TWI601724B - Imidazo quinoline derivatives and salts thereof, preparation process and pharmaceutical use thereof - Google Patents

Description

Imidazoquinoline derivatives and pharmaceutically acceptable salts thereof, preparation method thereof and application thereof in medicine

The present invention relates to a novel imidazoquinoline derivative, a pharmaceutically acceptable salt thereof, a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a cancer therapeutic agent, particularly as an mTOR and/or PI3K-kinase inhibitor use.

In the past half century, research on cancer treatment has made many progress. With the deepening of research on tumor genetics and biology, a number of intracellular tumor-related key signaling pathways have been discovered. Tumor cells rely on these pathways to achieve intracellular transduction of extracellular signals, regulate their own sustained proliferation, invasion and metastasis, and anti-apoptosis activities, while maintaining their malignant phenotypic characteristics, on the other hand by regulating specific genes and their protein products. Tolerance to treatment. The phospholipid 醯 inositol 3 kinase (PI3K)-AKT-mammalian rapamycin target (mToR) pathway has become one of the most important signaling pathways and has become a better target for tumor drug development.

As a key signaling pathway in the cell, PI3K-AKT-mTOR pathway is involved in the fine regulation of multiple processes such as cell cycle growth, protein synthesis, energy metabolism and survival and apoptosis after activation by various receptor signals.

Phosphatidylinositide 3-kinase (PI3K) belongs to the family of lipid kinases and can be classified into three classes according to its structural characteristics and substrate selectivity. Among them, the most in-depth study of PI3K is a heterodimeric protein consisting of p110 and p85 protein subunits, and each subunit has different subtypes, such as p110 α, p110 β. P85 α, p85 β, etc. Wherein the p85 regulatory subunit is activated by phosphorylation by interaction with the receptor tyrosine kinase, and the p110 catalytic subunit converts the phospholipid inositol diphosphate (PI2P) to the phospholipid inositol triphosphate (PI3P), The latter can further activate a plurality of downstream signal molecules to complete the conduction of the extracellular signals.

AKT, also known as protein kinase B, is a serine/threonine protein kinase and is a major downstream effector of PI3K. Phospholipid creatinine triphosphate produced by PI3K can induce intracellular AKT and phosphoinositide-dependent protein kinase 1 (PDK1) to be localized to and bound to the cell membrane. Activated PDK1 phosphorylates AKT and maximizes activity by interacting with mTOR complex 2. As the central link of the entire PI3K-AKT-mTOR signal, AKT relies on its kinase activity to regulate multiple downstream signals, and complete the regulation of processes such as protein synthesis and cell proliferation, making it one of the important potential targets.

Another key component of the PI3K-AKT-mTOR signal is the mammalian target of rapamycin (mTOR), which belongs to the class IV PI3K kinase and has the p110 subunit of the class 1 PI3K. Similar molecular structure. mTOR exists in two different complexes, mTORC1 and mTORC2, by binding to different protein molecules. mTORC1 is located downstream of AKT; mTORC2 is initiated by other mechanisms and is involved in the regulation of AKT activity. AKT attenuates the inhibitory effect of TSC protein on mTORC1 by phosphorylating TSC protein (tuberous sclerosis), allowing mTORC1 to be activated by GTPase. The activated mTOR is further specific to the ribosomal protein kinase p70S6K and the transcriptional regulatory protein 4EBP1. The transcription and translation of the gene, which ultimately completes the conduction process and enables the cell to respond to extracellular signals.

As a key regulatory pathway of cell function, PI3K-AKT-mTOR is closely related to the activation of proto-oncogenes and has a critical impact on the occurrence and development of tumors. As the most common abnormal signaling pathway in tumor cells, PI3K regulatory protein PTEN abnormality, AKT overexpression or overactivation can cause continuous activation of PI3K signal. These mutations are ubiquitous in a variety of solid tumors, such as breast cancer, lung cancer, colon cancer, pancreatic cancer, liver cancer, digestive tract tumors, etc., and are closely related to treatment tolerance and poor prognosis. Therefore, it is expected that the inhibition of PI3K, AKT and mTOR by developing small molecule compounds has a good development prospect as a tumor therapeutic drug.

For the PI3K-AKT-mTOR signaling pathway, there are currently several compounds that inhibit PI3K, AKT, mTOR activity or PI3K/mTOR dual inhibition in development and clinical trials. For example, BEZ235 is a dual-target small molecule inhibitor against PI3K and mTOR, and is now in the clinical I/II experimental phase for breast cancer. Studies on the PI3K/mTOR/Pim-1 inhibitor SF1126 have shown some activity in diffuse large B-cell lymphoma and certain solid tumors, and are currently in clinical phase I. A series of patent applications for mTOR and/or PI3K kinase inhibitors are currently disclosed, including WO2003097641, WO2005054237, WO2010038165 and WO2011022439.

In order to achieve better tumor treatment results and better meet market demand, we hope to develop a new generation of high-efficiency and low-toxic targets. Inhibitors of the PI3K-AKT-mTOR signaling pathway, particularly multi-target inhibitors. The present invention will provide a novel structure of mTOR/PI3K kinase inhibitor, and find that a compound having such a structure has good activity and exhibits an excellent anti-tumor cell proliferation effect.

The object of the present invention is to provide a novel imidazoquinoline derivative represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer and a diastereomer thereof. Constructs, mixtures thereof, and pharmaceutically acceptable salts thereof: Wherein Y is O or S; A is N or CR ¹⁰ ; R ¹ is a hydrogen atom or an alkyl group; and R ² and R ³ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a heterocyclic group, a halogen, a hydroxy group, a cyano group, an aryl group, a heteroaryl group, -OR ⁷ , -S(O) ₂ R ⁷ or -NR ⁸ R ⁹ , wherein the alkyl group, alkoxy group, heterocyclic group, aryl group or heteroaryl group Further substituted with one or more substituents selected from alkyl, halogen, cyano, amine, hydroxy, alkenyl, alkynyl, carboxy or carboxylate groups, if desired; R ⁴ is heteroaryl, wherein heteroaryl optionally further substituted by one or more groups selected from alkoxy, alkenyl group, alkynyl ^{group, -OR 7, -NHC (O)} NR 8 R 9, -NR 8 C (O) R 9, - Substituted with a substituent of NR ⁸ C(O)OR ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ R ⁹ ; each of R ⁵ and R ^{6 is} independently selected from a hydrogen atom, an alkyl group, a halogen or a cyano group. ; R ⁷ , R ⁸ and R ⁹ are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkenyl group, The cycloalkyl, heterocyclic, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of a hydroxyl group, an alkyl group, a halogen, and an alkane. Group, alkenyl group, alkynyl group, nitro, cyano, cycloalkyl, heterocyclyl, aryl or heteroaryl group substituents; R ¹⁰ is selected from hydrogen, alkyl, alkoxy, halo, a hydroxy, cyano, aryl, heteroaryl, -OR ⁷ , -S(O) ₂ R ⁷ or -NR ⁸ R ⁹ wherein the alkyl, alkoxy, aryl or heteroaryl group is further Substituted with one or more substituents selected from alkyl, halo, cyano, amine, hydroxy, alkenyl, alkynyl, carboxy or carboxylate groups; and n is 0 or 1.

In a preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof And mixtures thereof, and pharmaceutically acceptable salts thereof, which are a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof: Wherein, A, R ^{2 -} R ⁴ , n are as defined in the formula (I).

In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof And a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non- Enantiomers, mixtures thereof, and pharmaceutically acceptable salts thereof: Wherein, Y, R ^{2 -} R ⁴ , R ¹⁰ , n are as defined in the formula (I).

In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof And a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non- Enantiomers, mixtures thereof, and pharmaceutically acceptable salts thereof: Wherein, Y, R ^{2 -} R ⁴ , n are as defined in the formula (I).

Further, in a preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a construct, and mixtures thereof, and pharmaceutically acceptable salts thereof, wherein R ² and R ³ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a heterocyclic group, a halogen, -OR ⁷ or -S(O) ₂ R ⁷ , wherein the alkyl, alkoxy or heterocyclic group is further substituted by one or more substituents selected from an alkyl group, a halogen or a cyano group, as needed; R ^{7 is} selected from a hydrogen atom or an alkyl group.

In a preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof And mixtures thereof, and pharmaceutically acceptable salts thereof, wherein R ⁴ is pyridyl, wherein the pyridyl group is further further selected from one or more selected from the group consisting of alkoxyalkyl, alkenyl, alkynyl, -OR ⁷ , Substituted by a substituent of -NHC(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ C(O)OR ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ R ⁹ ; R ⁷ , R ⁸ and R ⁹ are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkenyl group, The cycloalkyl, heterocyclic, aryl or heteroaryl group is further optionally selected from one or more selected from the group consisting of hydroxyl, alkyl, halogen, alkoxy, alkenyl, alkynyl, nitro, cyano, cycloalkyl Or a substituent of a heterocyclic group is substituted.

In a preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof , and mixtures thereof, and pharmaceutically acceptable salts thereof, wherein R ¹⁰ is haloalkyl, preferably trifluoromethyl.

Typical compounds of the invention include, but are not limited to: Or tautomers, meso-forms, racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof.

The present invention relates to a compound of the formula (IA) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, and mixtures thereof, and Pharmaceutically acceptable salt: It can be used as an intermediate for the preparation of the compound of the formula (I), wherein: Y is O or S; X is a halogen; A is N or CR ¹⁰ ; R ¹ is a hydrogen atom or an alkyl group; and R ² and R ³ are each independently selected. From a hydrogen atom, an alkyl group, an alkoxy group, a heterocyclic group, a halogen, a hydroxyl group, a cyano group, an aryl group, a heteroaryl group, -OR ⁷ , -S(O) ₂ R ⁷ or -NR ⁸ R ⁹ , wherein An alkyl group, an alkoxy group, a heterocyclic group, an aryl group or a heteroaryl group is further optionally one or more selected from the group consisting of an alkyl group, a halogen, a cyano group, an amine group, a hydroxyl group, an alkenyl group, an alkynyl group, a carboxyl group or a carboxylic acid. Substituted with a substituent of the ester group; R ⁵ and R ⁶ are each independently selected from a hydrogen atom, an alkyl group, a halogen or a cyano group; and R ⁷ , R ⁸ and R ⁹ are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group. Or alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further protected by one or more Substituted with a substituent selected from a hydroxyl group, an alkyl group, a halogen, an alkoxy group, an alkenyl group, an alkynyl group, a nitro group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; R ^{10 is} selected from hydrogen Atom, alkyl, alkoxy, halogen, hydroxy , Cyano, aryl, ^{heteroaryl, -OR 7, -S (O)} 2 R 7 , or -NR ⁸ R ^9, wherein the alkyl, alkoxy, aryl or heteroaryl optionally further substituted by one Or a plurality of substituents selected from alkyl, halogen, cyano, amine, hydroxy, alkenyl, alkynyl, carboxy or carboxylate groups; and n is 0 or 1.

The invention further relates to a process for the preparation of a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and mixtures thereof, and A method of pharmaceutically acceptable salts thereof, the method comprising:

The compound of the formula (I) is catalyzed by a hydroxy catalyst in a solvent under basic conditions with an R ⁴ -substituted boronic acid ester or boric acid to give a compound of the formula (I). Wherein Y is O or S; X is a halogen; and A, n, R ¹ to R ⁶ are as defined above for the definition of formula (I).

The reagents providing basic conditions include organic bases and inorganic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, Inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate.

Catalysts include, but are not limited to, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, 1,1'-bis(dibenzylphosphine) dichlorodipentadium iron palladium, tris(dibenzylideneacetone) dipalladium. Palladium/carbon, Solvents used include, but are not limited to, dimethyl hydrazine, 1,4-dioxane, water or N,N-dimethylformamide.

The invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) according to the invention or a tautomer, a mesogen, a racemate, an enantiomer, a non- Enantiomers, and mixtures thereof Form, and pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present invention further relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and Use of a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same for the manufacture of a medicament for the treatment of a protein kinase dependent disease.

The present invention further relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and Use of a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same for the manufacture of a medicament for inhibiting mTOR and/or PI3K-kinase.

The present invention further relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and Use of a pharmaceutically acceptable salt or a pharmaceutical composition comprising the same for the preparation of a medicament for treating a cancer or a tissue hyperplasia disease, wherein the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer , malignant lymphoma, liver, kidney, bladder, prostate, breast and pancreatic cancers and sarcomas, and primary and recurrent solid tumors or leukemias of the skin, colon, thyroid, lungs and ovaries.

The invention also relates to a method of treating a protein kinase dependent disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, a mesogen, a racemate thereof, Enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.

The invention also relates to a method of inhibiting mTOR and/or PI3K-kinase activity A method comprising administering a therapeutically effective amount of a compound of formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof to a subject in need thereof And mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.

In other words, the present invention relates to a method for treating a cancer or a tissue hyperplasia comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemic form thereof. , enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, wherein the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, bile duct Carcinoma and sarcoma of cancer, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors or leukemia of skin, colon, thyroid, lung and ovary .

The present invention also relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, which is a drug for treating a protein kinase-dependent disease. A conformation, a mixture thereof, and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present invention also relates to a compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof, or a non-isomeric substance, which is a drug which inhibits mTOR and/or PI3K-kinase activity. An enantiomer, a mixture thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present invention also relates to a compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof, a diastereomer as a medicament for treating a cancer or a tissue hyperplasia-like disease. Isomers, mixtures thereof, and A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, liver, kidney, bladder, prostate , breast and sarcoma of the breast and pancreas, and primary and recurrent solid tumors or leukemia of the skin, colon, thyroid, lungs and ovaries.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring, coloring, and preservatives to provide a pleasing And delicious pharmaceutical preparations. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by a known technique which provides a sustained release effect over a longer period of time by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract. For example, water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.

Hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient with water A soft gelatin capsule in which a soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil is mixed provides an oral preparation.

The aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols A condensation product of a partial ester such as polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose, saccharin or arsenic. Spartan.

The oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.

The dispersible powders and granules suitable for the preparation of water suspension can be provided by dispersing powders and granules by adding water, and dispersing or wetting agents and suspending agents for mixing. Or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, for example Polyethylene oxide sorbitol monooleate. The emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

The pharmaceutical composition can be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerin to form a microemulsion. The injection or microemulsion can be injected into the bloodstream of the patient by a local injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant loop concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

The pharmaceutical composition may be sterile injectable water for intramuscular and subcutaneous administration Or in the form of an oil suspension. The suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be prepared as an injection.

The compounds of the invention may be administered in the form of a suppository for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug. Such materials include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

As is well known to those skilled in the art, the dosage of the drug depends on a variety of factors including, but not limited to, the activity of the particular compound employed, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, the patient Diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; alternatively, the preferred mode of treatment such as the mode of treatment, the daily amount of the compound of formula (I) or the type of pharmaceutically acceptable salt may be Validated according to traditional treatment protocols.

Detailed description of the invention

Terms used in the specification and claims have the following meanings unless stated to the contrary.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 carbon atoms, and more preferably 1 to 5 carbon atoms. The alkyl group of one carbon atom, more preferably an alkyl group having 1 to 3 carbon atoms, the most preferred methyl group. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4- Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3- Ethylhexyl, 2 2-Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec. Butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl , 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-di Methyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Butyl, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(P)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 3 carbon atoms. 10 carbon atoms, preferably containing 3 to 5 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene A polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.

The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings are fully conjugated π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring. . More preferably 4 members / 4 members, 4 members / 5 members, 4 members / 6 members, 5 members / 5 members or 5 members / 6 members of the monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to 5 to 20 members, each ring of the system sharing an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl group may be classified according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5 member/5 member or 5 member/6 member bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of which has a complete Conjugate π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, oxo, -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ , -S(O) _m NR ⁸ R ⁹ , -C(O)R ¹⁰ , -C(O)OR ¹⁰ or -S(O) _m R ¹⁰ .

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like. Preferred is a C _2-5 alkenyl group, more preferably a C _2-4 alkenyl group, and most preferably a C _2-3 alkenyl group. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio. , alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- Or 3-butynyl and the like. Preferred is a C _2-5 alkynyl group, more preferably a C _2-4 alkynyl group, and most preferably a C _2-3 alkynyl group. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio. , alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O). The hetero atom of _m (wherein m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms are carbon; the hetero atom is preferably N or oxygen. The heterocyclic group preferably contains 3 to 12 ring atoms, of which 1 to 4 are hetero atoms; more preferably 3 to 10 ring atoms, of which 1 to 3 are hetero atoms; preferably 5 to 6 ring atoms Among them, 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyranyl, tetrahydrofuranyl, thiomorpholinyl, homopiperazinyl and the like. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) _m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is classified into a monospiroheterocyclyl group, a dispiroheterocyclic group or a polyspiroheterocyclic group, preferably a monospiroheterocyclic group and a dispiroheterocyclic group, depending on the number of common spiro atoms between the ring and the ring. . More preferably 4 members / 4 members, 4 members / 5 members, 4 members / 6 members, 5 members / 5 members or 5 members / 6 members of the monospiroheterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

The term "fused heterocyclyl" refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the remaining rings The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 5 member/5 member or a 5 member/6 member bicyclic fused heterocyclic group. . Non-limiting examples of fused heterocyclic groups include:

The term "bridge heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A π-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridge heterocyclic groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include: with Wait.

The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, oxo, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably from 6 to 10 members, for example, Phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio. , alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, more preferably 5 members or 6 members, such as furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl. And imidazolyl, tetrazolyl, etc., preferably pyridyl or pyrazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "hydroxy" refers to an -OH group.

The term "hydroxyalkyl" refers to an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.

The term "halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

The term "amino" refers to -NH _2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "benzyl" refers to -CH ₂ - benzene.

The term "oxo" refers to =0.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.

The term "alkoxyalkyl" refers to an alkyl group substituted by an alkoxy group, wherein the alkoxy group, alkyl group is as defined above.

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

"Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently of each other by the corresponding number Substituent substitution. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amine group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

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

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.

R ⁷ to R ⁹ are as defined in the compound of the formula (I), and m is 0, 1 or 2.

Synthetic method of the present invention

In order to accomplish the synthetic purposes of the present invention, the present invention employs the following synthetic technical scheme: The present invention relates to a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of the formula (IA) is reacted with an R ⁴ -substituted boronic acid ester or boric acid under basic conditions in a solvent to obtain a compound of the formula (I). Wherein Y is O or S; X is a halogen; and A, n, R ¹ to R ⁶ are as defined above for the definition of formula (I).

The reagents providing basic conditions include organic bases and inorganic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, Inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate.

Catalysts include, but are not limited to, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, 1,1'-bis(dibenzylphosphine) dichlorodipentadium iron palladium, tris(dibenzylideneacetone) dipalladium. , palladium / carbon, solvents used include, but are not limited to: dimethyl hydrazine, 1,4-dioxane, water or N, N-dimethylformamide.

The present invention relates to a process for the preparation of a compound of the formula (II) or a pharmaceutically acceptable salt thereof, the process comprising:

The aniline compound (a) is reacted with a halogen or a nitro-substituted quinoline compound (b) in a solvent under acidic conditions to obtain a halogen, a nitro-substituted quinoline compound (c), and further a halogen or a nitro-substituted quinolin. The porphyrin compound (c) is reduced in a solvent to obtain a halogen, an amino-substituted quinoline compound (d), a halogen-substituted amino-substituted quinoline compound (d) in a solvent under basic conditions, and substituted with a halogen. The formate reaction gives a halogen-substituted imidazoquinolinone (IIB), and the halogen-substituted imidazoquinolinone (IIB) is alkylated in a solvent under basic conditions to obtain a halogen-substituted alkyl-imidazole. Quinolinone (IIA), halogen, alkyl-substituted imidazoquinolinone (IIA) and R ⁴ -substituted boronic acid ester or boric acid are catalyzed by a catalyst under basic conditions to obtain a general formula ( II) Compounds. Wherein X is a halogen; and A, n, R ¹ to R ⁴ are as defined in the formula (I).

Agents that provide acidic conditions include, but are not limited to, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid.

The alkaline conditions include organic bases and inorganic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium third butoxide, tetrabutyl. Ammonium bromide, including but not limited to sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.

Catalysts include, but are not limited to, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, 1,1'-bis(dibenzylphosphine) dichlorodipentadium iron palladium, tris(dibenzylideneacetone) dipalladium. , palladium / carbon, Raney nickel.

Reducing agents include, but are not limited to, Fe powder, Zn powder, or H ₂ .

Solvents used include, but are not limited to, acetic acid, methanol, ethanol, tetrahydrofuran, dichloromethane, dimethyl hydrazine, 1,4-dioxane, water or N,N-dimethylformamide.

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

The structure of the compound is determined by nuclear magnetic resonance ( ¹ H NMR) and/or mass spectrometry (MS). ^{The 1} H NMR shift (δ) is given in parts per million (ppm). ^{The 1} H NMR measurement was carried out using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ), and deuterated dimethyl hydrazine (DMSO- d ₆ ). Marked as tetramethyl decane (TMS).

The measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm chromatography column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm chromatography column).

The IC ₅₀ value was determined using a NovoStar plate reader (BMG, Germany).

The thin layer chromatography tannin plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheet, and the thin layer chromatography (TLC) detection reaction uses a specification of 0.15 mm to 0.2 mm. The tantalum sheet used for separation and purification of thin layer chromatography is used. The specifications are from 0.4 mm to 0.5 mm.

The rubber hose column generally uses Yantai Huanghai Silicone 200 to 300 mesh silicone as a carrier.

The basic alumina column generally uses FCP 200 to 300 mesh basic alumina as a carrier for the chromatography of the national medicine.

The known starting materials of the invention may be synthesized by or according to methods known in the art, or may be used in ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accali Chemical Technology (Accela ChemBio Inc) and Dari Chemicals are buying.

Unless otherwise stated in the examples, the reactions were all carried out under a nitrogen or argon atmosphere.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon having a volume of about 1 L.

The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and the operation is repeated 3 times.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature and is 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The systems used for the reaction were: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, petroleum ether and ethyl acetate systems. In the acetone system, the volume ratio of the solvent is adjusted depending on the polarity of the compound.

The system of the eluent for column chromatography and the system for developing the thin layer chromatography of the purified compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and In the acetone system, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline reagent such as triethylamine or an acidic reagent such as acetic acid may be added for adjustment.

Example 1 1-[5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-3-methyl-urea

first step 5-bromo-2-[[( E )-2-nitrovinyl]amino]benzoic acid

2-Amino-5-bromo-benzoic acid 1a (17.50 g, 81 mmol) was dissolved in a mixture of 670 mL of water and 85 mL of 37% hydrochloric acid, and the mixture was stirred for 6 hr. Nitromethane (49.40 g, 810 mmol) was slowly added dropwise to a mixture of 10 g of ice and 38.4 g of sodium hydroxide, and the reaction was stirred at 0 ° C for 35 minutes, stirred at room temperature for 45 minutes, and added dropwise to 100 g of ice water. The mixture with 119 mL of 37% hydrochloric acid was mixed with the solution of 1a and stirred at room temperature for 12 hours. Filtered to give a yellow solid which was dried in vacuo to give crude title product 5-bromo -2 - [[(E) -2- nitroethenyl] amino] benzoic acid 1b (40.0 g, yellow solid) was used without further purification Carry out the next reaction.

Second step 6-bromo-3-nitro-quinoline-4(3 H )-one

Add the crude 5-bromo-2-[[( E )-2-nitrovinyl]amino]benzoic acid 1b (19.20 g, 67 mmol) and potassium acetate (9.80 g, 100 mmol) to 200 mL of acetic anhydride The reaction was stirred at 120 ° C for 3.5 hours. The mixture was cooled to room temperature, placed in a refrigerator for 12 hours, and filtered under vacuum. The filter cake was washed with acetic acid (50 mL), water (50 mL), and dried in vacuo at 50 ° C to give the title product crude 6-bromo-3-nitro- Quinoline-4( 3H )-one 1c (6.90 g, brown solid).

third step 6-bromo-4-chloro-3-nitro-quinoline

Dissolve the crude 6-bromo-3-nitro-quinoline-4( 3H )-one 1c (6.90 g, 26 mmol) and 1 mL of N,N -dimethylformamide in 22 mL of hydrazine chloride. The reaction was stirred at 85 ° C for 4 hours. After cooling to room temperature, the reaction mixture was evaporated. mjjjjjjjjjjjjj

the fourth step 2-methyl-2-(4-nitrophenyl)propanenitrile

2-(4-Nitrophenyl)acetonitrile 1e (20.0 g, 0.12 mol) was dissolved in 100 mL of dichloromethane, and then iodomethane (52.50 g, 0.37 mol) and tetrabutylammonium bromide (1.99 g, 6 mmol), stirring in an ice bath for 5 minutes, and then adding sodium hydroxide solution until the solution turned from deep red to purple, and the reaction was stirred at room temperature for 12 hours. Dispensing, the aqueous phase was extracted with dichloromethane (30 mL×3), combined The organic phase was dried over anhydrous sodium sulfate (MgSO4jjjjjjjjjjjjj Carry out the next reaction.

the fifth step 2-(4-aminophenyl)-2-methyl-propanenitrile

The crude 2-methyl-2-(4-nitrophenyl)propanenitrile 1f (21.70 g, 0.11 mol), iron powder (63.90 g, 1.10 mol) and glacial acetic acid (20.50 g, 0.34 mol) were dissolved in 200 In mL of anhydrous methanol, the mixture was heated to reflux and stirred for 5 hours. The starting material was not completely reacted, and glacial acetic acid (8 g, 0.13 mol) was added thereto, and the reaction was continued for 2 hours. Filtration and concentration of the filtrate under reduced pressure, EtOAc (EtOAc) (EtOAc) Phenyl)-2-methyl-propanenitrile 1 g (20.0 g, reddish brown oil).

MS m/z (ESI): 161.1 [M+1]

Step 6 2-[4-[(6-bromo-3-nitroquinolin-4-yl)amino]phenyl]-2-methyl-propanenitrile

The crude 2-(4-aminophenyl)-2-methyl-propanenitrile 1 g (6.80 g, 0.076 mol) and crude 6-bromo-4-chloro-3-nitro-quinoline 1d (12.17 g, 0.076 mol) was dissolved in 60 mL of glacial acetic acid, and heated to 100 ° C to stir the reaction for 2 hours. It was cooled to room temperature, concentrated under reduced pressure, and ethyl acetate (100 mL) was added, and the pH was adjusted to 9 to 10 with a saturated potassium carbonate solution. The extract was separated, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, )amine Phenyl]-2-methyl-propanenitrile 1 h (5.30 g, yellow solid), yield: 30.5%.

Seventh step 2-[4-[(3-Amino-6-bromoquinolin-4-yl)amino]phenyl]-2-methyl-propanenitrile

2-[4-[(6-Bromo-3-nitroquinolin-4-yl)amino]phenyl]-2-methyl-propanenitrile 1 h (5.30 g, 13 mmol) was dissolved in 120 mL methanol To the solution, acetic acid (2.30 g, 39 mmol) was added, and iron powder (7.20 g, 0.13 mol) was added thereto with stirring, and the reaction was refluxed for 5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (100 mL) was evaporated. Drying over anhydrous sodium sulfate, filtration, and EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Propionitrile 1i (3.80 g, yellow solid).

Eighth step 2-[4-[(8-Bromo-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl]-2-methyl- Propiononitrile

Dissolve the crude 2-[4-[(3-amino-6-bromoquinolin-4-yl)amino]phenyl]-2-methyl-propanenitrile 1i (3.80 g, 9.90 mmol) in 30 mL Trichloromethane (2.8 mL, 19.90 mmol) was added to dichloromethane to make a mixed solution. Trichloromethyl chloroformate (3.0 g, 14.90 mmol) was dissolved in 10 mL of dichloromethane and stirred for 5 min. . Further, the above mixed solution was added dropwise, and the reaction was stirred for 1 hour under ice bath. The reaction mixture was quenched by the dropwise addition of 50 mL of water, and the solid was separated and evaporated to give the crude title product 2-[4-[(8-bromo-2-keto-2,3-dihydro-1 H - Imidazo[4,5- c ]quinolin-1-yl)phenyl]-2-methyl-propanenitrile 1j (3.40 g, yellow solid).

Step 9 2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl]- 2-methyl-propionitrile

The crude 2-[4-[(8-bromo-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl]-2-yl The base-propanenitrile 1j (3.40 g, 8.30 mmol) was dissolved in 80 mL of dichloromethane, and then iodomethane (1.80 g, 12.50 mmol) and tetrabutylammonium bromide (0.13 g, 0.40 mmol). 80 mL of 0.16 M sodium hydroxide solution was added and the reaction was stirred for 12 hours. The extract was separated, and the organic layer was washed with water (30 mL?? Base-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl]-2-methyl-propanenitrile 1k (2.0 g, yellow solid) Purification proceeds directly to the next reaction.

Step 10 1-(5-bromopyridin-2-yl)-3-methyl-urea

Dissolve 5-bromopyridin-2-amine 11 (1.0 g, 5.78 mmol) and N,N -diisopropylethylamine (2.8 mL, 17.34 mmol) in 20 mL of dichloromethane to prepare a mixed solution. Gas (635 mg, 2.14 mmol) was dissolved in 10 mL of dichloromethane, and the mixture was added dropwise over 30 minutes, stirred for 15 minutes, and then methylamine (17.3 mL, 34.68 mmol) was added dropwise, and the reaction was stirred for 48 hours. 100 mL of dichloromethane and 30 mL of water were added, filtered, and the extract was separated, and the organic phase was washed successively with saturated sodium chloride solution (30 mL×2) and water (30 mL×2). The residue was dried over anhydrous sodium sulfate (MgSO4) 1 m (300 mg, yellow solid), yield: 23.0%.

The eleventh step 1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridine]urea

1-(5-Bromo-2-pyridyl)-3-methyl-urea 1m (300 mg, 1.30 mmol), dipentazone diboron (497 mg, 1.96 mmol), 1,1'-bis (two Phenylphosphine)ferrocene]palladium dichloride (30 mg, cat.) and potassium acetate (382 mg, 3.90 mmol) were dissolved in 10 mL of dioxane, and heated to 90 ° C to stir the reaction for 3 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified eluted eluted eluted elut elut elut elut elut elut elut elut 3,2-Dioxaborolane-2-yl)-2-pyridine]urea 1 n (200 mg, yellow solid), yield: 55.0%.

MS m/z (ESI): 278.2 [M+1]

Step 12 1-[5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-3-methyl-urea

1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridine]urea 1n (145 mg, 0.53 mmol), crude 2-[4-[(8-bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazole[4,5- c ]quinoline -1-yl)phenyl]-2-methyl-propanenitrile 1k (200 mg, 0.48 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (20 mg, cat .) and sodium carbonate (151 mg, 1.43 mmol) were dissolved in 12 mL of a mixed solvent of dioxane and water (V/V = 5:1), and the mixture was heated to 110 ° C and stirred for 3 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted ]-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-3-methyl-urea 1 (13 mg, white solid), yield: 5.6%.

MS m/z (ESI): 492.3 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.38 (s, 1H), 8.99 (s, 1H), 8.08 (t, 2H), 7.78 (d, 2H), 7.76 (d, 2H), 7.73 ( d, 1H), 7.32 (d, 1H), 7.03 (s, 1H), 3.61 (s, 3H), 2.75 (d, 3H), 1.85 (s, 6H)

Example 2 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]carbamic acid methyl ester

first step 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

5-Bromopyridin-2-amine 11 (7.99 g, 46 mmol), dipentane diboron (17.60 g, 69 mmol), 1,1'-bis(diphenylphosphino)ferrocene] dichlorination Palladium (1.80 g, 2.30 mmol) and potassium acetate (11.29 g, 115 mmol) were dissolved in 150 mL of ethylene glycol dimethyl ether, and the mixture was heated to 80 ° C and stirred for 12 hours. The reaction mixture was concentrated with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 2a (3.60 g, gray solid). .

Second step 2-[4-[8-(6-Aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -1-yl]phenyl]-2-methyl-propanenitrile

The crude 2-[4-[(8-bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl ]-2-methyl-propionitrile 1k (1.50 g, 3.56 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Pyridyl-2-amine 2a (941 mg, 4.30 mmol) was dissolved in 25 mL of a mixture of dioxane and water (V/V = 4:1), then tetratriphenylphosphine palladium (150 mg, cat) .) and potassium carbonate (983 mg, 7.12 mmol), and the mixture was heated to 90 ° C and stirred for 2 hours. After cooling to room temperature, 20 mL of water was added, and the solid was separated, filtered, and then filtered, washed with ethyl acetate (5 mL × 4) and dried in vacuo to give the crude title product 2-[4-[8-(6-aminopyridine) -3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-methyl- Propionitrile 2b (1.30 g, grey solid), the product was taken to the next step without purification.

third step N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]carbamic acid methyl ester

The crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-1-yl]phenyl]-2-methyl-propanenitrile 2b (80 mg, 0.18 mmol) was dissolved in 20 mL dichloromethane, then triethylamine (56 mg, 0.55 mmol) and chloroformic acid The ester (37 mg, 0.37 mmol) was stirred for 2 hours under ice bath. Add 30 mL of dichloromethane, and wash with saturated sodium carbonate solution (30 mL), saturated ammonium chloride solution (20 mL×2) and saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, purified by preparative HPLC to chromatography eluent systems A resulting residue to give the title product N - [5- [1- [4- (2- cyano-propyl-2-yl) phenyl] Methyl 3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]carbamate 2 (7 Mg, white solid), Yield: 8.0%.

MS m/z (ESI): 493.51 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.31 (s, 1H), 9.1 (s, 1H), 8.30 (s, 1H), 8.10 (d, 1H), 7.95 (d, 1H), 7.89 (d, 2H), 7.85 (d, 1H), 7.76 (d, 2H), 7.60 (d, 1H), 7.07 (s, 1H), 3.69 (s, 3H), 3.62 (s, 3H), 1.83 ( s,6H)

Example 3 2-methyl-2-[4-[3-methyl-2-keto-8-[6-((tetrahydro- 2H -pyran-4-yl)amino)pyridin-3-yl] -2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile

first step 5-bromo- N- (tetrahydro-2 H -pyran-4-yl)pyridin-2-amine

5-Bromopyridin-2-amine 11 (2.0 g, 11.60 mmol), tetrahydropyran-4-one (5.22 g, 52.20 mmol) was dissolved in 35 mL of dichloroethane, and acetonitrile was added in portions. Sodium hydride (11 g, 52.20 mmol) was stirred and stirred for 12 h. The reaction was quenched by the addition of 20 mL of EtOAc (EtOAc) (EtOAc (EtOAc) The title product 5-bromo- N- (tetrahydro- 2H -pyran-4-yl)pyridin-2-amine 3a (2.98 g, white solid).

