WO2020200284A1 - Preparation method for tricyclic compound and use of same in field of medicine - Google Patents

Abstract

Provided are a tricyclic small molecule compound, a preparation method therefor, a pharmaceutical composition containing said compound, and use thereof in medicine. Said compound is used as a bromodomain protein 4 (BRD4) inhibitor, and can be used for preventing and/or treating diseases related to BRD4, such as malignant tumors.

Description

Preparation method of tricyclic compound and its application in medical field Technical field

The invention belongs to the field of medicine, and relates to a tricyclic small molecule compound, a preparation method thereof, a pharmaceutical composition containing the compound, and its application in medicine.

Background technique

Malignant tumor is a serious threat to human health. In recent years, its morbidity and mortality have been on the rise, and it has become a serious health problem facing the world. The occurrence and development of tumors is a multi-factor and multi-stage evolutionary process involving multiple gene mutations and epigenetic changes. Epigenetics refers to a genetic phenomenon that changes the expression level and function of a gene without changing the DNA sequence of a gene, and produces a heritable phenotype.

Histone post-translational modifications play an important role in epigenetic regulation. Methylation and acetylation on the lysine residues of histone tails are the most important histone modifications. Among them, histone acetylation can precisely regulate the structure and function of chromatin in cells. Bromodomain and extraterminal domain (BET) family proteins can bind to acetylated histones or non-histone proteins, and play a regulatory function of gene transcription related to cell growth and cell cycle. The BET protein family is a subclass of the bromodomain protein superfamily, which is characterized by two conserved bromodomains (BD1 and BD2) at the N-terminus and an extraterminal (ET) domain at the C-terminus. The family includes 4 members, namely BRD2, BRD3, BRD4 and BRDT. BRD2, BRD3, BRD4 are widely expressed in all body cells, and BRDT is only expressed in testicular tissues. BRD 4 regulates the expression of target genes by recruiting different transcription factors, such as Mediator, and positive transcription elongation factor b (p-TEFb), thus playing an important role in regulating cell cycle progress, transcription, inflammation, etc.

Studies have shown that BRD4 abnormalities are associated with many diseases. BRD4 gene translocation into the testicular nucleoprotein (NUT) locus produces BRD4-NUT fusion protein, which leads to the overexpression of c-Myc and promotes the formation of NUT midline carcinoma. BRD4 also plays an important role in many hematological tumors. The bromodomain protein BRD4 recruits p-TEFb by recognizing the acetylated lysine on histones, and then phosphorylates RNA polymerase II, which ultimately causes downstream gene expression, such as oncogenes. c-Myc gene, and abnormal expression of these genes can cause cancer and other diseases, including acute myeloid lymphoma, acute lymphocytic leukemia, lymphoma and various myeloma.

BRD4 small molecule inhibitors can interfere with the specific binding of BRDs domains and acetylated lysine, regulate the transcription of downstream related target genes, and then regulate downstream signaling pathways to treat diseases such as cancer and inflammation. The selective inhibitors that have been disclosed include WO2011054553, WO2013097052, WO2013158952, WO2014165127, WO2014206345, WO2016077378, WO2015081189, WO2016044067, WO2017177955 and WO2018137655. JQ1 is the most widely known drug of this kind, and JQ1 is an inhibitor of the BET family protein BRD4. As early as 2010, Filippakopoulos and others reported in the journal Nature that JQ1 exhibited anti-tumor properties on some specific cells and mouse models. JQ1 is currently widely used as a chemical probe to study the physiological functions of the BET protein and its relationship with diseases. A series of BRD4 inhibitor patents have been published, but there is still a need to develop new BRD4 inhibitors to meet market demand.

BRD4 inhibitors have good application prospects as drugs in the pharmaceutical industry. There are no drugs on the market. In order to achieve better therapeutic effects and meet market needs, we hope to develop BRD4 inhibitors with better activity and lower toxicity Agent.

Summary of the invention

The object of the present invention is to provide a compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, and The form of its mixture, and its pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, metabolites, isotopic derivatives,

Where Ar is

X is a nitrogen atom or a carbon atom; Y is -H or -OH;

时，X为碳原子； When Ar is

When, X is a carbon atom;

时，X为氮原子或碳原子； When Ar is

When, X is a nitrogen atom or a carbon atom;

T ¹为-C _1-3烷基、-CH ₂-C _3-6环烷基、

T ²为-O、-S、-NH、-N-CH ₃； R ⁰ is -(CH ₂ ) _n -heterocycloalkane, benzene ring, heteroaromatic ring, wherein the heterocycloalkane is 4-6 membered heterocycloalkane, and when the heteroatom on the heterocycloalkane is nitrogen, the nitrogen The hydrogen on the above can also be substituted by the following substituents: -C _1-3 alkyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl; R ⁰ is preferably

T ¹ is -C _1-3 alkyl, -CH ₂ -C _3-6 cycloalkyl,

T ² is -O, -S, -NH, -N-CH ₃ ;

R ¹ is -H, substituted or unsubstituted benzene ring, substituted or unsubstituted heteroaromatic ring; R ^{1 is} further -H, phenyl, 5-6 membered heteroaromatic ring, wherein the benzene Group or 5-6 membered heteroaromatic ring can be substituted by the following groups: halogen, -OH, -C _1-3 alkyl, -OC _1-4 alkyl, -C _1-3 alkylene-OC _1-3 alkyl;

R ¹ can be specifically

其中所述的-C _1-3烷基、-C _2-3烯烃基或杂环烷可被以下基团取代：-OH、-C _1-3烷基、-C _5-6环烷基、3-6元杂环基、C _1-3烷基取代的4-6元杂环基、5-10元杂芳基、-O-C _1-4烷基、-NH ₂、卤素或氰基； R ² is -H, halogen, -C _1-3 alkyl, -C _2-3 alkenyl, -C(O)OH, -C(O)OC _1-3 alkyl, -(CH ₂ ) _n- C _3-6 cycloalkyl, -(CH ₂ ) _n -heterocycloalkane, -OR ^a , -NR ^a R ^b ,

The -C _1-3 alkyl, -C _2-3 alkenyl or heterocycloalkane may be substituted by the following groups: -OH, -C _1-3 alkyl, -C _5-6 cycloalkyl, 3-6 membered heterocyclic group, 4-6 membered heterocyclic group substituted with C _1-3 alkyl, 5-10 membered heteroaryl, -OC _1-4 alkyl, -NH ₂ , halogen or cyano;

R ^a and R ^b are independently hydrogen, -C _1-3 alkyl, -C _1-4 alkylene-OH, -C _2-3 alkylene-NH-C _1-3 alkyl, -C _2-3 alkylene-N-(C _1-3 alkyl) ₂ , -C _2-3 alkylene-OC _1-3 alkyl;

R ^a and R ^b or together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl group that is unsubstituted or substituted by a T group, and T is -C _1-4 alkyl, -OH, and R _x7 substituted 4-6 membered heterocyclic group;

R _x1 , R _x2 , R _x3 , R _x4 , R _x5 and R _x6 are each independently -H, -OH, halogen, -C _1-3 alkyl, -C _2-3 alkenyl group; R _x1 , R _x2 , R _x3 , R _x4 , R _x5 , and R _{x6 are} more preferably -H, -CH ₃ ;

R _x7 is -H, -C _1-3 alkyl, -C _2-3 alkenyl, C _3-6 cycloalkyl; R _{x7 is} more preferably -H, -CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , cyclopropane;

R _y and R _z are each independently -H, -C _1-3 alkyl, and -C _2-3 alkene group; R _y and R _{z are} more preferably -H and -CH ₃ ;

其中所述的-C _1-3烷基、-C _2-3烯烃基或4-6元杂环烷可被以下基团取代：-OH、-C _1-3烷基、-C _5-6环烷基、4-6元杂环基、C _1-3烷基取代的4-6元杂环基、-O-C _1-4烷基； R ^{2 is} further preferably halogen, -C _1-3 alkyl, -C _2-3 alkenyl, -C(O)OH, -C(O)OC _1-3 alkyl, -C _3-6 cycloalkyl , 4-6 membered heterocycloalkane, -NR ^a R ^b ,

The -C _1-3 alkyl, -C _2-3 alkenyl or 4-6 membered heterocycloalkane can be substituted by the following groups: -OH, -C _1-3 alkyl, -C _5-6 Cycloalkyl, 4-6 membered heterocyclic group, C _1-3 alkyl substituted 4-6 membered heterocyclic group, -OC _1-4 alkyl;

其中-NR ^aR ^b为-NH ₂、-N(CH ₃) ₂、-N(CH ₃)-(CH ₂) ₂-NH-CH ₃、-N(CH ₃)-(CH ₂) ₂-NH-CH ₂CH ₃、-N(CH ₂CH ₃)-(CH ₂) ₂-NH-CH ₃、

R ² can specifically be -F, -Cl, -COOH, -NR ^a R ^b ,

Where -NR ^a R ^b is -NH ₂ , -N(CH ₃ ) ₂ , -N(CH ₃ )-(CH ₂ ) ₂ -NH-CH ₃ , -N(CH ₃ )-(CH ₂ ) _2- NH-CH ₂ CH ₃ , -N(CH ₂ CH ₃ )-(CH ₂ ) ₂ -NH-CH ₃ ,

R ³ is a 5-6 membered heteroaryl group, the heteroaryl group may be substituted by a C _1-3 alkyl group; R ³ may specifically be

R ⁴ is -H, halogen, -OC _1-3 alkyl, -SC _1-3 alkyl, -OC(O)-C _1-3 alkyl, -C(O)OC _1-3 alkyl; R ⁴ can be specifically -H, -Cl, -F, -OC _1-3 alkyl, -SC _1-3 alkyl, -OC(O)-C _1-3 alkyl, -C(O)OC _{1- 3} alkyl;

R ⁵ is -C _3-6 cycloalkyl; R ⁵ can specifically be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

R ⁶ and R ⁷ are each independently a hydroxy group or a -C _1-3 alkyl group; R ⁶ and R ^{7 are} further preferably a hydroxy group or a methyl group; R ⁸ is -H, -C _1-3 alkyl, -C _{3- 6} cycloalkyl;

结构还表示为

In the general formula

The structure is also expressed as

R ⁹ and R ¹⁰ are each independently -H, -OH, halogen, -C _1-3 alkyl, -C _1-3 alkylene-OH, -C _1-3 alkylene-NH-C _{1- 3} alkyl, -C _1-3 alkylene-N-(C _1-3 alkyl) ₂ , -C _1-3 alkylene-OC _1-3 alkyl; R ⁹ and R ^{10 are} more preferably- H, -OH, -C _1-3 alkyl, -C _1-3 alkylene -OH, -C _1-3 alkyl subunit -NH-C _1-3, -C _1-3 alkylene - OC _1-3 alkyl;

R ⁹ can specifically be -H, -OH;

R ¹⁰ may specifically be -CH ₂ -OC _1-3 alkyl;

R ¹¹ is -C _1-3 alkyl;

n is 0, 1, or 2.

According to the compound represented by general formula (I) and the pharmaceutically acceptable salt thereof according to the present invention, the compound is specifically:

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-phenyl-2-(tetrahydro-2H-pyran-4 -Yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(5-(2,3-Dihydro-1H-inden-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H -Pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(5-(Cyclopent-3-en-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[ 3,2-b]indol-7-yl)propan-2-ol;

2-Acetoxy-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl )Methyl)-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester;

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-7-(2-hydroxypropan-2-yl)-5-(phenyl(tetrahydro-2H -Pyran-4-yl)methyl)-1,5-dihydro-2H-pyrido[3,2-b]indol-2-one;

(2-Cyclopropyl-6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1Hbenzo(d)imidazol-4-yl)diphenylmethanol ；

2-(4-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(2-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(5-(1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-dimethyl-1H -1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(tetrahydrofuran-3-yl)-5H-pyrido[3,2-b ]Indol-7-yl)propan-2-ol;

4-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-7-(2-hydroxypropan-2-yl)-5H-pyrido[3, 2-b]indol-5-yl)tetrahydro-2H-pyran-3-ol;

4-(3-(1,4-Dimethyl-1H-,1,2,3-triazol-5-yl)-7-(2-hydroxypropan-2-yl)-5Hpyrido[3, 2-b]indol-5-yl]tetrahydrofuran-3-ol;

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(4-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(pyridin-2-yl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(4-methoxyphenyl)-2-(tetrahydro -2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2-(tetrahydro -2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(3-methoxyphenyl)-2-(tetrahydro -2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(3-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(5-(1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-dimethyl-1H -1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(5-(1-(2,3-Difluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-dimethyl-1H -1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(3-fluorophenyl)-2-(1-methyl Piperidin-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(3-fluorophenyl)-2-(1-(oxa Butyl-3-yl)piperidin-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(5-(2-(1-(cyclopropylmethyl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)-3-(1,4-dimethyl- 1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-2-carbonyl-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl Group)-2,5-dihydro-1H-pyrido[3,2-b]indole-7-carboxylic acid;

7-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2-(tetrahydro -2H-pyran-4-yl)ethyl)-5H-pyrrolo[3,2-b:4,5-c']dipyridine;

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2-(tetrahydro-2H-pyridine (Pyran-4-yl)ethyl)-7-(pyrrolidin-1-yl)-5H-pyrrolo[3,2-b:4,5-c']dipyridine;

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2-(tetrahydro-2H-pyridine (Pyran-4-yl)ethyl)-N,N-dimethyl-5H-pyrrolo[3,2-b:4,5-c']dipyridin-7-amine;

7-(azetidine-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methyl Oxyphenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[3,2-b:4,5-c']dipyridine;

7-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro- 2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridine;

N1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)-N1,N2-dimethylethane-1, 2-diamine;

1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)-4-methylpiperidin-4-ol;

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(methylthio)-5-(phenyl(tetrahydro-2H-pyridine) (Pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

7-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-phenyl-2-(tetrahydro-2H-pyran- 4-yl)ethyl)-5H-pyrrolo[3,2-b: 4,5-C']dipyridine;

6-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-phenyl-2-(tetrahydro-2H-pyran- 4-yl)ethyl)-5H-pyrrolo[3,2-b: 5,4-C']dipyridine;

(2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo(d)imidazol-7-yl)bis(pyridine -2-yl)methanol;

(2-Cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo(d)imidazol-4-yl)(tetrahydrofuran- 2-base) methanol hydrochloride;

(2-Cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo(d)imidazol-4-yl)(pyridine- 2-yl)(tetrahydrofuran-2-yl)methanol;

2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(3,5-dimethyl-1H-pyrazole-4 -Base) -1H-benzo[d]imidazole;

(2-Cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo(d)imidazol-4-yl)(6- Methylpyridin-2-yl)(tetrahydrofuran-2-yl)methanol;

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(3-(methoxymethyl)chroman-4-yl)- 5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(2-(2-methoxyethyl)-2,3-di Hydrobenzofuran-3-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

8-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-3-methyl-10-(phenyl(tetrahydro-2H-pyran-4-yl) (Methyl)-1,2,3,10-tetrahydrocyclopenta[g]pyrido[3,2-b]indol-3-ol;

(2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo(d)imidazol-7-yl)bis(thiazole -2-yl)methanol;

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran -4-yl)ethyl)-7-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-5H-pyrrolo[2,3-b:4,5-b ']Dipyridine;

2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(pyridin-4-yl)-1H-benzo[d] Imidazole

2-cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(2-methylnaphthalene-1-yl)-1H-benzene And [d]imidazole;

5-(2-Cyclopropyl-5-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazol-7-yl)- 6-methylquinoline;

2-(6-(3,5-Dimethylisoxazol-4yl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-4H-thiophene[2', 3': 4,5] pyrrole[3,2-b]pyridin-2-yl)propan-2-ol;

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4 -Yl)methyl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol;

6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl) Methyl)-2-(prop-1-en-2-yl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridine;

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl )-4H-furo[2',3': 4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol;

2-cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-ethyl-N-phenyl-N-(tetrahydro-2H -Pyran-4-yl)-1H-benzo[d]imidazol-4-amine;

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl )-4H-thieno[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol;

2-(5-(1-(2,4-Dichlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-dimethyl-1H -1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol;

5-isopropyl7-methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyridyl[3,2-b]indole- 5,7-dicarboxylic acid ester;

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(pyridin-2-yl(tetrahydrofuran-3-yl) (Methyl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol;

2-(4-(bis(pyridin-2-yl)methyl)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl -1,4-Dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propyl-2-ol;

7-(aziridin-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H- Pyran-4-yl)methyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridine;

4-(2-((3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)amino)ethyl)-1,3-dimethylpiperazin-2-one ；

N1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)-N1-ethyl-N2-methylethane- 1,2-diamine;

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran -4-yl)ethyl)-7-(4-isopropylpiperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5-b']bipyridine;

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran -4-yl)ethyl)-7-(4-(1-isopropylpiperidin-4-yl)piperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5- b']Bipyridine;

4-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl) ethyl)-5H-pyrrolo[2,3-b: 4,5-b']bispyridin-7-yl)morpholine;

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-7-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl )-5-(1-(2-Fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b: 4,5-b ']Bipyridine;

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran -4-yl)ethyl)-7-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5- b']Bipyridine;

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran -4-yl)ethyl)-7-(4-methylpiperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5-b']bipyridine;

7-(4-(1-Cyclopropylpiperidin-4-yl)piperazin-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazole-5- Yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b: 4,5- b']Bipyridine;

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran -4-yl)ethyl)-7-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5-b ']Dipyridine;

2-(4-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)phenyl)propyl-2-ol;

2-(4-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-3-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)propyl-2-ol;

8-(3,5-Dimethylisoxazol-4-yl)-10-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl) -3-Methyl-1,2,3,10-tetrahydrocyclopenta[g]pyrido[3,2-b]indol-3-ol;

8-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-fluoro-10-(phenyl(tetrahydro-2H-pyran-4-yl)methyl基)-1,10-dihydrocyclopenta[g]pyrido[3,2-b]indole-3(2H)-one;

10-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl基)-8,9-dihydrocyclopenta[f]pyrido[3,2-b]indole-7(5H)-one;

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5 ,7,8,9-tetrahydrocyclopenta[f]pyrido[3,2-b]indole;

3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5 ,7,8,9-tetrahydrocyclopenta[f]pyrido[3,2-b]indole-7-ol;

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-fluorophenyl)(tetrahydro-2H-pyran-4 -Yl)methyl)-1-methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propane-2- alcohol;

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(1-phenyl-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-1,4-dihydropyrrolo[2',3': 4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2- alcohol;

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((2-fluorophenyl)(tetrahydro-2H-pyran-4 -Yl)methyl)-1-methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2- alcohol;

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-1-methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl ) Propan-2-ol;

N1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)-N1-ethyl-N2-methylethane- 1,2-diamine;

2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(pyridin-2-yl(tetrahydro-2H-pyridine (Pyran-4-yl)methyl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol;

2-(6-(3,5-dimethylpyridin-4-yl)-4-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl )-1-Methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol.

