol) 乙酸钾，搅拌 5 min后，将 0.5 g (2 mmol) 5-溴 -2-3' -联吡啶溶于 1，4-二氧六环中加入反应瓶， 110 °C反应 1 h。 降至室温， 氮气 保护下依次加入中间体 9 0.5 g (1.1 mmol), Pd(dppf)Cl₂-CH₂Cl₂ 0.08 g (0.22 mmol), 碳酸铯 2.08 g (3.9 mmol), 2M的碳酸钠溶液 5 mL， 110 °C回流反应 4 h。 冷却， 投入冰水中， 抽 滤得灰白色粗品， 经硅胶柱层析 （洗脱液： 甲醇 /二氯甲烷 =1/50，V:V)， 得化合物实施例 5 目标产物 0.36 g，收率 61%。 MS (M+H⁺): 计算值 497.20， 实际值： 497.2。 1H NMR(400 MHz, CDC1₃) δ: 1.87 (s, 6H， -CH3x2), 3.70 (s, 3H, >NCH3), 7.27 (s, 2H, -ArHx2), 7.43 (s, 1H, pyridineH), 7.63〜7.81 (m， 6H， pyridineH, ArHx2, quinolineH), 8.29〜8.32 (d, J=7.6 Hz, 2H, pyridineH), 8.63 (s, 2H, quinolineH), 8.84 (s, 1H, quinolineH), 9.23 (s, 1H, pyridineH); ¹³C NMR (lOOMHz, CDCI3) δ: 28.1, 29.1, 37.3, 115.2, 118.4, 120.4, 123.4, 123.8, 126.0, 127.1, 129.3, 129.9, 131.0, 132.2, 134.1,134.3,134.8,143.8, 144.1， 147.9, 148.1， 149.8， 153.4, 153.8。 中间体 5-溴 -2-4' -联吡啶 10c 的合成

Dissolve 1.1 g (4.33 mmol) of diboronic acid pinacol ester in 10 mL of 1,4-dioxane, and add Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.08 g (0.22 mmol), 0.59 under nitrogen. g (6.02 mmol) potassium acetate, after stirring for 5 min, 0.5 g (2 mmol) of 5-bromo-2-3'-bipyridine was dissolved in 1,4-dioxane and added to the reaction flask at 110 °C. 1 h. At room temperature, add intermediate 9 0.5 g (1.1 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.08 g (0.22 mmol), cesium carbonate 2.08 g (3.9 mmol), 2M sodium carbonate, under nitrogen protection. 5 mL of the solution was refluxed at 110 ° C for 4 h. The mixture was cooled, poured into ice water, and filtered to give a white crystals of crude crystals, eluted on silica gel column (eluent: methanol/dichloromethane = 1/50, V:V) to give compound Example 5 target product 0.36 g, yield 61 %. MS (M+H ⁺ ): calc. 497.20, ??? 1H NMR (400 MHz, CDC1 ₃ ) δ: 1.87 (s, 6H, -CH3x2), 3.70 (s, 3H, >NCH3), 7.27 (s, 2H, -ArHx2), 7.43 (s, 1H, pyridineH), 7.63~7.81 (m, 6H, pyridineH, ArHx2, quinolineH), 8.29~8.32 (d, J=7.6 Hz, 2H, pyridineH), 8.63 (s, 2H, quinolineH), 8.84 (s, 1H, quinolineH), 9.23 (s, 1H, pyridineH); ¹³ C NMR (100MHz, CDCI3) δ: 28.1, 29.1, 37.3, 115.2, 118.4, 120.4, 123.4, 123.8, 126.0, 127.1, 129.3, 129.9, 131.0, 132.2, 134.1, 134.3, 134.8, 143.8, 144.1, 147.9, 148.1, 149.8, 153.4, 153.8. Synthesis of intermediate 5-bromo-2-4'-bipyridyl 10c

In a 100 mL three-necked flask, add 2 g (7.06 mmol) of 2-iodo-5-bromopyridine, 10 mL of 1,4-dioxane, and add 0.24 g (0.2 mmol) of tetratriphenylphosphine under nitrogen. Palladium, stirring for 10 min. 6 mL of 21% potassium carbonate aqueous solution and 3 mL of a 1.04 g (8.45 mmol) pyridine-4-boronic acid 1,4-dioxane solution were successively added, and reacted at 100 ° C for 4 h. After the temperature was lowered to room temperature, it was poured into ice water, and a solid was precipitated, and the mixture was stirred until the solid was separated, and then filtered to give a pale-yellow crude product. The crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/60, V: V) Compound 5-bromo-2-4'-bipyridine 1.35 g, yield 31%. 1H NMR (400MHz, CDC1 ₃ ) δ: 7.65 (d, J=8.4 Hz, 1H), 7.83 (d, J=4.4 Hz, 2H), 7.89-7.91 (dd, J=1.6Hz, 2Hz, 1H), 8.69 (d, J = 4.8 Hz, 2H), 8.75 (s, 1H); ¹³ CNMR (100 MHz, CDC1 ₃ ) δ: 120.7, 121.2, 121.8, 139.5, 145.2, 150.3, 151.1, 152.8. Example 6: 2-Methyl-2-ί4-ί3-methyl-2-oxo-8-"6-(pyridin-4-yl)pyridin-3-ylindole-indole-2,3-dihydrogen Imidazo-f 4,5-c1 quinolin-1-ylphenylpropanenitrile

0.54 g (2.12 mmol) of diboronic acid pinacol ester was dissolved in 5 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.04 g (0.11 mmol), 0.31 was added under nitrogen. g (3.3 mmol) potassium acetate, after stirring for 5 min, a solution of 0.25 g (1.1 mmol) of 5-bromo-2-4'-bipyridine in 1,4-dioxane was reacted at 110 ° C for 1 h. At room temperature, add intermediate 9 0.22 g (0.55 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.04 g (0.11 mmol), cesium carbonate 1.04 g (1.85 mmol), 2M sodium carbonate. 2 mL of the solution was refluxed at 110 ° C for 4 h. After cooling, it was poured into ice water, and filtered to give a crude-yellow-yield of EtOAc (EtOAc: m. 54%. MS (M+H+): calc. 497.20, actual: 497.2. 1H NMR (400 MHz, MeOD) δ: 1.61 (s, 6H, -CH3x2), 3.42 (s, 3H, >NCH3), 6.99 (d, J=1.6Hz, 1H, quinolineH), 7.37-7.39 (d, J=8.4Hz, 2H, -ArHx2), 7.50-7.52 (dd, J=2Hz, 8Hz, 1H, pyridineH), 7.58-7.60 (d, J=8.4Hz, 2H, -ArHx2), 7.62-7.64 (d , J=8 Hz, 2H, pyridineHx2), 7.70~7.71 (d, J=4.4Hz, 2H, pyridineH), 7.89-7.91 (d, J=8.8 Hz, 1H, pyridineH), 8.32 (d, J=1.6 Hz, 1H, quinolineH), 8.38 (s _: 1H, quinolineH), 8.56 (s, 1H, pyridineH); ¹³ C NMR (100MHz, MeOD) δ: 27.2, 28.2, 36.7, 114.7, 118.1, 120.8, 120.9, 123.0 , 123.6, 125.5, 126.7, 128.9, 129.4, 130.0, 132.3, 134.0, 134.1, 134.7, 135.0, 143.6, 143.7, 146.1, 147.4, 148.8, 152.5, 153.2. Synthesis of intermediate 5-bromo-2-(-methyl-1H-pyrazol-4-yl)pyridine 10d

In a 100 mL three-necked flask, add 2.2 g (10.5 mmol) of 1-methyl-4-B-pyridylboronic acid pinacol ester, dissolve 10 mL of 1,4-dioxane, and add 0.29 g (under nitrogen). 0.35 mmol) Pd(dppf)Cl ₂ -CH ₂ Cl ₂ , 5-bromo-2-iodopyridine 2g (7.06 mmol), cesium carbonate 6.91 g (21.2 mmol), 5 mL 2M sodium carbonate solution, 110 ° C reaction 4 h. After returning to room temperature, it was extracted with ice water and dichloromethane, and the crude filtrate was obtained. The crude material was purified by silica gel column chromatography (eluent: methanol / dichloromethane) Alkane = 1/60, V: V) gave the compound 5-bromo-2-(1-methyl-1H-pyrazol-4-yl)pyridine in 0.74 g, yield 44.2%. Example 7: 2-Methyl-2-ί4-ί3-methyl-2-oxo-8- "6-(1-methyl-1Η-pyrazol-4-yl)pyridin-3-ylindole - 1Η-2.3- Dihydroimidazo-c1 quinolin-1-ylphenylpropionitrile

将 0.64 g (2.52 mmol)联硼酸频哪醇酯溶于 4 mL 1，4-二氧六环中， 氮气保护下加入 Pd(dppf)Cl₂-CH₂Cl₂0.05 g (0.06 mmol), 0.37 g (3.78 mmol) 乙酸钾，搅拌 5 min后，加入 0.3 g (1.26 mmol) 5-溴 -2- ( 1-甲基 -1H-吡唑 -4-基）吡啶的 1,4-二氧六环溶液， 100 °C回流反应 1 h。 降至室温，氮气保护下依次加入中间体 9 0.27 g (0.64 mmol), Pd(dppf)Cl₂-CH₂Cl₂0.05 g (0.06 mmol), 碳酸铯 1.23 g (3.77 mmol), 2M的碳酸钠溶液 2 mL， 110 °C回流反应 4 h。 冷却， 投入冰水中，抽滤得灰黑色粗品，粗品经硅胶柱层析，（洗脱液： 甲醇 /二氯甲烷 =1/30， V:V), 得化合物实施例 7目标产物 0.23g，收率 72%。MS (M+H⁺): 计算值 500.21， 实际值： 500.1。 1H NMR (400 MHz, CDC1₃) δ: 1.85 (s, 6H， -CH3x2), 3.65 (s, 3H, >NCH3), 3.94 (s, 3H, >NCH3)_: 7.18 (d, J=1.6 Hz, IH, quinolineC5-H), 7.38-7.40 (d， J=8Hz， IH, quinolineC8-H), 7.49-7.52 (dd， J=2.2 Hz, 8.2Hz, IH, quinolineC7-H), 7.59〜7.61 (d， J=8.4 Hz, 2H, -ArHx2), 7.75〜7.79 (m， 3H, -ArHx2, pyridine-H), 7.87 (s， IH, pyrazole-H), 7.92 (s， IH, pyrazole-H), 8.15〜8.17 (d， J=8.8Hz, IH, pyridine-H), 8.45 (d, J=1.8Hz， IH, quinolineC2-H), 8.76 (s, IH, pyridineH); ¹³C NMR (100 MHz, CDCI3) δ: 27.8, 29.1, 37.2, 39.2, 115.2, 117.8, 119.1， 123.1, 123.2, 123.9, 125.5, 126.9, 128.8, 129.1, 129.2, 131.3, 132.2, 132.5, 134.2, 134.9, 135.0, 137.5, 143.5, 144.6， 147.6, 151.2, 153.4。 中间体 lOf的合成

0.64 g (2.52 mmol) of diboronic acid pinacol ester was dissolved in 4 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.05 g (0.06 mmol), 0.37 was added under nitrogen. g (3.78 mmol) potassium acetate, after stirring for 5 min, add 0.3 g (1.26 mmol) of 5-bromo-2-(1-methyl-1H-pyrazol-4-yl)pyridine to 1,4-dioxane The ring solution was refluxed at 100 ° C for 1 h. At room temperature, intermediate 9 0.27 g (0.64 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.05 g (0.06 mmol), cesium carbonate 1.23 g (3.77 mmol), 2M sodium carbonate were added sequentially under nitrogen. 2 mL of the solution was refluxed at 110 ° C for 4 h. The mixture was cooled, poured into ice water, and filtered to give a crude white solid. The crude product was subjected to silica gel column chromatography (eluent: methanol/dichloromethane = 1/30, V: V) The yield was 72%. MS (M+H ⁺ ): Calculated 500.21, actual: 500.1. 1H NMR (400 MHz, CDC1 ₃ ) δ: 1.85 (s, 6H, -CH3x2), 3.65 (s, 3H, >NCH3), 3.94 (s, 3H, >NCH3) _: 7.18 (d, J=1.6 Hz, IH, quinolineC5-H), 7.38-7.40 (d, J=8Hz, IH, quinolineC8-H), 7.49-7.52 (dd, J=2.2 Hz, 8.2Hz, IH, quinolineC7-H), 7.59~7.61 (d , J=8.4 Hz, 2H, -ArHx2), 7.75~7.79 (m, 3H, -ArHx2, pyridine-H), 7.87 (s, IH, pyrazole-H), 7.92 (s, IH, pyrazole-H), 8.15~8.17 (d, J=8.8Hz, IH, pyridine-H), 8.45 (d, J=1.8Hz, IH, quinolineC2-H), 8.76 (s, IH, pyridineH); ¹³ C NMR (100 MHz, CDCI3) δ: 27.8, 29.1, 37.2, 39.2, 115.2, 117.8, 119.1, 123.1, 123.2, 123.9, 125.5, 126.9, 128.8, 129.1, 129.2, 131.3, 132.2, 132.5, 134.2, 134.9, 135.0, 137.5, 143.5, 144.6, 147.6, 151.2, 153.4. Synthesis of intermediate lOf

In a 100 mL three-necked flask, add 1 g (3.5 mmol) of 2-iodo-5-bromopyridine, 5 mL of 1,4-dioxane, and add 0.12 g (0.1 mmol) of tetratriphenylphosphine under nitrogen. Palladium, reacted at 80 °C for 2 h. After cooling to room temperature, 10 ml of 21% potassium carbonate solution, 3 ml of a solution of 0.73 g (4.2 mmol) of quinoline-3-boronic acid in 1,4-dioxane were added in sequence, and the reaction was continued to 100 ° C for 4 h. After the temperature is lowered to room temperature, it is poured into ice water, and a yellow solid is precipitated. The mixture is stirred until the solid is completely precipitated, and then filtered to give a crude product which is applied to silica gel column chromatography (eluent: methanol/dichloromethane = 1/60, V: V) gave Intermediate 10f 0.73 g, yield 73%. 1H NMR (400MHz, CDC1 ₃ ) 5: 7.51-7.54 (t, J = 7.2 Hz, 7.6 Hz, 1H ), 7.68-7.72 (m, 2H, quinolineH), 7.84-7.87 (m, 2H, quinolineH), 8.65 (d, J = 1.6 Hz, 1H, Pyridine-H), 8.75 (d, J = 2 Hz, 1H, quinolineH), 9.45 (d, J = 2.4 Hz, 1H, quinolineH); ¹³ C NMR (100 MHz, CDC1 ₃ δ: 120.0, 121.5, 127.1, 127.5, 128.4, 129.2, 130.1, 130.5, 133.6, 139.4, 148.1, 148.7, 151.1, 153.1. Example 8: 2-Methyl-2-ί4-ί3-methyl-2-oxo-8- "6-(quinolin-3-yl)pyridin-3-yl-1Η-2,3-dihydro Imidazo-"4,5-c1 quinolin-1-ylphenylpropionitrile and its hydrochloride

 0.54 g (2.12 mmol) of diboronic acid pinacol ester was dissolved in 5 mL of 1,4-dioxane and added under nitrogen.

Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.04 g (0.11 mmol), 0.3 g (3.01 mmol) potassium acetate. After stirring for 5 min, 0.3 g (1.06 mmol) of intermediate 10f was dissolved in 1,4-dioxane. In the six rings, the reaction flask was added and reacted at 110 ° C for 1 h. At room temperature, add intermediate 9 0.22 g (0.55 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.04 g (0.11 mmol), carbonic acid fi 1.02 g (3.13 mmol), 2M sodium carbonate. 2 mL of the solution was refluxed at 110 ° C for 4 h. After cooling, it was poured into ice water, and filtered to give a white solid (yield: methanol / methylene chloride = 1/30, V: V). 98%. MS (M+H ⁺ ): Calcd. 547.22. 1H NMR (400 MHz, MeOD) δ: 1.80 (s, 6H, -CH3x2), 3.61 (s, 3H, -NCH3), 7.19 (d, J=1.5Hz, IH, quinolineH), 7.52 (d, IH, quinolineH) , 7.55-7.57 (d, J=8.4Hz, 2H, -ArHx2), 7.65~7.69 (m, 2H, quinolineHx2), 7.74-7.76 (d, J=8.4Hz, 2H, -ArHx2), 7.78-7.81 ( Dd, J=1.8Hz, 8.8Hz, IH, pyridineH), 7.83-7.87 (t, J=8 Hz, 2H, quinolineH 2), 8.00-8.02 (d, J=8.4Hz, 1H, quinolineH), 8.10~ 8.12 (d, J=8.8 Hz, IH, quinolineH), 8.56 (d, J=2Hz, IH, pyridineH), 8.66 (d, J=1.5Hz, IH, quinolineH), 8.71 (s, IH, pyridineH), 9.39 (d, J = 1.6 Hz, quinoline H); ¹³ C NMR (100 MHz, MeOD) δ: 27.7, 28.7, 37.0, 115.1, 118.2, 120.7, 123.2, 123.8, 125.8, 127.0, 127.2, 127.7, 128.2, 128.4, 129.1, 129.5, 130.4, 130.7, 131.0, 132.5, 134.1, 134.4, 134.5, 134.9, 143.7, 144.2, 147.4, 147.8, 148.6, 153.5.

 5 mg of the target product of Example 8 was placed in a 5 ml EP tube, and 2 ml of 1 mol/L hydrochloric acid was added thereto, sonicated to dissolve, and freeze-dried to obtain the hydrochloride of the objective product of Example 8 as a pale yellow solid. Intermediate 10g synthesis

In a 100 mL three-necked flask, add 1 g (3.5 mmol) of 2-iodo-5-bromopyridine, 5 mL of 1,4-dioxane, and add 0.12 g (0.1 mmol) of tetratriphenylphosphine under nitrogen. Palladium, reacted at 80 °C for 2 h. At room temperature, add 10 ml of 21% potassium carbonate solution, 3 ml of 1,4-dioxane solution containing 0.8 g (4.2 mmol) of 6-phenylpyridine-3-boronic acid to 100 °C to continue the reaction. h. After the temperature was lowered to room temperature, it was poured into ice water, and a solid was precipitated, and the mixture was stirred until the solid was separated, and then filtered to give a crude material which was applied to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1/10, V: V) gave a white solid intermediate 10 g 0.9 g. The yield was 82.2%. 1H NMR (400 MHz, MeOD) δ: 7.33-7.37 (m, 3H, -ArHX 3), 7.59 (d, J = 8.4 Hz, IH, Pyridine-H), 7.71 (d, J = 4.4, IH, pyridine -H), 7.81~7.86 (m, 3H, -ArHX 2, pyridine-H), 8.25 (d, J=8.4Hz, IH, Pyridine-H), 8.61 (s, IH, Pyridine-H), 9.06 ( s, IH, Pyridine-H); ¹³ C NMR (100 MHz, MeOD) δ: 120.0, 120.9, 121.5, 126.8, 128.6, 129.3, 132.1, 135.3, 137.9, 139.6, 147.1, 150.8, 152.5, 157.6 ο 9: 2-methyl-2-ί4-ί3-methyl-2-oxo-8-"6-(6-phenylpyridin-3-yl)pyridin-3-ylindole-1Η-2,3- Dihydroimidazolium "4,5-c1 quinolin-1-ylphenylpropionitrile and its hydrochloride

0.49 g (1.92 mmol) of diboronic acid pinacol ester was dissolved in 5 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.04 g (0.11 mmol) was added under N ₂ protection. 0.28 g (2.88 mmol) of potassium acetate. After stirring for 5 min, 0.3 g (0.96 mmol) of intermediate lOg was dissolved in 1,4-dioxane solution and reacted at 110 ° C for 1 h. At room temperature, under the protection of N ₂ , intermediate 9 0.21 g (0.55 mmol), 0.04 g (0.11 mmol) Pd(dppf)Cl ₂ -CH ₂ Cl ₂ , cesium carbonate 0.98 g (3.01 mmol), 2M carbonate 2 mL of sodium solution was refluxed at 110 °C for 4 h. After cooling, it was poured into ice water, and filtered to give white crystals. m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The yield was 28%. MS (M+H ⁺ ): calc. 573.23, calc. 1H NMR (400MHz, MeOD) δ: 1.76 (s, 6H, -CH3x2), 3.54 (s, 3H, >NCH3), 7.12 (s, 1H, quinolineH), 7.33-7.34 (m, 3H, -ArHx2, quinolineH ), 7.5 l(m, 2H, -ArHx2), 7.59 (m, 1H, quinolineH), 7.67-7.76 (m, 5H, -ArHx5), 7.82 (m, 2H, pyridineHx2), 8.06-8.08 (d, J =7.4Hz, 1H, pyridineH), 8.20-8.21 (d, J=5.7Hz, 1H, pyridineH), 8.45 (s, 1H, quinolineH), 8.67 (s, 1H, pyridineH), 9.05 (s, 1H, pyridineH ¹³ C NMR (100 MHz, MeOD) δ: 27.6, 28.6, 37.0, 114.9, 118.1, 120.2, 120.6, 123.2, 123.7, 126.0, 126.7, 126.9, 128.6, 129.1, 129.1, 129.9, 130.0, 131.9, 132.2, 133.8, 134.3, 134.6, 134.7, 135.0, 138.1, 143.6, 143.8, 147.4, 147.6, 153.3, 153.4, 157.5.

 5 mg of the target product of Example 9 was placed in a 5 ml EP tube, 2 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give the hydrochloride salt of the objective product of Example 9 as a pale yellow solid. Intermediate 10h

50 mL三颈瓶中， 加入 1 g (3.5 mmol) 2-碘 -5-溴吡啶， 5 mL 1,4-二氧六环溶解， 氮气保 护下加入 0.12 g (0.1 mmol)四三苯基磷钯， 80 °C反应 2 h。 降至室温， 依次加入 9 ml 21% 的碳酸钠水溶液， 含 0.8 g (4.2 mmol) 1-苯基 -1H-吡唑 -4-硼酸的 1，4-二氧六环溶液 5 ml, 升 至 100°C继续反应 4 h。 降至室温后， 将其投入冰水中， 有固体析出， 搅拌至固体析出完全， 抽滤， 得粗品， 经硅胶柱层析 （洗脱液： 乙酸乙酯 /石油醚 =1/10， V:V) 得白色固体中间 体 10h 0.86 g， 收率 82 %。 1H NMR (400 MHz, CDC1₃) δ: 7.28-7.32 (t， J=7.2Hz, 7.6Hz, 1H, -ArH), 7.38 (d, J=8.4 Hz, 1H, pyridineH), 7.43〜7.47 (t， J=7.2 Hz, 8.4 Hz, 2H, -ArHx2), 7.72-7.74 (dd， J=1.2 Hz, 7.6 Hz, 2H, -ArHx2), 7.76-7.78 (dd， J=1.2Hz, 8.4 Hz, 1H, pyridineH), 8.13 (s， 1H, PyrazoleH), 8.47 (s， 1H, PyrazoleH), 8.61(d, J=2.4Hz, 1H, pyridineH )； ¹³C NMR (100 MHz, CDC1₃) δ: 117.8, 119.1， 120.7, 124.0, 125.4, 126.9, 129.4, 139.0, 139.2, 139.7, 149.8, 150.5。 实施例 10: 2-甲基 -2-ί4-ί3-甲基 -2-氧代 -8-「6- ( 1-苯基 -1-Η-卩比唑 -4基）吡啶 -3-基 Ί -1Η-2.3-

In a 50 mL three-necked flask, add 1 g (3.5 mmol) of 2-iodo-5-bromopyridine, 5 mL of 1,4-dioxane, and add 0.12 g (0.1 mmol) of tetratriphenylphosphine under nitrogen. Palladium, reacted at 80 °C for 2 h. At room temperature, add 9 ml of 21% sodium carbonate aqueous solution, 5 g of 1,4-dioxane solution containing 0.8 g (4.2 mmol) of 1-phenyl-1H-pyrazole-4-boronic acid, and then raise to 5 ml. The reaction was continued at 100 ° C for 4 h. After the temperature was lowered to room temperature, it was poured into ice water, and a solid was precipitated, and the mixture was stirred until the solid was separated, and then filtered to give a crude material which was applied to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1/10, V: V) A white solid intermediate 10 h 0.86 g, yield 82%. 1H NMR (400 MHz, CDC1 ₃ ) δ: 7.28-7.32 (t, J = 7.2 Hz, 7.6 Hz, 1H, -ArH), 7.38 (d, J = 8.4 Hz, 1H, pyridineH), 7.43~7.47 (t , J=7.2 Hz, 8.4 Hz, 2H, -ArHx2), 7.72-7.74 (dd, J=1.2 Hz, 7.6 Hz, 2H, -ArHx2), 7.76-7.78 (dd, J=1.2Hz, 8.4 Hz, 1H , pyridineH), 8.13 (s, 1H, PyrazoleH), 8.47 (s, 1H, PyrazoleH), 8.61 (d, J = 2.4 Hz, 1H, pyridineH); ¹³ C NMR (100 MHz, CDC1 ₃ ) δ: 117.8, 119.1, 120.7, 124.0, 125.4, 126.9, 129.4, 139.0, 139.2, 139.7, 149.8, 150.5. Example 10: 2-Methyl-2-ί4-ί3-methyl-2-oxo-8-"6-(1-phenyl-1-indole-indolezol-4-yl)pyridin-3-yl Ί -1Η-2.3-

0.51 g (2 mmol) of diboronic acid pinacol ester was dissolved in 5 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.04 g (0.11 mmol), 0.30 was added under nitrogen. g (3 mmol) potassium acetate, after stirring for 5 min, 0.3 g (1 mmol) of the intermediate was dissolved in 1,4-dioxane for 10 h, added to the reaction flask, and reacted at 110 ° C for 1 h. At room temperature, add intermediate 9 0.21 g (0.55 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.04 g (0.11 mmol), cesium carbonate 0.98 g (3.01 mmol), 2M sodium carbonate. The solution was 2.7 mL and refluxed at 110 °C for 4 h. After cooling, it was poured into ice water, and filtered to give a pale-yellow crude crystals, eluted on silica gel column (eluent: methanol/dichloromethane = 1:30, V: V) to give a white solid. The rate is 60.8%. MS (M+H ⁺ ): Calcd. 562.23. 1H NMR (400MHz, MeOD) δ: 1.73 (s, 6H, -CH3x2), 3.55 (s, 3H, -NCH3), 7.09 (s, 1H, quinolineH), 7.19~7.21 (t, J=6.6Hz, 1H , pyrazoleH), 7.33~7.34 (t, J=6.8 Hz, 2H, -ArHx2), 7.44 (m, 2H, quinolineHx2), 7.49-7.50 (d, J=7.2 Hz, 2H, -ArHx2), 7.57-7.59 (d, J=7.2 Hz, 2H, -ArHx2), 7s.68~7.73 (m, 3H, -ArHx3) , 8.03-8.06 (m, 2H, pyridineHx2), 8.37 (s, 2H, PyrazoleH, quinolineH), 8.67 (s, 1H, pyridineH); ¹³ C NMR (100 MHz, MeOD) δ: 27.6, 28.6, 36.9, 115.0 , 117.8, 119.1, 119.8, 123.1, 123.8, 123.9, 125.6, 126.0, 126.8, 129.0, 129.3, 129.7, 130.0, 131.9, 132.6, 134.3, 134.7, 134.9, 139.0, 139.3, 143.6, 147.1, 150.3, 153.4.

 5 mg of the target product of Example 10 was placed in a 5 ml EP tube, force Q 1 mol/L hydrochloric acid 2 ml, sonicated to dissolve, and lyophilized to give the hydrochloride salt of the objective product of Example 10 as a pale yellow solid. Intermediate 10

2.63 g (10.2 mmol) of diboronic acid pinacol ester was dissolved in 20 mL of 1,4-dioxane, and 0.21 g (0.26 mmol) of Pd(dppf)Cl2-CH ₂ Cl2, 1.52 g (0.22 g) was added under nitrogen atmosphere. 15.3 mmol) Potassium acetate, after stirring for 5 min, add 1,3-dioxane solution containing 1.3 g (5.1 mmol) of 5-bromo-2-(3-fluorophenyl)pyridine, and react at 110 °C for 2 h. . At room temperature, 5-bromo-2-iodopyridine 1.47 g (5.1 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.21 g (0.26 mmol), cesium carbonate 5.06 g (15.3 mmol) were added sequentially under nitrogen atmosphere. , 2M sodium carbonate solution 13.7 mL, 100. C reflux reaction for 4 h. After cooling, it was poured into ice water, and filtered to give a crude white solid, which was applied to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1/5, V: V) to give Intermediate 10i 0.29 g, yield 17%. 1H NMR (400 MHz, MeOD) δ: 7.03~7.07 (t, J=1.6 Hz, 8 Hz, ΙΗ, ΑτΗ), 7.34-7.40 (q, 1H, ArH), 7.63~7.65 (d, J=8.4 Hz , 2H, -ArH, pyridine H), 7.68-7.70 (d, J= 8 Hz, 1H, pyridine H), 7.74-7.76 (d, J=8.4 Hz, 1H, pyridineH), 7.85-7.88 (dd, J = 2Hz, 8.4 Hz, 1H, pyridine H), 8.30~8.32 (dd, J=2 Hz, 8.4 Hz, 1H, pyridineH), 8.66 (d, J=2Hz, 1H, pyridineH), 9.11 (s, 1H, pyridineH); ¹³ C NMR (100 MHz, MeOD) δ: 113.5, 115.8, 120.7, 130.1, 132.5, 135.2, 139.6, 140.3, 147.3, 150.7, 152.3, 156.1, 161.8, 164.2. Example 11: 2-methyl-2-ί4-ί3-methyl-2-oxo-8-16-"6-(3-fluorophenyl)pyridin-3-ylindole-3-yl-1Η-2 , 3-dihydroimidazole 4,5-c1 quinolin-1-ylphenylpropionitrile and its hydrochloride

0.27 g (1.06 mmol) of diboronic acid pinacol ester was dissolved in 5 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.04 g (0.11 mmol), 0.26 was added under nitrogen. g (2.64 mmol) potassium acetate, after stirring for 5 min, a solution of 0.29 g (0.88 mmol) of intermediate 10 1,4-dioxane was added and reacted at 110 ° C for 1 h. After cooling to room temperature, intermediate 9 0.20 g (0.45 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.04 g (0.11 mmol), cesium carbonate 0.93 g (2.64 mmol), 2M sodium carbonate were added sequentially under nitrogen. The solution was 2.4 mL and refluxed at 110 °C for 4 h. The mixture was cooled, poured into ice water, and filtered to give a white crystals of crude crystals. The crude product was purified by silica gel column chromatography (eluent: methanol / methylene chloride = 1:30, V: V). 32.6%. MS (M+H ⁺ ): calc. 591.22, calc. 1H NMR (400 MHz, MeOD) δ: 1.64 (s, 6Η, -CH3x2), 3.40(s, 3H, >NCH3), 6.82-6.86 (t, J=7.2 Hz, 1H, -ArH), 6.94 (s , 1H, quinolineH), 7.16~7.21 (m, 1H, -ArH), 7.37-7.41 (t, J = 8Hz, 3H, -ArHx3), 7.43~7.45 (d, J=7.2 Hz, 2H, -ArHx2) , 7.47-7.53 (m, 2H, J=8 Hz, -ArH, quinolineH), 7.59~7.61 (d, J=8.4 Hz, 3H, quinolineH, pyridineHx2), 7.89-7.91 (d, J=8.4 Hz, 1H , pyridineH), 8.03~8.05 (d, J=8 Hz, 1H, pyridineH), 8.28 (s, 1H, quinolineH), 8.52 (s, 1H, pyridineH), 8.89 (s, 1H, pyridineH); ¹³ C NMR (100 MHz, MeOD) δ: 27.3, 28.4, 36.9, 113.2, 113.4, 114.8, 115.6, 115.8, 117.9, 120.2, 120.4, 122.1, 123.0, 123.7, 125.7, 126.8, 129.0, 129.6, 129.9, 130.0, 132.1, 132.5, 133.7, 134.1, 134.2, 134.6, 134.8, 140.2, 143.6, 147.3, 152.8, 153.2, 155.7, 161.6, 164.1.

5 mg of the target product of Example 11 was placed in a 5 ml EP tube, 2 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give a pale yellow solid. Synthesis of intermediate 10j

取 1.84 g (7.24 mmol)联硼酸频哪醇酯溶于 10 mL 1，4-二氧六环中， 氮气保护下加入 Pd(dppf)Cl₂-CH₂Cl₂0.25 g (0.31 mmol), 1.77 g (18.1 mmol)乙酸钾，搅拌 5 min后，将 1.41 g (6 mmol) 5-溴 -2-3' -联吡啶溶于 1，4-二氧六环中， 加入反应瓶， 于 110 °C反应 2 h。 降至室温， 氮气保护下依次加入 5-溴 -2-碘吡啶 1.19 g (4.2 mmol), Pd(dppf)Cl₂-CH₂Cl₂0.21 g (0.26 mmol), 碳酸铯 4.71 g (14.4 mmol), 2M的碳酸钠溶液 12.8 mL, 100 °C回流反应 4 h。 冷却， 投入 冰水中， 抽滤得紫黑色粗品， 经硅胶柱层析 （洗脱液： 甲醇 /二氯甲烷 =1 :40， V： V) 得中 间体 10j 0.49 g， 收率 26%。 1HNMR (400 MHz, CDC1₃) δ: 7.50 (brs, 1Η, pyridine-H), 7.67 (d， J=8 Hz, 1H， pyridine-H), 7.84 (d， J=8 Hz, 1H), 7.90 (d， J= 8.4 Ηζ,ΙΗ), 8.40 (t， J=7.2 Hz, 2H), 8.76 (s， 1H)， 8.83 (s， 1H)， 9.25 (s， 1H)， 9.43 (s， 1H); ¹³C NMR (100 MHz, CDC13) δ： 120.3, 120.4,121.4， 124.3, 132.9, 134.6, 135.1, 139.5, 147.7, 148.2, 149.5， 151.2, 152.6, 154.9。 实施例 12: 2-甲基 -2-ί4-ί3-甲基 -2-氧代 -8-ί6-「6- (吡啶 -3-基）吡啶 -3-基 Ί吡啶 -3-基 1Η-2,3- 二氢咪唑并 「4,5-c1 喹啉 -1-基 苯基 丙腈及其盐酸盐

1.84 g (7.24 mmol) of diboronic acid pinacol ester was dissolved in 10 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.25 g (0.31 mmol) was added under nitrogen. g (18.1 mmol) potassium acetate, after stirring for 5 min, 1.41 g (6 mmol) of 5-bromo-2-3'-bipyridine was dissolved in 1,4-dioxane and added to the reaction flask at 110 ° C reaction for 2 h. At room temperature, 1.29 g (4.2 mmol) of 5-bromo-2-iodopyridine, 0.21 g (0.26 mmol) of Pd(dppf)Cl ₂ -CH ₂ Cl _{2 and} 4.71 g (14.4 mmol) of cesium carbonate were added in sequence under nitrogen atmosphere. , 2M sodium carbonate solution 12.8 mL, reflux reaction at 100 °C for 4 h. The mixture was cooled, poured into ice water, and filtered to give a crude white crystals, which was obtained by silica gel column chromatography (eluent: methanol/dichloromethane = 1:40, V: V) to give intermediate 10j 0.49 g, yield 26%. 1HNMR (400 MHz, CDC1 ₃ ) δ: 7.50 (brs, 1 Η, pyridine-H), 7.67 (d, J=8 Hz, 1H, pyridine-H), 7.84 (d, J=8 Hz, 1H), 7.90 (d, J = 8.4 Ηζ, ΙΗ), 8.40 (t, J = 7.2 Hz, 2H), 8.76 (s, 1H), 8.83 (s, 1H), 9.25 (s, 1H), 9.43 (s, 1H) ¹³ C NMR (100 MHz, CDC13) δ: 120.3, 120.4, 121.4, 124.3, 132.9, 134.6, 135.1, 139.5, 147.7, 148.2, 149.5, 151.2, 152.6, 154.9. Example 12: 2-Methyl-2-ί4-ί3-methyl-2-oxo-8-ί6-"6-(pyridin-3-yl)pyridin-3-ylindole-3-yl 1 Η- 2,3-dihydroimidazo[4,5-c1 quinolin-1-ylphenylpropionitrile and its hydrochloride

0.48 g (1.9 mmol) of diboronic acid pinacol ester was dissolved in 10 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.06 g (0.07 mmol), 0.46 was added under nitrogen. g (4.7 mmol) potassium acetate, after stirring for 5 min, add 0.49 g (1.58 mmol) 1,4-dioxane solution of 5-bromo-2-3'-bipyridine, reacted at 110 ° C for 1 h. At room temperature, intermediate 10j 0.33 g (0.78 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.06 g (0.07 mmol), cesium carbonate 1.54 g (4.7 mmol), 2M sodium carbonate were added successively under nitrogen. 4.2 mL of the solution was refluxed at 110 ° C for 4 h. The mixture was cooled, poured into ice water, and filtered to give a crude purple-purified product, which was purified by silica gel column chromatography (eluent: methanol / methylene chloride = 1:50, V: V). The rate is 93%. MS (M+H ⁺ ): Calcd. 574.20. 1H NMR (400 MHz, MeOD) δ: 1.89 (s, 6 Η, -CH3x2), 3.68 (s, 3H, -CH3), 7.49-7.52 (m, 2H, -ArHx2), 7.64-7.66 (d, J= 8.4 Hz, 2H, -ArHx2), 7.77-7.79 (dd, J=2 Hz, 8.4 Hz, 1H, pyridineH), 7.85-7.91 (m, 4H, quinolineHx3, pyridineH), 7.93 (s, 1H, quinoline-H ), 8.15~8.17 (d, J=8.8 Hz, 1H, pyridineH), 8.39-8.43 (t, 2H, pyridineHx2), 8.57~8.58 (d, J=4 Hz, 2H, pyridineHx2), 8.81 (s, 1H _: pyridineH), 9.12 (s, 1H, pyridineH), 9.25 (s, 1H, pyridineH). ¹³ C NMR (100 MHz, MeOD) δ: 27.2, 28.2, 36.8, 114.8, 118.0, 120.3, 120.5, 123.0, 123.6 , 123.7, 125.6, 126.7, 128.9, 129.4, 130丄132.4, 133.0, 134.1, 134.2, 134.7, 135.0, 143.6, 143.9, 147.1, 147.4, 147.7, 148.8, 152.7, 153.3, 154.0.