Second step N- (tetrahydro-2 H -pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl Pyridin-2-amine

5-Bromo- N- (tetrahydro- 2H -pyran-4-yl)pyridin-2-amine 3a (2.98 g, 11.60 mmol), dipentafluorene diboron (3.54 g, 13.92 mmol), 1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (850 mg, 1.16 mmol) and potassium acetate (4.0 g, 40.60 mmol) were dissolved in 80 mL of dioxane and heated to 85 ° C to stir the reaction. 5 hours. Filter cake washed with ethyl acetate (100 mL), washed with diethyl ether (100 mL), and dried in vacuo to give the crude title product N - (tetrahydro -2 H - pyran-4-yl) -5- (4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 3b (3.52 g, mp. Carry out the next reaction.

third step 2-methyl-2-[4-[3-methyl-2-keto-8-[6-((tetrahydro- 2H -pyran-4-yl)amino)pyridin-3-yl] -2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile

N- (tetrahydro-2 H -pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Pyridin-2-amine

3b (60 mg, 0.24 mmol), crude 2-[4-[(8-bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazole[4,5- c ]quina Phenyl-1-yl)phenyl]-2-methyl-propanenitrile 1k (50 mg, 0.12 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (40 mg, 0.024 mmol) and potassium carbonate (50 mg, 0.36 mmol) were dissolved in 6 mL of ethylene glycol dimethyl ether and water (V/V = 1:1) mixed solvent, heated to 110 ° C and stirred for 2 hours. The reaction was further cooled to 87 ° C and the reaction was stirred for 12 hours. After cooling to room temperature, 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue gave the title product 2-methyl-2-[4-[3-methyl-2-keto-8-[6-((tetrahydro- 2H -pyran-4-yl)amine) Pyridin-3-yl]-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile 3 (20 mg, white solid), yield: 33.8 %.

MS m/z (ESI): 519.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.30 (s, 1H), 8.94 (s, 1H), 8.04 (d, 1H), 7.94 (d, 1H), 7.89 (d, 2H), 7.84 (d, 1H), 7.74 (d, 2H), 7.33 (d, 1H), 6.95 (d, 1H), 6.81 (d, 1H), 3.93 (s, 1H), 3.87-3.89 (m, 3H), 3.61(s,3H), 3.37-3.40(m,3H), 1.86(s,6H),1.42-1.45(m,2H)

Example 4 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]aminocarboxylic acid (tetrahydrofuran-3-ol) ester

In an ice bath, triphosgene (40 mg, 0.06 mmol) was dissolved in 3 mL of dichloromethane, and 2 mL of crude 2-[4-[8-(6-aminopyridin-3-yl)-3- Methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile 2b (50 mg, 0.12 Methyl) and N,N -diisopropylethylamine (50 mg, 0.35 mmol) in dichloromethane, stirred for 30 minutes, then 2 mL of dichlorofuran-3-ol (50 mg, 0.23 mmol) The methane solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product N - [5- [1- [4- (2- cyano-propyl-2-yl) phenyl] 3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5-c]quinolin-8-yl]pyridin-2-yl]carbamic acid (tetrahydrofuran-3- Alcohol) ester 4 (10 mg, white solid), yield: 15.8%.

MS m/z (ESI): 549.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.30 (s, 1H), 9.1 (s, 1H), 8.28 (s, 1H), 8.12 (d, 1H), 8.06 (s, 1H), 7.89 (d, 1H), 7.80 (d, 2H), 7.76 (d, 1H), 7.73 (d, 2H), 7.08 (s, 1H), 4.65 (s, 1H), 3.69 (s, 3H), 2.67 ( s, 1H), 2.32 (s, 1H), 2.15-2.25 (m, 2H), 1.90-2.05 (m, 2H), 1.83 (s, 6H)

Example 5 1-[5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-3-(pyridin-3-yl)urea

In an ice bath, triphosgene (50 mg, 0.06 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of crude 2-[4-[8-(6-aminopyridin-3-yl)-3- Methyl-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile 2b (50 mg, 0.12 mmol) And a solution of N,N -diisopropylethylamine (0.3 mL, 0.35 mmol) in dichloromethane, stirred for 20 min in ice-cooling, and then 2 mL of dichlorobenzene containing pyridin-3-amine (40 mg, 0.14 mmol) Methane was stirred at room temperature for 12 hours. The residue obtained was purified by EtOAc (EtOAc) (EtOAc) 3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-3-(pyridin-3-yl) Urea 5 (10 mg, white solid), yield: 15.7%.

MS m/z (ESI): 555.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.03 (s, 1H), 8.72 (d, 1H), 8.26 (s, 1H), 8.14 (t, 1H), 8.05 (d, 1H), 7.98 (d, 1H), 7.93 (d, 2H), 7.77 (t, 2H), 7.70 (d, 1H), 7.38 (t, 1H), 7.25 (s, 2H), 7.10 (d, 1H), 6.67 ( s, 2H), 3.63 (s, 3H), 1.87 (s, 3H), 1.83 (s, 3H)

Example 6 3-[5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-1-methyl-1-(tetrahydro-2 H -pyran-4-yl)urea

In an ice bath, triphosgene (30 mg, 0.06 mmol) was dissolved in 3 mL of dichloromethane, and 2 mL of crude 2-[4-[8-(6-aminopyridin-3-yl)-3- Methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile 2b (50 mg, 0.12 Add a solution of N,N -diisopropylethylamine (45 mg, 0.35 mmol) in methylene chloride, stir on ice for 30 min, then add 2 mL of N -methyltetrahydropyran-4-amine 6a (30 mg, 0.25 mmol) of dichloromethane was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj -3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-1-methyl-1-( Tetrahydro- 2H -pyran-4-yl)urea 6 (12 mg, white solid), yield: 18.5%.

MS m/z (ESI): 576.61 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.27 (s, 1H), 9.00 (s, 1H), 8.32 (s, 1H), 8.09 (d, 1H), 8.06 (s, 1H), 7.95 (d, 1H), 7.88 (d, 2H), 7.82 (d, 1H), 7.76 (d, 2H), 7.09 (s, 1H), 3.85-3.95 (m, 1H), 3.61 (s, 3H), 3.35-3.40 (m, 2H), 3.0-3.10 (m, 4H), 2.85 (s, 3H), 1.98-2.02 (m, 2H), 1.83 (s, 6H)

Example 7 1-[5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-3-(2-hydroxyethyl)urea

first step 2-(t-butyl(dimethyl)indenyl)oxyethylamine

2-Aminoethanol 7a (3.0 g, 49.50 mmol), triethylamine (10.5 mL, 74.30 mmol) and 4-dimethylaminopyridine (60 mg, cat.) were dissolved in 70 mL dichloromethane. Dimethyl tert-butylchlorodecane (8.10 g, 54.20 mmol) was stirred for 12 hours. Add 50 mL of dichloromethane, extract with saturated ammonium chloride solution (30 mL×3), wash with water (20 mL×2), saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure to give the title compound (2-(t-butyl(dimethyl) decyl) oxyethylamine 7b (8.50 g, brown liquid).

Second step 1-[2-((Tertiary butyldimethylmethyl)oxy)ethyl]-3-[5-[1-[4-(2-cyanopropyl-2-yl)phenyl] -3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]urea

In an ice bath, triphosgene (50 mg, 0.07 mmol) was dissolved in 3 mL of dichloromethane, and 2 mL of crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl was added. Benz-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile 2b (50 mg, 0.12 mmol And a solution of N,N -diisopropylethylamine (45 mg, 0.35 mmol) in dichloromethane, stirred in ice-bath for 30 min, and then added 2 mL of 2-(t-butyl(dimethyl) fluorenyl group Oxyethylamine 7b (60 mg, 0.35 mmol) in dichloromethane was stirred at room temperature and stirred for 12 hr. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjj [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 -c]quinoline-8-yl]pyridin-2-yl]urea 7c (30 mg, white solid), yield: 40.0%.

third step 1-[5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-3-(2-hydroxyethyl)urea

1-[2-((Tertiary butyldimethylmethyl)oxy)ethyl]-3-[5-[1-[4-(2-cyanopropyl-2-yl)phenyl) ]-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]urea 7c (30 mg, 0.05 Methyl acetate was dissolved in 8 mL of tetrahydrofuran, tetrabutylammonium fluoride (30 mg, 0.10 mmol) was added, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue obtained gave the title product 1-[5-[1-[4-(2-cyanopropyl-2-yl)phenyl]-3-methyl-keto-2,3-dihydro-1 H -Imidazole [4,5- c ]quinolin-8-yl]pyridin-2-yl]-3-(2-hydroxyethyl)urea 7 (10 mg, pale yellow solid), yield: 38.4%.

MS m/z (ESI): 522.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.01 (s, 1H), 8.12 (s, 1H), 8.10 (d, 2H), 7.89 (d, 2H), 7.75 (d, 2H), 7.72 (d, 2H), 7.08 (s, 1H), 3.66 (s, 3H), 3.62-3.65 (m, 2H), 3.22 (s, 2H), 1.84 (s, 6H)

Example 8 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-4-methyl-piperazine-1-carboxamide

In an ice bath, triphosgene (34 mg, 0.12 mmol) was dissolved in 5 mL of dichloromethane, and 5 mL of crude 2-[4-[8-(6-aminopyridin-3-yl)-3- Methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile 2b (100 mg, 0.23 Methyl acetate solution of N,N -diisopropylethylamine (90 mg, 0.69 mmol), stirred in ice-bath for 30 min, then added 4-methylpiperazine 8a (30 mg, 0.28 mmol), liter The reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product N - [5- [1- [4- (2- cyano-propyl-2-yl) phenyl] -3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-4-methyl-piperazine -1-carboxamide 8 (7 mg, pale yellow solid), yield: 5.4%.

MS m/z (ESI): 559.62 [M-1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.13 (s, 1H), 7.43-7.31 (m, 4H), 7.10-7.08 (m, 3H), 6.90-6.88 (m, 2H), 6.40 ( s, 1H), 2.93-2.90 (m, 7H), 2.12-2.08 (m, 7H), 1.05 (s, 6H)

Example 9 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-1-methyl-piperidine-4-carboxamide

Dissolve 1-methylpiperidine-4-carboxylic acid 9a (250 mg, 1.75 mmol) in 10 mL of dichloromethane, add hydrazine chloride (555 mg, 4.38 mmol), and add 2 drops of N,N - Dimethylcarbamide was stirred and reacted for 1 hour. The reaction mixture was concentrated under reduced pressure to give a white solid, 10 mL of methylene chloride to give a suspension, was added N, N - diisopropylethylamine (338 mg, 2.62 mmol), stirred for 10 minutes. Add the above suspension to 5 mL of crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H A solution of imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile 2b (80 mg, 0.18 mmol) in dichloromethane. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product N - [5- [1- [4- (2- cyano-propyl-2-yl) phenyl] -3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-1-methyl-piperidine -4-carboxamide 9 (15 mg, pale yellow solid), yield: 17.8%.

MS m/z (ESI): 560.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.67 (s, 1H), 9.02 (s, 1H), 8.34 (s, 1H), 8.12 (t, 2H), 7.96 (d, 1H), 7.87 (d, 2H), 7.76 (d, 2H), 7.65 (d, 1H), 7.10 (s, 1H), 3.62 (s, 3H), 2.70-2.90 (m, 4H), 2.55-2.69 (m, 4H) ), 2.33 (s, 1H), 1.90-2.00 (m, 3H), 1.83 (s, 6H)

Example 10 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-2-morpholine-acetamide

first step 2-Chloro- N- [5-[1-[4-(2-cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quinolin-8-yl]pyridin-2-yl]acetamide

The crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-1-yl]phenyl]-2-methyl-propanenitrile 2b (400 mg, 0.92 mmol) was dissolved in 20 mL of dichloromethane. EtOAc was evaporated. 1.10 mmol), the reaction was stirred for 1 hour, and the reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to give the title product crude 2-chloro - phenyl] -3-methyl-2-yl [5- [1- [4- (2-cyano-propyl-2-yl) - N -2,3-Dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]acetamide 10a (150 mg, m. Go directly to the next step.

MS m/z (ESI): 511.1 [M+1]

Second step N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-2-morpholine-acetamide

The crude 2-chloro- N- [5-[1-[4-(2-cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro- 1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]acetamide 10a (150 mg, 0.29 mmol), morpholine (0.35 mL, 0.88 mmol) and potassium carbonate (300) Mg, 1.47 mmol) was dissolved in 15 mL of acetonitrile and heated to 60 ° C to stir the reaction for 12 hours. Filtered, and the filtrate was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product N - [5- [1- [4- (2- cyano-propyl-2-yl) phenyl ]-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5-c]quinolin-8-yl]pyridin-2-yl]-2-morpholine-B Indoleamine 10 (20 mg, slightly yellow solid), yield: 12.2%.

MS m/z (ESI): 562.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.05 (s, 1H), 9.02 (s, 1H), 8.13 (s, 1H), 8.11 (d, 2H), 7.89 (d, 2H), 7.76 (d, 2H), 7.72 (d, 2H), 7.08 (s, 1H), 3.62-3.65 (m, 4H), 3.22 (s, 2H), 2.67 (s, 2H), 2.33 (s, 3H), 1.98-2.01 (m, 2H), 1.84 (s, 6H)

Example 11 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-2,2,2-trifluoro-acetamide

The crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-1-yl]phenyl]-2-methyl-propanenitrile 2b (50 mg, 0.11 mmol) was dissolved in 3 mL dichloromethane, triethylamine (167 mg, 0.17 mmol) and (2, 2,2-Trichloroethenyl) 2,2,2-trifluoroacetate 11a (29 mg, 0.147 mmol) was stirred for 1 hour. After adding 50 mL of water, the extract was separated, and the aqueous layer was extracted with dichloromethane (5 mL×2). The organic phase was combined and washed with saturated sodium chloride (10 mL), dried over anhydrous magnesium sulfate , resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product N - [5- [1- [4- (2- cyano-propyl-2-yl) phenyl] -3-methyl -2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-2,2,2-trifluoro-acetamide 11 (10 mg, white solid), yield: 17.2%.

MS m/z (ESI): 531.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.04 (s, 1H), 8.49 (s, 1H), 8.13 - 7.97 (m, 1H), 7.89-7.87 (m, 4H), 7.77-7.74 (m, 3H), 7.13 (s, 1H), 4.10 (s, 3H), 1.83 (s, 6H)

Example 12 2-methyl-2-[4-[3-methyl-2-keto-8-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2,3-dihydro -1 H -imidazo[4,5-c]quinolin-1-yl]phenyl]propanenitrile

first step (5-bromopyridin-2-yl)methyl methanesulfonate

5-bromopyridin-2-ol 12a (1.50 g, 2.80 mmol) was dissolved in 10 mL of dichloromethane under ice-bath, triethylamine (0.56 g, 5.60 mmol) was added, and methanesulfonyl chloride (0.49) was added dropwise. g, 4.30 mmol), stirred at room temperature for 1 hour. 20 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL×3). The title product was obtained as crude (5-bromopyridin-2-yl)methanesulfonate 12b (1.53 g, oily liquid).

Second step 5-bromo-2-((tetrahydrofuran-3-yl)oxy)pyridine

The crude (5-bromopyridin-2-yl) ester methanesulfonate 12b (1.53 g, 6 mmol) was dissolved in 20 mL of acetonitrile and potassium carbonate (1.66 g, 12 mmol) and tetrahydrofuran-3-ol (0.53) g, 6 mmol), heated to 75 ° C and stirred for 12 hours. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Pyridine 12c (1.05 g, yellow solid), yield: 71.0%.

third step 2-((tetrahydrofuran-3-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

5-Bromo-2-((tetrahydrofuran-3-yl)oxy)pyridine 12c (600 mg, 2.46 mmol), dipentane diboron (750 mg, 2.95 mmol), 1,1'-bis(diphenyl) Phosphine) ferrocene] palladium dichloride (183 mg, 0.25 mmol) and potassium acetate (482 mg, 4.92 mmol) were dissolved in 10 mL of dioxane, and heated to 115 ° C to stir the reaction for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. -((tetrahydrofuran-3-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 12d ( 1.0 g, yellow liquid), the product was directly subjected to the next reaction without purification.

the fourth step 2-methyl-2-[4-[3-methyl-2-keto-8-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2,3-dihydro -1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile

The crude 2-[4-[(8-bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl ]-2-methyl-propionitrile 1k (500 mg, 2.30 mmol), 2-((tetrahydrofuran-3-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyridine 12d (1.0 g, 3.40 mmol) was dissolved in 10 mL of a mixed solvent of dioxane and water (V/V = 5:1), then added four Triphenylphosphine palladium (258 mg, cat.) and sodium carbonate (500 mg, 4.60 mmol) were heated to 90 ° C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The resulting residue was purified to give the title product 2-methyl-2-[4-[3-methyl-2-keto-8-(6-((tetrahydrofuran-3-yl)oxy)pyridine- 3-yl)-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile 12 (100 mg, white solid), yield: 11.5%.

MS m/z (ESI): 506.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.00 (s, 1H), 8.12-8.08 (m, 2H), 7.90-7.88 (m, 3H), 7.76-7.68 (m, 3H), 7.03 ( s, 1H), 6.83 (d, 1H), 3.94-3.77 (m, 5H), 3.62 (s, 3H), 2.27-2.22 (m, 1H), 1.86 (s, 6H)

Example 13 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]tetrahydro-2 H -pyran-4-carboxamide

first step Tetrahydro-2 H -pyran-4-methyl fluorene chloride

In an ice bath, tetrahydro-2 H -pyran-4-carboxylate 13a (300 mg, 2.08 mmol) was dissolved in 10 mL of ethanol, and lithium hydroxide monohydrate (180 mg, 4.17 mmol) was added. The reaction was stirred at room temperature for 12 hours. The pH was adjusted to 2 with 10% aqueous EtOAc (EtOAc)EtOAc. The obtained residue was dissolved in 10 mL of tetrahydrofuran, and then dichloromethane (800 mg, 6.25 mmol) and 2 dropwise of N,N -dimethylformamide were added , and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give tetrahydro- 2H -pyran-4-methylindole chloride 13b.

Second step N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5-c]quinoline-8-yl]pyridin-2-yl]tetrahydro-2 H -pyran-4-carboxamide

The crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-1-yl]phenyl]-2-methyl-propanenitrile 2b (80 mg, 0.18 mmol) was dissolved in 3 mL of dichloromethane and then added N,N -diisopropylethylamine (800 mg, 6.25 (mmol), the ice bath was lowered to 0 ° C, tetrahydro- 2H -pyran-4-methylindole chloride 13b was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product N - [5- [1- [4- (2- cyano-propyl-2-yl) phenyl] -3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5-c]quinolin-8-yl]pyridin-2-yl]tetrahydro-2 H -pyran -4-carboxamide 13 (10 mg, white solid), yield: 10.0%.

MS m/z (ESI): 547.57 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.07 (s, 1H), 8.49 (s, 1H), 8. 875 (d, 1H), 8. 035 (d, 1H), 7.94 (d, 1H), 7. (d, 2H), 7.78 (d, 2H), 7.49 (d, 1H), 7.18 (s, 1H), 3.84 (d, 4H), 3.64 (s, 3H), 3.22 (t, 4H), 2.82 2.91 (m, 1H), 1.79 (s, 6H).

Example 14 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]pyridine-4-carboxamide

first step N- (5-bromopyridin-2-yl)pyridine-4-carboxamide

Pyridine-4-carboxylic acid (1.60 g, 13 mmol) was dissolved in 20 mL of dichloromethane and dichloromethane (3. The reaction mixture was concentrated under reduced pressure, 20 mL of dichloromethane was added 5-bromo-2-amine 11 (2.25 g, 13 mmol) and N, N - diisopropylethylamine (4.98 g, 39 mmol), The reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The residue, to give the title product N - (5- bromo-2-yl) pyridine-4-acyl-amine 14a (3.0 g, white solid), yield: 83.0%.

MS m/z (ESI): 280.0 [M+1]

Second step N- [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyridine-4-carboxamide

N- (5-Bromopyridin-2-yl)pyridine-4-carboxamide 14a (1.02 g, 3.67 mmol), dipentane diboron (1.40 g, 5.50 mmol), 1,1'-bis (two Phenylphosphine)ferrocene]palladium dichloride (268 mg, 0.37 mmol) and potassium acetate (720 mg, 7.34 mmol) were dissolved in 10 mL of ethylene glycol glycol dimethyl ether and heated to 80 ° C to stir the reaction 2 hour. Filtered, and the filtrate was concentrated under reduced pressure, by silica gel column chromatography and the obtained residue was purified B eluent system, to give the title product N - [5- (4,4,5,5- tetramethyl-1,3,2 - dioxaborolan-2-yl)pyridin-2-yl]pyridine-4-carboxamide 14b (720 mg, red oil), yield: 64.9%.

third step N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]pyridine-4-carboxamide

The crude 2-[4-[(8-bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl ]-2-methyl-propionitrile 1k (60 mg, 0.14 mmol), N- [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-yl)pyridin-2-yl]pyridine-4-carboxamide 14b (91 mg, 0.28 mmol), tetrakistriphenylphosphine palladium (6 mg, cat.) and potassium carbonate (48 mg, 0.35 mmol) Dissolved in 4 mL of a mixed solvent of dioxane and water (V/V = 4:1), and heated to 90 ° C to stir the reaction for 4 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product N - [5- [1- [4- (2- cyano-propyl-2-yl) phenyl] -3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]pyridine-4-carboxamide 14 (26 mg, white solid), Yield: 34.6%.

MS m/z (ESI): 540.4 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.00 (d, 2H), 8.86-8.84 (m, 2H), 8.39 (d, 1H), 8.28-8.22 (m, 3H), 7.82-7.80 (m, 4H), 7.76-7.74 (m, 1H), 7.64-7.62 (m, 2H), 3.72 (s, 3H), 1.88 (s, 6H)

Example 15 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]cyclopropamylamine

The crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-1-yl]phenyl]-2-methyl-propanenitrile 2b (50 mg, 0.16 mmol) was dissolved in 2 mL of dichloromethane and pyridine (18 mg, 0.23 mmol) (15 mg, 0.14 mmol), the reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product N - [5- [1- [4- (2- cyano-propyl-2-yl) phenyl] -3-Methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]cyclopropanoinamide 15 (11 Mg, white solid), Yield: 19.3%.

MS m/z (ESI): 503.4 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.82 (s, 1H), 8.21-8.18 (m, 3H), 7.80-7.78 (m, 3H), 7.62-7.60 (m, 3H), 7.22 (s, 1H), 3.71 (s, 3H), 1.87 (s, 6H), 1.62-1.90 (m, 1H), 1.14-1.12 (m, 2H), 0.94-0.92 (m, 2H)

Example 16 1-[5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-3-(tetrahydrofuran-3-yl)-urea

first step (tetrahydrofuran-3-yl) mesylate

Tetrahydrofuran-3-ol 16a (2.0 g, 22.73 mmol) was dissolved in 50 mL of dichloromethane under ice-water bath, triethylamine (4.8 mL, 34 mmol) was added, and methanesulfonium chloride (2.88 g, 25) was added dropwise. (mmol), the reaction was stirred at room temperature for 12 hours. The reaction mixture was poured into 100 mL of water, and the mixture was evaporated, evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The product was directly subjected to the next reaction without purification.

Second step 3-azido-tetrahydrofuran

The crude methanesulfonic acid (tetrahydrofuran-3-yl) ester 16b (1.56 g, 10 mmol) was dissolved in 10 mL of N,N -dimethylformamide and sodium azide (2.0 g, 30 mmol) was added. Heat to 100 ° C and stir for 4 hours. After adding 100 mL of ethyl acetate, it was washed with sodium bisulfite (100 mL × 2), dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated to give the title product crude product 3-azide-tetrahydrofuran 16c (730 mg, colorless oil The product was directly subjected to the next reaction without purification.

third step Tetrahydrofuran-3-amine

The crude 3-azido-tetrahydrofuran 16c (730 mg, 7.09 mmol) was dissolved in 10 mL of ethanol, and then palladium/carbon (73 mg, 10%) was added, and the mixture was replaced with hydrogen three times, and the reaction was stirred for 12 hours. Filtration and concentrating of the filtrate under reduced pressure afforded titled crude product THF (THF: EtOAc, EtOAc:

the fourth step 1-[5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-3-(tetrahydrofuran-3-yl)-urea

Under ice bath, the crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4, 5- c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile 2b (200 mg, 0.46 mmol) was dissolved in 20 mL of dichloromethane and N,N -diisopropylethylamine was added. (178 mg, 1.38 mmol), stir the reaction for 5 minutes, add triphosgene (69 mg, 0.23 mmol), stir for 40 minutes, then add tetrahydrofuran-3-amine 16d (80 mg, 0.92 mmol), and warm to room temperature. 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj -3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-3-(tetrahydrofuran-3- -urea 16 (20 mg, white solid), yield: 8.0%.

MS m/z (ESI): 548.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.443 (d, 1H), 8.860 (s, 1H), 8.274-8.230 (m, 2H), 7.782-7.785 (m, 4H), 7.660 (d, 2H) , 7.490 (m1H), 7.304 (s, 1H), 6.822 (d, 1H), 4.619-4.604 (m, 2H), 4.265-4.253 (m, 1H), 4.072-3.995 (m, 2H), 3.929-3.914 (m, 1H), 3.839-3.830 (m, 1H), 3.750 (s, 3H), 1.884 (s, 6H)

Example 17 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]carboxamide

first step N- (5-bromopyridin-2-yl)carhamamine

Under ice water, formic acid (9.20 g, 0.20 mol) was added to the reaction flask, and 5-bromopyridin-2-amine 11 (3.46 g, 0.02 mol) was added in portions, the reaction was stirred for 30 minutes, and acetic anhydride (3.10 g) was further added. , 0.03 mol), and the reaction was stirred at room temperature for 12 hours. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (50 mL×5). The organic phase was combined and washed with saturated sodium hydrogen carbonate (50 mL×3) and saturated sodium chloride solution (50 mL) dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product N - (5- bromo-2-yl) methyl Amides 17a (2.80 g, white solid) was used without purification in the next step.

MS m/z (ESI): 203.1 [M+1]

Second step N -[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carboxamide

Crude N- (5-bromopyridin-2-yl)carhamamine 17a (2.80 g, 14 mmol), dipentane diboron (5.33 g, 21 mmol), 1,1'-bis(diphenylphosphine) ) Ferrocene] palladium dichloride (572 mg, 0.70 mmol) and potassium acetate (3.43 g, 35 mmol) were dissolved in 20 mL of ethylene glycol glycol dimethyl ether, and heated to reflux for 1.5 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, by silica gel column chromatography using eluent A purification system resulting residue, to give the title product N - [5- (4,4,5,5- tetramethyl-1 , 3,2-Dioxaborolan-2-yl)pyridin-2-yl]carboxamide 17b (2.70 g, white solid), yield: 77.8%.

MS m/z (ESI): 249.2 [M+1]

third step N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]carboxamide

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl] -2-methyl-propionitrile 1k (60 mg, 0.14 mmol), N- [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-2-pyridyl]carzamide 17b (71 mg, 0.28 mmol), tetrakistriphenylphosphine palladium (6 mg, cat.) and potassium carbonate (48 mg, 0.35 mmol) dissolved in 2.5 mL dioxins In a mixed solvent of an alkane and water (V/V = 4:1), the mixture was heated to 80 ° C and stirred for 1 hour. Cooled to room temperature, the precipitated solid was filtered, the filter cake was dissolved in methanol and purified by thin layer chromatography developing solvent system A to give the title product N - [5- [1- [4- (2- cyanopropyl - 2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]- Indoleamine 17 (21 mg, white solid), yield: 32.8%.

MS m/z (ESI): 463.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.73 (s, 1H), 9.1 (s, 1H), 8.18-8.10 (m, 3H), 7.89-7.87 (m, 3H), 7.75-7.73 (m, 3H), 7.08 (d, 1H), 3.61 (s, 3H), 1.84 (m, 6H)

Example 18 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-2-methoxy-acetamide

The crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-1-yl]phenyl]-2-methyl-propanenitrile 2b (87 mg, 0.20 mmol) was dissolved in 5 mL dichloromethane, pyridine (32 mg, 0.40 mmol) and 2-methoxy - Ethyl chloride (33 mg, 0.30 mmol), stirred for 2.5 hours. After completion of the reaction, the solid was precipitated, filtered, and the cake was purified by silica gel chromatography to afford the title product N- [5-[1-[4-(2-cyanopropyl-2-yl)phenyl ]-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-2-methoxy- Acetamide 18 (62 mg, white solid), yield: 61.3%.

MS m/z (ESI): 507.4 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.82 (s, 1H), 8.27-8.20 (m, 3H), 7.81-7.79 (m, 3H), 7.63-7.61 (m, 3H), 7.01 (s, 1H), 4.06 (s, 2H), 3.72 (s, 3H), 3.35 (s, 3H), 1.87 (s, 6H)

Example 19 (5-(3-Methyl-1-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-2-one-2,3-dihydro-1 H -imidazole [4 ,5- c ]methyl quinoline-8-yl)pyridin-2-yl)carbamate

first step 6-bromo- N- [2-methyl-6-(trifluoromethyl)pyridin-3-yl]-3-nitroquinolin-4-amine

The crude 6-bromo-4-chloro-3-nitro-quinoline 1d (1.50 g, 5.22 mmol) was dissolved in 20 mL of glacial acetic acid and 2-methyl-6-(trifluoromethyl)pyridine was added with stirring. 3-Amine 19a (1 g, 5.68 mmol) was stirred for 2 h. The reaction mixture was poured into 40 mL of water, stirred for 30 minutes, filtered, and the filter cake was dissolved in 100 mL of dichloromethane, washed with saturated sodium hydrogen carbonate solution (30 mL), and the mixture was separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure afforded crude title compound 6-bromo- N- [2-methyl-6-(trifluoromethyl)pyridin-3-yl]-3-nitroquinolin-4-amine 19b ( 1.78 g, brown solid), product was taken to the next step without purification.

Second step 6-Bromo- N ⁴ -[2-methyl-6-(trifluoromethyl)pyridin-3-yl]quinoline-3,4-diamine

The crude 6-bromo- N- [2-methyl-6-(trifluoromethyl)pyridin-3-yl]-3-nitroquinolin-4-amine 19b (1.78 g, 4.17 mmol) was dissolved in 20 To a mixed solvent of mL ethanol and tetrahydrofuran (V/V = 1:1), iron powder (1.16 g, 20.80 mmol) and ammonium chloride (111 mg, 2.08 mmol) were added, and the reaction was stirred for 12 hours. Filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N ⁴ - [2- methyl-6- (trifluoromethyl) pyridin-3-yl] quinoline-3,4-diamine 19c (1.63 g, brown solid), the product was taken to the next step without purification.

MS m/z (ESI): 399.0 [M+1]

third step 8-bromo-1-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude 6-bromo- N ⁴ -[2-methyl-6-(trifluoromethyl)pyridin-3-yl]quinoline-3,4-diamine 19c (1.63 g, 4.11 mmol) was dissolved in 100 mL Trichloromethane (1 mL, 7.19 mmol) was added to dichloromethane to make a mixed solution. Trichloromethyl chloroformate (1.22 g, 4.11 mmol) was dissolved in 80 mL of dichloromethane, and then The above premixed mixed solution was added dropwise, and the mixture was naturally stirred to room temperature and stirred for 12 hours. The reaction mixture was quenched with aq. EtOAc (EtOAc) (EtOAc) -Bromo-1-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one 19d (1.48 g, brown solid), the product was taken to the next step without purification.

MS m/z (ESI): 422.0 [M+1]

the fourth step 8-bromo-3-methyl-1-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]-1 H -imidazole [4,5- c ]quinoline-2 (3 H )-ketone

The crude 8-bromo-1-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 19d (1.48 g, 3.50 mmol) was dissolved in 150 mL of dichloromethane, iodomethane (0.65 mL, 10.50 mmol) and tetrabutylammonium bromide (0.56 g, 1.75 mmol) were added, and 100 mL of hydrogen was added dropwise with stirring. A solution of sodium oxide (280 mg, 7 mmol) was stirred for 12 hours. Add 100 mL of water, extract the liquid, extract the aqueous phase with dichloromethane (100 mL×3), combine the organic phase, wash with saturated sodium chloride solution (100 mL×2), dry over anhydrous sodium sulfate, filter, filtrate Concentration by pressure gave the title product crude 8-bromo-3-methyl-1-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]-1 H -imidazole [4,5- c ] Quinoline-2( 3H )-one 19e (2.03 g, brown solid).

MS m/z (ESI): 439.2 [M+1]

the fifth step 8-(6-Aminopyridin-3-yl)-3-methyl-1-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-1 H -imidazole [4,5 - c ] quinoline-2(3 H )-one

The crude product was 8-bromo-3-methyl-1-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]-1 H -imidazole [4,5- c ]quinolin-2 ( 3 H )-ketone 19e (1.05 g, 2.40 mmol) was dissolved in 20 mL of N,N-dimethylformamide and added 5-(4,4,5,5-tetramethyl-1,3,2 - dioxaborolan-2-yl)pyridin-2-amine 2a (792 mg, 3.60 mmol), bis(triphenylphosphine)palladium dichloride (84 mg, 0.12 mmol) and potassium carbonate ( 830 mg, 6.00 mmol), and reacted at 100 ° C for 1 hour. The reaction mixture was filtered. EtOAc (3 mL). Concentration under reduced pressure gave the title product as crude---(6-aminopyridin-3-yl)-3-methyl-1-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)- 1H -Imidazo[4,5- c ]quinolin-2( 3H )-one 19f (1.01 g, mp.