The compound represented by the general formula I can be prepared by the following scheme,

Scheme 1: When Ar is

时，合成路线如下：

When, the synthetic route is as follows:

Where Ar ¹ is,

为

for

Compound (I-1) is coupled with the corresponding arylboronic acid (I-2) Suzuki in the presence of heating, basicity, and catalyst to obtain the compound of general formula (I-3), which provides basicity The reagents of the conditions are preferably potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium fluoride, etc.; the catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, acetic acid Palladium, tetratriphenylphosphine palladium, tris(dibenzylideneacetone) dipalladium, etc.; compound (I-3) undergoes intramolecular cyclization under the catalysis of a phosphine reagent to obtain compound (I-4), and the phosphine reagent is preferably 1 , 2-bis(diphenylphosphine)ethane (DPPE), triphenylphosphine, etc.; compound (I-4) reacts with the corresponding alcohol by Mitsunobu to obtain compound (I-6); compound (I-6) in palladium Catalyzed by Still coupling with the corresponding tin reagent to obtain compound (I), the catalyst used is preferably [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, palladium acetate, tetratriphenyl Phosphine palladium, tris(dibenzylideneacetone)dipalladium, etc.; after compound I is obtained, the functional group on the aromatic ring is further converted to obtain a specific target series compound.

Scenario 2,

时， Ar is

Time,

Compound (II-1) reacts with halogenating reagent to obtain compound of general formula (II-2). The halogenating reagent is preferably NBS, NCS, NIS, liquid bromine, etc.; compound (II-2) reacts with reducing agent to obtain compound of general formula (II -3), the reducing agent used is preferably stannous chloride, reduced iron powder, zinc powder, etc.; compound (II-3) is condensed with the corresponding acid chloride or carboxylic acid to obtain compound (II-4); compound (II-4) Under acidic conditions, compound (II-5) is obtained by intramolecular ring closure; compound (II-5) is Still coupled with tin reagent under palladium catalysis to obtain compound (II-6). The catalyst used is preferably [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride, palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, etc.; compound (II-6) and aryl format reagent Or the aryl lithium salt reacts to obtain compound (I);

Option 3.

时， Ar is

Time,

Compound (III-1) reacts with halogenating reagent to obtain compound (III-2) of general formula, and the halogenating reagent used is preferably NBS, NCS, NIS, etc.; compound (III-2) reacts with reducing agent to obtain compound of general formula (III-3) The reducing agent used is preferably stannous chloride, reduced iron powder, zinc powder, etc.; compound (III-3) is condensed with the corresponding acid chloride or carboxylic acid to obtain compound (III-4); compound (III-4) is under acidic conditions Compound (III-5) is obtained by closing the intramolecular ring; Compound (III-5) is Still coupled with tin reagent under palladium catalysis to obtain Compound (III-6). The catalyst used is preferably [1,1'-bis(二) Phenylphosphino)ferrocene]palladium dichloride, palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, etc.; compound (III-6) reacts with a reducing agent to obtain a compound of general formula (III-7), the reducing agent used is preferably stannous chloride, reduced iron powder, zinc powder, etc.; compound (III-7) reacts with sodium nitrite and sodium halide under acidic conditions to obtain compound (III-8); Compound (III-8) is coupled with aryl boronic acid or aryl boronic acid ester Suzuki in the presence of heating, alkaline, and catalyst to obtain the compound of general formula (I), which provides reagents for alkaline conditions Preferably potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium fluoride, etc.; the catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, palladium acetate, Triphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, etc.;

Option 4.

时， Ar is

Time,

Compound (III-8) is subjected to Buchwald-Hartwig coupling with an amine under heating, alkaline, and presence of a catalyst to obtain a compound of general formula (I). The reagent for alkaline conditions provided under this condition is preferably potassium carbonate, Cesium carbonate, potassium hydroxide, sodium hydroxide, cesium fluoride, sodium tert-butoxide, potassium tert-butoxide, etc.; the catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride , Palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, etc.;

Option 5.

时， Ar is

Time,

Compound (II-5) is reacted with di-tert-butyl dicarbonate to obtain compound (IV-1); compound (IV-1) is reduced to compound (IV-2) by a reducing agent, and the reducing agent used is preferably diisobutyl aluminum hydride Compound (IV-2) reacts with the corresponding ether under the conditions of triethyl boron and tert-butanol to obtain compound (IV-3); compound (IV-3) is oxidized with oxidizing agent to obtain compound (IV-4), The oxidant used is preferably active manganese dioxide, Dess-martin oxidant, pyridinium dichromate (PDC), etc.; compound (IV-4) is still coupled with tin reagent under palladium catalysis to obtain compound (IV-5). The catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, etc.; compound (IV -5) React with aryl lithium salt or aryl grating reagent to obtain the compound of general formula (I).

The pharmaceutically acceptable salts in the present invention refer to inorganic base salts, such as sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, ammonium salt, quaternary ammonium salt or aluminum salt; organic base salt, such as lysine Amino acid, arginine, diethylamine, triethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, dibenzylamine, piperidine, and other pharmaceutically acceptable salts The organic amine salt.

When the compound of the present invention contains at least one salt-forming nitrogen atom, it can be converted into the corresponding salt by reacting with the corresponding organic or inorganic acid in an organic solvent such as acetonitrile or tetrahydrofuran. Typical organic acids are oxalic acid, tartaric acid, maleic acid, succinic acid, methanesulfonic acid, benzoic acid, benzenesulfonic acid, toluenesulfonic acid, sulfamic acid, citric acid, glutamic acid, pyroglutamic acid, aspartic acid Acid, glucuronic acid, naphthalenesulfonic acid, glutaric acid, acetic acid, trifluoroacetic acid, malic acid, fumaric acid, salicylic acid, 4-aminosalicylic acid, lactic acid, palmitate, stearic acid, laurel Acid, cinnamic acid, alginic acid, ascorbate, typical inorganic acids are nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid.

When the compounds of the present invention have one or more asymmetric carbon atoms, they can exist in the following forms: optically pure enantiomers, pure diastereomers, mixtures of enantiomers, diastereomers Conformer mixture, racemic mixture of enantiomers, racemate or racemate mixture. All possible isomers, stereoisomers and mixtures of the compound of formula (II) are also within the scope of the present invention.

The present invention also provides a pharmaceutical composition comprising at least one compound or tautomers, mesoisomers, racemates, enantiomers, diastereomers, and In the form of mixtures, and their pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, metabolites, isotopic derivatives, and optionally one or more pharmaceutically acceptable carriers and/or diluents.

The pharmaceutical composition provided by the present invention can be prepared in any form, such as granules, powders, tablets, coated tablets, capsules, pills, syrups, drops, solutions, suspensions and emulsions, or sustained release of active ingredients Formulations, where examples of capsules include hard or soft gelatin capsules, and granules and powders may be in non-effervescent or effervescent forms.

The pharmaceutical composition of the present invention may further include one or more pharmaceutically or physiologically acceptable carriers, and these carriers will be appropriately formulated to facilitate administration. For example, the pharmaceutically or physiologically acceptable carrier can be saline, hot-pressed water, Ringer's solution, buffered saline, dextrose, maltodextrin, glycerol, ethanol, and mixtures thereof. The pharmaceutical composition of the present invention may also include pharmaceutically or physiologically acceptable additives, such as diluents, lubricants, binders, glidants, disintegrants, sweeteners, flavoring agents, wetting agents, and dispersing agents. , Surfactant, solvent, coating agent, foaming agent, or fragrance.

Examples of diluents that can be used include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate; examples of lubricants include, but are not limited to, talc, starch, magnesium or calcium stearate, and stone pine Examples of binders include, but are not limited to, microcrystalline cellulose, tragacanth, dextrose solution, gum arabic, gelatin solution, sucrose and starch paste; examples of glidants include, but are not limited to, colloidal two Silicon oxide; examples of disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methyl cellulose, agar, and carboxymethyl cellulose; Examples of sweeteners include, but are not limited to, sucrose, lactose, mannitol, and artificial sweeteners, such as sodium cyclamate and saccharin, and any number of spray-dried flavoring agents; examples of flavoring agents include, but are not limited to, from plants Extracted natural flavors, such as fruits, and better-tasting compounds, such as but not limited to peppermint and methyl salicylate; examples of humectants include, but are not limited to, propylene glycol monostearate, sorbitan monooleic acid Esters, diethylene glycol monolaurate and polyoxyethylene lauryl ether.

The pharmaceutical composition of the present invention can be administered by various routes according to traditional methods, including oral, intravenous, intraarterial, intraperitoneal, intrathoracic, transdermal, nasal, inhalation, rectal, ocular and subcutaneous introduction.

The pharmaceutically acceptable carriers optionally added to the pharmaceutical composition of the present invention are: water, alcohol, honey, mannitol, sorbitol, dextrin, lactose, caramel, gelatin, calcium sulfate, magnesium stearate , Talc, kaolin, glycerin, tween, agar, calcium carbonate, calcium bicarbonate, surfactants, cyclodextrin and its derivatives, phospholipids, phosphates, starches and their derivatives, silicon derivatives, One or more of celluloses and their derivatives, pyrrolidones, polyethylene glycols, acrylic resins, phthalates, acrylic copolymers and trimellitic esters.

It has been verified by pharmacological experiments that the compounds or pharmaceutical compositions provided by the present invention can treat tumors through BRD4, and the tumors are lymphoma, melanoma, glioma, gastrointestinal stromal tumor, prostate cancer, breast cancer, and ovarian cancer. Cancer, bladder cancer, lung cancer, rectal cancer, skin cancer, epithelial cell cancer, nasopharyngeal cancer, bone cancer, esophageal cancer or leukemia.

The general dosage range of the compound provided by the present invention is about 0.001 mg/Kg to 1000 mg/kg per day, preferably about 0.01 mg/kg to 100 mg/kg, more preferably about 0.1 to 20 mg/kg, the dosage range of the pharmaceutical composition It is calculated based on the amount of the above-mentioned compound contained.

The present invention also relates to the compounds according to the present invention or their tautomers, mesoisomers, racemates, enantiomers, diastereomers, and mixtures thereof, and their pharmacological use The use of salts, polymorphs, solvates, prodrugs, metabolites, isotopic derivatives, or pharmaceutical compositions according to the present invention in the preparation of drugs for the prevention and/or treatment of BRD4-mediated related diseases.

The BRD4-mediated related diseases include tumors.

The tumors are acute myeloid lymphoma, acute lymphocytic leukemia, lymphoma and various myeloma.

The present invention also relates to a method for preventing and/or treating tumors, the method comprising administering to a subject in need a therapeutically effective amount of the compound according to the present invention and a pharmaceutically acceptable salt or stereoisomer thereof or The pharmaceutical composition according to the present invention.

The present invention also relates to compounds according to the present invention and pharmaceutically acceptable salts or stereoisomers thereof, or pharmaceutical compositions according to the present invention for use in the prevention and/or treatment of tumors.

detailed description

Example 1: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-phenyl-2-(tetrahydro-2H- Pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

The first step N-methoxy-N-methyl-2-(tetrahydro-2H-pyran-4-yl)acetamide (1j)

Dissolve tetrahydropyran-4-acetic acid 1i (10.0g, 69.4mmol) in 30ml DCM, add CDI (12.39g, 76.4mmol) at 0°C, stir for half an hour, add dimethylhydroxylamine dihydrochloride (7.48g, 76.4mmol) and DIPEA (15mL, 138.8mmol). Stir at room temperature overnight. The reaction was monitored by TLC. After the reaction, the system was washed with 1M NaOH(aq) (50ml*2), citric acid (50ml*2), and saturated brine, dried with anhydrous sodium sulfate, filtered, and spin-dried to obtain N- Methoxy-N-methyl-2-(tetrahydro-2H-pyran-4-yl)acetamide 1j (9.0g), yellow oily liquid, yield 69%, without further purification.

The second step 1-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethyl-1-one (1k)

N-methoxy-N-methyl-2-(tetrahydropyran-4-yl)acetamide 1j (9.0g, 48mmol) was added to a 100ml three-necked flask. Sealed, under the protection of nitrogen, add 40ml anhydrous THF, stir evenly, cool to -70℃, dropwise add phenyl lithium (2M inTHF, 24ml, 48mmol). The color of the system gradually darkened. After stirring for 2 hours at -70°C, the reaction was quenched by NH ₄ Cl _(sat.) . Ethyl acetate (100ml) and water (100ml) were layered, the organic phase was washed with anhydrous saturated brine, dried with anhydrous sodium sulfate, filtered, spin-dried, column separation, PE/EA=100/10 eluted, and 1 -Phenyl-2--(tetrahydropyran-4-yl)ethyl-1-one 1k (4.0g), white solid, yield 41%.

The third step 1-phenyl-2--(tetrahydropyran-4-yl)ethyl-1-ol (1g)

Phenyl-4-tetrahydropyranone 1k (4.0g, 19.6mmol) was dissolved in 40ml of methanol, and sodium borohydride (1.12g, 29.4mmol) was added in portions at 0°C. After the addition, stir at room temperature for 1 hour, add water to quench (20ml), extract with EA (50ml*3), combine the organic phases, dry with anhydrous sodium sulfate, filter, column separation, PE/EA=90/10 elution, 1 g (2.2 g) of 1-phenyl-2--(tetrahydropyran-4-yl)ethyl-1-ol was obtained as a white solid with a yield of 55%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.19-7.33 (m, 5H), 5.12-5.13 (d, J = 4.8Hz, 1H), 4.58-4.63 (m, 1H), 3.81 (m, 2H), 3.20-3.26(t,J=12.0Hz,2H), 1.53-1.65(m,4H),1.36-1.42(m,1H), 1.12-1.23(m,2H).

Step 4 Methyl 4-(5-bromo-3-nitropyridin-2-yl)benzoate (1c)

Dissolve 2,5-dibromo-3-nitropyridine 1a (5.0g, 17.7mmol), 4-methoxycarbonylphenylboronic acid (3.19g, 17.7mmol), K ₃ PO ₄ (3.0M, 18ml) in 60ml Pd(dppf)Cl ₂ (1.30g, 732mmol) was added under the protection of THF and nitrogen, and the reaction was carried out at 80°C for 3 hours. EA (100ml) and water (100ml) were layered, the organic phase was dried, filtered, column separated, PE/EA=2/1 eluted to obtain 4-(5-bromo-3-nitropyridin-2-yl)benzene Methyl formate 1c (3.15g), white solid, yield 53%.

LCMS(ESI-MS) m/z: 337.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ9.10(s,1H),8.83(s,1H),8.02-8.04(d,J=8.0Hz,2H),7.64-7.66(d,J=8.0 Hz, 2H), 3.85 (s, 3H).

Step 5 3-Bromo-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester (1d)

Dissolve methyl 4-(5-bromo-3-nitropyridin-2-yl)benzoate 1c (200mg, 0.59mmol) and DPPE (295 mg, 0.74mmol) in 3ml o-dichlorobenzene at 180℃ React for 4 hours. Cool to room temperature, filter the precipitated solid, and wash the filter cake with DCM to obtain 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester 1d (90mg), off-white solid, yield 50%.

LCMS(ESI-MS)m/z:305.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.80 (s, 1H), 8.54 (s, 1H), 8.21-8.24 (m, 2H), 8.16 (s, 1H), 7.82-7.83 (m, 1H) ), 3.87(s, 3H).

Step 6 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester (1f)

Combine 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester 1d (90mg, 0.30mmol) and 1,4-dimethyl-5-(tributylstannyl) -1H-1,2,3-triazole 1e (126mg, 0.33mmol) was dissolved in 5ml DMF, and CuI (10mg, 0.045mmol), Pd(PPh ₃ ) ₄ (35mg, 0.03mmol) and 60mg TEA (0.6 mmol), reacted at 90°C for 3 hours under a nitrogen atmosphere, filtered through celite, spin-dried DMF, the resultant was slurried with DCM, filtered, and a solid was recovered, namely 3-(1,4-dimethyl-1H-1,2 ,3-Triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester 1f (24mg), yellow solid, yield 25%.