 5 mg of the target product of Example 12 was placed in a 5 ml EP tube, 2 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give the hydrochloride salt of the object product of Example 12 as a pale yellow solid. Synthesis of intermediate 10k

1.5 g (5.9 mmol) of diboronic acid pinacol ester was dissolved in 10 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.2 g (0.24 mmol) was added under nitrogen. g (14.7 mmol) potassium acetate, after stirring for 5 min, a solution of 1.15 g (4.9 mmol) of 5-bromo-2-4'-bipyridine in 1,4-dioxane was added and reacted at 110 ° C for 2 h. At room temperature, add 5-bromo-2-iodopyridine 1.2 g (4.2 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.16 g (0.2 mmol), and cesium carbonate 3.84 g (11.8 mmol) under nitrogen. , 2M sodium carbonate solution 18.8 mL, reflux reaction at 100 ° C for 4 h. After cooling, it was poured into ice water, and filtered to give a crude purple residue. EtOAc (EtOAc: m. The yield of go was 44.5%. 1H NMR (400 MHz, CDC1 ₃ ) δ: 7.70 (d, J = 8.4 Hz, 1H, pyridine-H), 7.90-7.95 (m, J = 4 Hz, 8.4 Hz, 4H), 8.43 (d, J= 8 Hz, 1H), 8.74 (d, J=5.2 Hz, 2H), 8.79 (s, 1H), 9.29 (s, 1H); ¹³ C NMR (lOOMHz, CDC1 ₃ ) δ: 120.5, 120.7, 121.0, 121.5 , 133.7, 135.2, 139.6, 145.7, 148.2, 150.5, 151.3, 152.6, 155.0. Example 13: 2-Methyl-2-ί4-ί3-methyl-2-oxo-8-ί6-"6-(pyridin-4-yl)pyridin-3-ylpyridin-3-yldihydrol Imidazo-"4,5-c1 quinolin-1-ylphenylpropionitrile and its hydrochloride

0.39 g (1.55 mmol) of diboronic acid pinacol ester was dissolved in 6 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.05 g (0.06 mmol) was added under nitrogen atmosphere, 0.38 g (3.88 mmol) potassium acetate, after stirring for 5 min, a solution of 0.4 g (1.29 mmol) of intermediate 10k in 1,4-dioxane was added and reacted at 110 ° C for 1 h. At room temperature, intermediate 9 0.27 g (0.64 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.05 g (0.06 mmol), cesium carbonate 1.01 g (3.1 mmol), 2M sodium carbonate were added sequentially under nitrogen. The solution was 2.7 mL and refluxed at 110 °C for 4 h. The mixture was cooled, poured into ice water, and filtered to give a crude purple-purified product, which was obtained by silica gel column chromatography (eluent: methanol / methylene chloride = 1:30, V: V). . MS (M+H ⁺ ): Calcd. 574.20. 1H NMR (400 MHz, MeOD) δ: 1.64 (s, 6H, -CH3x2), 3.42 (s, 3H, -NCH3), 6.99 (s, 1H, quinolineH), 7.39-7.41 (d, J=8 Hz, 2H, -ArHx2), 7.50-7.52 (d, J=8 Hz, 1H, quinolineH), 7.60-7.64 (m, -ArHx2, quinolineH, pyridineH), 7.70-7.74 (m, J=6 Hz, 3H, pyridineH X 3), 7.89-7.92 (d, J=8.8 Hz, 1H, pyridineH), 8.16~8.18 (d, J=8 Hz, 1H, pyridineH), 8.33 (s, 1H, quinoline-H), 8.37-8.39 (d, J = 4.8 Hz, 2H, pyridineH X 2), 8.55 (s, 1H, pyridineH), 9.01 (s, 1H, pyridineH); ¹³ C NMR (100 MHz, MeOD) δ: 27.3, 28.4, 36.9, 114.9 , 118.1, 120.6, 121.0, 121.2, 123.1, 123.7, 125.7, 126.8, 128.4, 129.0, 129.4, 130.3, 130.7, 132.5, 134.0, 134.3, 134.8, 135.1, 143.6, 144.0, 146.2, 147.6, 147.9, 149.3, 152.6 , 153.3, 153.9 ο 5 mg of the target product of Example 13 was placed in a 5 ml EP tube, 2 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give the hydrochloride salt of the object product of Example 13 as a pale yellow solid. Intermediate 10

0.94 g (3.72 mmol) of diboronic acid pinacol ester was dissolved in 6 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.07 g (0.09 mmol) was added under nitrogen atmosphere, 0.55 g (5.58 mmol) potassium acetate, after stirring for 5 min, 1,4-dioxane containing 0.44 g (1.86 mmol) of 5-bromo-2-(1-methyl-IH-pyrazol-4-yl)pyridine The six-ring solution was refluxed at 100 ° C for 1 h. The temperature was lowered to room temperature, and 0.5-bromo 2-iodopyridine 0.52 g (1.84 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.07 g (0.09 mmol), and cesium carbonate 1.81 g (5.56 mmol) were added thereto under nitrogen atmosphere. 5 mL of 2M sodium carbonate solution was refluxed at 110 °C for 4 h. The mixture was cooled, poured into ice water, and filtered and evaporated tolulululululululululululululululululululu 1H NMR (400 MHz, MeOD) 5: 3.86 (s, 3H, -CH3), 7.51 (d, J = 5.6 Hz, IH, pyrazole-H), 7.57 (d, J = 7.2 Hz, IH, pyridine-H ), 7.83 (d, J = 4.4 Hz, IH, pyrazole-H), 7.89 (s, IH, pyridine-H), 7.97 (s, IH, pyridine-H), 8.21 (d, IH, pyridine-H) , 8.61 (s, 1H, pyridine-H), 8.93 (s, 1H, pyridine-H); ¹³ C NMR (100M Hz, MeOD) δ: 38.7, 119.8, 119.9, 121.3, 121.9, 129.6, 131.2, 135.5, 137.6, 139.7, 146.7, 150.8, 151.6, 152.4. Example 14: 2-Methyl-2-ί4-ί3-methyl-2-oxo-8-ί6-"6-(1-methyl-1-indolylpyridin-4-yl)pyridine-3- Pyridin-3-yl-1H-Z3-dihydroimidazo[4,5-c1 quinolin-1-ylphenylpropanenitrile and its hydrochloride

0.11 g (0.43 mmol) of diboronic acid pinacol ester was dissolved in 4 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.01 g (0.017 mmol), 0.10 was added under nitrogen. After stirring for 5 min, a solution of 0.11 g (1.26 mmol) of intermediate 101 in 1,4-dioxane was added and refluxed at 100 ° C for 1 h. At room temperature, add intermediate 9 0.07 g (0.17 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.01 g (0.017 mmol), cesium carbonate 0.34 g (1.04 mmol), 2M sodium carbonate, under nitrogen protection. 1 mL of the solution was refluxed at 110 ° C for 4 h. The mixture was cooled, poured into ice water, and filtered, and then evaporated tolulululululululululululu %. MS (M+H ⁺ ): calc. 577.24, actual: 577.2. 1H NMR (400 MHz, MeOD) δ: 1.76 (s, 6Η, -CH3x2), 3.55 (s, 3H, -NCH3), 3.82 (s, 3H, -NCH3), 7.10 (s, IH, quinoline-H) , 7.42-7.44 (d, J=8.4Hz, IH, quinoline-H), 7.50-7.52 (d, J=8 Hz, 2H, -ArHx2), 7.55-7.57 (d, J=8 Hz, IH, pyridine -H), 7.62-7.64 (d, J=8 Hz, IH, pyridine-H), 7.70-7.73 (m, 3H _: -ArHx2, quinoline-H), 7.85 (s,lH, pyrazole-H), 7.89 (s, IH, pyrazole-H), 8.04-8.06 (d, J = 8.8 Hz, IH, pyridine-H), 8.11~8.13 (d, J=8 Ηζ, ΙΗ, pyridine-H), 8.43 (s, IH, quinoline-H), 8.66 (s, IH, pyridine-H), 8.92 (s, IH, pyridine-H); ¹³ C NMR (100 MHz, MeOD) δ: 27.5, 28.6, 37.0, 38.6, 115.0, 118.0, 119.5, 119.9, 122.3, 123.1, 123.7, 125.7, 126.8, 129.1, 129.3, 129.4, 130.4, 131.2, 132.3, 133.7, 134.3, 134.4, 134.6, 134.9, 137.4, 143.6, 144.0, 147.2, 147.5, 151.6, 153.2, 153.3.

5 mg of the target product of Example 14 was placed in a 5 ml EP tube, 2 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give the hydrochloride salt of the objective product of Example 14 as a pale yellow solid. (ii) Route 2:

 Route

Synthesis of intermediate 12

4 g (0.0248 mol) of 4-phenyl-piperidine was dissolved in 20 mL of acetic acid, and a mixture of 1.32 mL of concentrated sulfuric acid and 10 mL of acetic acid was added thereto at 25 ° C for 3 min. A mixture of 1.04 mL of nitric acid and 10 mL of acetic acid was added at 20 ° C for 3 min, 20 mL of concentrated sulfuric acid was added, and the temperature was raised to 58 ° C for 6 to 8 h. TLC plate monitoring, after the reaction is completed, the reaction solution is added to ice water, adjusted to pH 12 with 10% sodium hydroxide solution, extracted with ethyl acetate, dried, and dried to give a crude product. : methanol/dichloromethane/ammonia = 50: 500: 1, V: V: V) , obtained as pale yellow solid intermediate 12 4.7 g, yield 92.16%. 1H NMR (400 MHz, CD30D) δ: 1.47 (m, 2H, -CH ₂ -),

1.66 (d, J = 12.4 Hz, 2H), 3.04 (s, 1H, -NH-), 2.59 (m, 3H, -CH-, -CH ₂ -), 3.03 (d, J = 12.4 Hz,

-CH ₂ -), 7.20-7.22 (d, J = 8.8 Hz, 2H, ArH), 7.95-7.97 (d, J = 8.8 Hz, 2H, ArH); ¹³ C NMR (150 MHz, CD30D) 153.9, 145.9, 127.2, 123.2, 46.4, 42.6, 33.5. Synthesis of Intermediate 13

Add 100 1111^1^, 8.3 g (0.0606 mo 1) potassium carbonate to 100 1^ three-necked flask, and add 10 ml of 11 ¹ 1 solution containing 4.2 § (0.0204 1^)1) intermediate 12 under nitrogen protection. Then 4.5 mL of CbzCl was added dropwise. After completion of the reaction, 40 mL of water was added, stirred for 1 h, extracted with ethyl acetate and dried. The crude product was purified by chromatography EtOAcjjjjjjjj 1H NMR (400 MHz, CD30D) δ: 1.59~1.69 (m, 2H, -CH ₂ -), 1.83 (d, 2H, J = 12.0 Hz, -CH ₂ -), 2.75-2.83 (m, 1H, - CH-), 2.89 (s, 2H _: -CH ₂ -), 4.36 (s, 2H, -CH ₂ -), 5.15 (s, 2H, -CH ₂ -), 7.26-7.38 (m, 7H, ArH) , 8.11 (d, 2H, J = 8.8 Hz, ArH); ¹³ C NMR (150 MHz, CD30D) δ: 154.6, 152.6, 146.0, 136.4, 128.0, 127.5, 127.3, 127.2, 123.2, 66.5, 43.8, 41.9, 32.1. Synthesis of intermediate 14

4.57 g (0.0134 mol) of intermediate 13 was dissolved in an appropriate amount of methanol, and 15 ml of a hydrochloric acid solution of pH 4 to 5, 2.26 g (0.0404 mol) of iron powder was added, and the mixture was heated under reflux for 2 h. After completion of the reaction, the mixture was filtered with a celite funnel containing celite, and the filtrate was adjusted to basic with sodium carbonate solution, filtered, and the filtrate was evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1: 2, V: V) gave a white solid intermediate 14 3.7 g, yield 91.8%. 1H NMR (400 MHz, CD30D) δ: 1.60 (m, 2H, -CH ₂ -), 1.81 (m, 2H, -CH ₂ -), 2.55 - 2.61 (m, 1H, -CH-), 2.89 (m , 5H, Ar), 3.63 (s, 2H, -CH ₂ -), 4.37 (s, 2H, -CH ₂ -), 5.22 (s, 2H, -CH ₂ -), 6.64 (d, 2H, J= 8.4 Hz), 6.99 (d, 2H, J=8.4 Hz, ArH), 7.34 (m, 5H, ArH); ¹³ C NMR (150 MHz, CD30D) δ: 155.0, 144.7, 136.7, 135.2, 128.2, 127.7, 127.6, 127.1, 114.9, 66.7, 44.4, 41.3, 33.1. Synthesis of intermediate 15

3.7 g (0.012 mol) of intermediate 14, 70 ml of acetic acid, 3.1 g (0.011 mol) of intermediate 3 in a 250 ml single-necked flask were monitored by TLC for about 2 h. After completion of the reaction, the mixture was filtered, and then filtered, washed, and evaporated to give a yellow solid. Intermediate 15 5.6 g, yield 83.6% 1H NMR (400 MHz, CD30D) 1.60 (m, 2H, -CH ₂ -), 1.81 (m, 2H, -CH ₂ -), 2.55-2.61 (m, 1H, -CH-), 2.89 (m, 5H, Ar), 3.63 (s, 2H, -CH ₂ -), 4.37 (s, 2H, -CH ₂ -), 5.22 (s, 2H, -CH ₂ -), 6.64 (d, 2H, J=8.4 Hz), 6.99 (d, 2H, J=8.4Hz, ArH), 7.34 (m, 5H, ArH); ¹³ C NMR (150 MHz, CD30D) 155.0, 144.7, 136.7, 135.2, 128.2, 127.7, 127.6, 127.1, 114.9, 66.7, 44.4, 41.3, 33.1. Synthesis of intermediate 16

5.8 g (0.0103 mol) of intermediate 15 was dissolved in 116 mL of methanol, 58 mL of acetic acid, 58 mL of water, 2.9 g (0.0518 mol) of iron powder, heated at 90 ° C, refluxed, TLC monitored, about 1 h. Filtration, spinning off the methanol in the filtrate, extracting with dichloromethane, drying, and spinning to obtain a crude product, which was subjected to silica gel column chromatography (eluent: methanol/dichloromethane/ammonia = 8:480:1, V:V :V) gave pale yellow solid intermediate 16 4.5 g, yield 82%. 1H NMR (400 MHz, CD30D) δ: 1.58 (m, 2H, -CH ₂ -), 1.79 (s, 2H, J = 12.4 Hz, ArH), 2.56 (t, IH, -CH-), 2.84 (s , 2H, -CH ₂ -), 4.13 (s, 2H, -NH ₂ -), 4.29 (s, 2H, -CH ₂ -), 5.16 (s, 2H, -CH ₂ -), 6.08 (s, IH , -NH-), 6.60 (d, 2H, J=.8.2Hz, ArH), 7.03 (d, 2H, J=.8.2Hz, ArH), 7.37 (m, 5H, ArH), 7.48 (d, IH , J=.8.4Hz, ArH), 7.85 (d, IH, J=.8.2Hz, ArH), 7.95 (s, IH, ArH), 8.565 (s, IH, ArH); ¹³ C NMR (150 MHz, CD30D) δ: 155.2, 143.8, 141.9, 141.5, 136.8, 136.6, 135.8, 131.1, 128.7, 128.3, 127.8, 127.6, 127.6, 123.7, 123.2, 121.0, 114.6, 66.9, 44.5, 41.5, 33.1. Synthesis of intermediate 17

In a 250 ml three-necked flask, add 54 mL of dichloromethane and 1.13 mL of diphosgene. 4.5 g (0.0085 mol) of intermediate 16, 1.40 mL of Et ₃ N was dissolved in 70 mL of dichloromethane, placed in a dropping funnel, and added dropwise to the reaction flask at 0 ° C, and dripped at about 40 min, at 0 ° C. After 1.5 h of reaction, the sodium bicarbonate solution was quenched, stirred for 5 min, extracted with dichloromethane, and the crude was applied to silica gel column chromatography (eluent: methanol/dichloromethane/ammonia = 8: 480: 1, V: V: V) gave white solid intermediate 17 3.3 g, yield 70.2%. 1H NMR (400MHz, CD30D) δ: 1.92 (s, IH, -NH-), 2.15 (d, 2H, J=4.0 Hz, -CH ₂ -), 3.18 (m, 3H, -CH-, -CH ₂ -), 4.49 (d, 2H, J = 13.2 Hz, -CH ₂ -), 5.35 (s, 2H, -CH ₂ -), 7.28 (s, IH, ArH), 7.29-7.64 (m, 4H, ArH ), 7.80-7.85 (m, 5H, ArH), 8.15 (d, IH, J=9.2Hz, ArH), 9.03 (s, 1H _: ArH), 11.87 (s, IH, -NH-); ¹³ CNMR ( 150 MHz, CD30D) δ: 156.6, 155.6, 149.8, 145.0, 139.3, 136.6, 135.4, 134.4, 131.3, 131.1, 130.9, 130.3, 130.1, 129.6, 129.5, 124.4, 120.7, 118.2, 68.2, 46.1, 43.7, 42.8 Synthesis of Intermediate 18

 Dissolve 9.7 g (0.0175 mol) 17, 0.55 g (0.0017 mol) TBAB in 350 mL of dichloromethane, 1.54 g

(0.0385 mol) sodium hydroxide was dissolved in 187 mL of water and added to the reaction flask. After stirring for 5 min, 2.53 mL of methyl iodide was added and stirring was continued overnight. After completion of the reaction, the mixture was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1H NMR (400 MHz, CD30D, CDC13) 1.89 (d, 2H, J = 10.8 Hz, -CH ₂ -), 2.11 (d, 2H, J = 11.4 Hz, -CH ₂ -), 3.01 (t, 1H, J=12.2Hz, -CH-), 3.08 (s, 2H, -CH ₂ -), 3.78 (s, 3H, -CH ₃ -), 4.53 (s, 2H, -CH ₂ -), 5.31 (s, 2H, -CH ₂ -), 7.45- 7.56 (m, 6H, ArH), 7.61 (m, 4H, J = 8.2 Hz, ArH), 7.70 (d, IH, J = 17.8 Hz, ArH), 8.08 (d, IH, J = 9.0 Hz, ArH) , 8.88 (s, IH, ArH). ¹³ C NMR (150 MHz, CD30D, CDC13) δ: 155.1, 153.5, 147.6, 143.5, 136.7, 132.7, 132.5, 132.0, 130.3, 128.4, 127.9, 127.8, 123.1, 122.8 , 120.0, 116.1, 67.0, 44.4, 42.4, 33.0, 27.8. Synthesis of Intermediate 19

8.5 g (0.0149 mol) of intermediate 18 was dissolved in 85 mL of DMF and heated to 95 °C by adding 0.31 g (0.4417 mmol) of Pd(PPh ₃ ) ₂ Cl _{2 under} nitrogen. 3.1 g (0.0179 mol) of quinoline-3-boronic acid was dissolved in 34 ml of DMF, 7.89 g (0.0744 mol) of sodium carbonate was dissolved in 39.76 mL of water, and added to the reaction flask, and heated at 110 ° C for 2 h. After the completion of the reaction, the reaction mixture was poured into ice water, and the mixture was stirred until the solid was crystallized. Intermediate 19 7.5 g, yield 81.5%. 1H NMR (400 MHz, CD30D, CDC13) ^: 1.71 (d, 2H, J = 9.5 Hz, -CH ₂ -), 1.89 (d, 2H, -CH ₂ -), 2.86 (t, IH, -CH- ), 2.91 (s, 2H, -CH ₂ -), 3.68 (s, 3H, -CH ₃ -), 4.36 (s, 2H, -CH ₂ -), 5.17 (s, 2H, -CH ₂ -), 7.31 (d, IH, ArH), 7.34 (m, IH, ArH), 7.35~7.41 (d, 5H, ArH), 7.68 (m, IH, J=7.6 Hz, ArH), 7.76 (d, IH, J =8.1Hz, ArH), 7.89 (d, IH, ArH), 8.07 (m, 2H, J=2.4Hz, ArH), 8.23 (d, IH, J=8.8 Hz, ArH), 8.80~8.81 (s, 2H, ArH); ¹³ C NMR (150 MHz, CD30D, CDC13) δ: 149.1, 147.8, 147.2, 144.5, 134.8, 133.1, 132.8, 132.5, 132.4, 131.3, 129.6, 129.1, 128.6, 128.3, 127.8, 127.7, 127.6, 127.4, 126.9, 125.8, 123.0, 118.8, 115.2, 67.0, 44.3, 42.3, 33.1, 27.7. Synthesis of intermediate 20

Take 7.0 g (11.34 mmol) of intermediate 19 in 200 ml of methanol/dichloromethane (V: V=l:l) in a mixed solvent, add 7.32 g (116.0 mmol) of HCOONH ₄ , and warm up to 60 ° C in three batches. A total of 3.5 g of Pd/C was added, and the reaction was heated under reflux for 6 h. The Pd/C was removed by filtration, and the crude liquid was concentrated to give a crude product, which was subjected to silica gel column chromatography (eluent: methanol/dichloromethane/ammonia = 50:500:1) V: V: V) obtained white solid intermediate 20 3.5 g, material recovery 2.1 g (reusable) yield 63.6%.

1H NMR (400 MHz, CD30D, CDC13) ^: 1.78 (m, 2H, J = 15.4 Hz, -CH ₂ -), 1.96 (d, 2H, J = 12.5 Hz,

-CH ₂ -), 2.87 (t, 2H, J = 23.4 Hz, -CH ₂ -), 2.89 (m, IH, -CH-), 3.25 (d, 2H, J = 12.2 Hz, -CH ₂ -) , 3.74

(s, 3H, -CH ₃ ), 7.36 (s, IH, ArH), 7.57 (m, 4H, ArH), 7.64 (s, IH, ArH), 7.61 (s, IH, ArH), 7.89 (d,

IH, J = 12.2 Hz, ArH), 7.99 (d, IH, J = 1.4 Hz, ArH), 8.08 (d, IH, J = 8.4 Hz, ArH), 8.18 (s, IH, ArH), 8.24 (d , IH, J=8.9Hz, ArH), 8.80 (s, IH, ArH), 8.86 (s, IH, ArH); ¹³ C NMR (150 MHz, CD30D, CDC13) δ: 153.5, 148.3, 146.3, 143.7, 134.7, 133.6, 132.5, 132.4, 132.3, 130.0, 129.7, 129.6, 128.3, 128.1, 127.7, 127.6, 127.4, 126.9, 126.1, 122.8, 118.6, 115.0, 45.5, 41.6, 32.6, 27.2. Example 15: 3-Methyl-1-"4-indolyl-piperidyl-4-yl)phenyl 1 -8-(quinolin-3-yl)-l-imidazole and "4,5- Cl quinoline-2 (3H)-one

Ol G (0.21 mmol) Intermediate 20 was dissolved in 20 ml of CH ₂ C1 ₂ , then 0.14 ml (1O mmol) Et ₃ N, 0.06 ml (0.85 mmol) CH ₃ C0C1 was added and stirred at room temperature for 1 h. After completion of the reaction, the crude product was obtained by chromatography (jjjjjjjjjjjj , the yield was 72.7%. MS (M+H ⁺ ): Calcd. 528.23. 1H NMR (400 MHz, CD30D, CDC13) δ: 1.65 (t, 2H, J = 12.2 Hz, -CH ₂ -), 1.96 (t, 2H, J = 16.8 Hz, -CH ₂ -), 2.11 (s, 3H, -CH ₃ ), 2.69 (t, IH, J = 12.4 Hz, -CH-), 2.91 (t, IH, J = 11.4 Hz, -CH ₂ -), 3.23 (t, IH, J = 12.6 Hz , -CH ₂ -), 3.66 (s, 3H, -CH ₃ ), 3.94 (d, IH, J = 12.8Hz, -CH ₂ -), 4.27 (s, IH, -CH ₂ -), 7.26 (s , IH, quinoline-H), 7.48 (s, 4H, -Ar), 7.58 (t, IH, quinoline-H), 7.73 (t, IH, quinoline-H), 7.78 (d, IH, J=12.2 Hz , quinoline-H), 7.88 (d, IH, J=8.4Hz, quinoline-H), 8.04 (d, IH, J=8.4Hz, quinoline -H), 8.07 (s, 1H, quinoline-H), 8.16 (d, 1H, J=8.4Hz, quinoline -H), 8.71 (s, 1H, quinoline-H), 8.71-8.76 (d, 2H, quinoline -H); ¹³ C NMR (150 MHz, CD30D, CDC13) δ: 169.3, 153.4, 148.5, 147.4, 146.5, 143.9, 134.7, 133.4, 132.8, 132.3, 132.3, 130.3, 129.8, 129.5, 128.5, 128.2, 128.1, 127.6, 127.4, 127.0, 126.1, 122.9, 118.6, 115.0, 48.7, 48.5, 48.3, 48.1, 47.9, 46.6, 41.9, 41.7, 33.4, 32.2, 27.4, 20.7. Example 16: l-(4-n- 4H-U,4-Triazolyl-3-carbonyl)piperidin-4-yl)phenyl 3-methyl-8-(quinolin-3-yl 1H- Imidazo-"4,5-cl-quinoline-2 (H-ketone)

0.15 g (0.31 mmol) of intermediate 20 was dissolved in 30 ml of CH ₂ C1 ₂ , 0.1 g (0.52 mmol) of EDCI, 0.07 g (0.53 mmol) of HOBT was added, stirred until dissolved and 0.03 g (0.27 mmol) 1,2 was added. , 4-triazole-3-carboxylic acid, stirred at room temperature for 12 h, detected by TLC. After completion of the reaction, the crude product was purified by chromatography (jjjjjjjjjjjj , the yield was 55.6%. MS (M+H ⁺ ): Calcd. 581.21. 1H NMR (400 MHz, CD30D, CDCB) 1.65 (t, 2H, J = 12.2 Hz, -CH ₂ -), 1.96 (t, 2H, J = 16.8 Hz, -CH ₂ -), 2.69 (t, IH, J=12.4 Hz, -CH-), 2.91 (t, IH, J=11.4 Hz, -CH ₂ -), 3.23 (t, IH, J=12.6 Hz, -CH ₂ -), 3.66 (s, 3H, -CH ₃ ), 3.94 (d, IH, J = 12.8 Hz, -CH ₂ -), 4.27 (s, IH, -CH ₂ -), 7.26 (s, IH, quinoline-H), 7.48 (s, 4H , -Ar), 7.58 (t, IH, quinoline-H), 7.73 (t, IH, quinoline-H), 7.78 (d, IH, J=12.2 Hz, quinoline-H), 7.88 (d, IH, J =8.4Hz, quinoline-H), 8.04 (d, IH, J=8.4Hz, quinoline-H), 8.07 (s, IH, quinoline-H), 8.16 (d, IH, J=8.4Hz, quinoline -H ), 8.54 (s, IH), 8.71 (s, IH, quinoline-H), 8.71-8.76 (d, 2H, quinoline -H); ¹³ C NMR (150 MHz, CD30D, CDC13) δ: 169.3, 153.4, 151, 148.5, 147.4, 146.5, 143.9, 134.7, 133.4, 132.8, 132.3, 132.3, 130.3, 129.8, 129.5, 128.5, 128.2, 128.1, 127.6, 127.4, 127.0, 126.1, 122.9, 118.6, 115.0, 48.7, 48.5, 48.3, 48.1, 47.9, 46.6, 41.9, 41.7, 33.4, 32.2, 27.4. Example 17: 3-Methyl-1-ί4-"1-(2-hydroxyethyl)piperidin-4-yl 1phenyl 8-(quinolin-3-yl)-1?-imidazole and "4 , 5-cl quinoline-2 ( 3H) - ketone

0.07 g (0.14 mmol) of intermediate 20 was dissolved in 22 ml of CH ₂ C1 ₂ , and 0.05 g (0.261 mmol) of EDCI, 0.04 g (0.296 mmol) of HOBT was added to the solution. After stirring until dissolved, 0.02 g (0.263 mmol) of ethanol was added. Acid, stirring at room temperature 12 h, TLC detection. After completion of the reaction, the residue was purified by EtOAc EtOAcjjjjjjjjj , the yield was 92.0%. MS (M+H ⁺ ): Calcd. 544.21. 1H NMR (400 MHz, CD30D, CDC13) δ: 0.94 (m, 2H, -CH ₂ -), 1.71 (d, 2H, -CH ₂ -), 2.56 (t, IH, J = 12. 4 Hz, - CH ₂ -), 2.69 (t, IH, J = 12.2 Hz, -CH-), 2.89 (t, IH, J = 12. 2 Hz, -CH ₂ -), 3.17 (s, IH, -CH ₂ - ), 3.40 (s, 3H, -CH ₃ ), 3.97 (t, 2H, -CH ₂ -), 4.46 (d, IH, J = 13.2Hz, -CH ₂ -), 6.99 (s, IH, quinoline- H), 7.24 (m, 4H, -Ar), 7.32 (m, IH, quinoline-H), 7.51 (m, 2H, quinoline-H), 7.61 (d, IH, J=8.8 Hz, quinoline-H) , 7.79 (d, IH, J=8.4 Hz, quinoline-H), 7.82 (s, IH, quinoline-H), 7.93 (d, IH, J=8.8Hz, quinoline-H), 8.45 (d, IH, J=1.6 Hz, quinoline-H), 8.50 (s, IH, quinoline-H); ¹³ C NMR (150 MHz, CD30D, CDC13) 169.7, 153.5, 148.8, 147.2, 146.8, 144.2, 134.9, 133.4, 133.1, 132.5, 132.4, 130.8, 129.9, 129.6, 128.7, 128.6, 128.3, 128.2, 127.7, 127.5, 127.2, 126.2, 123.0, 118.7, 115.1, 59.5, 43.8, 42.7, 42.1, 33.3, 32.3, 27.7. Example 18: 3-Methyl-1-ί4-"1-(2-hydroxypropionyl)piperidine-41)-phenyl 8-(quinolin-3-yl)-1?-imidazole and "4, 5-cl quinoline-2 (3H)-one

0.15 g (0.31 mmol) of intermediate 20 was dissolved in 22 ml of CH ₂ C1 ₂ , 0.08 g (0.41 mmol) of EDCI, 0.06 g (0.45 mmol) of HOBT was added, stirred until dissolved and 0.03 g (0.33 mmol) of L-lactic acid was added. Stir at room temperature for 12 h, TLC detection. After completion of the reaction, the crude product was obtained by chromatography (jjjjjjjjjjjjj , the yield was 92.0%. MS (M+H ⁺ ): Calcd. 558.24, found: 558.2. 1H NMR (400 MHz, CD30D, CDC13) δ: 1.26 (d, 3H, J = 6.4 Hz, -CH ₃ ), 1.56 (t, 2H, J = 10.8 Hz, -CH ₂ _), 1.82-1.91 (m , 2H, -CH ₂ -), 2.62-2.71 (m, 2H, -CH-), 3.09 (t, IH, J=11.8 Hz, - CH-), 3.50 (s, 3H, -CH ₃ ), 3.69 (s, 2H, -CH ₂ -), 3.78 (s, IH, -CH ₂ -), 4.43 (s, IH, -CH ₂ -), 4.63 (t, IH, -OH), 7.09 (d, IH , J=15.6 Hz, quinoline -H), 7.31~7.41 (m, 5H, -Arx4, quinoline-H), 7.56-7.66 (m, 3H, quinoline-H), 7.87 (d, 1H, J=9.2Hz , quinoline-H), 7.95 (d, IH, J=7.6Hz, quinoline-H), 8.01 (d, IH, quinoline-H), 8.53 (s, IH, quinoline-H), 8.63 (d, 1H, J=12.4 Hz, quinoline-H); ¹³ C NMR (150 MHz, CD30D, CDC13) δ: 173.0, 172.9, 153.1, 146.9, 146.6, 143.8, 134.3, 132.8, 132.2, 131.9, 130.5, 129.5, 129.1, 128.4, 128.0, 127.4, 127.2, 127.0, 126.8, 125.6 , 122.7, 118.2, 114.7, 64.0, 45.1, 42.7, 41.8, 33.3, 32.2, 27.4, 21.1. Example 19: 3-Methyl-l-"4-(1-methanesulfonylpiperidin-4-yl)-phenyl 1-8-(quinolin-3-yl)-1H-imidazole and "4 , 5-cl quinoline-2 (3H)-one

0.1 g (0.21 mmol) of the intermediate 20 was dissolved in 20 ml of CH ₂ Cl ₂ , then 0.14 ml (1O mmol) Et ₃ N, 0.03 ml (0.39 mmol) CH ₃ S0 ₂ C1 was added and stirred at room temperature for 1 h. After completion of the reaction, the crude product was obtained by EtOAcjjjjjjjjjjjjjjjjjjjjjj g, yield 77.6%. MS (M+H+): Calcd. 564.20, found: 564.2. 1H NMR (400 MHz, CD30D, CDC13) ^: 1.83 (m, 2H, J = 10.9 Hz, -CH ₂ -), 1.96 (d, 2H, J = 11.7 Hz, -CH ₂ -), 2.76-2.82 ( m, 4H, -CH-, -CH ₃ -), 3.65 (s, 3H, -CH ₃ -), 3.87 (d, 2H, J = 10.5 Hz, -CH ₂ -), 4.13 (s, 2H, - CH ₃ -), 7.26 (s, IH, quinoline-H), 7.48 (s, 4H, -Ar), 7.58 (t, IH, J=6.9Hz, quinoline-H), 7.71 (t, IH, J= 6.8 Hz, quinoline-H), 7.78 (d, IH, J=7.6 Hz, quinoline-H), 7.89 (d, IH, J=8.3 Hz, quinoline-H), 8.01 (d, IH, J=8.0 Hz , quinoline-H), 8.07 (s, IH, quinoline-H), 8.16 (d, IH, J=8.6 Hz, quinoline-H), 8.70 (s, IH, quinoline-H), 8.76 (s, IH, quinoline-H) ¹³ C NMR (150 MHz, CD30D, CDC13) δ: 153.6, 148.7, 147.4, 146.7, 144.1, 135.0, 133.6, 133.1, 132.6, 132.4, 130.6, 130.0, 129.7, 128.7, 128.3, 127.1, 127.5 , 127.3, 126.3, 123.0, 118.8, 115.2, 46.1, 41.5, 34.5, 32.6, 27.6. Example 19-a: (RVl-(4-n-i2-hydroxypropionyl)piperidin-4-yl)phenyl 3-methyl-8-(quinolin-3-yl 1H-imidazolium "4 , 5-cl quinoline-2 (H ketone

Compound 20 (0.2 g, 0.41 mmol) was dissolved in CH ₂ C1 ₂ (50 ml), EDCI (0.12 g, 0.63 mmol) was added, HOBT (0.08, 0.59 mmol) was stirred and dissolved, then D-lactic acid (0.04 g, 0.4) was added. Methyl) stirred at room temperature for 12 h, detected by TLC, the reaction was completed, the liquid was dried to dryness, and the crude material was purified by silica gel column chromatography [eluent (methanol: dichloromethane: ammonia) = 50:500:1 (v:v: v) ] After purification, the title compound of Example 19-a was obtained. 1H NMR (400 MHz, CD ₃ OD, CDCI3) . 1.35 (d, 3H, J=8.0Hz, -CH ₃ ), 1.64 (t, 2H, J=12.0Hz, -CH ₂ _), 1.97-2.14 ( m, 2H, -CH ₂ -), 2.94 (m, 1H, -CH-), 3.18 (t, 1H, -CH-), 3.68 (s, 3H, -CH ₃ ), 3.83 (d, 1H, - CH ₂ -), 4.50 (d, 1H, -CH ₂ -), 4.78 (s, 1H, -CH ₂ -), 7.28 (d, 1H, J=8.0Hz, quinoline -H), 7.47-7.50 (m , 4H, -ArX 4), 7.57 (m, 1H, quinoline-H), 7.71 (m, 2H, J=28Hz, quinoline-H), 7.86 (d, 1H, J=8.0Hz, quinoline-H), 8.10 (d, 2H, quinoline-H), 8.21 (d, 1H, J=8.0Hz, quinoline-H), 8.76 (d, 2H, J=24Hz, quinoline-H). ¹³ C NMR (100 MHz, CD ₃ OD, CDC1 ₃ ) ···173.3, 153.5, 149.1, 147.2, 144.4, 135.0, 133.5, 133.2, 132.5, 131.2, 129.8, 129.7, 129.0, 128.9, 128.4, 127.8, 127.6, 127.2, 126.1, 123.2, 118.9, 115.3, 64.0, 45.4, 45.1, 43.1, 43.0, 42.4, 33.8, 33.5, 32.6, 29.6, 29.2, 27.9, 21.8, 21.2.