MS m/z (ESI): 451.2 [M+1]

Step 6

(5-(3-Methyl-1-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-2-one-2,3-dihydro-1 H -imidazole [4 ,5- c ]methyl quinoline-8-yl)pyridin-2-yl)carbamate

The crude product was 8-(6-aminopyridin-3-yl)-3-methyl-1-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-1 H -imidazole [4 ,5- c ]quinoline-2( 3H )-one 19f (400 mg, 0.89 mmol) was dissolved in 5 mL of dichloromethane, and then triethylamine (180 mg, 1.77 mmol) A solution of methyl chloroformate (92 mg, 0.97 mmol) in methylene chloride (m.hhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh -(3-methyl-1-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-2-one-2,3-dihydro-1 H -imidazole [4,5 - c] quinolin-8-yl) pyridin-2-yl) methyl amine 19 (10 mg, white solid), yield: 2.2%.

MS m/z (ESI): 510.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.38 (s, 1H), 9.09 (s, 1H), 8.45 (d, 1H), 8.31 (s, 1H), 8.16 (t, 2H), 7.96 (d, 1H), 7.85 (d, 1H), 7.65 (d, 1H), 6.91 (s, 1H), 3.70 (s, 3H), 3.65 (s, 3H), 2.44 (s, 3H)

Example 20 2-methyl-2-[4-[3-methyl-2-keto-8-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-2,3- Dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile

first step 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine

5-Bromopyridin-2-ol 12a (500 mg, 2.87 mmol), potassium carbonate (1.20 g, 8.61 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (800 mg, 3.44 mmol) Dissolved in 15 mL of acetonitrile, heated to reflux and stirred for 3 hours, then cesium carbonate (1.87 g, 5.74 mmol) was added and the reaction was continued for 1 hour. After cooling to room temperature, filtration, the filter cake was washed with ethyl acetate (10 mL×3), and the filtrate was concentrated under reduced pressure. The filter cake was 20 mL of n-hexane and ethyl acetate (V/V = 1:1) The mixed solvent was beaten, filtered, and the filter cake was washed with a mixed solvent of n-hexane and ethyl acetate (V/V = 1:1) (10 mL × 3), and the filtrate was concentrated under reduced pressure to give the crude title product 5-br. 2,2,2-Trifluoroethoxy)pyridine 20a (1.0 g, yellow solid).

Second step 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy) Pyridine

The crude 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine 20a (1.0 g, 4 mmol), dipentane diboron (1.20 g, 4.80 mmol), 1,1'-double (Diphenylphosphine)ferrocene]Palladium dichloride (300 mg, cat.) and potassium acetate (800 mg, 8 mmol) were dissolved in 20 mL of dioxane, and heated to reflux for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjj ,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine 20b (2.0 g, yellow liquid). reaction.

third step 2-methyl-2-[4-[3-methyl-2-keto-8-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-2,3- Dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl] 2-methyl-propionitrile 1k (200 mg, 0.48 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl 2-(2,2,2-trifluoroethoxy)pyridine 20b (216 mg, 0.71 mmol), tetratriphenylphosphine palladium (53 mg, cat.) and sodium carbonate (101 mg, 0.95 mmol) Dissolved in 10 mL of a mixed solvent of dioxane and water (V/V = 5:1), and heated to 90 ° C to stir the reaction for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced vacuo. 6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl] Propionitrile 20 (70 mg, white solid), yield: 28.0%.

MS m/z (ESI): 518.3 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.99 (s, 1H), 8.11-8.09 (m, 2H), 7.87-7.85 (m, 2H), 7.74-7.72 (m, 2H), 7.16- 7.14 (m, 1H), 7.01 (s, 1H), 6.48 (d, 2H), 4.90-4.83 (m, 2H), 3.60 (s, 3H), 1.82 (s, 6H)

Example 21 2-methyl-2-[4-[3-methyl-8-[6-[(1-methylpiperidin-4-yl)oxy]pyridin-3-yl]-2-one-2 ,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile

first step 5-bromo-2-[(1-methylpiperidin-4-yl)oxy]pyridine

Dissolve 5-bromopyridin-2-ol 12a (200 mg, 1.15 mmol) in 15 mL of tetrahydrofuran and add triphenylphosphine (453 mg, 1.73 mmol) and diethyl azodicarboxylate (250 mg, 1.44 mmol) The reaction was stirred for 30 minutes, and a further 5 mL of a solution of 1-methylpiperidin-4-ol (165 mg, 1.44 mmol) in tetrahydrofuran was added and the reaction was continued for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj (190 mg, white solid), yield: 60.0%.

MS m/z (ESI): 273.1 [M+1]

Second step 2-[(1-Methylpiperidin-4-yl)oxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)pyridine

5-Bromo-2-[(1-methylpiperidin-4-yl)oxy]pyridine 21a (200 mg, 0.74 mmol), dipentane diboron (225 mg, 0.89 mmol), 1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride (70 mg, cat.) and potassium acetate (150 mg, 1.50 mmol) were dissolved in 10 mL of dioxane and heated to reflux and stirred for 3 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness crystals. 3,2-Dioxaborolan-2-yl)pyridine 21b (182 mg, black liquid).

third step 2-methyl-2-[4-[3-methyl-8-[6-[(1-methylpiperidin-4-yl)oxy]pyridin-3-yl]-2-one-2 ,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl] 2-methyl-propionitrile 1k (120 mg, 0.29 mmol), crude 2-[(1-methylpiperidin-4-yl)oxy]-5-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborolan-2-yl)pyridine 21b (182 mg, 0.57 mmol), tetrakistriphenylphosphine palladium (50 mg, cat.) and potassium carbonate (120 mg , 0.67 mmol) was dissolved in 6 mL of a mixed solvent of dioxane and water (V/V = 1:1), heated to 120 ° C to stir the reaction for 2 hours, and then cooled to 90 ° C for 12 hours. After cooling to room temperature, 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×2). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography. The residue gave the title product 2-methyl-2-[4-[3-methyl-8-[6-[(1-methylpiperidin-4-yl)oxy]pyridin-3-yl]- 2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile 21 (10 mg, white solid).

MS m/z (ESI): 533.4 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.01 (s, 1H), 8.11 (d, 1H), 8.06 (s, 1H), 7.92 (d, 1H), 7.78 (d, 2H), 7.76 (d, 2H), 7.74 (d, 1H), 7.03 (s, 1H), 6.82 (d, 1H), 3.610 (s, 3H), 3.43-3.44 (m, 1H), 2.73 (s, 3H), 2.17-2.19(m,4H), 2.01-2.10(m,4H),1.85(s,6H)

Example 22 2-[4-[8-[6-(2-methoxyethoxy)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [ 4,5- c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile

first step 2-[(5-bromopyridin-2-yl)oxy]ethanol

Dissolve 5-bromopyridin-2-ol 12a (5.0 g, 28 mmol) in 30 mL of acetonitrile, add cesium carbonate (18.58 g, 57 mmol), and add 2-bromoethanol (2 mL, 28 mmol) dropwise. The reaction was stirred at 80 ° C for 12 hours. The mixture was cooled to room temperature, filtered, EtOAc EtOAc (EtOAc) Bromopyridin-2-yl)oxy]ethanol 22a (5.0 g, colorless oil).

Second step 5-bromo-2-(2-methoxyethoxy)pyridine

The crude 2-[(5-bromopyridin-2-yl)oxy]ethanol 22a (1.0 g, 4.50 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled to 0 ° C, and then sodium hydride (260 mg, 9 mmol) was added, and iodine methane (0.45 mL, 6.80 mmol) was added dropwise, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. 2-methoxyethoxy)pyridine 22b (1.0 g, pale yellow oil).

third step 2-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

The crude 5-bromo-2-(2-methoxyethoxy)pyridine 22b (1.0 g, 4.30 mmol), dipentane diboron (1.27 g, 5 mmol), 1,1'-bis(diphenyl) Phosphine) ferrocene] palladium dichloride (157 mg, cat.) and potassium acetate (1.26 g, 12.90 mmol) were dissolved in 20 mL of dioxane, and heated to reflux for 3 hours. The mixture was cooled to room temperature, filtered, and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, 2-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 22c ( 1.0 g, black liquid), the product was directly subjected to the next reaction without purification.

the fourth step 2-[4-[8-[6-(2-methoxyethoxy)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [ 4,5- c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl] 2-methyl-propionitrile 1k (100 mg, 0.24 mmol), crude 2-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)pyridine 22c (200 mg, 0.36 mmol), tetrakistriphenylphosphine palladium (26 mg, cat.) and sodium carbonate (50 mg, 0.647 mmol) dissolved in 6 mL of a mixed solvent of dioxane and water (V/V = 5:1) was heated to 90 ° C and stirred for 12 hours. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjj Pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-yl Base-propionitrile 22 (30 mg, light brown solid), yield: 8.5%.

MS m/z (ESI): 494.4 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.84 (s, 1H), 8.22 (d, 1H), 8.13 (d, 1H), 7.65 (d, 2H), 7.53 (d, 1H), 7.39 (d) , 1H), 7.19 (s, 1H), 6.84 (d, 1H), 6.61 (d, 1H), 6.19-6.17 (m, 1H), 3.81-3.79 (m, 2H), 3.75 (s, 3H), 3.73-3.71 (m, 2H), 3.49 (s, 3H), 1.90 (s, 6H)

Example 23 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-1 H -pyrazole-3-carboxamide

first step 1 H -pyrazole-3-methylindole chloride

Dissolve 1 H -pyrazole-3-carboxylic acid 23a (300 mg, 2,68 mmol) in 10 mL of dichloromethane, add hydrazine chloride (1020 mg, 8.04 mmol) and 2 drops of N,N -dimethyl Formylamine was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude- 1H -pyrazole-3-carboyl chloride 23b.

Second step N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-1 H -pyrazole-3-carboxamide

The crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-1-yl]phenyl]-2-methyl-propanenitrile 2b (80 mg, 0.18 mmol) was dissolved in 12 mL dichloromethane, triethylamine (1 mL, 7.12 mmol) The crude product 1 H -pyrazole-3-methylindole chloride 23b was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product N - [5- [1- [4- (2- cyano-propyl-2-yl) phenyl] -3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-1 H -pyrazole-3 - Methotrexate 23 (7 mg, white solid), yield: 7.0%.

MS m/z (ESI): 529.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.07 (s, 1H), 8.49 (s, 1H), 8. 875 (d, 1H), 8. 035 (d, 1H), 7.94 (d, 1H), 7. (d, 2H), 7.78 (d, 2H), 7.62 (d, 1H), 7.49 (d, 1H), 7.18 (s, 1H), 6.31 (s, 1H), 3.65 (s, 3H), 1.81 ( s,6H)

Example 24 5-[1-[4-(2-cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c] quinolin-8-yl] - N - (2- methoxyethyl) pyridine-2-Amides

first step 5-bromo- N- (2-methoxyethyl)pyridine-2-carboxamide

Dissolve 5-bromopyridine-2-carboxylic acid 24a (1.0 g, 5 mmol) in 40 mL dichloromethane, add 2-methoxyethylamine (450 mg, 6 mmol), 1-(3-dimethylamino) Propyl)-3-ethylcarbodiimide hydrochloride (1.90 g, 10 mmol) and 1-hydroxybenzotriazole (135 mg, 1 mmol) were stirred for 3 h. The reaction was washed with water (10 mL × 2), saturated sodium chloride solution (10 mL × 2), the organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 5-bromo - N - ( 2-Methoxyethyl)pyridine-2-carboxamide 24b (1.50 g, brown liquid).

Second step N- (2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2- Formamide

The crude 5-bromo- N- (2-methoxyethyl)pyridine-2-carboxamide 24b (1.20 g, 5 mmol), dipentane diboron (1.90 g, 7.50 mmol), 1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride (400 mg, cat.) and potassium acetate (1.0 g, 10 mmol) were dissolved in 40 mL of dioxane, and the mixture was heated to reflux and stirred for 3 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and then mixed with 50 mL of n-hexane and ethyl acetate (V/V = 1:1) mixed solvent, filtered, and the filter cake was n-hexane and ethyl acetate (V/V=1) :1) Washing with a mixed solvent (10 mL × 3), and the filtrate was concentrated under reduced pressure to give the titled crude product N- (2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1 , 3,2-Dioxaborolan-2-yl)pyridine-2-carboxamide 24c (2.0 g, yellow liquid).

third step 5-[1-[4-(2-cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c] quinolin-8-yl] - N - (2- methoxyethyl) pyridine-2-Amides

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl] 2-methyl-propionitrile 1k (200 mg, 0.48 mmol), crude N- (2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2 - dioxaborolan-2-yl)pyridine-2-carboxamide 24c (218 mg, 0.71 mmol), tetrakistriphenylphosphine palladium (53 mg, cat.) and sodium carbonate (100 mg, 0.95 mmol) was dissolved in 12 mL of a mixed solvent of dioxane and water (V/V = 5:1), and the mixture was heated to 90 ° C and stirred for 12 hours. After cooling to room temperature, the mixture was filtered with EtOAc (EtOAc) (EtOAc). -2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl] -N -(2- Methoxyethyl)pyridine-2-carboxamide 24 (80 mg, off-white solid), yield: 32%.

MS m/z (ESI): 521.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.06 (s, 1H), 8.62-8.55 (m, 2H), 8.19-8.16 (m, 1H), 8.04-8.00 (m, 2H), 7.90- 7.88 (m, 3H), 7.78-7.76 (m, 2H), 7.18-7.17 (m, 1H), 3.93-3.92 (m, 2H), 3.63 (s, 3H), 3.50 (s, 3H), 3.33 3.31 (m, 2H), 1.84 (s, 6H)

Example 25 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-propenylamine

The crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-1-yl]phenyl]-2-methyl-propanenitrile 2b (50 mg, 0.12 mmol) was dissolved in 10 mL dichloromethane, triethylamine (0.048 mL, 0.03 mmol) Acetylhydrazine chloride (32 mg, 0.03 mmol) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product N - [5- [1- [4- (2- cyano-propyl-2-yl) phenyl] -3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-propenylamine 25 (20 mg , pale yellow solid), Yield: 36.0%.

MS m/z (ESI): 489.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.02 (s, 1H), 8.38 (s, 1H), 8.22 (d, 1H), 8.13 (d, 1H), 7.97 (d, 1H), 7.89 (d, 2H), 7.76 (d, 2H), 7.68 (d, 1H), 7.12 (s, 1H), 6.61-7.71 (m, 1H), 6.34 (d, 1H), 5.815 (d, 1H), 3.62(s,3H), 1.84(s,6H)

Example 26 3-[5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]-1,1-dimethyl-urea

3-[5-[1-[4-(1-Cyano-1-methyl-ethyl)phenyl]-3-methyl-2-keto-imidazo[4,5- c ]quinoline- 8-yl]-2-pyridyl]-1,1-dimethyl-urea

The crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-1-yl]phenyl]-2-methyl-propanenitrile 2b (60 mg, 0.55 mmol) was dissolved in 15 mL of dichloromethane and N,N -diisopropylethylamine (118 mg, 0.92 (mmol), the ice bath was lowered to 0 ° C, N,N -dimethylformamidine chloride 26a (60 mg, 0.55 mmol) was added dropwise , and the reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj -3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-1,1-dimethyl -urea 26 (10 mg, white solid), yield: 11.0%.

MS m/z (ESI): 505.4 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.28 (s, 1H), 9.26 (s, 1H), 9.00 (s, 1H), 8.11 (d, 1H), 8.07 (s, 1H), 7.90 (t, 3H), 7.75 (d, 2H), 7.68 (d, 1H), 7.05 (s, 1H), 3.62 (s, 3H), 2.95 (s, 6H), 1.84 (s, 6H)

Example 27 2-[4-[8-[6-(Cyanomethoxy)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 - c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile

first step 2-[(5-bromopyridin-2-yl)oxy]acetonitrile

Dissolve 5-bromopyridin-2-ol 12a (100 mg, 0.57 mmol), 2-bromoacetonitrile (85 mg, 0.69 mmol), potassium carbonate (236 mg, 1.71 mmol) and cesium carbonate (556 mg, 1.71 mmol) The reaction was stirred for 12 hours in 5 mL of acetonitrile. Filtration, the filtrate was added to 5 mL of dichloromethane, and then washed with water (20 mL×2), EtOAc (EtOAc) Crude 2-[(5-bromopyridyl) Pyridin-2-yl)oxy]acetonitrile 27a (250 mg, as colorless oil).

Second step 2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy]acetonitrile

The crude 2-[(5-bromopyridin-2-yl)oxy]acetonitrile 27a (250 mg, 1.08 mmol), dipentane diboron (330 mg, 1.30 mmol), 1,1'-bis (diphenyl) Phosphine) ferrocene] palladium dichloride (80 mg, cat.) and potassium acetate (215 mg, 2.16 mmol) were dissolved in 5 mL of dioxane, and heated to reflux for 3 hours. After cooling to room temperature, the reaction mixture was concentrated to dryness crystals crystals crystals -yl)pyridin-2-yl]oxy]acetonitrile 27b (148 mg, EtOAc).

third step 2-[4-[8-[6-(Cyanomethoxy)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 - c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl] 2-methyl-propionitrile 1k (120 mg, 0.29 mmol), crude 2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) Alkan-2-yl)pyridin-2-yl]oxy]acetonitrile 27b (148 mg, 0.57 mmol), tetrakistriphenylphosphine palladium (50 mg, cat.) and potassium carbonate (120 mg, 0.67 mmol) dissolved in 6 mL of a mixed solvent of dioxane and water (V/V = 1:1) was heated to 120 ° C and stirred for 2 hours. After cooling to room temperature, 15 mL of water was added, and ethyl acetate (15 mL×3) was evaporated. The organic phase was combined and dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography. The title product 2-[4-[8-[6-(cyanomethoxy)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [ 4,5- c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile 27 (11 mg, white solid).

MS m/z (ESI): 475.3 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.99 (s, 1H), 8.26 (s, 1H), 8.08 (d, 1H), 7.86 (d, 2H), 7.77 (d, 1H), 7.74 (d, 2H), 7.16 (d, 1H), 6.99 (s, 1H), 6.46 (d, 1H), 5.02 (s, 2H), 3.61 (s, 3H), 1.82 (s, 6H)

Example 28 1-ethyl-3-[5-[3-methyl-1-(4-methylnonylphenyl)-2-keto-2,3-dihydro-1 H -imidazole [4,5- c Quinoline-8-yl]pyridin-2-yl]urea

first step 6-bromo- N- (4-methylnonylphenyl)-3-nitro-quinolin-4-amine

4-Methylmercaptoaniline (357 mg, 2.09 mmol) and crude 6-bromo-4-chloro-3-nitro-quinoline 1d (600 mg, 2.09 mmol) were dissolved in 10 mL glacial acetic acid and stirred. hour. Add 50 mL of water, filter, dissolve the solid in 30 mL of ethyl acetate and 30 mL of saturated sodium bicarbonate solution, extract the liquid, extract the aqueous phase with ethyl acetate (30 mL × 3), combine the organic phase, and saturate The sodium chloride solution was washed (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title product crude product 6-bromo- N- (4-carbamidophenyl)-3-nitro-quine Phenyl-4-amine 28a (470 mg, yellow solid).

MS m/z (ESI): 419.9 [M-1]

Second step 6-bromo- N ⁴ -(4-methylnonylphenyl)quinoline-3,4-diamine

The crude 6-bromo- N- (4-methylnonylphenyl)-3-nitro-quinolin-4-amine 28a (470 mg, 1.11 mmol) was dissolved in 20 mL methanol and THF (V/V=1) :1) In a mixed solvent, Raney nickel (162 mg, 1.89 mmol) was added, and the hydrogen was replaced three times, and the reaction was stirred for 1 hour. Filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N ⁴ - (4- phenyl methyl sulfone-yl) quinoline-3,4-diamine 28b (500 mg, brown solid) was used without further purification Carry out the next reaction.

third step 8-bromo-1-(4-methylindenylphenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

Trichloromethyl chloroformate (339 mg, 1.14 mmol) was dissolved in 10 mL of dichloromethane under ice-bath, and crude 6-bromo- N ⁴ -(4-carbamidophenyl)quinoline-3 was obtained. 4-Diamine 28b (407 mg, 1.04 mmol) and triethylamine (0.17 mL, 1.24 mmol) were dissolved in 20 mL of dichloromethane, and the solution was slowly added dropwise, and the mixture was stirred for 30 minutes under ice bath. 20 mL of water was added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with dichloromethane (20 mL×3). The organic phase was combined and washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate The filtrate was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc) The title product was obtained as crude 8-bromo-1-(4-methylmercaptophenyl)-1 H -imidazo[4,5- c ]quinolin-2( 3H )-one 28c (377 mg, brown solid). The product was directly subjected to the next reaction without purification.

MS m/z (ESI): 419.9 [M+1]

the fourth step 8-bromo-3-methyl-1-(4-methylnonylphenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude 8-bromo-1-(4-methylindenylphenyl)-1 H -imidazo[4,5-c]quinolin-2(3 H )-one 28c (377 mg, 0.90 mmol) was dissolved in 28 To the dichloromethane, tetrabutylammonium bromide (29 mg, 0.09 mmol) and methyl iodide (0.28 mL, 4.50 mmol) were added, and 20 mL of 0.15 M sodium hydroxide solution was added dropwise with stirring, and the reaction was stirred for 1.5 hours. Add 50 mL of water, extract with methylene chloride (50 mL × 3), and combine the organic phase, washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, washed with ethyl (2 mL × 2), to give the crude title product 8-bromo-3-methyl-1- (4-methyl phenyl sulfone-yl) -1 H - imidazo [4,5- c] quinolin-2 ( 3H )-one 28d (200 mg, brown solid).

MS m/z (ESI): 432.0 [M+1]

the fifth step 1-(5-bromopyridin-2-yl)-3-ethyl-urea

5-Bromopyridin-2-amine 11 (1.0 g, 5.78 mmol) was dissolved in 5 mL of chloroform, ethyl isocyanate (0.43 g, 6.07 mmol) was added, and the mixture was stirred at 110 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjj -yl)-3-ethyl-urea 28e (1.10 g, off-white solid).

MS m/z (ESI): 246.31 [M+1]

Step 6 1-ethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]urea

The crude 1-(5-bromopyridin-2-yl)-3-ethyl-urea 28e (0.94 g, 3.85 mmol), dipentane diboron (1.17 g, 4.62 mmol), 1,1'-bis ( Diphenylphosphine)ferrocene]palladium dichloride (281 mg, 0.39 mmol) and potassium acetate (754 mg, 7.70 mmol) were dissolved in 8 mL of ethylene glycol glycol dimethyl ether and heated to 80 ° C for stirring. Reaction for 2 hours. Filtration, washing with 5 mL of water and 10 mL of ethyl acetate, extracting and separating, the organic phase was washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Chromatography The residue obtained was purified using eluent B to give the title product 1-ethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxabor Cyclopentane-2-yl)pyridin-2-yl]urea 28f (230 mg, yellow powder), yield: 20.5%.

MS m/z (ESI): 292.31 [M+1]

Seventh step 1-ethyl-3-[5-[3-methyl-1-(4-methylnonylphenyl)-2-keto-2,3-dihydro-1 H -imidazole [4,5- c Quinoline-8-yl]pyridin-2-yl]urea

Crude 8-bromo-3-methyl-1-(4-methylsulfonylphenyl)imidazo[4,5- c ]quinolin-2-one 28d (40 mg, 0.10 mmol), 1-ethyl -3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]urea 28f (32 mg, 0.11 mmol), tetrakistriphenylphosphine palladium (5.30 mg, cat.) and sodium carbonate (19.60 mg, 0.19 mmol) were dissolved in 2.5 mL of a mixture of dioxane and water (V/V = 4:1) and heated. The reaction was stirred at reflux for 3 hours. Add 10 mL of water, and extract with ethyl acetate (10 mL×3). The organic phase is combined and washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous magnesium sulfate Chromatography of the residue obtained from EtOAc EtOAc (EtOAc: EtOAc: 3-Dihydro- 1H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]urea 28 (7 mg, white solid), yield: 12.2%.

MS m/z (ESI): 517.1 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.29 (s, 1H), 9.03 (s, 1H), 8.28 (d, 2H), 8.12 (d, 2H), 8.00 (d, 2H), 7.71 (d, 1H), 7.39 (d, 1H), 7.07 (d, 1H), 3.62 (s, 3H), 3.38 (s, 3H), 3.18-3.20 (m, 2H), 1.16 (t, 3H)

Example 29 5-[1-[4-(2-cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c] quinolin-8-yl] - N - (1- methyl-piperidin-4-yl) pyridine-2-Amides

first step (1-methylpiperidin-4-yl)carbamic acid tert-butyl ester

Piperidine-4-aminocarbamic acid tert-butyl ester 29a (1.06 g, 5.30 mmol), formaldehyde (0.61 g, 7.55 mmol), sodium acetoxyborohydride (2.20 g, 10 mmol) dissolved in 20 mL of dichloro Ethane was stirred for 12 hours. The reaction mixture was added with 50 mL of water and 50 mL of EtOAc. EtOAc. The third butyl formate 29b (1.0 g, white solid) was taken directly to the next step without purification.

Second step 1-methylpiperidin-4-amine trifluoroacetate

The crude (1-methylpiperidin-4-yl)carbamic acid tert-butyl ester 29b (1.0 g, 4.67 mmol) was dissolved in 20 mL of dichloromethane, and then 20 mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. The reaction mixture was concentrated to dryness crystals crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

third step 5-bromo- N- (1-methylpiperidin-4-yl)pyridinium

The crude 1-methylpiperidin-4-amine trifluoroacetate 29c (0.60 g, 4.67 mmol) was dissolved in 20 mL dichloromethane, then 5-bromopicamic acid (420 mg, 7 mmol), 1- (3) -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (500 g, 7 mmol), 1-hydroxybenzotriazole (110 mg, 2.24 mmol) and N,N-diiso Propylethylamine (680 mg, 14 mmol) was stirred for 12 hours. The reaction solution was added 20mL of water, extracted with dichloromethane (20 mL × 2), organic phases were combined, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 5-bromo - N - (1- methylpiperidin Pyridin-4-yl)pyridinamide 29d (0.83 g, yellow liquid).

the fourth step N- (1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 2-carbamamine

The crude 5-bromo- N- (1-methylpiperidin-4-yl)pyridinium 29d (830 mg, 2.79 mmol), dipentane diboron (1.06 g, 4.18 mmol), 1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, cat.) and potassium acetate (820 mg, 8.37 mmol) were dissolved in 40 mL of dioxane, and the mixture was heated to 90 ° C and stirred for 12 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure to give the crude title product N - (1- methyl-piperidin-4-yl) -5- (4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)pyridine-2-carboxamide 29e (600 mg, black liquid).

the fifth step 5-[1-[4-(2-cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c] quinolin-8-yl] - N - (1- methyl-piperidin-4-yl) pyridine-2-Amides

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl] 2-methyl-propionitrile 1k (100 mg, 0.23 mmol), N- (1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyridine-2-carboxamide 29e (100 mg, 0.30 mmol), tetrakistriphenylphosphine palladium (13 mg, cat.) and potassium carbonate (98) Mg, 0.70 mmol) was dissolved in 3 mL of a mixed solvent of dioxane and water (V/V = 2:1), and heated to 125 ° C to stir the reaction for 4 hours. The reaction mixture was concentrated under reduced pressure and purified tolulululululu 2-keto-2,3-dihydro -1 H - imidazo [4,5- c] quinolin-8-yl] - N - (1- methyl-piperidin-4-yl) pyridine-2- Indole 29 (30 mg, colorless oil), yield: 38.0%.

MS m/z (ESI): 560.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.17 (s, 1H), 8.72 (d, 1H), 8.6 (d, 1H), 8.23 (d, 1H), 8.12 (d, 1H), 8.09 (d, 1H), 8.00 (d, 1H), 7.92-7.86 (m, 2H), 7.83-7.76 (m, 3H), 3.65 (s, 1H), 3.52-3.44 (m, 2H), 3.43-3.19 (m, 1H), 3.19-3.05 (m, 2H), 2.84-2.76 (m, 3H), 2.08-1.97 (m, 3H), 1.96-1.79 (m, 9H)

Example 30 2-[4-[8-[6-(difluoromethoxy)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 - c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile

first step 5-bromo-2-(difluoromethoxy)pyridine

5-Bromopyridin-2-ol 12a (300 mg, 0.57 mmol), difluoroiodomethane (0.4 mL, 5.17 mmol), potassium carbonate (700 mg, 5.17 mmol) dissolved in 10 mL N,N -dimethyl The formamide was stirred and heated to 40 ° C for 12 hours. 20 mL of water and 20 mL of ethyl acetate were added to the reaction mixture, and the mixture was separated, and the organic phase was washed with water (15 mL×2). 2-(Difluoromethoxy)pyridine 30a (500 mg, as colorless oil).

MS m/z (ESI): 223.9 [M+1]

Second step 2-(Difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Crude 5-bromo-2-(difluoromethoxy)pyridine 30a (300 mg, 1.34 mmol), dipentane diboron (408 mg, 1.61 mmol), 1,1'-bis(diphenylphosphine) Ferrocene] palladium dichloride (49 mg, cat.) and potassium acetate (400 mg, 4.02 mmol) were dissolved in 20 mL of dioxane, and the mixture was heated to 120 ° C and stirred for 2 hours. After cooling to room temperature, 40 mL of dichloromethane was added, and the filtrate was evaporated. 3,2-Dioxaborolan-2-yl)pyridine 30b (500 mg, black liquid).

MS m/z (ESI): 272.1 [M+1]

third step 2-[4-[8-[6-(difluoromethoxy)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 - c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl] 2-methyl-propionitrile 1k (100 mg, 0.23 mmol), crude 2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)pyridine 30b (500 mg, 0.19 mmol), tetrakistriphenylphosphine palladium (40 mg, cat.) and potassium carbonate (95 mg, 0.69 mmol) dissolved in 10 mL The solvent mixture of methane and water (V/V = 1:1) was heated to 120 ° C and stirred for 3 hours. After cooling to room temperature, 15 mL of water was added, and ethyl acetate (15 mL×3) was evaporated. The title product 2-[4-[8-[6-(difluoromethoxy)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [ 4,5- c ]quinolin-1-yl]phenyl]-2-methyl-propanenitrile 30 (7 mg, brown liquid), yield: 6.0%.

MS m/z (ESI): 486.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.35 (br, 1H), 8.58 (s, 1H), 8.08 (s, 2H), 7.93 (d, 2H), 7.63 - 7.77 (m, 4H). (s, 1H), 7.03 (d, 1H), 3.84 (s, 3H), 1.92 (s, 6H)

Example 31 2-methyl-2-[4-[3-methyl-2-keto-8-[5-[(tetrahydrofuran-3-yl)-oxy]-pyridin-3-yl]-2,3- Dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile

first step 3-bromo-5-[(tetrahydrofuran-3-yl)oxy]pyridine

Dissolve 5-bromopyridin-3-ol 31a (1.0 g, 5.70 mmol) in 20 mL of tetrahydrofuran, add triphenylphosphine (1.79 g, 6.84 mmol) and four Hydrofuran-3-ol (0.75 g, 8.60 mmol), diisopropyl azodicarboxylate (1.38 g, 6.84 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. (Tetrahydrofuran-3-yl)oxy]pyridine 31b (1.10 g, as colorless oil).

Second step 3-[(tetrahydrofuran-3-yl)oxy]-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl) Pyridine

The crude 3-bromo 5-[(tetrahydrofuran-3-yl)oxy]pyridine 31b (1.10 g, 4.50 mmol), dipentane diboron (1.37 g, 5.40 mmol), 1,1'-bis(diphenyl) Phosphine) Ferrocene] Palladium dichloride (164 mg, 0.23 mmol) and potassium acetate (1.32 g, 13.50 mmol) were dissolved in 20 mL of dioxane, and the mixture was stirred and refluxed for 3 hours. Filtration and concentration of the filtrate under reduced pressure, EtOAc (EtOAc) (EtOAc (EtOAc) 3-yl)oxy]-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)pyridine 31c (2.60 g, Black liquid), the product was directly subjected to the next reaction without purification.

third step 2-methyl-2-[4-[3-methyl-2-keto-8-[5-[(tetrahydrofuran-3-yl)-oxy]-pyridin-3-yl]-2,3- Dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile

The crude 2-[4-[(8-bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5-c]quinolin-1-yl)phenyl ]-2-methyl-propionitrile 1k (150 mg, 0.35 mmol), crude 3-[(tetrahydrofuran-3-yl)oxy]-5-(4,4,5,5-tetramethyl-[1 , 3,2]-dioxaborolan-2-yl)pyridine 31c (300 mg, 0.53 mmol) was dissolved in 6 mL of a mixed solvent of dioxane and water (V/V = 5:1). Tetrakistriphenylphosphine palladium (40 mg, cat.) and sodium carbonate (74 mg, 0.70 mmol) were added, and the mixture was heated to 90 ° C and stirred for 12 hours. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated, evaporated, evaporated,jjjjjjjjj 8-(5-[(tetrahydrofuran-3-yl)-oxy]-pyridin-3-yl]-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl] Phenyl]propanenitrile 31 (30 mg, white solid), yield: 5.7%.

MS m/z (ESI): 506.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.87 (s, 1H), 8.27-8.20 (m, 3H), 7.83 (t, 3H), 7.65 (d, 2H), 7.54-7.45 (m, 1H) , 7.17 (s, 1H), 5.04 (s, 1H), 4.09-4.03 (m, 3H), 3.99-3.94 (m, 1H), 3.75 (s, 3H), 2.35-2.28 (m, 1H), 2.23 -2.19(m,1H), 1.89(s,6H)

Example 32 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]methyl quinolin-8-yl]pyridin-3-yl]carbamate

first step Methyl N- (5-bromo-pyridin-3-yl)carbamate

Dissolve 5-bromopyridin-3-amine 32a (1.0 g, 5.80 mmol) in 20 mL of dichloromethane, and slowly add 5 mL of dichlorochloride containing methyl chloroformate (1.5 mL, 17.34 mmol). The methane solution was stirred at room temperature and stirred for 1 hour. 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL×3). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by a silica gel column chromatography. The residue, to give the title product N - (5- bromo - pyridin-3-yl) methyl amine 32b (1.20 g, yellow solid), yield: 90.0%.