LCMS(ESI-MS)m/z:322.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ11.90(s,1H), 8.58(s,1H), 8.30–8.32(d,J=8.4Hz,1H), 8.20–8.21(s,1H), 8.12(d,J=1.6Hz,1H), 7.34–7.36(dd,J=8.4,1.6Hz,1H), 3.98(s,3H), 3.89(s,3H), 2.27(s,3H).

Step 7 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-phenyl-2-(tetrahydro-2H-pyran-4) -Yl)ethyl)-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester (1h)

1f (107mg, 0.33mmol), 1g (136mg, 0.66mmol) and triphenylphosphonium (173mg, 0.66mmol) were dissolved in 5mL of dry THF, and DIAD (133mg, 0.66mmol) was added. Stir at room temperature overnight, spin dry the reaction system, prepare and separate by TLC, develop with DCM/MeOH=20/1 to obtain the target compound 1h (55mg), off-white solid, the yield is 33%.

LCMS(ESI-MS) m/z: 510.0[M+H] ⁺ .

Step 8 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-phenyl-2-(tetrahydro-2H-pyridine) (Pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol (1)

Dissolve 1h (700mg, 1.37mmol) in 15mL of anhydrous THF, add 6.9mL of methylmagnesium bromide (2M in THF) in an ice-salt bath (-10°C). After the addition, the mixture was stirred overnight at room temperature, and saturated aqueous ammonium chloride solution was added to quench the reaction, and the solid was filtered off. The filtrate was diluted with 50mL of dichloromethane, washed with water (50mL*2), the organic phase was dried over anhydrous magnesium sulfate, filtered, spin-dried, column separated, eluted with DCM/MeOH=20/1 to obtain 400mg of crude product. The product can be collected by beating with an appropriate amount of THF to obtain 1 (101mg) as a white solid with a yield of 14%.

LCMS(ESI-MS) m/z: 510.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.44-8.48 (m, 2H), 7.85 (s, 1H), 7.46-7.48 (d, J = 9.2Hz, 1H), 7.26-7.32 (m, 6H), 6.09-6.13(t,J=5.6Hz,1H),3.81-3.93(m,2H),3.78(s,3H),3.10-3.15(m,2H),2.45-2.49(m,2H),2.20( s, 3H), 1.89-1.92 (m, 2H), 1.72 (s, 3H), 1.69 (s, 3H), 1.36-1.50 (m, 4H).

Example 2: 2-(5-(2,3-Dihydro-1H-inden-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazole-5- Yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

The first step 5-(2,3-dihydro-1H-inden-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H -Pyrido[3,2-b]indole-7-carboxylic acid methyl ester (2a)

1f (150mg, 0.47mmol), 2b (129mg, 0.93mmol) and triphenylphosphonium (245mg, 0.93mmol) were dissolved in 9mL of dry THF, and DIAD (188mg, 0.93mmol) was added. Stir at room temperature overnight, spin dry the reaction system, prepare and separate by TLC, develop with DCM/MeOH=20/1 to obtain target compound 2a (120mg), off-white solid, yield 56%.

LCMS(ESI-MS) m/z: 438.1[M+H] ⁺ .

The second step 2-(5-(2,3-dihydro-1H-inden-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl )-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol(2)

Dissolve 2a (120mg, 0.27mmol) in 10mL anhydrous THF, add 5.0mL methylmagnesium bromide (2M in THF) in an ice salt bath (-10℃). After the addition, the mixture was stirred at room temperature overnight, the reaction was quenched by adding saturated aqueous ammonium chloride solution, and the solid was filtered off. The filtrate was diluted with 30mL of dichloromethane, washed with water (30mL*2), the organic phase was dried over anhydrous magnesium sulfate, filtered, spin-dried, column separated, eluted with DCM/MeOH=20/1 to obtain 140mg of crude product. This product can be collected by beating a proper amount of THF to obtain 2 (80mg), a white solid, with a yield of 67%.

LCMS(ESI-MS) m/z: 438.2[M+H] ⁺ .

¹ H NMR(400MHz, CDCl ₃ )δ8.39–8.45(m,2H),7.95(s,1H),7.41–7.47(m,2H),7.32–7.36(t,J=7.35Hz,1H), 7.13–7.17(t,J=7.35Hz,1H), 6.95–6.97(d,J=6.96Hz,1H), 6.69(s,1H), 6.46(s,1H), 3.67(s,3H), 3.11 --3.28(m,2H), 2.83(m,1H), 2.37(m,1H), 2.03(m,3H), 1.73(s,6H), 1.24(s,1H).

Example 3: 2-(5-(Cyclopent-3-en-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H -Pyrido[3,2-b]indol-7-yl)propan-2-ol

The first step 5-(cyclopent-3-en-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[ 3,2-b)Indole-7-carboxylic acid methyl ester (3a)

1f (200mg, 0.62mmol), 3b (105mg, 1.24mmol) and triphenylphosphorus (325mg, 1.24mmol) were dissolved in 10mL of dry THF, and DIAD (250mg, 1.24mmol) was added. Stir at room temperature overnight, spin dry the reaction system, prepare and separate by TLC, develop with DCM/MeOH=20/1 to obtain the target compound 3a (146mg), off-white solid, the yield is 61%.

LCMS(ESI-MS) m/z: 388.1[M+H] ⁺ .

The second step 2-(5-(cyclopent-3-en-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H- Pyrido[3,2-b]indol-7-yl)propan-2-ol (3)

Dissolve 3a (146mg, 0.38mmol) in 10mL anhydrous THF, add 8.0mL methylmagnesium bromide (2M in THF) in an ice salt bath (-10°C). After the addition, the mixture was stirred at room temperature overnight, the reaction was quenched by adding saturated aqueous ammonium chloride solution, and the solid was filtered off. The filtrate was diluted with 30mL of dichloromethane, washed with water (30mL*2), the organic phase was dried over anhydrous magnesium sulfate, filtered, spin-dried, column separated, eluted with DCM/MeOH=20/1 to obtain 130mg of crude product. The product can be collected by beating with an appropriate amount of MeOH to obtain 2-(5-(cyclopent-3-en-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazole) -5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol 3 (50mg), white solid, yield 34%.

LCMS(ESI-MS) m/z: 388.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.44-8.45 (m, 2H), 8.36-8.38 (d, J = 8.8Hz, 1H), 7.78 (s, 1H), 7.61 (s, 1H), 7.41 7.43(d,J=8.8Hz,1H),5.99(s,2H),5.60-5.62(m,1H),4.01(s,3H),3.09-3.16(m,2H),2.82-2.87(m, 2H), 2.33(s, 3H), 1.70(s, 6H).

Example 4: 2-Acetoxy-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran) -4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester

The first step is 3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester( 4a)

Combine 3-bromo-5-hydropyridine[3,2-b]oxindole-7-carboxylic acid methyl ester 1d (2.0g, 6.5mmol) and phenyl (tetrahydro-2H-pyran-4-yl) methanol Int1 (2.5g, 13mmol) was dissolved in 50ml THF, added triphenylphosphorus (3.4g, 13mmol), protected by nitrogen, stirred under ice bath conditions for 0.5 hours, added DIAD (2.6g, 13mmol), slowly warmed to room temperature, reaction 6 Hour, TLC monitoring, the raw material reaction is complete, the sample is directly mixed with silica gel, and the Flash column is purified to obtain 3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[ 3,2-b]Indole-7-carboxylic acid methyl ester 4a (1.1 g, 2.3 mmol), the yield was 35.3%.

LCMS(ESI-MS) m/z: 479.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.60 (d, J = 1.8Hz, 1H), 8.49-8.38 (m, 2H), 8.08-7.97 (m, 2H), 7.52-7.43 (m, 2H), 7.42-7.28 (m, 3H), 5.46 (d, J = 11.0 Hz, 1H), 4.01 (s, 4H), 3.85 (dd, J = 11.6, 3.6 Hz, 1H), 3.55 (td, J = 11.6, 2.0Hz, 1H), 3.37 (td, J = 11.6, 2.0 Hz, 1H), 3.12 (dt, J = 11.6, 3.6 Hz, 1H), 1.98 (d, J = 13.5 Hz, 1H), 1.68-1.50 ( m,1H),1.46-1.29(m,1H),1.02(d,J=13.4Hz,1H).

The second step 3-bromo-7-(methoxycarbonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indino Dole 1-oxide (4b)

4a (1.1g, 2.3mmol) was dissolved in 20mL DCM, and mCPBA (793.5mg, 4.6mmol) was added under ice bath conditions. Stir at room temperature overnight, monitored by TLC, the raw material reaction is complete, 1M NaOH aqueous solution, saturated sodium bisulfite aqueous solution wash the reaction solution, Flash column purification, obtain 4b (930mg, 1.87mmol), yield 81.6%.

¹ H NMR(400MHz, CDCl ₃ )δ8.90(d,J=8.3Hz,1H), 8.39(s,1H), 8.33(d,J=1.1Hz,1H), 8.04(dd,J=8.3, 1.2Hz,1H), 7.62(d,J=1.2Hz,1H),7.50–7.44(m,2H),7.41–7.35(m,2H),7.34–7.30(m,1H),5.46(d,J =11.0Hz,1H),4.09–4.03(m,1H),4.01(s,3H),3.89–3.83(m,1H),3.78–3.71(m,1H),3.56(td,J=11.9,2.1 Hz, 1H), 3.38 (td, J = 12.0, 2.1 Hz, 1H), 3.12 (dt, J = 11.3, 3.6 Hz, 1H), 1.66-1.52 (m, 1H), 1.37 (qd, J = 12.1, 4.2Hz, 1H), 1.05-0.97 (m, 1H).

The third step 2-acetoxy-3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7 -Methyl carboxylate (4c)

4b (780mg, 1.52mmol) was dissolved in 5mL acetic anhydride, heated at 145°C under reflux for 2 hours, TLC monitored, the raw material reaction was complete, water was added, washed with saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, and dried with anhydrous sodium sulfate , Spin dry, and purify by Flash column to obtain methyl 2-acetoxy-3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3, 2-b] Indole-7-carboxylate 4c (530 mg, 0.95 mmol), the yield was 63.1%.

LCMS(ESI-MS) m/z: 538.0[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ8.41(s,1H),8.32(d,J=8.3Hz,1H),8.11(s,1H),7.99(dd,J=8.2,1.2Hz,1H) ,7.47(d,J=6.9Hz,2H),7.36(t,J=7.2Hz,2H),7.33-7.29(m,1H),7.26(s,1H),5.45(d,J=11.0Hz, 1H), 4.05 (d, J = 11.4 Hz, 1H), 4.01 (s, 3H), 3.86 (d, J = 11.7 Hz, 1H), 3.55 (dd, J = 12.9, 10.7 Hz, 1H), 3.43- 3.31 (m, 1H), 3.10 (q, J = 11.3 Hz, 1H), 2.44 (s, 3H), 1.70-1.51 (m, 1H), 1.45-1.31 (m, 1H), 1.05 (d, J = 13.4Hz, 1H).

The fourth step 2-acetoxy-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran- 4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester (4)

Dissolve 4c (200mg, 0.37mmol) in 5mL DMF, add CuI (7.6mg, 0.04mmol), 1e (157.5mg, 0.4mmol), Pd (PPh ₃ ) ₄ (42.7mg, 0.4mmol), nitrogen protection, The reaction was heated at 95°C for 4 hours, monitored by TLC, the raw material reaction was complete, water was added, extracted with EA, washed with saturated sodium chloride, dried with anhydrous sodium sulfate, and purified by Flash column to obtain methyl 2-acetoxy-3-(1,4 -Dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3, 2-b] Indole-7-carboxylate 4 (28 mg), pale yellow solid.

LCMS(ESI-MS) m/z: 554.2[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ8.48(s,1H),8.42-8.34(m,1H),8.04(d,J=8.3Hz,1H),7.70(d,J=3.2Hz,1H) ,7.43(d,J=7.5Hz,2H),7.38-7.26(m,3H),5.59(s,1H),4.14-3.98(m,4H),3.92(s,1H),3.85(d,J = 11.2 Hz, 1H), 3.55 (d, J = 17.2 Hz, 3H), 3.33 (t, J = 11.8 Hz, 1H), 3.08 (d, J = 11.2 Hz, 1H), 2.05 (d, J = 2.4 Hz, 6H), 1.68-1.52 (m, 1H), 1.42 (d, J = 12.8 Hz, 1H), 1.24 (td, J = 7.3, 1.9 Hz, 1H), 1.09 (s, 1H).

Example 5: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-7-(2-hydroxypropan-2-yl)-5-(phenyl( Tetrahydro-2H-pyran-4-yl)methyl)-1,5-dihydro-2H-pyrido[3,2-b]indol-2-one

The first step is 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(2-hydroxypropane-2-yl)-5-(phenyl(tetra Hydrogen-2H-pyran-4-yl)methyl)-1,5-dihydro-2H-pyrido[3,2-b]indol-2-one(5)

The 4 (180mg, 0.32mmol) was dissolved in 5ml of anhydrous THF was added _{CH 3 MgBr (1M in THF,} 2mL, 2mmol), stirred at room temperature to react for 4 h, TLC monitoring, the reaction was complete starting material, quenched with water, extracted with EA, Wash with saturated NaCl aqueous solution, dry with anhydrous sodium sulfate, and purify by Flash column to obtain 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(2-hydroxypropane) -2-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,5-dihydro-2H-pyrido[3,2-b]indole-2 -Ketone 5 (68 mg, 0.13 mmol), pale yellow solid.

LCMS(ESI-MS) m/z: 512.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 8.04 (d, J = 8.4 Hz, 1H), 7.92-7.86 (m, 1H), 7.67 (s, 1H), 7.42-7.27 (m, 5H), 7.26 ( d, J = 1.1 Hz, 1H), 5.49 (d, J = 10.3 Hz, 1H), 4.07 (s, 3H), 4.02 (s, 1H), 3.93-3.83 (m, 1H), 3.53 (t, J = 11.7Hz, 1H), 3.41-3.31 (m, 1H), 2.97 (d, J = 11.5Hz, 1H), 2.20 (s, 3H), 2.00 (d, J = 3.9 Hz, 1H), 1.96 (s ,1H),1.70(s,6H),1.58(d,J=12.3Hz,1H),1.39(dd,J=12.6,4.4Hz,1H),1.11(d,J=13.3Hz,1H),0.87 (d,J=7.0Hz,1H).

Example 6: (2-Cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1Hbenzo[d]imidazol-4-yl) Diphenylmethanol

The first step is methyl 2-amino-5-bromo-3-nitrobenzoate (6b)

Compound 6a (1.5g, 7.653mmol) was dissolved in acetic acid (20mL), and liquid bromine (3.26g, 19.1mmol) was slowly added dropwise. After the reaction was stirred at room temperature for 2 hours, the acetic acid was spin-dried, and then petroleum ether was added to make the slurry. After filtration, washing with petroleum ether, and air drying, the title compound 6b (1.2 g, 4.36 mmol) was obtained with a yield of 57%.

LCMS(ESI-MS)m/z:277[M+H] ⁺ _.

Step 2 Methyl 2,3-diamino-5-bromobenzoate (6c)

Compound 6b (1.2g, 4.36mmol) was dissolved in ethanol (40mL) and tetrahydrofuran (10mL), then ammonium chloride (2.31g, 43.6mmol) and zinc powder (2.83g, 43.6mmol) were added and heated to reflux for 20 hours , Filtered, washed with ethyl acetate, spin-dried and added saturated sodium bicarbonate solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by plate chromatography to obtain the title compound 6c (0.6 g, 2.448mmol), the yield is 56%.

LCMS(ESI-MS)m/z:247[M+H] ⁺ _.

Step 3 Methyl 2-amino-5-bromo-3-(cyclopropaneamido)benzoate (6d)

Compound 6c (0.6g, 2.4mmol) was dissolved in dichloromethane (10mL), triethylamine (0.495g, 4.9mmol) was added and then cyclopropionyl chloride (0.254g, 2.4mmol) was added dropwise, after stirring for 2h at room temperature, the reaction complete. The reaction solution was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to obtain the title compound 6d (0.58g, 1.853mmol) with a yield of 75%.

LCMS(ESI-MS)m/z:313[M+H] ⁺ _.

Fourth step 6-bromo-2-cyclopropyl-1H-benzo[d]imidazole-4-carboxylic acid methyl ester (6e)

Compound 6d (580mg, 1.966mmol) was dissolved in acetic acid (4mL), heated in microwave under argon atmosphere and stirred at 150℃ for 1h. After cooling, spin dry, extract three times with dichloromethane, wash with saturated sodium bicarbonate, dry with anhydrous sodium sulfate, filter, concentrate and purify by plate chromatography to obtain the title compound 6e (350 mg, 1.19 mmol) with a yield of 64%.

LCMS(ESI-MS)m/z:297[M+H] ⁺ _.

The fifth step 2-cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H benzo[d]imidazole-4-carboxylic acid methyl ester (6f)

Compound 6e (300mg, 1.02mmol), compound 1a (1161mg, 3.02mmol) and palladium tetrakistriphenylphosphorus (230mg, 0.2mmol) were dissolved in 1,4-dioxane (5mL), under argon protection Stir under microwave heating at 150°C for 1h. After the reaction is complete, the reaction solution is extracted three times with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by plate chromatography to obtain the title compound 6f (120mg, 0.38mmol) , The yield is 38%.

LCMS(ESI-MS)m/z:312[M+H] ⁺ _.