(3) Route 3

 Route 3 Synthesis of Intermediate 22

8.0 g (25.9 mmol) of intermediate 21 was dissolved in 150 ml of acetic acid, and 7.0 g (24.4 mmol) of intermediate 3 was added dropwise, and stirred at room temperature for 2 h. After completion of the reaction, the mixture was filtered and washed with water to give a pale yellow solid, 22 11.5 g, yield 80%. 1H NMR (400 MHz, CDC13) δ: 2.49 (s, 2H, -CH ₂ -), 3.68 (s, 2H, -CH ₂ -), 4.12 (s, 2H, -CH ₂ -), 5.12 (s, 2H, -CH ₂ -) _: 6.02 (s, 1H, =CH-), 7.04 (d, 2H, J=7.4 Hz, -Ar), 7.25~7.32 (m, 7H, -Ar), 7.63 (d, 1H, J=8.4Hz _: quinoline H), 7.69 (s, 1H, quinoline H), 7.75 (d, 1H, J=8.1Hz, quinoline-H), 9.31 (s, 1H _: quinoline-H), 10.44 ( s, 1H, -NH-); ¹³ C NMR (150 MHz, CDC13) δ: 155.0, 148.7, 146.6, 144.8, 138.9, 138.7, 136.4, 135.3, 134.1, 133.9, 131.6, 129.3, 128.4, 128.2, 127.7, 127.6, 126.0, 123.0, 121.3, 120.7, 120.0, 119.1, 66.8, 43.5, 40.2, 29.4, 26.8. Synthesis of intermediate 23

11.5 g (20.59 mmol) of intermediate 22 was dissolved in 180 ml of methanol, completely dissolved, and then 100 ml of a mixed solution of CH ₃ COOH and 100 ml of water was added, and 5.8 g of Fe powder was heated and refluxed for 3-5 h. After the reaction is completed, the mixture is filtered, Na ₂ C0 ₃ ( aq) is adjusted to pH, and filtered with suction. The filtrate is taken from methanol, extracted with dichloromethane, dried, and then evaporated to dryness. Liquid: methanol/dichloromethane/ammonia = 12.5: 500:1, V: V: V), obtained as a white solid intermediate 23 10.5 g, yield 9.65 %. Synthesis of intermediate 24

 1.29 g (6.52 mmol) of diphosgene was dissolved in 20 ml of dichloromethane and placed in a 100 ml three-necked flask. 3.0 g (5.68 mmol) of intermediate 23, 0.69 g (6.81 mmol) of triethylamine was dissolved in 45 ml of dichloromethane, placed in a dropping funnel, and added dropwise to the reaction flask at 0 ° C for about 40 min. After completion, the reaction was carried out at 0 ° C for 1.5 h, the sodium bicarbonate solution was quenched, stirred for 5 min, extracted with dichloromethane, and then evaporated to dryness. Synthesis of intermediate 25

2.55 g (4.60 mmol) of intermediate 24, 0.15 g (0.47 mmol) of TBAB was dissolved in 100 mL of dichloromethane, 50 ml of 1% NaOH solution was added, stirred for 5 min, then 0.72 ml (11.56 mmol) of methyl iodide was added, TLC Detection. After completion of the reaction, the mixture was extracted with methylene chloride. EtOAc (EtOAc) 78.5%. 1H NMR (400 MHz, CDCB) 2.62 (s, 2H, -CH ₂ -), 3.62 (s, 3H, -CH ₃ -), 3.75 (t, 2H, -CH ₂ -), 4.21 (d, 2H, J=2.4Hz, -CH ₂ -), 5.18 (s, 2H, O-CH2-), 6.16 (d, IH, =CH-), 7.28-7.32 (m, 2H, -Ar), 7.34-7.40 ( m, 4H, -Ar), 7.43 (d, 2H, J=8.4 Hz, -Ar), 7.54 (m, IH, -Ar), 7.59 (d, 2H, J=8.4 Hz, quinoline-H), 7.93 (d, IH, J=9.2 Hz, quinoline-H), 8.74 (s, IH, quinoline-H), ¹³ C NMR (150 MHz, CDC13) δ: 155.2, 153.4, 143.2, 142.1, 136.6, 134.6, 134.3 , 133.3, 132.3, 131.8, 130.4, 128.4, 128.2, 128.1, 127.9, 127.8, 126.4, 123.2, 122.8, 122.5, 120.2, 116.0, 67.0, 43.7, 40.6, 27.8, 27.0. Synthesis of intermediate 26

 2.0 g (3.52 mmol) of intermediate 25 was dissolved in 20 mL of DMF and 0.08 g (0.11 mmol) was added under nitrogen.

Pd(PPh3)2C12 was heated to 95 °C. 0.73 g (4.22 mmol) of quinoline-3-boronic acid was dissolved in 9 ml of DMF, 1.86 g (0.0744 mol) of sodium carbonate was dissolved in 3 mL of water, and added to the reaction flask, and heated at 110 ° C for 2 h. After the reaction, add 200 ml of water and stir. The solid was precipitated, and the crude product was filtered,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1H NMR (400 MHz, CDCB) 2.60 (s, 2H, -CH ₂ -), 3.63 (s, 3H, -CH ₃ -), 3.78 (s, 2H, -CH ₂ -), 4.20 (s, 2H, -CH ₂ -), 5.20 (d, 2H, J = 13.6 Hz, -CH ₂ -), 6.11 (d, 1H, J = 22.4 Hz, -CH-, 7.31~7.41 (m, 6H, quinoline -Hx4, -Arx2), 7.48 (d, 3H, J=8.4 Hz, -Ar), 7.58-7.65 (m, 4H, -Ar), 7.84 (d, 1H, J=8.8 Hz, quinoline-H), 7.91 (s , 1H, quinoline-H), 8.03-8.20 (m, 2H, quinoline-H), 8.75 (s, 1H, quinoline-H), 8.86 (s, 1H, quinoline-H); ¹³ C NMR (150 MHz, CDC13) δ: 155.1, 153.3, 149.0, 147.2, 144.2, 142.4, 136.6, 134.7, 133.8, 132.3, 132.1, 131.1, 129.6, 129.4, 129.0, 128.5, 128.4, 127.9, 127.8, 127.6, 127.5, 127.0, 126.4, 125.7, 123.1,

122.8, 122.2, 118.7, 115.1, 67.0, 53.3, 43.7, 40.5, 27.2, 27.4. Synthesis of intermediate 27

2.0 g (3.24 mmol) of intermediate 26 was dissolved in 50 ml of methanol/dichloromethane (V: V=l: l) in a mixed solvent, 2.09 g (33.14 mmol) of HCOONH _{4 was added} , and the temperature was raised to 60 ° C in three batches. Add 1 g of Pd/C, heat and reflux for 6 h, remove Pd/C by filtration, and concentrate the crude liquid to silica gel column chromatography (eluent: methanol/dichloromethane/ammonia = 50:500:1, V : V: V) White solid intermediate 27 0.97 g, material recovery 0.6 g (reusable yield 61. 1%. 1H NMR (400 MHz, CD ₃ OD, CDCl ₃ ) δ: 2.32 (s, 2H, -CH ₂ -), 2.89 (m, 2H, -CH ₂ -), 3.32 (s, 2H, -CH ₂ -), 3.43 (s, 3H, -CH ₃ -), 4.33 (s, 1H, -NH-) , 6.03 (s, 1H, =CH-), 7.13 (s, 1H, quinoline- H), 7.26~7.31 (m, 2H, quinoline-H), 7.33 (d, 1H, J=7.4 Hz, quinoline- H ), 7.43 (d, 2H, J=8.4 Hz, -Ar), 7.47 (m, 2H, -Ar), 7.66 (d, 1H, J=8.8 Hz, quinoline-H), 7.75~7.79 (m, 2H) , quinoline—H), 7.90 (d, 1H, J=8.9 Hz, quinoline-H), 8.54 (s, 2H, quinoline-H); ¹³ C NMR (150 MHz, CD ₃ 0D, CDC1 ₃ ) δ: 155.3 , 148.1, 146.3, 143.7, 142.5, 134.4 , 134.0, 133.4, 133.2, 132.2, 131.9, 130.1, 129.7, 129.4, 128.2, 127.7, 127.6, 127.4, 126.9, 126.6, 126.0, 125.8, 123.7, 122.8, 118.4,

114.9, 44.0, 41.9, 27.2, 26.2. Example 20: 3-Methyl-l-"4-(1-ethenyl-1,2,3,6-tetrahydropyridin-4-yl)-phenyl 1-8-(quinoline-3- -1H-imidazo-"4,5-cl-quinolin-2(3H)-one and its hydrochloride

Take O. lg (0.21 mmol) of Intermediate 27 was dissolved in 20 ml CH ₂ C1 _2, were added _{0.14 ml (1.0 mmol) Et 3} N, 0.06 ml (0.85 mmol) CH 3 COCl, stirred at room temperature lh. After completion of the reaction, the crude product was obtained by chromatography (jjjjjjjjjjjj , the yield was 72.7%. MS (M+H ⁺ ): 520.22, calc.: 526.2. 1H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) δ: 1.13 (s, IH, -CH ₂ -), 2.07 (m, 2H, -CH ₂ -), 2.50 (s, IH, -CH ₂ -) , 2.57 (s, IH, -CH ₂ -), 3.60 (s, 3H, -CH3-), 3.62-4.09 (m, 3H, -CH ₃ -), 4.18 (s, IH, -CH ₂ -), 6.14 (d, IH, =CH-), 7.31 (d, IH, J=7.2 Hz, quinoline - H), 7.45-7.50 (m, 3H, quinoline - H), 7.57 (d, 2H, J=8.4 Hz , -Ar), 7.62-7.67 (m, 2H, -Ar), 7.84 (m, IH, quinoline-H), 7.94 (m, 2H, quinoline-H), 8.11 (d, IH, J=8.8 Hz, Quinoline - H), 8.72 (m, 2H, quinoline -H); ¹³ C NMR (150 MHz, CD30D, CDC1 ₃ ) δ: 168.5, 153.5, 149.5, 148.6, 146.7, 142.1, 136.4, 135.4, 134.9, 133.9, 133.6, 130.3, 130.0, 128.9, 128.5, 128.1, 127.5, 127.2, 126.9, 126.3, 125.3, 123.1, 122.7, 122.0, 121.3, 121.1, 118.7, 115.2, 45.6, 42.0, 29.4, 27.6, 26.9, 21.3.

 5 mg of the target product of Example 20 was placed in a 5 ml EP tube, 2 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give the hydrochloride salt of the objective product of Example 20 as a pale yellow solid. Example 21: 1-(4-indole-indol-1,2,4-triazole-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3- Methyl-8-(quinolin-3-yl)-1Η-imidazolium "4,5-cl-quinoline-2 (H-ketone and its hydrochloride)

0.15 g (0.31 mmol) of intermediate 27 was dissolved in 30 ml of CH ₂ Cl ₂ , O. lg (0.52 mmol) EDCI, 0.07 g (0.53 mmol) HOBT was added, stirred until dissolved and 0.03 g (0.27 mmol) 1,2 was added. , 4-triazole-3-carboxylic acid, Stir at room temperature for 12 h, TLC detection. After completion of the reaction, the residue was purified by EtOAc EtOAcjjjjjjjjj , the yield was 55.5%. MS (M+H ⁺ ): calc. 579.22, calc.: 579.2. 1H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) δ: 1.86 (d, 2H, J=22.3 Hz, -CH ₂ -), 2.84 (s, 3H, -CH ₃ -), 3.11 (s, 1H, -CH ₂ -), 3.18 (s, 1H, -CH ₂ -), 3.52 (s, IH, -CH ₂ -), 3.58 (s , IH, -CH ₂ -), 6.45 (s,lH,-CH-), 6.70 (m, 2H, quinoline-H), 6.82-6.88 (m, 4H, Ar-H), 6.94 (d, 1H, J=8.1 Hz, quinoline-H), 7.07 (d, 1H, J=7.7 Hz, quinoline-H), 7.18 (d, 2H, quinoline-H), 7.36 (t, 2H, quinoline-H), 7.94 ( s, IH, triazole-H), 8.00 (d, IH, J=7.6 Hz, quinoline-H); ¹³ C NMR (150 MHz, CD ₃ OD, CDC1 ₃ ) δ: 153.6, 148.8, 146.8, 144.2, 141.4 , 135.0 133.9, 133.7, 132.5, 130.8, 130.1, 128.7, 128.4, 128.1, 127.8, 127.4, 126.6, 126.3, 125.6, 123.2, 122.2, 121.7, 118.9, 117.6, 115.3, 110.5, 46.5, 43.5, 39.8, 28.0.

 5 mg of the objective product of Example 21 was placed in a 5 ml EP tube, 5 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give a pale yellow solid. Example 22: 3-Methyl-1-ί4-"1-(2-hydroxyethyl)- 1,2,3,6-tetrahydropyridin-4-yl 1-phenyl 8-(quinoline- 3-yl)-1,1-imidazolium "4,5-cl-quinolin-2 (3H)-one and its hydrochloride

0.07 g (0.14 mmol) of intermediate 27 was dissolved in 22 ml of CH ₂ C1 ₂ , 0.05 g (0.261 mmol) of EDCI, 0.04 g (0.296 mmol) of HOBT was added, stirred until dissolved and 0.02 g (0.263 mmol) of glycolic acid was added. Stir at room temperature for 12 h, TLC detection. After completion of the reaction, the crude product was obtained by chromatography (jjjjjjjjjjjjj , yield 87%. MS (M+H ⁺ ): Calcd. 542.21. 1H NMR (400MHz, CD ₃ OD , CDC1 ₃ ) δ: 1.83 (s, 2Η, -CH ₂ -), 2.75 (t, 1H, J=5.2 Hz, -CH ₂ -), 2.87 (s, 3H, - CH ₃ -), 3.05 (t, IH, J = 5.2 Hz, -CH ₂ -), 3.22 (s, IH, -CH ₂ -), 3.42 (m, 3H, -CH ₂ -), 5.34 (d, IH, =CH-), 6.56 (m, IH, quinoline-H), 6.72-6.76 (m, 3H, quinoline-H), 6.84 (d, 2H, J=8.0 Hz, -Ar), 6.89-6.94 ( m, 2H, -Ar), 7.11 (d, IH, J=8.8 Hz, quinoline-H), 7.19-7.23 (m, 2H, quinoline-H), 7.36 (d, IH, J=8.9 Hz, quinoline- H), 7.98 (s, 2H, quinoline-H); "CNMR (150MHz, CD ₃ OD, CDC1 ₃ ) δ: 169.5, 153.5, 148.4, 146.5, 143.9, 141.9, 134.8, 133.9, 133.6, 132.4, 132.2, 130.3, 130.0, 129.6, 128.5, 128.0 , 127.6, 127.2, 126.4, 126.2, 126.1, 123.0, 122.0, 120.5, 118.6, 115.1, 59.8, 42.7, 40.4, 38.7, 27.5.

 5 mg of the target product of Example 22 was placed in a 5 ml EP tube, 2 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to obtain the hydrochloride salt of the objective product of Example 22 as a yellow solid. Example 23: 3-Methyl-1- ί4-"1-(2-hydroxypropionyl)-1,2,3,6-tetrahydropyridin-4-yl 1-phenyl 8-(quinoline- 3-yl) -1Η-imidazolium "4,5-cl-quinolin-2(3H)-one and its hydrochloride

0.15 g (0.31 mmol) of intermediate 9 was dissolved in 22 ml of CH ₂ C1 ₂ and 0.08 g (0.41 mmol) of EDCI was added.

0.06 g (0.45 mmol) HOBT, stir to dissolve, then add 0.03 g (0.33 mmol) L-lactic acid, stir at room temperature for 12 h, and detect by TLC. After completion of the reaction, the residue was purified by EtOAc EtOAcjjjjjjjjj , the yield was 64.7%. MS (M+H ⁺ ): Calcd. 556.23, found: 556.2. 1H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) δ: 2.44 (d, 2H, J = 21.8 Hz, -CH ₂ -), 3.50 (s, 3H, -CH3-), 3.57 (s, 2H, - CH ₂ -), 4.10 (s, 1H, -CH ₂ -), 4.22 (s, 4H, -CH ₃ -, -CH ₂ -), 4.14 (m, 1H, -CH-), 6.01 (d, 1H , J= 18.6 Hz, =CH-), 7.19 (d, 1H, J=6.2H z, quinoline-H), 7.36-7.40 (m, 3H, quinoline-H), 7.49-7.56 (m, 4H, - Ar), 7.74 (d, 1H, J=8.6 Hz, quinoline-H), 7.82-7.89 (m, 2H, quinoline-H), 8.00 (d, 1H, J=8.8 Hz, quinoline-H), 8.62 ( s, 2H, quinoline-H); ¹³ C NMR (150MHz, CD3OD, CDCI3) δ: 173.3, 153.4, 148.3, 146.4, 143.7, 141.8, 134.7, 133.7, 133.6, 132.2, 132.1, 130.1, 130.0, 128.4, 127.9 , 127.6, 127.5, 127.1, 126.2, 126.1, 126.0, 123.0, 122.0, 120.9, 118.5, 115.0, 64.5, 44.2, 41.5, 29.1, 27.4, 20.3.

5 mg of the target product of Example 23 was placed in a 5 ml EP tube, 2 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give the hydrochloride salt of the objective product of Example 23 as a pale yellow solid. Example 24: 3-Methyl small 4-4-"1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl 1-phenyl 8-(quinolin-3-yl) -IH-imidazolium "4,5-cl-quinolin-2 (3H)-one and its hydrochloride

0.1 g (0.21 mmol) of intermediate 27 was dissolved in 20 ml of CH ₂ C1 ₂ , then 0.14 ml (1.O mmol) Et ₃ N, 0.03 ml (0.39 mmol) CH ₃ S0 ₂ C1 was added and stirred at room temperature for 1 h. After completion of the reaction, the crude product was obtained by EtOAcjjjjjjjjjjjjjjjjjj g, yield 77%. MS (M+H ⁺ ): Calcd. 562.18. 'HNMR (400 MHz, CD ₃ OD, CDCI3) δ: 3.42 (s, 2H, -CH ₂ -), 3.58 (s, 3H, -CH ₃ -), 4.23 (m, 2H, -CH ₂ -), 4.39 (s, 3H, -CH3-), 4.69 (s, 2H, -CH ₂ -), 6.91 (s, IH, =CH-), 8.09 (s, IH, quinoline-H), 8.24 (d, 2H , J=8.0 Hz, quinoline-H), 8.28 (t, IH, J=7.4 Hz, quinoline-H), 8.36 (d, 2H, J=8.2 Hz, -Ar), 8.40 (t, 2H, J= 8.1 Hz, -Ar), 8.64 (d, IH, J=8.7 Hz, quinoline-H), 8.73 (s, 2H, quinoline-H), 8.90 (d, 2H, J=8.8 Hz, quinoline-H), 9.52 (s, 2H, quinoline-H); ¹³ C NMR (150 MHz, CD ₃ OD, CDC1 ₃ ) 153.5, 148.5, 146.7, 143.6, 142.0, 135.0, 134.4, 133.9, 133.6, 132.2, 132.0, 130.1, 128.6 , 128.2, 127.7, 127.4, 126.6, 126.4, 123.2, 121.3, 118.7, 115.1, 44.8, 42.4, 35.1, 27.7, 27.3.

 5 mg of the target product of Example 24 was placed in a 5 ml EP tube, 2 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give the hydrochloride salt of the objective product of Example 24 as a gray solid. Example 24-a: 3-Methyl-8-(quinolin-3-yl-l-i4-n-(tetrahydro-2H-pyran-4-carbonyl)-1 3,6-tetrahydropyridine-4 -yl)phenyl) -1Η-imidazolium "4,5-cl-quinoline-2 3H

Dissolve 0.4 g (0.83 mmol) of intermediate 27 in 70 ml of dichloromethane, add EDCI (0.19 g, 0.99 mmol), hydrazine (0.13 g, 0.99 mmol), stir and dissolve, then add tetrahydropyran-4-carboxylic acid 0.11 g (0.84 mmol), stirring at room temperature for 12 h, TLC detection, the reaction is finished, directly lyophilized to give a crude product. The solution (methanol: methylene chloride) = 1 : 30 (v: v). 'HNMR (400 MHz, CDC1 ₃ ) δ : 1.23 (s, 2H, -CH ₂ -), 1.58-1.76 (t, 2H, -CH ₂ -), 1.96 (s, 2H, -CH ₂ -) _: 2.61 ~2.67(d, 2H, J = 26.0 Hz, -CH ₂ -), 3.50(s, 2H, -CH ₂ -), 3.68(s, 3H, -CH ₃ -), 4.04(s, 2H, -CH ₂ -) 6.16 (d, IH, J=32.4Hz, =CH-), 7.40-7.54 (m, 4H, ArH), 7.62-7.70 (m, 4H, quinoline-H), 7.90 (s, IH, quinoline -H), 8.01-8.05 (m, 2H, quinoline-H), 8.21~8.22 (d, IH, J=6.8Hz, quinoline-H), 8.79(s, 2H, quinoline-H). ¹³ C NMR ( 100 MHz, CDC1 ₃ ) δ: 173.0, 153.5, 149.2, 147.3, 144.6, 142.1, 134.9, 134.1, 133.8, 133.1, 132.7, 131.4, 129.7, 129.1, 128.7, 127.8, 127.1, 126.5, 125.9, 123.3, 121.3, 118.8, 115.3, 67.2, 44.9, 42.5, 38.6, 37.8, 29.6, 29.0, 28.3, 27.8. Example 24-b: 1-(4-indole-(cyclobutylcarbonyll,2 6-tetrahydropyridine-4 -yl)phenyl 3-methyl-8-(quinolin-3-yl 1H-imidazo-"4,5-cl-quinoline-2 3H ketone

0.4 g (0.82 mmol) of intermediate 27 was dissolved in 60 ml of dichloromethane, Et ₃ N 0.6 ml (4.3 mmol) was added, and cyclobutyl carbonyl chloride 0.4 ml (3.5 mmol) was added dropwise, and stirred at room temperature for 1-2 h, TLC monitoring After completion of the reaction, the mixture was directly concentrated to give a crude product. EtOAc m. m. , Yield: 38.3%. 'HNMR (400 MHz, CDC1 ₃ ) δ : 2.18-2.23 (m, 2H, -CH ₂ -), 2.37-2.44 (m, 2H, -CH ₂ -), 2.59 (s, 2H, -CH ₂ -) , 3.31 -3.37 (m, IH, -CH-), 3.58-3.61 (t, IH, -CH-) 3.68 (s, 3H, -CH ₃ ), 3.85~3.87 (t, IH, -CH-), 4.05 (s, IH, -CH-), 4.29 (s, IH, -CH-), 6.12-6.23 (d, IH, J=45.2Hz, =CH-), 7.39-7.54 (m, 4H, ArH) , 7.61~7.63 (d, 2H, J=8.0Hz, quino line-H), 7.68-7.72 (t, 2H, quinoline-H), 7.88-7.90 (d, IH, J=8.4Hz, quinoline-H) , 7.97-8.01 (d, IH, J=16.4Hz, quinoline-H), 8.05-8.07 (d, IH, J=8.0Hz, quinoline-H), 8.20-8.22 (d, IH, J=8.0Hz, quinoline-H), 8.79 (s, IH, quinoline-H), 8.86~8.88 (d, IH, J=8.0Hz, quinoline-H). ¹³ C NMR (100 MHz, CDCI3) δ: 173.3, 153.5, 149.2 , 147.3, 144.6, 142.3, 134.9, 134.0, 133.0, 132.7, 131.4, 129.7, 129.1, 128.6, 127.8, 127.1, 126.5, 126.0, 125.9, 123.3, 123.2, 121.6, 118.8, 115.3, 44.4, 42.3, 41.7, 38.4 , 37.6, 37.3, 29.6, 28.1, 27.8, 27.2, 25.0, 17.9. Example 24-c: 1-(4-indole-(-hydroxy-3-methylbutyridyl U 6-tetrahydropyridin-4-yl)phenyl 3-methyl-8-(quinolin-3-yl) -1H-imidazolium "4,5-cl-quinoline-2 3H ketone

The 0.5g (1.03mmol) of Intermediate 27 was dissolved in 10 ml methylene chloride solvent, was added _{Et 3 N 0.3 ml (2.15 mmol} ), stand; 0.39 ml (3.1 mmol) β - hydroxy isovaleric acid was dissolved in 10 ml Add EDCI (0.29 g, 1.51 mmol), HOBT (0.21 g, 1.51 mmol), and add the above-mentioned reserve solution, stir at room temperature for 12 h, TLC detection, the reaction is finished, directly condensed and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography eluting elut elut elut elut elut elut elut elut elut 'HNMR (400 MHz, DMSO) δ 1.19-1.25 (m, 6Η, 2x-CH ₃ ), 2.51 (s, 2H, -CH ₂ -), 2.60 (s, 2H, -CH ₂ -), 3.70 (s , 3H, -CH ₃ ), 3.78-3.82(m, 2H, -CH ₂ -), 4.20-4.30 (t, 2H, -CH ₂ -), 6.38-6.42 (d, 1H, J=14.0 Hz, = CH-), 7.28 (d, 1H, J=8.0 Hz, ArH), 7.64-7.68 (m, 3H, ArH), 7.75~7.85 (m, 4H, quinoline-H), 8.00-8.02 (d, 1H, J=8.0 Hz, quinoline-H), 8.10~8.17 (m, 3H, quinoline-H), 8.87-8.91 (d, 1H, J=16.0Hz, quinoline-H), 9.01 (s, 1H, quinoline-H ¹³ C NMR (100 MHz, DMSO) δ : 171.6, 153.5, 149.2, 147.4, 144.7, 142.0, 134.9, 134.2, 133.0, 132.7, 131.5, 129.7, 129.2, 128.7, 127.8, 127.2, 126.6, 125.9, 123.2 , 122.8, 121.0, 118.8, 115.3, 69.2, 45.7, 45.0, 43.6, 43.1, 42.4, 38.0, 29.6, 28.0, 27.2, 21.8, 21.4. Example 24-d: 3-methyl small (4-Π- ( Morpholine-4-carbonyl U 6-tetrahydropyridin-4-yl)phenyl 8-(quinolin-3-yl 1H-imidazo[4,5-cl-quinoline-2 (H ketone)

将 0.3 g ( 0.62 mmol) 中间体 27溶于 20 ml二氯甲烷中， 加入 Et₃N 0.4 ml (3.1mmol)， 滴加 4-吗啉甲酰氯 0.3 1^ (2.47 11^101)， 常温搅拌1-211， TLC监测反应结束， 直接旋干浓缩 得粗品， 粗品经硅胶 G柱层析 [洗脱液 （甲醇： 二氯甲烷） =1 : 10 (v:v) ]纯化后得实施例 24-d目标化合物 0.17 g，产率 45.9% 'HNMR (400MHZ， CDC1₃) δ： 2.81 ( s, 2H, -CH₂-)， 3.48 ( s， 4H， 2x-CH₂-), 3.69 ( s, 2H, -CH₂-)， 3.83 ( s, 8H， 4x-CH₂-), 6.34 (s, 1H, =CH-)， 7.59 (s, 1H, ArH), 7.78-7.87 (m， 3H, ArH), 8.04-8.06 (d, 1H, J=8.0Hz， quino line-H), 8.17〜8.23 (m， 2H, quinoline-H), 8.37〜8.39 ( d， 1H, J=8.0Hz， quino line-H)， 8.95 (s， 1H, quinoline-H), 9.03 (s， 1H, quinoline-H). ¹³C NMR (100 MHz, CDC1₃ ) δ : 163.7, 153.6, 149.2, 147.3, 144.6， 142.5, 135.0, 134.9, 134.0, 133.2, 132.7, 132.5, 131.4, 129.7, 129.5, 129.1, 128.6, 127.9, 127.7, 127.1, 126.6, 126.0, 123.2, 123.0, 118.8， 115.4， 66.6， 47.2, 46.6， 43.9, 43.6, 27.9, 27.3.

The 0.3 g (0.62 mmol) of Intermediate 27 was dissolved in 20 ml of dichloromethane, was added _{Et 3 N 0.4 ml (3.1mmol)} , 4-morpholine-carbonyl chloride was added dropwise 0.3 1 ^ (11 ^ 101 2.47), stirred at room temperature 1-211, TLC was used to complete the reaction. The crude product was purified by EtOAc (EtOAc). -d target compound 0.17 g, yield 45.9% 'HNMR (400MHZ, CDC1 ₃ ) δ: 2.81 ( s, 2H, -CH ₂ -), 3.48 ( s, 4H, 2x-CH ₂ -), 3.69 ( s, 2H, -CH ₂ -), 3.83 ( s, 8H, 4x-CH ₂ -), 6.34 (s, 1H, =CH-), 7.59 (s, 1H, ArH), 7.78-7.87 (m, 3H, ArH ), 8.04-8.06 (d, 1H, J=8.0Hz, quino line-H), 8.17~8.23 (m, 2H, quinoline-H), 8.37~8.39 ( d, 1H, J=8.0Hz, quino line- H), 8.95 (s, 1H, quinoline-H), 9.03 (s, 1H, quinoline-H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ : 163.7, 153.6, 149.2, 147.3, 144.6, 142.5, 135.0 , 134.9, 134.0, 133.2, 132.7, 132.5, 131.4, 129.7, 129.5, 129.1, 128.6, 127.9, 127.7, 127.1, 126.6, 126.0, 123.2, 123.0, 118.8, 115.4, 66.6, 47.2, 46.6, 43.9, 43.6, 27.9, 27.3.

 Route 4 Synthesis of Intermediate 29

1.0 g (3.0 mmol) of intermediate 28 was dissolved in 150 ml of acetic acid, 0.78 g (2.7 mmol) of intermediate 3 was added, and the mixture was stirred at room temperature for 2 ho, and then filtered, washed with water to give a pale yellow solid 29 1.5 g, yield 93.75% . 1H NMR (400 MHz, CDC1 ₃ ) δ: 1.68 (m, IH, -CH ₂ -), 2.04 (s, 2H, -CH ₂ -), 2.26 (s, 2H, -CH ₂ -), 4.63 (s , 2H, -CH-), 5.15 (m, 2H, O-CH2-), 6.47 (s, IH, =CH-), 7.09 (d, 2H, J=8.0 Hz, -Ar), 7.34 (s, 2H, quinoline -H), 7.37 (s, 5H, -Ar), 7.74 (m, 2H, -Ar), 7.86 (d, IH, J=8.0 Hz, -Ar), 9.36 (s, IH, quinoline - H), 10.52 (s, IH, -NH); ¹³ C NMR (150 MHz, CDC1 ₃ ) δ: 154.0, 149.1, 147.0, 145.3, 139.2, 138.4, 136.8, 135.7, 131.9, 129.6, 128.8, 128.4, 127.9 , 127.7, 126.4, 123.1, 120.3, 119.4, 66.7, 53.3, 52.1, 36.5, 34.8, 30.2. Synthesis of intermediate 30

 1.5 g (2.6 mmol) of intermediate 29 was dissolved in 30 ml of methanol, completely dissolved and then added with 15 ml of CH3COOH.

A mixed solution of 15 ml of water, 0.72 g (0.13 mol) of Fe powder, heated to reflux for 3-5 h. After the reaction is completed, the mixture is filtered, and the pH is adjusted to be basic with Na ₂ C0 ₃ ( aq). The mixture is filtered with suction, and the filtrate is taken from methanol, extracted with methylene chloride, dried, and dried to give a crude product. Liquid: methanol/dichloromethane/ammonia = 8: 480: 1, V: V: V) , obtained as white solid intermediate 30 1.1 g, yield 77.46% o 1H NMR (400 MHz, CDC13) δ: 1.68 ( s, IH, -CH ₂ -), 1.94 (d, 2H, J=8.0 Hz, -CH ₂ -), 2.16 (d, 2H, J=9.2 Hz, -CH ₂ -), 3.07 (m, IH, -CH ₂ -), 4.16 (s, 2H, -CH-), 4.58 (s, 2H, NH ₂ -), 5.17 (s, 2H, CH ₂ -), 6.21 (m, 2H, =CH-), 6.56 (d, 2H, J=8.0 Hz, -Ar), 7.17 (d, 2H, J = 7.6 Hz, -Ar), 7.28 (m, 5H, -Ar), 7.48 (m, IH, quinoline-H), 7.82 (d, IH, J = 9.6 Hz, quinoline -H), 7.94 (s, IH, quinoline-H), 8.55 (s, IH, quinoline-H); ¹³ C NMR (150 MHz, CDC1 ₃ ) δ: 153.9, 143.8, 142.8, 141.8, 136.6, 136.0, 132.8, 132.4, 131.0, 130.9, 128.7, 128.3, 127.9, 127.7, 127.5,

125.8, 125.3, 123.3, 123.2, 121.1, 114.2, 65.6, 53.3, 52.1, 36.3, 34.7, 30.0. Synthesis of intermediate 31

0.43 g (2 mmol) of diphosgene was dissolved in 13 ml of dichloromethane and placed in a 100 ml three-necked flask. Take 1.1 g (2 mmol) of intermediate 30, 0.24 g (2.4 mmol) of triethylamine dissolved in 45 ml of dichloromethane, placed in a dropping funnel, and added dropwise to the reaction flask at 0 ° C for about 20 min. After completion, the reaction was carried out at 0 ° C for 1 h, the sodium bicarbonate solution was quenched, stirred for 5 min, extracted with dichloromethane, and then evaporated to dryness to give a crude product, which was purified by silica gel column chromatography (eluent: methanol/dichloromethane/ammonia = 12.5: 500: 1, V: V: V) , obtained as a white solid intermediate 31 0.9 g, yield 78.26%. 1H NMR (400 MHz, CDC1 ₃ ) δ: 1.68 (s, IH, -CH ₂ -), 1.94 (d, 2H, J = 8.0 Hz, -CH ₂ -), 2.16 (d, 2H, J = 9.2 Hz , -CH ₂ -), 3.07 (m, IH, -CH ₂ -), 4.16 (s, 2H, -CH-), 4.58 (s, 2H, NH ₂ -), 5.17 (s, 2H, CH ₂ - ), 6.21 (m, 2H, =CH-), 7.10 (d, 2H, J=8.0 Hz, -Ar), 7.20 (d, 2H, J=7.6Hz, -Ar), 7.28 (m, 5H, - Ar), 7.48 (m, IH, quinoline -H), 7.82 (d, IH, J=9.6 Hz, quinoline -H), 7.94 (s, IH, quinoline -H), 8.55 (s, IH, quinoline -H ¹³ C NMR (150 MHz, DMF) δ: 155.4, 147.3, 144.8, 142.8, 139.1, 136.4, 136.1, 134.1, 131.7, 131.2, 130.6, 130.4, 130.0, 129.4, 127.7, 124.3, 124.1, 120.5, 118.0 , 67.6, 55.2, 54.0, 37.6, 36.3, 30.8. Synthesis of intermediate 32

0.8 g (1.4 mmol) of intermediate 31, 0.04 g (0.13 mmol) of TBAB was dissolved in 30 mL of dichloromethane, 17 ml of 1% NaOH solution was added, and after stirring for 5 min, 0.72 ml (1.64 g, 11.56 mmol) of iodine was added. Methane, TLC detection. After completion of the reaction, the mixture was extracted with methylene chloride. EtOAc (EtOAc:EtOAc: The rate is 95.1%. 1H NMR (400 MHz, CDC1 ₃ ) 1.78 (m, 1H, -CH ₂ -), 2.04 (s, 2H, -CH ₂ -), 2.28 (d, 2H, J = 17.1 Hz, -CH ₂ -), 3.11 (m, IH, -CH ₂ -), 3.61 (s _: 3H, -CH ₃ -), 4.65 (s, 2H, -CH-x2), 5.11 (m, 2H, 0-CH ₂ -), 6.56 (s, IH, =CH-), 7.27 (d, IH, J=7.2 Hz, -Ar), 7.31 (m, 5H, -Ar), 7.40 (d, 2H, J=8.4 Hz, -Ar), 7.53 (m, 3H, -Ar l, quinoline -Hx2), 7.90 (d, IH, J=9.0 Hz, quinoline-H), 8.71 (s, IH, quinoline-H); ¹³ C NMR (150 MHz, CDC1 ₃ ) δ:

153.9, 153.4, 143.5, 141.3, 136.7, 133.4, 132.5, 130.3, 130.0, 129.6, 128.3, 127.9, 127.8, 126.3, 123.1, 122.7, 120.1, 116.0, 66.6, 53.2, 52.0, 36.4, 34.7, 30.1, 27.7. Synthesis of Intermediate 33

0.74 g (1.2 mmol) of intermediate 32 was dissolved in 15 mL of DMF and heated to 95 °C by adding 0.03 g (0.04 mmol) of Pd(PPh ₃ ) ₂ Cl _{2 under} nitrogen. 0.26 g (1.5 mmol) of quinoline-3-boronic acid was dissolved in 3 ml of DMF, 0.66 g of sodium carbonate was dissolved in 3 mL of water, and added to the reaction flask, and heated at 110 ° C for 2 h. After the completion of the reaction, 20 ml of water was added to the residue, and the solid was crystallized. EtOAc (EtOAc:EtOAc: The yield was 97.47%. Ii NMR (400 MHz, CDC1 ₃ ) δ: 1.37 (m, IH, -CH ₂ -), 1.96 (m, IH, -CH ₂ -), 2.21 (m, 2H, -CH ₂ -), 2.46 (m , 2H, -CH ₂ -), 3.82 (s, 3H, -CH ₃ -), 4.82 (s, 2H, -CH-x2), 5.31 (s, 2H, 0-CH ₂ -), 6.72 (s, lH,=CH-), 7.42-7.49 (m, 5H, -Ar), 7.60 (d, IH, J=1.6 Hz, quinoline-H), 7.67 (s, 2H, -Ar), 7.72-7.78 (m , 3H, quinoline-H), 7.80-7.85 (m, 2H, -Ar), 8.04 (m, IH, quinoline-H), 8.12 (s, IH, quinoline-H), 8.20 (d, IH, quinoline- H), 8.36 (d, IH, J=8.3 Hz, quinoline—H), 8.93 (s, IH, quinoline-H), 9.05 (d, IH, J=2.1 Hz, quinoline—H); ¹³ C NMR ( 150 MHz, CDC1 ₃ ) δ: 153.3, 148.9, 147.2, 144.3, 141.6, 134.6, 133.9, 132.7, 132.4, 131.9, 131.1, 129.5, 129.2, 128.9, 128.3, 128.2, 127.7, 127.5, 127.0, 126.3, 125.6, 123.0, 118.6, 115.1, 66.5, 53.2, 52.0, 36.5, 34.6, 29.4, 27.6. Synthesis of intermediate 34

0.65 g (1 mmol) of intermediate 33 was dissolved in 50 ml of methanol/dichloromethane (V: V=4:1) in a mixed solvent, 0.64 g (10 mmol) of HCOONH4 was added, and the mixture was heated to 60 ° C in three batches. Pd/C a total of 0.3 g, heated to reflux for 6 h, filtered to remove Pd / C, the mother liquid was concentrated to obtain a crude product, by silica gel column chromatography (eluent: methanol / dichloromethane / ammonia = 12.5: 500: 1, V : V: V) gave white solid intermediate 34 0.2 g, yield 39.22%. 1H NMR (400 MHz, CD ₃ OD, CDCI3) δ: 1.57 (m, IH, -CH ₂ -), 1.83~1.91 (m, 2H, -CH ₂ -), 2.00 (m, IH, -CH ₂ - ), 2.15 (d, IH, J = 17.2 Hz, -CH ₂ -), 2.79 (m, 1H, -CH ₂ -), 3.51 (s, 3H, -CH ₃ -), 4.21 (s, 2H, - CH-x2), 6.42 (d, IH, J=12.0 Hz, =CH-), 7.21 (s, IH, -Ar), 7.33 (d, 2H, J=8.7 Hz, quinoline-H), 7.38 (t , IH, J=7.5Hz, -Ar), 7.47 (d, 2H, J=8.7 Hz, -Ar), 7.54-7.60 (m, 2H, quinoline-H), 7.73 (d, IH, quinoline-H) , 7.86 (d, 2H, quinoline-H), 8.00 (d, IH, quinoline - H), 8.61 (s, IH, quinoline-H); ¹³ C NMR (150 MHz, CD3OD, CDCI3) δ: 148.4, 146.6 , 144.0, 141.7, 134.5, 133.5, 133.3, 132.3, 132.0, 131.5, 130.8, 130.5, 129.8, 128.2, 127.6, 127.5, 127.0, 126.0, 125.8, 122.9, 118.5, 115.0, 53.1, 52.2, 36.9, 34.3, 29.3 , 27.5. Example 25: 3-methyl small "4-(8-ethylindenyl-8-azabicyclo"3,2,11-oct-3-en-3-yl)phenyl 1-8- (quinoline -3- -IH-imidazo-"4,5-cl-quinolin-2(3H)-one and its hydrochloride

O. lg (0.20 mmol) Intermediate 34 was dissolved in 20 mL CH ₂ C1 ₂ , then 0.14 ml (1.0 mmol) Et ₃ N, 0.06 ml (0.85 mmol) CH ₃ C0C1 was added and stirred at room temperature for 1 h. After completion of the reaction, the crude product was obtained by chromatography (jjjjjjjjjjjjj The yield is 65%. MS (M+H ⁺ ): 552.13, calc.: 552.2. 1H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) δ: 1.34 ( s, IH, -CH ₂ -), 1.68 (t, 2H, J = 10.9 Hz, -CH ₂ -), 2.03 (d, IH, J = 16.6 Hz, -CH ₂ -), 2.21 (d, IH, J = 16.9 Hz, -CH ₂ -), 2.76 (m, IH , -CH ₂ -), 3.36 (m, 3H, -CH ₃ -), 4.23 (m, IH, -CH-), 4.34 (s, 3H, -CH ₃ -), 4.58 (m, IH, -CH -), 6.26 (m, IH, =CH-), 7.08 (d, IH, quinoline-H), 7.22 (d, 2H, quinoline-H), 7.26 (m, IH, quinoline-H), 7.32-7.44 (m, 4H, -Ar), 7.61 (d, 2H, J=8.2 Hz, quinoline-H), 7.69 (m, 2H, J=8.86 Hz, quinoline-H), 7.83 (d, 2H, J=8.4 Hz, quinoline-H), 8.48~8.50 (d, 2H, quinoline-H); ¹³ C NMR (150 MHz, CD ₃ OD, CDC1 ₃ ) δ: 167.1, 166.5, 153.2, 148.0, 146.2, 143.3, 141.0, 134.4, 133.4, 133.3, 132.0, 131.7, 129.6, 129.2, 128.3, 128.1, 127.6, 127.3, 126.9, 126.1, 125.9, 122.8, 118.3, 114.7, 54.6, 53.3, 50.6, 49.7, 37.0, 29.6, 20.4.