MS m/z (ESI): 232.9 [M+1]

Second step Methyl N- [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]carbamate

Methyl N- (5-bromo-pyridin-3-yl)carbamate 32b (1.0 g, 4.30 mmol), dipentane diboron (1.33 g, 5.20 mmol), 1,1'-bis(diphenyl Phosphine) ferrocene] palladium dichloride (157 mg, 0.21 mmol) and potassium acetate (1.26 g, 12.90 mmol) were dissolved in 20 mL of dioxane, and heated to 100 ° C for 3 hours. The mixture was cooled to room temperature, and the mixture was evaporated. Concentration gave the title product crude N- [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]amine Methyl carbamate 32c (1.60 g, black oil), product was taken to the next step without purification.

third step N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]methyl quinolin-8-yl]pyridin-3-yl]carbamate

The crude 2-[4-[(8-bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl ]-2-methyl-propionitrile 1k (100 mg, 0.24 mmol), crude N- [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) Methyl alk-2-yl)pyridin-3-yl]carbamate 32c (100 mg, 0.36 mmol) was dissolved in 12 mL of a mixture of dioxane and water (V/V = 5:1). Phenylphosphine palladium (27 mg, cat.) and sodium carbonate (50 mg, 0.47 mmol) were heated to 90 ° C and stirred for 12 hours. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated. The obtained residue was purified to give the title product N- [5-[1-[4-(2-cyanopropyl-2-yl)phenyl]-3-methyl-2-one- Methyl 2,3-dihydro- 1H -imidazo[4,5- c ]quinolin-8-yl]pyridin-3-yl]carbamate 32 (30 mg, mp.). %.

MS m/z (ESI): 493.3 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.00 (s, 1H), 9.05 (s, 1H), 8.54 (s, 1H), 8.17-8.13 (m, 2H), 7.78 (s, 1H) , 7.87-7.83 (m, 3H), 7.75 (d, 2H), 7.14 (s, 1H), 3.75 (s, 3H), 3.63 (s, 3H), 1.78 (s, 6H)

Example 33 2-cyano- N- [5-[1-[4-(2-cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]acetamide

first step 2-cyanoethyl chloro

2-Cyanoacetic acid 33a (1.0 g, 11.70 mmol) was dissolved in 20 mL of dichloromethane under ice-bath, and chlorobenzene (1.90 g, 14.10 mmol) and 4 drops of N,N -dimethylformamide The mixture was naturally stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound md.

Second step 2-cyano- N- [5-[1-[4-(2-cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]acetamide

The crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-1-yl]phenyl]-2-methyl-propanenitrile 2b (80 mg, 0.18 mmol) was dissolved in 15 mL dichloromethane, triethylamine (0.1 mL, 0.55 mmol) 2-Cyanoacetonitrile chloride 33a 33b (500 mg, 4.83 mmol) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product 2-cyano - N - [5- [1- [ 4- (2- cyano-cyclopropyl-2- Phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]acetamide 33 (15 mg, pale yellow solid), yield: 16.0%.

MS m/z (ESI): 502.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.04 (s, 1H), 8.42 (s, 1H), 8.20 (d, 1H), 8.16 (d, 1H), 7.96 (d, 1H), 7.85 (d, 2H), 7.76 (d, 2H), 7.68 (d, 1H), 7.12 (s, 1H), 3.35 (s, 2H), 3.62 (s, 3H), 1.84 (s, 6H)

Example 34 2-[4-[8-(6-ethynylpyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -1-yl]phenyl]-2-methylpropionitrile

first step 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

5-Bromo-2-methoxypyridine 34a (1.50 g, 8 mmol), dipentane diboron (2.43 g, 9.60 mmol), 1,1'-bis(diphenylphosphino)ferrocene] Palladium chloride (580 mg, 0.80 mmol) and potassium acetate (1.18 g, 12.0 mmol) were dissolved in 25 mL of ethylene glycol glycol dimethyl ether, and the mixture was heated to 80 ° C and stirred for 1 hour. After cooling to room temperature, 30 mL of petroleum ether was added to the reaction mixture, which was filtered through a funnel padded with ruthenium dioxide, and the filtrate was concentrated under reduced pressure, and 50 ml of ethyl acetate and n-hexane (V/V = 1:5) mixed solvent was added. Filter with a funnel padded with cerium oxide, using 50 mL of ethyl acetate and n-hexane (V/V = 1:5) The mixed solvent was eluted, and the filtrate was concentrated under reduced pressure to give the titled crude product 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Base)pyridine 34b (2.0 g, semi-oil semi-solid), the product was taken directly to the next reaction without purification.

MS m/z (ESI): 236.2 [M+1]

Second step 2-[4-[8-(6-ethoxypyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quina Polin-1-yl]phenyl]-2-methylpropionitrile

The crude 2-[4-[(8-bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl ]-2-methyl-propionitrile 1k (100 mg, 0.24 mmol), crude 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclic pentan-2-yl)pyridine 34b (73 mg, 0.31 mmol) was dissolved in 6 mL of a mixture of dioxane and water (V/V = 5:1), then tetratriphenylphosphine palladium (27 mg) , cat.) and sodium carbonate (38 mg, 0.36 mmol), and the mixture was heated to 90 ° C and stirred for 3 hours. After cooling to room temperature, 20 mL of water and 20 mL of methylene chloride were added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (20 mL×3). The obtained residue was purified by silica gel column chromatography eluting to afford the title product 2-[4-[8-(6-ethoxypyridin-3-yl)-3-methyl-2-one- 2,3-Dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-methylpropanenitrile 34c (90 mg, m.p.).

MS m/z (ESI): 450.2 [M+1]

third step 2-[4-[8-(6-Bromopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline- 1-yl]phenyl]-2-methylpropionitrile

2-[4-[8-(6-ethoxypyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-1-yl]phenyl]-2-methylpropanenitrile 34c (45 mg, 0.10 mmol) was dissolved in 3 mL of N,N-dimethylformamide, followed by 1 drop of water and phosphine tribromide (220 mg, 0.80 mmol), heated to 100 ° C and stirred for 30 minutes. After cooling to room temperature, the reaction mixture was poured into 20 mL of ice water, and the mixture was extracted with ethyl acetate (20 mL × 3), and the organic phase was combined, washed with saturated sodium chloride solution (20 mL × 4), dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified to silica gel column chromatography to afford the title product 2-[4-[8-(6-bromopyridin-3-yl)-3-methyl- 2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-methylpropanenitrile 34d (44 mg, white solid) Rate: 88.0%.

MS m/z (ESI): 500.2 [M+1]

the fourth step 2-methyl-2-[4-[3-methyl-2-keto-8-[6-(trimethylmethyl)ethynyl]pyridin-3-yl]-2,3-dihydro- 1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile

2-[4-[8-(6-Bromopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline 1-yl]phenyl]-2-methylpropanenitrile 34d (38 mg, 0.08 mmol) and ethynyltrimethylnonane (37 mg, 0.38 mmol) dissolved in 6 mL of tetrahydrofuran and N,N-dimethyl Methionine (V/V=2:1) mixed solvent, then add 1.25 mL of triethylamine, then add 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5.30 mg, cat .) and cuprous iodide (4.30 mg, 0.02 mmol), the mixture was heated to 50 ° C and stirred for 1 hour, and then raised to 60 ° C to stir the reaction for 3 hours. After cooling to room temperature, 20 mL of water and 20 mL of ethyl acetate were added, and the mixture was separated, the aqueous phase was extracted with ethyl acetate (20 mL×3), and the organic phase was combined and washed with saturated sodium chloride solution (20 mL×4) After drying over anhydrous sodium sulfate, the mixture was filtered, and the filtrate was evaporated to dryness. Keto-8-[6-(trimethylsulfonyl)ethynyl]pyridin-3-yl]-2,3-dihydro-1 H -imidazole [4,5- c ]quinolin-1-yl] Phenyl]propionitrile 34e (15 mg, brown solid), yield: 38.0%.

MS m/z (ESI): 516.2 [M+1]

the fifth step 2-[4-[8-(6-ethynylpyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -1-yl]phenyl]-2-methylpropionitrile

2-methyl-2-[4-[3-methyl-2-keto-8-[6-(trimethylsulfonyl)ethynyl]pyridin-3-yl]-2,3-dihydro -1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile 34e (15 mg, 0.03 mmol) dissolved in 3 mL of methanol and tetrahydrofuran (V/V = 5:1) mixed solvent Further, potassium carbonate (8 mg, 0.06 mmol) was added, and the reaction was stirred for 1 hour. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified to silica gel column chromatography to afford the title product 2-[4-[8-(6-ethynylpyridin-3-yl)-3-methyl 2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-methylpropanenitrile 34 (6 mg, white solid) Yield: 46.2%.

MS m/z (ESI): 444.5 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.89 (s, 1H), 8.62 (d, 1H), 8.27 (d, 1H), 7.82-7.86 (m, 3H), 7.65 (d, 2H), 7.56 - 7.60 (m, 1H), 7.52 (d, 1H), 7.29 (d, 1H), 3.76 (s, 3H), 3.26 (s, 1H), 1.90 (s, 6H)

Example 35 1-methyl-3-[5-[3-methyl-2-keto-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1 H -imidazole [4, 5- c ]quinoline-8-yl]pyridin-2-yl]urea

first step 6-bromo-3-nitro- N- [3-(trifluoromethyl)phenyl]quinolin-4-amine

The crude 6-bromo-4-chloro-3-nitro-quinoline 1d (2.87 g, 10 mmol) was dissolved in 70 mL of glacial acetic acid, and 3-(trifluoromethyl)aniline 35a (1.77 g, 11 mmol), the reaction was stirred for 12 hours. The reaction solution was poured into 100 mL of water, stirred for 30 minutes, filtered, and the filter cake was washed with water (20 mL×2), and the filter cake was dissolved in 200 mL of ethyl acetate and tetrahydrofuran (V/V=1:1) mixed solvent. Wash with saturated sodium bicarbonate solution (30 mL). Extract liquid separation, the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo-3-nitro - N - [3- (trifluoromethyl) phenyl] quinolin-4 -amine 35b (3.85 g, yellow solid).

Second step 6-bromo- N ⁴ -[3-(trifluoromethyl)phenyl]quinoline-3,4-diamine

The crude 6-bromo-3-nitro- N- [3-(trifluoromethyl)phenyl]quinolin-4-amine 35b (3.85 g, 9.34 mmol) was dissolved in 100 mL methanol and tetrahydrofuran (V/V = 1:1) In a mixed solvent, Raney nickel (1.29 g, 15 mmol) was added, and the hydrogen was replaced three times, and the reaction was stirred for 12 hours. Filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N ⁴ - [3- (trifluoromethyl) phenyl] quinoline-3,4-diamine 35c (3.0 g, black oil), The product was directly subjected to the next reaction without purification.

third step 8-bromo-1-[3-(trifluoromethyl)phenyl]-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude 6-bromo- N ⁴ -[3-(trifluoromethyl)phenyl]quinoline-3,4-diamine 35c (3.0 g, 7.85 mmol) was dissolved in 60 mL of dichloromethane, then three Ethylamine (1.3 mL, 9.42 mmol) was combined into a mixed solution, and trichloromethyl chloroformate (2.56 g, 8.64 mmol) was dissolved in 100 mL of dichloromethane, and the above-mentioned pre-mixed solution was added dropwise. The reaction was stirred at 0 ° C for 1 hour. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc) Title product crude 8-bromo-1-[3-(trifluoromethyl)phenyl]-1 H -imidazole [4,5- c ]quinolin-2( 3H )-one 35d (2.20 g, yellow solid The product was directly subjected to the next reaction without purification.

MS m/z (ESI): 408.1 [M+1]

the fourth step 8-bromo-3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude product was 8-bromo-1-[3-(trifluoromethyl)phenyl]-1 H -imidazole [4,5- c ]quinolin-2( 3H )-one 35d (2.30 g, 5.60 mmol) Dissolved in 35 mL of dichloromethane, adding methyl iodide (1.44 g, 10.10 mmol) and tetrabutylammonium bromide (0.10 g, 0.28 mmol), and adding 35 mL of sodium hydroxide (336 mg, 8.40) with stirring. Aqueous solution of mmol) was stirred at room temperature for 12 hours. Add 150 mL of water, extract with methylene chloride (100 mL × 3), combine the organic phase, wash with saturated sodium chloride solution (100 mL × 2), dry over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. column chromatography system, eluent B resulting residue, to give the title product, 8-bromo-3-methyl-1- [3- (trifluoromethyl) phenyl] -1 H - imidazo [4,5- c ] Quinoline-2( 3H )-one 35e (1.60 g, yellow solid), yield: 69.0%.

MS m/z (ESI): 424.1 [M+1]

the fifth step 8-(6-Aminopyridin-3-yl)-3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazole [4,5- c ]quinoline-2 ( 3 H )-ketone

8-Bromo-3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one 35e (500 mg , 1.18 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 2a (320 mg, 1.42 Ment) dissolved in 20 mL of ethylene glycol dimethyl ether and water (V/V = 1:1) mixed solvent, then added tetrakistriphenylphosphine palladium (262 mg, 0.24 mmol) and potassium carbonate (450 mg , 3.54 mmol), heated to 110 ° C and stirred for 3 hours. After cooling to room temperature, 40 mL of water was added, and the solid was crystallized, filtered, and then filtered, and then filtered, and the mixture was stirred for 20 minutes with 50 mL of ethyl acetate, filtered and dried in vacuo to give the title product 8-(6-aminopyridin-3-yl)- 3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 35f (200 mg, pale yellow solid) , Yield: 40.0%.

Step 6 1-methyl-3-[5-[3-methyl-2-keto-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1 H -imidazole [4, 5- c ]quinoline-8-yl]pyridin-2-yl]urea

8-(6-Aminopyridin-3-yl)-3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazole [4,5- c ]quinoline-2 ( 3H )-ketone 35f (200 mg, 0.46 mmol) was dissolved in 10 mL dichloromethane. N,N -diisopropylethylamine (0.4 mL, 2.30 mmol). N -Phenylformamidine chloride (216 mg, 1.38 mmol) was stirred for 20 minutes and then allowed to warm to room temperature and stirred for 20 min. A solution of 1.2 mL of 2 M methylamine in tetrahydrofuran was added and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjj 3-(Trifluoromethyl)phenyl]-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]urea 35 (10 mg, yellow Oily), yield: 5.0%.

MS m/z (ESI): 493.3 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.30 (s, 1H), 8.28 (d, 1H), 8.24 (s, 2H), 8.18 (d, 2H), 8.02 (s, 2H), 7.73 (d,1H), 7.37(s,1H), 7.21(d,1H), 3.76(s,3H),2.88(s,3H)

Example 36 1-[5-[1-(3-Fluoro-2-methyl-phenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-8-yl]pyridin-2-yl]-3-methyl-urea

first step 6-bromo- N- (3-fluoro-2-methyl-phenyl)-3-nitro-quinolin-4-amine

The crude 6-bromo-4-chloro-3-nitro-quinoline 1d (3.50 g, 12.20 mmol) was dissolved in 50 mL of glacial acetic acid and 3-fluoro-2-methyl-phenylamine 36a (1.67 g, 13.40 Methyl), the reaction was stirred for 12 hours. The reaction solution was poured into 100 mL of ice water, suction filtered, and the filter cake was washed with water (20 mL × 2). The filter cake was dissolved in 100 mL of dichloromethane and washed with saturated sodium hydrogen carbonate solution (30 mL). Extract liquid separation, the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N - (3- fluoro-2-methyl-phenyl) - 3-nitro - quinoline 4-Amine 36b (4.0 g, brown solid).

Second step 6-bromo- N ⁴ -(3-fluoro-2-methyl-phenyl)quinoline-3,4-diamine

The crude 6-bromo- N- (3-fluoro-2-methyl-phenyl)-3-nitro-quinolin-4-amine 36b (4.0 g, 10.60 mmol) was dissolved in 50 mL of methanol and THF. /V = 1:1) In a mixed solvent, Raney nickel (1.29 g, 15 mmol) was added, and the hydrogen was replaced three times, and the reaction was stirred for 12 hours. Filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N ⁴ - (3- fluoro-2-methyl-phenyl) - quinoline-3,4-diamine 36c (3.80 g, brown solid), the product The next reaction was carried out without purification.

third step 8-bromo-1-(3-fluoro-2-methyl-phenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude 6-bromo- N ⁴ -(3-fluoro-2-methyl-phenyl)quinoline-3,4-diamine 36c (3.80 g, 11 mmol) was dissolved in 40 mL dichloromethane. Triethylamine (2 mL, 13.20 mmol) was mixed into a solution, and triphosgene (3.58 g, 12 mmol) was dissolved in 60 mL of dichloromethane, and the above-mentioned pre-mixed solution was added dropwise to the room. The reaction was stirred at temperature for 12 hours. The reaction mixture was washed with water (100 mL), EtOAc (EtOAc m. H -Imidazole [4,5- c ]quinolin-2( 3H )-one 36d (2.10 g, brown solid).

the fourth step 8-bromo-1-(3-fluoro-2-methyl-phenyl)-3-methyl-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

Crude 8-bromo-1-(3-fluoro-2-methyl-phenyl)-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 36d (2.10 g, 5.64 mmol Dissolved in 50 mL of dichloromethane, adding methyl iodide (2.0 g, 14.10 mmol) and tetrabutylammonium bromide (1.80 g, 5.58 mmol), and adding 20 mL of sodium hydroxide (564 mg, An aqueous solution of 14.10 mmol) was stirred at room temperature for 12 hours. The mixture was allowed to stand and the aqueous layer was extracted with dichloromethane (100 mL×3). The organic phase was combined and washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate and filtered. Title product crude 8-bromo-1-(3-fluoro-2-methyl-phenyl)-3-methyl-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 36e (4.0 g, brown solid), the product was taken to the next step without purification.

MS m/z (ESI): 386.0 [M+1]

the fifth step 8-(6-Aminopyridin-3-yl)-1-(3-fluoro-2-methyl-phenyl)-3-methyl-1 H -imidazole [4,5- c ]quinoline-2 (3 H )-ketone

The crude 8-bromo-1-(3-fluoro-2-methyl-phenyl)-3-methyl-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 36e ( 500 mg, 1.30 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 2a (313 mg , 1.42 mmol) dissolved in 20 mL of a mixture of dioxane and water (V/V = 1:1), followed by tetrakistriphenylphosphine palladium (146 mg, 0.13 mmol) and sodium carbonate (275 mg, 2.60 mmol) The mixture was heated to 90 ° C and stirred for 12 hours. After cooling to room temperature, the celite was filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The mixture was stirred for 30 minutes, filtered, and the filtered cake was washed with ethyl acetate (5 <RTI ID=0.0></RTI><RTIgt; Methyl-phenyl)-3-methyl- 1H -imidazole[4,5- c ]quinolin-2( 3H )-one 36f (200 mg, yellow solid), yield: 38.5%.

MS m/z (ESI): 400.1 [M+1]

Step 6 1-[5-[1-(3-Fluoro-2-methyl-phenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-8-yl]pyridin-2-yl]-3-methyl-urea

8-(6-Aminopyridin-3-yl)-1-(3-fluoro-2-methyl-phenyl)-3-methyl-1 H -imidazole [4,5- c ]quinoline- 2( 3H )-one 36f (300 mg, 0.75 mmol) was dissolved in 10 mL of dichloromethane. N,N -diisopropylethylamine (1.3 mL, 7.51 mmol). N -Phenylformamidine chloride (351 mg, 2,25 mmol) was stirred for 1 hour. Additional methylamine hydrochloride (254 mg, 3.76 mmol) was added and stirred at room temperature for 12 h. Add 50 mL of water, extract and separate the liquid. The organic phase is washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure and purified by eluent column chromatography with eluent system A The residue obtained gave the title product 1-[5-[1-(3-fluoro-2-methyl-phenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]Quinolin-8-yl]pyridin-2-yl]-3-methyl-urea 36 (50 mg, pale yellow solid).

MS m/z (ESI): 457.3 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.34 (s, 1H), 8.98 (s, 1H), 8.13 (s, 1H), 8.07-8.05 (m, 1H), 7.86-7.03 (m, 1H), 7.58-7.54 (m, 4H), 7.46-7.44 (m, 2H), 6.17-6.96 (m, 1H), 3.59 (s, 3H), 2.70 (d, 3H), 1.19 (s, 3H)

Example 37 N- [5-[3-Methyl-2-keto-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1 H -imidazole [4,5- c ]quina Methyl phenyl-8-yl]pyridin-2-yl]carbamate

8-(6-Aminopyridin-3-yl)-3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazole [4,5- c ]quinoline-2 ( 3H )-ketone 35f (150 mg, 0.34 mmol) was dissolved in 10 mL dichloromethane, triethylamine (174 mg, 1.72 mmol) was added and the mixture was cooled to 0 ° C, and methyl chloroformate (65 mg) was added dropwise. , 0.68 mmol), and the reaction was stirred for 1 hour. The reaction mixture was quenched by the addition of 30 mL of saturated aqueous ammonium chloride. The mixture was extracted with dichloromethane (10 mL×3). The obtained residue was purified to afford the title product N- [5-[3-methyl-2-keto-1-[3-(trifluoromethyl)phenyl]-2,3-di. Hydrogen-1 H -imidazole [4,5- c ]quinolin-8-yl]pyridin-2-yl]carbamic acid methyl ester 37 (27 mg, white solid), yield: 87.0%.

MS m/z (ESI): 494.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.37 (s, 1H), 9.04 (s, 1H), 8.20 (d, 1H), 8.14 (d, 1H), 8.03-8.08 (m, 2H), 7.90 -7.96 (m, 2H), 7.87 (d, 1H), 7.78 (d, 1H), 7.13 (s, 2H), 3.68 (s, 3H), 3.62 (s, 3H)

Example 38 2-methyl-2-[4-[3-methyl-2-keto-8-[5-(2,2,2-trifluoroethoxy)pyridin-3-yl]-2,3- Dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile

first step 3-bromo-5-(2,2,2-trifluoroethoxy)pyridine

5-Bromopyridin-3-ol 31a (522 mg, 3 mmol), cesium carbonate (2.93 g, 9 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.39 g, 6 mmol Dissolved in 15 mL of acetonitrile and stirred for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded the crude title product 3-bromo-5-(2,2,2-trifluoroethoxy) Pyridine 38a (768 mg, yellow liquid) was taken directly to the next step without purification.

Second step 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2,2,2-trifluoroethoxy) Pyridine

The crude 3-bromo-5-(2,2,2-trifluoroethoxy)pyridine 38a (768 mg, 3 mmol), diammonium diboron (991 mg, 3.90 mmol), 1,1'- double (Diphenylphosphine)ferrocene]Palladium dichloride (132 mg, cat.) and potassium acetate (882 mg, 9 mmol) were dissolved in 10 mL of dioxane, and the mixture was heated to reflux and stirred for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced vacuo. m. m. 2-Dioxaborolan-2-yl)-5-(2,2,2-trifluoroethoxy)pyridine 38b (210 mg, brown liquid), yield: 23.0%.

third step 2-methyl-2-[4-[3-methyl-2-keto-8-[5-(2,2,2-trifluoroethoxy)pyridin-3-yl]-2,3- Dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl] 2-methyl-propionitrile 1k (168 mg, 0.40 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -5-(2,2,2-trifluoroethoxy)pyridine 38b (182 mg, 0.60 mmol), tetratriphenylphosphine palladium (92 mg, cat.) and potassium carbonate (166 mg, 1.20 mmol) It was dissolved in 6 mL of a mixed solvent of dioxane and water (V/V = 1:1), and heated to 110 ° C to stir the reaction for 3 hours. After cooling to room temperature, 20 mL of water was added, and extracted with ethyl acetate (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification of A gave the title product 2-methyl-2-[4-[3-methyl-2-keto-8-[5-(2,2,2-trifluoroethoxy)pyridin-3-yl -2,3-Dihydro- 1H -imidazo[4,5- c ]quinolin-1-yl]phenyl]propanenitrile 38 (190 mg, yellow solid), yield: 91.0%.

MS m/z (ESI): 518.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.05 (s, 1H), 8.39 (s, 1H), 8.16 (m, 2H), 8.07 (s, 1H), 7.88 (d, 2H), 7.76 (d, 2H), 7.62 (s, 1H), 7.17 (s, 1H), 4.94 (m, 2H), 3.63 (s, 3H), 1.82 (s, 6H)

Example 39 2-methoxy- N- [5-[3-methyl-2-keto-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]acetamide

first step 2-methoxyethyl hydrazine chloride

3-methoxyacetic acid 39a (2.16 g, 0.24 mmol) was dissolved in 20 mL of dichloromethane under ice-bath, and dichloromethane (2.74 mL, 0.29 mmol) and 2 drops of N,N-dimethylform The amine was naturally stirred at room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure toield md.

Second step 2-methoxy- N- [5-[3-methyl-2-keto-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]acetamide

8-(6-Aminopyridin-3-yl)-3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazole [4,5- c ]quinoline-2 ( 3H )-ketone 35f (60 mg, 0.14 mmol) was dissolved in 10 mL of dichloromethane. N,N -diisopropylethylamine (180 mg, 1.40 mmol) was added, and the mixture was cooled to 0 ° C. 2-Methoxyethyl hydrazine chloride 39b (280 mg, 2.60 mmol) was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue, to give the title product 2-methoxy - N - [5- [3- methyl-2-keto-1 [3-(Trifluoromethyl)phenyl]-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]acetamide 39 (10 Mg, yellow viscous solid), yield: 13.0%.

MS m/z (ESI): 508.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.25 (s, 1H), 9.05 (s, 1H), 8.22 (s, 2H), 8.16 (d, 1H), 8.11 (d, 2H), 8.04 (d, 1H), 7.90-8.0 (m, 2H), 7.84 (d, 1H), 7.14 (s, 1H), 4.08 (s, 2H), 3.62 (s, 3H), 3.37 (s, 3H)

Example 40 1-[5-[1-(4-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl Pyridin-2-yl]-3-methyl-urea

first step 6-bromo- N- (4-fluorophenyl)-3-nitro-quinolin-4-amine

The crude 6-bromo-4-chloro-3-nitro-quinoline 1d (2.90 g, 10 mmol) was dissolved in 50 mL of glacial acetic acid, and 4-fluoroaniline 40a (1.22 g, 11 mmol) was added dropwise. 3 hours. The reaction solution was poured into 100 mL of ice water, stirred for 30 minutes, filtered, and the filter cake was dissolved in 200 mL of a mixed solvent of ethyl acetate and tetrahydrofuran (V/V = 1:1), and washed with a saturated sodium hydrogen carbonate solution (30) mL). Extract liquid separation, the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N - (4- fluorophenyl) -3-nitro - quinolin-4-amine 40b ( 3.30 g, pale yellow solid), the product was taken to the next step without purification.

Second step 6-bromo- N ⁴ -(4-fluorophenyl)quinoline-3,4-diamine

The crude 6-bromo- N- (4-fluorophenyl)-3-nitro-quinolin-4-amine 40b (3.30 g, 9.10 mmol) was dissolved in 100 mL methanol and THF (V/V = 1:1 In a mixed solvent, Raney nickel (1.20 g, 14 mmol) was added, and the hydrogen was replaced three times, and the reaction was stirred for 12 hours. Filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N ⁴ - (4- fluorophenyl) quinoline-3,4-diamine 40c (2.56 g, yellow oil), was used without purification for The next step is to react.

third step 8-bromo-1-(4-fluorophenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude 6-bromo- N 4-(4-fluorophenyl)quinoline-3,4-diamine 40c (2.56 g, 7.70 mmol) was dissolved in 40 mL dichloromethane and then triethylamine (1.3 mL) , 9.24 mmol), a mixed solution was prepared, and triphosgene (2.50 g, 8.47 mmol) was dissolved in 60 mL of dichloromethane, and the above-premixed mixed solution was added dropwise under ice bath, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAcjjjjd Beating, the title product 8-bromo-1-(4-fluorophenyl)-1 H -imidazole [4,5- c ]quinolin-2( 3H )-one 40d (2.0 g, pale yellow solid) Yield: 72.5%.

MS m/z (ESI): 360.1 [M+1]

the fourth step 8-bromo-1-(4-fluorophenyl)-3-methyl-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

Dissolve 8-bromo-1-(4-fluorophenyl)-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 40d (2.10 g, 5.90 mmol) in 50 mL of dichloro Methane, adding methyl iodide (2.08 g, 14.70 mmol) and tetrabutylammonium bromide (190 mg, 0.59 mmol), and adding 20 mL of an aqueous solution containing sodium hydroxide (588 mg, 14.70 mmol), while stirring, room The reaction was stirred at temperature for 12 hours. The layers were separated and the aqueous layer was extracted with methylene chloride (100 mL×3). Phenyl)-3-methyl- 1H -imidazole[4,5- c ]quinolin-2( 3H )-one 40e (2.50 g, brown solid).

MS m/z (ESI): 374.2 [M+1]

the fifth step 8-(6-Aminopyridin-3-yl)-1-(4-fluorophenyl)-3-methyl-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude product was 8-bromo-1-(4-fluorophenyl)-3-methyl-1 H -imidazole[4,5- c ]quinolin-2( 3H )-one 40e (500 mg, 1.34 mmol) , 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 2a (354 mg, 1.61 mmol) was dissolved in 15 mL of dioxane and water (V/V = 5:1) mixed solvent, then added tetrakistriphenylphosphine palladium (155 mg, 0.13 mmol) and sodium carbonate (284 mg, 2.68 mmol), heated to 90 ° C and stirred Reaction for 12 hours. The mixture was cooled to room temperature, dried over anhydrous sodium -1 H - imidazo [4,5- c] quinolin -2 (3 H) - one 40f (700 mg, brown solid) was used without purification in the next step.

MS m/z (ESI): 386.1 [M+1]

Step 6 1-[5-[1-(4-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl Pyridin-2-yl]-3-methyl-urea

The crude product is 8-(6-aminopyridin-3-yl)-1-(4-fluorophenyl)-3-methyl- 1H -imidazole[4,5- c ]quinolin-2( 3H ) - one 40f (516 mg, 1.34 mmol) was dissolved in 50 mL of dichloromethane was added N, N - diisopropylethylamine (2 mL, 13.40 mmol), the ice bath was lowered to 0 deg.] C, was added dropwise N - phenyl Formazan chloride (0.5 mL, 4.02 mmol), stirred for 20 minutes, then warmed to room temperature and stirred for 30 minutes. Additional methylamine hydrochloride (452 mg, 6.70 mmol) was added and stirred at room temperature for 12 h. After suction filtration, the obtained crude product was recrystallized from methylene chloride and methanol (V/V = 20:1) to give the title product 1-[5-[1-(4-fluorophenyl)-3-methyl-2 -keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-3-methyl-urea 40 (50 mg, gray solid) , Yield: 8.4%.

MS m/z (ESI): 443.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.85 (s, IH), 8.13 (s, 1H), 8.03-8.01 (m, 1H), 7.80-7.79 (m, 1H), 7.63-7. m, 4H), 7.45-7.41 (m, 3H), 7.28-7.26 (m, 1H), 7.11 (s, 1H), 3.55 (s, 3H), 2.71 (s, 3H)

Example 41 N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-3-yl]-2-methoxyacetamide

first step (5-bromo-pyridin-3-yl)boronic acid

5-Bromopyridin-3-amine 32a (2.0 g, 11.56 mmol), dipentane diboron (3.52 g, 13.80 mmol), 1,1'-bis(diphenylphosphino)ferrocene] dichlorination Palladium (400 mg, cat.) and potassium acetate (3.97 g, 40.46 mmol) were dissolved in 80 mL of dioxane, and the mixture was heated to 90 ° C and stirred for 12 hours. Filtration and concentration of the filtrate under reduced pressure, 50 mL of dichloromethane and 50 mL of saturated sodium chloride solution were added, and the mixture was separated, and the aqueous phase was concentrated under reduced pressure to give crude title compound (5-bromo-pyridin-3-yl)boronic acid 41a ( 2.54 g, light yellow solid), the product was taken to the next step without purification.

Second step 2-[4-[8-(5-Aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -1-yl]phenyl]-2-methylpropionitrile

The crude 2-[4-[(8-bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl ]-2-methyl-propionitrile 1k (500 mg, 1.19 mmol), crude (5-bromo-pyridin-3-yl)boronic acid 41a (703 mg, 2.38 mmol) dissolved in 40 mL of dimethyl ether and The solvent was mixed with water (V/V = 1:1), and tetrakistriphenylphosphine palladium (275 mg, 0.24 mmol) and potassium carbonate (493 mg, 3.57 mmol) were further added, and the mixture was heated to 120 ° C and stirred for 4 hours. After cooling to room temperature, 50 mL of water was added, and the mixture was filtered, and the residue obtained was purified by eluent chromatography eluting to afford the title product 2-[4-[8-(5-aminopyridine-3- 3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-methylpropanenitrile 41b ( 100 mg, orange-yellow solid), Yield: 19.0%.

third step N- [5-[1-[4-(2-Cyanopropyl-2-yl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-3-yl]-2-methoxyacetamide

2-[4-[8-(5-Aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quina Phenyl-1-yl]phenyl]-2-methylpropanenitrile 41b (65 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL) and N,N -diisopropylethylamine (58 mg, 0.45 mmol) The ice bath was lowered to 0 ° C, and 2-methoxyethyl chlorobenzene (33 mg, 0.30 mmol) was added dropwise, and the mixture was stirred for 1 hour. The reaction was quenched by the addition of 10 mL of water. The organic layer was washed with saturated aqueous ammonium chloride (10 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained is purified to give the title product N- [5-[1-[4-(2-cyanopropyl-2-yl)phenyl]-3-methyl-2- keto-2,3- Dihydro- 1H -imidazo[4,5- c ]quinolin-8-yl]pyridin-3-yl]-2-methoxyacetamide 41 (5 mg, yellow solid), yield: 6.6% .

MS m/z (ESI): 507.4 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.09 (s, 1H), 9.05 (s, 1H), 8.77 (s, 1H), 8.25 (s, 1H), 8.17 (d, 2H), 7.85 (d, 2H), 7.76 (d, 2H), 7.16 (s, 1H), 3.63 (s, 3H), 3.42 (s, 3H), 2.34 (s, 2H), 1.79 (s, 6H)

Example 42 1-[5-[1-(2-methoxypyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quina Porphyrin-8-yl]pyridin-2-yl]-3-methyl-urea

first step 6-bromo- N- (2-methoxypyridin-3-yl)-3-nitro-quinolin-4-amine

The crude 6-bromo-4-chloro-3-nitro-quinoline 1d (4.0 g, 13.90 mmol) was dissolved in 30 mL of glacial acetic acid and 2-methoxypyridin-3-amine 42a (1.90 g, 15 Methyl), the reaction was stirred for 12 hours. The reaction solution was poured into 200 mL of water, filtered, and the filter cake was dissolved in 150 ml of dichloromethane and washed with saturated sodium bicarbonate (50 mL). Extract liquid separation, the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N - (2- methoxy-pyridin-3-yl) -3-nitro - quinolin - 4-Amine 42b (4.30 g, grey solid).