The sixth step (2-cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1Hbenzo[d]imidazol-4-yl) two Phenyl alcohol (6)

Compound 6f (120mg, 0.38mmol) was dissolved in dry tetrahydrofuran (5mL). Phenyllithium (1.9mL, 1.9mmol) was added at -78C. After the addition, the temperature was raised to room temperature and the reaction was completed for 24h. The reaction solution was washed with water, extracted three times with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by plate chromatography to obtain the title compound 6 (7mg, 0.016mmol) with a yield of 5%.

LCMS(ESI-MS)m/z:436[M+H] ⁺ _.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.74 (s, 1H), 7.46 (m, 2H), 7.26 (d, J = 9.8 Hz, 9H), 6.91 (s, 1H), 6.21 (s, 1H), 3.77 (s, 3H), 2.34 (s, 1H), 1.99 (s, 3H), 1.00 (m, 4H).

Example 7: 2-(4-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyridine) (Pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

The first step 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(methoxycarbonyl)-5-(phenyl(tetrahydro-2H- Pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole 1-oxidation (7a)

Dissolve 4b (990mg, 2.0mmol) in 20mL DMF, add CuI (38.0mg, 0.2mmol), 1e (849.2mg, 2.2mmol), Pd (PPh ₃ ) ₄ (231.1mg, 0.2mmol), nitrogen protection, The reaction was heated at 95°C for 4 hours, monitored by TLC, the raw material reaction was complete, water was added, extracted with EA, washed with saturated sodium chloride, dried with anhydrous sodium sulfate, and purified by Flash column to obtain 7a (930 mg, 1.82 mmol) with a yield of 90.9%.

LCMS(ESI-MS) m/z: 512.2[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ8.48(s,1H),8.42-8.34(m,1H),8.04(d,J=8.3Hz,1H),7.70(d,J=31.9Hz,1H) ,7.43(d,J=7.5Hz,2H),7.39-7.25(m,3H),5.59(s,1H),4.06-4.00(m,3H),3.92(s,1H),3.85(d,J = 11.3Hz, 1H), 3.55 (d, J = 17.0Hz, 3H), 3.33 (t, J = 11.8Hz, 1H), 3.08 (d, J = 12.9Hz, 1H), 2.05 (m, 6H), 1.59(d,J=11.7Hz,1H), 1.40(t,J=12.4Hz,1H), 1.09(s,1H).

The second step 4-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester (7b)

Dissolve 7a (300mg, 0.58mmol) in 5mL of toluene, add pyridine (176.3mg, 2.32mmol), phosphorus oxychloride (177.8mg, 1.16mmol), nitrogen protection, heating at 80℃ for 4 hours, TLC monitoring, raw materials The reaction is complete, the solvent is spin-dried, and the flash column is purified to obtain 4-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetra Hydrogen-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester 7b (173 mg, 0.32 mmol), yield 56.2%.

LCMS(ESI-MS) m/z: 530.2[M+H]+.

The third step 2-(4-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran) -4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol (7)

Dissolve 7b (173mg, 0.32mmol) in 5ml anhydrous THF, add CH3MgBr (1M in THF, 2ml, 2mmol), stir the reaction at room temperature for 4 hours, TLC monitoring, raw material reaction is complete, add water to quench, EA extraction, saturated NaCl Wash with aqueous solution, dry with anhydrous sodium sulfate, and purify by Flash column to obtain 2-(4-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5- (Phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol 7 (43mg, 0.08mmol) , Yield 25%, white solid.

LCMS(ESI-MS) m/z: 530.4[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ8.51(d,J=8.4Hz,1H), 8.38(d,J=1.4Hz,1H), 7.82(d,J=7.0Hz,1H), 7.57(s ,2H),7.45(s,1H),7.39(t,J=7.4Hz,2H),7.28(s,1H),6.85(d,J=10.7Hz,1H),4.07(d,J=11.5Hz ,1H),3.98(s,3H),3.86(d,J=10.8Hz,1H),3.59(t,J=12.0Hz,1H), 3.34(t,J=11.9Hz,1H), 3.23(d ,J＝12.2Hz,1H),2.35(s,3H),2.08(m,1H),1.61(d,J＝2.3Hz,4H),1.59(d,J＝2.2Hz,3H),1.49–1.34 (m, 2H), 0.86 (m, 1H).

Example 8: 2-(2-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyridine) (Pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

The first step is methyl 2-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran- 4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate (8a)

Dissolve 7a (300mg, 0.58mmol) in 5mL of toluene, add pyridine (176.3mg, 2.32mmol), phosphorus oxychloride (177.8mg, 1.16mmol), nitrogen protection, heating at 80℃ for 4 hours, TLC monitoring, raw materials After the reaction is complete, spin off the solvent and purify by Flash column to obtain methyl 4-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl) (Tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate 8a (40mg, 0.07mmol), yield 13.0%.

LCMS(ESI-MS)m/z:530.23[M+H] ⁺ .

The second step 2-(2-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran) -4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol (8)

The 8a (40mg, 0.07mmol) was dissolved in 5ml of anhydrous THF was added _{CH 3 MgBr (1M in THF,} 1ml, 1mmol), stirred at room temperature to react for 4 h, TLC monitoring, the reaction was complete starting material, quenched with water, extracted with EA, Wash with saturated NaCl aqueous solution, dry with anhydrous sodium sulfate, and purify by Flash column to obtain 2-(2-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)- 5-(Phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol 8 (9mg), White solid.

LCMS(ESI-MS) m/z: 530.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 8.35 (d, J = 8.3 Hz, 1H), 8.07-7.92 (m, 1H), 7.82 (s, 1H), 7.54-7.39 (m, 3H), 7.31 ( dt,J=14.9,7.7Hz,3H),5.66-5.48(m,1H),4.03(s,3H),3.95-3.80(m,1H),3.66-3.47(m,2H), 3.38(t, J = 11.8Hz, 1H), 3.15 (s, 2H), 2.39 (s, 3H), 2.00 (t, J = 12.1Hz, 1H), 1.74 (d, J = 2.0 Hz, 6H), 1.60 (d, J = 12.5Hz, 1H), 1.52-1.36 (m, 1H), 1.13 (t, J = 11.3Hz, 1H).

Example 9: 2-(5-(1-(2,4-Dichlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-di Methyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Using a synthetic method similar to that in Example 1, the title product 9 was obtained.

LCMS(ESI-MS)m/z:578.2[M+H] ⁺ .

Example 10: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(tetrahydrofuran-3-yl)-5H-pyrido[3 ,2-b)indol-7-yl)propan-2-ol

The first step is 3-bromo-5-(tetrahydrofuran-3-yl)-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester (10a)

Compound 1d (2g, 6.56mmol), 10b (0.866g, 9.84mmol), PPh ₃ (3.44g, 13.12mmol) and dry THF (30mL) were sequentially added to a dry three-necked flask, protected by nitrogen, and stirred under ice-salt bath conditions 30min, DIAD (2.64g, 13.12mmol) was added dropwise to the reaction solution, after the addition was completed, it was naturally warmed to room temperature and stirred overnight. Add EA/water (30mL/30mL), stir for 5 minutes and then separate the liquids, extract the aqueous phase with EA (20ml×3), combine the organic phases and wash with saturated brine (20ml×3), dry and mix the sample, column chromatography Purification (EA/PE=0%-100%) gave the title compound 10a (350 mg, 0.936 mmol), a white solid, with a yield of 14.2%.

LCMS(ESI-MS) m/z: 377.1[M+H] ⁺ .

The second step 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(tetrahydrofuran-3-yl)-5H-pyrido[3,2-b ]Indole-7-carboxylic acid methyl ester (10b)

Compound 10a (250mg, 0.667mmol), tetratriphenylphosphine palladium (77mg, 0.0667mmol), CuI (25mg, 0.1333mmol), dry DMF (10mL), TEA (202mg, 2.0mmol) and compound 1e (516mg, 1.333) mmol) was sequentially added to a dry three-necked flask, protected by nitrogen, heated to 100 ℃ in an oil bath and stirred for 4 h. After cooling to room temperature, add saturated KF aqueous solution (5mL) and stir for 30 minutes, then add EA/water (30mL/20mL), stir for 5 minutes and then separate the liquids, the aqueous phase is extracted with EA (15ml×3), the organic phases are combined and saturated Washed with brine (20ml×3), dried and mixed the sample, purified by column chromatography (MeOH/DCM=0%-20%) to obtain the title compound 10b (200mg, 0.511mmol) as a white solid, the yield was 76.7%.

LCMS(ESI-MS)m/z:392.3[M+H] ⁺ .

The third step 2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(tetrahydrofuran-3-yl)-5H-pyrido[3, 2-b)Indol-7-yl)propan-2-ol (10)

Under nitrogen protection, dissolve compound 10b (180mg, 0.460mmol) in 30ml dry THF, stir under ice-water bath for 10min, add MeMgBr (4.6mL, 1M/THF) dropwise to the reaction flask with a syringe, and the addition is complete Then naturally warm to room temperature and stir overnight. The reaction was quenched by adding saturated NH ₄ Cl aqueous solution (10 mL) under ice bath conditions, the solid was filtered off, the filtrate was extracted with EA (30ml×3), the organic phases were combined and washed with saturated brine (15ml×3), anhydrous magnesium sulfate After drying, the sample was concentrated and mixed, and purified by column chromatography (MeOH/DCM=0%-10%) to obtain the title compound 10 (75 mg, 0.192 mmol), a white solid, with a yield of 41.7%.

LCMS(ESI-MS)m/z:392[M+H] ⁺ .

¹ H NMR(400MHz, MeOD)δ8.50-8.44(m,1H), 8.32-8.24(m,2H), 8.01(d,J=1.3Hz,1H), 7.50(dd,J=8.3,1.4Hz ,1H),5.78-5.69(m,1H),4.41(ddd,J=13.6,9.4,3.0Hz,2H),4.07(s,4H),3.84(td,J=9.4,7.1Hz,1H), 2.68-2.58 (m, 1H), 2.36 (s, 3H), 2.29 (dt, J = 9.8, 5.3 Hz, 1H), 1.65 (s, 6H).

Example 11: 4-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-7-(2-hydroxypropan-2-yl)-5H-pyridine And [3,2-b]indol-5-yl)tetrahydro-2H-pyran-3-ol

The first step 3,7-Dioxabicyclo[4.1.0]heptane (11b)

Compound 11a (500mg, 5.95mmol) was dissolved in dichloromethane (10.0mL), added m-CPBA (1.13g, 6.54mmol), stirred at room temperature for 4h, found that the raw material disappeared, and quenched with an aqueous solution of sodium thiosulfate , Extracted with dichloromethane three times, the organic phase was washed with sodium bicarbonate water, washed with water, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 11b (290mg, 2.89mmol), the yield was 48.7%.

The second step 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(3-hydroxytetrahydro-2H-pyran-4-yl)-5H -Pyrido[3,2-b]indole-7-carboxylic acid (11c)

Compound 11b (270mg, 2.7mmol) and 1f (288mg, 1.0mmol) were dissolved in DMF (5.0mL), cesium carbonate (1.02g, 3.4mmol) was added, and heated at 110℃ and stirred for 8h under nitrogen protection. After cooling, spin dry, extract three times with dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate and purify by plate chromatography to obtain compound 11c (200mg, 0.49mmol) with a yield of 49%.

The third step Methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(3-hydroxytetrahydro-2H-pyran-4-yl) -5H-pyrido[3,2-b]indole-7-carboxylate (11d)

Compound 11c (200mg, 0.49mmol) was dissolved in methanol (2.0mL), and TMSCHN ₂ (5ml) was added and stirred overnight at room temperature. After the reaction was completed, it was extracted with dichloromethane, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, concentration, and plate chromatography to obtain compound 11d (50mg, 0.118mmol), yield 24%.

Step 5 4-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-7-(2-hydroxypropan-2-yl)-5H-pyrido [3,2-b]Indol-5-yl)tetrahydro-2H-pyran-3-ol(11)

Compound 11d (50mg, 0.12mmol) was dissolved in THF (2.0mL), and methylmagnesium bromide (0.4mL, 1.2mmol) was added under ice bath. After stirring at room temperature overnight, the reaction was completed. The reaction solution was washed with water, extracted three times with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by plate chromatography to obtain the title compound 11 (21.0 mg, 0.05 mmol) with a yield of 42%.

LCMS(ESI-MS) m/z: 422.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.46(d,J=1.7Hz,1H), 8.34(s,1H), 8.14(d,J=8.2Hz,1H), 7.87(s,1H) ,7.38(dd,J=8.2,1.3Hz,1H), 5.25(s,1H),5.06(s,1H),4.56(s,2H), 4.15(d,J=14.8Hz,1H),3.99( s, 3H), 3.92 (s, 2H), 3.74 (d, J = 7.0 Hz, 1H), 2.28 (d, J = 4.0 Hz, 3H), 2.04 (d, J = 12.3 Hz, 1H), 1.79- 1.68(m,1H), 1.52(s,6H).

Example 12: 4-(3-(1,4-Dimethyl-1H-,1,2,3-triazol-5-yl)-7-(2-hydroxypropan-2-yl)-5H pyridine And [3,2-b]indol-5-yl]tetrahydrofuran-3-ol

Using a synthetic method similar to that of Example 11, the title product 12 was obtained.

LCMS(ESI-MS) m/z: 408.2[M+H] ⁺ .

¹ H NMR (400MHz, MeOD) δ8.48 (d, J = 1.7Hz, 1H), 8.31 (d, J = 8.3Hz, 1H), 8.23 (d, J = 1.7Hz, 1H), 8.00 (d, J = 1.3Hz, 1H), 7.51 (dd, J = 8.3, 1.4 Hz, 1H), 5.31 (s, 1H), 4.67 (d, J = 3.4 Hz, 1H), 4.55-4.40 (m, 2H), 4.33(dd,J=9.7,6.0Hz,1H),4.06(s,3H),3.77(dd,J=9.8,5.7Hz,1H),2.36(s,3H),1.65(s,6H).

Example 13: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(4-fluorophenyl)-2-( Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Using a synthetic method similar to that of Example 1, the title product 13 was obtained.

LCMS(ESI-MS)m/z:528.3[M+H] ⁺ .

Example 14: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(pyridin-2-yl)-2-( Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

The first step 1-(pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethane-1-one (14b)

Take a 250mL three-necked flask, add compound 14a (5.06g, 32.04mmol), N ₂ protection, add THF (50mL), cool to -65℃, dropwise add n-butyllithium/n-hexane (15mL, 37.39mmol, 2.5M) , Stir at low temperature for 2h. Compound 1j (5g, 26.7mmol) was dissolved in 10mL THF, then added dropwise to the reaction solution, slowly warming to room temperature, then to 60℃, and reacting for 2h. TLC monitoring, a new point was formed, the reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with EA, dried over anhydrous sodium sulfate, concentrated, and purified by Flash column to obtain a pale yellow oil as compound 14b (3.2g, 15.6mmol) , The yield is 48.65%.

The second step 1-(pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol (14c)

Take a 250mL single-necked flask, add compound 14b (3.2mg, 15.59mmol), MeOH (60mL), ice bath, and then add NaBH ₄ (1.18g, 31.18mmol) in small batches, and then raise to 25℃ for 16h. TLC monitoring showed that the raw material reaction was complete and new spots were formed. Water was added to the reaction solution, MeOH was concentrated, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 14c (3.2g, 15.44mmol) as a pale yellow solid with a yield of 99%.

Using a synthesis method similar to that of Example 1, replacing 1j with 14c, the title product 14 was obtained with a yield of 3%.

LCMS(ESI-MS) m/z: 511.4[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.61-8.58(m,1H), 8.53(d,J=1.7Hz,1H), 8.23(s,1H), 8.17(d,J=8.2Hz, 1H),7.86(s,1H),7.74-7.69(m,1H),7.47(dd,J=8.2,1.3Hz,1H),7.30(dd,J=7.6,4.6Hz,2H),6.36-6.31 (m, 1H), 5.15 (s, 1H), 3.97 (s, 3H), 3.75 (d, J = 11.9 Hz, 1H), 3.67 (d, J = 11.1 Hz, 1H), 2.99 (td, J = 11.2, 10.2, 2.9 Hz, 2H), 2.62 (d, J = 6.8 Hz, 2H), 2.24 (s, 3H), 1.83 (d, J = 12.6 Hz, 1H), 1.49 (s, 6H), 1.39- 1.30 (m, 2H), 1.23 (s, 2H).

Example 15: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(4-methoxyphenyl)-2 -(Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Using a synthetic method similar to that in Example 1, the title product 15 was obtained.

LCMS(ESI-MS) m/z: 540.4[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.47(d,J=1.7Hz,1H), 8.14(d,J=8.2Hz,1H), 8.06(s,1H),7.84(s,1H) ,7.43(dd,J=8.3,1.3Hz,1H),7.36-7.22(m,2H),6.90-6.75(m,2H),6.18(dd,J＝10.3,5.5Hz,1H),5.16(s ,1H),3.90(s,3H),3.72(dt,J=11.7,2.8Hz,1H),3.65(s,4H),2.97(dtt,J=11.3,8.0,3.8Hz,2H),2.65- 2.53(m,1H),2.38(dd,J=14.0,6.5Hz,1H),2.19(s,3H),1.82(d,J=12.8Hz,1H),1.48(s,6H),1.36-1.13 (m,5H).

Example 16: 5-isopropyl 7-methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyridyl[3,2-b ]Indole-5,7-dicarboxylate

Using a synthetic method similar to that in Example 1, the title product 16 was obtained.

LCMS(ESI-MS) m/z: 408.2[M+H] ⁺ .