 5 mg of the target product of Example 25 was placed in a 5 ml EP tube, 2 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give the hydrochloride salt of the objective product of Example 25 as a pale yellow solid. Example 26: 1-(4-ί8-ΠΗ-1,2,4-triazole-3-carbonyl 8-azabicyclo "3.2.11 oct-3-en-3-yl)phenyl 3-methyl -8-(quinolin-3-yl 1H-imidazole "4,5-cl-quinoline-2

0.17 g (0.33 mmol) of intermediate 34 was dissolved in 30 ml of CH ₂ C1 ₂ and O. lg (0.52 mmol) EDCI was added. 0.07 g (0.53 mmol) HOBT, stir to dissolve, then add 0.03 g (0.27 mmol) 1,2,4-triazole-3-carboxylic acid, stir at room temperature for 12 h, TLC. The reaction was completed, and the residue was evaporated to dryness. The rate is 60%. MS (M+H ⁺ ): Calcd. 605.22, actual: 605.2. 1H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) δ: 1.03 (s, 1 Η, -CH ₂ -), 2.28 (t, 1H, J = 16.6 Hz, -CH ₂ -), 3.13 (m, 2H, -CH ₂ -), 3.49(s, 3H, -CH ₃ -), 4.24(m, 4H, -CH ₂ -x2, -CH-x2), 6.42 (d, 1H, J=4.3 Hz, =CH- ), 7.25 (s, 1H, quinoline-H), 7.33 (d, 3H, J=7.7 Hz, quinoline-H), 7.50-7.53 (m, 4H, -Ar), 7.75-7.83 (m, 3H, quinoline) -H), 7.99 (d, 1H, J=8.8 Hz, quinoline-H), 8.16 (s, 1H, triazole-H), 8.63-8.66 (d, 2H, quinoline-H); ¹³ C NMR (150 MHz , CD ₃ OD, CDCI3) δ: 153.4, 148.3, 146.4, 143.5, 141.3, 134.8, 133.53, 132.9, 132.8, 132.0, 129.9, 129.2, 128.6, 128.2, 127.8, 127.5, 127.2, 126.2, 123.0, 118.6, 115.0 , 54.8, 51.8, 38.1, 34.4, 29.7, 27.7.

 5 mg of the target product of Example 26 was placed in a 5 ml EP tube, 5 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give the hydrochloride salt of the objective product of Example 26 as a white solid. Example 27: 3-Methyl-144-"8-(2-hydroxyethyl)-8-azabicyclo "3, 2, 1 oct-3-en-3-yl 1 phenyl 8- ( Quinoline-3-yl)-1H-imidazo[4,5-cl-quinolin-2-one and its hydrochloride

0.07 g (0.14 mmol) of intermediate 34 was dissolved in 22 ml of CH ₂ Cl ₂ , 0.05 g (0.261 mmol) of EDCI, 0.04 g (0.296 mmol) of HOBT was added, stirred until dissolved, then 0.02 g (0.263 mmol) of glycolic acid was added, room temperature Stir for 12 h, TLC detection. After completion of the reaction, the crude product was obtained by chromatography (jjjjjjjjjjjjj , yield 89%. MS (M+H ⁺ ): calcd. 567.23, calc.: 567.2 o 1H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) δ: 1.06 , 1 Η, -CH ₂ -), 1.60 (m, 1 Η, -CH ₂ -), 1.86 (m, 3H, -CH ₂ -), 2.20 (m, 1H, -CH ₂ -), 3.47 (s, 6H, -CH ₃ -x2), 4.06 (m, 1H, -CH- ), 4.18 (d, 1H, -CH-), 6.33 (m, 1H, =CH-), 7.20 (d, 1H, J=4.4 Hz, quinoline-H), 7.31 (d, 2H _: J=7.9 Hz , quinoline-Hx l,-ArHx l), 7.36-7.43 (m, 3H, -Ar), 7.52 (d, 2H, J=4.1 Hz, quinoline-H) _: 7.70 (d, IH, J=8.7 Hz, quinoline-H), 7.84 (d, 2H, J=5.6 Hz, quinoline-H), 8.00 (d, IH, J=8.8 Hz, quinoline-H), 8.59 ( s, 2H, quinoline-H); ¹³ C NMR (150 MHz, CD ₃ OD, CDC1 ₃ ) δ: 167.8, 166.9, 153.5, 148.8, 146.9, 144.2, 141.2, 134.9, 134.1, 133.4, 132.4, 132.3, 130.8 , 129.9, 129.5, 128.6, 128.2, 127.6, 127.2, 126.5, 126.1, 123.1, 118.6, 115.2, 59.8, 52.3, 51.5, 37.4, 35.0, 30.2, 28.1.

 5 mg of the target product of Example 27 was placed in a 5 ml EP tube, 2 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give the hydrochloride salt of the objective product of Example 27 as a yellow solid. Example 28: 3-Methyl-144-"8-(2-hydroxypropionyl)-8-azabicyclo "3, 2, 1 oct-3-en-3-yl 1 phenyl 8- ( Quinoline-3-yl)-1H-imidazo[4,5-cl-quinolin-2 (

0.15 g (0.29 mmol) of intermediate 34 was dissolved in 22 ml of CH ₂ C1 ₂ , and 0.08 g (0.41 mmol) of EDCI was added.

0.06 g (0.45 mmol) HOBT, stir to dissolve, add 0.03 g (0.33 mmol) L-lactic acid, stir at room temperature for 12 h, and detect by TLC. After completion of the reaction, it was dried to dryness and purified by silica gel column chromatography (eluent: methanol / methylene chloride / ammonia = 50: 500:

1 , V: V: V) gave a white solid. MS (M+H ⁺ ): calc. 582.24, calc.: 582.2 o ^l H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) δ: 1.03 (s, IH, -CH ₂ -), 1.12 (d, 3H , J=6.4

Hz, -CH ₃ -), 1.84-2.16 (m, 4H, -CH ₂ -x2), 2.93-3.16 (m, IH, -CH ₂ -), 3.50(s, 3H, -CH ₃ -), 4.20 (s, 2H, -CH-x2), 4.72 (m, IH, -CH-O), 6.39 (s, IH, =CH-), 7.23-7.36 (m, 3H, quinoline — H), 7.41~7.55 (m, 5H, quinoline-H), 7.73~8.01 (m, 4H, -Ar), 8.62 (d, 2H, quinoline-H); ¹³ C NMR (150 MHz, CD ₃ OD, CDCI3) δ: 170.9, 170.1, 153.3, 148.3, 146.4, 143.6, 141.1, 134.6, 133.6, 133.4, 132.0, 130.0, 129.8, 129.5, 129.1, 128.8, 128.2, 127.4, 127.1, 126.2, 122.9, 118.4, 114.9, 65.5, 53.3, 51.2, 37.6, 34.7, 30.0, 27.8, 21.0.

5 mg of the target product of Example 28 was placed in a 5 ml EP tube, 2 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give the hydrochloride salt of the objective product of Example 28 as a gray solid. Example 29: 3-methyl small "4-(8-methylsulfonyl-8-azabicyclo"3,2,1-buxo-3-en-3-yl)phenyl 1-8- (quin Benzan-3-yl)-1H-imidazo[4,5-cl-quinolin-2(3H)-one and its hydrochloride

0.1 g (0.2 mmol) of intermediate 34 was dissolved in 20 ml of CH ₂ C1 ₂ , then 0.14 ml (1.Ommol) Et ₃ N, 0.03 ml (0.39 mmol) CH ₃ S0 ₂ C1 was added and stirred at room temperature for 1 h. After completion of the reaction, the crude product was obtained by chromatography. EtOAcjjjjjjjjjjjj g, yield 61%. MS (M+H ⁺ ): calc. 588.20, calc. 1H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) δ: 1.84 (m, 2H, -CH ₂ -), 2.08 (d, IH, J = 9.5 Hz, -CH ₂ -), 2.19 (d, IH, J=17.2 Hz, -CH ₂ -), 2.67 (s, 3H, -CH3-), 2.91 (d, IH, J=15.8 Hz, -CH ₂ -), 3.43 (d, 3H, -CH ₃ -) , 3.70 (s, IH, -CH ₂ -), 4.26 (d, 2H, J=5.1 Hz, -CH-), 6.32 (d, IH, J=5.0 Hz, =CH-), 7.16 (s, IH , quinoline—H), 7.28 (d, 2H, J=8.0 Hz, quinoline-H), 7.33 (t, IH, J=7.4Hz, quinoline- H), 7.39 (d, 2H, J=8.0 Hz, - Ar), 7.46-7.52 (m, 2H, -Ar), 7.68 (d, IH, J=8.6 Hz, quinoline—H), 7.78 (d, 2H, J=8.1 Hz, quinoline- H), 7.94 (d , IH, J=8.8 Hz, quinoline- H), 8.55 (s, 2H, quinoline- H); ¹³ C NMR (150 MHz, CD3OD, CDCI3) δ: 153.5, 148.5, 146.7, 143.8, 141.2, 134.9, 133.9 , 133.4, 132.7, 132.2, 130.3, 130.0, 129.8, 128.6, 128.5, 128.3, 127.7, 127.6, 127.3, 126.3, 126.2, 123.1, 118.6, 115.1, 55.4, 54.9, 40.3, 36.8, 35.2, 30.1, 27.6.

 5 mg of the target product of Example 29 was placed in a 5 ml EP tube, 2 ml of 1 mol/L hydrochloric acid was added, sonicated to dissolve, and lyophilized to give the hydrochloride salt of the objective product of Example 29 as a gray solid.

(5) Route 5

Synthesis of intermediate 35

Add 100 mL of THF, 3.96 g (28.65 mmol) of potassium carbonate to a 100 mL three-necked flask, and add 10 mL of THF solution containing 2.0 g (9.65 mmol) of 1-(4-nitrophenyl)piperazine under nitrogen. 1.64 mL of CbzCl (12.06 mmol) was added dropwise. After completion of the reaction, 40 mL of water was added, stirred for 1 h, extracted with ethyl acetate and dried. The crude product was purified byjjjjjjlililililililililililililililili Ii NMR (400 MHz, CD ₃ OD) δ: 3.45 (s, 4H, -CH ₂ -x2), 3.70 (t, 4H, J=5.18Hz, -CH ₂ -x2), 5.20 (s, 2H, - CH ₂ -), 6.83 (d, 2H, J = 9.32 Hz, ArH), 7.28 (s, 2H, ArH), 7.39 (d, 3H, J = 3.84 Hz, ArH), 8.15 (d, 2H, J= 9.28 Hz, ArH) o ¹³ C NMR (150 MHz, CD ₃ OD) 154.5, 138.9, 136.3, 128.6, 128.2, 128.1, 125.9, 113.0, 67.5, 46.9, 43.1. Synthesis of Intermediate 36

3.17 g (9.29 mmol) of intermediate 35 was dissolved in an appropriate amount of methanol, and 15 mL of a hydrochloric acid solution of pH 4 to 5, 1.56 g (27.8 6 mmol) of iron powder was added, and the mixture was heated under reflux for 2 h. After completion of the reaction, it was filtered with a celite funnel containing diatomaceous earth, and the filtrate was adjusted to basic with sodium carbonate solution, and filtered with suction. The filtrate was extracted with CH ₂ C1 ₂ , dried over anhydrous MgSO _{4 , and} dried. Chromatography (eluent: ethyl acetate: petroleum ether = 1 : 1, V: V)

90.7%. 'H NMR (400 MHz, CD ₃ OD) δ: 2.98 (m, 4H, -CH ₂ -x2), 3.50 (s, 2H, -NH ₂ -), 3.65 (t, 4H, -CH ₂ -x2, J=4.56 Hz) , 5.19 (s, 2H, -CH ₂ -), 6.63 (d, 2H, J=8.6 Hz, ArH), 6.79 (d, 2H, J=8.6Hz, ArH), 7.33~ 7.40 (m, 5H, ArH); "C NMR (150 MHz, CD ₃ OD) δ: 154.9, 143.9, 140.7, 136.5, 128.3, 127.8, 127.7, 119.0, 115.8, 66.9, 50.9, 43.8 Synthesis of Intermediate 37

2.6 g (8.35 mmol) of intermediate 36, 52 mL of acetic acid, 2.2 g (7.65 mmol) of 3-nitro-4-chloro-6-bromo-quinoline in a single-necked flask were monitored by TLC for about 2 h. After the reaction was filtered, the filter cake was washed with water to give a yellow solid intermediate 37 3.8 g, yield 89%; 1H NMR (400 MHz , CD 3 OD) 3.22 (s, 4H, -CH 2 -x2), 3.70 (s, 4H, -CH ₂ -x2), 5.18 (s, 2H, -CH ₂ -), 6.96-7.11 (m, 4H, ArH), 7.26-7.38 (m, 5H, ArH), 7.70-7.84 (m, 3H , quinoline-H), 9.44 (s, 41H, quinoline-H), 10.77 (s, 1H, -NH-); ¹³ C NMR (150 MHz, CD ₃ OD) δ: 155.2, 150.4, 148.9, 147.2, 146.4 , 136.5, 135.6, 131.8, 131.7, 129.9, 128.5, 128.1, 128.0, 127.7, 125.3, 125.0, 120.1, 119.0, 117.5, 67.4, 49.2, 43.5. Synthesis of Intermediate 38

3.8 g ( 6.76 mmol) of intermediate 37 was dissolved in 76 mL of methanol, 38 mL of acetic acid, 38 mL of water, 1.89 g (33.75 mmol) of iron powder, heated at 90 ° C, refluxed, TLC monitored, about 1 h. After suction filtration, the methanol in the filtrate was spun out, and then the sodium carbonate solution was added to make a basic solution. The mixture was filtered, extracted with dichloromethane, dried, and then evaporated to dryness. The crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethyl)浣/Ammonia = 12: 480: 1, V: V: V) , obtained as a pale yellow foamy solid intermediate # 38 3.1 g , yield 86%; 1H NMR (400 MHz, CD ₃ OD) δ: 2.98 (s, 4H, -CH ₂ -x2), 3.61 (t, 4H, -CH ₂ -x2, J = 4.4 Hz), 5.14 (s, 2H, -CH ₂ -), 5.95 (s, 2H, -NH ₂ -) , 6.59 (d, 2H, J=4.4 Hz, ArH), 6.79 (d, 2H, J=8.36 Hz, ArH), 7.29-7.35 (m, 5H, ArH), 7.44 (d, 1H, J=8.64 Hz , quinoline-H), 7.80 (d, 1H, J=8.8 Hz, quinoline-H), 7.91 (s, 1H, quinoline-H), 8.52 (s, 1H, quinoline-H); ¹³ C NMR (150 MHz , CD ₃ OD) δ: 155.1, 145.2, 143.4, 141.6, 136.9, 136.5, 134.9, 130.7, 128.9, 128.4, 128.0, 127.8, 127.3, 124.9, 123.2, 120.9, 118.8, 116.2, 115.8, 67.2, 50.5, 43.8. Synthesis of Intermediate 39

In a 250 mL three-necked flask, 3.1 g (5.8 mmol) of intermediate 38 was dissolved in 72 mL of dichloromethane, added with triethylamine 1.0 rnL, 0.77 mL of diphosgene dissolved in 35 mL of dichloromethane. In a dropping funnel, add dropwise to a three-necked flask at 0 °C, drip at about 40 min, react at 0 °C for 1.5 h, quench with sodium bicarbonate solution, stir for 5 min, extract with dichloromethane, and pass the crude product through silica gel. Column chromatography (eluent: methanol / methylene chloride / aqueous ammonia = 8: 480:1, V: V: V) afforded white solid intermediate 39 2.3 g, yield 70.1%. Synthesis of Intermediate 40

1.8 g (3.22 mmol) of intermediate 39 was dissolved in 60 mL of dichloromethane, and 0.12 g (0.37 mmol) of TBAB, 0.3 g (7.5 mmol) of sodium hydroxide was dissolved in 36 mL of water and added to the reaction flask, and stirred for 5 min. After adding 0.6 mL of methyl iodide, stirring was continued overnight. After completion of the reaction, the mixture was extracted with methylene chloride, dried, and evaporated to dryness. EtOAcjjjjjjjjjjj 1.68 g yield 91%; 1H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) δ: 3.30 (s, 4 Η, -CH ₂ -x2), 3.62 (s, 3H, -CH ₃ ), 3.72 (t 4H , -CH ₂ -x2, J=4.4 Hz), 5.18 (s, 2H, -CH ₂ -), 7.08 (d, 2H, J=8.64 Hz, ArH), 7.31-7.38 (m, 8H, ArHx7, quinoline -Hx l), 7.54 (d, 1H, J=8.92 Hz, quinoline-H), 7.91 (d, 1H, J=9.04 Hz, quinoline-H), 8.71 (s, IH, quinoline-H); ¹³ C NMR (150 MHz, CD ₃ OD, CDC1 ₃ ) δ: 155.0, 153.7,

151.8, 143.4, 136.4, 132.4, 131.9, 130.1, 128.9, 128.4, 128.3, 128.0, 127.8, 125.8, 122.9, 122.8,

119.9, 116.9, 116.1, 67.1, 48.6, 43.3, 27.7. Synthesis of intermediate 41

1.58 g (2.76 mmol) of intermediate 40 was dissolved in 15 mL of DMF in a three-necked flask and heated to 95 °C by the addition of 0.06 g (0.09 mmol) of Pd(PPh ₃ ) ₂ Cl _{2 under} nitrogen. 0.57 g (3.3 mmol) of quinoline-3-boronic acid was dissolved in 7.0 ml of DMF, and 1.46 g (13.77 mmol) of sodium carbonate was dissolved in 7.0 mL of water. The above two solutions were added to the reaction flask and heated at 110 °C. 2 h. After the completion of the reaction, the reaction mixture was poured into ice water, and the mixture was stirred until the solid was precipitated, and then filtered to give a crude product, which was purified by silica gel column chromatography (eluent: methanol / methylene chloride = 1/40, V: V) Solid intermediate 41 1.36 g , yield 80%; 1H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) δ: 3.33 (s, 4 Η, -CH ₂ -x2), 3.72 (s, 7H, -CH ₃ xl , -CH ₂ -x2), 5.21 (s, 2H, -CH ₂ -), 7.17 (d, 2H, J=8.3 Hz, ArH), 7.41 (d, 2H, J=8.2 Hz, ArH), 7.51 ( s, 1H, quinoline-H), 7.56 (t, IH, J=7.3 Hz, quinoline-H), 7.71 (t, IH, J=7.4 Hz, quinoline-H), 7.82 (d, IH, J=7.96 Hz, quinoline-H), 7.96 (d, IH, J=8.64 Hz, quinoline-H), 8.06 (d, IH, J=8.3 Hz, quinoline-H), 8.12 (s, IH, quinoline-H), 8.21 (d, IH, J=8.8 Hz, quinoline-H), 8.81 (s, IH, quinoline-H), 8.91 (s, IH, quinoline-H); ¹³ C NMR (150 MHz, CD ₃ OD, CDC1 ₃ ) δ: 155.1, 153.9, 152.1, 148.7, 146.7, 144.0, 136.1, 134.6, 133.5, 132.4, 132.3, 130.4, 130.1, 129.9, 129.2, 128.3, 127.9, 127.7, 127.6, 127.1, 126.0, 125.9, 122.9, 118.8, 116.8, 115.3, 67.2, 43.2, 27.6 . Synthesis of Intermediate 42

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TZS.80/Cl0ZN3/X3d t79C6.0/M0Z OAV Example 30-a: l-(4-(4-(4H-l,2,4-triazol-3-carbonyl)piperazin-1-yl)phenyl)-3-methyl-8- ( Quinoline-3-yl)-IH-imidazo[4,5-c]quinoline-2(3H)-one

Intermediate 42 (0.28 g, 0.58 mmol) was dissolved in 50 ml CH ₂ Cl ₂ was added EDCI (0.17 g, 0.89 mmol) ,

HOBT ( O. l lg, 0.83 mmol) was stirred and dissolved, and 1H-1,2,4-triazole-3-carboxylic acid (0.07 g, 0.62 mmol) was added and stirred at room temperature for 12 h, TLC detection, reaction was complete, liquid rotation The crude product was dried, and the crude material was purified by silica gel column chromatography (eluent (methanol: methylene chloride: ammonia) = 50:500:1 (v:v:v)]. , yield 36% 1H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) 5: 2.90 (t, 2H, -CH ₂ -), 3.07 (t, 2H, -CH ₂ -) , 3.70 (s, 2H, -CH ₂ ) , 3.85 (s, 3H, -CH ₃ ) , 4.15 (t, 2H, -CH ₂ ) , 7.55 (d, 2H, J=8.8 Hz, quinoline-H) , 7.64 (s, IH, ArH ), 7.78 (d, 3H, J=8.8Hz, ArHx3), 7.92 (t, IH, quinoline-H), 8.17(m, 3H, quinoline-H), 8.29 (m, 2H, quinoline-H), 8.53 (s, IH, quinoline-H), 9.14 (d, IH, J=2.0Hz, quinoline-H), 9.20 (s, 1H, triazole-H), ¹³ C NMR (100 MHz, CD ₃ OD, CDC1 ₃ ): 164.3, 164.0, 163.7, 154.0, 151.0, 146.4, 136.0, 135.5, 134.7, 134.2, 133.2, 131.9, 131.7, 131.0, 130.3, 129.7, 129.2, 128.7, 127.1, 120.8, 118.5, 117.2, 51.1, 50.1, 29.2.

(vi) Route 6

 Route six

Synthesis of intermediate 43

0.15 g (3.75 mmol) of NaH was suspended in 10 mL of purified DMSO in a three-necked flask. 0.3 mL (3.8 mmol) of ethylene glycol monomethyl ether was added dropwise under nitrogen atmosphere. After stirring at room temperature for 30 min, add 5 -Bromo-2-chloropyridine 0.5 g (2.6 mmol), reacted at 60 ° C for 1 h, the reaction was extracted with methylene chloride and water. The organic layer was dried and concentrated to give a crude material. : ethyl acetate / petroleum ether = 1: 10, V: V ) to give a white oil of intermediate 43 0.5 g, yield 83.3%; 1H NMR (400 MHz , DMSO) δ: 3.42 (s, 3H, -CH 3 -), 3.71 (t, 2H, J=4.62 Hz, -CH ₂ -), 4.42 (t, 2H, J=4.64 Hz, -CH ₂ -), 6.70 (d, IH, J=8.8 Hz, pyridine- H), 7.61 (m, IH, pyridine-H), 8.16 (s, IH, pyridine-H); ¹³ C NMR (150 MHz, DMSO) δ: 162.2, 147.2, 140.9, 112.8, 111.6, 70.7, 65.2, 58.9, 29.5 Synthesis of intermediate 45

1.09 g (4.3 mmol) of diboronic acid pinacol ester was dissolved in 8 mL of 1,4-dioxane in a three-necked flask, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.09 g was added under nitrogen protection ( 0.11 mmol), 0.6 g (6.46 mmol) potassium acetate, stirred at room temperature for 5 min, then added 1,4-dioxane containing 0.5 g (2.15 mmol) of 5-bromo-2-(2-methoxyethanol)pyridine 5 mL of the ring solution, the reaction 2 at room temperature was lowered to room temperature, and the bromoquinoline derivative 0 (2.15 mmol) was added in sequence under nitrogen.

Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.09 g (0.11 mmol), cesium carbonate 2.1 g ( 6.45 mmol), 2 mL sodium carbonate solution 5 mL,

90 ° [reflow reaction for 4 h. After cooling to room temperature, pour into ice water, solid precipitated, filtered to give a crude white crude, crude Silica gel column chromatography (eluent: methanol / methylene chloride = 1 : 60, V: V) ield of white solid intermediate 45 0.24 g, yield 18%; 1H NMR (400 MHz, CDC1 ₃ ) δ: 1.76 ( d, 2H, J = 10.7 Hz, -CH ₂ -), 1.97 (m, 1H, -CH ₂ -), 2.85 (t, 1H, -CH-), 2.97 (s, 2H, -CH ₂ -), 3.42 (s, 3H, -CH ₃ -), 3.66 (s, 3H, -CH ₃ -), 3.72 (t, 2H, J=4.42 Hz, -CH ₂ -), 4.45 (m, 4H, -CH ₂ -x2), 5.20 (s, 2H, -CH ₂ -), 6.75 (d, 1H, J=8.6 Hz, pyridine-H), 7.13 (s, 1H, quinoline-H), 7.32-7.42 (m, 5H , -Ar), 7.48 (s, 4H, -ArH), 7.50-7.53 (m, 1H, pyridine-H), 7.70 (m, 1H, pyridine-H), 8.02 (d, 1H, J=2.04 Hz, quinoline-H), 8.12 (d, 1H, J=8.8 Hz, quinoline—H), 8.74 (s, 1H, quinoline—H); ¹³ C NMR (150 MHz, CDC1 ₃ ) δ: 163.1, 155.1, 153.5,

147.7, 144.6, 144.3, 136.7, 136.6, 134.7, 133.4, 132.2, 131.1, 129.3, 128.7, 128.6, 128.4, 127.9, 125.3, 123.0, 117.2, 115.2, 111.09, 70.8, 67.0, 65.0, 58.9, 44.4, 42.5, 33.1, 27.7. Synthesis of intermediate 46

0.2 g (0.31 mmol) of intermediate 45 was dissolved in 40 mL of methanol/dichloromethane (V: V=l: l) mixed solvent, 0.2 g (3.17 mmol) of HCOONH ₄ was added, and Pd was added when the temperature was raised to 60 °C. /C 0.05 g, heating and refluxing for 5-6 h, Pd/C was removed by filtration, and the crude liquid was concentrated to give a crude product. The crude material was purified by silica gel column chromatography (eluent: methanol/dichloromethane/methanol = 50: 500:1) V: V: V) obtained as a white solid intermediate 46 0.15 g, yield 94.9 %; 1H NMR (400 MHz, CD ₃ OD, CDCI3) δ: 2.18 (d, 2H, J = 12.8 Hz, -CH ₂ -) , 2.25 (m, 2H, -CH ₂ -), 3.04 (t, 1H, J = 11.8 Hz, -CH-), 3.17 (t, 2H, J = 11.8 Hz, -CH ₂ -), 3.47 (s, 3H, -CH ₃ -), 3.63 (d, 2H, J = 12.4 Hz, -CH ₂ -), 3.73 (s, 3H, -CH3-), 3.79 (s, 2H, -CH ₂ -), 4.43 ( s, 2H, -CH ₂ -), 6.81 (d, 1H, J = 8.4 Hz, pyridine-H), 7.17-7.58 (m, 4H, -Ar), 7.62 (d, 2H, J = 8.0 Hz, pyridine -H), 7.80 (d, 1H, J=8.8 Hz, quinoline-H), 8.03 (s, 1H, quinoline -H), 8.17 (d, 1H, J=8.8 Hz, quinoline-H), 8.85 (s , 1H, quinoline-H); ¹³ C NMR (150 MHz, CD3OD, CDCI3) δ: 163.9, 154.3, 146.9, 145.2, 143.8, 137.7, 136.0, 134.2, 132.2,

130.8, 130.3, 129.6, 129.3, 129.2, 127.1, 123.7, 117.9, 115.8, 111.7, 71.3, 65.7, 59.4, 44.9, 40.7, 30.2, 28.4. Example 31: 3-Methyl-l-"4-(l-methylsulfonylpiperidin-4-yl)-phenyl l-8-"6-(2-methoxyethoxy)pyridine-3 Synthesis of -l-lH-imidazo[4,5-cl-quinolin-2(3H)-one

0.15 g (0.29 mmol) of intermediate 46 was dissolved in 30 mL of CH ₂ C1 ₂ , then 0.21 mL ( 1.51 mmol) Et ₃ N, 0.05 mL (0.65 mmol) CH ₃ S0 ₂ C1 was added and stirred at room temperature for 1 h. After completion of the reaction, the crude product was purified by chromatography (jjjjjjjjjjjjjj g, yield 58.8%; MS (M+H ⁺ ): calc. 1H NMR (400 MHz, CD ₃ OD, CDCI3) δ: 1.97 (m, 2H, -CH ₂ -), 2.10 (m, 2H, -CH ₂ -), 2.85-2.92 (m, 6H, -CH ₃ - Xl, -CH ₂ -xl, CH-xl), 3.47 (s, 3H, -CH ₃ -), 3.71 (s, 3H, -CH ₃ -), 3.78 (d, 2H, J=4.2Hz, -CH ₂ -), 4.00 (d _: 2H, J = 11.6 Hz, -CH ₂ -), 4.46 (s, 2H, -CH ₂ -), 6.78 (d, 1H, J = 8.6 Hz, pyridine-H), 7.15 (s, 1H, pyridine-H), 7.51-7.58 (m, 4H, -Arx4, pyridine-H l), 7.76 (d, 2H, J=8.88 Hz, quinoline-H), 8.01 (s, 1H, quinoline -H), 8.13 (d, 1H, J=8.88 Hz, quinoline-H), 8.78 (s, 1H, quinoline -H); ¹³ C NMR (150 MHz, CD ₃ OD, CDC1 ₃ ) δ: 163.7, 154.2 , 147.7, 145.0, 144.4, 137.3, 135.5, 133.8, 132.5, 130.8, 130.2, 129.8, 129.3, 129.2, 129.1, 128.9, 127.4, 126.4, 123.5, 117.7, 115.7, 111.6, 71.2, 65.6, 59.3, 46.8, 42.2 , 35.0, 33.1, 28.2.

中间体 19a的合成

Synthesis of intermediate 19a

In a three-necked flask, 5.05 g (19.9 mmol) of diboronic acid pinacol ester was dissolved in 30 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.4 g was added under nitrogen protection ( 0.49 mmol), 2.92 g (29.7 mmol) of potassium acetate. After stirring for 5 min, add 12 g of 1,4-dioxane solution containing 2.0 g (3.47 mmol) of 5-bromo-N-ethylpyridin-2-amine. , heat up to 110 ° C reaction 2h. Down to room temperature, intermediate 19a 2.88 g (4.97 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.4 g (0.49 mmol), cesium carbonate 6.8 g (20.9 mmol), 2M carbonic acid were added sequentially under N ₂ protection. The sodium solution was 26 mL, and the reaction was refluxed at 110 ° C for 3-4 h. After cooling, the solid was precipitated in ice water, and filtered to give a white-white crude product. EtOAc (EtOAc: m. Rate: 36.5%. 1H NMR (400 MHz, CDC1 ₃ ) δ: 1.22 (t, 2H, J = 7.2 Hz, -CH ₃ -), 1.76 (m, 2H, J = 11.08 Hz, -CH ₂ -), 1.98 (m, 2H , -CH ₂ ), 2.83 (m, 1H, -CH ₂ ), 2.97 (t, 2H, -CH ₂ ), 3.27 (m, 2H, -CH ₂ ), 3.66 (s, 3H, -CH ₃ ), 4.41 (s, 2H, -CH ₂ ) , 4.67 (t, 1H, -NH) , 5.18 (s, 1H, -CH ₂ ) , 6.28 (d, 2H, J=8.64Hz, -CH=) , 7.07 ( s, ΙΗ , ΑτΗ), 7.33 (t, 2H, quinoline-H), 7.38 (d, 4H, J=6.6Hz, ArHx4), 7.47 (s, 4H, ArHx4), 7.70 (d, 1H, J=8.8 Hz, Pyriding-H), 8.04(s, 1H, Pyriding-H), 8.09 (d, 1H, J=8.8Hz, Pyriding-H), 8.72 (s, 1H, quinoline-H). ¹³ C NMR (100 MHz, CDC1 ₃ ) : 146.5, 135.3, 131.8, 130.9, 128.8, 128.4, 127.9, 127.8, 125.3, 116.1, 106.3, 67.1, 44.5, 42.4, 36.7, 33.1, 27.8, 14.8. Synthesis of intermediate 20a

3⁄4 1.22g (1.99 mmol) Intermediate 19a was dissolved in 200 ml of methanol/dichloromethane (V:V=3:1) mixed solvent, 1.25 g (19.8 mmol) of HCOONH ₄ was added, and Pd was added when the temperature was raised to 60 °C. /C 0.22 g, heated to reflux for 2-3 h, filtered to remove Pd / C, the crude liquid was concentrated to give a crude product, the crude material was purified by silica gel column chromatography [eluent: methanol / dichloromethane = 1:0, (v:v) ] White solid 20a 0.76 g, Yield: 80%. 1H NMR (400 MHz, CDC1 ₃ ) δ: 1.26 (t, 3H, J = 7.2 Hz, -CH ₃ -), 1.89 (m, 2H, -CH ₂ -), 2.06 (d, 2H, J = 12.8 Hz , -CH ₂ ), 2.91 (m, 3H, -CH ₂ , -CH), 3.28 (t, 2H, J=7.2Hz, -CH ₂ ), 3.36 (d, 2H, J=11.2Hz, -CH ₂ ), 3.70 (s, 3H, -CH ₃ ), 6.43 (d, 1H, J=8.8 Hz, ArH), 7.10 (s, ΙΗ, ΑτΗ), 7.33 (d, 1H, J=6.8 Hz, ArH), 7.50 (m, 4H, ArH), 7.75 (d, 1H, J=8.8 Hz, ArH), 7.99 (s, 1H, ArH), 8.08 (d, 1H, J=9.2 Hz, ArH), 8.74 (s, 1H, ArH). ¹³ C NMR (100 MHz, CDC1 ₃ ): 157.9, 153.6, 147.5, 145.3, 143.4, 135.7, 135.5, 133.0, 131.3, 129.7, 129.4, 128.5, 128.1, 125.6, 123.5, 122.7, 115.8, 107.1, 45.3, 41.2, 36.2, 32.1, 27.4, 14.8. Example 32: 8- 6-(ethylamino)pyridin-3-yl 3-methyl-1-ί4-indole-(methylsulfonyl)piperidin Pyridin-4-yl)phenyl 1H-imidazole

"4,5-cl quinoline-2 (H ketone)

Take 0.2 g (0.4mmol) of Intermediate 20a was dissolved in 30 ml CH ₂ C1 _2, the force Jie into _{0.3 ml (2.0 mmol) Et 3} N, 0.06 ml (0.8 mmol) CH 3 S0 2 C1, stirred at room temperature 1 h. After completion of the reaction, the residue was evaporated to dryness mjjjjjjjjjjjjjjjjjjjjjj : 43.5%. 1H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) δ: 1.26 (m, ₃ Η, -CH ₃ -), 1.92 (m, 2H, -CH ₂ -), 2.11 (t, 2H, J = 12.0 Hz, -CH ₂ ), 2.84 (m, 4H, -CH ₃ , -CH) , 3.11 (s, 2H, -CH ₂ ), 3.32 (t, 2H, J=8.0Hz, -CH ₂ ), 3.69 (s, 3H, -CH ₃ ), 4.00 (d, 2H, J = 12.0 Hz, -CH ₂ ), 6.37 (d, 1H, J = 8.0 Hz, ArH) 7.10 (s, 1H, ArH), 7.43 (d, 1H , J=8.0Hz, ArH), 7.50 (s, 4H, ArH), 7.70 (d, 1H, J=8.0Hz, ArH), 7.97 (s, 1H, ArH), 8.12 (d, 1H, J=8.0 Hz, ArH), 8.76 (s, 1H, ArH). ¹³ C NMR (100 MHz, CD ₃ OD, CDCI3): 157.6, 153.6, 146.9, 145.2, 144.1, 136.1, 135.3, 133.6, 131.9, 131.0, 128.9, 128.3, 125.3, 124.2, 123.0, 116.2, 115.4, 106.5, 96.6, 46.4, 43.3, 41.6, 36.9, 34.9, 32.7, 29.6, 28.8, 14.6.