Second step 6-bromo- N ⁴ -(2-methoxypyridin-3-yl)quinoline-3,4-diamine

The crude 6-bromo- N- (2-methoxypyridin-3-yl)-3-nitro-quinolin-4-amine 42b (4.30 g, 11.50 mmol) was dissolved in 60 mL of methanol and tetrahydrofuran (V/ In a mixed solvent of V = 1:1), Raney nickel (1.50 g, 14 mmol) was added, and the hydrogen was replaced three times, and the reaction was stirred for 12 hours. Filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N ⁴ - (2- methoxy-pyridin-3-yl) quinoline-3,4-diamine 42c (3.20 g, gray solid), the product is not The next reaction was carried out directly by purification.

third step 8-bromo-1-(2-methoxypyridin-3-yl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude 6-bromo- N ⁴ -(2-methoxypyridin-3-yl)quinoline-3,4-diamine 42c (3.20 g, 9.20 mmol) was dissolved in 50 mL dichloromethane. Ethylamine (1.6 mL, 11 mmol) was mixed into a mixed solution, and triphosgene (3.03 g, 10 mmol) was dissolved in 50 mL of dichloromethane, and the above-mentioned premixed mixed solution was added dropwise while stirring, and the reaction was stirred for 1 hour. . The reaction was quenched with EtOAc (EtOAc (EtOAcMeOHMeOHMeOHMeOHMeOH -(2-methoxypyridin-3-yl)-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 42d (3.0 g, pale yellow solid) Carry out the next reaction.

MS m/z (ESI): 371.0 [M+1]

the fourth step 8-bromo-1-(2-methoxypyridin-3-yl)-3-methyl-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude product was 8-bromo-1-(2-methoxypyridin-3-yl)-1 H -imidazole [4,5- c ]quinolin-2( 3H )-one 42d (12.0 g, 32.30 mmol) Dissolve in 50 mL of dichloromethane, add methyl iodide (10 mL, 160 mmol) and tetrabutylammonium bromide (1.04 g, 3.23 mmol), add 80 mL of sodium hydroxide (2.58 g, 64.60). An aqueous solution of mmol) was stirred at room temperature for 48 hours. The layers were separated, and the aqueous layer was extracted with methylene chloride (150 mL?). Oxypyridin-3-yl)-3-methyl- 1H -imidazole[4,5- c ]quinolin-2( 3H )-one 42e (10.0 g, brown oil), product Carry out the next reaction.

the fifth step 8-(6-Aminopyridin-3-yl)-1-(2-methoxypyridin-3-yl)-3-methyl-1 H -imidazole [4,5- c ]quinoline-2 ( 3 H )-ketone

The crude product was 8-bromo-1-(2-methoxypyridin-3-yl)-3-methyl- 1H -imidazole[4,5- c ]quinolin-2( 3H )-one 42e (100 Mg, 0.26 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 2a (54 mg, 0.39 mmol) dissolved in 5 mL of N , N -dimethylformamide, followed by 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, cat.) and potassium carbonate (90 mg, 0.65 mmol), heated to 100 ° C and stirred for 30 minutes. The mixture was cooled to room temperature, filtered, EtOAc EtOAc EtOAc (EtOAc) Pyridin-3-yl)-1-(2-methoxypyridin-3-yl)-3-methyl-1 H -imidazole [4,5- c ]quinoline-2(3 H )-one 42f (85 mg, brown oil), the product was taken to the next step without purification.

Step 6 1-[5-[1-(2-methoxypyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quina Porphyrin-8-yl]pyridin-2-yl]-3-methyl-urea

The crude product is 8-(6-aminopyridin-3-yl)-1-(2-methoxypyridin-3-yl)-3-methyl-1 H -imidazole [4,5- c ]quinoline- 2( 3H )-one 42f (100 mg, 0.25 mmol) was dissolved in 5 mL of dichloromethane. N,N -diisopropylethylamine (323 mg, 2.50 mmol) was added and the mixture was cooled to 0 ° C. N -Phenylformamidine chloride (117 mg, 0.75 mmol) was added and stirred for 1 hour. Additional methylamine hydrochloride (84 mg, 1.25 mmol) was added and stirred at room temperature for 12 h. After adding 10 mL of water and extracting with dichloromethane (20 mL×3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system A. The title product 1-[5-[1-(2-methoxypyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]Quinoline-8-yl]pyridin-2-yl]-3-methyl-urea 42 (25 mg, light brown solid), yield: 22.0%.

MS m/z (ESI): 456.1 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.38 (s, 1H), 9.1 (s, 1H), 8.53 (s, 1H), 8.20-8.16 (m, 2H), 8.12 (d, 1H) , 8.01 (d, 1H), 7.65 (t, 2H), 7.49 (s, 1H), 7.37 (s, 1H), 7.12 (s, 1H), 3.71 (s, 3H), 3.62 (s, 3H), 2.74(s,3H)

Example 43 N- [5-[3-Methyl-2-keto-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1 H -imidazole [4,5- c ]quina Phenyl-8-yl]pyridin-2-yl]propenylamine

8-(6-Aminopyridin-3-yl)-3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazole [4,5- c ]quinoline-2 ( 3H )-ketone 35f (60 mg, 0.14 mmol) was dissolved in 10 mL of dichloromethane. N , N -diisopropylethylamine (120 μL, 0.70 mmol) was added, and the mixture was cooled to 0 ° C. Propylene hydrazine chloride (38 mg, 0.41 mmol) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product N - [5- [3- methyl-2-yl-1- [3- (trifluoromethyl Phenyl]-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]propenylamine 43 (11 mg, yellow solid), yield : 18.0%.

MS m/z (ESI): 490.1 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.08 (s, 1H), 8.23 (s, 1H), 8.16 (d, 1H), 8.12 (d, 1H), 7.78 (t, 1H), 7.85 (d, 1H), 7.40 (t, 2H), 7.38 (d, 2H), 7.15 (s, 1H), 6.60-6.74 (m, 1H), 6.35 (d, 2H), 5.70 (d, 1H), 3.62(s,3H)

Example 44 2-[4-[8-(5-ethynylpyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -1-yl]phenyl]-2-methyl-propanenitrile

first step 3-bromo-5-[(trimethyldecyl)ethynyl]pyridine

3,5-Dibromopyridine 44a (200 mg, 0.08 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (60 mg, 0.08 mmol) and cuprous iodide ( 20 mg, 0.08 mmol) was dissolved in 5 mL of triethylamine, ethynyltrimethyl decane (130 mg, 1.26 mmol) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and 100 mL of water and 150 mL of dichloromethane were added to extract, and the organic phase was washed with water (100 mL×2), saturated sodium hydrogen carbonate solution (50 mL×3), and saturated sodium chloride solution. (50 mL × 2), dried over anhydrous sodium sulfate, filtered, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The product was directly subjected to the next reaction without purification.

Second step 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-[(trimethyldecyl)ethynyl]pyridine

The crude 3-bromo-5-[(trimethyldecyl)ethynyl]pyridine 44b (300 mg, 1.17 mmol), dipentyl diboron (325 mg, 1.23 mmol), 1,1'-bis (two Phenylphosphine)ferrocene]palladium dichloride (86 mg, 0.12 mmol) and potassium acetate (240 mg, 2.34 mmol) were dissolved in 5 mL of dioxane and heated to 110 ° C for 3 hours. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified eluting with eluent column chromatography to afford the title product 3-(4,4,5,5-tetramethyl-1,3,2-diox. Heteroborolan-2-yl)-5-[(trimethyldecyl)ethynyl]pyridine 44c (210 mg, yellow oil), yield: 62.0%.

MS m/z (ESI): 302.3 [M+1]

third step 2-[4-[8-(5-ethynylpyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -1-yl]phenyl]-2-methyl-propanenitrile

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl] 2-methyl-propionitrile 1k (100 mg, 0.23 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -5-[(Trimethyldecyl)ethynyl]pyridine 44c (150 mg, 0.46 mmol), tetrakistriphenylphosphine palladium (40 mg, cat.) and sodium carbonate (80 mg, 0.46 mmol) dissolved in 8 mL of a mixed solvent of dioxane and water (V/V = 3:1) was heated to 110 ° C and stirred for 3 hours. The mixture was cooled to room temperature, filtered, and then filtered, mjjjjjjjjjjjjjjjjjjjjj [4-[8-(5-ethynylpyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline-1 -Phenyl]-2-methyl-propanenitrile 44 (15 mg, white solid), yield: 16.0%.

MS m/z (ESI): 444.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.05 (s, 1H), 8.61 (d, 2H), 8.05 (d, 1H), 7.82-7.87 (m, 2H), 7.72 (d, 2H) , 7.65 (d, 1H), 7.40-7.50 (m, 1H), 7.05 (s, 1H), 3.61 (s, 3H), 1.80 (s, 6H)

Example 45 (E) - N - [5- [1- [4- (2- cyano-propyl-2-yl) phenyl] -3-methyl-2,3-dihydro-2-yl -1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-but-2-enylamine

The crude 2-[4-[8-(6-aminopyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] quinolin-1-yl] phenyl] -2-methyl - propionitrile 2b (80 mg, 0.18 mmol) was dissolved in 5 mL of dichloromethane, was added triethylamine (51 μ L, 0.37 mmol) , the ice bath was After dropping to 0 ° C, ( E )-but-2-enyl chloride 45a (29 mg, 0.28 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (E) - N - [5- [1- [4- (2- yl-cyanopropyl Phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-but-2 - eneamine 45 (23 mg, yellow solid), yield: 25.0%.

MS m/z (ESI): 503.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.02 (s, 1H), 8.31-8.37 (m, 1H), 8.22 (d, 1H), 8.13 (d, 1H), 7.97 (d, 1H) , 7.89(d,2H), 7.76(d,2H), 7.68(d,1H),7.09-7.12(m,1H),5.92-6.02(m,1H),5.14-5.22(m,1H),3.62 (s, 3H), 1.82 (s, 6H), 1.24 (s, 3H)

Example 46 N- [5-[1-(3-fluoro-2-methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quina Phenyl-8-yl]pyridin-2-yl]propenylamine

8-(6-Aminopyridin-3-yl)-1-(3-fluoro-2-methyl-phenyl)-3-methyl-1 H -imidazole [4,5- c ]quinoline- 2( 3H )-one 36f (200 mg, 0.50 mmol) was dissolved in 10 mL of dichloromethane, triethylamine (101 mg, 1 mmol) was added, and the mixture was cooled to 0 ° C, and propylene chloride 25a was added dropwise. 50 mg, 1.10 mmol), and the reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product N - [5- [1- (3- fluoro-2-methylphenyl) -3-methyl - 2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]propenylamine 46 (4 mg, white solid) : 0.2%.

MS m/z (ESI): 454.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.96 (s, 1H), 9.08 (s, 1H), 8.23 (s, 1H), 8.17 (d, 1H), 7.98-7.97 (m, 1H) , 7.89-7.88 (m, 1H), 7.61-7.58 (m, 4H), 7.09 (s, 1H), 6.66-6.59 (m, 1H), 6.36-6.31 (m, 1H), 5.83-5.80 (m, 1H), 3.64 (s, 3H), 2.04 (s, 3H)

Example 47 2-methoxy- N- [5-[1-(2-methoxypyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4 ,5- c ]quinoline-8-yl]pyridin-2-yl]acetamide

The crude product is 8-(6-aminopyridin-3-yl)-1-(2-methoxypyridin-3-yl)-3-methyl-1 H -imidazole [4,5- c ]quinoline- 2( 3H )-one 42f (100 mg, 0.25 mmol) was dissolved in 15 mL dichloromethane. N,N -diisopropylethylamine (97 mg, 0.75 mmol). 2-Methoxyethyl hydrazine chloride 39b (41 mg, 0.38 mmol) was added dropwise, and the mixture was stirred to room temperature and stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, to the resulting thin layer chromatography eluent systems A residue, to give the title product 2-methoxy - N - [5- [1- ( 2- methoxy-pyridin-3-yl )-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]acetamidamine 47 (36 mg , yellow solid), yield: 30.5%.

MS m/z (ESI): 471.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.19 (s, 1H), 8.99 (s, 1H), 8.49-8.47 (m, 1H), 8.24 - 8.23 (m, 1H), 8.10-8.08 ( m, 3H), 7.92-7.91 (m, 1H), 7.83-7.82 (m, 1H), 7.33-7.30 (m, 1H), 7.14 (s, 1H), 4.05 (s, 2H), 3.74 (s, 3H), 3.59 (s, 3H), 3.34 (s, 3H)

Example 48 (E) - N - [5- [1- (2- methoxy-pyridin-3-yl) -3-methyl-2,3-dihydro-2-yl -1 H - imidazo [4,5 - c ] quinoline-8-yl]pyridin-2-yl]-but-2-enylamine

The crude product is 8-(6-aminopyridin-3-yl)-1-(2-methoxypyridin-3-yl)-3-methyl-1 H -imidazole [4,5- c ]quinoline- 2 (3 H) - one 42f (100 mg, 0.25 mmol) was dissolved in 5 mL of dichloromethane, was added triethylamine (70 μ L, 0.50 mmol) , the ice bath was lowered to 0 deg.] C, solution of (E) - But-2-eneindole chloride 45a (32 mg, 0.30 mmol) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (E) - N - [5- [1- (2- methoxy-pyridin-3-yl) -3 -methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-but-2-enylamine 48 ( 10 mg, yellow solid), yield: 0.5%.

MS m/z (ESI): 467.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.86 (s, 1H), 8.495 (d, 1H), 8.39 (d, 1H), 8.30 (s, 1H), 8.25 (d, 1H), 7.095 (d) , 1H), 7.83 (d, 1H), 7.72 (d, 1H), 7.20-7.26 (m, 1H), 7.07-7.15 (m, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 1.46(s,3H)

Example 49 2-[4-[8-[5-(2-fluoroethoxy)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4, 5- c ]quinolin-1-yl]phenyl]-2-methylpropanenitrile

first step 3-bromo 5-(2-fluoroethoxy)pyridine

Dissolve 5-bromopyridin-3-ol 31a (100 g, 0.58 mmol) in 10 mL of tetrahydrofuran, add triphenylphosphine (680 mg, 0.69 mmol) and 2-fluoroethanol (44 mg, 0.69 mmol), ice Under a bath, diisopropyl azodicarboxylate (140 mg, 0.69 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc m. 5-(2-Fluoroethoxy)pyridine 49a (40 mg, colorless oil), yield: 31.0%.

MS m/z (ESI): 220.0 [M+1]

Second step 3-(2-Fluoroethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)pyridine

3-Bromo 5-(2-fluoroethoxy)pyridine 49a (1.30 g, 5.91 mmol), dipentane diboron (1.65 g, 6.50 mmol), 1,1'-bis(diphenylphosphine) Ferrocene] palladium dichloride (216 mg, 0.30 mmol) and potassium acetate (1.73 g, 17.70 mmol) was dissolved in 60 mL of dioxane, and the reaction was stirred under reflux for 2 hours. After cooling to room temperature, 100 mL of dichloromethane was added, and the mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure to give the title product: 3-(2-fluoroethoxy)-5-(4,4,5,5- Methyl-[1,3,2]-dioxaborolan-2-yl)pyridine 49b (1.57 g, black liquid).

MS m/z (ESI): 268.2 [M+1]

third step 2-[4-[8-[5-(2-fluoroethoxy)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4, 5- c ]quinolin-1-yl]phenyl]-2-methylpropanenitrile

The crude 2-[4-[(8-bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl ]-2-methyl-propionitrile 1k (80 mg, 0.19 mmol), crude 3-(2-fluoroethoxy)-5-(4,4,5,5-tetramethyl-[1,3, 2]-Dioxaborolan-2-yl)pyridine 49b (61 mg, 0.23 mmol) was dissolved in 6 mL of a mixed solvent of dimethylacetamide and water (V/V = 5:1). Further, 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7 mg, cat.) and potassium carbonate (79 mg, 0.57 mmol) were added, and the mixture was heated to 120 ° C and stirred for 3 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was separated. The organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to give the title product 2-[4-[8-[5-(2-fluoroethoxy)pyridin-3-yl]-3-methyl-2- keto-2, 3- Hydrogen- 1H -imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-methylpropanenitrile 49 (10 mg, white solid), yield: 11.0%.

MS m/z (ESI): 482.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.88 (s, 1H), 8.25-8.33 (m, 3H), 7.83 (d, 2H), 7.65 (d, 2H), 7.31-7.34 (m, 1H) , 7.07-7.15 (m, 2H), 4.90 (t, 1H), 4.78 (t, 1H), 4.38 (t, 1H), 4.31 (t, 1H), 3.75 (s, 3H), 1.88 (s, 6H) )

Example 50 [5-[1-(2-Methoxypyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline- Methyl 8-yl]pyridin-2-yl]carbamate

The crude product is 8-(6-aminopyridin-3-yl)-1-(2-methoxypyridin-3-yl)-3-methyl-1 H -imidazole [4,5- c ]quinoline- 2( 3H )-one 42f (50 mg, 0.13 mmol) was dissolved in 5 mL dichloromethane, triethylamine (0.2 mL, 0.28 mmol) was added, and the mixture was cooled to 0 ° C, and methyl chloroformate was added dropwise. 0.01 mL, 0.14 mmol), the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj Keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]carbamic acid methyl ester 50 (2.3 mg, yellow solid) : 4.0%.

MS m/z (ESI): 457.3 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.39 (s, 1H), 9.03 (s, 1H), 8.52 (s, 1H), 8.19-8.13 (m, 3H), 7.96-7.83 (m, 3H), 7.37 (s, 1H), 7.18 (s, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 3.63 (s, 3H)

Example 51 1-(3-Chloro-4-fluorophenyl)-8-[5-(2-fluoroethoxy)pyridin-3-yl]-3-methyl-1 H -imidazole [4,5- c ] Quinoline-2(3 H )-one

first step 6-bromo- N- (3-chloro-4-fluorophenyl)-3-nitroquinolin-4-amine

The crude 6-bromo-4-chloro-3-nitro-quinoline 1d (2.0 g, 6.99 mmol) was dissolved in 50 mL of glacial acetic acid and 3-chloro-4-fluoroaniline 51a (1.12 g, 7.69 mmol). The reaction was stirred for 12 hours. The reaction solution was poured into 200 mL of water, filtered, and the filtered cake was dissolved in 150 ml of dichloromethane and washed with saturated sodium hydrogen carbonate (30 mL). Extract liquid separation, the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N - (3- chloro-4-fluorophenyl) -3-nitro-quinolin-4 Amine 51b (2.35 g, yellow solid).

Second step 6-bromo- N ⁴ -(3-chloro-4-fluorophenyl)quinoline-3,4-diamine

The crude 6-bromo- N- (3-chloro-4-fluorophenyl)-3-nitroquinolin-4-amine 51b (2.35 g, 5.93 mmol) was dissolved in 100 mL of methanol and then R. 2.0 g), the hydrogen was replaced three times, and the reaction was stirred for 12 hours. Filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N ⁴ - (3- chloro-4-fluorophenyl) quinoline-3,4-diamine 51c (2.0 g, tan solid), was used without Purification proceeds directly to the next reaction.

third step 8-bromo-1-(3-chloro-4-fluorophenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude 6-bromo- N ⁴ -(3-chloro-4-fluorophenyl)quinoline-3,4-diamine 51c (2.0 g, 5.48 mmol) was dissolved in 20 mL of dichloromethane and then added The amine (660 mg, 6.50 mmol) was mixed into a mixed solution, and triphosgene (1.79 g, 6 mmol) was dissolved in 20 mL of dichloromethane, and the above-premixed mixed solution was added dropwise under ice-cooling, and the reaction was stirred for 12 hours. . The reaction was quenched by the addition of 60 mL of EtOAc EtOAc. EtOAc. yl) -1 H - imidazo [4,5- c] quinolin -2 (3 H) - one 51d (2.14 g, tan solid), was used without purification in the next step.

the fourth step 8-bromo-1-(3-chloro-4-fluorophenyl)-3-methyl-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

Dissolve the crude 8-bromo-1-(3-chloro-4-fluorophenyl)-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 51d (2.10 g, 5.37 mmol) In 50 mL of dichloromethane, add methyl iodide (1.7 mL, 26.80 mmol) and tetrabutylammonium bromide (0.17 g, 0.54 mmol), and add 20 mL of sodium hydroxide (0.43 g, 10 mmol) with stirring. The aqueous solution was stirred for 12 hours. After adding 50 mL of water and extracting with methylene chloride (50 mL × 2), the organic phase was combined, dried over anhydrous sodium sulfate -fluorophenyl)-3-methyl- 1H -imidazole[4,5- c ]quinolin-2( 3H )-one 51e (2.0 g, m.p.). .

the fifth step 1-(3-Chloro-4-fluorophenyl)-8-[5-(2-fluoroethoxy)pyridin-3-yl]-3-methyl-1 H -imidazole [4,5- c ] Quinoline-2(3 H )-one

Crude 8-Bromo-1-(3-chloro-4-fluorophenyl)-3-methyl-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 51e (120 mg , 0.30 mmol), crude 3-(2-fluoroethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2 -yl)pyridine 49b (95 mg, 0.36 mmol) was dissolved in 10 mL of a mixture of ethylene glycol dimethyl ether and water (V/V = 1:1), followed by tetrakistriphenylphosphine palladium (68 mg, cat) .) and potassium carbonate (120 mg, 0.88 mmol), and the mixture was heated to 110 ° C and stirred for 3 hours. After cooling to room temperature, 20 mL of water was added to precipitate a solid, solid was dissolved in 5 mL of dichloromethane, and the obtained residue was purified by EtOAc (EtOAc) Phenyl)-8-[5-(2-fluoroethoxy)pyridin-3-yl]-3-methyl-1 H -imidazole[4,5- c ]quin-2-(3 H )-one 51 (50 mg, yellow solid), yield: 36.0%.

MS m/z (ESI): [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.05 (s, 1H), 8.38 (d, 1H), 8.32 (d, 1H), 8.17 (d, 1H), 8.13 (d, 1H), 8. (d,1H), 7.81-7.79 (m, 2H), 7.39 (s, 1H), 7.29 (s, 1H), 4.92-4.84 (m, 1H), 4.79-4.71 (m, 1H), 4.44 - 4.37 (m, 1H), 4.35-4.29 (m, 1H), 3.61 (s, 3H)

Example 52 N- [5-[1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 - c ]quinoline-8-yl]pyridin-2-yl]-2-methoxyacetamide

first step 6-bromo- N- [4-fluoro-3-(trifluoromethyl)phenyl]-3-nitroquinolin-4-amine

The crude 6-bromo-4-chloro-3-nitro-quinoline 1d (2.87 g, 10 mmol) was dissolved in 30 mL of glacial acetic acid, and 4-fluoro-3-(trifluoromethyl)aniline 35a was added with stirring. (1.97 g, 11 mmol), the reaction was stirred for 2 hours. 50 mL of water was added, stirred for 30 minutes, filtered, and the filter cake was collected to give crude title compound 6-bromo- N- [4-fluoro-3-(trifluoromethyl)phenyl]-3-nitroquinoline-4 -Amine 52b (4.10 g, yellow solid).

Second step 6-bromo- N ⁴ -[4-fluoro-3-(trifluoromethyl)phenyl]quinoline-3,4-diamine

The crude 6-bromo- N- [4-fluoro-3-(trifluoromethyl)phenyl]-3-nitroquinolin-4-amine 52b (4.10 g, 9.50 mmol) was dissolved in 100 mL methanol and THF. (V/V = 1:1) In a mixed solvent, Raney nickel (2.10 g) was added, and the hydrogen was replaced three times, and the reaction was stirred for 12 hours. Filtered, the filtrate was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N ⁴ - [4- fluoro-3- (trifluoromethyl) phenyl] -3,4-quinoline Amine 52c (3.40 g, EtOAc) elute

third step 8-bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude 6-bromo- N ⁴ -[4-fluoro-3-(trifluoromethyl)phenyl]quinoline-3,4-diamine 52c (3.40 g, 8.50 mmol) was dissolved in 50 mL dichloromethane. Then, triethylamine (1.5 mL, 10.20 mmol) was added to prepare a mixed solution, and trichloromethyl chloroformate (2.80 g, 9.35 mmol) was dissolved in 50 mL of dichloromethane, and the mixture was prepared in an ice bath. The solution was added dropwise, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was diluted with 30 mL of saturated sodium hydrogen carbonate solution, and the mixture was stirred for 30 minutes, and extracted with dichloromethane (50 mL × 3). The organic phase was combined and filtered to give a solid. the filtrate was concentrated under reduced pressure, the solid were combined to give the crude title product 8-bromo-1- [4-fluoro-3- (trifluoromethyl) phenyl] -1 H - imidazo [4,5- c] quinoline -2( 3H )-one 52d (3.60 g, red-brown solid).

the fourth step 8-bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

Crude 8-bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 52d (3.60 g , 6.50 mmol) was dissolved in 100 mL of dichloromethane, iodomethane (1.3 mL, 25.50 mmol) and tetrabutylammonium bromide (548 mg, 1.70 mmol) were added, and 40 mL of sodium hydroxide was added dropwise with stirring. An aqueous solution of 1.02 g, 25.50 mmol) was stirred at room temperature for 12 hours. After adding 150 mL of water and extracting with methylene chloride (100 mL × 4), EtOAcjjjjjjjjjjjjjjjj 8-bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one 52e (3.0 g, yellow solid), Yield: 78.9%.

MS m/z (ESI): 442.2 [M+1]

the fifth step 8-(6-Aminopyridin-3-yl)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl--1 H -imidazole [4,5- c ] Quinoline-2(3 H )-one

8-Bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 52e (1 g, 2.30 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 2a ( 608 mg, 2.76 mmol) dissolved in 40 mL of a mixture of ethylene glycol dimethyl ether and water (V/V = 1:1), followed by tetrakistriphenylphosphine palladium (531 mg, 0.46 mmol) and potassium carbonate (952 Mg, 6.90 mmol), heated to 120 ° C and stirred for 12 hours. After cooling to room temperature, 50 mL of water was added, and the solid was crystallised. [4-Fluoro-3-(trifluoromethyl)phenyl]-3-methyl--1 H -imidazo[4,5- c ]quinolin-2(3 H )-one 52f (420 mg, gray Solid), the product was directly subjected to the next reaction without purification.

MS m/z (ESI): 452.1 [M-1]

Step 6 N- [5-[1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 - c ]quinoline-8-yl]pyridin-2-yl]-2-methoxyacetamide

The crude product is 8-(6-aminopyridin-3-yl)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl--1 H -imidazole [4,5- c ] Quinoline-2( 3H )-one 52f (150 mg, 0.33 mmol) was dissolved in 5 mL of dichloromethane, triethylamine (0.25 mL, 1.65 mmol) was added, and the ice bath was dropped to 0 ° C. Methoxyethyl chlorohydrin 39b (72 mg, 0.66 mmol) was stirred at room temperature for 12 hr. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc (EtOAc) concentrated and purified by thin-layer chromatography A purification to the resulting residue was developing solvent system, to give the title product N - [5- [1- [4- fluoro-3- (trifluoromethyl) phenyl] -3-methyl - 2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-2-methoxyacetamide 52 (90 mg, Light yellow solid), Yield: 52.0%.

MS m/z (ESI): 526.3 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.28 (s, 1H), 9.04 (s, 1H), 8.33 (d, 1H), 8.29 (d, 1H), 8.12-8.16 (m, 3H) , 7.88-7.96 (m, 3H), 7.17 (s, 1H), 4.09 (s, 2H), 3.62 (s, 3H), 3.38 (s, 3H)

Example 53 N- [5-[1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 - c ] methyl quinoline-8-yl]pyridin-2-yl]carbamate

The crude product is 8-(6-aminopyridin-3-yl)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl--1 H -imidazole [4,5- c ] Quinoline-2( 3H )-one 52f (150 mg, 0.33 mmol) was dissolved in 5 mL of dichloromethane, triethylamine (0.5 mL, 1.65 mmol) was added, and the mixture was cooled to 0 ° C. Methyl chloroformate (0.1 mL, 0.40 mmol) was stirred at room temperature and stirred for 12 h. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc (EtOAc) concentrated and purified by thin-layer chromatography A purification to the resulting residue was developing solvent system, to give the title product N - [5- [1- [4- fluoro-3- (trifluoromethyl) phenyl] -3-methyl - Methyl 2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]carbamate 53 (72 mg, white solid) Yield: 42.7%.

MS m/z (ESI): 512.1 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.41 (s, 1H), 9.04 (s, 1H), 8.32 (d, 1H), 8.26 (d, 1H), 8.13-8.15 (m, 2H) , 7.79-7.95 (m, 4H), 7.16 (s, 1H), 3.69 (s, 3H), 3.62 (s, 3H)

Example 54 N- [5-[1-(3-chloro-4-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -8-yl]pyridin-2-yl]-2-methoxyacetamide

first step 8-(6-Aminopyridin-3-yl)-1-(3-chloro-4-fluorophenyl)-3-methyl-1 H -imidazole[4,5- c ]quinoline-2 (3 H )-ketone

Crude crude 8-bromo-1-(3-chloro-4-fluorophenyl)-3-methyl-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 51e (500 Mg, 1.23 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 2a (320 mg, 1.48 mmol) dissolved in a mixture of 10 mL of ethylene glycol dimethyl ether and water (V/V = 1:1), followed by tetrakistriphenylphosphine palladium (280 mg, 0.24 mmol) and potassium carbonate (510 mg) , 3.70 mmol), heated to 120 ° C and stirred for 12 hours. After cooling to room temperature, 50 mL of water was added, and the obtained solid was washed with ethyl acetate (5 mL×3) and dried in vacuo to give the title product as crude 8-(6-aminopyridin-3-yl)-1-(3- Chloro-4-fluorophenyl)-3-methyl-1 H -imidazole [4,5- c ]quinolin-2( 3H )-one 54a (200 mg, m.p.). The next step is to react.

Second step N- [5-[1-(3-chloro-4-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -8-yl]pyridin-2-yl]-2-methoxyacetamide

The crude product was 8-(6-aminopyridin-3-yl)-1-(3-chloro-4-fluorophenyl)-3-methyl- 1H -imidazole[4,5- c ]quinoline-2 ( 3H )-ketone 54a (100 mg, 0.24 mmol) was dissolved in 5 mL of dichloromethane, triethylamine (70 mg, 0.71 mmol) was added, the ice bath was dropped to 0 ° C, and 2-methoxy B was added dropwise. Chlorochloride 39b (30 mg, 0.29 mmol) was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product N - [5- [1- (3- chloro-4-fluorophenyl) -3-methyl-2 -keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]-2-methoxyacetamide 54 (15 mg, light Yellow solid), Yield: 13.6%.

MS m/z (ESI): 492.1 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.03 (s, 1H), 8.31 (d, 1H), 8.16-8.12 (m, 3H), 7.96-7.91 (m, 2H), 7.80-7.79 ( m, 2H), 7.25 (s, 1H), 4.09 (s, 2H), 3.61 (s, 3H), 3.37 (s, 3H)

Example 55 [5-[3-Methyl-1-(2-methylpyridin-3-yl)-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline-8 Methyl-pyridin-2-yl]aminocarbamate

first step 6-bromo- N- (2-methylpyridin-3-yl)-3-nitroquinolin-4-amine

The crude 6-bromo-4-chloro-3-nitro-quinoline 1d (3.0 g, 10.43 mmol) was dissolved in 50 mL of N,N -dimethylacetamide and 2-methylpyridine-3- The amine 55a (1.24 g, 11.48 mmol) and N,N -diisopropylethylamine (8.07 g, 62.58 mmol) were stirred and stirred at 80 ° C for 12 hours. After adding 200 mL of water and 200 mL of ethyl acetate, the extract was separated, and the aqueous phase was extracted with ethyl acetate (100 mL×3). The organic phase was combined, washed with water (100 mL×3), dried over anhydrous sodium sulfate, filtered, filtrate concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue, to give the title product 6-bromo - N - (2- methyl-pyridin-3-yl) -3-nitro-quinolin-4 -amine 55b (2.47 g, yellow solid), yield: 66.0%.

Second step 6-bromo- N ⁴ -(2-methylpyridin-3-yl)quinoline-3,4-diamine

Dissolve 6-bromo- N- (2-methylpyridin-3-yl)-3-nitroquinolin-4-amine 55b (2.0 g, 5.59 mmol) in 80 mL of methanol, add 40 mL of acetic acid, and stir. Iron powder (1.88 g, 33.52 mmol) was added, and the mixture was heated to 80 ° C and stirred for 45 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. -Bromo- N ⁴ -(2-methylpyridin-3-yl)quinoline-3,4-diamine 55c (1.81 g, m.

third step 8-bromo-1-(2-methylpyridin-3-yl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude 6-bromo- N ⁴ -(2-methylpyridin-3-yl)quinoline-3,4-diamine 55c (1.81 g, 5.52 mmol) was dissolved in 50 mL dichloromethane. The amine (671 mg, 6.63 mmol) was combined to form a mixed solution, and triphosgene (1.80 g, 6.08 mmol) was dissolved in 50 mL of dichloromethane, and the above-prepared mixed solution was added dropwise thereto under ice-cooling, and the reaction was stirred for 1 hour. The reaction was quenched by the addition of 30 mL EtOAc EtOAc EtOAc. -Bromo-1-(2-methylpyridin-3-yl)-1 H -imidazo[4,5- c ]quinolin-2( 3H )-one 55d (1.95 g, mp. The next reaction was carried out directly by purification.

the fourth step 8-bromo-3-methyl-1-(2-methylpyridin-3-yl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

Dissolve the crude 8-bromo-1-(2-methylpyridin-3-yl)-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 55d (1.95 g, 5.50 mmol) in 40 mL of dimethyl sulfoxide was added methyl iodide (900 μ L, 13.75 mmol) and cesium carbonate (4.80 g, 16.50 mmol), stirred for 3 hours. The reaction was quenched by the addition of 100 mL of water, filtered, and the filtrate was evaporated with ethyl acetate (50 mL×3). The organic phase was combined and washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate pressure concentrated solids were combined to give the crude title product 8-bromo-3-methyl-1- (2-methyl-pyridin-3-yl) -1 H - imidazo [4,5- c] quinolin-2 (3 H )-ketone 55e (1.0 g, dark brown solid).

the fifth step 8-(6-Aminopyridin-3-yl)-3-methyl-1-(2-methylpyridin-3-yl)-1 H -imidazole [4,5- c ]quinoline-2 (3 H )-ketone

Crude 8-bromo-3-methyl-1-(2-methylpyridin-3-yl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one 55e (500 mg , 1.36 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 2a (400 mg, 1.63 Ment) dissolved in a mixture of 10 mL of ethylene glycol dimethyl ether and water (V/V = 3:2), followed by tetrakistriphenylphosphine palladium (214 mg, 0.27 mmol) and potassium carbonate (560 mg, 4.08) Methyl), heated to 110 ° C and stirred for 3 hours. After cooling to room temperature, 20 mL of water and 20 mL of methylene chloride were added, and the mixture was separated. The aqueous layer was extracted with dichloromethane (20 mL×3). The title product was obtained as crude 8-(6-aminopyridin-3-yl)-3-methyl-1-(2-methylpyridin-3-yl)-1 H -imidazole [4,5- c ]quinoline -2( 3H )-one 55f (400 mg, dark brown solid).