¹ H NMR(400MHz, CDCl ₃ )δ9.07(s,1H), 8.64(s,1H), 8.60(s,1H), 8.36(d,J=8.0Hz,1H), 8.21(d,J= 8.0Hz, 1H), 5.5 (m, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 2.41 (s, 3H), 1.58 (d, J = 6.4 Hz, 6H).

Example 17: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-( Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Using a synthetic method similar to that of Example 14, the title product 17 was obtained.

LCMS(ESI-MS)m/z:528.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.48 (d, J = 1.7Hz, 1H), 8.22-8.07 (m, 2H), 7.93 (td, J = 7.8, 1.8Hz, 1H), 7.80 ( s, 1H), 7.43 (dd, J = 8.3, 1.3 Hz, 1H), 7.36-7.22 (m, 2H), 7.07 (ddd, J = 10.8, 8.0, 1.3 Hz, 1H), 6.35 (dd, J = 10.3,5.4Hz,1H), 5.16(s,1H),3.91(s,3H),3.76-3.70(m,1H), 3.64(d,J=10.7Hz,1H),3.04-2.91(m,2H) ), 2.67(t,J=12.4Hz,1H),2.42-2.33(m,1H),2.21(s,3H),1.86(d,J=12.4Hz,1H),1.47(d,J=2.2Hz ,5H),1.33-1.17(m,4H).

Example 18: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2 -(Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Using a synthetic method similar to that in Example 14, the title product 18 was obtained.

LCMS(ESI-MS)m/z:540[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.44(d,J=1.7Hz,1H),8.14-8.06(m,2H),7.86(d,J=7.3Hz,2H),7.40(dd, J = 8.3, 1.3 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.03-6.97 (m, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.27 (dd, J = 10.0 ,5.7Hz,1H),5.18(s,1H),3.91(s,3H),3.78-3.64(m,3H),3.46(s,3H),2.99(t,J=11.3Hz,2H),2.38 -2.29(m,1H),2.21(s,3H),1.84(d,J=12.0Hz,1H), 1.50(d,J=7.6Hz,6H),1.21(s,4H).

Example 19: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(3-methoxyphenyl)-2 -(Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Using a synthetic method similar to that in Example 1, the title product 15 was obtained.

LCMS(ESI-MS) m/z: 540.2[M+H] ⁺ .

Example 20: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(3-fluorophenyl)-2-( Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Using a synthetic method similar to that of Example 1, the title product 20 was obtained.

LCMS(ESI-MS)m/z:528.2[M+H] ⁺ .

Example 21: 2-(5-(1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-di Methyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Using a synthetic method similar to that of Example 1, the title product 21 was obtained.

LCMS(ESI-MS) m/z: 546.2[M+H] ⁺ .

Example 22: 2-(5-(1-(2,3-Difluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-di Methyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Using a synthetic method similar to that of Example 1, the title product 22 was obtained.

LCMS(ESI-MS) m/z: 546.2[M+H] ⁺ .

Example 23: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(3-fluorophenyl)-2-( 1-methylpiperidin-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

The first step is tert-butyl 4-(2-(methoxy(methyl)amino)-2-carbonylethyl)piperidine-1-carboxylate (23b)

Compound 23a (4.86g, 20mmol) and 23h (2.91g, 30mmol) were dissolved in DCM (100mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.76mg , 30mmol), 1-hydroxybenzotriazole (4.05g, 30mmol) and triethylamine (8.08g, 80mmol), after 24h at room temperature, the reaction is complete. The reaction solution was washed with water, extracted with dichloromethane three times, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by plate chromatography to obtain the title compound 23b (4g, 13.98mmol) with a yield of 70%.

LCMS(ESI-MS)m/z:309.3[M+Na] ⁺ .

The second step tert-butyl 4-(2-(3-fluorophenyl)-2-carbonylethyl)piperidine-1-carboxylate (23c)

Dissolve 23b (4g, 13.98mmol) in 50mL dry THF, dry ice bath (-78℃), add 35mL m-fluorophenyl magnesium bromide (1M in THF). After the addition, the mixture was stirred at room temperature overnight, the reaction was quenched by adding saturated aqueous ammonium chloride solution, and the solid was filtered off. The filtrate was diluted with 100mL dichloromethane, washed with water (50mL*2), the organic phase was dried over anhydrous magnesium sulfate, filtered, spin-dried, and purified by column chromatography to obtain the title compound 23c (3g, 9.34mmol) with a yield of 66%.

LCMS(ESI-MS)m/z:344.2(M+Na) ⁺ .

The third step tert-butyl 4-(2-(3-fluorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate (23d)

Compound 23c (1.7g, 5.29mmol) was dissolved in methanol (40mL), sodium borohydride (0.2g, 15.88mmol) was added, and then stirred at room temperature overnight, the reaction was quenched by adding acetic acid, and then spin-dried, adding water and ethyl acetate After extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to obtain the title compound 23d (1.5g, 4.643mmol), with a yield of 87%

LCMS(ESI-MS)m/z:346.3[M+Na] ⁺ .

Step 4 Methyl 5-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)-3-(1,4-dimethyl -1H-1,2,3-triazol-5-yl)-5H pyrido[3,2-b]indole-7-carboxylate (23e)

Compound 23d (1g, 3.095mmol) and 1f (497mg, 1.547mmol) were dissolved in dry tetrahydrofuran (30mL), and triphenylphosphine group (810mg, 3.095mmol and DIAD (625mg, 3.095mmol) were added and protected under argon. Stir at room temperature for 14h, spin dry, add water and extract three times with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and purify by column chromatography after concentration to obtain title compound 23e (700mg, 1.182mmol), yield 72 %

LCMS(ESI-MS) m/z: 627.5[M+H] ⁺ .

Step 5 Tert-butyl 4(2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(2-hydroxypropane-2-yl) -5H pyrido[3,2-b]indol-5-yl]-2-(3-fluorophenyl)ethyl]piperidine-1-carboxylate (23f)

Compound 23e (700 mg, 1.182 mmol) was dissolved in 20 mL of anhydrous THF, in a dry ice bath (-78°C), and 8 mL of methyl magnesium bromide (2M in THF) was added. After the addition, the mixture was stirred at room temperature overnight, the reaction was quenched by adding saturated aqueous ammonium chloride solution, and the solid was filtered off. The filtrate was diluted with 50mL of dichloromethane, washed with water (50mL*2), the organic phase was dried over anhydrous magnesium sulfate, filtered, spin-dried, and separated by preparative TLC, eluted with DCM/MeOH=10/1, to give the crude target product 23f (350mg , 0.559mmol), the yield is 50%.

LCMS(ESI-MS) m/z: 627.5[M+H] ⁺ .

Step 6 2-(3-(1,4-Dimethyl-1H-,1,2,3-triazol-5-yl)-5-(1-(3-fluorophenyl)-2-( Piperidin-4-yl)ethyl)-5H pyrido[3-2-b]indol-7-yl]propan-2-ol (23g)

Compound 23f (350mg, 0.559mmol) was dissolved in DCM (5.0mL), TFA (5mL) was added, and the reaction was stirred at room temperature for 2h, and the reaction was complete. The reaction solution was spin-dried and added methanol to neutralize with saturated potassium carbonate, filtered, concentrated and purified by plate chromatography to obtain the title compound 23g (280mg, 0.531mmol) with a yield of 95%.

LCMS(ESI-MS)m/z:527.5[M+H] ⁺ .

Step 7 2-(3-(1,4-Dimethyl-1H-,1,2,3-triazol-5-yl)-5-(1-(3-fluorophenyl)-2(1 -Methylpiperidin-4-yl)ethyl)-5H pyrido[3-2-b]indol-7-yl]propan-2-ol (23)

Compound 23g (90mg, 0.1711mmol) was dissolved in dichloromethane (5mL), acetic acid (10mg, 0.1711mmol) and formaldehyde (36mg, 1.2mmol) were added, the reaction was stirred at room temperature for 30 minutes, then sodium acetate borohydride ( 109mg, 0.5133mmol), after stirring for 13h at room temperature, the reaction is complete. The reaction solution was quenched with water, extracted with dichloromethane three times, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by plate chromatography to obtain the title compound 23 (13 mg, 0.024 mmol), with a yield of 14%.

LCMS(ESI-MS) m/z: 541.4[M+H] ⁺ .

¹ H NMR(400MHz,MeOD)δ8.53(d,J=1.7Hz,1H), 8.35(dd,J=8.4,0.6Hz,1H), 8.02(s,1H),7.92(s,1H), 7.54(dd,J=8.4,1.3Hz,1H),7.33(td,J=8.1,5.9Hz,1H),7.13(t,J=7.8Hz,2H),7.02(td,J=8.4,2.5Hz ,1H),6.33(dd,J=11.1,4.9Hz,1H),3.91(s,3H),3.43(d,J=12.8Hz,1H), 3.32(d,J=10.3Hz,1H),2.88 –2.74(m,2H),2.70(s,4H),2.52(ddd,J=14.1,8.9,4.9Hz,1H), 2.30(d,J=15.0Hz,1H), 2.23(s,3H), 1.73 (d, J = 14.6 Hz, 1H), 1.62 (d, J = 6.8 Hz, 8H), 1.37-1.23 (m, 1H).

Example 24: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(3-fluorophenyl)-2-( 1-(oxbutan-3-yl)piperidin-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Using a synthesis method similar to that of Example 23, the title product 24 was prepared.

LCMS(ESI-MS) m/z: 583.5[M+H] ⁺ .

¹ H NMR(400MHz,MeOD)δ8.55(d,J=1.7Hz,1H), 8.35(d,J=8.4Hz,1H), 8.04(s,1H), 7.98-7.90(m,1H), 7.54(dd,J＝8.4,1.3Hz,1H),7.34(td,J＝8.2,6.0Hz,1H),7.17-7.09(m,2H),7.03(ddd,J＝10.6,8.0,2.5Hz, 1H), 6.35(dd,J=11.1,4.9Hz,1H),4.81-4.63(m,4H),4.15(s,1H),3.91(s,3H),3.41(d,J=11.7Hz,1H ), 3.30 (s, 1H), 2.89-2.76 (m, 1H), 2.56 (s, 3H), 2.33 (d, J = 14.4 Hz, 1H), 2.23 (s, 3H), 1.62 (d, J = 6.7Hz, 9H), 1.38 (s, 1H).

Example 25: 2-(5-(2-(1-(cyclopropylmethyl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)-3-(1,4- Dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

Using a synthetic method similar to that of Example 23, the title product 25 was prepared.

LCMS(ESI-MS)m/z:581.1[M+H] ⁺ .

¹ H NMR (400MHz, MeOD) δ8.55 (d, J = 1.6 Hz, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.07 (s, 1H), 7.94 (s, 1H), 7.55 ( dd,J=8.4,1.4Hz,1H),7.33(td,J=8.2,6.1Hz,1H), 7.14(td,J=9.8,9.3,2.0Hz,2H), 7.02(td,J=8.5, 2.5Hz, 1H), 6.35 (dd, J = 11.2, 4.9 Hz, 1H), 3.92 (s, 3H), 3.53 (dd, J = 41.5, 12.8 Hz, 2H), 2.89-2.75 (m, 3H), 2.66(t,J=12.7Hz,2H), 2.60-2.49(m,1H), 2.31(d,J=14.5Hz,1H), 2.23(s,3H),1.89-1.43(m,9H),1.34 (d,J=3.8Hz,1H),0.99(dt,J=7.8,3.2Hz,1H),0.72-0.61(m,2H),0.30(dt,J=6.0,4.7Hz,2H).

Example 26: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-2-carbonyl-5-(phenyl(tetrahydro-2H-pyran-4 -Yl)methyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-7-carboxylic acid

The first step 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-2-carbonyl-5-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-7-carboxylic acid (26)

Dissolve 4 (150mg, 0.27mmol) in 3ml MeOH, add 3ml H ₂ O, potassium carbonate (372.6mg, 2.7mmol), stir the reaction at room temperature for 4 hours, TLC monitoring, the raw material reaction is complete, 3M hydrochloric acid adjusted to PH<7 , Spin dry the solvent and prepare by HPLC to obtain 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-carbonyl-5-(phenyl(tetrahydro-2H -Pyran-4-yl)methyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-7-carboxylic acid 26 (10 mg), yellow solid.

LCMS(ESI-MS)m/z:498.5[M+H] ⁺ .

Example 27: 7-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2 -(Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[3,2-b:4,5-c']dipyridine

The first step 5-bromo-6'-chloro-3-nitro-2,3'-bipyridine (27b)

Compound 27a (5.0g, 21mmol) Compound 1a (4.9g, 17mmol), potassium phosphate (13g, 63mmol), THF (50ml) was added Pd(dppf)Cl2 (1.4g, 2mmol), and refluxed at 80°C for 4h. Cool, add water, extract with EA, wash once with saturated aqueous sodium chloride solution, concentrate, and pass through Flash column to obtain compound 27b (1.2 g, 3.8 mmol) with a yield of 22%.

The second step 3-bromo-7-chloro-5H-pyrrolo[3,2-B: 4,5-C']dipyridine (27c)

Compound 27b (3g, 9.5mmol), DPPE (4.5g, 11.4mmol) was added with dichlorobenzene (40ml), heated to 180 degrees, refluxed for 6h, cooled, filtered, washed with DCM, the filter cake was slurried with DCM, filtered to obtain compound 27c (1.1g, 3.9mmol), the yield is 41%.

The third step 7-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole(27d)

Compound 27c (1.1g, 3.9mmol), compound 5 (3g, 7.7mmol), tetrakistriphenylphosphonium palladium (0.45g, 0.39mmol), cuprous iodide (38mg, 0.2mmol), TEA (1.1g, 11.7 mmol) was dissolved in DMF (20ml), heated to 90°C for 6h. Concentrated on the Flash column to obtain compound 27d (400 mg, 1.34 mmol) with a yield of 34%.

The fourth step 7-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2 -(Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[3,2-b: 4,5-C']dipyridine (27)

Compound 27d (100mg, 0.33mol), compound 27e (79mg, 0.33mmol), triphenylphosphonium (172mg, 0.66mmol) DIAD (133mg, 0.66mmol), add DCM (5ml) and stir overnight at room temperature. After passing through the Flash column, compound 27 (20 mg, 0.04 mmol) was obtained with a yield of 12%.

LCMS(ESI-MS) m/z: 517.2[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.66-8.55(m,2H), 8.06(d,J=1.8Hz,1H),7.83-7.74(m,1H),7.42(d,J=8.1 Hz, 1H), 7.28-7.16 (m, 1H), 7.02-6.92 (m, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.55 (dd, J = 10.5, 5.3 Hz, 1H), 3.82 (d,J=1.7Hz,3H),3.77(d,J=10.9Hz,1H),3.73-3.64(m,1H),3.39(s,3H),3.03(s,2H),2.71(t, J = 12.1Hz, 1H), 2.29 (d, J = 13.0 Hz, 1H), 2.15 (s, 3H), 2.00 (s, 1H), 1.38 (d, J = 9.2 Hz, 1H), 1.25 (s, 3H).

Example 28: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2-(tetrahydro -2H-pyran-4-yl)ethyl)-7-(pyrrolidin-1-yl)-5H-pyrrolo[3,2-b:4,5-c']dipyridine

The first step 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2-(tetrahydro- 2H-pyran-4-yl)ethyl)-7-(pyrrolidin-1-yl)-5H-pyrrolo[3,2-b:4,5-c']dipyridine(28)

Compound 27 (100mg, 0.19mmol), tetrahydropyrrole (28mg, 0.386mmol), cesium carbonate (190mg, 0.58mmol) were dissolved in DMF (10ml) and reacted at 150°C for 78 hours. Cool, add water, extract with EA, wash once with saturated aqueous sodium chloride solution, concentrate, and pass through Flash column to obtain compound 28 (0.01 g, 0.018 mmol) with a yield of 9%.

LCMS(ESI-MS)m/z:552[M+H] ⁺ .

Example 29: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2-(tetrahydro -2H-pyran-4-yl)ethyl)-N,N-dimethyl-5H-pyrrolo[3,2-b:4,5-c']dipyridine-7-amine

Using a synthetic method similar to that of Example 28, the title product 29 was obtained.

LCMS(ESI-MS)m/z:526.2[M+H] ⁺ .

Example 30: 7-(azetidin-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1- (2-Methoxyphenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[3,2-b:4,5-c']dipyridine

Using a synthetic method similar to that of Example 28, the title product 30 was obtained.

LCMS(ESI-MS) m/z: 538.2[M+H] ⁺ .

Example 31: 7-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2- (Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridine

Using a synthetic method similar to that in Example 27, the title product 31 was obtained.

LCMS(ESI-MS)m/z:505.2[M+H] ⁺ .

Example 32: N1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-( Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)-N1,N2-dimethylethyl Alkyl-1,2-diamine

Using a synthetic method similar to that of Example 28, the title product 32 was obtained.

LCMS(ESI-MS)m/z:557.2[M+H] ⁺ .

Example 33: 1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-( Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)-4-methylpiperidine-4 -alcohol

Using a synthetic method similar to that of Example 28, the title product 33 was obtained.

LCMS(ESI-MS) m/z: 584.5[M+H] ⁺ .