 Route eight

 Synthesis of intermediate 26a

Compound 25 0.7 g (1.2 mmol) was dissolved in Ί ml DMF in a three-necked flask, vacuumed, and added under nitrogen. Pd(PPh ₃ ) ₂ Cl ₂ 0.03g (0.04 mmol), heated to about 95 °C, 2-phenylpyridine-5-boric acid 0.29 g (1.5 mmol) dissolved in 3 ml DMF and added to the three-necked flask Then, Na ₂ C0 ₃ solution (4 ml water, 0.65 g NaCO ₃ ) was added to a three-necked flask, and the reaction was heated at 95 ° C -100 ° C for 2 h. After the reaction was completed, 200 ml of water was added and stirred, and the crude product was filtered. The crude product was purified by silica gel chromatography eluting elut elut elut elut eluting Synthesis of intermediate 27a

0.6 g (0.93 mmol) of the intermediate 26a was dissolved in 250 ml of a methanol/dichloromethane=4:1 mixed solvent, and HCOONH ₄ 0.65 g (10.3 mmol) was added thereto, and Pd/C was added in portions when the temperature was raised to 60 °C. 0.18 g, heated to reflux for 8 h, filtered to remove Pd / C, the crude liquid was concentrated to give the crude compound, the crude material was purified by silica gel column chromatography [eluent: (dichloromethane) I (methanol) I (ammonia) = 500 / 50/1] Intermediate 27a 0.36 g (Yield: 76.6%). Example 33: 1-(4-(1-(4Η-1,2,4-triazol-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl) 3-methyl-8-(6-phenyl-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

Intermediate 27a (0.2 g, 0.39 mmol) was dissolved in 35 ml DMF, EDCI (0.08 g, 0.42 mmol) was added, HOBT (0.05 g, 0.38 mmol) was stirred and dissolved, and 1H-1, 2, 4 was added in portions. - Triazole-3-carboxylic acid (0.05 g, 0.44 mmol), DIEA 0.2 ml (1.17 mmol), stirred at room temperature for 12 h, TLC detection, the reaction is finished, the liquid is dried to dryness, and the crude material is chromatographed on silica gel G column [ Eluent (methanol: methylene chloride) = 50:500 (v: v) 1 After purification, the compound of Example 2, 0.08 g, yield 33.3%. 1H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) : 1.38 ( s, 2H, -CH ₂ -), 3.02 (m, 2H, -CH ₂ -), 3.37 (s, 2H, -CH ₂ ), 3.73 (s, 3H, -CH ₃ ), 6.32 (d, 1H, -CH=), 7.30 (s, 1H, quinoline-H), 7.38 (s, 1H, quinoline-H), 7.46 (t, 3H, quinoline -H), 7.55 (m, 4H, ArHx4), 7.7 l(m, 3H, quinoline-H), 7.89 (m, 1H, quinoline-H), 7.95 (m, 2H, quinoline-H), 8.19 (d , 1H, J=8.8Hz, quinoline-H), 8.56 (s, 1H, triazole-H), 8.81 (d, 1H, J=3.6Rz, quinoline-H), ¹³ C NMR (100 MHz, CD ₃ OD , CDCI3): 156.5, 153.6, 147.4, 144.1, 142.3, 138.1, 134.9, 133.7, 133.5, 133.1, 132.3, 130.4, 129.7, 129.1, 128.7, 128.5, 126.6, 126.1, 123.1, 122.0, 121.6, 120.5, 120.3, 118.1, 115.2, 43.2, 33.7, 29.4, 27.0c

 (9) Route 9:

中间体 26b的合成

Synthesis of intermediate 26b

Compound 25 1.0 g (1.76 mmol) was dissolved in 10 ml of DMF, placed in a three-necked flask, vacuumed, and added with Pd(PPh ₃ ) ₂ Cl ₂ 0.04 g (0.06 mmol) under nitrogen, heated to 95 ° C is reacted for about 1-2 h, and 0.35 g (2.1 mmol) of 2-methoxy-3-methylpyridine-5-borate is dissolved in 5 ml of DMF and added to the three-necked reaction solution, followed by Na ₂ C0 ₃ solution (4.5 ml water, 0.93 g Na ₂ CO3 ) was added to a three-necked flask and heated to 110 ° C for 2 h. After the reaction was completed, 200 ml of water was added and stirred to obtain a crude product. The crude product was chromatographed on silica gel G column [ Eluent: (methanol) I (dichloromethane) = 1/50 (v: v)] Intermediate 26b 0.9 g (Yield: 84.1 %). Synthesis of intermediate 27b

0.8 g (1.3 mmol) of intermediate 26b was dissolved in 250 ml of a mixed solvent of methanol/dichloromethane=4:1, and HCOONH ₄ 0.85 g (13.5 mmol) was added, and Pd/C was added in portions when the temperature was raised to 60 °C. 0.08 g, heated reflux reaction, TLC was used to monitor the end of the reaction, Pd/C was removed by filtration, and the crude liquid was concentrated to give the crude compound. The crude material was chromatographed on silica gel G column [eluent: (dichloromethane) I (methanol) I (ammonia) = 500/50/1] Intermediate 27b 0.6 g (Yield: 96.8 %). Example 34: 1-(4-Π-ί4Η-1,2,4-triazol-3-carbonyl)-1 3,6-tetrahydropyridin-4-yl)phenyl)-8-6-A Oxy-5-A Pyridin-3-yl 3-methyl-IH-imidazo-cl-quinoline-2 (H-ketone

Intermediate 27b (0.26 g, 0.58 mmol) was dissolved in 15 ml of DMF, EDCK 0.17 g, 0.89 mmol), HOBT (0.12 g, 0.89 mmol) was stirred and dissolved, and 1H-1, 2, 4- was added in portions. Triazole-3-carboxylic acid (0.05 g, 0.44 mmol) DIEA 0.2 ml (1.17 mmol), stirred at room temperature for 12 h, TLC, the reaction was finished, and the liquid was dried to dryness. solution (methanol: methylene chloride) = 50: 500 (v: v)] the title compound after purification affording Example 34 0.1 g, yield: 30.3% 1H NMR (400 MHz , CD 3 OD, CDC1 3) δ: 1.27 ( s, 2H, J = 15.6 Hz, -CH ₂ -), 2.16 ( s, 3H, -CH ₃ -), 2.85 (d, 2H, J = 18.4 Hz, -CH ₂ ), 3.73 (s, 3H, -CH ₃ ), 3.95 (s, 3H, -CH ₃ ) , 4.49 (d, 2H, -CH ₂ ), 6.23 (d, IH, -CH=) , 7.25 (s, IH, quinoline-H) , 7.32 (s, IH, quinoline-H), 7.58 (t, 2H, quinoline-H), 7.83-7.99 (m, 4H, ArHx4), 8.13 (d, IH, J=8.6Hz, quinoline-H), 8.31 ( s, IH, triazole-H), 8.79 (s, IH, quinoline-H), ¹³ C NMR (100 MHz, CD ₃ OD, CDC1 ₃ ) : 162.0, 153.5, 148.9, 145.3, 143.5, 141.9, 141.5, 140.4 , 136.6, 135.3, 134.7, 134.2, 133.7, 131.6, 130.1, 129.6, 128.5, 128.1, 127.5, 126.4, 126.0, 122.9, 121.9, 121.5, 120.8, 117.0, 116.7, 115.1, 110.5, 53.1, 45.2, 42.8, 39.5, 27.4, 15.4.

 (10) Road:

Route ten Synthesis of intermediate 19b

1. 5 g (2.63 mmol) of intermediate 18 was dissolved in 15 mL of DMF in a three-necked flask, vacuumed under nitrogen, and added to 0.06 g (0.08 mmol) of Pd(PPh ₃ ) ₂ Cl ₂ to 95 ° C. -100 °C reaction for 2-3 h. 0.59 g (3.16 mmol) of 1-phenylpyrazole-4-boronic acid was dissolved in 5.0 ml of DMF for use; 1.39 g (13.1 mmol) of sodium carbonate was dissolved in 7.2 mL of water; the above two kinds of spare solutions were added to the reaction flask, 110 Heat at °C for 3 h. After the completion of the reaction, the reaction mixture was poured into ice water, and the mixture was stirred until the solid was precipitated, and the crude product was obtained by filtration, and the crude product was subjected to silica gel column chromatography [eluent: methanol/dichloromethane = 1/40, (V:V)] , white solid 19b 1.45g, yield 87% o 1H NMR (400 MHz, CDC1 ₃ ) δ : 1.72 (d, 2Η, -CH ₂ -, J = 9.8 Hz), 1.91 (d, 2H, -CH ₂ -, J = 11.2 Hz), 2.81-2.90 (m, 3H, -CH-, -CH ₂ ), 3.66 (s, 3H, -CH ₃ ), 4.35 (s, 2H, -CH ₂ -), 5.18 ( s, 2H, -CH ₂ -), 7.31 (d, 3H, ArH, J = 3.6 Hz), 7.38 (m, 6H, ArH), 7.49 (s, 4H, ArH), 7.55 (s, 1H, ArH) , 7.62 (d, 2H, ArH, J=8.0Hz), 7.71 (d, 1H, ArH, J=8.8 Hz), 7.87 (s, 1H, ArH), 8.15 (d, 1H, ArH, J=8.8 Hz ), 8.74 (s, 1H, ArH). ¹³ C NMR (100MHz, CDC1 ₃ ) δ: 155.1 , 153.5, 148.2, 147.7, 143.2, 139.6, 138.3, 138.1, 136.7, 133.2, 130.8, 130.1, 129.7, 129.6, 129.4, 128.7, 128.4, 128.3, 127.9, 127.8, 126.9, 126.6, 125.6, 123.7, 123.4, 123.0, 119.1, 118.8, 115.8, 115.6, 115.2, 67.1, 67.0, 44.3, 44.2, 42.5, 42.3, 33.1, 27.8. Synthesis of intermediate 20b

1.4 g (2.2 mmol) of intermediate 19b was dissolved in 250 ml of a mixed solvent of methanol/dichloromethane = 4:1, and HCOONH ₄ 1.4 g (22 mmol) was added, and Pd/C was added in portions when the temperature was raised to 60 °C. 0.28 g, heating under reflux for 8 h, the Pd/C was removed by filtration, and the crude liquid was concentrated to give the crude compound. The crude material was purified by silica gel column chromatography [eluent: (dichloromethane) I (methanol) I (ammonia) =500/ 50/1] Intermediate 20b 1.04 g (Yield: 94.5 %). 1H NMR (400MHz, CDC1 ₃ ) δ: 2.81 (s, 3H, =CH-), 3.17 (d, 1H, -CH-, J = 12.2H), 3.34 (s, 3H, -CH3), 4.23 (s , 8H, -CH2-), 6.82 (s, 1H, ArH), 6.99-7.05 (m, 2H, ArH), 7.14 (t, 2H, ArH, J=7.6Hz), 7.23 (t, 2H, ArH, J=8.1Hz), 7.31 (d, 3H, ArH, J=8.0 Hz), 7.51 (d, 1H, ArH, J=8.5Hz), 7.73 (d, 1H, ArH, J=8.7Hz) _: 8.47 ( s, 1H, -NH). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ: 153.3, 145.9, 142.0, 139.0, 137.4, 133.1, 130.3, 129.6, 128.9, 128.6, 128.4, 128.0, 126.6, 125.9, 124.2, 123.1, 122.7, 118.8, 115.2, 114.7, 48.4, 48.2, 47.9, 47.7, 47.5, 47.3, 47.1, 43.7, 39.3, 29.2, 27.0. Example 35: (SVl-(4-n-i2-hydroxypropenyl) Piperidin-4-yl)phenyl)-3-methyl-8-indole-phenyl-1H-pyrazol-4-yl 1H-imidazo[4,5-cl-quinoline-2 (H-ketone)

Dissolve 0.1 ml (1.4 mmol) of L-lactic acid in 5 ml of DMF, add EDCI (0.25 g, 1.54 mmol), HOBT (0.18 g, 1.54 mmol), and add a small amount of intermediate 20b, DIEA 0.2 ml after dissolution. The intermediate 20b was gradually added to 0.3 g (0.7 mmol), and the mixture was stirred at room temperature for 2 h. EtOAc was evaporated. EtOAc was evaporated. The crude product was purified by silica gel chromatography eluting elut elut elut elut elut elut elut elut elut Ii NMR (400MHz, CDC1 ₃ ) δ: 1.36 (s, 3H, -CH3), 1.72 (s, 2H, -CH2-), 1.97 (d, 2H, -CH2-, J=14.8Hz), 2.76 (s , 1H, =CH-), 2.93 (s, lH,=CH-), 3.14 (s, 1H, =CH-), 3.64 (s, 3H, -CH3), 3.82 (s, 1H, -CH-) , 4.49 (d, 1H, -CH-, J=5.5Hz), 4.78 (s, 1H, -CH2-), 7.17 (s, 1H, -CH2-), 7.33 (s, 1H, ArH), 7.48 ( s, 8H, ArH), 7.62 (d, 2H, -CH2-, J=7.4Hz), 7.68 (d, IH, ArH, J=8.3Hz, 7.88 (d, IH, ArH, J=12.9Hz), 8.10 (d, IH, ArH, J = 8.4 Hz), 8.71 (s, IH, -OH). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ: 173.4, 153.5, 146.9, 143.6, 139.7, 138.3, 133.6, 131.3, 130.5, 129.6, 129.4, 128.9, 126.9, 125.4, 126.9, 123.4, 123.0, 119.1, 115.8, 115.3, 64.0, 45.3, 45.0, 43.1, 42.9, 42.5, 42.4, 33.8, 33.5, 32.6, 32.5, 27.8, 21.8, 21.2.

 Example 35-b 4-(4-(3-Methyl-2-oxo-8-(l-phenyl-IH-pyrazol-4-yl)-2,3-dihydro-IH-imidazole [4,5-c]quinolin-1-yl)phenyl)piperidine-1-carbaldehyde

 The title compound was prepared in a similar manner.

(11) Route 11:

Synthesis of intermediate 19c

1.0 g (1.75 mmol) of intermediate 18 was dissolved in 10 mL of DMF in a three-necked flask, vacuumed under nitrogen, and heated to 95 ° C -100 by adding 0.04 g (0.05 mmol) of Pd(PPh ₃ ) ₂ Cl ₂ °C reaction for 2-3 h. 0.42 g (2.1 mmol) of 2-phenylpyridin-5-boronic acid was dissolved in 4.0 ml of DMF for use; 0.93 g (8.7 mmol) of sodium carbonate was dissolved in 4.8 mL of water; the above two stock solutions were added to the reaction flask, 95 ° After the reaction was completed at C -110 °C for 3 ho, the reaction solution was poured into ice water, and the mixture was stirred until all solids were precipitated. The crude product was obtained by filtration, and the crude product was purified by silica gel column chromatography [eluent: methanol/dichloromethane = 1 /40, (V:V)], obtained white solid 19c 0.87 g, yield 77%. ¹ H NMR (400 MHz, CDCl ₃ ) δ _: 1.82 (m, 2H, -CH ₂ -), 2.06 (d, 2H, J = 12 Hz, -CH ₂ -), 2.88 (t, IH, J = 12, - CH-), 2.99 (s, 2H, -CH ₂ -), 3.68 (s, 3H, -CH ₃ ), 4.45 (s, 2H, -CH ₂ -), 5.20 (s, 2H, -CH ₂ -) , 7.26 (s, IH, ArH), 7.35-7.46 (m, 8H, ArH), 7.51 (s, IH, ArH), 7.69 (s, 2H, ArH), 7.82 (d, IH, J=8.8Hz, ArH), 8.01 (d, 2H, J=7.6Hz, ArH), 8.21 (d, IH, J=8.8Hz, ArH), 8.54 (s, IH, ArH), 8.78 (s, IH, ArH). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ : 156.0, 155.1, 153.4, 147.8, 147.6, 144.5, 138.2, 136.7, 134.2, 133.2, 132.5, 131.2, 129.4, 129.1, 128.7, 128.5, 128.3, 127.8, 127.8, 126.4 , 125.3, 123.0, 119.6, 118.1, 115.1, 67.0, 44.4, 42.5, 33.0, 27.7. Synthesis of intermediate 20c

0.68 g (1.1 mmol) of intermediate 19c was dissolved in 150 ml of a methanol/dichloromethane=4:1 mixed solvent, and HCOONH ₄ 0.7 g (11.1 mmol) was added thereto, and Pd/ was added in portions when the temperature was raised to 60 °C. C 0.08g, heated to reflux for 6-8 h, filtered to remove Pd / C, the mother liquid was concentrated to give the crude compound, the crude product was chromatographed on silica gel G column [eluent: (dichloromethane) / (methanol) I (ammonia) =500/50/1] Intermediate 20c 0.46 g (Yield: 85 %). 'HNMR (400MHZ, CDC1 ₃ ) δ: 2.15-2.25 (m, 4H, -CH ₂ - X 2), 3.08-3.17 (m, 3H, -CH ₂ -, CH-), 3.55 (d, 2H, J = 12.8 Hz, -CH ₂ -), 3.74 (s, 3H, -CH ₃ ), 7.29 (s, 1H, ArH), 7.47-7.54 (m, 3H, ArH), 7.58-7.64 (t, 4H, J=8Hz, ArH), 7.83 (d, 1H, J=8Hz, ArH), 7.90 (d, 2H, J=8, ArH), 7.94 (d, 2H, J=8, ArH), 8.22 (d, 1H, J=8Hz, ArH), 8.45 ( s, 1H, ArH), 8.84 (s, 1H, ArH). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ: 156.3, 146.9, 135.0, 134.5, 132.3, 130, 2, 129.0, 128.5, 128.2, 126.4, 125.9, 120.6, 117.9, 44.0, 39.6, 29.4, 27.4. Example 36: (SVl-(4-n-i2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8 - 6-Phenylpyridin-3-yl 1H-imidazole and "4,5-cl-quinoline-2 (H-ketone)

 0.3 g (0.6 mmol) of the intermediate 20c was dissolved in 50 ml of a mixed solvent of dichloromethane (methanol = 1 : 1), and was taken up; 0.1 ml (1.2 mmol) of L-lactic acid was dissolved in 5 ml of dichloromethane. Add EDCI (0.22 g, 1.2 mmol), HOBT (0.16 g, 1.2 mmol), stir for 10-30 min, add the intermediate solution of intermediate 20c, DIE A 0.2 ml, stir at room temperature for 12 h, TLC detection, reaction The crude product was concentrated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

(12) Two:

路线十二

Route twelve

Synthesis of intermediate 19d

6.21 g (24.4 mmol) of diboronic acid pinacol ester was dissolved in 90 mL of 1,4-dioxane in a three-necked flask, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.77 g was added under nitrogen protection ( 0.94 mmol), 5.53 g (56.4 mmol) of potassium acetate. After stirring for 5 min, add 20 mL of 1,4-dioxane solution containing 4.4 g (18.8 mmol) of 5-bromo-2-3-bipyridine. The reaction was carried out at 110 ° C for 2-3 ho to room temperature. Under the protection of N ₂ , intermediate 18 5.38 g (9.4 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.77 g (0.94 mmol), cesium carbonate 18.37 were added. g (56.4 mmol), 50 mL of 2M sodium carbonate solution, reflux reaction at 90 °C for 4 h. After cooling, the solid was precipitated in ice water, and filtered to give a pale-white crude product, which was purified by silica gel G column chromatography (eluent: methanol/dichloromethane = 1:40, (v:v)) to give white solid 19d 0.87 g. Rate: 34.5%. 1H NMR (400 MHz, CD ₃ OD, CDC1 ₃ ) : 1.79 (d, 2H, J = 11.48 Hz, -CH ₂ ), 2.03 (d, 2H, J = 12.2 Hz, -CH ₂ _), 3.36 (s , 2H, -CH ₂ -), 3.73 (s, 3H, -CH ₃ ), 4.38 (d, IH, J = 12.72 Hz, -CH ₂ -), 5.17 (s, IH, -CH ₂ -), 7.32 (d, IH, quinoline-H), 7.35 (m, 5H, -Ar X 5), 7.45 (m, IH, quinoline-H), 7.54-7.59 (m, 4H, -ArX 4), 7.80 (m, 2H, quinoline-H), 7.89 (d, IH, J=8.84Hz, quinoline-H), 8.20 (d, IH, J=8.88 Hz, quinoline-H), 8.37 (d, IH, J=8.0 Hz, quinoline-H), 8.58 (d, 2H, quinoline-H), 8.84 (s, IH, quinoline-H), 9.14 (s, IH, quinoline-H). ¹³ C NMR (100 MHz, CD ₃ OD, CDC1 ₃ ), 152.9, 149.0, 147.8, 147.5, 146.9, 143.9, 134.6, 134.2, 134.0, 133.9, 132.7, 132.3, 130.3, 129.5, 128.4, 128.3, 128.1, 127.6, 127.4, 125.4, 123.7, 122.8, 120.0, 118.0 , 114.9, 66.9, 44.1, 42.0, 32.7, 27.4. Synthesis of intermediate 20d

 1.0 g (1.5 mmol) of intermediate 19d was dissolved in 150 ml of a mixed solvent of methanol / dichloromethane = 4:1,

HCOONH ₄ 1.0 g (15.0 mmol), when the temperature is raised to 60 °C, Pd/C 0.1g is added in batches. After heating and refluxing for 6-8 h, Pd/C is removed by filtration, and the mother liquid is concentrated to obtain crude compound. The crude product is passed through silica gel G column. Chromatography [eluent: (dichloromethane) / (methanol) I (ammonia) = 500/25/1] Intermediate 20d 0.5 g (Yield: 66.6%). Example 37: (SV8-i "2,3'-bipyridine 1-5-yl)-1-ί4-Π-ί2-hydroxypropionyl)piperidin-4-yl)phenyl 3-methyl -1H-imidazo-"4,5-cl-quinoline-2 3H ketone

Intermediate 20d 0.3 g (0.59 mmol) was dissolved in 50 ml of a mixed solvent of dichloromethane/methanol = 10:1, and DIEA 0.2 ml was added, and used; 0.09 ml (1.17 mmol) of L-lactic acid was dissolved in 10 ml. Add EDCI (0.25 g, 1.3 mmol), HOBT (0.17 g, 1.3 mmol) in dichloromethane for 10-30 min. Add the intermediate solution of the intermediate 20d, stir at room temperature for 12 h, TLC detection, reaction is complete. The crude product was concentrated to give a crystallite. 1H NMR (400 MHz, CD ₃ OD, CDCI3) . 1.14 (d, 2H, J = 6.36 Hz, -CH ₂ ), 1.53 (m, 2H, -CH ₂ _), 1.86 (m, 2H, -CH ₂ -), 2.58 (m, IH, -CH ₃ ), 2.98 (s, 3H, -CH ₃ -), 3.5 (s, IH, -CH ₃ -), 3.60 (d, IH, J = 12.48 Hz, - CH-), 3.74 (s, IH, -CH ₂ -), 4.40 (d, IH, J = 12.64 Hz, -CH-), 7.09 (d, IH, J=6.6Hz, quinoline-H), 7.16 ( m, IH, -ArH), 7.33 (m, 4H, -ArX 4), 7.56 (d, 2H, J=8.04Hz, quinoline-H), 7.63 (d, IH, J=8.72Hz, quinoline-H) , 7.87 (s, IH, quinoline-H), 7.99 (d, lH, J=8.8Hz, quinoline-H), 8.14 (d, 2H, J=6.52Hz, quinoline-H), 8.32 (s, IH, quinoline-H), 8.43 (s, IH, quinoline-H), 8.60 (s, IH, quinoline-H), 8.96 (s, IH, quinoline-H). ¹³ C NMR (100 MHz, CD ₃ OD, CDC1 ₃ ) : 173.3, 161.1, 153.6, 153.3, 149.6, 148.0, 147.4, 147.3, 144.4, 134.9, 134.1, 134.3, 133.3, 132.5, 130.9, 129.9, 128.8, 128.5, 126.7, 125.8, 125.1, 123.9, 123.2, 120.2 , 118.3, 118.2, 115.2, 110.1, 64.1, 48.7, 45.2, 40.1, 27.8, 20.9.

(13) Route 13

Synthesis of intermediate 19e

1.0 g (1.75 mmol) of intermediate 18 was dissolved in 10 mL of DMF in a three-necked flask, vacuumed, and 0.04 g (0.06 mmol) of Pd(PPh ₃ ) ₂ Cl _{2 was} added under nitrogen to heat to 95 °C. 0.35 g (2.1 mmol) of 2-methoxy-3-methylpyridine-5-boronic acid was dissolved in 5.0 ml of DMF for use; 0.93 g (8.8 mmol) of sodium carbonate was dissolved in 5.5 mL of water; Add the reaction flask and heat at 110 °C for 2 h. After the completion of the reaction, the reaction mixture was poured into ice water, and the mixture was stirred until the solid was precipitated, and the crude product was obtained by filtration. The crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/40, V: V) The solid 19e was 0.85 g, and the yield was 78.7%. 'HNMR (400MHZ, CDC1 ₃ ) δ : 1.75~1.78 (m, 2H, J=10.4 Hz, -CH2-), 1.98 (s, 2H, --CH2-), 2.18 (s, 3H, -CH3), 2.82-2.88 (m, 2H, J=24.4 Hz, -CH-), 2.95 (s, 2H, -CH2-), 3.68 (s, 3H, -CH3), 3.92 (s, 3H, -CH3), 5.17 (s, 2H, -CH2-), 4.40 (s, 2H, -CH2-), 5.17 (s, 2H, --CH2-), 7.14 (s, 1H, ArH), 7.33-7.36 (m, 5H, J=12.8 Hz, ArH), 7.48 (s, 4H, ArH), 7.71~7.73 (d, 1H, J=8.8Hz, quinoline-H), 7.85 (s, 1H, quinoline-H), 8.13~8.15 ( d, 1H, J=8.8Hz, quinoline-H), 8.76 (s, 1H, quinoline-H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ : 162.1, 155.2, 153.6, 147.7, 144.4, 142.1, 136.7 , 135.3, 133.4, 132.2, 131.0, 129.4, 128.8, 128.5, 128.0, 127.9, 125.8, 123.0, 120.5, 117.3, 115.4, 67.1, 53.4, 44.5, 42.6, 33.2, 27.8, 16.0. Synthesis of intermediate 20e

 0.8 g (1.3 mmol) of intermediate 19e was dissolved in a mixture of methanol / dichloromethane = 4:1 in 125 ml,

HCOONH ₄ 0.82 g (13.0 mmol), Pd/C 0.08 g was added in batches when heated to 60 °C, and heated to reflux for 6-8 h. After that, Pd/C was removed by filtration, and the mother liquid was concentrated to give the crude compound. The crude product was purified by silica gel column chromatography [eluent: (dichloromethane) / (methanol) / (aqueous) =500/25/1] 0.35 g (Yield: 55.6%). 1H NMR (400 MHz, CDC13) δ: 2.12-2.18 (m, 4H, J=24.8, -CH ₂ - X 2), 2.20 (s, 3H, -CH ₃ ), 3.03 (m, 1H, -CH- ), 3.12-3.15 (m, 2H, J=15.4, -CH ₂ -), 3.56-3.59 (d, 2H, J=12.2, -CH ₂ -), 3.71 (s, 3H, -CH3), 3.94 ( s, 3H, -CH ₃ ), 4.33 (s, 1H, -NH-), 7.14 (s, 1H, ArH), 7.41~7.44 (m, 1H, ArH), 7.54-7.61 (m, 4H, J= 27.4, ArHX 4), 7.75~7.77 (d, 1H, quinoline-H), 7.80 (s, 1H, quinoline-H), 8.12-8.14 (d, 1H, J=8.8, quinoline-H), 8.78 (s , 1H, quinoline-H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ: 161.9, 153.5, 146.0, 143.6, 141.4, 136.8, 135.3, 133.4, 131.8, 130.0, 129.4, 128.8, 128.5, 128.2, 126.1, 122.8, 120.7, 117.0, 115.1, 53.1, 48.9, 48.7, 48.5, 48.3, 48.1, 44.0, 40.1, 29.8, 27.5, 15.6. Example 38: (8) Small (4-(1-(2-hydroxypropionamidine) ()piperidin-4-yl)phenyl)-8-(6-methoxy-5-methylpyridin-3-yl)-3-methyl-1 oxime-imidazo[4,5-cl-quinoline -2 (H ketone

 0.30 g (0.73 mmol) of the intermediate 20e was dissolved in 50 ml of a mixed solvent of dichloromethane/methanol = 10:1, and 0.2 ml of DIEA was added, and used; 0.11 ml ( 1.46 mmol) of L-lactic acid was dissolved in 10 ml. In dichloromethane, add EDC 0.31 g, 1.61 mmol), HOBT (0.22, 1.61 mmol), stir for 10-30 min, add the intermediate solution of intermediate 20e, stir at room temperature for 12 h, TLC detection, reaction is complete, concentrate The crude product was purified by silica gel chromatography eluting elut elut elut elut elut elut elut eluts

(14) Route 14:

 Route 14 Intermediate 19f Synthesis

In a three-necked flask, 3.7 g (14.6 mmol) of diboronic acid pinacol ester was dissolved in 30 mL of 1,4-dioxane, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.3 g was added under nitrogen protection ( 0. 4 mmol), 2.15 g (21.9 mmol) of potassium acetate. After stirring for 5 min, add 1.74 g (7.3 mmol) of 5-bromo-2-(1-methyl-1H-pyrazol-4-yl)pyridine. 10 mL of 1,4-dioxane solution, warmed to 110 °C and reacted for 2-3 h. Down to room temperature, intermediate 18 2.1 g (3.65 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.3 g (0.4 mmol), cesium carbonate 7.14 g (21.9 mmol), 2M carbonate were added sequentially under N ₂ protection. 17 mL of sodium solution was refluxed at 90 °C for 4 h. After cooling, the solid was precipitated in ice water, and filtered to give a pale-white crude product. EtOAc (EtOAc: m. Rate: 37.8%. iHNMR OO MHz, CDC1 ₃ ) δ: 1.68 (t, 2Η, J=12 Hz, -CH ₂ -), 1.90 (d, 2H, J=12 Hz, -CH ₂ -), 2.90 (m, 3H, - CH ₂ -, -CHj-) 3.58 (s, 3H, -CH ₃ ), 3.82 (s, 3H, -CH ₃ ), 4.29 (d, 2H, J=12.4 Hz, -CH ₂ -), 5.06 (s , 2H, -CH ₂ -), 7.09 (s, 1H, ArH), 7.18-7.25 (m, 5H, ArH), 7.36 (d, 1H, J=8Hz, ArH), 7.42 (s, 4H, ArH) , 7.52 (d, 1H, J=7.6Hz, ArH), 7.74 (d, 1H, J=8Hz, ArH), 7.85 (s, 1H, ArH), 7.92 (s, 1H, ArH), 8.05 (d, 1H, J=7.6Hz, ArH), 8.26 (s, 1H, ArH), 8.73 (s, 1H, ArH). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ : 155.0, 153.3, 150.5, 147.8, 146.7, 146.4, 142.8, 136.9, 136.1, 134.6, 134.5, 132.4, 131.9, 131.2, 130.2, 129.0, 128.7, 128.3, 127.9, 127.5, 127.2, 125.9, 122.8, 122.0, 119.4, 119.0, 117.5, 114.7, 66.7, 44.0, 43.8, 41.8, 41.6, 38.2, 32.7, 32.4, 27.2. Synthesis of intermediate 20f 0.8 g (1.2 mmol) of intermediate 19f was dissolved in 150 ml of a methanol/dichloromethane=4:1 mixed solvent, and HCOONH ₄ 0.8 g (12.3 mmol) was added thereto, and Pd/C was added in portions while heating to 60 °C. 0.16 g, heating and refluxing for 6-8 h, the Pd/C was removed by filtration, and the crude liquid was concentrated to give the crude compound. The crude product was purified by silica gel column chromatography [eluent: (dichloromethane) / (methanol) / (ammonia) = 500/50/1] Intermediate 20f 0.35 g, (Yield: 55.6%). 1H NMR (400 MHz, CDC1 ₃ ) δ : 1.05 (m, 2H, -CH ₂ -), 1.94-2.03 (m, 3H, -CH ₂ , -NH-), 2.92 (m, 2H, -CH ₂ - ), 3.33 (d, 2H, J=12 Hz, -CH ₂ -), 3.51 (s, 3H, -CH ₃ ), 3.76 (s, 3H, -CH ₃ ), 7.26 (s, 3H, ArH), 7.37 (d, 2H, J=8Hz, ArH), 7.43 (d, 2H, J=8Hz, ArH), 7.54 (d, 1H, J=7.2, ArH), 7.62 (d, 1H, J=7.2, ArH ), 7.77 (d, 1H, J=8.8, ArH), 7.83 (s, 1H, ArH), 8.05 (d, 1H, J=8.8, ArH), 8.79 (s, 1H, ArH). ¹³ C NMR ( 100 MHz, CDC1 ₃ ) δ : 153.3, 146.6, 145.0, 140.1, 137.4, 136.4, 135.2, 132.5, 132.2, 129.9, 128.4, 128.4, 128.2, 128.0, 126.6, 123.3, 120.4, 118.1, 114.4, 43.9, 39.3, 38.4, 29.1, 27.6. Example 39: (S)-l-(4-n-i2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-ί6-Π- Methyl-1H-pyrazol-4-yl)pyridin-3-yl 1H-imidazole and "4,5-cl-quinoline-2 (H-ketone)

 Dissolve 0.09 ml (1.2 mmol) of L-lactic acid in 5 ml of DMF, add EDCI (0.25 g, 1.28 mmol), HOBT (0.17 g, 1.28 mmol), stir and dissolve, add a small amount of intermediate 20f, dissolve in DIEA 0.2 ml. The intermediate 20f 0.3 g (0.58 mmol) was added, and the mixture was stirred at room temperature for 2 h. EtOAc was evaporated. The crude product was purified by silica gel chromatography eluting elut elut elut elut elut elut elut elut elut

(15) Route 15:

Route 15 Intermediate 115B: 3- (4-

oc Compound 115A (4 g, 20.96 mmol) was dissolved in 10 ml of acetic acid, and 0.92 ml (20.96 mmol) of fuming nitric acid and 1 ml of concentrated sulfuric acid dissolved in 10 ml of acetic acid were added dropwise. After the addition, the mixture was stirred for 5 min, and added to 20 The mL concentrated sulfuric acid was heated to 58 ° C and allowed to react overnight (the reaction was monitored by LC-MS) and cooled to room temperature. The reaction solution was poured into ice water, the pH was adjusted to 9 with a NaOH solution, and extracted with dichloromethane. The organic phase was combined, dried, and evaporated to give 4 g of reddish brown liquid, yield 92.38%. LC-MS: 207 [M+l] ⁺ , < _/RTI > = _R = 1.250 min.

Oc

Intermediate 115B (4 g, 19.39 mmol) was dissolved in 40 ml of dichloromethane, then 3.26 ml of triethylamine was added and 20 ml was added dropwise A solution of 4.66 g (21.33 mmol) of di-tert-butyl dicarbonate in dichloromethane, stirred at room temperature for 2 h, washed with saturated sodium bicarbonate, dried and evaporated to dryness. %. LC-MS: 251 [M+l - 56] ⁺ , t,,,,,,,,,,,,,,,,,,,,,,

Intermediate 115C (6.7 g, 19.39 11^101) was dissolved in 301 dimethylformamide, and 21.9 g (96.95 mmol) of water and stannous chloride were added portionwise and stirred at room temperature overnight. The reaction solution was slowly poured into 300 ml of saturated sodium bicarbonate solution and 300 ml of dichloromethane, and the pH was adjusted to 11 with 10% sodium hydroxide solution, and the aqueous phase was extracted with dichloromethane, and the organic phase was combined. The water was washed twice, washed with an equal amount of saturated brine, and the organic phase was dried and evaporated to dryness to give 5.4 g of crude red brown liquid. LC-MS: 221 [M+l] ⁺ , _&lt ; &quot;&&&&&&&&&&&&&&&&&& Acridine-1-carboxylic acid tert-butyl ester

中间体 115 ( 3.9 g， 13.92 mmol) 溶于 40 ml醋酸中， 加入 2.9 g ( 6.96 mmol) 中间体

Intermediate 115 (3.9 g, 13.92 mmol) was dissolved in 40 mL of EtOAc.