MS m/z (ESI): 383.2 [M+1]

Step 6 [5-[3-Methyl-1-(2-methylpyridin-3-yl)-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline-8 Methyl-pyridin-2-yl]aminocarbamate

The crude product was 8-(6-aminopyridin-3-yl)-3-methyl-1-(2-methylpyridin-3-yl)-1 H -imidazole [4,5- c ]quinoline-2 ( 3H )-ketone 55f (80 mg, 0.21 mmol) was dissolved in 10 mL of dichloromethane. N,N -diisopropylethylamine (135 mg, 1.05 mmol) was added, and the mixture was cooled to 0 ° C. Methyl chloroformate (22 mg, 0.23 mmol) was taken up to room temperature and stirred 1 hr. The reaction was quenched by the addition of 10 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL) with saturated sodium bicarbonate (25 mL×2), saturated ammonium chloride (25 mL×2) and saturated The sodium salt solution was washed (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. 1-(2-methylpyridin-3-yl)-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl Methyl carbamide 55 (8 mg, light brown solid), yield: 8.9%.

MS m/z (ESI): 441.4 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.37 (s, 1H), 9.06 (s, 1H), 8.78 (d, 1H), 8.15 (d, 2H), 8.10 (d, 1H), 7.94 (d, 1H), 7.88 (d, 1H), 7.80 (d, 1H), 7.59-7.62 (m, 1H), 6.98 (s, 1H), 3.68 (s, 3H), 3.64 (s, 3H), 2.36(s,3H)

Example 56 [5-[1-(3-Chloro-4-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline-8 Methyl-pyridin-2-yl]aminocarbamate

The crude product was 8-(6-aminopyridin-3-yl)-1-(3-chloro-4-fluorophenyl)-3-methyl- 1H -imidazole[4,5- c ]quinoline-2 ( 3H )-one 54a (40 mg, 0.01 mmol) was dissolved in 10 mL of dichloromethane, triethylamine (28 mg, 0.29 mmol) was added, and the mixture was cooled to 0 ° C, and methyl chloroformate was added dropwise. Mg, 0.11 mmol), and the reaction was stirred for 12 hours. After adding 10 mL of water and extracting with dichloromethane (10 mL×3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system A. The title product [5-[1-(3-chloro-4-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quina Methyl oxo-8-yl]pyridin-2-yl]carbamate 56 (8 mg, brown solid), yield: 17.7%.

MS m/z (ESI): 441.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.41 (s, 1H), 9.03 (s, 1H), 8.25 (s, 1H), 8.15-8.1 (m, 1H), 7.95-7.88 (m, 2H), 7.80 (d, 1H), 7.70-7.61 (m, 2H), 7.24 (s, 1H), 4.13 (s, 3H), 3.69 (s, 3H)

Example 57 2-cyano- N- [5-[3-methyl-2-keto-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1 H -imidazole [4, 5- c ]quinoline-8-yl]pyridin-2-yl]acetamide

8-(6-Aminopyridin-3-yl)-3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazole [4,5- c ]quinoline-2 ( 3H )-ketone 35f (70 mg, 0.16 mmol) was dissolved in 10 mL of dichloromethane, 0.5 mL of N,N -diisopropylethylamine was added, the mixture was cooled to 0 ° C, and 2-cyano B was added dropwise. Chloroplatin 33b (500 mg, 4.85 mmol) was further added to 4-dimethylaminopyridine (10 mg, cat.), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched by the addition of 20 mL of saturated sodium hydrogen carbonate solution, and extracted with dichloromethane (50 mL). The organic phase was successively saturated with sodium bicarbonate (25 mL×2) and saturated ammonium chloride solution (25 mL) ×2) Washed with a saturated sodium chloride solution (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Cyano- N- [5-[3-methyl-2-keto-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1 H -imidazole [4,5- c ]Quinoline-8-yl]pyridin-2-yl]acetamide 57 (15 mg, red solid), yield: 18.8%.

MS m/z (ESI): 503.3 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.05 (s, 1H), 9.04 (s, 1H), 8.22 (s, 1H), 8.15 (d, 1H), 8.09 (t, 3H), 7.92 (br, 2H), 7.86 (d, 1H), 7.12 (s, 1H), 5.75 (s, 2H), 3.62 (s, 3H)

Example 58 8-(5-Acetylpyridin-3-yl)-3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazole [4,5- c ]quinoline-2 ( 3 H )-ketone

8-Bromo-3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one 35e (150 mg , 0.36 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-[(trimethyldecyl) Ethynyl]pyridine 44c (128 mg, 0.43 mmol), tetrakistriphenylphosphine palladium (85 mg, cat.) and sodium carbonate (165 mg, 1.07 mmol) were dissolved in 6 mL of dioxane and water (V/V = 2:1) In a mixed solvent, the mixture was heated to 110 ° C and stirred for 3 hours. 15 mL of water and 25 mL of dichloromethane were added, and the extract was separated. The organic phase was washed with water (15 mL×2) and saturated sodium chloride solution (15 mL×2), dried over anhydrous magnesium sulfate and filtered. The resulting residue was purified by EtOAc (EtOAc) eluting Base- 1H -imidazole [4,5- c ]quinolin-2( 3H )-one 58 (25 mg, yellow solid), yield: 15.8%.

MS m/z (ESI): 445.3 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.06 (s, 1H), 8.62 (s, 1H), 8.54 (s, 1H), 8.22 (s, 1H), 8.14 (d, 1H), 8.03 (t, 2H), 7.97 (t, 2H), 7.77 (s, 1H), 7.12 (s, 1H), 3.61 (s, 3H)

Example 59 8-(5-Acetylpyridin-3-yl)-1-(2-methoxypyridin-3-yl)-3-methyl-1 H -imidazole [4,5- c ]quinoline-2 ( 3 H )-ketone

The crude product was 8-bromo-1-(2-methoxypyridin-3-yl)-3-methyl- 1H -imidazole[4,5- c ]quinolin-2( 3H )-one 42e (59 Mg, 0.20 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-[(trimethyldecyl) Ethyl acetyl] pyridine 44c (50 mg, 0.13 mmol), tetrakistriphenylphosphine palladium (30 mg, cat.) and sodium carbonate (41 mg, 0.39 mmol) dissolved in 8 mL of dioxane and water (V/V =3:1) In a mixed solvent, the mixture was heated to 110 ° C and stirred for 3 hours. 15 mL of water and 25 mL of dichloromethane were added, and the extract was separated. The organic phase was washed with water (15 mL×2) and saturated sodium chloride solution (15 mL×2), dried over anhydrous magnesium sulfate and filtered. The residue obtained was purified by EtOAc (EtOAc) eluting Methyl-1 H -imidazole [4,5- c ]quinolin-2( 3H )-one 59 (6 mg, brown solid), yield: 11.3%.

MS m/z (ESI): 408.3 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.06 (s, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.51 (d, 1H), 8.20-8.15 (m, 2H) , 8.00 (d, 1H), 7.89 (s, 1H), 7.37 (t, 1H), 7.20 (s, 1H), 4.56 (s, 1H) 3.78 (s, 3H), 3.63 (s, 3H)

Example 60 2-[4-[8-[5-(Cyanomethoxy)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 - c ]quinolin-1-yl]phenyl]-2-methylpropionitrile

first step 2-[(5-bromopyridin-3-yl)oxy]acetonitrile

5-Bromopyridin-3-ol 31a (500 mg, 2.87 mmol), potassium carbonate (1.20 g, 8.61 mmol) and 2-bromoacetonitrile (420 mg, 3.50 mmol) were dissolved in 10 mL acetonitrile and stirred for 1.5 hours. . The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The title product 2-[(5-bromopyridin-3-yl)oxy]acetonitrile 60a (360 mg, m.

Second step 2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]oxy]acetonitrile

2-[(5-Bromopyridin-3-yl)oxy]acetonitrile 60a (360 mg, 1.50 mmol), dipentane diboron (457 mg, 1.80 mmol), 1,1'-bis(diphenyl) Phosphine) ferrocene] palladium dichloride (110 mg, 0.15 mmol) and potassium acetate (441 mg, 4.50 mmol) are dissolved in 20 mL of dioxane and heated to 85 ° C. Reaction for 3 hours. The mixture was cooled to room temperature, passed through a pad of celite, and the filtrate was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 2-[[5-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)pyridin-3-yl]oxy]acetonitrile 60b (560 mg, EtOAc).

third step 2-[4-[8-[5-(Cyanomethoxy)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 - c ]quinolin-1-yl]phenyl]-2-methylpropionitrile

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl] 2-methyl-propionitrile 1k (100 mg, 0.24 mmol), crude 2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) Alkan-2-yl)pyridin-3-yl]oxy]acetonitrile 60b (375 mg, 0.48 mmol), bis(triphenylphosphine)palladium dichloride (50 mg, cat.) and potassium carbonate (100 mg, 0.72 mmol) was dissolved in 15 mL of a mixed solvent of N , N -dimethylformamide and water (V/V=2:1), and the mixture was heated to 100 ° C and stirred for 3 hours. The mixture was cooled to room temperature, and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Filtration, the filtrate was concentrated under reduced pressure and purified to purified tolud eluted to elute to afford the title product 2-[4-[8-[5-(cyanomethoxy)pyridin-3-yl]-3- Methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl]-2-methylpropanenitrile 60 (16 mg, brown solid ), yield: 14.1%.

MS m/z (ESI): 475.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.06 (s, 1H), 8.41 (d, 1H), 8.17 (t, 2H), 8.1 (d, 1H), 7.89 (d, 2H), 7.75 (t, 2H), 7.61 (s, 1H), 7.18 (s, 1H), 5.34 (s, 2H), 3.63 (s, 3H), 1.83 (s, 6H)

Example 61 2-cyano- N- [5-[1-(2-methoxypyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4, 5- c ]quinoline-8-yl]pyridin-2-yl]acetamide

The crude product is 8-(6-aminopyridin-3-yl)-1-(2-methoxypyridin-3-yl)-3-methyl-1 H -imidazole [4,5- c ]quinoline- 2( 3H )-one 42f (80 mg, 0.20 mmol) was dissolved in 6 mL of dichloromethane, triethylamine (0.20 mL, 0.40 mmol) was added, and the mixture was cooled to 0 ° C. Chloroplatin 33b (31 mg, 0.30 mmol) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product 2-cyano - N - [5- [1- ( 2- methoxy-pyridin-3-yl) - 3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl]pyridin-2-yl]acetamide 61 (18 mg, yellow Solid), Yield: 19.4%.

MS m/z (ESI): 466.2 [M+1]

¹ H HMR (400 MHz, DMSO- d ₆ ): δ 11.04 (s, 1H), 9.04 (s, 1H), 8.52 (d, 1H), 8.30 (s, 1H), 8.13-8.20 (m, 3H) , 7.88-7.97 (m, 2H), 7.37 (t, 1H), 7.19 (s, 1H), 4.02 (d, 2H), 3.78 (s, 3H), 3.63 (s, 3H)

Example 62 2-[4-[8-[6-(methoxymethyl)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 - c ]quinolin-1-yl]phenyl]-2-methylpropionitrile

first step Methyl 5-bromopyridinecarboxylate

5-Bromopicolinic acid 62a (1.81 g, 8.97 mmol) was dissolved in 47 mL of methanol, and then argon chloride (4.7 mL, 19.27 mmol) was added under stirring, and the mixture was heated to 65 ° C and stirred for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and then 100 mL of saturated sodium hydrogen carbonate solution and 100 mL of ethyl acetate. The extract was separated and the organic layer was dried with mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

Second step (5-bromopyridin-2-yl)methanol

The crude methyl 5-bromopicolinate 62b (560 mg, 2.60 mmol) was dissolved in 20 mL of ethanol, sodium borohydride (197 mg, 5.20 mmol) was added, and the mixture was heated to 60 ° C and stirred for 4 hours. After cooling to room temperature, the reaction was quenched by the addition of 20 mL of EtOAc. EtOAc (EtOAc) Bromopyridin-2-yl)methanol 62c (256 mg, as colorless oil).

third step 5-bromo-2-(methoxymethyl)pyridine

The crude (5-bromopyridin-2-yl)methanol 62c (256 mg, 1.36 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled to 0 ° C in ice water, and then potassium butoxide (230 mg, 2 mmol) was added and stirred. After 30 minutes, another 3 drops of methyl iodide were added, and the reaction was stirred at room temperature for 12 hours. 50 mL of water and 50 mL of ethyl acetate were added, and the mixture was separated and evaporated. 200 mg, light yellow solid), the product was taken to the next step without purification.

the fourth step 2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Cyclopentan-2-yl)pyridine

Crude 5-bromo-2-(methoxymethyl)pyridine 62d (200 mg, 0.99 mmol), dipentazone diboron (330 mg, 1.30 mmol), 1,1'-bis(diphenylphosphine) Ferrocene] palladium dichloride (20 mg, cat.) and potassium acetate (290 mg, 2.90 mmol) were dissolved in 10 mL of ethylene glycol dimethyl ether, and heated to 80 ° C to stir the reaction for 3 hours. Filtration and concentration of the filtrate under reduced pressure afforded the crude title product 2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2-yl)pyridine 62e (500 mg, mp.

the fifth step 2-[4-[8-[6-(methoxymethyl)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 - c ]quinolin-1-yl]phenyl]-2-methylpropionitrile

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl] 2-methyl-propionitrile 1k (115 mg, 0.27 mmol), crude 2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)pyridine 62e (82 mg, 0.32 mmol), tetrakistriphenylphosphine palladium (63 mg, cat.) and potassium carbonate (113 mg, 0.82 mmol) dissolved in 2 mL B In a mixed solvent of glycol dimethyl ether and water (V/V = 1:1), the mixture was heated to 100 ° C and stirred for 8 hours. After cooling to room temperature, 20 mL of water and 20 mL of ethyl acetate were added, and the mixture was separated, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product 2-[4-[8-[6-(methoxymethyl)pyridin-3-yl]-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [ 4,5- c ]quinolin-1-yl]phenyl]-2-methylpropanenitrile 62 (30 mg, m.p.).

MS m/z (ESI): 464.5 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.03 (s, 1H), 8.49 (s, 1H), 8.14 (d, 1H), 7.97 (d, 1H), 7.78 (d, 2H), 7.76 (d, 2H), 7.72 (d, 1H), 7.40 (d, 1H), 7.1 (d, 1H), 4.55 (s, 2H), 3.62 (s, 3H), 3.39 (s, 3H), 1.82 ( s,6H)

Example 63 8-(5-ethynylpyridin-3-yl)-3-methyl-1-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]-1 H -imidazole [4,5 - c ] quinoline-2(3 H )-one

The crude product was 8-bromo-3-methyl-1-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]-1 H -imidazole [4,5- c ]quinolin-2 ( 3 H )-ketone 19e (250 mg, 0.34 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5 -[(Trimethyldecyl)ethynyl]pyridine 44c (124 mg, 0.41 mmol), tetrakistriphenylphosphine palladium (40 mg, cat.) and sodium carbonate (80 mg, 0.69 mmol) dissolved in 10 mL In a mixed solvent of methane and water (V/V = 1:1), the mixture was heated to 120 ° C and stirred for 3 hours. Add 50 mL of dichloromethane, wash with water (15 mL×2) and saturated sodium chloride solution (15 mL×2) successively, dry over anhydrous magnesium sulfate, and then filtered, and the filtrate is concentrated under reduced pressure. The obtained residue was purified to give the title product, 8-(5-ethynylpyridin-3-yl)-3-methyl-1-[2-methyl-6-(trifluoromethyl)pyridin-3-yl] -1 H - imidazo [4,5- c] quinolin -2 (3 H) - -one 63 (17 mg, yellow solid), yield: 10.8%.

MS m/z (ESI): 460.1 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.56 (s, 1H), 8.73 (d, 2H), 8.48 (t, 2H), 8.21 (d, 1H), 8.02 (d, 2H), 7.03 (s, 1H), 3.69 (s, 3H), 2.47 (s, 3H)

Example 64 (5-(1-(3-Fluoro-2-methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline- Methyl 8-yl)pyridin-2-yl)carbamate

8-(6-Aminopyridin-3-yl)-1-(3-fluoro-2-methyl-phenyl)-3-methyl-1 H -imidazole [4,5- c ]quinoline at 0 °C Porphyrin-2( 3H )-one 36f (160 mg, 0.40 mmol) was dissolved in 50 mL of dichloromethane, triethylamine (45 mg, 0.44 mmol) was added, and then 10 mL of methyl chloroformate was slowly added dropwise. 42 mg, 0.44 mmol) in dichloromethane, 1 h at 0 ° C, then triethylamine (90 mg, 0.88 mmol) and methyl chloroformate (84 mg, 0.88 mmol). 50 mL of a saturated sodium hydrogencarbonate solution was added, the layers were separated, and the organic layer was evaporated. Methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl)pyridin-2-yl)carbamic acid Methyl ester 64 (22 mg, white solid), yield: 12.0%.

MS m/z (ESI): 458.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.88 (d, 1H), 8.27 (m, 2H), 8.05 (d, 1H), 7.93 (s, 1H), 7.80 (d, 1H), 7.66 (d, 1H), 7.41-7.30 (m, 2H), 7.17 (s, 1H), 7.16 (s, 1H), 3.87 (s, 3H), 3.76 (s, 3H), 2.15 (s, 3H)

Example 65 2-(4-(8-(5-(2-fluoroethoxy)-6-methylpyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl)-2-methylpropanenitrile

first step 5-bromo-3-(2-fluoroethoxy)-2-methylpyridine

5-bromo-2-methylpyridin-3-ol 65a (1.0 g, 5.30) in an ice water bath Methyl), 2-fluoroethanol (374 mg, 5.80 mmol) and triphenylphosphine (1.67 g, 6.30 mmol) were dissolved in 40 mL of tetrahydrofuran, and diisopropyl azodicarboxylate (1.29 g, 6.30) was slowly added dropwise. (mmol), the reaction was stirred for 1 hour under ice-water bath, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. 3-(2-Fluoroethoxy)-2-methylpyridine 65b (1.54 g, m.

Second step 3-(2-Fluoroethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine

The crude 5-bromo-3-(2-fluoroethoxy)-2-methylpyridine 65b (1.54 g, 5.30 mmol), dipentane diboron (1.60 g, 6.40 mmol), 1,1'- double (Diphenylphosphine)ferrocene]Palladium dichloride (190 mg, 0.26 mmol) and potassium acetate (1.0 g, 10.60 mmol) were dissolved in 20 mL of dioxane, and stirred at 120 ° C for 2 hours. The mixture was cooled to room temperature, then evaporated, evaporated, evaporated, evaporated, evaporated. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 65c (3.0 g, mp. One step reaction.

MS m/z (ESI): 282.3 [M+1]

third step 2-(4-(8-(5-(2-fluoroethoxy)-6-methylpyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl)-2-methylpropanenitrile

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazole[4,5- c ]quinolin-1-) was added to the reaction flask Phenyl]-2-methyl-propanenitrile 1k (550 mg, 1.31 mmol), crude 3-(2-fluoroethoxy)-2-methyl-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 65c (440 mg, 1.57 mmol), 1,1'-bis(diphenylphosphino)ferrocene] Palladium chloride (48 mg, cat.), potassium carbonate (540 mg, 3.92 mmol) and 12 mL of N , N -dimethylacetamide were stirred and stirred at 120 ° C for 3 hours. After cooling to room temperature, 120 mL of dichloromethane and 100 mL of water were added, and the mixture was separated. The organic phase was washed with water (25 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give the title product 2-(4-(8-(5-(2-fluoroethoxy)-6-methylpyridin-3-yl)-3-methyl-2-one Base-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl)-2-methylpropanenitrile 65 (230 mg, white solid), yield: 35.0 %.

MS m/z (ESI): 496.4 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.88 (s, 1H), 8.27-8.31 (m, 1H), 8.05-8.08 (m, 1H), 7.78-7.84 (m, 3H), 7.62-7.68 (m) , 2H), 7.32 (s, 1H), 7.13 (s, 1H), 4.93 (t, 1H), 4.81 (t, 1H), 4.31 (t, 1H), 4.24 (t, 1H), 3.75 (s, 3H), 2.56 (s, 3H), 1.87 (s, 6H)

Example 66 2-(4-(8-(5-(2-methoxyethoxy)pyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [ 4,5- c ]quinolin-1-yl)phenyl)-2-methylpropanenitrile

first step 3-bromo-5-(2-methoxyethoxy)pyridine

Dissolve 5-bromopyridin-3-ol (500 mg, 2.87 mmol), 2-methoxyethanol (213 mg, 2.80 mmol) and triphenylphosphine (900 mg, 3.40 mmol) in 20 mL of tetrahydrofuran, 0 Diisopropyl azodicarboxylate (680 mg, 3.40 mmol) was added dropwise at °C, and the mixture was reacted at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The product 3-bromo-5-(2-methoxyethoxy)pyridine 66b (550 mg, white solid), yield: 83.0%.

MS m/z (ESI): 279.1 [M+1]

Second step 3-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

3-bromo-5-(2-methoxyethoxy)pyridine 66b (550 mg, 2.40 mmol), dipentazone diboron (720 mg, 2.80 mmol), 1,1'- was added to the reaction flask. Bis(diphenylphosphino)ferrocene]palladium dichloride (88 mg, 0.12 mmol) and potassium acetate (706 mg, 7.20 mmol) and 15 mL of dioxane, plus The reaction mixture was refluxed for 3 hours, and the reaction mixture was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjj Filtration and concentration of the filtrate under reduced pressure afforded crude title product: 3-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclic pentan-2-yl)pyridine 66c (500 mg, black liquid).

third step 2-(4-(8-(5-(2-methoxyethoxy)pyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [ 4,5- c ]quinolin-1-yl)phenyl)-2-methylpropanenitrile

2-[4-[(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazole[4,5- c ]quinolin-1-) was added to the reaction flask Phenyl]-2-methyl-propanenitrile 1k (400 mg, 0.95 mmol), crude 3-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)pyridine 66c (300 mg, 1.07 mmol), tetrakis(triphenyl)phosphine palladium (110 mg, 0.095 mmol), sodium carbonate (210) Mg, 1.90 mmol) and 6 mL of a mixed solvent of dioxane and water (V/V = 5:1), stirred at 90 ° C for 16 hours, concentrated under reduced pressure, purified by HPLC preparative chromatography with eluent system A The residue obtained gave the title product 2-(4-(8-(2-methoxyethoxy)pyridin-3-yl)-3-methyl-2- keto-2, 3- Hydrogen-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl)-2-methylpropanenitrile 66 (100 mg, m.p.).

MS m/z (ESI): 494.4 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.02 (s, 1H), 8.29 (d, 1H), 8.14-8.11 (m, 1H), 7.99-7.96 (m, 2H), 7.86 (s, 1H) ), 7.76 (s, 1H), 7.60 (s, 1H), 7.40-7.35 (m, 2H), 7.15 (s, 1H), 4.24 - 4.22 (m, 2H), 3.71-3.69 (m, 2H), 3.61(s,3H), 3.33(s,3H),1.82(s,6H)

Example 67 1-(4-(Fluoro-3-(trifluoromethyl)phenyl)-8-(5-(2-methoxyethoxy)pyridine)-3-yl)-3-methyl-1 H -imidazole [4,5- c ]quinoline-2(3 H )-one

8-Bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 52e (315 mg, 0.72 mmol) was dissolved in 10 mL of tetrahydrofuran and added 3-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)pyridine 66c (300 mg, 1.07 mmol), bis(triphenylphosphine)palladium dichloride (25 mg, 0.036 mmol) and potassium carbonate (248 mg, 1.80 mmol) Then, 2 mL of water was added, and the mixture was reacted at 100 ° C for 1 hour. The reaction mixture was filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated. The filtrate was concentrated under reduced pressure, and the residue obtained was purified to purified crystals eluted eluted elution -methoxyethoxy)pyridine)-3-yl)-3-methyl-1 H -imidazole [4,5- c ]quinolin-2( 3H )-one 67 (30 mg, white solid) , Yield: 8.2%.

MS m/z (ESI): 513.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.07 (s, 1H), 8.30 (d, 2H), 8.13 (t, 3H), 8.02 (d, 1H), 8.00 (t, 1H), 7.35 ( s, 1H), 7.25 (s, 1H), 4.18 (d, 2H), 3.72 (d, 2H), 3.63 (s, 3H), 2.51 (s, 3H)

Example 68 2-(4-(8-(5-(2-methoxyethoxy)-6-methylpyridin-3-yl)-3-methyl-2-keto-2,3-dihydro- 1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl)-2-methylpropanenitrile

first step 5-bromo-3-(2-methoxyethoxy)-2-methylpyridine

5-Bromo-2-methylpyridin-3-ol 68a (1.0 g, 5.35 mmol), 2-methoxyethanol (488 mg, 6.42 mmol) and triphenylphosphine (1.68 g, 6.42 mmol) Dissolved in 50 mL of tetrahydrofuran, and slowly dropwise added diisopropyl azodicarboxylate (1.30 g, 6.42 mmol), and allowed to react to room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. mL water, The organic phase was washed with a saturated aqueous solution of sodium chloride (50 mL). Methoxyethoxy)-2-methylpyridine 68b (962 mg, pale yellow oil), yield: 73.1%.

MS m/z (ESI): 248.0 [M+2]

Second step 3-(2-methoxyethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Pyridine

5-Bromo-3-(2-methoxyethoxy)-2-methylpyridine 68b (960 mg, 3.90 mmol), dipentane diboron (1.19 g, 4.68 mmol), 1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride (100 mg, cat.) and potassium acetate (1.34 g, 13.65 mmol) dissolved in 50 mL of dioxane, reacted at 100 ° C for 4 hours, algae The reaction mixture was filtered, and then filtered, evaporated, evaporated, evaporated, evaporated, evaporated, -methoxyethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 68c (1.55 g, s, brown oil), product was used for the next step without purification.

MS m/z (ESI): 294.3 [M+2]

third step 2-(4-(8-(5-(2-methoxyethoxy)-6-methylpyridin-3-yl)-3-methyl-2-keto-2,3-dihydro- 1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl)-2-methylpropanenitrile

2-(4-(8-Bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl)- 2-methyl-propionitrile 1k (210 mg, 0.50 mmol), 3-(2-methoxyethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)pyridine 68c (440 mg, 1.50 mmol), tetrakis(triphenyl)phosphine palladium (116 mg, 0.10 mmol) and potassium carbonate (210 mg, 0.15 mmol) was dissolved in 30 mL of dimethyl ether and water (V/V = 1:1) in a mixed solvent, and reacted at 120 ° C for 4 hours. The reaction solution was filtered through celite, and ethyl acetate (100 mL) was added. The extract was extracted with ethyl acetate (100 mL×2), EtOAcjjjjjjjjj 4-(8-(5-(2-methoxyethoxy)-6-methylpyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H - Imidazo[4,5- c ]quinolin-1-yl)phenyl)-2-methylpropanenitrile 68 (98 mg, EtOAc).

MS m/z (ESI): 508.4 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.86 (s, 1H), 8.25 (d, 1H), 8.00 (s, 1H), 7.79 (m, 3H), 7.64 (d, 2H), 7.30 (s, 1H), 7.15 (s, 1H), 4.16 (t, 2H), 3.86 (t, 2H), 3.74 (s, 3H), 3.51 (s, 3H), 2.54 (s, 3H), 1.87 (s, 6H) )

Example 69 8-(5-(2-Methoxyethoxy)-6-methylpyridin-3-yl)-3-methyl-1-(3-(trifluoromethyl)phenyl)-1 H -imidazole [4,5- c ]quinoline-2(3 H )-one

8-Bromo-3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one 35e (211 mg , 0.50 mmol), 3-(2-methoxyethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane Pentan-2-yl)pyridine 68c (440 mg, 1.50 mmol), tetrakis(triphenyl)phosphine palladium (116 mg, 0.10 mmol) and potassium carbonate (210 mg, 1.50 mmol) were dissolved in 30 mL of dimethyl ether. The reaction mixture was reacted with water (V/V=1:1) at 120 ° C for 4 hours, and the reaction solution was filtered through celite, 100 mL ethyl acetate was added, and the layers were separated, and the aqueous phase was extracted with ethyl acetate (100 mL×2) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated evaporated. -6-methylpyridine)-3-yl)-3-methyl-1-(3-(trifluoromethyl)phenyl)-1 H -imidazole [4,5- c ]quinoline-2 ( 3H )-ketone 69 (132 mg, pale yellow solid), yield: 52.0%.

MS m/z (ESI): 509.4 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.88 (s, 1H), 8.27 (d, 1H), 8.16 (s, 1H), 7.74-7.91 (m, 2H), 7.86-7.83 (m, 3H), 7.30 (s, 1H), 6.99 (s, 1H), 4.06 (t, 2H), 3.85 (t, 2H), 3.75 (s, 3H), 3.53 (s, 3H), 2.55 (s, 3H)

Example 70 8-(5-(2-Fluoroethoxy)-6-methylpyridin-3-yl)-3-methyl-1-(3-(trifluoromethyl)phenyl)-1 H -imidazole [4,5- c ]quinoline-2(3 H )-one

8-Bromo-3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one 35e (300 mg , 0.71 mmol) dissolved in 6 mL of N , N -dimethylformamide, followed by 3-(2-fluoroethoxy)-2-methyl-5-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)pyridine 65c (299 mg, 1.07 mmol), bis(triphenylphosphine)palladium dichloride (25 mg, 0.036 mmol) , potassium carbonate (245 mg, 1.78 mmol) and 2 mL of water, reacted at 100 ° C for 1 hour, the reaction solution was washed with water (50 mL × 2), then extracted with ethyl acetate (30 mL × 3), combined organic phase, anhydrous The organic layer was dried (MgSO4), filtered, evaporated, evaporated 3-yl)-3-methyl-1-(3-(trifluoromethyl)phenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one 70 (40 mg , white solid), Yield: 11.4%.

MS m/z (ESI): 497.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.89 (s, 1H), 8.29-8.18 (m, 2H), 7.91 (s, 2H), 7.85-7.80 (m, 4H), 6.98 (s, 1H), 4.91(s,1H), 4.79(s,1H), 4.18(d,2H), 3.75(s,3H),2.56(s,3H)

Example 71 2-(4-(8-(5-(difluoromethoxy)pyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 - c ]quinolin-1-yl)phenyl)-2-methylpropanenitrile

3-(Difluoroethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 71a (190 mg , 0.70 mmol, prepared by the well-known method "patent EP1726584", 2-[4-[(8-bromo-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [ 4,5- c ]quinolin-1-yl)phenyl]-2-methyl-propanenitrile 1k (150 mg, 0.36 mmol), 1,1'-bis(diphenylphosphino)ferrocene] Palladium chloride (13 mg, 0.018 mmol) and potassium carbonate (150 mg, 1.08 mmol) were sequentially dissolved in 6 mL of a mixed solvent of N , N -dimethylacetamide and water (V/V=5:1). The reaction was stirred at 120 ° C for 2 hours, 20 mL of dichloromethane was added, filtered, and the filtrate was washed with water (10 mL × 2), and the organic layer was dried over anhydrous sodium sulfate. The residue obtained was purified to give the title product 2-(4-(8-(5-(2-difluoromethoxy)pyridin-3-yl)-3-methyl-2-one-2 , 3-dihydro- 1H -imidazo[4,5- c ]quinolin-1-yl)phenyl)-2-methylpropanenitrile 71 (36 mg, white solid).

MS m/z (ESI): 486.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.07 (s, 1H), 8.47-8.50 (d, 1H), 8.34-8.37 (d, 1H), 8.16-8.20 (d, 1H), 7.98-8.03 (dd , 1H), 7.85-7.90 (d, 2H), 7.74-7.80 (d, 2H), 7.68 (br, 1H), 7.39 (s, 1H), 7.21 (s, 1H), 3.63 (s, 3H), 1.82(s,6H)

Example 72 2-(4-(8-(5-(Difluoromethoxy)-6-methylpyridin-3-yl)-3-methyl-2-keto-2,3-dihydro-1 H - Imidazo[4,5- c ]quinolin-1-yl)phenyl)-2-methylpropanenitrile

3-(Difluoroethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine 72a (200 mg, 0.70 mmol, prepared by the known method "Patent EP1726584"), 2-[4-[(8-bromo-3-methyl-2-keto-2,3-dihydro-) 1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl]-2-methyl-propanenitrile 1k (150 mg, 0.36 mmol), 1,1'-bis(diphenylphosphine) Ferrocene] palladium dichloride (13 mg, 0.018 mmol) and potassium carbonate (150 mg, 1.08 mmol) were dissolved in 6 mL of N , N -dimethylacetamide and water (V/V=5:1). In a mixed solvent, the reaction was stirred at 120 ° C for 2 hours, 50 mL of dichloromethane was added, washed with water (15 mL × 2), and the organic layer was dried over anhydrous sodium sulfate. The obtained residue was purified to give the titled product 2-(4-(8-(5-(difluoromethoxy)-6-methylpyridin-3-yl)-3-methyl-2. -keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl)phenyl)-2-methylpropanenitrile 72 (26 mg, yellow solid) : 14.6%.