Example 34: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(methylthio)-5-(phenyl(tetrahydro -2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

The first step is methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-(methylthio)-5-(phenyl(tetrahydro-2H) -Pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate (34a)

Dissolve 7g (150mg, 0.28mmol) in 5ml of anhydrous DMF, add sodium methyl mercaptan (72mg, 1.04mmol), react in microwave at 90°C for 1 hour, monitored by TLC, the reaction of the raw materials is complete, add methyl iodide (198.6mg, 1.4 mmol), react at room temperature for 2 hours, monitored by LC-MS, the raw materials are reacted completely, add water, extract with EA, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and purify by Flash column to obtain methyl 3-(1,4-dimethyl Group-1H-1,2,3-triazol-5-yl)-4-(methylthio)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H- Pyrido[3,2-b]indole-7-carboxylate 34a (130mg, 0.24mmol), yield 85.6%.

LCMS(ESI-MS) m/z: 542.4[M+H]+.

The second step 2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-(methylthio)-5-(phenyl(tetrahydro- 2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol (34)

Dissolve 34a (130mg, 0.24mmol) in 5ml anhydrous THF, add CH3MgBr (1M in THF, 2ml, 2mmol), stir the reaction at room temperature for 4 hours, TLC monitoring, the reaction of the raw materials is complete, quenched with water, extracted with EA, saturated NaCl Washed with aqueous solution, dried with anhydrous sodium sulfate, purified by Flash column, 2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-(methylthio) -5-(Phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol 34 (35mg, 0.06mmol), yield 26.9%, pale yellow solid.

LCMS(ESI-MS) m/z: 542.4[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ8.45–8.35(m,1H), 8.32(d,J=6.4Hz,1H), 7.70–7.60(m,1H), 7.53(dd,J=12.0,7.5 Hz,2H),7.45–7.40(m,1H),7.35(q,J=8.3Hz,2H), 7.29(d,J=7.2Hz,1H),4.06(d,J=11.6Hz,1H), 3.96(s,3H),3.90–3.77(m,1H),3.57(t,J=11.7Hz,1H),3.31(q,J=13.3,12.9Hz,1H),3.17(s,1H),2.35 (s, 3H), 2.11 (d, J = 12.4 Hz, 4H), 1.78–1.72 (m, 2H), 1.59 (d, J = 2.7 Hz, 3H), 1.56 (s, 3H), 0.97–0.87 ( m,1H),0.77(d,J=13.1Hz,1H).

Example 35: 7-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-phenyl-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrrolo[3,2-b: 4,5-C']dipyridine

Using a synthetic method similar to that of Example 31, the title product 35 was obtained.

LCMS(ESI-MS)m/z:487.2[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.70–8.60(m,2H), 8.25(d,J=1.8Hz,1H), 7.47(dd,J=7.7,4.4Hz,3H), 7.28( dd,J=8.2,6.5Hz,2H),7.24–7.17(m,1H),6.38(dd,J=10.5,5.6Hz,1H),3.88(s,3H),3.71(dd,J=23.1, 11.3Hz,2H),3.08–2.94(m,2H),2.84(s,1H),2.41(dt,J=13.9,6.6Hz,1H), 2.17(s,3H),1.83(d,J=12.1 Hz, 1H), 1.42 (d, J = 10.7 Hz, 1H), 1.24 (s, 3H).

Example 36: 6-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-phenyl-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrrolo[3,2-b: 5,4-C']dipyridine

The first step 5-bromo-2'-chloro-3-nitro-2,4'-bipyridine (36b)

Dissolve 4,5-dibromo-3-nitropyridine 1a (10.0g, 35.5mmol), 36a (6.1g, 39.0mmol), K ₃ PO ₄ (3.0M, 35.3ml) in 100ml THF, under nitrogen protection Pd(DPPF)Cl ₂ (2.6 g, 3.55 mmol) was added, and the reaction was carried out at 80° C. for 3 hours. EA (100ml) and water (100ml) were layered, the organic phase was dried, filtered, column separated, and eluted with PE/EA=2/1 to obtain 5-bromo-2'-chloro-3-nitro-2,4' -Bipyridine 36b (6.5g), white solid, yield 59.1%.

LCMS(ESI-MS)m/z:316[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ9.15(d,J=2.0Hz,1H), 8.93(d,J=2.0Hz,1H), 8.53(dd,J=5.1,0.7Hz,1H) , 7.71 (dd, J = 1.6, 0.7 Hz, 1H), 7.55 (dd, J = 5.1, 1.5 Hz, 1H).

The second step 3-bromo-6-chloro-5H-pyrrolo[3,2-B: 5,4-C']dipyridine (36c)

Dissolve 5-bromo-2'-chloro-3-nitro-2,4'-bipyridine 36b (4.0g, 12.7mmol) and DPPE (6.0g, 15.2mmol) in 40mL o-dichlorobenzene in 180 Reaction at °C for 4 hours. Cool to room temperature, remove dichlorobenzene by distillation under pressure, and dissolve the sample with DCM, pass the column with DCM:MeOH to obtain 3-bromo-6-chloro-5H-pyrrolo[3,2-B:5,4-C'] Dipyridine 36c (1.0 g), white solid, yield 28%.

LCMS(ESI-MS) m/z: 283.9[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.32 (s, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 2.1Hz, 1H), 8.10 (dd, J = 5.2, 0.7Hz, 1H).

The third step 3-bromo-6-chloro-5-(1-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[3,2-B: 5 ,4-C')dipyridine (36d)

36c (240mg, 0.85mmol) and 1g (210.2mg, 1.02mmol), triphenylphosphonium (445.9mg, 1.7mmol) were dissolved in 20mL of dry THF, and DIAD (343.7mg, 1.7mmol) was added. Stir at room temperature overnight, spin dry the reaction system, prepare and separate by TLC, develop with DCM/MeOH=20/1 to obtain the target compound 3-bromo-6-chloro-5-(1-phenyl-2-(tetrahydro-2H-pyridine) (Pyran-4-yl)ethyl)-5H-pyrrolo[3,2-B: 5,4-C']dipyridine (36d) (280 mg), off-white solid, yield 70%.

LCMS(ESI-MS)m/z:322.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ8.62(d,J=1.8Hz,1H), 8.36(d,J=5.0Hz,1H), 8.24(d,J=5.0Hz,1H), 7.70(dd ,J=5.3,1.9Hz,1H),7.36(d,J=5.5Hz,2H),7.35-7.27(m,3H),5.10-4.90(m,1H),3.88(m,1H),3.78( dt,J=11.3,3.4Hz,1H),3.16-3.02(m,2H),2.43(m,2H),1.91-1.82(m,1H),1.5-1.18(m,4H),

The fourth step 6-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-phenyl-2-(tetrahydro-2H- Pyran-4-yl)ethyl)-5H-pyrrolo[3,2-b: 5,4-C']dipyridine (36)

Add 3-bromo-6-chloro-5-(1-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[3,2-B ：5,4-C']Dipyridine 36d (180mg, 0.4mmol) and Int-1 (170.4mg, 0.44mmol), and then CuI (11.4mg, 0.06mmol), Pd(PPh ₃ ) ₄ (46.2 mg, 0.04mmol) and 110.9ul TEA (0.8mmol), reacted at 90℃ for 3 hours under nitrogen atmosphere, filtered through celite, spin-dried DMF, and passed through the column to obtain the target compound 6-chloro-3-(1,4- Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrole And [3,2-b: 5,4-C']dipyridine (36) (55mg), off-white solid, yield 33%.

LCMS(ESI-MS) m/z: 487.3[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.73(d,J=1.6Hz,1H), 8.39(d,J=5.1Hz,1H), 8.34(d,J=5.0Hz,1H), 8.04 (s,1H),7.55-7.44(m,2H),7.36(t,J=7.5Hz,2H),7.32-7.29(m,1H),7.28(d,J=6.9Hz,1H),3.84( d, J = 2.3Hz, 3H), 3.82–3.66 (m, 2H), 3.15–3.00 (m, 2H), 2.74 (dt, J = 12.3, 5.7 Hz, 1H), 2.14 (s, 3H), 1.89 --1.80(m,1H),1.43-1.15(m,5H).

Example 37: (2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazol-7-yl )Bis(pyridin-2-yl)methanol

The first step (2-cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazol-7-yl) Bis(pyridin-2-yl)methanol (37)

2-Bromopyridine (660mg, 4.18mmol) was added to a dry three-necked flask, replaced with argon, 4ml of anhydrous THF was added, n-butyllithium (1.67ml, 4.18mmol) was added dropwise at -78°C, stirred for 30min, Compound 6f (130 mg, 0.418 mmol) was dissolved in 2 ml of anhydrous THF, added dropwise to the reaction solution, and stirred at -78°C for 1 h. 30ml of water was added dropwise to quench under ice bath, 60ml of EA was added for extraction, the organic phase was washed with saturated brine and dried, and purified by column chromatography with sample mixing and eluted with pure methanol to obtain the title compound 37 (53mg, 0.121mmol), yield 29% .

LCMS(ESI-MS) m/z: 438.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.52(dt,J=4.7,1.5Hz,2H),7.99-7.80(m,3H),7.74-7.62(m,3H),7.38(m,2H ), 7.06 (d, J = 1.5 Hz, 1H), 3.83 (s, 3H), 2.57 (tq, J = 12.3, 7.3, 6.1 Hz, 1H), 2.06 (s, 3H), 1.42-1.18 (m, 4H).

Example 38: (2-Cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazol-4-yl )(Tetrahydrofuran-2-yl)methanol hydrochloride

The first step 1-(tert-butyl)4-methyl-6-bromo-2-cyclopropyl-1H-benzo[d]imidazole-1,4-dicarboxylate (38b)

Compound 6e (4.5g, 15.25mmol) was dissolved in DCM (100ml), and (Boc) ₂ O (5.0g, 22.88mmol), Et ₃ N (4.6g, 45.75mmol) and DMAP ( 93mg, 0.7625mmol), then stirred at room temperature for three hours, add 100ml of water, stir for 5min to separate the layers, extract the aqueous phase with DCM (50ml x 2), combine the organic phases, wash once with saturated aqueous NaCl, dry with anhydrous sodium sulfate, and concentrate After passing through the column (EA/PE=0%-30%), the target product 38b (5.2 g, 13.20 mmol) was obtained as a white solid with a yield of 86.5%.

LCMS(ESI-MS)m/z:395.2[M+H] ⁺ .

The second step 6-bromo-2-cyclopropyl-4-formyl-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester (38c)

Dissolve morpholine (925mg, 10.63mmol) in dry THF (50ml), under nitrogen protection, drop DIBAL-H (6.75ml, 10.12mmol) into the solution under ice bath conditions, and stir at 0℃ for 3h. Dissolve raw material 38b (2g, 5.06mmol) in THF (2ml), slowly add dropwise to the reaction solution, continue to stir for 10min after the addition is complete, slowly add DIBAL-H (3.75ml, 5.57mmol) dropwise to the reaction solution After the addition is complete, continue stirring for 20 minutes. Use dilute hydrochloric acid (1N, 5ml) to slowly add dropwise to the reaction solution to quench the reaction, add EA (30ml) and citric acid aqueous solution (50ml) and stir for 10min, then separate the liquids, extract the aqueous phase with EA (30ml x 2), combine the organics Phase, washed twice with saturated NaCl aqueous solution, dried with anhydrous sodium sulfate, concentrated and passed through the column (EA/PE=0%-20%) to obtain the target product 38c (1.3g, 3.56mmol) as a white solid with a yield of 70.4%.

LCMS(ESI-MS) m/z: 365.1[M+H] ⁺ .

The third step 6-bromo-2-cyclopropyl-4-(hydroxy(tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester (38d)

Compound 38c (1.3g, 3.57mmol) was dissolved in dry THF (35ml), and Et ₃ B (35.7g, 35.7mmol) was added dropwise to the reaction solution under ice-bath conditions. After the addition, stirring was continued for 10 minutes, and t -BuOOH (3.57ml, 21.42mmol) was added dropwise to the reaction solution, stirred for 10min, then removed the ice bath, and continued stirring at room temperature for 20min. Add ammonia water (4ml) dropwise to quench the reaction, add 15ml water and continue to stir for 5min, extract with EA (20ml x 3), combine the organic phases, wash once with saturated NaCl aqueous solution, dry with anhydrous sodium sulfate, and concentrate through the column (EA/PE=0 %-30%) to obtain the target product 38d (900 mg, 2.06 mmol) as a yellow oil with a yield of 57.7%.

LCMS(ESI-MS) m/z: 437.2[M+H] ⁺ .

The fourth step 2-cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-(hydroxy(tetrahydrofuran-2-yl)methyl) -1H-Benzo[d]tert-Butyl]imidazole-1-carboxylate (38f)

Compound 38d (200mg, 0.4577mmol), 38e (354mg, 0.915mmol), Pd ₂ (dba) ₃ (42mg, 0.0458mmol), CsF (278mg, 1.83mmol) and Cy ₃ P (26mg, 0.0915mmol) were added to the microwave Into the tube, add the solvent dioxane (10ml) to dissolve it, replace with nitrogen and seal the tube. As for heating to 110℃ in an oil bath and stirring for 3h. After cooling to room temperature, it is directly concentrated and mixed, and purified by column chromatography (EA/PE=0%:- 100%) to obtain the title compound 38f (140 mg, 0.309 mmol) with a yield of 67.5%.

LCMS(ESI-MS)m/z:454.4[M+H] ⁺ .

The fifth step (2-cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazol-4-yl) (Tetrahydrofuran-2-yl)methanol hydrochloride (38)

Compound 38f (60mg, 0.132mmol) was added to a 10ml single-necked flask, and DCM (4ml) was added to dissolve it. HCl/MeOH (1.32ml, 5.29mmol) was added dropwise to the reaction solution. After dripping, stirring at room temperature for 4h, concentrated to remove the solvent. The product was dried in vacuo, and lyophilized by adding water to obtain the title compound 10038 (51 mg, 0.132 mmol) as a white solid with a yield of 100%.

LCMS(ESI-MS) m/z: 354.2[M+H] ⁺ .

¹ H NMR(400MHz,MeOD)δ7.79(s,1H), 7.62(d,J=2.8Hz,1H), 5.15(d,J=4.0Hz,0.5H), 5.01(d,J=6.2Hz ,0.5H), 4.27 (s, 1H), 4.13 (d, J = 1.8 Hz, 3H), 3.87-3.77 (m, 1H), 3.72 (dt, J = 11.2, 6.9 Hz, 1H), 2.61 (dq ,J=8.4,3.7Hz,1H), 2.50-2.38(m,3H), 2.11-1.78(m,4H), 1.53(dq,J=44.5,3.3Hz,4H).

Example 39: (2-Cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazol-4-yl )(Pyridin-2-yl)(tetrahydrofuran-2-yl)methanol

The first step is 6-bromo-2-cyclopropyl-4-(tetrahydrofuran-2-carbonyl)-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester (39a)

Compound 38d (400mg, 0.915mmol) was dissolved in DCM (30ml), Dess-Martin reagent (582mg, 1.373mmol) was added, and the mixture was stirred at room temperature for 2h. Saturated Na ₂ S ₂ SO ₃ solution (10ml) was added, and the mixture was stirred for 10 min. The liquid and the aqueous phase were extracted with DCM (10ml x 2), the organic phases were combined, washed once with saturated NaHCO ₃ aqueous solution, dried over anhydrous sodium sulfate, and concentrated through the column (EA/PE=0%-20%) to obtain the target product 39a (250mg , 0.574 mmol), pale yellow solid, yield 62.8%. LCMS(ESI-MS) m/z: 435.2[M+H] ⁺ .

The second step 2-cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-(tetrahydrofuran-2-carbonyl)-1H-benzo [d] Imidazole-1-tert-butyl ester-formic acid (39b)

Compound 39a (200mg, 0.460mmol), 1e (356mg, 0.920mmol), Pd ₂ (dba) ₃ (42mg, 0.046mmol), CsF (280mg, 1.84mmol) and Cy ₃ P (26mg, 0.092mmol) were added to the microwave Into the tube, add the solvent dioxane (10ml) to dissolve it, replace with nitrogen and seal the tube. As for heating to 110℃ in an oil bath and stirring for 3h. After cooling to room temperature, it is directly concentrated and mixed, and purified by column chromatography (EA/PE=0%:- 100%) to obtain the title compound 39b (60 mg, 0.133 mmol) with a yield of 28.9%.

LCMS(ESI-MS)m/z:352.2[M-100] ⁺ .

The third step (2-cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazol-4-yl) (Pyridin-2-yl)(tetrahydrofuran-2-yl)methanol (39)

Dissolve 2-bromopyridine (203mg, 1.286mmol) in dry THF (2ml), under nitrogen protection, drop n-BuLi (0.51ml, 2.5M) into the solution at -78°C and continue stirring for 30min. Dissolve the raw material 39b (58mg, 0.1286mmol) in THF (0.5ml), slowly add dropwise to the reaction solution, continue to stir for 10min after the dropwise addition is complete, slowly add DIBAL-H (3.75ml, 5.57mmol) dropwise to the reaction In the liquid, continue stirring for 30 min after the addition is complete. Slowly add saturated ammonium chloride aqueous solution dropwise to the reaction solution to quench the reaction, separate the layers, extract the aqueous phase with EA (5ml x 2), combine the organic phases, wash once with saturated NaCl aqueous solution, dry with anhydrous sodium sulfate, and concentrate through the column (MeOD/DCM=0%-10%) The target product 10038 (30 mg, 0.070 mmol) was obtained as a white solid with a yield of 54.3%.

LCMS(ESI-MS) m/z: 431.3[M+H] ⁺ .