中间体 116( 3.2 g， 6.068 mmol)溶于 30 ml N，N-二甲基甲酰胺中，分批加入 6.85 g( 30.34 mmol)水和氯化亚锡，室温搅拌 4h。将反应液缓慢倒入 300 ml饱和碳酸氢钠溶液和 300 ml 二氯甲烷中， 用 10%氢氧化钠溶液调节 pH至 11， 分液， 水相用二氯甲烷萃取， 合并有机 相， 用等量的水洗涤 2次， 再用等量的饱和食盐水洗涤， 干燥有机相， 蒸干得 2.8 g黄色固 体粗品， 粗收率 93.33%。 此中间未经纯化直接用于下一步反应。 中间体 118: 3- (4- ( 8-溴 -2-羰基 -2,3-二氢 -1H-咪唑并 [4，5-c]喹啉 -1-基） 苯基） 哌啶 -1-羧酸 叔丁酯 4, stirring at room temperature for 3 hours, adding 250 ml of water, adjusting the pH to 7 with 10% sodium hydroxide solution, then extracting with dichloromethane, combining the organic phase, drying, and evaporated to dryness to give a crude product. The eluent: methanol: dichloromethane = 1:50) gave a reddish brown solid (3.2 g, yield: 87.17%). LC-MS: 527, 529 [ M + l] +, t R = 2.998 min Intermediate 117: 3- (4- ((3-amino-6-bromo-quinolin-4-yl) amino) phenyl) Piperidine-1-carboxylic acid tert-butyl ester

Intermediate 116 (3.2 g, 6.068 mmol) was dissolved in 30 mL of N-N-dimethylformamide, and 6.85 g (30.34 mmol) of water and stannous chloride were added in portions and stirred at room temperature for 4 h. The reaction solution was slowly poured into 300 ml of saturated sodium bicarbonate solution and 300 ml of dichloromethane, and the pH was adjusted to 11 with 10% sodium hydroxide solution, and the aqueous phase was extracted with dichloromethane, and the organic phase was combined. The amount of water was washed twice, and then washed with an equal amount of saturated brine. The organic phase was dried and evaporated to dryness to afford 2.8 g of crude yellow solid. This intermediate was used directly in the next reaction without purification. Intermediate 118: 3-(4-(8-Bromo-2-carbonyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)piperidine-1 - tert-butyl carboxylate

Intermediate 117 (2.8 g, 5.65 mmol) was dissolved in dichloromethane (25 mL), 2.35 ml ( 16.95 mmol) of triethylamine was added, and 0.838 g (2.825 mmol) of triphosgene was dissolved in 25 ml of dichloromethane. The solution in the solution was kept at 0 ° C for 4 h after the addition. 50 ml of saturated sodium bicarbonate solution was added dropwise, and the aqueous layer was separated with dichloromethane. The organic phase was combined, dried and evaporated to dryness. : 20), obtained as a yellow solid, 1.3 g, yield 44.82%. LC-MS: 523, 525 [M+l]+, t _R = 2.424 min. Intermediate 119: 3- (4- (4-bromo-3-) Methyl-2-carbonyl-2,3-dihydro-1H-imidazo[4,5-c]quinoline) phenyl) piperidine-1-carboxylic acid tert-butyl ester

 118 119

 Intermediate 118 (1.3 g, 2.48 mmol) was dissolved in 50 mL dichloromethane. EtOAc (EtOAc, m. Methyl iodide, stirred at rt overnight, EtOAc (EtOAc)EtOAc. This intermediate was used directly in the next reaction without purification. Intermediate 120: 3-(4-(3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)B-pyridin-3-yl)-2-carbonyl-2, 3-Dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl) piperidine-1-carboxylic acid tert-butyl ester

Intermediate 119 (0.8 g, 1.24 mmol) was dissolved in 10 mL of EtOAc. EtOAc (EtOAc: EtOAc. Mol 2 mol 1 / L sodium carbonate solution, 0.101 g (0.124 mmol) Pd(dppf)Cl ₂ .CH ₂ Cl ₂ , heated to 110 ° C, reacted for 5 h, cooled to room temperature. Distilled off the dioxane, dissolved in 50 ml of saturated sodium bicarbonate solution and 50 ml of dichloromethane, partitioned, the aqueous phase was extracted with dichloromethane, the organic phase was combined, dried and evaporated to dryness. Chromatography (eluent: methanol: methylene chloride = 1 : 10) gave 0.712 g. LC-MS: 616 [M+l]+, _&lt ; &quot;&&&&&&&&&&&&&&&&&&& -yl)-1-(4-piperidin-3-yl)phenyl)-1H-imidazo[4,5-c]quinolin-2(3H)-one hydrochloride

The intermediate 120 (0.712 g, 1.16 mmol) was dissolved in 20 ml of dichloromethane, cooled to 0-10 ° C, hydrogen chloride gas was introduced into the reaction system, and reacted for 1 h, and filtered to obtain 610 mg of solid, yield 95.31%. . LC-MS: 516 [M+l] ⁺ , _&lt ;RTI ID=0.0 _&gt ; _&gt ; -8-ί6-Π-methyl-1H-pyrazol-4-yl)pyridin-3-yl 1H-imidazo[4,5-cl-quinoline-2 (H

Intermediate 121 (30 mg, 0.054 mmol) was dissolved in dichloromethane (3 mL), and 16 mg (0.081 mmol) of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 11 Mg (0.081 mmol) 1-hydroxybenzotriazole and 6 mg (0.081 mmol) of hydroxyacetic acid, 27 mg (0.27 mmol) of triethylamine. Add 10 ml of saturated sodium bicarbonate solution, stir for 10 min, and separate the liquid. The aqueous phase is extracted with dichloromethane. The organic phase is combined, dried and evaporated to dryness. 10) Example 14 target compound 14 mg, yield 43.75%. LC-MS: 574 [M+l] ⁺ , t _R = 1.634 min. 1H NMR (400 MHz, CDC1 ₃ ) δ 8.83 (d, J= 4.1 Hz, 1H), 8.60 - 8.06 (m, 3H), 8.02 - 7.92 (m, 1H), 7.90 - 7.78 (m, 1H), 7.78 - 7.64 (m, 1H), 7.62 - 7.44 (m, 5H) , 7.23 (s, 1H), 4.94 - 4.70 (m, 1H), 4.35 - 4.20 (m, 2H), 3.99 (s, 3H), 3.84 - 3.58 (m, 5H), 3.24 - 3.04 (m, 1H) , 3.02 - 2.72 (m, 2H), 2.30 - 2.19 (m, 1H), 2.06 - 1.79 (m, 3H). Example 41: 3-methyl-8-ί6-Π-methyl-1H-pyrazole 4-yl)pyridin-3-yl-l-i4-n-(methylsulfonyl)piperidin-3-yl)phenyl)-1H-imidazo-"4,5-cl-quinoline-2 3H ketone

Intermediate 121 (30 mg, 0.054 mmol) was dissolved in dichloromethane (3 mL), EtOAc (EtOAc) Add 10 ml of saturated sodium bicarbonate solution, stir for 20 min, and separate the mixture. The aqueous phase is extracted with dichloromethane. The organic phase is combined, dried and evaporated to dryness. 10) Example 41 The target compound was 23 mg, yield 71.83%. LC-MS: 594 [M+l] ⁺ , t _R = 1.765 min. 1H NMR (400 MHz, CDC1 ₃ ) δ 8.81 (s, 1H), 8.54 (s, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.69 - 7.46 (m, 6H), 7.26 (s, 1H), 3.97 (s, 4H), 3.89 (d, J = 11.1 Hz, 1H), 3.70 (s, 3H), 3.14 - 3.04 (m, 1H), 2.93 - 2.70 (m, 5H), 2.18 (d, J = 11.0 Hz, 1H), 2.03 - 1.63 (m, 3H). Example 42: 1-(4-Π-ί4Η-1,2,4-triazol-3-carbonyl)piperidin-3-yl)phenyl-3-methyl-8-ί6-Π-methyl- 1H-pyrazol-4-yl)pyridin-3-yl V 1 H-imidazo and "4,5-cl quino-2 3H ketone

10.9 mg (0.097 mmol) of 1,2,4-triazole-3-carboxylic acid was dissolved in 5 ml of dichloromethane, and 45.2 mg (0.119 mmol) of 2-(7-nitrobenzotriazole) was added. Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate, add 21.9 mg (0.216 mmol) triethylamine under ice bath, stir for 30 min, add 30 mg of intermediate 121 (0.054 mmol), stir at room temperature overnight. After TLC, after the reaction was completed, 10 ml of a saturated sodium hydrogencarbonate solution was added, and the mixture was stirred for 20 min, and the aqueous layer was separated, and the organic phase was combined, dried and evaporated to dryness. The crude product was purified by preparative silica gel chromatography (methanol: methylene chloride = 1:1). LC-MS: 611 [M+l] ⁺ , t _R = 1.546 min. This product was dissolved in 75% ethanol, adjusted to pH 1 with 1 M HCl, stirred for 0.5 h, and evaporated to dryness. 1H NMR (400 MHz, DMSO+D20) δ 9.45 (s, 1H), 8.71 - 8.54 (m, 2H), 8.53 - 8.31 (m, 3H), 8.19 (s, 1H), 8.12 - 8.01 (m, 1H), 7.97 - 7.60 (m, 5H), 7.16 (d, J= 5.3 Hz, 1H), 5.41 - 4.36 (m, 1H), 3.90 (d, J

 3H), 3.70 (s, 3H), 3.52 - 3.16 (m, 2H), 3.02 - 2.88 (m, 1H), 2.24 - 1.40 (m, 5H). Example 43: l-(4-n-(YRV2 -hydroxypropionyl)piperidin-3-yl)phenyl-3-methyl-8-ί6-oxime-methyl-1H-pyrazol-4-yl)oxidin-3-yl 1H-imidazole "4,5-cl quinoline-2 (

50 mg (0.09 mmol) of intermediate 121, 25.9 mg (0.135 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 20.7 mg (0.135 mmol) of 1-hydroxy Benzotriazole and 13.5 mg (0.135 mmol) of D-lactic acid were dissolved in 5 mL of dichloromethane, then 59.2 mg (0.585 mmol) of triethylamine was added and stirred at room temperature overnight. After TLC detection, after completion of the reaction, 10 mL of a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was stirred for 20 minutes, and the layers were separated, and the aqueous phase was extracted with dichloromethane. The crude product was purified by silica gel chromatography eluting eluting eluting eluting LC-MS: 588 [M+l] ⁺ , t _R = 1.634 min. 1H NMR (400 MHz, CDC1 ₃ ) δ 8.81 (d, J = 4.5 Hz, 1H), 8.61 - 8.32 (m, 1H), 8.22 (d, J = 9.1 Hz, 1H), 8.18 - 8.02 (m, 1H), 8.00 - 7.78 (m, 2H), 7.76 - 7.65 (m, 1H), 7.60 - 7.40 (m, 5H), 7.32 - 7.18 (m, 1H), 4.93 - 4.52 (m, 2H), 4.00 - 3.80 (m, 5H), 3.71 (s, 3H), 3.25 - 3.08 (m, 1H), 3.02 - 2.65 (m, 2H), 2.30 - 2.18 (m, 1H), 2.05 - 1.80 (m, 2H), 1.48 - 1.36 (m, 3H). Example _44: i- -n-S)^-hydroxypropionyl)piperidin-3-yl Phenyl-3-methyl-8-ί6-indole-methyl-1H-pyrazol-4-yl)-portion-3-yl 1H-imidazole and "4,5-cl-quinoline-2 (H-ketone)

50 mg (0.09 mmol) of intermediate 121, 25.9 mg (0.135 mmol) 1-(3- Carbodiimide hydrochloride, 20.7 mg (0.135 mmol) 1-hydroxybenzotriazole and 13.5 mg (0.135 mmol) L-lactic acid, dissolved in 5 mL of dichloromethane, then added 59.2 mg (0.585 mmol) Ethylamine was stirred at room temperature overnight. After TLC detection, after completion of the reaction, 10 mL of a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was stirred for 20 minutes, and the layers were separated, and the aqueous phase was extracted with dichloromethane. The crude product was purified by silica gel chromatography eluting eluting eluting eluting This product was dissolved in 75% ethanol, adjusted to pH 1 with 1 M HC1, stirred for 0.5 h, and evaporated to dryness to give the hydrochloride. LC-MS: 588 [M + l] +, t R = 1.634 min 1H NMR (400 MHz, DMSO + D 2 0) δ 9.39 (s, 1H), 8.71 - 8.08 (m, 5H), 8.05 - 7.91. (m, 1H), 7.88 - 7.48 (m, 5H) _: 7.18 (d, J= 12.3 Hz, 1H), 4.70 - 4.05 (m, 2H), 3.91 (s, 3H), 3.67 (s, 3H), 3.34 - 2.64 (m, 5H), 2.15 - 1.77 (m, 4H), 1.40 - 1.02 (m, 3H). Example 45: 1-ί4-indole-ethylpiperidin-3-yl)phenyl-3 -Methyl-8-ί6-Π-methyl-1H-pyrazol-4-yl)pyridin-3-yl 1H-imidazole and "4,5-cl-quinoline-2 3H ketone

Under ice-water bath, 18 mg (0.45 mmol) of 60% sodium hydride was suspended in 5 mL of tetrahydrofuran. After stirring for 5 minutes, 50 mg (0.09 mmol) of intermediate 121 was added. After stirring for 10 minutes, 14 mg (0.09 mmol) was added dropwise. Ethyl iodide, stirred at room temperature for 3 hours. After TLC detection, after completion of the reaction, 10 mL of water was added dropwise, extracted with dichloromethane, and the aqueous phase was extracted with dichloromethane. The crude product was purified by silica gel chromatography eluting eluting eluting eluting eluting This product was dissolved in 75% ethanol, adjusted to pH 1 with 1 M HC1, stirred for 0.5 h, and evaporated to dryness to give the hydrochloride. LC-MS: 544 [M+l]+, t _R = 1.476 min. 1H NMR (400 MHz, DMSO+D20) δ 9.39 (d, J = 5.6 Hz, 1H), 8.61 - 8.26 (m, 5H), 8.22 - 8.12 (m, 1H), 8.00 - 7.10 (m, 6H), 3.94 (s, 3H), 3.68 (s, 3H), 3.60 - 3.22 (m, 6H), 3.04 - 2.63 (m, 2H), 2.12 - 1.67 (m, 3H), 1.15 - 0.98 (m, 3H).

(16) Route 16:

 Route 16 Intermediate 125B: 4-(4-Nitrophenyl) piperidine

/ ~ / ~ \ HN0 ₃ /H ₂ S0 ₄ Π—^ I ~ \

/ \ / ^NH ^ 0 ₂ N- V- ( NH

 \=/ \ _ I AcOH \=/ , ~~ '

 125A 125B

将 9.8 g (48 mmol) 中间体 125B溶于 60 mL二氯甲烷中， 加入 8.04 mL (57.6 mmol) 三乙胺， 滴加 11.52 g 二碳酸二叔丁酯溶于 20 mL二氯甲烷的溶液， 室温搅拌过夜。 TLC 检测， 反应结束后， 用饱和碳酸氢钠水溶液洗涤， 干燥， 旋干， 获得粗产物 15.9 g， 黄色 油状物， 粗产率大于 100%。 此粗品中间体未经纯化直接用于下一步反应。 中间体 125D: 4- (4-硝基苯基） 哌啶 -1-羧酸叔丁酯

12 g (74.4 mmol) of compound 125A was dissolved in 60 mL of acetic acid, and 3.5 mL (74.4 mol) of fuming nitric acid and 3.96 mL (74.4 mmol) of concentrated sulfuric acid in 20 mL of acetic acid were added dropwise, and stirred for 5 minutes. 60 mL of concentrated sulfuric acid was added and reacted at 58 ° C for 8 hours. After LC-MS detection, after the reaction was completed, the reaction solution was poured into ice water, the pH was adjusted to 9 with sodium hydroxide solution, extracted with dichloromethane, dried, and dried to give 9.8 g of product as a yellow solid, yield 63.8. %. LC-MS: 207 [M+l] ⁺ , _&lt ;RTI ID=0.0 _&gt ;

9.8 g (48 mmol) of intermediate 125B was dissolved in 60 mL of dichloromethane, 8.04 mL (57.6 mmol) of triethylamine was added, and a solution of 11.52 g of di-tert-butyl dicarbonate dissolved in 20 mL of dichloromethane was added dropwise. Stir at room temperature overnight. The mixture was washed with a saturated aqueous solution of sodium bicarbonate, dried, and dried to give a crude product (15.9 g, yellow oil). This crude intermediate was used in the next reaction without purification. Intermediate 125D: 4-(4-Nitrophenyl)piperidine-1-carboxylic acid tert-butyl ester

In an ice water bath, 15.9 g (48 mmol) of intermediate 125C was dissolved in 75 mL of N'N-dimethylformamide, and 54.1 g (240 mmol) of stannous chloride dihydrate was added in portions over 30 min. Stir for 3 hours. After TLC detection, after the reaction was completed, a 10% aqueous sodium hydroxide solution was added dropwise to the reaction solution to pH 8-9, and the mixture was filtered. The filtrate was extracted with dichloromethane, and the filter cake was washed with dichloromethane. brine, dried, rotary dried to obtain the product 12.4 g, yellow oil, yield 93.9% o LC-MS: 221 [M + l-56] +, t R = 1.792 min intermediate 125: 4- (4- ((6-Bromo-3-nitroquinolin-4-yl)amino)phenyl) piperidine-1-carboxylic acid tert-butyl ester

 Dissolve 3.4 g (12. 3 mmol) of intermediate 125D in 40 mL of acetic acid and add 1.77 g (6.15 mmol) of 6-bromo

冰水浴下， 将 2.6 g (4.93 mmol) 中间体 125溶于 20 mL N，N-二甲基甲酰胺中， 在 30 分钟分钟内， 分批加入 5.56 g (24.65 mmol) 二水合二氯化锡， 室温搅拌过夜。 TLC检测， 反应结束后， 向反应液中滴加 10%氢氧化钠水溶液， 至 pH值 8-9， 过滤， 滤液用二氯甲烷 萃取， 滤饼用二氯甲烷洗涤， 合并有机相， 水洗， 盐水洗， 干燥， 旋干获得产品 1.1 g， 黄 色固体， 产率 44.9%。 LC-MS: 497,499 [M+l]+， t_R= 2.209 min. 中间体 127: 4- (4- ( 8-溴 -2-氧代 -2,3-二氢 -1H-咪唑并 [4，5-c]喹啉 -1-基） 苯基） 哌啶 -1-羧酸 叔丁酯 4-chloro-3-nitroquinoline was stirred at room temperature for 5 hours. After TLC detection, after the reaction was completed, it was filtered, and the filter cake was washed with acetic acid and dried in vacuo to give 2.6 g of product, yellow powder, yield: 81.25%. LC-MS: 527, 529 [M+l] ⁺ _&lt ;RTI ID=0.0 _&gt ; Tert-butyl-1-carboxylate

Under ice-water bath, 2.6 g (4.93 mmol) of intermediate 125 was dissolved in 20 mL of N,N-dimethylformamide, and 5.56 g (24.65 mmol) of tin dichloride dihydrate was added in portions over 30 minutes. Stir at room temperature overnight. After TLC detection, after the reaction was completed, a 10% aqueous sodium hydroxide solution was added dropwise to the reaction solution to pH 8-9, and the mixture was filtered. The filtrate was extracted with dichloromethane, and the filter cake was washed with dichloromethane. Washed with brine, dried and dried to dryness afforded product 1.1 g, yellow solid, yield 44. LC-MS: 497,499 [M + l] +, t R = 2.209 min Intermediate 127: 4- (4- (8-bromo-2-oxo-2,3-dihydro -1H- imidazo [4 , 5-c]quinolin-1-yl)phenyl) piperidine-1-carboxylic acid tert-butyl ester

In an ice water bath, ll g (2.2 mmol) of intermediate 126 was dissolved in 20 mL of dichloromethane, 1.01 mL (3.3 mmol) of triethylamine was added, and a solution of 0.33 g of triphosgene dissolved in 10 mL of dichloromethane was added dropwise. Stir for 3 hours in an ice bath. After the reaction, the mixture was quenched by the addition of 60 mL of saturated aqueous sodium hydrogencarbonate and stirred for 10 minutes. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The crude product was subjected to silica gel column chromatography (eluent: methylene chloride/methanol = 10/1, V/V) LC-MS: 523, 525 [M+l] ⁺ , _&lt ; &quot; _&gt ;&&&&&&&&&&&&&&&&&& -Imidazo[4,5-c]quinolin-1-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

0.8 g (1.5 mmol) of intermediate 127 was dissolved in 30 mL of dichloromethane, and 0.048 g (0.15 mmol) of tetrabutylammonium bromide and 30 mL of 10% aqueous sodium hydroxide solution were added, stirred for 10 minutes, and added to 0.64 mL ( 4.5 mmol) methyl iodide, stirred for 4 hours. After TLC detection, after completion of the reaction, the mixture was allowed to stand for separation, the organic phase was separated, the aqueous phase was extracted with dichloromethane, and the organic phase was combined and dried to give 0.99 g of product as a yellow solid. LC-MS: 537, 539 [M+l] ⁺ ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)piperidine-1-carboxylic acid Butyl ester

Under a nitrogen atmosphere, 0.5 g (0.93 mmol) of intermediate 128 and 0.424 g (1.49 mmol) of Intermediate 9A were dissolved in 15 mL of dioxane, and 1.92 g (5.49 mmol) of cesium carbonate and 5 mL of 2M sodium carbonate aqueous solution were added and added. 0.076 g (0.093 mmol) [1,1-bis(di-phenylphosphino)ferrocene]palladium chloride, heated at 110 ° C for 5 hours. After TLC detection, after completion of the reaction, most of the dioxane was spun off, water was added, and the mixture was extracted with dichloromethane, and the organic phases were combined, dried and dried to give a crude product. The crude product was purified by silica gel column chromatography eluting eluting eluting eluting eluting eluting eluting +, t _R = 2.183 min. Intermediate 130: 3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(4- Piperidin-4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

In an ice water bath, 0.388 g (0.616 mmol) of Intermediate 129 was dissolved in 20 mL of dichloromethane, then 2.5 mL of trifluoroacetic acid was added and stirred at 0 ° C for 1 hour. After TLC detection, after completion of the reaction, the reaction mixture was sparged, dichloromethane was added, the pH was adjusted to basic with triethylamine, and dried to give a crude product. The crude product was purified by silica gel column chromatography eluting eluting eluting eluting eluting elution LC-MS: 516 [M+l] ⁺ _&lt ;RTI ID=0.0 _&gt ; _&gt ; )-1-(4-Π-(methylsulfonyl)piperidin-4-yl)phenyl)-1Η-imidazolium "4,5-cl-quinoline-2 3H

115 mg (0.223 mmol) of intermediate 130 was dissolved in 5 mL of dichloromethane, 33.9 mg (0.335 mmol) of triethylamine was added, and then 30.7 mg (0.268 mmol) of methanesulfonyl chloride was added and stirred at room temperature overnight. After TLC, after completion of the reaction, 10 mL of a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was stirred for 20 minutes, and the layers were separated, and the aqueous phase was extracted with dichloromethane. The crude product was purified by silica gel chromatography chromatography eluting eluting eluting LC-MS: 594 [M + l] +, t R = 1.734 min 1H NMR (400 MHz, CDCl 3 + MeOD) δ 8.82 (s, 1H), 8.39 (s, 1H), 8.19 (d, J =. 8.7 Hz, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.86 (d, J= 8.8 Hz, 1H), 7.69 (d, J= 6.2 Hz, 1H), 7.57 (q, J= 8.4 Hz, 4H), 7.50 (d, J= 8.4 Hz, 1H), 7.21 (s, 1H), 4.00 (s, 5H), 3.74 (s, 3H), 2.99 - 2.78 (m, 6H), 2.15 - 1.94 (m, 4H). Example 47: 1-(4-Π-ί2-hydroxyethyl)piperidin-4-yl)phenyl)-3-methyl-8-ί6-Π-methyl- 1H-pyrazol-4-yl)pyridin-3-yl 1H-imidazole and "4,5-cl-quinoline-2 (H-ketone)

100 mg (0.194 mmol) of intermediate 130, 55.6 mg (0.29 mmol) of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 39.2 mg (0.29 mmol) of 1-hydroxyl Benzotriazole and 17.7 mg (0.233 mmol) of glycolic acid were dissolved in 5 mL of dichloromethane, then 58.7 mg (0.58 mmol) of triethylamine was added and stirred at room temperature overnight. After the reaction was completed, 10 mL of a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was stirred for 20 minutes, and the layers were separated, and the aqueous phase was extracted with dichloromethane. The crude product was purified by silica gel chromatography eluting elut elut elut elut elut elut This product was dissolved in 75% ethanol, adjusted to pH 1 with 1 M HC1, stirred for 0.5 h, and evaporated to dryness to give the hydrochloride. . LC-MS: 574 [M + l] +, t R = 1.609 min 1H NMR (400 MHz, DMSO + D 2 0) δ 9.51 (s, 1H), 8.93 - 8.80 (m, 1H), 8.67 - 8.43 (m, 3H), 8.43 - 8.05 (m, 3H), 7.82 - 7.63 (m, 4H), 7.17 (d, J = 22.8 Hz, 1H), 4.62 - 4.47 (m, 1H), 3.99 (d, J = 6.0 Hz, 3H) _: 3.95 - 3.78 (m, 2H), 3.70 (s, 3H), 3.42 (d, J= 11.2 Hz, 1H), 3.29 - 3.00 (m, 2H), 2.94 - 2.67 (m, 1H), 2.18 - 1.47 (m, 4H). Example 48: 1-(4-indole-1,2,4-triazol-3-carbonyl)piperidin-4-yl)phenyl 3- Methyl-8-ί6-Π-methyl-1H-pyrazol-4-yl)pyridin-3-yl V 1 H-imidazole and 4,5-cl -2 3H ketone

 39.4 mg (0.349 mmol) of 1,2,4-triazole-3-carboxylic acid and 162.28 mg (0.426 mmol) in an ice water bath

2-( 7-Azabenzotriazole) -Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate dissolved in 5 mL of dichloromethane, adding 97 mg (0.96 mmol) of triethylamine After stirring at 0 ° C for 30 minutes, additional 100 mg (0.194 mmol) of intermediate 130 was added and stirred at room temperature overnight. After TLC, after completion of the reaction, 10 mL of a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was stirred for 20 minutes, and the layers were separated, and the aqueous phase was extracted with dichloromethane. The crude product was purified by silica gel chromatography eluting elut elut elut elut elut elut LC-MS: 611 [M + l, t R = 1.573 min Ή NMR (400 MHz, CDC1 3) δ 8.81 (s, 1H), 8.42 (s, 1H), 8.26 - 7.98 (m, 4H), 7.81. (d, J = 8.8 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.58 - 7.49 (m, 5H), 7.46 - 7.40 (m, 1H), 7.24 (s, 1H), 5.02 - 4.94 (m , 1H), 4.00 (s, 3H), 3.71 (s, 3H), 3.41 - 3.31 (s, 1H), 3.14 - 2.93 (m, 2H), 2.24 - 2.13 (m, 2H), 2.08 - 1.86 (m , 3H).

(17) Route 17:

 Route 17 Intermediate 134: 4-(4-(8-Bromo-3-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinoline-1- Tert-butyl)phenyl)piperidine-1-carboxylate

0.3 § (0.57 11^101) of intermediate 127 was suspended in 70 1 of dichloromethane, 0.18 g of TBAB (0.057 mmol) and 40 ml of 10% sodium hydroxide solution were added, stirred for 10 minutes, and 0.12 ml (1.55) was added with stirring. Ethyl iodide was stirred at room temperature overnight. TLC (DCM: MeOH=10:1) showed that a small amount of starting material was not reacted, and then added 0.12 ml of ethyl iodide, stirred at room temperature for 4 h, leaving a small amount of starting material, separating organic phase, water The layers were extracted with 40 ml of methylene chloride. The combined organic layers were washed with 40 ml of water, and the aqueous layer was extracted with an equal volume of methylene chloride. The organic phase was combined, dried and filtered to give a crude product. Purification by silica gel column chromatography (ethyl acetate)ield LC-MS: 551, 553 [M+l] ⁺ _&lt ;RTI ID=0.0 _&gt ; -yl)B-pyridin-3-yl)-2-oxo-2,3-de[4,5-c]quinolin-1-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

Under nitrogen, 0.305 g ( 1.278 mmol) of compound 9B, 0.389 g ( 1.534 mmol) of diboronic acid pinacol ester, 0.376 g (3.834 mmol) of potassium acetate and 0.083 g (0.102 mmol) of Pd(dppf)Cl ₂ .CH ₂ Cl _{2 was} suspended in 10 ml of dioxane, heated to 95 ° C for 2 hours, and TLC (ethyl acetate) showed the reaction was completed. The crude reaction solution was cooled to room temperature, and 0.47 g (0.852 mmol) of Intermediate 134, 1.166 g (3.578 mmol) of cesium carbonate, 5 ml of dioxane, 2.5 ml of 2M sodium carbonate solution and 0.07 g (0.085 mmol) of Pd ( Dppf)Cl ₂ .CH ₂ Cl _{2 was} heated to 110 ° C and stirred for 6 hours. TLC (DCM: MeOH = 10:1) showed the reaction was completed, cooled, evaporated to dioxane, dissolved in 20 ml of dichloromethane and 20 In ml of water, the organic phase is separated, the aqueous phase is extracted with 20 ml of dichloromethane, and the organic phase is combined, dried, evaporated to dryness, and purified by silica gel column (dichloromethane:methanol = 30:1 to 10:1) to give 0.409 g of product. , yield 76%. LC-MS: 630 [M+l] ⁺ , _&lt ; &quot;&&&&&&&&&&&&&&&&&&& -3-yl)-1-(4-(piperidin-4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

0.21 g (0.33 mmol) of intermediate 135 was dissolved in 10 ml of dichloromethane, cooled to 0 to 10 ° C, and dried with hydrogen chloride gas for 1 h, a large amount of precipitate appeared, TLC (DCM:MeOH = 10:1) ) shows that the reaction is complete, suction filtration, Vacuum dried 155 mg of the hydrochloride salt, yield 77.9%. Example 49: 3-ethyl-1-ί4-Π-ί2-hydroxyethyl)piperidin-4-yl)phenyl)-8-ί6-oxime-methyl-1H-pyrazol-4-yl Pyridin-3-yl 1H-imidazolium "4,5-cl-quinoline-2 (H

50 mg (0.083 mmol) of intermediate 136 hydrochloride, 9.43 mg (0.124 mmol) of glycolic acid, 16.8 mg (0.124 mmol) of HOBt and 23.8 mg of EDCI (0.124 mmol) were suspended in 4 ml of dichloromethane, 54.6 mg (0.54 mmol) Triethylamine, stirred at room temperature overnight, TLC (DCM: MeOH = 10:1). The reaction mixture was taken, and 10 ml of saturated sodium hydrogen carbonate solution was added and stirred for 0.5 hour, and the organic phase was separated. The organic phase was combined, dried and evaporated to dryness. LC-MS: 588 [M+l]+, t _R = 1.683 min. 1H NMR (400 MHz, CDC1 ₃ ) δ 8.85 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.24 (d , J= 8.8 Hz, 1H), 8.02 - 7.98 (m, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.70 (d, J= 7.8 Hz, 1H), 7.61 - 7.48 (m, 4H) , 7.45 (d, J= 8.0 Hz, 1H), 7.24 (s, 1H), 4.85 (d, J= 12.9 Hz, 1H), 4.29 - 4.14 (m, 4H), 4.04 (s, 3H), 3.73 - 3.68 (m, 2H), 3.24 - 2.86 (m, 3H), 2.09 (s, 2H), 1.92 - 1.71 (m, 2H), 1.56 (t, J = 7.2 Hz, 4H). Example 50: 3- Ethyl-8-ί6-Π-methyl-1H-pyrazol-4-yl)pyridin-3-yl 1-(4-n-(methylsulfonyl)piperidin-4-yl)phenyl) 1H-imidazo-"4,5-cl-quinoline-2 3H

50 mg (0.0455 mmol) of the hydrochloride salt of compound 136 was suspended in 4 ml of dichloromethane, and then added 33.6 mg of triethylamine (0.33 mmol) and succinium 14.3 mg (0.125 mmol) of methanesulfonyl chloride, and stirred at room temperature overnight. TLC (DCM: MeOH = 10:1) showed that the reaction was completed, and 15 ml of saturated sodium hydrogen carbonate solution was added and stirred for 1 hour. The aqueous phase was extracted with 2×15 ml of methylene chloride. EtOAc was evaporated. . LC-MS: 608 [M+l] ⁺ , t _R = 1.792 min.1H NMR (400 MHz, CDCl ₃ +MeOD) δ 8.87 (s, 1H), 8.40 (s, 1H), 8.20 (d, J= 8.9 Hz, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.88 (d, J= 9.0 Hz, 1H), 7.70 (d, J= 8.3 Hz, 1H), 7.59 (q, J = 8.5 Hz, 4H), 7.53 (d, J= 8.1 Hz, 1H), 7.22 (s, 1H), 4.27-4.19 (m, 2H), 4.01 - 3.98 (m, 5H), 2.95 -2.92 (m, 6H) ), 2.13 (d, J = 12.4 Hz, 2H), 2.08 - 1.91 (m, 2H), 1.56 (t, J = 7.1 Hz, 3H). Example 51: 1-(4-Π-ί4Η-1, 2,4-triazol-3-carbonyl)piperidin-4-yl)phenyl 3-ethyl-8-ί6-oxime-methyl-1H-pyrazole-4-yl)pyridin-3-yl V 1 H-imidazo-"4,5-cl-quino-23H ketone

50 mg (0.0455 mmol) of compound 136 hydrochloride, 18.8 mg (0.166 mmol) of 1H-1,2,4-triazole-3-carboxylic acid, 22.413⁄4 (0.16611^101) 11081 and 31.813⁄4 £00 41^Dichloromethane, adding 58.8 mg (0.581 mmol) of triethylamine, stirring at room temperature overnight, TLC (DCM:MeOH = 10:1) showed that most of the starting materials were unreacted, and added 10 mg of 1H-1,2,4- Triazole-3-carboxylic acid, 47 mg HATU and 30 mg triethylamine, stirred at room temperature overnight, TLC (DCM: MeOH = 10:1) showed that most of the starting material was finished, and 15 ml of saturated sodium hydrogen carbonate solution was added and stirred. The organic phase is separated, the aqueous phase is extracted with a mixture of 5×10 ml of dichloromethane (about 10:1), and then extracted with 2×10 ml of dichloromethane. The organic phase is combined, dried, filtered, evaporated and evaporated. Methylene chloride:methanol = 10:1) mp. LC-MS: 625 [M + l] +, t R = 1.579 min.1H NMR (400 MHz, CDCl 3 + MeOD) δ 8.89 (s, 1H), 8.45 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.71 - 7.50 (m, 7H), 7.26 (s, 1H), 4.93 ( s, 1H), 4.01 (s _: 5H), 3.19-2.99 (m, 3H), 2.23 - 1.60 (m, 6H), 1.56 (t, J = 7.2 Hz, 3H). Example 52: 1-(4 -Π-ί4Η-1,2,4-triazole-3-carbonyl)piperidin-4-yl)phenyl 3-ethyl-8-ί6-oxime-methyl-1H-pyrazole-4-yl Pyridin-3-yl V 1 H-imidazolium "4,5-cl-quinolin-23H ketone

 50 mg (0.0455 mmol) of compound 136 hydrochloride, 18.8 mg (0.166 mmol) of 1H-1,2,4-triazole-3-carboxylic acid, 22.4 13⁄4 (0.166 11^101) 11081 and 31.8 13⁄4 £00 Suspended in 4 1 ^ dichloromethane, added 58.8 mg

(0.581 mmol) triethylamine, stirred at room temperature overnight, TLC (DCM:MeOH = 10:1) showed that most of the starting materials were unreacted, and added 10 mg of 1H-1,2,4-triazole-3-carboxylic acid. 47 mg HATU and 30 mg triethylamine, stirred at room temperature overnight, TLC

(DCM: MeOH = 10:1), which indicated that most of the starting materials were reacted. Add 15 ml of saturated sodium hydrogen carbonate solution and stir for 0.5 hour. The organic phase was separated and the aqueous phase was mixed with 5×10 ml of dichloromethane (about 10:1). Extraction, extraction with 2×10 ml of dichloromethane, EtOAc (EtOAc m. The rate is 21.2%. LC-MS: 625 [M + l] +, t R = 1.579 min 1H NMR (400 MHz, CDCl 3 + MeOD) δ 8.89 (s, 1H), 8.45 (s, 1H), 8.22 (d, J =. 8.8 Hz, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.71 - 7.50 (m, 7H), 7.26 (s, 1H), 4.93 ( s, 1H), 4.01 (s _: 5H), 3.19 - 2.99 (m, 3H), 2.23 - 1.60 (m, 6H), 1.56 (t, J = 7.2 Hz, 3H).