MS m/z (ESI): 500.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.06 (s, 1H), 8.22-9.19 (d, 1H), 8.15-8.18 (d, 1H), 7.95-7.99 (dd, 1H), 7.84-7.88 (d , 2H), 7.74-7.78 (d, 2H), 7.63 (br, 1H), 7.30 (s, 1H), 7.17-7.20 (d, 1H), 3.63 (s, 3H), 2.44 (s, 3H), 1.82(s,6H)

Example 73 8-(5-(2-Fluoroethoxy)pyridine)-3-yl)-3-methyl-1-(3-(trifluoromethyl)phenyl)-1 H -imidazole [4,5- c ] quinoline-2(3 H )-one

3-(2-Fluoroethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)pyridine 49b (127 mg, 0.47 mmol), 8-bromo-3-methyl-1-[3-(trifluoromethyl)phenyl]-1 H -imidazole [4,5- c ]quinoline-2 (3 H )-ketone 35e (100 mg, 0.24 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (9 mg, 0.012 mmol) and potassium carbonate (98 mg, 0.71 mmol) Dissolved in 6 mL of N , N -dimethylacetamide and water (V/V=5:1) mixed solvent, stirred at 120 ° C for 2 hours, added with 30 mL of dichloromethane and 20 mL of water, layered, The aqueous phase was extracted with methylene chloride (15 mL). EtOAc (EtOAc m. The obtained residue was purified to give the title product, 8-(5-(2-fluoroethoxy)pyridin-3-yl)-3-methyl-1-(3-(trifluoromethyl)phenyl). -1 H - imidazo [4,5- c] quinolin -2 (3 H) - -one 73 (33 mg, yellow oil). yield: 29.0%

MS m/z (ESI): 483.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.27 (s, 1H), 8.32 - 8.36 (d, 1H), 8.23 - 8.31 (m, 2H), 8.14 - 8.19 (m, 2H), 8.06 - 8.13 (m) , 2H), 7.97-8.03 (m, 1H), 7.37-7.42 (m, 1H), 7.21-7.26 (d, 1H), 4.87 (t, 1H), 4.75 (t, 1H), 4.37 (t, 1H) ), 4.31 (t, 1H), 3.66 (s, 3H)

Example 74 1-(3-Fluoro-2-methylphenyl)-8-(5-(2-fluoroethoxy)pyridine)-3-yl)-3-methyl-1 H -imidazole [4,5- c ] quinoline-2(3 H )-one

8-Bromo-1-(3-fluoro-2-methyl-phenyl)-3-methyl-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one 36e (150 Mg, 0.39 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (14 mg, 0.019 mmol) and potassium carbonate (160 mg, 1.16 mmol) were dissolved in 6 mL of N , N - dimethylacetamide and water (V / V = 10: 1 ) mixed solvent, was added 3- (2-fluoroethoxy) -5- (4,4,5,5 -[1,3,2]-dioxaborolan-2-yl)pyridine 49b (207 mg, 0.78 mmol), stirred at 120 ° C for 2 h, then added 10 mL dichloromethane and 6 mL water. The layers were separated and the aqueous phase was extracted with methylene chloride (15 mL). EtOAc (EtOAc) The obtained residue was purified to give the title product 1-(3-fluoro-2-methylphenyl)-8-(5-(2-fluoroethoxy)pyridin-3-yl)-3. Methyl- 1H -imidazole[4,5- c ]quinolin-2( 3H )-one 74 (20 mg, yellow oil), yield: 11.5%.

MS m/z (ESI): 447.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.08 (s, 1H), 8.29-8.32 (d, 1H), 8.14 - 8.19 (m, 2H), 7.99-8.03 (dd, 1H), 7.55-7.60 (m) , 2H), 7.49-7.53 (d, 1H), 7.34-7.37 (d, 1H), 7.12 (s, 1H), 4.89 (t, 1H), 4.77 (t, 1H), 4.40 (t, 1H), 4.32(t,1H), 3.65(s,3H), 2.04(s,3H)

Example 75 1-(3-Fluoro-2-methylphenyl)-8-(5-(2-fluoroethoxy)-6-methylpyridin-3-yl)-3-methyl-1 H -imidazole [ 4,5- c ]quinoline-2(3 H )-one

Add 8-bromo-1-(3-fluoro-2-methyl-phenyl)-3-methyl-1 H -imidazole [4,5- c ]quinoline-2 (3 H ) to the reaction tube. )-ketone 36e (150 mg, 0.39 mmol), 3-(2-fluoroethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)pyridine 65c (218 mg, 0.78 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (14 mg, 0.019 mmol), Potassium carbonate (160 mg, 1.16 mmol) and 6 mL of N , N -dimethylacetamide and water (V/V=10:1) in a mixed solvent, stirred at 120 ° C for 2 hours, added 20 mL of dichloromethane And 4 mL of water, EtOAc, EtOAc (EtOAc)EtOAc. The obtained residue was purified by EtOAc (EtOAc) eluting Pyridin-3-yl)-3-methyl- 1H -imidazole [4,5- c ]quinolin-2( 3H )-one 75 (7 mg, yellow solid), yield: 3.9%.

MS m/z (ESI): 461.4 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.90 (s, 1H), 8.25-8.32 (d, 1H), 8.19 (s, 1H), 7.82-7.89 (dd, 1H), 7.46-7.53 (m, 1H) ), 7.33-7.42 (m, 2H), 7.19-7.23 (d, 1H), 7.00-7.30 (d, 1H), 4.95 (t, 1H), 4.83 (t, 1H), 4.29 (t, 1H), 4.22(t,1H), 3.77(s,3H), 2.58(s,3H), 2.16(s,3H)

Example 76 2-((5-(1-(3-fluoro-2-methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-8-yl)pyridin-3-yl)oxy)acetonitrile

Add 8-bromo-1-(3-fluoro-2-methyl-phenyl)-3-methyl-1 H -imidazole [4,5- c ]quinoline-2 (3 H ) to the reaction tube. )-ketone 36e (150 mg, 0.39 mmol), crude 2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridin-3-yl)oxy)acetonitrile 60b (447 mg, 1.72 mmol), tetratriphenylphosphine palladium (90 mg, 0.078 mmol), potassium carbonate (160 mg, 1.16 mmol) and 6 mL of dimethyl ether and Water (V/V=1:1) mixed solvent, reacted at 110 ° C for 1.5 hours, then reacted at 90 ° C for 16 hours, added 50 mL of ethyl acetate and 20 mL of water, layered, and the organic phase was sequentially water (15 mL × 2) It was washed with a saturated sodium chloride solution (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. (1-(3-Fluoro-2-methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl Pyridin-3-yl)oxy)acetonitrile 76 (3.8 mg, brown solid), yield: 3.0%.

MS m/z (ESI): 440.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.09 (s, 1H), 8.39 (s, 1H), 8.20 (t, 2H), 8.06 (s, 1H), 7.99 (d, 1H), 7.59 (t, 2H), 7.55 (d, 1H), 7.12 (s, 1H); 5.32 (s, 2H), 3.64 (s, 3H), 2.03 (s, 3H)

Example 77 1-(5-(1-(3-fluoro-2-methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole[4,5- c ]quina Porphyrin-8-yl)pyridin-3-yl)-3-methylurea

first step 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine

5-bromopyridin-3-amine (1.0 g, 5.70 mmol), dipentane diboron (1.74 g, 6.84 mmol), 1,1'-bis(diphenylphosphino)ferrocene were sequentially added to the reaction flask. Palladium dichloride (420 mg, 0.57 mmol), potassium acetate (1.12 g, 11.40 mmol) and 10 mL of dioxane, reacted at 110 ° C for 3 hours, the reaction solution was filtered over celite, and the filter cake was washed with dichloromethane. (10 mL × 2), the filtrate was concentrated under reduced pressure to give crude title compound 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 3-Amine 77b (1.25 g, black liquid), product was used in the next step without purification.

Second step 8-(5-Aminopyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-3-methyl-1 H -imidazole [4,5- c ]quinoline-2 ( 3 H )-ketone

Add 8-bromo-1-(3-fluoro-2-methyl-phenyl)-3-methyl-1 H -imidazole [4,5- c ]quinoline-2 (3 H ) to the reaction flask. -ketone 36e (200 mg, 0.52 mmol), crude 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- Amine 77b (137 mg, 0.62 mmol), tetratriphenylphosphine palladium (120 mg, 0.10 mmol), sodium carbonate (165 mg, 1.55 mmol) and 6 mL of dioxane and water (V/V = 3:1) The solvent was mixed, and the mixture was reacted at 110 ° C for 2.5 hours, and further reacted at 90 ° C for 16 hours. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. 3-fluoro-2-methylphenyl)-3-methyl-1 H -imidazo[4,5-c]quinoline-2(3 H )-one 77c (207 mg, mp. It was used in the next step without purification.

MS m/z (ESI): 400.3 [M+1]

third step 1-(5-(1-(3-fluoro-2-methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole[4,5- c ]quina Porphyrin-8-yl)pyridin-3-yl)-3-methylurea

The crude product is 8-(5-aminopyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-3-methyl-1 H -imidazole [4,5- c ]quinoline- 2( 3H )-ketone 77c (206 mg, 0.52 mmol) was dissolved in 10 mL of dichloromethane. phenyl chloroformate (242 mg, 1.55 mmol) was added and the mixture was reacted at 0 ° C for 20 min. After 1 hour, a solution of 1.3 mL of 2 M methylamine tetrahydrofuran was added, and the mixture was reacted at room temperature for 16 hours. The reaction mixture was concentrated under reduced vacuo. -(3-fluoro-2-methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl)pyridine -3-yl)-3-methylurea 77 (10 mg, yellow solid), yield: 5.0%.

MS m/z (ESI): 457.4 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.4 (s, 1H), 8.82 (s, 1H), 8.67 (s, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 8.15 (d, 1H), 7.97(s,1H), 7.78(d,1H); 7.48-7.52(m,1H),7.35(d,1H),7.17(s,1H),6.09(s,1H),3.71(s , 3H), 3.09 (d, 2H), 2.08 (s, 3H)

Example 78 1-(5-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5 - c ]quinoline-8-yl)pyridin-2-yl)-3-methylurea

8-Bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 52e (400 mg, 0.91 mmol) was dissolved in 10 mL of N,N -dimethylformamide, followed by 1-methyl-3-[5-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)-2-pyridine]urea 1n (378 mg, 1.36 mmol), tetratriphenylphosphine palladium (210 mg, 0.18 mmol) and potassium carbonate ( 377 mg, 2.73 mmol), and reacted at 110 ° C for 1 hour. 50 mL of water was added to the mixture. The resulting residue was purified to give the titled product 1-(5-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-methyl-2-one -2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl)pyridin-2-yl)-3-methylurea 78 (20 mg, white solid) 4.3%.

MS m/z (ESI): 511.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.89 (s, 1H), 8.31-8.24 (m, 2H), 7.93-7.80 (m, 3H), 7.56-7.53 (m, 3H), 7.32-7.29 (m) , 2H), 3.75 (s, 3H), 3.04 (s, 3H)

Example 79 1-(5-(1-(3-chloro-3-2-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-8-yl)pyridin-2-yl)-3-methylurea

first step 6-bromo- N- (3-chloro-2-fluorophenyl)-3-nitroquinolin-4-amine

Dissolve 6-bromo-4-chloro-3-nitro-quinoline 1d (1.50 g, 5.22 mmol) in 30 mL of acetic acid, add 3-chloro-2-fluoroaniline (832 mg, 5.72 mmol), stir the reaction 3 hours, the reaction solution was poured into 30 mL of ice water, stirred for 15 minutes, filtered, and the filter cake was dissolved in 100 mL of ethyl acetate and 100 mL of tetrahydrofuran, and then washed with saturated sodium hydrogen carbonate solution (50 mL), and the organic phase was combined. , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N - (3- chloro-2-fluorophenyl) -3-nitro-quinolin-4-amine 79a (2.0 g , white solid), the product was used in the next step without purification.

Second step 6-bromo- N ⁴ -(3-chloro-2-fluorophenyl)quinoline-3,4-diamine

The crude 6-bromo- N- (3-chloro-2-fluorophenyl)-3-nitroquinolin-4-amine 79a (2.0 g, 5.10 mmol) was dissolved in 70 mL of tetrahydrofuran and methanol (V/V = 1:1) In a mixed solvent, lanthanyl nickel (1.0 g, cat.) was added, and the hydrogen was replaced three times. The reaction was stirred for 16 hours, and the reaction mixture was filtered. the crude 6-bromo - N ⁴ - (3- chloro-2-fluorophenyl) quinoline-3,4-diamine 79b (1.0 g, dark brown solid) was used without purification in the next reaction.

third step 8-bromo-1-(3-chloro-2-fluorophenyl)-1 H -imidazo[4,5-c]quinoline-2(3 H )-one

6-Bromo- N ⁴ -(3-chloro-2-fluorophenyl)quinoline-3,4-diamine 79b (1.80 g, 4.90 mmol) and triethylamine (1 mL, 5.90 mmol) were dissolved in 50 Solution A was formed in mL of dichloromethane, and (trichloromethyl)carbonate (1.60 g, 5.40 mmol) was dissolved in 50 mL of dichloromethane, cooled to 0 ° C, and solution A was added dropwise to the solution. The reaction mixture was stirred at room temperature for 16 hours, and the mixture was evaporated, evaporated, evaporated. The resulting residue was slurried with 8 mL of dichloromethane, filtered and the solid was dried in vacuo to give crude title product 8-bromo-1- (3-chloro-2-fluorophenyl) -1 H - imidazo [4,5-c] Quinoline-2( 3H )-one 79c (1.90 g, white solid) was used for the next step without purification.

the fourth step 8-bromo-1-(3-chloro-2-fluorophenyl)-3-methyl-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude product was 8-bromo-1-(3-chloro-2-fluorophenyl)-1 H -imidazole [4,5-c]quinolin-2( 3H )-one 79c (1.90 g, 4.80 mmol). Methyl iodide (0.9 mL, 14.40 mmol) and tributylammonium bromide (310 mg, 0.96 mmol) were dissolved in 30 mL of dichloromethane, and 15 mL of sodium hydroxide (576 mg, 14.40 mmol) was added and stirred. After the reaction was carried out for 16 hours, the reaction mixture was poured into water (30 mL), EtOAc (EtOAc) The ester was beaten, filtered, and dried in vacuo to give the title product as crude-bromo-1-(3-chloro-2-fluorophenyl)-3-methyl- 1H -imidazole[4,5- c ]quinoline- 2( 3H )-one 79d (1.70 g, light yellow solid), product was used for the next step without purification.

the fifth step 1-(5-(1-(3-chloro-3-2-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-8-yl)pyridin-2-yl)-3-methylurea

Crude 8-Bromo-1-(3-chloro-2-fluorophenyl)-3-methyl-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 79d (203 mg , 0.50 mmol) dissolved in 10 mL of N,N -dimethylformamide, followed by 1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2 - dioxaborolan-2-yl)-2-pyridine]urea 1n (208 mg, 0.75 mmol), tetrakistriphenylphosphine palladium (115 mg, 0.10 mmol) and potassium carbonate (207 mg, 1.50) The reaction mixture is stirred at 110 ° C for 1 hour. The reaction mixture is extracted with water (20 mL) and ethyl acetate (30 mL×3). The residue obtained was purified by eluent system A to give the title product 1-(5-(1-(3-chloro-3-2-fluorophenyl)-3-methyl-2- </RTI> -Dihydro- 1H -imidazo[4,5- c ]quinolin-8-yl)pyridin-2-yl)-3-methylurea 79 (50 mg, white solid), yield: 21.0%.

MS m/z (ESI): 477.1 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.39 (s, 1H), 9.05 (s, 1H), 8.25 (s, 1H), 8.14 (d, 1H), 7.89-8.01 (m, 3H), 7.51-7.70 (m, 4H), 7.21 (s, 1H). 3.64 (s, 3H), 2.74 (s, 3H)

Example 80 (5-(1-(3-Chloro-2-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline-8 Methyl-pyridin-2-yl)carbamate

8-Bromo-1-(3-chloro-2-fluorophenyl)-3-methyl-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 79d (203 mg, 0.50 mmol) dissolved in 10 mL of N,N -dimethylformamide and added (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) Methyl-2-yl)pyridin-2-yl)carbamate 80a (208 mg, 0.75 mmol), tetratriphenylphosphine palladium (115 mg, 0.10 mmol) and potassium carbonate (207 mg, 1.50 mmol), 110 The mixture was reacted for 1 hour, and the mixture was extracted with water (20 mL) and ethyl acetate (30 mL×3). The resulting residue was purified to give the title product (5-(1-(3-chloro-2-fluorophenyl)-3-methyl-2- keto-2,3-dihydro-1 H -imidazole Methyl [4,5- c ]quinolin-8-yl)pyridin-2-yl)carbamate 80 (35 mg, white solid).

MS m/z (ESI): 475.9 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.06 (s, 1H), 8.26 (s, 1H), 8.16 (d, 1H), 7.87-7.97 (m, 6H), 7.62 (d, 1H), 7.25(s,1H), 3.64(d,6H)

Example 81 1-Methyl-3(5-(3-methyl-1-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-2-one- 2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl)pyridin-2-yl)urea

first step 8-bromo-3-methyl-1-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-1 H -imidazole [4,5- c ] Quinoline-2(3 H )-one

8-Bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 52e (200 mg, 0.45 mmol) was dissolved in 10 mL of N,N -dimethylformamide, and 1-methylpiperazine (91 mg, 0.91 mmol) and potassium carbonate (251 mg, 1.82 mmol), 75 After reacting for 48 hours at ° C, 10 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (20 mL×3). The resulting residue was purified to give the title product, 8-bromo-3-methyl-1-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)- 1H -Imidazo[4,5- c ]quinolin-2( 3H )-one 81a (150 mg, white solid).

MS m/z (ESI): 522.3 [M+1]

Second step 1-Methyl-3(5-(3-methyl-1-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-2-one- 2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl)pyridin-2-yl)urea

8-Bromo-3-methyl-1-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-1 H -imidazole [4,5- c Quinoline-2( 3H )-one 81a (100 mg, 0.19 mmol) was dissolved in 5 mL of N,N -dimethylformamide and added 1-methyl-3-[5-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridine]urea 1n (80 mg, 0.29 mmol), tetratriphenylphosphine palladium ( 44 mg, 0.038 mmol) and potassium carbonate (79 mg, 0.58 mmol), and reacted at 110 ° C for 1 hour. 10 mL of water was added to the reaction mixture and extracted with dichloromethane (20 mL×3). The organic layer was dried (MgSO4), filtered, evaporated 4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-2-one-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline- 8-yl)pyridin-2-yl)urea 81 (4 mg, off-white solid), yield: 3.5%.

MS m/z (ESI): 591.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.41 (s, 1H), 9.00 (s, 1H), 8.17 (d, 1H), 8.09-7.97 (m, 5H), 7.90 (d, 2H), 7.59 (d, 1H), 7.32 (d, 2H), 6.99 (s, 1H), 3.61 (s, 1H), 3.17 (d, 1H), 3.04-3.00 (m, 4H), 2.75 (s, 3H) , 2.56(s,3H), 2.29(s,3H)

Example 82 1-(5-(1-(2,3-dimethylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -8-yl)pyridin-2-yl)-3-methylurea

first step 6-bromo-N-(2,3-dimethylphenyl)-3-nitroquinolin-4-amine

6-Bromo-4-chloro-3-nitro-quinoline 1d (1.50 g, 5.22 mmol), 2,3-dimethylaniline (0.67 mL, 5.40 mmol) and 5 mL of acetic acid were sequentially added to the reaction flask. the reaction was stirred for 16 hours, the reaction solution was poured, filtered off with suction, the filter cake was washed with 20 mL water and washed with water (5 mL), and dried in vacuo to give crude title product 6-bromo - N - (2,3- dimethylphenyl) - 3-Nitroquinolin-4-amine 82a (3.0 g, yellow solid), product was used for the next step without purification.

MS m/z (ESI): 371.8 [M+1]

Second step 6-bromo- N ⁴ -(2,3-dimethylphenyl)quinoline-3,4-diamine

The crude 6-bromo- N- (2,3-dimethylphenyl)-3-nitroquinolin-4-amine 82a (3.0 g, 8 mmol) was dissolved in 50 mL of tetrahydrofuran and methanol (V/V = 1:1) In a mixed solvent, Raney nickel (1.0 g, cat.) was added, and the hydrogen was replaced three times. The reaction was stirred for 2 hours, and the reaction mixture was suction filtered. The filter cake was washed with methanol (20 mL), and the filtrate was concentrated under reduced pressure. the crude title product 6-bromo - N ⁴ - (2,3- dimethylphenyl) quinoline-3,4-diamine 82b (1.80 g, yellow solid) was used without purification in the next reaction.

MS m/z (ESI): 342.2 [M+1]

third step 8-bromo-1-(2,3-dimethylphenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude 6-bromo- N ⁴ -(2,3-dimethylphenyl)quinoline-3,4-diamine 82b (1.80 g, 5.26 mmol), triphosgene (1.72 g, 5.80) was sequentially added to the reaction flask. Methyl) (triethylamine) (0.9 mL, 6.30 mmol) and 20 mL of methylene chloride, stirred for 16 hrs, 100 mL water was added, and the layers were separated. The aqueous phase was washed with dichloromethane (20 mL×3). phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 8-bromo-1- (2,3-dimethylphenyl) -1 H - imidazo [4,5- c] quinoline -2( 3H )-one 82c (1.60 g, yellow solid), product was used in the next step without purification.

MS m/z (ESI): 368.0 [M+1]

the fourth step 8-bromo-1-(2,3-dimethylphenyl)-3-methyl-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude 8-bromo-1-(2,3-dimethylphenyl)-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 82c (1.60 g) was added to the reaction flask. , 4.34 mmol), methyl iodide (0.8 mL, 13 mmol), tetrabutylammonium bromide (280 mg, 0.87 mmol) and sodium hydroxide (520 mg, 13 mmol), stirred for 4 hours, 15 mL water and The title compound was obtained as a crude product (yield: 8-bromo-1). -(2,3-dimethylphenyl)-3-methyl-1 H -imidazo[4,5- c ]quinolin-2( 3H )-one 82d (1.60 g, yellow solid) Purified directly for the next step of the reaction.

MS m/z (ESI): 384.2 [M+1]

the fifth step 1-(5-(1-(2,3-dimethylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -8-yl)pyridin-2-yl)-3-methylurea

The crude 8-bromo-1-(2,3-dimethylphenyl)-3-methyl-1 H -imidazole [4,5- c ]quinoline-2(3 H )- was added to the reaction flask in turn. Ketone 82d (600 mg, 1.57 mmol), 1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Base-2-pyridine]urea 1n (522 mg, 1.88 mmol), tetratriphenylphosphine palladium (181 mg, 0.16 mmol), sodium carbonate (333 mg, 3.14 mmol) and 10 mL of dioxane and water (V /V=5:1) The mixed solvent was reacted at 90 ° C for 16 hours, the reaction solution was suction filtered, the filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by HPLC preparative chromatography to eluent system A. , the title product 1-(5-(1-(2,3-dimethylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]Quinoline-8-yl)pyridin-2-yl)-3-methylurea 82 (100 mg, yellow solid), yield: 14.0%.

MS m/z (ESI): 453.4 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.37 (s, 1H), 9.1 (s, 1H), 8.15 (d, 1H), 7.10 (d, 1H), 7.89 (d, 1H), 7.60- 7.57 (m, 1H), 7.54-7.50 (m, 3H), 7.43-7.40 (m, 2H), 6.99 (s, 1H), 3.63 (s, 3H), 2.74 (s, 3H), 1.98 (s, 3H), 1.07 (s, 3H)

Example 83 1-(5-(1-(3-chloro-2-methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole[4,5- c ]quina Porphyrin-8-yl)pyridin-2-yl)-3-methylurea

first step 6-bromo- N ⁴ -(3-chloro-2-methylphenyl)quinoline-3,4-diamine

6-Bromo-4-chloro-3-nitro-quinoline 1d (1.60 g, 5.56 mmol), 3-chloro-2-methylaniline (866 mg, 6.10 mmol) and 20 mL of acetic acid were sequentially added to the reaction flask. The reaction was stirred for 16 hours. The reaction solution was poured into 30 mL of water, filtered, filtered, washed with water (5 mL), dried in vacuo, and the residue was dissolved in 100 mL of tetrahydrofuran and methanol (V/V = 1:1) In a mixed solvent, Raney nickel (1.0 g, cat.) was added, and the reaction was stirred for 3 hours, and the Raney nickel was removed by filtration, and the filtrate was concentrated under reduced pressure to give crude title compound 6-bromo- N ⁴ -(3-chloro-2- Methylphenyl)quinoline-3,4-diamine 83a (1.50 g, yellow solid) was used for the next step without purification.

Second step 8-bromo-1-(3-chloro-2-methylphenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude 6-bromo- N ⁴ -(3-chloro-2-methylphenyl)quinoline-3,4-diamine 83a (1.36 g, 3.76 mmol) and triethylamine (455 mg, 4.50 mmol) were dissolved 20 mL of triphosgene (1.23 g, 4.13 mmol) in dichloromethane was added dropwise to 100 mL of dichloromethane at 0 ° C. The reaction was stirred at room temperature for 16 hours. 50 mL of sodium hydrogencarbonate solution was added and stirred for 5 minutes. layer, the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 8-bromo-1- (3-chloro-2-methylphenyl) -1 H - imidazo [4,5- c Quinoline-2( 3H )-one 83b (1.55 g, black solid), product was used in the next step without purification.

third step 8-bromo-1-(3-chloro-2-methylphenyl)-3-methyl-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude product was 8-bromo-1-(3-chloro-2-methylphenyl)-1 H -imidazole [4,5- c ]quinolin-2( 3H )-one 83b (1.55 g, 4.00 mmol) Methyl iodide (2.85 g, 0.02 mol) and tetrabutylammonium bromide (129 mg, 0.40 mmol) were dissolved in 50 mL of dichloromethane, and 5 mL of sodium hydroxide (320 mg, 8.0 mmol) was added dropwise and stirred. After the reaction was carried out for 10 hours, 50 ml of water was added, and the mixture was combined with methylene chloride (50 mL × 3), and the organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate The title product was crude 8-bromo-1-(3-chloro-2-methylphenyl)-3-methyl- 1H -imidazole[4,5- c ]quinolin-2( 3H )-one 83c ( 1.50 g, yellow solid), product was used in the next step without purification.

the fourth step 1-(5-(1-(3-chloro-2-methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole[4,5- c ]quina Porphyrin-8-yl)pyridin-2-yl)-3-methylurea

The crude 8-bromo-1-(3-chloro-2-methylphenyl)-3-methyl-1 H -imidazole [4,5- c ]quinoline-2 (3 H ) was added to the reaction flask in this order. -ketone 83c (300 g, 0.74 mmol), 1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-2-pyridine]urea 1n (248 mg, 0.89 mmol), tetratriphenylphosphine palladium (86 mg, 0.074 mmol), sodium carbonate (158 mg, 1.49 mmol) and 10 mL of dioxane and water ( V/V=5:1) The mixed solvent was reacted at 90 ° C for 4 hours, 20 mL of water was added, and extracted with ethyl acetate (20 mL×3), and the organic phase was combined and washed with saturated sodium chloride solution (20 mL). The residue was dried over anhydrous sodium sulfate (MgSO4). -3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl)pyridin-2-yl)-3-methylurea 83 ( 300 mg, yellow solid), yield: 84.9%.

MS m/z (ESI): [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.4 (s, 1H), 9.03 (s, 1H), 8.18 (s, 1H), 8.175 (d, 1H), 7.91 (d, 1H), 7.62 7.61 (m2H), 7.59-7.55 (m, 3H), 3.63 (s, 3H); 3.18 (d, 3H), 2.74 (s, 3H)

Example 84 1-methyl-3-(5-(3-methyl-1-(2-methyl-3-(trifluoromethyl)phenyl)-2-one-2,3-dihydro-1 H -imidazole [4,5- c ]quinolin-8-yl)pyridin-2-yl)urea

first step 6-bromo- N- (2-methyl-3-(trifluoromethyl)phenyl)-3-nitroquinolin-4-amine

6-Bromo-4-chloro-3-nitro-quinoline 1d (1.65 g, 5.70 mmol), 2-methyl-3-(trifluoromethyl)aniline (1.10 g, 6.30 mmol) was added to the reaction mixture. And 20 mL of acetic acid, stirring for 16 hours, adding 20 mL of water, suction filtration, washing the filter cake with water (5 mL), and drying in vacuo to give the title product crude 6-bromo- N- (2-methyl-3-(3) Fluoromethyl)phenyl)-3-nitroquinolin-4-amine 84a (1.0 g, yellow solid), product was used in the next step without purification.

Second step 8-bromo-1-(2-methyl-3-(trifluoromethyl)phenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude 6-bromo- N- (2-methyl-3-(trifluoromethyl)phenyl)-3-nitroquinolin-4-amine 84a (1.0 g, 2.35 mmol) was added sequentially to the reaction flask. Iron powder (660 mg, 11.70 mmol), ammonium chloride (63 mg, 1.17 mmol) and 40 mL of ethanol and water (V/V = 3:1) mixed solvent, reacted at 85 ° C for 3 hours, and the reaction solution was concentrated under reduced pressure. After adding 10 mL of water and 10 mL of EtOAc, EtOAc. The obtained residue was dissolved in 20 mL of dichloromethane, triethylamine (335 mg, 2.82 mmol) and triphosgene (900 mg, 2.58 mmol) were added, the reaction was stirred for 16 hours, and 40 mL of saturated aqueous sodium hydrogencarbonate was added and extracted. separation, the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 8-bromo-1- (2-methyl-3- (trifluoromethyl) phenyl) -1 H - imidazole [4,5- c ]Quinolin-2( 3H )-one 84b (1.12 g, m.p.).

third step 8-bromo-3-methyl-1-(2-methyl-3-(trifluoromethyl)phenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude product was 8-bromo-1-(2-methyl-3-(trifluoromethyl)phenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one 84b (1.12 g, 2.65 mmol), methyl iodide (1.89 g, 13.28 mmol) and tetrabutylammonium bromide (86 mg, 0.26 mmol) were dissolved in 10 mL of dichloromethane, then 5 mL sodium hydroxide (210 mg, 5.30 mmol) Aqueous solution, stirring for 10 hours, adding 10 mL of water, and extracting with dichloromethane (20 mL × 3), the organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude title product 8-bromo-3-methyl-1- (2-methyl-3- (trifluoromethyl) phenyl) -1 H - imidazo [4,5- c] quinolin Porphyrin-2( 3H )-one 84c (1.0 g, gray solid), product was used in the next step without purification.

the fourth step 1-methyl-3-(5-(3-methyl-1-(2-methyl-3-(trifluoromethyl)phenyl)-2-one-2,3-dihydro-1 H -imidazole [4,5- c ]quinolin-8-yl)pyridin-2-yl)urea

The crude 8-bromo-3-methyl-1-(2-methyl-3-(trifluoromethyl)phenyl)-1 H -imidazole [4,5- c ]quinoline- 2( 3H )-ketone 84c (200 mg, 0.46 mmol), 1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Cyclopentan-2-yl)-2-pyridine]urea 1n (150 mg, 0.55 mmol), tetratriphenylphosphine palladium (53 mg, 0.046 mmol), sodium carbonate (97 mg, 0.92 mmol) and 5 mL A mixed solvent of oxane and water (V/V = 5:1), reacted at 90 ° C for 4 hours, added with 20 mL of water, extracted with ethyl acetate (20 mL × 3), combined organic phases, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, EtOAcjjjjjjjjjjjjjjjj 1-(2-methyl-3-(trifluoromethyl)phenyl)-2-one-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl Pyridin-2-yl)urea 84 (40 mg, gray solid), yield: 17.5%.

MS m/z (ESI): 507.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.38 (s, 1H), 9.05 (s, 1H), 8.12-8.07 (m, 2H), 7.95-7.90 (m, 2H), 7.88 (s, 1H) ), 7.75-7.51 (m, 3H), 6.87 (s, 1H), 3.63 (s, 3H), 2.73 (s, 3H), 2.22 (s, 3H)

Example 85 (5-(3-Methyl-1-(2-methyl-3-(trifluoromethyl)phenyl)-2-one-2,3-dihydro-1 H -imidazole [4,5- c ] methyl quinoline-8-yl)pyridin-2-yl)carbamate

Add 8-bromo-3-methyl-1-(2-methyl-3-(trifluoromethyl)phenyl)-1 H -imidazole [4,5- c ]quinoline-2 to the reaction flask. ( 3H )-ketone 84c (200 mg, 0.46 mmol), (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Methyl pyridin-2-yl)carbamate 80a (150 mg, 0.55 mmol), tetratriphenylphosphine palladium (53 mg, 0.046 mmol), sodium carbonate (97 mg, 0.90 mmol) and 5 mL of dioxane The mixed solvent of water (V/V = 5:1) was reacted at 90 ° C for 4 hours, and the reaction liquid was concentrated under reduced pressure, and the obtained residue was purified by a thin layer chromatography to afford the title product (5-(3- 1-(2-methyl-3-(trifluoromethyl)phenyl)-2-one-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline-8- Methyl pyridin-2-yl)carbamate 85 (20 mg, yellow solid), yield: 8.7%.

MS m/z (ESI): 508.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.39 (s, 1H), 9.06 (s, 1H), 8.15-8.12 (m, 2H), 8.09 (d, 1H), 7.97-7.92 (m, 2H) ), 7.91-7.85 (d, 1H), 7.76-7.73 (m, 2H), 6.92 (s, 1H), 3.7 (s, 3H), 3.64 (s, 3H), 2.21 (s, 3H)

Example 86 1-methyl-3-(5-(3-methyl-2-keto-1-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1 H -imidazole [4, 5- c ]quinolin-8-yl)pyridin-2-yl)urea

first step 6-bromo-3-nitro- N- (2-(trifluoromethyl)phenyl)quinolin-4-amine

6-Bromo-4-chloro-3-nitro-quinoline 1d (2.90 g, 10 mmol) and 2-trifluoromethylaniline (1.80 g, 11 mmol) were dissolved in 30 mL of acetic acid and stirred for 16 hours. Add 30 mL of ice-water mixture, stir for 15 minutes, filter, filter cake and dissolve with 50 mL of ethyl acetate and 30 mL of tetrahydrofuran, wash with saturated sodium bicarbonate solution (50 mL), layer, organic sodium sulfate dried, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo-3-nitro - N - (2- (trifluoromethyl) phenyl) quinolin-4-amine 86a (660 mg, yellow solid) The product was used in the next step without purification.