¹ H NMR(400MHz,MeOD)δ8.55(d,J=4.8Hz,1H),7.83(s,1H),7.74(td,J=7.8,1.8Hz,1H),7.36(s,2H), 7.28-7.16(m,1H),5.31(s,1H),3.90(s,4H),3.76(dt,J=8.0,6.5Hz,1H),2.22(s,4H),1.99-1.74(m, 4H), 1.20-1.08 (m, 4H).

Example 40: 2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(3,5-dimethyl-1H- Pyrazol-4-yl)-1H-benzo[d]imidazole

The first step 4-bromo-2,6-dinitroaniline (40b)

Compound 40a (15g, 81.9mmol) and 300ml of acetic acid were added to a 500ml single-necked flask, and Br ₂ (7.5ml, 122.8mmol) was slowly added dropwise under ice bath, after dripping, it was naturally raised to room temperature and stirred overnight. After the reaction was completed, the solvent was evaporated to dryness, the solid was washed with a large amount of petroleum ether, filtered, and the filter cake was washed with PE and dried to obtain the title compound 40b (17 g, 64.8 mmol) with a yield of 79.2%.

LCMS(ESI-MS) m/z: 262.2[M+H] ⁺ .

The second step 5-bromo-3-nitrobenzene-1,2-diamine (40c)

Compound 40b (5g, 19mmol) was dissolved in 200ml ethanol and 60ml THF, Zn powder (12.4g, 190mmol) was added under ice bath, then NH ₄ Cl (10g, 190mmol) was added, and stirred at 70°C for 3h. Cool, filter off the black insolubles, evaporate the solvent, add EA and saturated sodium bicarbonate solution to wash twice, and then wash the organic phase with saturated brine, dry and concentrate the sample, and purify by column chromatography (petroleum ether: ethyl acetate Ester = 1:1) to obtain the title compound 40c (3.5 g, 15 mmol) with a yield of 79%.

LCMS(ESI-MS)m/z:232.1[M+H] ⁺ .

The third step N-(2-amino-5-bromo-3-nitrophenol)cyclopropanecarboxamide (40d)

Compound 40c (1.2g, 5.17mmol) was dissolved in DCM 100ml, added triethylamine (1.1g, 10.34mmol), added cyclopropylformyl chloride (537mg, 5.17mmol) dropwise in ice water bath, after dripping, warm to room temperature overnight . After quenching with water, the layers were separated, and the DCM phase was dried and mixed with column chromatography to obtain the title compound 40d (1 g, 3.33 mmol) with a yield of 64%.

LCMS(ESI-MS) m/z: 300.1[M+H] ⁺ .

The fourth step 5-bromo-2-cyclopropyl-7-nitro-1H-benzo[d]imidazole (40e)

Compound 40d (1.5g, 5mmol) was dissolved in 10ml of acetic acid, replaced with nitrogen, and reacted at 150°C under microwave for 1h. After cooling, evaporate the acetic acid to dryness, add EA, wash with saturated sodium bicarbonate solution, and then wash the organic phase with saturated brine. The sample was dried and concentrated by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain the title compound 40e (570 mg, 2.02 mmol) with a yield of 40.4%.

LCMS(ESI-MS)m/z:282.1[M+H] ⁺ .

The fifth step 2-cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-nitro-1H-benzo[d]imidazole( 40g)

Compound 40e (570mg, 2.02mmol), 1e (1.95g, 5.05mmol), tetrakistriphenylphosphine palladium (251mg, 0.202mmol), CuI (76mg, 0.404mmol), triethylamine (408mg, 4.04mmol) were added to Add 8ml of 1,4-Dioxane to a 20ml microwave tube, after Ar2 replacement, microwave reaction at 150℃ for 1h. After cooling, it was diluted by adding EA, washed twice with water, and the organic phase was dried and concentrated and mixed with sample column chromatography. The pure EA was eluted to obtain 40 g (500 mg, 1.67 mmol) of the title compound with a yield of 83%.

LCMS(ESI-MS) m/z: 299.1[M+H] ⁺ .

The sixth step 2-cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazole-7-amine (40h )

Compound 40g (1.2g, 4.01mmol), palladium carbon 300mg, dissolved in 50ml EA, replaced with hydrogen for three times, and stirred overnight at room temperature. After the reaction, the palladium carbon was filtered off, and the filter cake was washed with EA. After concentration, the title compound 40h (1.0 g, 2.67 mmol) was obtained with a yield of 93%.

LCMS(ESI-MS) m/z: 269.1[M+H] ⁺ .

The seventh step 2-cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-iodo-1H-benzo[d]imidazole (40i )

Compound 40h (100mg, 0.373mmol), p-toluenesulfonic acid (283mg, 1.49mmol) were dissolved in 10ml of acetonitrile and 5ml of water, stirred at -5°C for 10min, KI (155mg, 0.934mmol), NaNO ₂ (51mg, 0.74mmol) was dissolved in 5ml of water, added dropwise to the reaction solution, and reacted at -5°C for 1.5h after dropping. Water and EA were added for extraction, the organic phase was washed with saturated brine, dried and purified by column chromatography (methanol:dichloromethane=1:10) to obtain the title compound 40i (60mg, 0.158mmol), with a yield of 42.4%.

LCMS(ESI-MS) m/z: 380.2[M+H] ⁺ .

Step 8 2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(3,5-dimethyl-1H-pyridine) (Azol-4-yl)-1H-benzo[d]imidazole (40)

Compound 40i (100mg, 0.264mmol), compound 40j (60mg, 0.264mmol), Pd(dppf)Cl ₂ (20mg, 0.0264mmol), potassium carbonate (92mg, 0.66mmol), water 1ml, 1,4-Dioxane 4ml were added to In the microwave tube, argon replacement. Microwave reaction at 120°C for 1h. Water and EA were added for extraction, and the sample-mixed column chromatography (methanol:dichloromethane=1:20) eluted the title compound 40 (11mg, mmol) with a yield of 12%.

LCMS(ESI-MS) m/z: 348.2[M+H] ⁺ .

¹ H NMR (400MHz, MeOD) δ7.44 (s, 1H), 7.01 (d, J = 1.6Hz, 1H), 3.99 (s, 3H), 2.30 (s, 3H), 2.18 (s, 7H), 1.14(d,J=7.3Hz,4H).

Example 41: (2-Cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazol-4-yl )(6-methylpyridin-2-yl)(tetrahydrofuran-2-yl)methanol

Using a synthetic method similar to that of Example 39, the title product 41 was obtained.

LCMS(ESI-MS)m/z:445.5[M+H] ⁺ .

¹ H NMR (400MHz, MeOD) δ 8.06 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.61 (d, J = 1.4 Hz, 1H), 7.51 ( s, 1H), 5.23 (s, 1H), 3.95 (s, 4H), 3.82 (q, J = 6.6 Hz, 1H), 2.72 (s, 3H), 2.62 (td, J = 8.6, 4.4 Hz, 1H ), 2.24 (s, 3H), 1.97-1.78 (m, J = 6.9 Hz, 4H), 1.50 (dd, J = 8.5, 5.9 Hz, 2H), 1.43-1.33 (m, 2H).

Examples 42 and 43: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(3-(methoxymethyl)chroman -4-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

The first step is the synthesis of compound 2-(allyloxy)benzaldehyde (42b)

Compound 42a (20.0 g, 164 mmol), bromopropylene (22.0 g, 180 mmol), potassium carbonate (34.0 g, 246 mmol) were dissolved in acetonitrile (200 mL), and the system was heated to reflux for 3 hours. The reaction was monitored by TLC, the reaction solution was cooled to room temperature and poured into water, extracted twice with ethyl acetate, the combined organic phase was washed with water, dried, and concentrated to obtain crude 42b (20.0 g).

The second step is the synthesis of compound 2-(allyloxy)benzaldehyde oxime (42c)

Compound 42b (20.0 g, 124 mmol) and hydroxylamine hydrochloride (12.8 g, 186 mmol) were dissolved in ethanol (200 mL), and 11% sodium hydroxide solution (112.4 g) was slowly added dropwise at room temperature, and stirred at room temperature for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate three times, and the organic phase was washed with water, dried, and concentrated to obtain crude 42c (20.0 g).

¹ H NMR (400MHz, CDCl ₃ ) δ8.55 (s, 1H), 7.89 (s, 1H), 7.72-7.74 (m, 1H), 7.30-7.34 (m, 1H), 6.88-6.97 (m, 2H) ), 6.00-6.09 (m, 1H), 5.28-5.43 (m, 2H), 4.58-4.59 (m, 2H).

The third step is the synthesis of compound 3a, 4-dihydro-3H-chromeno[4,3-c]isoxazole (42d)

Compound 42c (20.0g, 113mmol) and catalytic amount of triethylamine (114mg, 1.13mmol) were dissolved in dichloromethane (1200mL), the system was cooled to 0-5°C, and 4% sodium hypochlorite solution (1200mL) ), control the temperature at 0-5°C and stir for 2 hours. TLC detection, pour the reaction solution into water for phase separation. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered and concentrated to obtain 42d crude product (12.0 g).

LCMS(ESI-MS) m/z: 176.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 7.78 (d, 1H, J = 7.6 Hz), 7.31-7.35 (m, 1H), 6.94-7.02 (m, 2H), 4.66-4.71 (m, 2H), 4.06-4.11 (m, 1H), 3.87-3.94 (m, 2H).

The fourth step is the synthesis of compound 3-(hydroxymethyl)chroman-4-one (42e)

In a hydrogenation flask, compound 42d (12.0g, 68.4mmol) and boric acid (8.41g, 137mmol) were dissolved in a mixture of methanol and water (120mL, v/v=5/1), replaced with nitrogen three times, and added Lanney Nickel (12.0g). It was replaced with hydrogen gas 3 times, and stirred at room temperature for 5 hours. The catalyst was removed by filtration, the filter cake was washed with methanol, and the filtrate was concentrated to obtain the crude product 42e (6.0 g).

1H NMR(400MHz,CDCl3)δ7.88-7.90(m,1H),7.47-7.51(m,1H),6.96-7.04(m,2H),4.57-4.61(m,1H),4.38-4.44(m ,1H), 3.88-3.98 (m, 2H), 3.00-3.04 (m, 1H).

Step 5 Synthesis of compound 3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)chroman-4-one (42f)

Compound 42e (6.0g, 33.7mmol) and tetrahydropyran (11.2g, 135mmol) were dissolved in dichloromethane (60mL), a catalytic amount of p-toluenesulfonic acid (580mg, 3.37mmol) was added, and stirred at room temperature for 2 hours . The water phase was added, and the water phase was extracted twice with dichloromethane, the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered and concentrated to obtain 42f crude product (8.0 g).

The sixth step compound 3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)chroman-4-ol synthesis (42g)

Compound 42f (8.0 g, 30.5 mmol) was dissolved in methanol (80 mL), the system was cooled to 0-5° C., sodium borohydride (1.2 g, 30.5 mmol) was added in batches, and the reaction was incubated for 1 hour. Saturated ammonium chloride solution was added dropwise to the system, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered and concentrated to obtain crude E10_14. The crude product was subjected to column chromatography to obtain 42g pure product (4.0g , 15.3mmol) The yield was 50%.

LCMS(ESI-MS)m/z:247.3[M-OH] ⁺ .

The seventh step is the synthesis of compound 4-(benzyloxy)-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)chroman (42h)

Compound 42g (4.0g, 15.2mmol) was dissolved in a mixed solution of tetrahydrofuran and dimethylformamide (60mL, v/v=5/1), the system was cooled to 0-5°C, and sodium hydride (308mg , 15.2mmol), incubate for 1 hour. Benzyl bromide (2.6 g, 15.2 mmol) was added dropwise to the system, and the reaction was incubated for 2 hours. The reaction solution was poured into ice water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a 42h crude product (5.0 g).

Step 8: Synthesis of compound (4-(benzyloxy)chroman-3-yl)methanol (42i)

Dissolve compound 42h (5.0g, 14.1mmol) in methanol (50mL), cool the system to 0-5°C, add a catalytic amount of pyridinium p-toluenesulfonate (355mg, 1.41mmol), slowly warm to room temperature and stir for 4 hours . The reaction solution was poured into water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered and concentrated to obtain crude E10-16. The crude product was subjected to column chromatography to obtain pure 42i product (2.4g, 8.89mmol) The yield was 63%.

LCMS(ESI-MS) m/z: 293.3[M+Na] ⁺ .

Step 9 Synthesis of compound 4-(benzyloxy)-3-(methoxymethyl)chroman (42j)

Compound 42i (2.4 g, 8.89 mmol) was dissolved in tetrahydrofuran (60 mL), the system was cooled to 0-5° C., sodium hydride (356 mg, 8.89 mmol) was added in batches, and the temperature was kept for 1 hour. Iodomethane (1.3 g, 8.89 mmol) was added dropwise to the system, and the temperature was slowly raised to room temperature for 2 hours. The reaction solution was poured into ice water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered and concentrated to obtain crude E10_17. The crude product was subjected to column chromatography to obtain 42j pure product (2.0g, 7.11mmol) ), the yield is 80%.

LCMS(ESI-MS)m/z:307.2[M+Na] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.17-7.36 (m, 7H), 6.82-6.91 (m, 2H), 4.56-4.67 (m, 2H), 4.18-4.38 (m, 3H), 3.62-3.66 (m,1H),3.46-3.50(m,1H),3.24-3.38(m,4H),2.42-2.47(m,1H).

The tenth step is the synthesis of 3-(methoxymethyl)chroman-4-ol (42k)

Compound 42j (500 mg, 1.76 mmol) was dissolved in methanol (10 mL) in a hydrogenation flask, replaced with nitrogen three times, 10% palladium carbon (50 mg) was added, replaced with hydrogen gas three times, and stirred overnight at room temperature. Three reactions were thrown in parallel. After the reaction, the palladium carbon was removed by filtration, the filter cake was washed with methanol, and the filtrate was concentrated to obtain a crude product. The crude product was subjected to column chromatography to obtain a 42k pure product (750 mg, 1.32 mmol) with a yield of 75%.

LCMS(ESI-MS)m/z:177.1[M-17] ⁺ .

The eleventh step 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(3-(methoxymethyl)chromane-4 -Yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol (42&43)

Using a synthetic method similar to that in Example 1, replacing 1 g with 42k, the title products 42 and 43 were obtained with a yield of 17%. 42 (20 mg, 0.042 mmol), 42 (40 mg, 0.081 mmol), the yield was 17%.

42: LCMS(ESI-MS) m/z: 498.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO--d ₆ ) δ 8.38-8.40 (m, 2H), 8.03 (s, 1H), 7.49 (d, J = 8Hz, 1H), 7.03-7.05 (m, 1H), 6.95-6.97(m,1H),6.82-6.84(m,1H),6.22(d,J=6Hz,1H),4.40-4.41(m,1H),4.26-4.27(m,1H),3.70(s , 3H), 3.06-3.22(m, 2H), 3.00(s, 6H), 2.17(s, 3H), 1.77(s, 3H), 1.76(s, 3H).

43: LCMS(ESI-MS) m/z: 498.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.59(s,1H), 8.51(d,J=8.4Hz,1H), 8.08(s,1H), 7.58(d,J=8.4Hz,1H) ,7.02-7.06(m,2H),6.68-7.78(m,2H), 6.37(d,J=10Hz,1H), 4.38-4.44(m,2H), 3.69(s,3H), 3.40-3.45( m, 2H), 3.29 (s, 3H), 3.17-3.20 (m, 2H), 2.12 (s, 3H), 1.76 (s, 3H), 1.67 (s, 3H).

Examples 44 and 45: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(2-(2-methoxyethyl) Synthesis of -2,3-dihydrobenzofuran-3-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol

The first step is the synthesis of compound 4-methoxybutyric acid methyl ester (44b)

44a (50.0 g, 0.58 mol), trimethyl orthoformate (117.0 g, 1.1 mol) and MeOH (200 mL) were sequentially added to the reaction flask, and concentrated sulfuric acid (5 mL) was added dropwise with stirring at room temperature. The system was heated to reflux for overnight reaction, monitored by TLC. The reaction solution was lowered to room temperature, poured into water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered and concentrated to obtain 44b pure product (27g, 0.2mol), the yield was 35.2%.

¹ H NMR(400MHz, CDCl ₃ )δ3.67(s,3H), 3.42-3.39(t,J=6.4Hz,2H), 3.32(s,3H),2.42-2.38(t,J=7.6Hz, 2H), 1.91-1.88 (m, 2H).

The second step is the synthesis of compound 4-methoxybutyric acid (44c)

Compound 44b (27.0g, 0.2mol) was dissolved in methanol/water (250mL/50mL), and LiOH.H2O (12.9g, 0.3mol) was added. The reaction system was stirred at room temperature for 2 hours. The reaction was detected by TLC. 1M hydrochloric acid solution was added dropwise to the reaction solution to pH=3-4, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered and concentrated to obtain 44c pure product (18g, 0.15mol) ), the yield is 75%.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.47-3.42 (m, 2H), 3.34 (s, 3H), 2.48-2.44 (m, 2H), 1.94-1.87 (m, 2H).

The third step is the synthesis of compound N,4-dimethoxy-N-methylbutanamide (44d)

Compound 44c (18g, 0.15mol) was dissolved in dichloromethane (180mL), and HOBt (31.1g, 0.23mol), EDCI (43.9g, 0.23mol), TEA (46.2g, 0.46mol) and dimethylhydroxylamine salt were added sequentially Acid salt (17.8g, 0.18mol). The reaction system was stirred at room temperature for 4 hours. The reaction was detected by TLC, the reaction solution was washed with water, saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated to obtain 44d crude product, column chromatography to obtain 44d pure product (12g, 74.5mmol), the yield was 48.6%.