(18) Route 18:

 Route 18

Synthesis of intermediate 19g

1.05 g (4.16 mmol) of diboronic acid pinacol ester was dissolved in 10 mL of 1,4-dioxane in a three-necked flask, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.14 g was added under nitrogen atmosphere ( 0.17 mmol), 1.02 g (10.4 mmol) of potassium acetate. After stirring for 5 min, add 10 mL of 1,4-dioxane solution containing 0.68 g (3.47 mmol) of 6-bromo-4-azaindole. After reacting for 2 h at 110 °C. Down to room temperature, intermediate 18 1.0 g (1.74 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.14 g (0.17 mmol), cesium carbonate 3.39 g (10.4 mmol), 2M carbonic acid were added sequentially under N ₂ protection. 9 mL of sodium solution was refluxed at 90 °C for 4 h. After cooling, the solid was precipitated in ice water, and filtered to give a crude white solid, which was purified by silica gel G column chromatography (eluent: methanol/dichloromethane = 1:50, (v:v) to give a white solid 19 g 0.87 g. Rate: 41%. 1H NMR (400 MHz, CDC1 ₃ ) δ: 1.54 (t, 2H, J = 10.8 Hz, -CH ₂ -), 1.74 (d, 2H, J = 12.3 Hz, -CH ₂ -), 2.71 (d, IH , J=12.0 Hz, -CH ₂ -), 2.77 (d, IH, J=24.6 Hz, -CH ₂ -), 3.59 (s, 3H, -CH ₃ ), 4.14 (s, 2H, =CH-) , 4.19 (d, 2H, J=12.8 Hz, =CH-), 5.06 (s, 2H, =CH-), 6.55 (d, IH, J=2.8 Hz, =CH-), 7.09 (s, IH, ArH), 7.22 (m, IH, ArH), 7.28 (m, 4H, ArH), 7.36 (s, 4H, ArH), 7.39 (d, 2H, J = 3.1 Hz ArH), 7.60 (s, IH, ArH ), 7.69 (d, IH, J=8.7 Hz, ArH), 8.01 (d, IH, J=8.8 Hz, ArH), 8.15 (s, IH, ArH), 8.66 (s, IH, ArH). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ: 155.3, 147.8, 143.6, 140.8, 136.7, 132.7, 131.8, 130.0, 129.9, 129.6, 128.9, 128.7, 128.4, 128.2, 127.8, 127.5, 126.9, 122.8, 118.1, 117.2, 115.1, 101.3, 67.0, 44.2, 41.9, 32.7, 27.4. Synthesis of intermediate 20g

Take 0.87 g (1.43 mmol) of 19 g of the intermediate in 50 ml of methanol/dichloromethane (V:V=1:1) mixed solvent, add 0.9 g (14.3 mmol) of HCOONH ₄ , and add Pd when the temperature is raised to 60 °C. /C 0.32 g, heated to reflux for 2-3 h, The Pd/C was removed by filtration, and the crude liquid was concentrated to give a crude material. The crude product was purified by silica gel column chromatography [eluent: methanol/dichloromethane/ammonia = 50:500: 1, (v:v:v)] 0.52 g, yield 76.5%. Example 53: (SVl-i4-n-i2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-indole-pyrrolo "3,2-blpyridine-6- -1H-imidazo-"4,5-cl-quinoline-2 3H ketone

Dissolve 0.06 ml (0.76 mmol) of L-lactic acid in 5 ml of DMF, add EDCI (0.16 g, 0.83 mmol), HOBT (0.11, 0.83 mmol), stir and dissolve, add a small amount of intermediate 20g, dissolve and slowly slowly intermediate 20g 0.18 g (0.38 mmol) was added, and the mixture was stirred at room temperature for 12 h. TLC was obtained. EtOAc was evaporated. Column chromatography [eluent (methanol: dichloromethane: ammonia) = 50:500: 1 (v: v: v)]. Ii NMR (400MHz, CDC1 ₃ ) δ: 1.29 (d, 3H, J=5.8 Hz, -CH ₃ ), 1.58 (m, 2H, -CH2-), 1.83 (m, 2H, -CH ₂ -), 2.71 (s, IH, -CH-), 2.88 (s, IH, -CH ₂ -), 3.12 (s, IH, -CH ₂ -), 3.62 (s, 3H, -CH ₃ ), 3.89 (s, IH , -CH ₂ -), 4.11 (s, IH, -NH-), 4.49 (s, IH, -CH ₂ -), 4.60 (d, IH, -OH-), 6.58 (s, IH, ArH), 7.09 (d, IH, J = 14.8 Hz, ArH), 7.42 (s, 5H, ArH), 7.63 (d, IH, J = 14.8 Hz, ArH), 7.74 (d, IH, J = 8.4 Hz ArH), 8.05 (d, IH, J=8.4 Hz, ArH), 8.12 (d, IH, J=7.6 Hz, ArH), 8.69 (s, IH, ArH). ¹³ C NMR (100 MHz, CDCI3) δ: 173.1, 153.6, 147.3, 145.2, 143.7, 141.1, 137.0, 133.0, 131.8, 130.0, 128.8, 128.6, 128.3, 128.1, 127.0, 125.9, 122.9, 118.1, 115.2, 101.5, 64.0, 45.1, 42.0, 33.3, 27.5, 20.4. (19) Route 19:

 Route 19

Synthesis of intermediate 19h

3.28 g (12.9 mmol) of boronic acid pinacol ester was dissolved in 10 mL of 1,4-dioxane in a three-necked flask, and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.44 g was added under nitrogen protection ( 0.54 mmol), 5.27 g (53.75 mmol) of potassium acetate. After stirring for 5 min, a solution of 2.0 g (10.75 mmol) of 2-methyl-3-amino-5-bromopyridine in 1,4-dioxane was added. mL, warmed to 110 °C and reacted for 2 h. Down to room temperature, intermediate 18 3.08 g (5.37 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ 0.44 g (0.54 mmol), cesium carbonate 10.51 g (32.26 mmol), 2M carbonic acid were added sequentially under N ₂ protection. The sodium solution was 5.69 g, and the reaction was refluxed at 100 ° C for 4 h. After cooling, the 1,4-dioxane was evaporated under reduced pressure, and the mixture was evaporated. mjjjjjjjjjjjjjjjj Methane = 1 : 50, ( _V:V )] obtained as a white solid 19h 2.95 g, yield: 32.9% 1H NMR (400 MHz, CDC1 ₃ ) δ: 1.58 (m, 2H, -CH ₂ -), 1.85 (d , 2H, J=11.3 Hz, -CH ₂ -), 2.28 (s, 3H, -CH ₃ -), 2.71 (m, 2H, J=14.3 Hz, -CH ₂ -), 3.57 (s, 3H, - CH ₃ -), 3.60 (s, 2H, -CH ₂ -), 4.30 (s, 2H, -CH ₂ -), 5.01 (d, 2H, J = 28.0 Hz, -CH ₂ -), 6.77 (m, 1H, quinoline-H), 7.06 (s, 1H, quinoline-H), 7.18 - 7.36 (m, 9H, -Arx9), 7.58 (d, 1H, J=8.24 Hz, quinoline-H), 7.71 (s, 1H _: quinoline-H), 8.02 (t, 1H, J=8.24 Hz, quinoline-H), 8.66 (d, 1H, J=5.72 Hz, quinoline-H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ : 155.2, 153.6, 147.7, 144.5, 143.0, 140.2, 137.2, 137.0, 135.5, 134.2, 133.3, 132.3, 131.1, 131.0, 128.6, 128.4, 127.9, 127.8, 126.4, 126.0, 123.0, 118.9, 118.1, 115.2, 67.0 , 44.3, 42.2, 3 2.8, 27.8, 20.0. Intermediate 2 0h synthesis

2.45 g (4.1 mmol) of intermediate 19h was dissolved in 180 ml of dichloromethane, 1 ml of pyridine (12.28 mmol) was added, and 0.36 ml (4.92 mmol) of methylsulfonyl chloride was added dropwise at 0 ° C in an ice bath, stirred at 0 °C. After the reaction was completed, the mixture was extracted with water and methylene chloride. Alkane = 1:50, (v:v)] obtained as a brownish brown solid 20h 1.34 g, yield: 48.6%. 1H NMR (400 MHz, CDC1 ₃ ) 1.91 (m, 2H, -CH ₂ -), 1.94 (d, 2H, -CH ₂ -), 2.56 (s, 3H, -CH ₃ -), 2.87 (m, 2H , -CH ₂ -), 2.95 (s, 3H, -CH ₃ -), 3.67 (s, 3H, -CH ₃ -), 4.32 (d, 2H, J = 12.84 Hz, -CH ₂ -), 5.15 ( s, 2H, -CH ₂ -), 7.17 (s, IH, quinoline-H), 7.28 - 7.35 (m, 5H, -Arx5), 7.47 (s, 4H, -Arx4), 7.70 (d, IH, J =8.64 Hz, quinoline-H), 7.76 (s, IH, quinoline-H), 8.13 (d, IH, J=8.72 Hz, quinoline-H), 8.28 (s, IH, quinoline-H), 8.78 (s , IH, quinoline-H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ: 153.6, 150.3, 147.9, 147.8, 144.7, 144.5, 144.1, 135.1, 134.5, 134.3, 134.2, 134.1, 133.1, 132.7, 131.5, 131.3, 130.3, 129.7, 129.2, 128.6, 128.4, 128.2, 127.9, 127.8, 127.7, 126.3, 125.9, 125.8, 118.6, 118.5, 117.5, 115.3, 44.3, 42.0, 40.3, 37.2, 32.4, 27.8, 20.6. Synthesis of intermediate 21h

0.35 g (0.51 mmol) of the intermediate was dissolved in 50 ml of methanol/dichloromethane (V:V=4:1) mixed solvent for 20 h, 0.33 g (5.17 mmol) of HCOONH ₄ was added, and Pd was added when the temperature was raised to 60 °C. /C 0.04 g, heated to reflux for 2-3 h, filtered to remove Pd / C, the mother liquid was concentrated to give a crude product, the crude material was purified by silica gel column chromatography [eluent: methanol / dichloromethane / ammonia = 50:500:1 , (v: v: v)] gave a white solid, 21H, 0.19 g, yield: 67.9%. 1H NMR (400 MHz, CD ₃ OD) 1.62 (s, 1H, -CH ₂ -), 2.46 (m, 4H, -CH ₂ -x2), 2.98 (s, 4H, -CH ₃ -, -CH ₂ - ), 3.40 (s, 3H, -CH ₃ -), 3.71 (s, IH, -CH ₂ -), 3.85 (s, 2H, -CH ₂ -), 4.09 (s, 3H, -CH ₃ -), 7.58 (s, IH, quinoline-H), 7.70 (d, 2H, quinoline-H), 8.01 - 8.20 (m, 4H, -Arx4), 8.48 (m, 2H, quinoline-H), 9.22 (s, IH , quinoline-H). ¹³ C NMR (100 MHz, CD ₃ OD) δ: 154.6, 153.4, 147.1, 144.6, 135.8, 135.2, 134.9, 133.1, 132.8, 132.4, 131.6, 131.2, 130.9, 129.5, 129.2, 127.8 , 127.6, 127.2, 124.1, 119.2, 116.0, 45.0, 41.0, 40.3, 30.2, 28.5, 20.7. Example 54: (SVN-i5-n-i4-n-i2-hydroxypropionyl)piperidin-4- Phenyl 3-methyl-2-oxo-2,3-dihydro-IH-imidazolium "4,5-cl-quinoline-8-yl 2-methylpyridine

 Dissolve 0.04 ml (0.55 mmol) L-lactic acid in 10 ml DMF and add EDCI 0.11 g (0.61 mmol), HOBT

After 0.08 g of 0.61 mmol) was stirred and dissolved, a small amount of the intermediate was added for 21 h. After dissolution, the intermediate 21 h 0.15 g (0.28). Add all, add at room temperature, stir for 12 h at room temperature, TLC detection, the reaction is finished. DMF is evaporated under reduced pressure, and then extracted with water and 10% isopropyl alcohol in dichloromethane. The organic layer is dried over anhydrous magnesium sulfate and evaporated. G column chromatography [eluent: methanol / dichloromethane = 50: 500 v]. 1H NMR 400 MHz, CDC1 ₃ ) δ: 1.26 (d, 2H, J=22.88 Hz, -CH ₂ -), 1.64 (m, 2H, -CH ₂ -), 2.06 (m, 2H, -CH ₂ -) , 2.60 (s, 3H, -CH3-), 2.85 (m, 1H, J=13.56 Hz, -CH-), 2.97 (s, 2H, -CH ₂ -), 3.01 (s, 2H, -CH ₂ - ), 3.30 (s, 3H, -CH3-), 3.71 (s, 3H, -CH ₃ -), 4.49 (m, 1H, -CH-), 7.30 (m, 2H, quinoline-H), 7.52 - 7.76 (m, 4H, -Arx4), 7.80 (m, 2H, J=8.52 Hz, quinoline-H), 8.18 (m, 2H, J=8.68 Hz, quinoline-H), 8.37 (m, 1H, J=8.4 Hz, quinoline-H), 8.81 (d, 1H, J=3.64 Hz, quinoline-H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ: 173.6, 161.9, 153.9, 150.8, 147.4, 144.6, 144.3, 135.2 , 134.6, 133.2, 132.8, 132.2, 131.1, 131.0, 130.7, 130.3, 130.0, 129.5, 129.3, 128.7, 128.2, 128.0, 127.0, 126.8, 126.3, 123.4, 118.8, 118.6, 115.5, 64.4, 45.3, 42.1, 40.3 , 32.5, 29.8, 28.0, 20.3.

(20:20)

 Route twenty

中间体 127 (0.5 g， 0.955mmol)溶于 15 ml二氯甲烷中，加入 0.031 g (0.096 mmol)四丁基 溴化铵， 15 ml 10%的氢氧化钠溶液， 搅拌 10 min后加入 0.18 ml (2.865 mmol)氘代碘甲烷， 室温搅拌 3.5 h， 静置分液， 水相用二氯甲烷萃取， 合并有机相， 干燥， 蒸干得 0.469 g黄 色固体， 收率 90.89% LC-MS: 540,542 [M+l]+， t_R= 2.790 min. 中间体 112: 4-(4-(3-氘代甲基 -8-(6-(1-甲基 -1H-吡唑 -4-基) B比啶 -3-基) -2-氧代 -2,3-二氢 -1H-咪 唑并 [ 4，5-c]喹啉 -1-基)苯基)哌啶 -1-羧酸叔丁酯 Intermediate 111 : 4-(4-(8-Bromo-3-deuteromethyl-2-oxo-2,3-dihydro-1 oxime-imidazo[4,5-c]quinolin-1-yl Phenyl) piperidine-1-carboxylic acid tert-butyl ester

Intermediate 127 (0.5 g, 0.955 mmol) was dissolved in 15 ml of dichloromethane, then added 0.031 g (0.096 mmol) of tetrabutylammonium bromide, 15 ml of 10% sodium hydroxide solution, stirred for 10 min, then added 0.18 ml (2.865 mmol) deuterated iodomethane, stirred at room temperature for 3.5 h, and then partitioned. The aqueous phase was extracted with methylene chloride. The organic phase was combined, dried and evaporated to dryness to yield 0.469 g of a yellow solid, yield 90.89% LC-MS: 540,542 [M + l] +, t R = 2.790 min intermediate 112: 4- (4- (3-deuterated methyl-8- (6- (l-methyl -1H- pyrazol-4-yl) B-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)piperidine-1-carboxylic acid Butyl ester

 Boc

Intermediate 111 (0.469 g, 0.87 mmol) was dissolved in 5 ml of 1,4-dioxane. Under a nitrogen atmosphere, 0.373 g (1.31 mmol) of Intermediate 9A, 1.7 g (3.48 mmol) 6 ml 2 mol/L sodium carbonate solution, 0.101 g (0.09 mmol) [l,l-bis(di-phenylphosphino)ferrocene]palladium chloride, heated to 110 °C, reacted for 6 h, cooled To room temperature. Distilled off the dioxane, dissolved in 20 ml of saturated sodium bicarbonate solution and 20 ml of dichloromethane, separated, the aqueous phase was extracted with dichloromethane, and the organic phase was combined, dried and evaporated to dryness. Chromatography (eluent: methanol: methylene chloride = 1: 20) afforded 0.436 g of solid, yield 81.04%. LC-MS: 619 [M + l] +, t R = 2.376 min Intermediate 113: 3- deuterated methyl-8- (6- (l-methyl -1H- pyrazol-4-yl) B Bispin-3-yl)-1-(4-(piperidin-4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

中间体 112 (0.235 g， 0.38 mmol)溶于 20 ml二氯甲烷中， 冷却至 0-10 °C， 向反应体系 中通入氯化氢气体， 反应 1.5 h， 过滤得 201 mg固体粗品， 直接用于下一步反应。 实施例 55: 3-氘代甲基 -8-ί6-Π-甲基 -1H-吡唑 -4-基)吡啶 -3-基 )-1-(4-Π- (甲磺酖基)哌啶 -4-基) 苯基 1H-咪唑并「4,5-cl喹啉 -2 3H 酮

The intermediate 112 (0.235 g, 0.38 mmol) was dissolved in 20 ml of dichloromethane, cooled to 0-10 ° C, and hydrogen chloride gas was introduced into the reaction system for 1.5 h, and filtered to obtain 201 mg of crude solid, which was directly used for The next step is to react. Example 55: 3-Deuterated methyl-8-ί6-fluorenyl-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(4-indole-(methylsulfonyl)piperidinyl Pyridin-4-yl)phenyl 1H-imidazolium "4,5-cl-quinoline-2 3H ketone

Intermediate 113 (285 mg, 0.38 mmol) was dissolved in dichloromethane (3 mL), EtOAc (EtOAc) Add 10 ml of saturated sodium bicarbonate solution, stir for 20 min, and separate the mixture. The aqueous phase is extracted with methylene chloride. The organic phase is combined, dried and evaporated to give a crude product. 10) The target compound of Example 55 was obtained in 136 mg, yield 59.91%. LC-MS:. 597 [M + l] +, t R = 1.822 min 1H NMR (400 MHz, MeOD) δ 8.97 (s, 1H), 8.39 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.73 (d, J = 5.9 Hz, 1H), 7.58 (dt, J = 18.2, 9.0 Hz, 5H), 7.26 (s, 1H), 4.01 (s, 3H), 2.95 - 2.89 (m, 2H), 2.91 (s, 3H), 2.27 - 1.52 (m, 7H).

(21) Route 20

Intermediate 1201: 5-(((6-Chloropyridine-3-yl)amino-methylene)-2,2-dimethyl-1,3-dioxane -4,6-

将 5 g (38.8 mmol)2-氯 -5-氨基吡啶和 7.2 g (38.8 mmol) 5- (甲氧基甲烯 )-2，2-二甲基 -1,3- 二氧 -4,6-二酮悬浮于 100 mL异丙醇中， 加热至回流 2小时。 TLC检测， 反应结束后， 旋干 溶剂， 获得产品 10.5 g， 淡黄白色固体， 产率 95.8%。 LC-MS: 283 [M+l]⁺，t_R= 1.775 min. 中间体 1202: 6-氯 -1,5-萘啶 -4-醇

5 g (38.8 mmol) 2-chloro-5-aminopyridine and 7.2 g (38.8 mmol) 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxo-4,6 The -dione was suspended in 100 mL of isopropanol and heated to reflux for 2 hours. After TLC detection, after completion of the reaction, the solvent was evaporated to give a product (10.5 g, pale yellow solid, yield: 95.8%). LC-MS: 283 [M + l] +, t R = 1.775 min Intermediate 1202: 6-chloro-1,5-naphthyridin-4-ol

1201 1202 500 mL of a biphenyl-diphenyl ether mixed solvent was heated to 220 ° C, and 10.5 g (37.1 mmol) of the intermediate 1201 was added portionwise to the solvent, and the mixture was stirred at 220 ° C for 5 minutes. After completion of the reaction, the mixture was cooled to room temperature, and 1 L of petroleum ether was added to the reaction mixture to precipitate a large solid. The precipitate was collected by filtration, washed with petroleum ether, and dried under reduced pressure to give 4.9 g of product as a pale solid, yield 73.1%. LC-MS: 181 [M+l] ⁺ , _&lt ; &quot; _&gt ; _&gt ;

 1202 1203

Under ice water bath, 4.9 g (27.1 mmol) of intermediate 1202 and 5.5 g (54.2 mmol) of potassium nitrate were slowly added to 40 mL of concentrated sulfuric acid, and reacted at 100 ° C for 1 hour. After TLC detection, after completion of the reaction, the mixture was cooled to room temperature, and the reaction solution was slowly poured into ice water to precipitate a large amount of solid, and the precipitate was collected by filtration, and dried under reduced pressure to give a product (yel. LC-MS: 226 [M+l] ⁺ , _&lt ; &quot; _&gt ; _&gt ; _&gt ;

 1203 1204

中间体 1204 (0.8 g粗品， 3.28 mmol)溶于 15 ml乙酸中， 加入 0.79 g (4.92 mmol)中间体 5， 室温搅拌过夜， 加入 60 ml水， 过滤， 固体在干燥器内抽干， 得 1.14 g黄色固体粉末， 收率 94.52%。 LC-MS: 368 [M+l]⁺, t_R =2.360 min。 中间体 502: 2-^ (6-氯 -3-氨基 -1,5-萘啶 -4-基氨基)苯基) -2-甲基丙腈 4.2 g (17.2 mmol) of the intermediate 1203 was suspended in 15 mL of DMF, and a solution of 3.5 g (22.4 mmol) of phosphorus oxychloride in 10 DMF was added, and the mixture was stirred for 3 minutes, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into ice water, suction filtered, and dried to give 3.8 g of a green solid, yield 90.5%. LC-MS: 244 [M+l] ⁺ , _&lt ; &quot;&&&&&&&&&&&&&&&&&& Phenyl)-2-methylpropionitrile

Intermediate 1204 (0.8 g crude, 3.28 mmol) was dissolved in 15 ml of EtOAc. EtOAc (EtOAc: EtOAc) g yellow solid powder, yield 94.52%. LC-MS: 368 [M+l] ⁺ , t _R = 2.360 min. Intermediate 502: 2-(6-chloro-3-amino-1,5-naphthyridin-4-ylamino)phenyl)-2-methylpropanenitrile

Intermediate 501 (1.14 g, 6.56 mmol) was dissolved in 10 mL of N-N-dimethylformamide. EtOAc (EtOAc) The reaction solution was slowly poured into 100 ml of saturated sodium hydrogencarbonate solution and 100 ml of dichloromethane, and the pH was adjusted to 11 with 10% sodium hydroxide solution, and the aqueous phase was extracted with dichloromethane, and the organic phase was combined. The organic layer was washed with saturated brine, dried and evaporated to dryness. LC-MS: 338 [M+l] ⁺ , t _R = 1.999 min. Intermediate 503: 2-(4- 8-Chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)phenyl -2-methylpropionitrile

The intermediate 502 (1.5 g, 3.1 mmol) was dissolved in 15 ml of dichloromethane, then added with 1.3 ml ( 9.3 mmol) of triethylamine, and 0.46 g (1.55 mmol) of triphosgene was dissolved in 15 ml of dichloride. The solution in methane was kept at 0 °C for 2.5 h after the addition. 30 ml of saturated sodium bicarbonate solution was added dropwise, and the aqueous layer was separated with dichloromethane. The organic phase was combined, dried and evaporated to dryness. : 10), get yellow solid 0.5 g, yield 44.33%. LC-MS: 364 [M+l] +, t _R = 1.926 min. Intermediate 504: 2-(4-(8-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][l,5]naphthyridine- 1-yl)phenyl)-2-methylpropionitrile

 Intermediate 503 (0.5 g, 1.37 mmol) was dissolved in 10 mL dichloromethane. EtOAc (EtOAc: EtOAc. Methyl iodide was stirred at room temperature for 2 h, and the aqueous layer was extracted with methylene chloride. The organic phase was combined, dried and evaporated to dryness to yield 0.41 g. Example 56: 2-Methyl-2-(4-(-methyl-8-ί6-indole-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-oxo-2 ,3-dihydro-1H-imidazo-"4,5-cl"1,51-naphthyridin-1-yl)benzene-propanenitrile

Intermediate 504 (0.1 g, 0.265 mmol) was dissolved in 5 ml of 1,4-dioxane. Under a nitrogen atmosphere, 0.11 g (0.397 mmol) of Intermediate 9A, 0.259 g (0.794 mmol) of cesium carbonate, 1 Mol 2 mol/L sodium carbonate solution, 0.0075 g (0.005 mmol) [1,1-bis(diphenylphosphino)ferrocene]palladium chloride, heated to 110 ° C, reacted for 15 h, cooled to room temperature . Distilled off the dioxane, dissolved in 10 ml of saturated sodium bicarbonate solution and 10 ml of dichloromethane, partitioned, the aqueous phase was extracted with dichloromethane, and the organic phase was combined, dried and evaporated to dryness. Chromatography (eluent: methanol: methylene chloride = 1 : 10). LC-MS: 501 [M + l] +, t R = 1.990 mine 1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 8.61 (d, J = 1.9 Hz, 1H), 8.45 (d, J = 9.0 Hz, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.24 (s, 1H), 8.09 (dd, J = 8.4, 2.3 Hz, 1H), 7.98 (s, 1H), 7.78 (d , J = 8.5 Hz, 2H), 7.67 (d, J= 8.5 Hz, 2H), 7.59 (d, J= 8.3 Hz, 1H), 3.92 (s, 3H), 3.63 (s, 3H), 1.93 (s , 6H). Biological activity experiment The biological activity test of the compounds of the present application is as follows:

 1. mTOR kinase activity assay: Compound inhibition of mTOR protein kinase activity was determined using an in vitro enzyme activity assay. A test kit supplied by Invitrogen was used to detect the activity of inhibiting mTOR protease. The experimental principle is as follows: MTOR kinase, fluorescein-labeled substrate and ATP are mixed, and after the reaction, EDTA and sputum-labeled primary antibody are added. During the mTOR kinase chemical reaction, the antibody recognizes a phosphorylated and fluorescein-labeled substrate that enhances the "Time-Resolved Fluorescence Resonance Energy Transfer" (TR-FRET) effect. The TR-FRET effect is calculated by the ratio of the receptor luciferin signal to the donor chirp signal. The amount of antibody bound to the tracer is directly proportional to the amount of substrate phosphorylated after the reaction, and in this way, the activity of the kinase can be detected. In this assay, the substrate for mTOR kinase is 4E binding protein 1 (GFP-4EBP1) linked to green fluorescent protein.

 1.1 Materials and Instruments:

 4-Hydroxyethylpiperazineethanesulfonic acid (HEPES, Sigma, Cat# SH3375), ethylene glycol-bis-(2-aminoethylether)tetraacetic acid (EGTA, Sigma, Cat# E3889), manganese chloride (MnC12, Sigma, Cat# Ml 787), Tween-20 (Amesco), 1,4 dithiothreitol (DTT, Merck, CB233155),

Adenosine triphosphate (ATP, sigma, A7699), a mammalian target of rapamycin (mTOR, Invitrogen, Cat# PV4753), an antibody against the 46th threonine phosphorylated 4E-binding protein 1 (LanthaScreenTM Tb-anti- p4E-BP1 (pThr46) Antibody, Invitrogen, Cat# PV4757

(GFP-4E-BP1, Invitrogen, Cat# PV4759), TR-FRET Diluent (TR-FRET Dilution Buffer, Invitrogen, Cat# PV3574), Proxi Plate, Black (ProxiPlate, Black, PerkinElmer, Detection Plate), 384-well Plates (384-well plates, Corning, dilution plates), Nunc PP plates (Nunc PP plate, Corning, dilution plates), Envision-2104 plate reader (Perkin Elmer).

 1.2 Solution and reagent preparation:

1.2.1 IX detection buffer stock: 50 mM HEPES H 7.5, 1 mM EGTA, 0.01% Tween-20, 10 mM MnCl ₂ , mM DTT.

 1.2.2 Substrate working solution: 4 mL 2.5 x substrate (1000 reactions): 3.8 mL lx assay solution, 191 μL GFP-4E-BP1 (20.96 μΜ stock solution), 10 ATP (10 mM). Final concentration: 0.4 μΜ GFP-4E-BP1; 10 Μ ΑΤΡ.

 1.2.3 mTOR working solution: 4 mL 2.5x mTOR (1000 reactions): 4 mL.

 1.2.4 lx test solution; 7.5 L mTOR (0.4 mg/mL stock solution), final concentration 0.3 g/mL.

1.2.5 Detection of working solution: 10 mL 2x detection buffer (1000 reactions): 9.6 mL of TR-FRET dilution, 11.5 Tb-anti-p4E-BPl antibody (stock 3.49 μΜ), 400 EDTA (storage 500 mM) , final concentration: 2 nM Tb-anti-p4E-BP1 antibody, 10 mM EDTA.

 1.3 Test steps:

 1.3.1 Add 50 μΐ of 100 μΜ of the compound of the present application diluted in dimethyl sulfoxide (DMSO) to a 38-well dilution plate.

 1.3.2 Dilute the compound in 1:1 ratio with dimethyl sulfoxide (DMSO) (10 dilutions plus a zero concentration). 1.3.3 Transfer 2.5 μl of the diluted compound (compound in Table 1) to the corresponding well (containing 47.5 μ of test solution per well) and shake for a few seconds.

1.3.4 Add 4 L mTOR working solution to the 384-well black Proxi plate.

1.3.5 Add 2 diluted compounds to the assay plate (3 replicate wells per concentration).

1.3.6 Incubate for 15 minutes at room temperature.

1.3.7 Add 4 L of substrate working solution.

mTOR, 0.4 μΜ GFP-4E-BP1, 10 μΜ三磷酸腺苷 (ATP) . 用 1% 二甲基亚砜（DMSO)稀释化合物至浓度为： 1 μΜ, 0.33 μΜ, 0.11 μΜ,1.3.8 Final mTOR reaction concentration: 0.3

mTOR, 0.4 μΜ GFP-4E-BP1, 10 μΜ adenosine triphosphate (ATP). Dilute the compound to 1 μm, 0.33 μΜ, 0.11 μΜ with 1% dimethyl sulfoxide (DMSO).

0.037 μΜ, 0.0123 μΜ, 0.00411 μΜ, 0.00137 μΜ, 0.000457 μΜ, 0.000152 μΜ,

0.000051 μΜ, Ο μΜ;.

1.3.9 Incubate for 30 minutes at room temperature.

 1.3.10 Add 10 test solution, final working concentration: Tb-anti-p4E-BPl antibody 2 nM, EDTA 10 mM. 1.3.11 Incubate for 30 minutes at room temperature.

 1.3.12 Use the Envision reader to detect the reading of TR-FRET. The excitation light is 340 nm, the emission light 1 is 495 nm, and the emission light 2 is 520 nm. Ratio = 520 nm / 495 nm is the TR-FRET value

1.3.13 Data analysis and calculation of 50% inhibition rate (IC50):

 Calculate the 50% inhibition rate using a nonlinear regression equation:

Y=bottom+ (top-bottom)/(l+10 ^A ((LogIC50-X)*HillSlope)), X: concentration of compound (logarithm to base 10), Y: TR-FRET value (520 nm) Ratio to 495 nm), top and bottom: the same high peak as Y (Plateaus in same units as Y), 50% inhibition (logIC50): The same logarithm as X (the same log units as X). Table 1: Inhibitory activity of mTOR enzyme

(mTOR, IC ₅₀ nM) -Methyl-2-{4-[3-methyl-2-oxo-8-(6-phenylpyridin-3-yl)-1Η-2,3-dihydromimi

 < 10 oxazo[4,5-c]quinoline] phenyl}propionitrile-methyl-2-{4-[3-methyl-2-oxo-8-( 1-phenyl-1H -pyrazol-4-yl) -1Η-2,3-

<10 Dihydroimidazo[4,5-c]quinolin-1-yl]phenyl}propionitrile-methyl-2-{4- {3-methyl-2-oxo-8-[6-( 3-fluorophenyl)pyridin-3-yl]-1Η-2,3-

<100 dihydroimidazo[4,5-c]quinolin-1-yl]phenyl}propionitrile-methyl-2-{4- {3-methyl-2-oxo-8-[6-( 4-fluorophenyl)pyridin-3-yl] -1Η-2,3-

< 10 dihydroimidazo[4,5-c]quinolin-1-yl]phenyl}propionitrile-methyl-2- {4- {3-methyl-2-oxo-8- [ 6- (pyridin-3-yl)pyridin-3-yl] - 1Η-2,3-

< 10 dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile-methyl-2-{4- {3-methyl-2oxo-8-[ 6- ( Pyridin-4-yl)pyridin-3-yl]-1Η-2,3-

<10 Dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile-methyl-2-{4-{3-methyl-2-oxo-8- [6- (1-methyl-1H-pyrazol-4-yl)pyridine

 <10-3-yl]-1Η-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile-methyl-2-{4-{3-A 5-oxo-8-[6-(quinolin-3-yl)pyridin-3-yl-1Η-2,3-

<500 dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile-methyl-2-{4-{3-methyl-2-oxo-8- [6- (6-Phenylpyridin-3-yl)pyridin-3-yl]

 <500 -1Η-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile-methyl-2-{4-{3-methyl-2-oxo -8-[6-(1-Phenyl-1-HB-pyrazol-4-yl)pyridine

 <500 -3-yl] -1Η-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile-methyl-2-{4-{3-A 5-oxo 8-{6-[6-(3-fluorophenyl)pyridin-3-yl]pyridinyl

 <500 pyridine-3-yl}-111-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile-methyl-2-{4-{3- Methyl-2-oxo-8-{6-[6-(pyridin-3-yl)pyridin-3-yl]

 <500 pyridin-3-yl}-111-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile-methyl-2-{4-{3- Methyl-2-oxo-8-{6- [6-(B-pyridin-4-yl)pyridin-3-yl]

<500 pyridin-3-yl}-111-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile 2-methyl-2-{4-{3-methyl-2-oxo-8-{6-[6-(1-methyl small H pyrazol-4-yl)pyridin-3-yl]pyridine -3-yl}-1Η-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl} <500 propionitrile

 3-methyl-1-[4-(1-acetylpiperidin-4-yl)phenyl]-8-(quinolin-3-yl)-1H-imidazole

 < 10 and [4,5-c]quinoline-2 (3H)-one

1-(4-(1-(4Η-1,2,4-triazol-3-carbonyl)piperidin-4-yl)phenyl)-3-methyl-8-(quinoline

 < 10 -3-yl) -1H-imidazo[4,5-c]quinoline-2(3H)-one

3-methyl-1-{4-[1-(2-hydroxyacetyl)piperidin-4-yl]phenyl}-8-(quinolin-3-yl)

 < 10 -1H-imidazo[4,5-c]quinoline-2(3H)-one

3-methyl-1-{4-[1-(2-hydroxypropionyl)piperidine-4()-phenyl}-8-(quinolin-3-yl)

 < 10 -1H-imidazo[4,5-c]quinoline-2(3H)-one

3-Methyl small [4-(1-methanesulfonylpiperidine-4-yl)-phenyl]-8-(quinolin-3-yl)-1H-

< 10 imidazo[4,5-c]quinoline-2 (3H)-one

3-Methyl small [4-(1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl)-phenyl]-8- (quin

 <10 oxalin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

1-(4-(1-(1Η-1,2,4-triazol-3-carbonyl)-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-3-

< 10 methyl-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

3-methyl-1-{4-[1-(2-hydroxyacetyl)-1,2,3,6-tetrahydropyridin-4-yl]-phenyl }-8-

< 10 (quinolin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

3-methyl-1-{4-[1-(2-hydroxypropionyl)-1,2,3,6-tetrahydropyridin-4-yl]-phenyl }-8-

< 10 (quinolin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

3-methyl-1-{4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-phenyl }-8-

< 10 (quinolin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

3-Methyl small [4-( 8-acetyl-8-azabicyclo[3, 2,1]-oct-3-en-3-yl)benzene

 <10 base]-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

1-(4-(8-(1Η-1,2,4-triazol-3-carbonyl)-8-azabicyclo[3.2.1]oct-3-ene-3-yl)

Phenyl)-3-methyl-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one < 10 3-Methyl small {4-[8-(2-hydroxyacetyl)-8-azabicyclo[3, 2, 1]-oct-3-ene-3-

<10 base]phenyl}-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

3-methyl small {4-[8-(2-hydroxypropionyl)-8-azabicyclo[3, 2, 1]-oct-3-ene-3-

<100-yl]phenyl}-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

3-Methyl small [4-(8-methylsulfonyl-8-azabicyclo[3, 2, 1]-oct-3-en-3-yl)benzene

 <10 base]-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

(3-Methyl-1-[4-(1-methanesulfonylpiperazine-4-yl)-phenyl]-8-(quinolin-3-yl)-1H-

< 10 imidazo[4,5-c]quinoline-2 (3H)-one)

3-Methyl small [4-(1-methanesulfonylpiperidine-4-yl)-phenyl]-8-[6-(2-methoxyethoxy)

 <100 base) pyridine-3-yl]-1H-imidazo[4,5-c]quinoline-2(3H)-one

(R)-l-(4-0(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(;quinoline-3-

<100 base) -1H-imidazo[4,5-c]quinoline-2(3H)-one

3-methyl-8-(quinolin-3-yl)- 1 -(4-(1-(tetrahydro-2H-pyran-4-carbonyl)-1 ,2,3,6-tetrahydro)

 <100 pyridine-4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

1-(4-(1-(cyclobutylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-methyl-8-(quinoline

 <100 -3-yl) -1H-imidazo[4,5-c]quinoline-2(3H)-one

1-(4-(1-(3-hydroxy-3-methylbutanoyl)-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-3-methyl

 <100 benzyl-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

3-methyl-1-(4-(1-(morpholine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-8- (quinine

 <100 phenyl-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

1-(4-(4-(4Η-1,2,4-triazol-3-carbonyl)piperazine-1-yl)phenyl)-3-methyl-8-(quinoline

 < 10 -3-yl) -1H-imidazo[4,5-c]quinoline-2(3H)-one

8-(6-(ethylamino)pyridine-3-yl)-3-methyl-1-(4-(1-(methylsulfonyl)piperidin-4-yl)

 <100 phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

 1-(4-(1-(4Η-1,2,4-triazol-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzene

-8-(6-methoxy-5-methylpyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]quinoline <500-2(3H)-one (S)-l-(4-00hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-0phenyl-1H-

<500 pyrazole-4-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

(S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-phenylpyridine

 <500 -3-yl) -1H-imidazo[4,5-c]quinoline-2(3H)-one

(S)-8-([2,3'-dipyridyl]-5-yl)-1-(4-(1-(2-hydroxypropionyl)piperidin-4-yl)benzene

 <500 base) -3-methyl-1H-imidazo[4,5-c]quinoline-2(3H)-one

(S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-8-(6-methoxy-5-methylpyridyl

 <100 pyridine-3-yl)-3-methyl-1H-imidazo[4,5-c]quinoline-2(3H)-one

(S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-(1-methyl)

 <500 -1H-pyrazol-4-yl)orridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

1-(4-(1-(2-hydroxyacetyl)piperidin-3-yl)phenyl)-3-methyl-8-(6-(1-methyl-1H-

<10 pyrazol-4-yl)pyridine-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)B-pyridin-3-yl)-1-(4-(1-(methylsulfonyl))

 <10 piperidin-3-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

1-(4-(1-(4Η-1,2,4-triazol-3-carbonyl)piperidin-3-yl)phenyl-3-methyl-8-(6-(1-

<10-methyl-1H-pyrazol-4-yl) B-pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one 1-(4-G- ((R)-2-hydroxypropionyl)piperidin-3-yl)phenyl-3-methyl-8-(6-G-methyl

 <100-1H-pyrazol-4-yl)-p-pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one l-(4-(l-( (S)-2-hydroxypropionyl)piperidin-3-yl)phenyl-3-methyl-8-(6-(1-methyl)

 <100-1H-pyrazol-4-yl)-orridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

1-(4-(1-ethylpiperidin-3-yl)phenyl-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridinium

 1000 pyridine-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)B-pyridin-3-yl)-1-(4-(1-(methylsulfonyl))

 <10 piperidin-4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

1-(4-(1-(2-hydroxyacetyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-(1-methyl-1H-

<10 pyrazol-4-yl)pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one 1-(4-(1-(1Η-1,2,4-triazol-3-carbonyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-(l-

<10

 Methyl-1H-pyrazol-4-yl)B-pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

3-ethyl-1-(4-(1-(2-hydroxyacetyl)piperidin-4-yl)phenyl)-8-(6-(1-methyl-1H--

<100

 Pyrazole-4-yl)pyridine-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

3-ethyl-8-(6-(1-methyl-1H-pyrazol-4-yl)B-pyridin-3-yl)-1-(4-(1-(methylsulfonyl))

 <100

 Piperidin-4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

1-(4-(1-(4Η- 1,2,4-triazolyl-3-carbonyl)piperidin-4-yl)phenyl)-3-ethyl-8-(6-(1 -

<100

 Methyl-1H-pyrazol-4-yl)B-pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one

(S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(1Η-pyrrole

 10

 [3,2-b]pyridine-6-yl)-1Η-imidazo[4,5-c]quinoline-2(3Η)-one

3-deuterated methyl-8-(6-(1-methyl-lΗ-pyrazol-4-yl)pyridin-3-yl)-1-(4-(1-(methane)

 <10

 Acyl)piperidin-4-yl)phenyl)-1Η-imidazo[4,5-c]quinoline-2 (3 fluorenone)

2-methyl-2-(4-(3-methyl-8-(6-(1-methyl-1)-pyrazol-4-yl)pyridin-3-yl)-2-oxo

 <10

 -2,3-dihydro-1Η-imidazo[4,5-c] [1,5]naphthyridin-1-yl)phenyl)-propanenitrile

2. PBK-alpha enzyme activity assay: PBK alpha-ADP Glo Assay was used. In the determination of PBK enzyme activity

Promega's test kit (Promega, Cat. No. V9101) was used to test the inhibitory effect of compounds on PBK enzyme activity. The adenosine diphosphate (ADP) produced is quantified throughout the enzymatic reaction. The values obtained can be used to calculate the activity of PBK.