Second step 6-bromo- N ⁴ -(2-(trifluoromethyl)phenyl)quinoline-3,4-diamine

The crude 6-bromo-3-nitro- N- (2-(trifluoromethyl)phenyl)quinolin-4-amine 86a (660 mg, 1.60 mmol) was dissolved in 20 mL of tetrahydrofuran and methanol (V/V = 1:1) In a mixed solvent, lanthanyl nickel (500 g, cat.) was added, and the hydrogen was replaced three times. The reaction was stirred for 16 hours, and the lanthanide was removed by filtration. The filtrate was dried over anhydrous sodium to give crude title product 6-bromo - N ⁴ - (2- (trifluoromethyl) phenyl) quinoline-3,4-diamine 86b (500 mg, yellow oil), was used without purification in the The next step is the reaction.

third step 8-bromo-1-(2-(trifluoromethyl)phenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

Triphosgene (425 mg, 1.43 mmol) was dissolved in 10 mL of dichloromethane to give solution A, cooled to 0 ° C, and then crude 6-bromo- N ⁴ -(2-(trifluoromethyl)phenyl)quine Porphyrin-3,4-diamine 86b (500 mg, 1.30 mmol) and triethylamine (0.3 mL, 1.56 mmol) were dissolved in 10 mL of dichloromethane to give solution B, and then solution B was added dropwise to solution A. After the completion of the dropwise addition, the reaction was carried out for 16 hours at room temperature, and a solution of 30 mL of aq. Product crude 8-bromo-1-(2-(trifluoromethyl)phenyl)-1 H -imidazo[4,5- c ]quinolin-2( 3H )-one 86c (530 mg, yellow oil The product was used in the next step without purification.

the fourth step 8-bromo-3-methyl-1-(2-(trifluoromethyl)phenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

Crude 8-bromo-1-(2-(trifluoromethyl)phenyl)-1 H -imidazole [4,5- c ]quinolin-2( 3H )-one 86c (530 mg, 1.30 mmol) , iodomethane (0.3 mL, 3.90 mmol) and tetrabutylammonium bromide (85 mg, 0.26 mmol) were dissolved in 30 mL of dichloromethane, and 10 mL aqueous sodium hydroxide (156 mg, 3.90 mmol) was added and stirred. After 16 hours, 20 mL of water and 50 mL of dichloromethane were added, the layers were separated, and the aqueous phase was extracted with dichloromethane (30 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated. beating 10 mL ethyl acetate, to give the crude title product 8-bromo-3-methyl-1- (2- (trifluoromethyl) phenyl) -1 H - imidazo [4,5- c] quinolin-2 ( 3H )-ketone 86d (280 mg, pale yellow solid), product was used for the next step without purification.

MS m/z (ESI): 424.1 [M+1]

the fifth step 1-methyl-3-(5-(3-methyl-2-keto-1-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1 H -imidazole [4, 5- c ]quinolin-8-yl)pyridin-2-yl)urea

Crude 8-bromo-3-methyl-1-(2-(trifluoromethyl)phenyl)-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 86d (280 Mg, 0.66 mmol), 1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2 -pyridine]urea 1n (274 mg, 0.99 mmol), tetratriphenylphosphine palladium (152 mg, 0.13 mmol) and potassium carbonate (273 mg, 1.98 mmol) were dissolved in 10 mL of N,N -dimethylformamidine. The amine was stirred at 100 ° C for 1 hour, 15 mL of water was added, and ethyl acetate (30 mL × 3) was evaporated. The residue obtained was purified by eluent system A to give the title product 1-methyl-3-(5-(3-methyl-2- keto-1-(2-(trifluoromethyl)phenyl) , 3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl)pyridin-2-yl)urea 86 (36 mg, white solid), yield: 11.0%.

MS m/z (ESI): 493.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.40 (s, 1H), 9.03 (s, 1H), 7.96-8.18 (m, 7H), 7.89 (d, 1H), 7.51 (t, 2H), 6.74(d,1H), 3.63(s,3H), 2.73(s,3H)

Example 87 1-(5-(1-(2-chloro-3-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -8-yl)pyridin-2-yl)-3-methylurea

first step 6-bromo- N- (2-chloro-3-fluorophenyl)-3-nitroquinolin-4-amine

Dissolve 6-bromo-4-chloro-3-nitro-quinoline 1d (2.0 g, 6.96 mmol) and 2-chloro-3-fluoroaniline (1,10 g, 7.65 mmol) in 20 mL of acetic acid and stir After reacting for 16 hours, 50 mL of ethyl acetate was added, and the mixture was washed with saturated sodium hydrogen sulfate (50 mL). The product was crude 6-bromo- N- (2-chloro-3-fluorophenyl)-3-nitroquinolin-4-amine 87a (4.0 g, m.

Second step 6-bromo- N ⁴ -(2-chloro-3-fluorophenyl)quinoline-3,4-diamine

The crude 6-bromo- N- (2-chloro-3-fluorophenyl)-3-nitroquinolin-4-amine 87a (4.0 g, 6.96 mmol) was dissolved in 100 mL of tetrahydrofuran and methanol (V/V = 1:1) In a mixed solvent, Raney nickel (2.0 g, cat.) was added, and the hydrogen was replaced three times. The reaction was stirred for 4 hours, and the lanthanide was filtered to remove Raney nickel. The filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. and concentrated to give the crude title product 6-bromo - N ⁴ - (2- chloro-3-fluorophenyl) quinoline-3,4-diamine 87b (3.0 g, yellow solid) was used without purification in the next Step reaction.

third step 8-bromo-1-(2-chloro-3-fluorophenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

Dissolve triphosgene (2.5 g, 8.35 mmol) in 25 mL of dichloromethane to obtain solution A, cool to 0 ° C, and then 6-bromo- N ⁴ -(2-chloro-3-fluorophenyl)quinoline- 3,4-Diamine 87b (3.0 g, 6.96 mmol) and triethylamine (2.9 mL, 15.08 mmol) were dissolved in 25 mL of dichloromethane to obtain solution B, and then B solution was added dropwise to solution A, and added dropwise. After completion, the reaction was carried out for 16 hours at room temperature, 50 mL of water was added, and the mixture was stirred for 30 minutes, filtered, and the filter cake was further purified with methylene chloride, filtered, and dried in vacuo to give the title product as crude 8-bromo-1-(2-chloro-3) - fluorophenyl) -1 H - imidazo [4,5- c] quinolin -2 (3 H) - one 87c (1.72 g, yellow solid) was used without purification in the next reaction.

the fourth step 8-bromo-1-(2-chloro-3-fluorophenyl)-3-methyl-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude product was 8-bromo-1-(2-chloro-3-fluorophenyl)-1 H -imidazole [4,5- c ]quinolin-2( 3H )-one 87c (1.72 g, 4.38 mmol). Methyl iodide (8 mL, 13.10 mmol) and tetrabutylammonium bromide (85 mg, 0.26 mmol) were dissolved in 50 mL of dichloromethane, ice-cooled to 0 ° C, and 11 mL aqueous sodium hydroxide (520 mg, 13.10 mmol), the reaction was stirred at room temperature for 16 hours, then added with 20 mL of water and 50 mL of dichloromethane. the filtrate was concentrated under reduced pressure, then 20 mL ethyl acetate mixture was filtered, the filter cake was dried to give the crude title product 8-bromo-1- (2-chloro-3-fluorophenyl) -3-methyl -1 H - Imidazo[4,5- c ]quinolin-2( 3H )-one 87d (1.0 g, pale yellow solid).

the fifth step 1-(5-(1-(2-chloro-3-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -8-yl)pyridin-2-yl)-3-methylurea

Crude 8-Bromo-1-(2-chloro-3-fluorophenyl)-3-methyl-1 H -imidazole [4,5- c ]quinolin-2(3 H )-one 87d (250 mg , 0.61 mmol), 1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- Pyridine]urea 1n (200 mg, 0.74 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (23 mg, 0.031 mmol) and potassium carbonate (250 mg, 1.85 mmol) ) Dissolved in 4 mL of a mixed solvent of N,N -dimethylformamide and water (V/V=3:1), stirred at 120 °C for 2 hours, added with 20 mL of dichloromethane and 10 mL of water, and stirred. After filtration for 30 minutes, the filter cake was beaten with a mixed solvent of dichloromethane and methanol (V/V = 20:1), filtered, and the filter cake was dried in vacuo to give the title product 1-(5-(1-(2-chloro-3) -fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl)pyridin-2-yl)-3- Methylurea 87 (40 mg, grey solid), yield: 13.6%.

MS m/z (ESI): 477.1 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.39 (s, 1H), 9.06 (s, 1H), 8.19 (s, 1H), 8.11-8.16 (d, 1H), 7.85-7.95 (m, 2H) ), 7.76-7.84 (m, 2H), 7.56-7.67 (m, 2H), 7.48-7.54 (m, 1H), 7.00 (s, 1H), 3.65 (s, 3H), 2.70-2.77 (d, 3H) )

Example 88 1-(5-(1-(4-chloro-2-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -8-yl)pyridin-2-yl)-3-methylurea

first step 6-bromo- N- (4-chloro-2-methylphenyl)-3-nitroquinolin-4-amine

6-Bromo-4-chloro-3-nitro-quinoline 1d (1.5wg, 5.20 mmol) and 4-chloro-2-methylaniline (810 mg, 5.72 mmol) were dissolved in 20 mL of acetic acid and stirred. After 16 hours, 30 mL of ice-water mixture was added, stirred for 15 minutes, filtered, and the filter cake was dissolved in 50 mL of acetate and 30 mL of tetrahydrofuran, washed with saturated sodium bicarbonate solution (50 mL), and separated. sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 6-bromo - N - (4- chloro-2-methylphenyl) -3-nitro-quinolin-4-amine 88a (2.20 g, yellow oil The product was used in the next step without purification.

Second step 6-bromo- N ⁴ -(4-chloro-2-methylphenyl)quinoline-3,4-diamine

The crude 6-bromo- N- (4-chloro-2-methylphenyl)-3-nitroquinolin-4-amine 88a (2.20 g, 5.60 mmol) was dissolved in 100 mL of tetrahydrofuran and methanol (V/V = 1:1) In a mixed solvent, Raney nickel (1.0 g, cat.) was added, and the hydrogen was replaced three times. The reaction was stirred for 16 hours, and the lanthanide was filtered to remove Raney nickel. The filtrate was dried over anhydrous sodium sulfate and filtered. concentrated under pressure to give the crude title product 6-bromo - N ⁴ - (4- chloro-2-methylphenyl) quinoline-3,4-diamine 88b (1.60 g, yellow oil), was used without purification Used directly in the next step of the reaction.

third step 8-bromo-1-(4-chloro-2-methylphenyl)-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

Dissolve triphosgene (1.50 g, 4.84 mmol) in 50 mL of dichloromethane to obtain solution A, cool to 0 ° C, and then 6-bromo- N ⁴ -(4-chloro-2-methylphenyl)quinoline -3,4-Diamine 88b (1.60 g, 4.40 mmol) and triethylamine (1.0 mL, 5.28 mmol) were dissolved in 50 mL of dichloromethane to give solution B, and then B solution was added dropwise to solution A, After the addition was completed, the reaction was carried out for 16 hours at room temperature, 20 mL of sodium bicarbonate solution was added, and the mixture was extracted with dichlorobenzene (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, beating with 10 mL of dichloromethane, to give crude title product 8-bromo-1- (4-chloro-2-methylphenyl) -1 H - imidazo [4,5- c] quinolin -2 (3 H) - Ketone 88c (1.60 g, light yellow solid), product was used in the next step without purification.

the fourth step 8-bromo-1-(4-chloro-2-methylphenyl)-3-methyl-1 H -imidazo[4,5- c ]quinolin-2(3 H )-one

The crude product was 8-bromo-1-(4-chloro-2-methylphenyl)-1 H -imidazole [4,5- c ]quinolin-2( 3H )-one 88c (1.60 g, 4.10 mmol) , iodomethane (10 mL, 12.30 mmol) and tetrabutylammonium bromide (265 mg, 0.82 mmol) were dissolved in 50 mL of dichloromethane, ice-cooled to 0 ° C, and 15 mL of aqueous sodium hydroxide (500 mg) was added dropwise. The mixture was stirred at room temperature for 16 hours, added with 50 mL of water and extracted with dichloromethane (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated. Ethyl acetate was slurried, filtered, and the filter cake was dried to give the title product crude product: 8-bromo-1-(4-chloro-2-methylphenyl)-3-methyl- 1H -imidazole [4,5- c ] Quinoline-2( 3H )-one 88d (1.0 g, light yellow solid), product was used in the next step without purification.

MS m/z (ESI): 402.1 [M+1]

the fifth step 1-(5-(1-(2-chloro-3-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -8-yl)pyridin-2-yl)-3-methylurea

The crude product was 8-bromo-1-(4-chloro-2-methylphenyl)-3-methyl- 1H -imidazole[4,5- c ]quinolin-2( 3H )-one 88d (201 Mg, 0.50 mmol), 1-methyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2 -pyridine]urea 1n (208 mg, 0.74 mmol), tetratriphenylphosphine palladium (115 mg, 0.10 mmol) and potassium carbonate (207 mg, 1.50 mmol) were dissolved in 5 mL of N,N -dimethylformamidine. The amine was stirred at 110 ° C for 2 hours, 10 mL of water was added, and ethyl acetate (30 mL × 3) was evaporated. The residue obtained was purified by eluent system A to give the title product 1-(5-(1-(2-chloro-3-fluorophenyl)-3-methyl-2- keto-2,3-dihydro- 1H -Imidazo[4,5- c ]quinolin-8-yl)pyridin-2-yl)-3-methylurea 88 (31 mg, white solid), yield: 13.1%.

MS m/z (ESI): 473.1 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.39 (t, 1H), 9.01 (t, 1H), 8.09-8.17 (m, 2H), 7.78 (t, 1H), 7.63-7.66 (m, 5H) ), 7.49 (d, 1H), 6.95-6.97 (m, 1H), 3.62 (s, 3H), 2.75 (s, 3H), 2.09 (s, 3H)

Examples 89 to 103 were prepared according to the similar procedures previously described.

Example 89 1-(5-(1-(4-fluoro-2-methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole[4,5- c ]quina Porphyrin-8-yl)pyridin-2-yl)-3-methylurea

MS m/z (ESI): 457.2 [M+1]; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.39 (s, 1H), 9.02 (s, 1H), 8.10-8.18 (m) , 2H), 7.64-7.66 (m, 3H), 7.52-7.62 (m, 2H), 7.50 (t, 1H), 6.97 (d, 1H), 3.63 (s, 3H), 2.74 (s, 3H), 2.09(s,3H)

Example 90 1-(5-(1-(3-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl Pyridin-2-yl)-3-methylurea

Brown solid; MS m / z (ESI) : 443.3 [M + 1]; 1 HNMR (400 MHz, DMSO- d 6): δ 9.42 (s, 1H), 9.02 (s, 1H), 8.19-8.24 (d , 1H), 8.10-8.15 (d, 1H), 7.88-7.93 (dd, 1H), 7.75-7.82 (m, 1H), 7.64-7.72 (m, 3H), 7.52-7.63 (m, 3H), 7.17 -7.22(d,1H), 3.61(s,3H), 2.70-2.76(d,3H)

Example 91 (5-(1-(3-Chloro-2-methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline- Methyl 8-yl)pyridin-2-yl)carbamate

Yellow solid; MS m/z (ESI): 474.2 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ): δ 10.4 (s, 1H), 9.04 (s, 1H), 8.17-8.12 (m) , 2H), 7.88-7.82 (m, 4H), 7.63-7.57 (m, 2H), 7.04 (s, 1H), 3.69 (s, 3H), 3.63 (s, 3H), 2.14 (s, 3H)

Example 92 (5-(1-(2,3-Dimethylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline-8 Methyl-pyridin-2-yl)carbamate

Yellow solid; MS m/z (ESI): 454.2 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ): δ 10.41 (s, 1H), 9.02 (s, 1H), 8.15 (d, 1H) ), 8.12(d,1H), 7.93-7.86(m,2H), 7.79-7.77(m,1H),7.54-7.52(m,1H), 7.41-7.40(m,2H),7.05-7.04(m , 1H), 3.64 (s, 3H), 3.59 (s, 3H), 2.37 (s, 3H), 1.94 (s, 3H)

Example 93 (5-(1-(2-Chloro-3-fluorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline-8 Methyl-pyridin-2-yl)carbamate

Gray solid; MS m/z (ESI): 478.1 [M+1]; ¹ H NMR (400 MHz, DMSO - d ₆ ): δ 10.40 (s, 1H), 9.07 (s, 1H), 8.20 (s, 1H) ), 8.13-8.17 (m, 1H), 7.93-7.98 (dd, 1H), 7.86-7.92 (m, 2H), 7.75-7.85 (m, 3H), 7.05 (s, 1H), 3.70 (s, 3H) ), 3.65 (s, 3H)

Example 94 1-(5-(1-(2,6-dimethylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline -8-yl)pyridin-2-yl)-3-methylurea

As a yellow solid; MS m / z (ESI) : 453.4 [M + 1]; 1 HNMR (400 MHz, DMSO- d 6): δ 9.45 (s, 1H), 9.03 (s, 1H), 8.11-8.08 (m , 2H), 7.9 (d, 1H), 7.56 (s, 1H), 7.53-7.51 (m, 3H), 7.44-7.42 (m, 2H), 6.92 (s, 1H), 3.65 (s, 3H), 2.72(s,3H), 2.00(s,6H)

Example 95 (5-(3-Methyl-2-keto-1-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline- Methyl 8-yl)pyridin-2-yl)carbamate

As a white solid; MS m / z (ESI) : 494.3 [M + 1]; 1 HNMR (400 MHz, DMSO- d 6): δ 10.36 (s, 1H), 9.05 (d, 1H), 7.92-8.17 (m , 8H), 7.85 (t, 1H), 6.80 (s, 1H), 3.69 (s, 3H), 3.64 (s, 3H)

Example 96 1-(5-(1-(2,4-dichlorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazo[4,5- c ]quinoline- 8-yl)pyridin-2-yl)-3-methylurea

Gray solid; MS m/z (ESI): 493.2 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ): δ 9.41 (s, 1H), 9.08 (s, 1H), 8.20 (s, 1H) ), 8.10-8.16 (m, 1H), 7.86-7.96 (m, 2H), 7.75-7.85 (m, 2H), 7.58-7.67 (m, 2H), 7.49-7.54 (m, 1H), 7.00 (s) , 1H), 3.65 (s, 3H), 2.70-2.76 (d, 3H)

Example 97 (5-(1-(2,4-Dichlorophenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline-8- Methyl pyridin-2-yl)carbamate

Yellow solid; MS m/z (ESI): 494.0 [M-1]; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.40 (s, 1H), 9.06 (s, 1H), 8.27 (s, 1H) ), 8.12-8.21 (m, 2H), 7.88-8.02 (m, 3H), 7.77-7.87 (m, 2H), 7.05 (s, 1H), 3.70 (s, 3H), 3.64 (s, 3H)

Example 98 1-methyl-3-(5-(3-methyl-2-keto-1-(2-methylphenyl)-2,3-dihydro-1 H -imidazole [4,5- c ] Quinoline-8-yl)pyridin-2-yl)urea

Gray-white solid; MS m/z (ESI): 439.2 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.14 (s, 1H), 8.86 (d, 1H), 8.24-8.20 (m, 2H) ), 7.80 (d, 1H), 7.58-7.47 (m, 5H), 7.10 (s, 1H), 6.81 (d, 1H), 3.77 (s, 3H), 3.05 (s, 3H), 2.22 (s, 3H)

Example 99 (5-(3-Methyl-2-keto-1-(2-methylphenyl)-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-8-yl) Methyl pyridin-2-yl)carboxylate

As a white solid; MS m / z (ESI) : 440.2 [M + 1]; 1 HNMR (400 MHz, CDCl 3): δ 8.86 (s, 1H), 8.27 (s, 1H), 8.21 (d, 1H), 8.10(s,1H), 8.09(d,1H), 7.80(d,1H), 7.63-7.49(m,5H),7.13(s,1H),3.87(s,3H),3.76(s,3H) , 2.21(s,3H)

Example 100 (5-(1-(4-Chloro-2-methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline- Methyl 8-yl)pyridin-2-yl)carbamate

White solid; MS m/z (ESI): 416.2 [M + 1]; ¹ HNMR (400 MHz, DMSO - d ₆ ): δ 8.97 (s, 1H), 8.04 (d, 1H), 7.94 (s, 1H) ), 7.75-7.84 (m, 2H), 7.62 (t, 2H), 7.36 (d, 1H), 6.91 (s, 1H), 6.49 (d, 1H), 6.25 (s, 1H), 3.62 (s, 3H), 2.56 (s, 3H), 2.08 (s, 3H)

Example 101 (5-(3-Methyl-2-keto 1-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline-8 Methyl-pyridin-3-yl)carbamate

Pale yellow solid; MS m / z (ESI) : 494.2 [M + 1]; 1 HNMR (400 MHz, DMSO- d 6): δ 10.01 (s, 1H), 9.08 (s, 1H), 8.51 (s, 1H), 8.17-8.19 (m, 3H), 7.88-8.03 (m, 5H), 7.22 (s, 1H), 3.74 (s, 3H), 3.63 (s, 3H)

Example 102 (5-(1-(3-Chloro-2-methylphenyl)-3-methyl-2-keto-2,3-dihydro-1 H -imidazole [4,5- c ]quinoline- Methyl 8-yl)pyridin-3-yl)carbamate

White solid; MS m/z (ESI): 474.1 [M+1]; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.99 (s, 1H), 9.08 (s, 1H), 8.52 (s, 1H) ), 8.03-8.16 (m, 3H), 7.62-7.98 (m, 2H), 7.55-7.62 (m, 2H), 7.10 (s, 1H), 3.75 (s, 3H), 3.64 (s, 3H), 2.15(s,3H)

Example 103 (5-(3-Methyl-2-keto-1-(3-trifluoromethylphenyl)-2,3-dihydro-1 H -imidazole[4,5- c ]quinoline-8- Ethyl pyridin-2-yl)carbamate

White solid; MS m/z (ESI): 508.1 [M + 1]; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.34 (s, 1H), 9.26 (s, 1H), 8.64 (s, 1H) ), 8.13-8.29 (m, 5H), 7.75-8.09 (m, 3H), 7.16 (s, 1H), 4.15-4.17 (m, 2H), 3.39 (s, 3H), 1.30 (t, 3H)

Test case: Biological evaluation

Test Example 1. Determination of inhibition of mTOR kinase activity by a compound of the present invention

Inhibition of in vitro mTOR kinase activity was tested by the following method.

In this experiment, K-LISA ^TM mTOR (recombinant) activity kit (Activity Kit), NO: CBA104, commercially available from MERCK.

The in vitro cell assay described below can determine the inhibitory activity of the test compound on mTOR kinase. The test compound is dissolved in dimethyl hydrazine according to the concentration required for the experiment, and the substrate is coated on a microplate. Formulated in 1 × buffer, 1 × buffer with ATP and DTT was diluted to give 200 μ M ATP, and 2000 μ M DTT solution, an appropriate amount of enzyme mTOR mixed with 1 × buffer, final concentration of 2 ng / μ L. Were added 50 μ L ATP and DTT was added to each microtiter plate, 1 μ L of test compound in DMSO (blank and controls only pure DMSO plus 1 μ l) and 50 μ L of the enzyme solution (control added only 50 μ L 1×buffer). After thoroughly mixing the tubes, the cells were incubated at 30 ° C for 45 minutes, washed with a washing solution, dried, and repeated 3 times. The primary antibody was added and incubated for 1 hour. The plate was washed with washing solution, dried, repeated 3 times, and the secondary antibody was added and incubated for 1 hour. Wash the plate with washing solution, control dry, repeat 3 times, add TMB, and develop color for 5 to 15 minutes. The reaction was terminated by the addition of a stop solution. The absorbance was measured at a wavelength of 450 nm on a novostar microplate reader. IC ₅₀ values for compounds may be obtained by calculating the test compound at various concentrations for inhibition of mTOR activity value.

Activity of the compounds of the invention

The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC ₅₀ values are shown in Table 1 below.

Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on the proliferation of mTOR kinase.

Test Example 2: Determination of PI3K Kinase Activity by Compounds of the Invention

Inhibition of PI3K kinase activity in vitro was tested by the following method.

The PI3K (p110 α/p85 α) kinase used in this experiment was purchased from Invitrogen (Cat. No. PV4788) and Millipore (Cat. No. 14-602).

The in vitro cell assay described below can determine the proliferation inhibitory activity of the test compound against PI3K kinase, and the test compound is dissolved in dimethylhydrazine according to the concentration required for the experiment. 1 × buffer formulation, every 10 mL 1 × buffer plus 10 μ L DTT. ATP was diluted with 1X buffer to give a 10 μM ATP solution. An appropriate amount of PIP2:PS Lipid substrate (Invitrogen, Cat. No. PV5100), PI3K (p110 α/p85 α) enzyme was mixed with 1× buffer. To each tube was added EP 50 μ l ATP solution, respectively, 1 μ L of test compound in DMSO (blank and controls only pure DMSO plus 1 μ L) and 50 μ L of the enzyme - substrate mixture (control added only 50 μ L 1×buffer). After thoroughly mixing the tubes, they were incubated at 37 ° C for 45 minutes and then at 4 ° C for 10 minutes. For each concentration of the test compound and the control, two parallel holes were set in each blank. Each well was measured by reading chemiluminescence analyzer BIOTEK FLX800 fluorescence in each well after adding 50 μ L reaction system described above and 50 μ L Kinase-Glo ^® reaction solution (purchased from Promega, NO V3772), shaken at room temperature 1 hour after mixing .

Activity of the compounds of the invention

The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC ₅₀ values are shown in Table 2.

Conclusion: The preferred compounds of the invention have a significant inhibitory effect on PI3K kinase activity.

Test Example 3, proliferation of breast cancer cell MCF-7 by the compound of the present invention Inhibition assay

The following in vitro assay was used to determine the proliferation inhibitory activity of the compounds of the invention against breast cancer cell line -MCF-7.

The in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound on tumor cells, and its activity can be expressed by an IC ₅₀ value. The general protocol for such an experiment is as follows: First, MCF-7 cells (purchased in Institute of biochemistry and cell biology) are seeded on a 96-well culture plate at a suitable cell concentration of 4000 cells/mL, and then the cells are placed in a carbon dioxide incubator. Incubate at 37 ° C, allow them to grow overnight, replace the medium with a series of concentration gradients (10000, 1000, 100, 10, 1, 0.1 nM) of the test compound solution, and return the plate to the incubator continuously. Cultivate for 72 hours. After 72 hours, the test compound was assayed for inhibition of cell proliferation activity using CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Dojindo). The IC ₅₀ value can be calculated from the inhibition values of the test compound for the cells by a series of different concentrations.

Activity of the Compounds of the Invention The biological activity of the compounds of the present invention was obtained from the above analysis, and the calculated IC ₅₀ values are shown in Table 3 below:

Conclusion: The compounds of the present invention all have significant proliferation inhibitory activity against MCF-7 cells.

Test Example 4: Inhibition of proliferation of prostate cancer cell line PC-3 by the compound of the present invention

The following in vitro test was conducted to determine the proliferation inhibitory activity of the compound of the present invention against prostate cancer cell line-PC-3.

The in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound on tumor cells, and the inhibitory activity of the compound can be expressed by an IC ₅₀ value. The experimental protocol is briefly described as follows: firstly, DMEM-F12 is supplemented with 10% FBS (purchased from Gibco) as a complete medium for PC-3 cells (purchased in Institute of biochemistry and cell biology) at a suitable cell concentration of 2000 cells/mL medium. The cells were seeded on a 96-well culture plate, and then cultured overnight in a constant temperature incubator at 37 ° C under 5% CO ₂ . After the cells were attached, the medium was changed to fresh medium containing a gradient of the test compound (10000, 1000, 100, 10, 1, 0.1 nM). Thereafter, the cell culture plate was continuously cultured for 72 hours under the aforementioned conditions. After 72 hours, the inhibitory activity of the compound against cell proliferation was measured by the CCK8 method. IC ₅₀ values for compounds may be obtained by calculating the test compound at various concentrations for inhibition of cell proliferation values.

Activity of the compounds of the invention: The biological activity of the compounds of the invention is obtained from the above analysis, and the calculated IC ₅₀ values are shown in Table 4 below:

Conclusion: The compounds of the present invention all have significant proliferation inhibitory activity against PC-3 cells.

Pharmacokinetic evaluation

Test Example 5, Pharmacokinetic test of the compound of the present invention

1. Summary

Rats were used as test animals, and the compound of Example 35, the compound of Example 36, the compound of Example 37, the compound of Example 40, the compound of Example 42 and the Example 82 were administered by gavage by LC/MS/MS method. The concentration of the drug in the plasma at different times after the compound, the compound of Example 83, the compound of Example 84, the compound of Example 86, the compound of Example 87 and the compound of Example 88. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

2, the test plan

2.1 Test drugs

Example 35 compound, Example 36 compound, Example 37 compound, Example 40 compound, Example 42 compound, Example 82 compound, Example 83 compound, Example 84 compound, Example 86 compound, Example 87 compound and Example 88 compound.

2.2 Test animals

There were 44 healthy adult SD rats, half male and half female, with an average of 11 groups, 4 in each group, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.

2.3 Drug preparation

An appropriate amount of the sample was weighed, 0.5% CMC-Na was added, and a 0.5 mg/ml suspension was prepared by ultrasonication.

2.4 Administration

44 SD rats, half male and half female, divided into 11 groups on average, fasted overnight After the administration, the dosage was 5.0 mg/kg, and the administration volume was 10 ml/kg.

3, operation

The compound of Example 35, the compound of Example 36, the compound of Example 37, the compound of Example 40, the compound of Example 42, the compound of Example 82, the compound of Example 83, the compound of Example 84, and the compound of Example 86 were administered by gavage in rats. The compound of Example 87 and the compound of Example 88 were collected for 0.1 ml before and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours after administration, and placed in a heparinized tube at 3500 rpm. The plasma was separated by centrifugation for 5 min and stored at 20 °C. Eat 2 hours after administration. The content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method. The linear range of the method was 1.00 to 2000 ng/ml; plasma samples were analyzed by methanol precipitation protein analysis.

4, pharmacokinetic parameters results

The pharmacokinetic parameters of the compounds of the invention are as follows:

Conclusion: The compounds of the present invention have good drug metabolism absorption and have obvious pharmacokinetic advantages.

Claims (11)

a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable compound thereof salt: Wherein Y is O; A is CR ¹⁰ ; R ¹ is a hydrogen atom or an alkyl group; and R ² and R ³ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen group, a hydroxyl group, a cyano group, and -S ( O) ₂ R ⁷ , wherein the alkyl group and the alkoxy group are further substituted by one or more substituents selected from the group consisting of halogen and cyano; R ⁴ is pyridyl, wherein the pyridyl group is further selected by one or more Substituted from a substituent of -NHC(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ C(O)OR ⁹ ; R ⁵ and R ⁶ are each independently selected from a hydrogen atom and an alkane And R ⁷ , R ⁸ and R ⁹ are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group and a heteroaryl group, wherein the alkyl group, the alkenyl group, and the cycloalkane group The base and the heterocyclic group are further substituted by one or more substituents selected from the group consisting of a hydroxyl group, an alkyl group, a halogen, an alkoxy group, a cyano group, a cycloalkyl group and a heterocyclic group, as needed; R ^{10 is} selected from a hydrogen atom and an alkane And a halogen, wherein the alkyl group is further substituted by one or more halogens as needed; and n is 0. a compound as described in claim 1 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable drug thereof A salt which is a compound of the formula (II) or a pharmaceutically acceptable salt thereof: Wherein, A, R ^{2 -} R ⁴ , n are as defined in the first item of the patent application. a compound as described in claim 1 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable drug thereof A salt which is a compound of the formula (III) or a pharmaceutically acceptable salt thereof: Wherein, Y, R ^{2 -} R ⁴ , R ¹⁰ , n are as defined in the first item of the patent application. The compound of any one of claims 1 or the tautomer, meso, racemate, enantiomer, diastereomer, and mixtures thereof, And a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is haloalkyl. a compound as described in claim 1 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable drug thereof A salt is used wherein R ¹⁰ is trifluoromethyl. A compound or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: A compound (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, and a mixture thereof according to the first aspect of the invention. And a method of pharmaceutically acceptable salts thereof, the method comprising: The compound of the formula (IA) is reacted with an R ⁴ -substituted boronic acid ester or boric acid under basic conditions to give a compound of the formula (I): wherein: Y is O; X is a halogen; A, n, R ¹ to R The definition of ⁶ is as described in item 1 of the patent application. A medicinal composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a tautomer, a mesogen, a racemate, an enantiomer thereof The construct, diastereomer, and mixtures thereof, and pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. A compound according to any one of claims 1 to 6 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof Form, pharmaceutically acceptable salt thereof, or use of the pharmaceutical composition described in claim 8 of the patent application A medicament for the treatment of a protein kinase dependent disease is prepared. A compound according to any one of claims 1 to 6 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof The use of a form, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8 for the preparation of a medicament for inhibiting mTOR and/or PI3K-kinase. A compound according to any one of claims 1 to 6 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof A form, a pharmaceutically acceptable salt thereof, or a use of the pharmaceutical composition according to claim 8 for the preparation of a medicament for treating a cancer or a tissue hyperplasia, wherein the cancer is selected from the group consisting of melanoma and papillary Thyroid, cholangiocarcinoma, colon, ovarian, lung, malignant lymphoma, liver, kidney, bladder, prostate, breast and pancreatic cancer and sarcoma, and primary and recurrent skin, colon, thyroid, lung and ovary Solid tumor or leukemia.