 2.1 Detection reagent: PIK3CA/PIK3R1 was purchased from Invitrogen (Cat. No.: PV4788): The active kinase was diluted with kinase dilution III; mixed with bovine serum albumin (BSA) at a ratio of 1:4 (5X dilution), and finally the concentration of BSA Is 50 ng/ml; composition of Kinase Assay I: 25 mM MOPS, pH 7.2, 12.5 mM β-glycerophosphate, 25 mM magnesium chloride, 5 mM EGTA, 2 mM EDTA. Add 0.25 mM DTT to Kinase Assay I before use 250 μΜ adenosine triphosphate (ATP); Test solution: Dissolve 0.55 mg of ATP in 4 ml of Kinase Assay I, dispense 200 μl per tube and store at -20 °C. Substrate: phosphatidylinositol (4,5) diphosphate [Phosphatidylinositol (4,5) bis-phosphate]; this substrate was diluted to 125 μM with kinase assay I. Final concentrations are: 10 M PIP2, 10 M ATP, 1% DMSO, 0.0005-10 Μ compound.

 2.2 Test steps:

2.2.1 Add 50 μΐ of 100 μΜ compound diluted with dimethyl sulfoxide (DMSO) to 384 Hole in the dilution plate. The compound was diluted with dimethyl sulfoxide (DMSO) in a ratio of 1:3 (10 dilutions plus a zero concentration).

 2.2.2 Transfer 5 μ∑ of the diluted compound to the corresponding 384-well black Proxi plate (containing 47.5 μ∑ of detection solution per well) and shake for a few seconds.

2.2.3 Add 2 L of 2.5xPBK working solution to the 384-well black Proxi plate.

 2.2.4 Add 2 diluted compounds to the assay plate (3 replicate wells per concentration).

2.2.5 Incubate for 2 hours at room temperature.

2.2.6 Addition of 5 L ADP Glo Reagent

2.2.7 Incubate for 40 minutes at room temperature.

2.2.8 Add ΙΟμΙ^kinase detection reagent.

2.2.9 Incubate for 40 minutes at room temperature.

2.2.10 is detected with the Envision reader.

2.3 Data analysis and calculation of 50% inhibition rate (IC50): IC _{5Q was} calculated using Prism5 software. The results showed that many compounds inhibited the activity of mTOR protease. The activity of the mTOR protease of the compound is inhibited in the range of 0.5 to several hundred nanomoles, as shown in Table 1. The compounds of the present application were used to determine whether PBK enzyme activity can be inhibited. Tests have shown that these compounds inhibit PBK activity (Table 2). Table 2: Compounds inhibit PBK enzyme activity

3. Western Blot: 应用 Western Blot技术检测 S6和 Akt蛋白激酶磷酸化水平， 可以证明 mTOR抑制剂体外活性。其基本原理是经过 PAGE分离的蛋白质样品，转移到固相载体（例 如硝酸纤维素薄膜） 上， 固相载体以非共价键形式吸附蛋白质， 且能保持电泳分离的多肽 类型及其生物学活性不变。 以固相载体上的蛋白质或多肽作为抗原， 与对应的抗 S6和 Akt 磷酸化的抗体起免疫反应， 再与酶标记的第二抗体起反应， 经过底物显色以检测电泳分离 的 S6和 Akt蛋白磷酸化水平。

3. Western Blot: Western Blot was used to detect the phosphorylation levels of S6 and Akt protein kinases, which can demonstrate the in vitro activity of mTOR inhibitors. The basic principle is that a protein sample separated by PAGE is transferred to a solid phase carrier (eg For example, on a nitrocellulose membrane, the solid phase carrier adsorbs the protein in the form of a non-covalent bond, and can maintain the type of the polypeptide separated by electrophoresis and its biological activity. The protein or polypeptide on the solid phase carrier is used as an antigen, and the corresponding anti-S6 and Akt phosphorylated antibodies are immunoreacted, and then reacted with the enzyme-labeled second antibody, and the substrate is developed to detect the electrophoretically separated S6 and Akt protein phosphorylation level.

3.1 Materials and instruments

 Phospho-Akt (Ser473) (D9E) XP® Rabbit mAb (CST, Cat# 4060S)

Akt (pan) (C67E7) Rabbit mAb (CST, Cat# 469 IS)

β-Actin Antibody (CST, Cat# 4967S)

 Phospho-S6 Ribosomal Protein (Ser235/236) (CST, Cat# 4858S)

S6 Ribosomal Protein (5G10) (CST, Cat# 2217S)

 NuPAGE® Novex 12% Bis-Tris Gel 1.0 mm, 12 Well (Invitrogen, NP0342BOX )

RIPA Lysate (Thermo Prod# 89900)

Complex phosphatase inhibitor tablets (Roche, Cat# 04693132001; Sigma Cat# P5726; Sigma Cat# P0044) NC membrane (Millipore, Cat#HATF00010)

Semi-dry transfer instrument (BioRad 170-3940)

Electrophoresis (Invitrogen, Cat#EI0001)

 3.2 Solution and reagent preparation

 Preparation of RIPA Complete Lysate: Dissolve a complete-EDTA free tablet (Roche, Cat# 04693132001) in 10 ml of RIPA buffer and add 100 μl of Phosphatase inhibitor cocktail II (Sigma Cat# P5726) and 1 OO of Phosphatase inhibitor cocktail III, respectively. Sigma Cat# P0044), mix evenly.

 3.3 Experimental steps and results analysis

 3.3.1 Preparation of protein sample: Collect cells, wash twice with PBS (300g; 5min), add a certain volume of RIPA lysate according to the amount of cells, cleave on ice for 30min; centrifuge at 10 °C for 10min, collect the lysate supernatant; The BCA protein quantification kit (Pierce, Cat#23227) was used to determine the protein concentration; the sample to be loaded was taken, and the loading buffer was added and boiled for 10 min. 3.3.2 Protein electrophoresis: Protein samples were subjected to NuPAGE® Novex 12% Bis-Tris Gel 1.0 mm, 12 Well protein gel electrophoresis.

3.3.3 semi-dry rotation: After electrophoresis, remove the gel and equilibrate in the membrane buffer for 10 min; take two thick filter paper and NC membrane, and immerse in the membrane buffer for 10 min; use semi-dry membrane The protein was transferred to the NC membrane at 21 V for 30 min.

3.3.4 Immunoblotting: After blocking the NC membrane with 5% BSA at room temperature, anti-S6 (CST, Cat# 2217S, Cat# 4858S) Or Akt (CST, Cat# 4060S, Cat# 4691S) protein and its phosphorylated antibody at 4 ° C overnight, after washing the membrane, add HRP-labeled anti-rabbit IgG (CST, Cat #7074), wash the membrane at room temperature for 1 hour. The ECL substrate (Thermo, Prod #34095) was added for dark room exposure to detect the expression level of the protein of interest.

3.4 Data analysis and calculation of 50% inhibition rate (EC _5Q ): EC _{5Q was} calculated using Prism5 software, and the results indicate that the compounds of the present application have an inhibitory effect on phosphorylation of S6 and Akt protein kinases, which phosphorylate S6 and Akt protein kinases. The inhibitory activity EC _5Q was less than 150 nM, see Table 3.

 Table 3: Compounds inhibit the phosphorylation activity of S6 and Akt protein kinases

4. CTG 细胞存活试验：

4. CTG cell survival test:

 ATP is a must in living cell metabolic activity, and its content is linear with the number of living cells. Based on this principle, the CTG chemical luminescence cell viability assay is a general method for detecting the number of viable cells in cultured cells. The addition of CellTiter-Glo (CTG) reagent induces cell lysis and produces a chemiluminescent signal proportional to the amount of ATP in the well plate, allowing chemiluminescence readings to measure cell viability in the well plate.

4.1 Experimental materials and instruments

4.1.1 Materials: Test compound, cell basal medium, RPMI Medium 1640 (Invitrogen, Cat#l 1875-093), fetal bovine serum (FBS): Hyclone FETAL BOVINE SERUM DEFINED (Invitrogen, Cat#SH30070.03) , Antibiotics: Penicilin Streptomycin (Invitrogen, Cat#l 5140-122), Phosphate Buffer (Coming Cellgro, Cat#R21-040-CV), Cell Digestion: 0.25% Trypsin-EDTA (Invitrogen, Cat#25200-056 ), CTG Test Kit: Promega, Cat#G7571, 96-well flat bottom: Blackboard: NUNC, Cat#165305, T25 Culture flask: NUNC, Cat#156367, T75 Culture flask: NUNC, Cat#156439; Cell MV-4 -11, ATCC Item No.: CRL-9591; Cell BT474, ATCC Item No.: HTB-20; Cell 786-0, ATCC Item No.: CRL-1932. 4.2 Experimental Instruments: Carbon Dioxide Incubator, SANYO-MCO-20AIC, Biosafety Cabinet: BSC-1360-LIIA2, Desktop High Speed Refrigerated Centrifuge: SorvallST 16R, Microplate Fast Oscillator: QB-9001, M3 Reader: SpectraMax M3, microscope: OLYMPUS-CKX41/CKX31.

 4.3 Solution and reagent preparation: Preparation of cell growth medium: RPMI Medium l640+10% FBS+ antibiotic, other: trypsin digest, phosphate buffer (PBS), DMSO, CTG test kit

 4.4 Experimental steps:

 4.4.1 Cell resuscitation: Remove the cryotube from the liquid nitrogen container, directly immerse it in 37 Ό水裕, shake it from time to time to melt it as soon as possible, remove the cryotube from the Jk 37' Ό water bath, transfer it to the biological safety cabinet, open Cap, aspirate the cell suspension with a pipette, add to the centrifuge tube and add dropwise more than 0 times the culture solution, mix; centrifuge. lOOOOrpm, 5min; discard the supernatant, add the cell growth medium and resuspend the cells, all The cell suspension was inoculated into a T25 flask, and the culture flask was allowed to stand for culture: the next day, the secondary culture solution was replaced, and the culture was continued.

 4.4.2 Cell passage: When the cells grow to logarithmic growth phase, when the confluence is 80%-903⁄4, remove the cells into the biosafety cabinet, discard the culture solution, and wash the cells with PBS for 1-2 times, take an appropriate amount of 0.25%. Trypsiii-EDTA cell digestive juice was added to the culture flask, placed in a 37-inch carbon dioxide incubator for 25 min, and the appropriate amount of cell growth medium containing 10% FBS was added to terminate the digestion, gently pipetted, transferred to a centrifuge tube, centrifuged lOCK pm, 5 min, The cells are made into cell suspensions for passage and experimental use.

 4.4.3 Cell plating

 4.4,3.1 Preparation of cell suspension: When cells are grown to logarithmic growth phase, confluence is 80%-90%. Remove the cells into the biosafety cabinet, discard the old culture solution, and wash the cells 1-2 times with PBS. Add an appropriate amount of 0.25% Trypsin-EDlA cell digest to the flask and place in a 37 Ό dicarbonyl carbonyl incubator.

2-5mio, add appropriate amount of cell growth medium containing 0% FBS to terminate digestion, gently blow, transfer to a centrifuge tube, centrifuge i000r m, 5mm, count, adjust the final concentration of cell suspension to the appropriate concentration (cell viability) More than 90%).

 4.4.3.2 Add the cell suspension that has been adjusted to the final concentration to the 96-well plate, i()0ui per well.

 4.4, 3.3 Culture in 37Ό, 5% CO2 incubator

 4.4.4 Drug treatment

4.4.4.1 Preparation of the liquor test compound stock solution: The test compound is dissolved in the final solution I3MSO, the method is WmNL 4.4, 4.2 test compound tJ gradient dilution solution: First, take the iui test compound stock solution to 49 1 with 10% FBS In the cell growth medium, the highest concentration of the compounded tl was 20uM and the DMSO concentration was 0.2%. Then 20uM of the test compound was used in the cell growth medium containing 0.2% DMS(). Dilute 9 methods 3 times, for a total of 10 concentration gradients.

 4.4.4.3 Addition of wine test compound: Add the prepared gradient test compound dilution to the cell culture plate, lOOui per well. At this time, the highest concentration of the test compound is WuM, and the final concentration of DMSO is 0.1%. Gradient two replicate wells, and set blank control wells containing only 0.1% DMSO cell growth medium without cells) and negative control wells (cells and 1% DMS0 cell growth medium).

4.4.4.4 Add a test compound and apply a doubling time in a 37 ° C, 5% CO ₂ incubator.

 4.4.5 Detection and data analysis

 4.4.5.1 Detection: Take out the cell culture plate, take out lOO culture solution in each well and discard it, then add the prepared CTG substrate to the culture plate. 50ui per well. Immediately after the addition, oscillate on the oscillating plate fast oscillator for 2m and then rest the i0mm in the dark, balance the illuminating signal, and read the plate in the M3.

 4.4.5, 2 Data analysis: Statistical analysis of data was performed using GrqAPad mapping software.

 . Test Results

 The results of the inhibitory activity of the compounds of the present application against tumor cell lines are shown in Table 4.

35 <1000

35 <1000

 39 about 1000

 53 <500 <200

 54 <500

 47 <500 <200

 46 <500 <200

 48 <200 <500

 49 <500 <500

 50 about 1000 about 1000

 51 about 1000 about 1000

 40 <200 <200

 41 <50 <50

 42 <100 <500

 43 about 1000 <200

 43 about 500 <200

 44 <1000 <500

 44 <200

5. Solubility and pharmacokinetic characteristics:

 Pharmacokinetic characteristics

 5.1 Animal test

 The test compound of the present application was orally administered to SD rats, and its bioavailability and pharmacokinetic properties in rat plasma were measured.

 5.2 Test method:

 Route of administration: Administration by intragastric administration (PO) at a dose of 6 mg/kg, a final concentration of 1 mg/mL, and a dose of 10 mL/kg.

5.3 Whole blood sample collection: Blood is taken from the jugular vein of the animal, about 30 (^L each time. Blood is taken once before administration, 0.25 hours after administration, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 Blood was taken 24 hours an hour. The collected blood samples were at 4 ° C. After centrifugation at 2000 rpm for 5 min, the obtained plasma was transferred to a polyethylene microcentrifuge tube and stored in a -80 ° C refrigerator.

 5.4 Biological sample analysis method

 LC/MS/MS biological sample analysis method

 5.5 Test results

 The half-life of the test compound in animals and the six-hour compound, the concentration in blood and the experimental results of AUC are shown in the table.

Table 5 Solubility and Pharmacokinetic Characteristics of the Compounds of the Present Application

Claims

Wo! 1. From the formula I solvate, polymorph or prodrug:

 Formula I  among them,  A is a monocyclic or bicyclic aryl or heteroaryl group;  B is a monocyclic aryl or heteroaryl group; Is 1-5 substituents selected from H; d- ₆ alkyl, d- ₆ alkoxy optionally substituted by one or more groups selected from the group consisting of halogen, cyano, amino, hydroxy and trifluoromethyl a c _{2 -6} alkenyl group or a c _{2 -6} block group; or an optionally substituted saturated or unsaturated monocyclic or bicyclic heterocyclic group containing one or more hetero atoms, the substituent being one or more a group selected from the group consisting of R^CC R6S0 ₂ and R^SO, wherein the group is selected from a C _1-6 alkyl group, a monocyclic or bicyclic cycloalkane optionally substituted with at least one of a hydroxy group, a thiol group, an amino group and a halogen. a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms, a monocyclic or bicyclic heteroaryl group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms; R _{2 is} selected from the group consisting of H, C^alkyl, C alkoxy, C^alkenyl or C^ block; R _{3 is} selected from the group consisting of H, d ₆ alkyl, C alkoxy, Cw alkylamino, and at least one of R ₇ CONR ₈ -, R ₇ S0 ₂ NR ₈ - and BR^SON R ₈ -, wherein, and independently Is selected from the group consisting of 11, d- ₆ alkyl, C _{2 -6} alkenyl or C _{2 -6} block; R4 is at least one group selected from the group consisting of: H; halogen; hydroxy; amino; cyano; d- ₆ alkyl optionally substituted by halogen, d- ₆ alkoxy, C _{2 -6} alkenyl, C ₂ _ ₆ a block group; and a monocyclic or bicyclic aryl or heteroaryl group optionally substituted by halogen; X is selected from CH or N.  The compound, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof according to claim 1, wherein A is selected from a phenyl group, a pyridyl group, an imidazolyl group or a quinolyl group; or, B is selected From pyridyl or imidazolyl. The compound according to claim 1 or 2, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein, selected from H; or optionally one or more selected from the group consisting of a cyano group and a hydroxyl group a group substituted with a d ₄ alkyl group; or an optionally substituted saturated or unsaturated monocyclic heterocyclic group containing one or more hetero atoms, the substituent being one or more selected from the group consisting of R^CC R6S0 a group of ₂ and R^SO, wherein: a d- ₄ alkyl group optionally substituted with at least one of a hydroxy group, a thiol group, an amino group and a halogen, a monocyclic heteroaryl group having one or more hetero atoms, The hetero atom is selected from the group consisting of nitrogen, oxygen and sulfur Or R _{2 is at} least one selected from the group consisting of H, CM alkyl, CM alkoxy, CM alkylamino, and R ₇ CONR ₈ -, R ₇ S0 ₂ NR ₈ -, and R6SONR ₈ -, wherein, and independently Or a group selected from the group consisting of H, halogen, hydroxy, amino, cyano, d- ₄ alkyl optionally substituted by halogen, and monocyclic ring optionally substituted by halogen Or a bicyclic aryl or heteroaryl group.  The compound, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof according to any one of claims 1 to 3, wherein, when it is selected from a heterocyclic group and the hetero atom is N, A substituent is attached to the N atom. 5. A compound according to any one of claims 1-4 claim, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein is selected from d_ ₃ alkyl substituted with cyano; or The alkyl groups in R ₂ , R ₇ and are independently selected from the group consisting of d ₃ alkyl groups, wherein H of the alkyl group is optionally substituted by D; or R _{3 is} selected from H; or R 4 is at least one group selected from the group consisting of : H, halogen, CM alkyl, phenyl optionally substituted by halogen, pyridyl or imidazolyl.  6. Salts, solvates, polymorphs or prodrugs of formula II:

Formula II C is selected from a monocyclic or bicyclic aryl or heteroaryl group,  D is selected from a saturated or unsaturated mono- or bi-heterocyclic ring containing one or two nitrogen heteroatoms; R _{2 is} selected from the group consisting of H, C^alkyl, C alkoxy, C^alkenyl or C^ block; R _{5 is} selected from the group consisting of R ₆ CO, R ₆ SO ₂ or R ^ SO, wherein, selected from the group consisting of a d ₆ alkyl group, a monocyclic or bicyclic cycloalkyl group optionally substituted with at least one of a hydroxy group, a decyl group, an amino group and a halogen, a saturated or unsaturated monocyclic or bicyclic heterocyclic group of a plurality of heteroatoms, a monocyclic or bicyclic heteroaryl group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms; R6 is selected from any of the following groups: H, d- ₆ alkyl, d- ₆ alkoxy, C _{2 -6} alkenyl, C _{2 -6} block, monocyclic or bicyclic aryl, containing one or more selected from saturated or unsaturated monocyclic hetero atoms nitrogen, oxygen and sulfur atoms or bicyclic heterocyclic group containing one or more monocyclic ring selected from nitrogen, oxygen and sulfur heteroatoms atoms or bicyclic heteroaryl group, d_ ₆ Alkyl-S0 ₂ NH- _;  X is selected from CH or N. 7. A compound according to claim 6, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, Wherein, in Formula II, C is selected from the group consisting of quinolyl, indenyl, pyridyl or imidazolyl.  The compound according to claim 6 or 7, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein D is selected from one of the following structures:

The compound according to any one of claims 6-8, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, wherein R _{2 is} selected from CM alkyl; or, R _{5 is} selected from R6CO- And R^SO or R^SO-, wherein, selected from the group consisting of d- ₄ alkyl optionally substituted with at least one of a hydroxy group, a thiol group, an amino group and a halogen, a saturated monocyclic heterocyclic group containing one or more hetero atoms or A monocyclic or bicyclic heteroaryl group containing one or more heteroatoms selected from nitrogen, oxygen or sulfur atoms.  The compound according to any one of claims 1 to 9, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, and any one or more of H thereof is substituted by the corresponding isotope D, T a compound, wherein the compound is the following compound:  2-methyl-2-{4-[3-methyl-2-oxo-8-(6-phenylpyridin-3-yl)-1Η-2,3-dihydroimidazo[4,5- c] quinolin-1-yl]phenyl}propionitrile;  2-methyl-2-{4-[3-methyl-2-oxo-8-(1-phenyl-1H-pyrazol-4-yl)-1Η-2,3-dihydroimidazo[ 4,5-c]quinolin-1-yl]phenyl}propionitrile;  2-methyl-2-{4-{3-methyl-2-oxo-8-[6-(3-fluorophenyl)pyridin-3-yl]-1Η-2,3-dihydroimidazolium [4,5-c]quinolin-1-yl]phenyl}propionitrile;  2-methyl-2-{4-{3-methyl-2-oxo-8-[6-(4-fluorophenyl) B-pyridin-3-yl]-1Η-2,3-dihydro Imidazo[4,5-c]quinolin-1-yl]phenyl}propionitrile;  2-methyl-2-{4-{3-methyl-2-oxo-8-[6-(pyridin-3-yl)pyridin-3-yl]-1Η-2,3-dihydroimidazolium [4,5-c]quinolin-1-yl}phenyl}propionitrile;  2-methyl-2-{4-{3-methyl-2-oxo-8-[6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]-1Η- 2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;  2-methyl-2-{4-{3-methyl-2-oxo-8-[6-(quinolin-3-yl)pyridin-3-yl]-1Η-2,3-dihydroimidazole And [4,5-c]quinolin-1-yl}phenyl}propionitrile; 2-methyl- ₂ -{4-{3-methyl-2-oxo-8-[6-(6-phenylpyridin-3-yl)pyridin-3-yl]-1Η-2,3- Dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile; 2-methyl-2-{4-{3-methyl-2-oxo-8-[6-(1-phenyl-1-HB-biazole-yl)pyridin-3-yl]-1Η-2 , 3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;  2-methyl-2-{4-{3-methyl-2-oxo-8-{6-[6-(3-fluorophenyl)pyridin-3-yl]pyridin-3-yl}-111 -2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;  2-methyl-2-{4-{3-methyl-2-oxo-8-{6-[6-(4-fluorophenyl)pyridin-3-yl]pyridin-3-yl}-111 -2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;  2-methyl-2-{4-{3-methyl-2-oxo-8-{6-[6-(pyridin-3-yl)pyridin-3-yl]pyridin-3-yl}-1 2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;  2-methyl-2-{4-{3-methyl-2-oxo-8-{6-[6-(pyridin-4-yl)pyridin-3-yl]pyridin-3-yl}-1 2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;  2-methyl-2-{4-{3-methyl-2-oxo-8-{6-[6-(1-methyl-1-H-pyrazol-4-yl)pyridin-3-yl Pyridin-3-yl}-1Η-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl}propionitrile;  3-methyl-1-[4-(1-acetylpiperidin-4-yl)phenyl]-8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline -2 ( 3H) Ketone  L-(4-(l-(4H-l,2,4-Triazolyl-3-carbonyl)piperidin-4-yl)phenyl)-3-methyl-8-(quinolin-3-yl -1H-imidazo[4,5-c quinolin-2(3H)-one;  3-methyl-1-{4-[1-(2-hydroxyacetyl)piperidin-4-yl]phenyl}-8-(quinolin-3-yl)-1H-imidazo[4, 5 -c] quinoline-2 (3H)-one;  3-Methyl small {4-[1-(2-hydroxypropionyl)piperidin-4-yl])-phenyl}-8-(quinolin-3-yl)-1H-imidazo[4, 5 -c] quinoline-2 (3H)-one;  3-methyl-1-[4-(1-methanesulfonylpiperidin-4-yl)-phenyl]-8-(quinolin-3-yl)-1H-imidazo[4, 5-c] Quinoline-2 (3H)-one;  3-Methyl small [4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-8-(quinolin-3-yl)-1H-imidazole [4, 5-c]quinoline-2(3H)-one and its hydrochloride;  Ϊ́-(4-(1-(1Η-1,2,4-triazol-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-methyl -8-(quinolin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one and its hydrochloride;  3-methyl-1-(4-[1-(2-hydroxyacetyl)-1,2,3,6-tetrahydropyridin-4-yl]-phenyl}-8-(quinoline-3- -1H-imidazo[4,5-c]quinolin-2(3H)-one and its hydrochloride; 3-methyl-1-(4-[1-(2-hydroxypropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]-phenyl}-8-(quinoline-3- -1H-imidazo[4,5-c]quinolin-2(3H)-one and its hydrochloride; 3-methyl-1-(4-[l-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-phenyl}-8-(quinolin-3-yl) -1H-imidazo[4,5-c]quinolin-2(3H)-one and its hydrochloride;  3-Methyl-[4-(8-acetyl-8-azabicyclo[3,2,1]-oct-3-yl-3-yl)phenyl]-8-(quinolin-3-yl)- 1H-imidazo[4,5-c]quinolin-2(3H)-one and its hydrochloride;  Ϊ́-(4-(8-(1Η-1,2,4-triazol-3-carbonyl)-8-azabicyclo[3.2.1]oct-3-en-3-yl)phenyl) - 3-methyl-8- (quinoline -3-yl)-1H-imidazole [4,5-c]quinoline-2(3H)-one and its hydrochloride;  3-methyl small {4-[8-(2-hydroxyacetyl)-8-azabicyclo[3,2,1]-oct-3-en-3-yl]phenyl}-8- (quin Benz-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-one and its hydrochloride;  3-methyl small {4-[8-(2-hydroxypropionyl)-8-azabicyclo[3,2,1]-oct-3-en-3-yl]phenyl}-8- (quin Benz-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-one and its hydrochloride;  3-methyl-[4-(8-methylsulfonyl-8-azabicyclo[3,2,1]-oct-3-en-3-yl)phenyl]-8-(quinoline-3- -1H-imidazo[4,5-c]quinolin-2(3H)-one and its hydrochloride;  3-methyl-1-[4-(1-methanesulfonylpiperazin-4-yl)-phenyl]-8-(quinolin-3-yl)-1H-imidazo[4, 5-c] Quinoline-2 (3H)-one; or  3-methyl-1-[4-(1-methanesulfonylpiperidin-4-yl)-phenyl]-8-[6-(2-methoxyethoxy)pyridin-3-yl]- 1H-imidazo[4,5-c]quinolin-2(3H)-one;  (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(4-methyl-6-(1Η-1, 2,4-triazol-3-yl)oxapyridin-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-one;  (S)-8-(6-(2-hydroxypropan-2-yl) B-pyridin-3-yl)-1-(4-(1-(2-hydroxypropionyl)piperidin-4-yl) Phenyl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-one;  (S)-l-(4-00hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-GH-pyrrolo[3,2-b]pyridine-6-yl) - 1H-imidazo[4,5-c]quinoline-2(3H)-one;  (S)-N-(5-(l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-2-oxo-2,3- Dihydro-1H-imidazo[4,5-c quinolin-8-yl)-2-methylpyridin-3-yl)methanesulfonamide;  (S)-l-(4-(l-(2-Hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(1-phenyl-1H-pyrazole-4- -1H-imidazolium [4,5-c]quinoline-2(3H)-one;  (S)-l-(4-(l-(2-Hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(1-(pyridin-3-yl)-1H- Pyrazol-4-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one; (S)-8-(l-(3-fluorophenyl)-1H-pyrazol-4-yl)-1-(4-(1-(2-hydroxypropionyl)piperidin-4-yl)benzene 3-methyl-1H-imidazo[4,5-c]quinoline-2(3H)-one; (S)-l-(4-(l-(2-Hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-phenylpyridin-3-yl)-1H -imidazo[4,5-c]quinoline-2(3H)-one;  (S)-8-([2,3'-bipyridyl]-5-yl)-1-(4-(1-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3- Methyl-1H-imidazo[4,5-c quinolin-2(3H)-one;  (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazole) 4-yl)pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one;  (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-8-(6-methoxy-5-methylpyridin-3-yl)- 3-methyl-1H-imidazo[4,5-c]quinoline-2(3H)-one;  (S)- 1 -(4-(1-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-(tetrahydro-2H-pyran-4) -yl)pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one;  (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-8-(6-(2-methoxyethoxy) B-pyridin-3 -yl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-one.  (^)-^4-0(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(quinolin-3-yl)-1H-imidazo[4,5 -c]quinoline-2(3H)-one  3-methyl-8-(quinolin-3-yl)-1-(4-(1-(tetrahydro-2H-pyran-4-carbonyl)-1,2,3,6-tetrahydropyridine- 4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one  1-(4-(1-(Cyclobutylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-methyl-8-(quinolin-3-yl) -1H-imidazo[4,5-c]quinoline-2(3H)-one  1-(4-(1-(3-hydroxy-3-methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-methyl-8- (quin Benz-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one  3-methyl-1-(4-(1-(morpholine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-8-(quinoline-3- -1H-imidazo[4,5-c]quinoline-2(3H)-one  1-(4-(4-(4Η-1,2,4-triazol-3-carbonyl)piperazin-1-yl)phenyl)-3-methyl-8-(quinolin-3-yl) -1H-imidazo[4,5-c quinolin-2(3H)-one  8-(6-(Ethylamino)pyridin-3-yl)-3-methyl-1-(4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)-1H-imidazole [4,5-c] quinoline-2(3H)-one  1-(4-(1-(4Η-1,2,4-triazol-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-methyl 8-(6-phenylpyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one 1-(4-(1-(4Η-1,2,4-triazol-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-8-(6 -methoxy-5-methylpyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]quinoline-2(3H)-one (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-0phenyl-1H-pyrazol-4-yl) -1H-imidazo[4,5-c]quinoline-2(3H)-one  (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-phenylpyridin-3-yl)-1H -imidazo[4,5-c]quinoline-2(3H)-one  (S)-8-([2,3'-dipyridyl]-5-yl)-1-(4-(1-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3 -methyl-1H-imidazole [4,5-c]quinoline-2(3H)-one  (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-8-(6-methoxy-5-methylpyridin-3-yl)- 3-methyl-1H-imidazo[4,5-c]quinoline-2(3H)-one  (S)-l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazole) 4-yl)B-pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one  1-(4-(1-(2-hydroxyacetyl)piperidin-3-yl)phenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazole-4- Pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one  3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl) B-pyridin-3-yl)-1-(4-(1-(methylsulfonyl)piperidine- 3-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one  L-(4-(l-(4H-l,2,4-triazol-3-carbonyl)piperidin-3-yl)phenyl-3-methyl-8-(6-(1-methyl) -1H-pyrazol-4-yl)oxidin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one  L-(4-(l-((R)-2-hydroxypropanoyl)piperidin-3-yl)phenyl-3-methyl-8-(6-(1-methyl-1H-pyrazole- 4-yl)B-pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one  L-(4-(l-((S)-2-hydroxypropanoyl)piperidin-3-yl)phenyl-3-methyl-8-(6-(1-methyl-1H-pyrazole- 4-yl)B-pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one  1-(4-(1-ethylpiperidin-3-yl)phenyl-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl) B-pyridin-3 -yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one  3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl) B-pyridin-3-yl)-1-(4-(1-(methylsulfonyl)piperidine- 4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one  1-(4-(1-(2-hydroxyacetyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl) B-pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one  1-(4-(1-(1Η-1,2,4-triazol-3-carbonyl)piperidin-4-yl)phenyl)-3-methyl-8-(6-(1-A) -1H-pyrazol-4-yl)oxidin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one 3-ethyl-1-(4-(1-(2-hydroxyacetyl)piperidin-4-yl)phenyl)-8-(6-(1-methyl-1H-pyrazol-4-yl) Pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-one 3-ethyl-8-(6-(l-methyl-1H-pyrazol-4-yl) B-pyridin-3-yl)-l-(4-(l-(methylsulfonyl)piperidine- 4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one  1-(4-(1-(4Η-1,2,4-triazol-3-carbonyl)piperidin-4-yl)phenyl)-3-ethyl-8-(6-(1-A) -1H-pyrazol-4-yl)-p-pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-one (S)-l-(4-( L-(2-Hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-8-(1Η-pyrrolo[3,2-b]pyridin-6-yl)-1H-imidazole [4,5-c]quinoline-2(3H)-one (S)-N-(5-(l-(4-(l-(2-hydroxypropionyl)piperidin-4-yl)phenyl)-3-methyl-2-oxo-2,3- dihydro -1H- imidazo ^[4, 5-c] quinolin-8-yl) - ² - methyl-pyridin-3-yl) methanesulfonamide  3-deuterated methyl-8-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-1-(4-(1-(methylsulfonyl)piperidine- 4-yl)phenyl)-1H-imidazo[4,5-c]quinoline-2(3H)-one  2-methyl-2-(4-(3-methyl-8-(6-(1-methyl-1H-pyrazol-4-yl) B-pyridin-3-yl)-2-oxo- 2,3-dihydro-1H-imidazolium [4,5-c] [1,5]naphthyridin-1-yl)phenyl)-propionitrile;  4-(4-(3-Methyl-2-oxo-8-(1-phenyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-imidazo[4,5- c]quinolin-1-yl)phenyl)piperidine-1-carbaldehyde.  A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier.  12. A compound, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof according to any one of claims 1 to 10 for the preparation of one or both of the mTOR, PBK, S6 and Akt protein kinases. Application in one or more drugs.  13. The compound according to any one of claims 1 to 10, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof, for the preparation of a prophylactic and therapeutic agent with mTOR, PBK, S6 and Akt protein kinases The use of drugs for the treatment of two or more related diseases.  The compound according to any one of claims 1 to 10, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof for the preparation of a medicament for preventing and treating a tumor, a metabolic disease and/or a cardiovascular disease Application in .  15. Use according to claim 13, wherein the disease is selected from the group consisting of a tumor, a metabolic disease and/or a cardiovascular disease. The use according to any one of claims 14 to 15, wherein the tumor is selected from the group consisting of breast cancer, lung cancer, acute leukemia, renal cancer, prostate cancer, neuroendocrine tumor, endometrial cancer, and pancreatic cancer; The metabolic disease is selected from the group consisting of diabetes and obesity; the cardiovascular disease is selected from the group consisting of atherosclerosis.