LCMS(ESI-MS)m/z:162.0[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 3.68 (s, 3H), 3.45-3.42 (m, 2H), 3.33 (s, 3H), 3.18 (s, 3H), 2.53-2.50 (m, 2H), 1.94-1.89 (m, 2H).

The fourth step is the synthesis of compound 4-methoxy-1-(2-methoxyphenyl)butan-1-one (44f)

Compound 44e (5g, 26.7mmol) was dissolved in anhydrous tetrahydrofuran (100mL) and replaced with nitrogen 3 times. The temperature of the system was cooled to -70°C, and n-BuLi (11.8 mL, 29.4 mmol) was slowly added dropwise. After stirring the system at -70°C for 1 hour, 44d (6.5g, 40.1mmol) was added dropwise. Four reactions were cast in parallel, stirred at -70°C for 2 hours, detected by TLC, quenched by dropping saturated ammonium chloride solution, extracted twice with ethyl acetate, combined the organic phases, washed with water, dried with anhydrous sodium sulfate, filtered and concentrated to obtain The 44f crude product was purified by column chromatography (16 g, 76.9 mmol), and the yield was 72%.

LCMS(ESI-MS) m/z: 209.2[M+H]+.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.68-7.66 (m, 1H), 7.44-7.42 (m, 1H), 7.01-6.94 (m, 2H), 3.90 (s, 3H), 3.45-3.42 (m ,2H), 3.32(s,3H),3.06-3.03(m,2H), 1.99-1.95(m,2H).

Step 5 Synthesis of the compound 2-bromo-4-methoxy-1-(2-methoxyphenyl)butan-1-one (44g)

Compound 44f (16 g, 76.9 mmol) was dissolved in dichloromethane (320 mL). The system was cooled to 0°C, and bromine (12.2g, 76.9mmol) was slowly added dropwise, and stirred at room temperature for 0.5 hours. TLC detection, the reaction solution was washed with water, dried with anhydrous sodium sulfate, filtered and concentrated to obtain crude E11_7, column chromatography to obtain 44g pure product (20g, 69.7mmol), the yield was 91%.

LCMS(ESI-MS)m/z:287.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.73-7.71 (m, 1H), 7.51-7.46 (m, 1H), 7.05-6.96 (m, 2H), 5.61-5.57 (m, 1H), 3.92 (s ,3H), 3.62-3.53 (m, 2H), 3.35 (s, 3H), 2.51-2.45 (m, 1H), 2.25-2.19 (m, 1H).

Step 6 Synthesis of the compound 2-bromo-1-(2-hydroxyphenyl)-4-methoxybutan-1-one (44h)

Compound 44f (20g, 69.7mmol) was dissolved in dichloromethane (400mL), the system was cooled to -10°C, boron tribromide (10mL) was slowly added dropwise, and the temperature was controlled at -10°C and stirred for 10 minutes. TLC detection, the reaction solution was poured into ice water, extracted twice with dichloromethane, the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered and concentrated to obtain crude E11-8, column chromatography to obtain 44h pure product (6g, 22.1 mmol), the yield was 31.6%.

¹ H NMR (400MHz, CDCl ₃ ) δ 11.91 (s, 1H), 7.83-7.81 (m, 1H), 7.53-7.49 (m, 1H), 7.03-7.01 (m, 1H), 6.95-6.91 (m , 1H), 5.49-5.46 (m, 1H), 3.64-3.50 (m, 2H), 3.35 (s, 3H), 2.44-2.32 (m, 2H).

Step Seven: Synthesis of the compound 2-(2-methoxyethyl)benzofuran-3(2H)-one (44i)

Compound 44h (6 g, 22 mmol) was dissolved in methanol (120 mL), and sodium carbonate (2.3 g, 22 mmol) was added at room temperature. The system was stirred at room temperature for 20 minutes. The reaction was monitored by TLC. The reaction solution was poured into water and extracted twice with ethyl acetate. The organic phases were combined and washed with water, dried and concentrated to obtain crude 44i. Column chromatography gave pure 44i (2g, 10.4mmol). The yield was 47.6%. .

¹ H NMR (400MHz, CDCl ₃ ) δ 7.68-7.58 (m, 2H), 7.14-7.06 (m, 2H), 4.72-4.69 (m, 1H), 3.63-3.57 (m, 2H), 3.30 (s , 3H), 2.29-2.26 (m, 1H), 2.01-1.96 (m, 1H).

Step 8: Synthesis of compound 2-(2-methoxyethyl)-2,3-dihydrobenzofuran-3-ol (44j)

Compound 44i (2g, 10.4mmol) was dissolved in methanol (40mL), the system was cooled to 0°C, sodium borohydride (0.4g, 10.4mmol) was added, and the mixture was stirred at 0°C for 1 hour. The reaction was monitored by TLC, the reaction solution was added with water, extracted with ethyl acetate, the combined organic phases were washed with water, dried, and concentrated to obtain crude 44j, which was obtained by thin layer chromatography (1.5 g, 7.7 mmol) with a yield of 75%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.44-7.21 (m, 2H), 6.94-6.82 (m, 2H), 5.15-5.13 (m, 1H), 4.68-4.53 (m, 1H), 3.67-3.52 (m, 2H), 3.37 (s, 3H), 2.40-2.14 (m, 2H).

Step 9 Compound 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(2-(2-methoxyethyl)-2 Synthesis of ,3-Dihydrobenzofuran-3-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol (44&45)

Using a synthetic method similar to that in Example 1, replacing 1 g with 42j, the title products 44 and 45 were obtained, and purified by perp-HPLC to obtain 44 (30 mg, 0.06 mmol), 45 (30 mg, 0.06 mmol), and the yield was 10 %.

LCMS(ESI-MS) m/z: 498.2[M+H] ⁺ .

44: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.61-8.49 (m, 1.4H), 8.21-8.13 (m, 1.6H), 7.57-7.46 (m, 1H), 7.41-7.38 (m, 1H), 7.27-7.17 (m, 1H), 7.13-7.10 (m, 1H), 6.95-6.89 (m, 1H), 6.82-6.76 (m, 1H), 6.67-6.64 (m, 1H), 5.24- 5.13(m,1H),4.09(s,1H),3.77(s,2H),3.40-3.27(m,2H),3.10-3.09(m,3H),2.36(s,1H),2.01(s, 2H), 1.61-1.60 (m, 4H), 1.54-1.41 (m, 2H), 1.26 (s, 1H), 1.18 (s, 1H).

45: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.62-8.55 (m, 1.5H), 8.22-8.20 (m, 1.5H), 7.57-7.48 (m, 1H), 7.37-7.33 (m, 1H), 7.12-7.01 (m, 3H), 6.89-6.73 (m, 2H), 5.04-5.00 (m, 1H), 4.09-3.79 (m, 3H), 3.53 (m, 2H), 3.08-3.03 ( m, 3H), 2.36-2.02 (m, 5H), 1.61 (s, 3H), 1.31-1.27 (m, 3H).

Example 46&47: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(pyridin-2-yl(tetrahydrofuran- 3-yl)methyl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol (46&47)

The first step N-methoxy-N-methyltetrahydrofuran-3-carboxamide (46b)

46a (10.0 g, 86.2 mmol) was dissolved in 200 mL of dichloromethane, CDI (20.95 g, 129.3 mmol) was added at 0°C, and then heated to room temperature and stirred for 1 hour. Dimethylhydroxylamine hydrochloride (12.67 g, 129.3 mmol) and DIPEA (22.07 g, 172.4 mmol) were added. After the addition, stir overnight at room temperature.

The reaction system was washed successively with saturated citric acid, sodium bicarbonate, and brine, and the organic phase was collected, dried, filtered, and spin-dried. The column was separated by PE/EA = 4/1 and eluted with iodine to develop the color to obtain the target compound 46b (9.8 g), colorless oil, yield 66%.

The second step pyridin-2-ylmagnesium bromide (46d)

At room temperature, 1088c (5.0g, 31.6mmol) was dissolved in 10mL of anhydrous tetrahydrofuran, and i-PrMgCl (3.0M, 11.6mL, 34.8mmol, 1.1eq) was added dropwise. After the addition, stir at room temperature for 3 hours. The system is brown-black, spare.

The third step pyridin-2-yl (tetrahydrofuran-3-yl) methanol (46e)

Take compound 46b (5.0 g, 31.6 mmol) and dissolve it in 18 mL of anhydrous tetrahydrofuran, add dropwise 46d (31.6 mmol) prepared above at room temperature. After dropping, continue stirring overnight at room temperature. After quenching the reaction with saturated ammonium chloride, it was diluted with EA, washed with water, the organic phase was collected, dried, filtered, column separated, and eluted with PE/EA=4/1 to obtain the target compound 46e (3.4g) as a light yellow liquid. The rate is 61%.

LCMS(ESI-MS) m/z: 178.1[M+H] ⁺ .

Step 4 Pyridin-2-yl (tetrahydrofuran-3-yl) methanol (46f)

46e (1.0 g, 5.65 mmol) was dissolved in 5 mL of methanol, and sodium borohydride (257 mg, 6.78 mmol) was added at 0°C. After the addition, stir at room temperature for 2 hours. After the reaction is complete, the system is spin-dried, the EA/H2O layer is separated, the organic phase is collected, dried, and filtered to obtain the target compound 46f (575 mg) as a yellow liquid.

LCMS(ESI-MS) m/z: 180.2[M+H] ⁺ .

Step 5 Methyl 6-bromo-1-methyl-4-(pyridin-2-yl(tetrahydrofuran-3-yl)methyl)-1,4-dihydropyrrolo[2',3':4, 5]Pyrrolo[3,2-b]pyridine-2-carboxylate (46h)

In a 50mL single-mouth flask, add 46g (230mg, 0.75mmol), 46f (147mg, 0.82mmol), CMBP (cas: 157141-27-0, 271mg, 1.125mmol) and 8mL o-dichlorobenzene in sequence, and react at 150℃ 4 hours. LCMS monitors the reaction. After the reaction was completed, the sample was loaded by wet method, PE/EA=4/1 eluted, and 46h (286mg) was obtained as a yellow solid with a yield of 76%. (TLC shows that there are two mixtures of the same molecular weight, and the retention time on LCMS is basically the same.)

LCMS(ESI-MS) m/z: 469.2[M+H] ⁺ .

The sixth step is methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(pyridin-2-yl(tetrahydrofuran-3- (Yl)methyl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridine-2-carboxylate (46j)

In a 100mL single-mouth flask, add 46h (320mg, 0.64mmol), tin reagent (300mg, 0.78mmol), CuI (11.4mg, 0.06mmol), PCy3 (35.8mg, 1.28mmol), Pd2(dba)3 (117mg , 1.28mmol), and 8mL DMF under nitrogen protection, react at 100°C for 3 hours. LCMS monitors the reaction. The DMF was spin-dried, dissolved with DCM/MeOH=1/1, the suspension was prepared and separated by TLC, and developed with DCM/MeOH=20/1 to obtain 46j (200mg) as a yellow solid with a yield of 60%.

LCMS(ESI-MS) m/z: 518.4[M+H] ⁺ .

The seventh step 2-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(pyridin-2-yl(tetrahydrofuran-3 -Yl)methyl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol (46&47)

46j (200mg, 0.39mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, cooled to 0°C, methylmagnesium bromide (1.0M, 3.9mL, 10eq) was added, after the addition, it was naturally warmed to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride solution, the solid was filtered off, the organic phase was spin-dried, the residue was dissolved in dichloromethane, TLC preparation and separation, DCM/MeOH=20/1 development, 46 (30mg, white solid, TLC showed Rf Larger spots), 47 (14 mg, white solid, TLC shows spots with smaller Rf), the yield is 22%.

LCMS(ESI-MS)m/z:486.4[M+H] ⁺ .

46: ¹ H NMR(400MHz,DMSO-d ₆ )δ8.51–8.53(m,1H), 8.17–8.21(m,2H), 7.69–7.73(m,1H), 7.53–7.55(d,J= 8.0Hz,1H), 7.23–7.26(m,1H), 6.24(s,1H), 5.64–5.67(d,J=11.6Hz,1H), 5.26(s,1H), 4.18(s,3H), 3.95(s,3H),3.82-3.90 (m,2H),3.65-3.71(m,1H),3.54-3.58(m,1H),2.24(s,1H),1.93(m,1H),1.57( s, 3H), 1.56 (s, 3H), 1.20 (s, 1H).

47: ¹ H NMR(400MHz,DMSO-d ₆ )δ8.56–8.58(d,J=6.4Hz,1H), 8.23–8.24(d,J=1.6Hz,1H), 7.72(s,1H), 7.55–7.59(m,1H),7.16–7.19(m,2H),6.19(s,1H),5.33–5.36(d,J=11.2Hz,1H), 4.40(s,3H), 3.94(s, 3H), 3.15--3.88(m, 2H), 3.64--3.67(m, 1H), 2.31(s, 3H), 1.91--2.00(m, 2H), 1.80(s, 3H), 1.78(s, 3H) ,1.58-1.67(m,2H).

Example 48: 2-(4-(bis(pyridin-2-yl)methyl)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)- 1-Methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propyl-2-ol

The first step is 5-bromo-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (48a)

Dissolve 1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (10g, 71.9mmol) in dichloromethane (200mL), add N-bromosuccinimide (12.8g, 71.9mmol) under ice bath ) After stirring at room temperature overnight. Purified by Flash column chromatography (PE/EA 0-10%), 48a (7.6 g, 34.9 mmol) was obtained with a yield of 48.5%.

¹ H NMR(400MHz,DMSO-d ₆ )δ6.88(d,J=4.2Hz,1H), 6.30(d,J=4.2Hz,1H), 3.82(s,3H), 3.71(s,3H) .

The second step 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylic acid methyl ester (48b)

Under nitrogen, compound 48a (7.6g, 34.9mmol), bis(pinacolato) diboron (10.6g, 41.7mmol), 1,1'-bisdiphenylphosphine ferrocene dichloride palladium (2.5 g, 3.4mmol) and potassium acetate (6.8g, 6.9mmol) in N,N-dimethylformamide (100mL) solution was heated to 100 ℃ for 2 hours, cooled and diluted with ethyl acetate (800mL), washed with water ( 500mL*5), dried over Na2SO4, filtered, and concentrated to obtain crude compound 48b (11.8g, 44.5mmol).

LCMS(ESI-MS) m/z: 266.2[M+H] ⁺ .

The third step 5-(5-bromo-3-nitropyridin-2-yl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (48c)

Under nitrogen, compound 48b (11.8g, 44.5mmol), 2,5-dibromo-3-nitropyridine (14.1g, 50mmol), 1,1'-bisdiphenylphosphine ferrocene dichloride palladium A mixed solution of 1,4-dioxane (100mL) and water (5mL) (3.3g, 4.5mmol) and potassium phosphate (18.9g, 89.0mmol) was heated to 100°C and stirred for 2 hours. After cooling, ethyl acetate was added Ester (600mL) was diluted, washed with water (400mL*3), dried over Na ₂ SO ₄ , filtered, concentrated, Flash column (PE/EA 0-10%) to obtain the title compound 48c (6.6g, 19.4mmol), the yield was 43.6 %.

LCMS(ESI-MS) m/z: 340.1[M+H] ⁺ .

Step 4 6-Bromo-1-methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester (48d )

Under nitrogen, a solution of compound 48c (6.6g, 19.4mmol) and triethyl phosphite (10.0g, 60.2mmol) in dichlorobenzene (100mL) was heated to 160°C and stirred for 4 hours, cooled to room temperature, filtered, and filtered. The cake was washed with dichloromethane and dried to obtain the title compound 48d (1.4 g, 4.5 mmol) with a yield of 23.2%.

LCMS(ESI-MS) m/z: 308.1[M+H] ⁺ .

Step 5 6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-1,4-dihydropyrrolo[2',3' :4,5]pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester (48e)

Under nitrogen, compound 90d (300mg, 0.97mmol), 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (600mg, 1.55mmol) and tetrakis (three A solution of phenylphosphorus) palladium (100mg, 0.08mmol) in DMF (10mL) was heated to 100°C for 2 hours. After cooling, it was diluted with ethyl acetate (100mL), washed with water (100mL*3), dried with Na2SO4, filtered, and concentrated. Flash column (PE/EA 0-100%) to obtain compound 90e (280 mg, 0.86 mmol) with a yield of 88.7%.

LCMS(ESI-MS)m/z:325.2[M+H] ⁺ .

The sixth step 4-(bis(pyridin-2-yl)methyl)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl -1,4-Dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester (48f)

Under nitrogen, the compound 90e (280mg, 0.86mmol), 2,2'-(bromomethylene)bipyridine (320mg, 1.28mmol) and potassium carbonate (250mg, 1.81mmol) were mixed with N,N-dimethylformaldehyde The amide (10mL) solution was heated to 50°C and reacted for 4 hours. After cooling, it was diluted with ethyl acetate (100mL), washed with water (50mL*5), dried over Na ₂ SO ₄ , filtered, concentrated, and flashed through the column (DCM/MeOH 0～ 10%) to obtain the title compound 90f (120 mg, 0.24 mmol) with a yield of 28.2%.

LCMS(ESI-MS) m/z: 493.4[M+H] ⁺ .

The seventh step 2-(4-(bis(pyridin-2-yl)methyl)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1 -Methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propyl-2-ol (48)

Under nitrogen, a THF (10mL) solution of compound 90f (120mg, 0.24mmol) was cooled to 0°C, methylmagnesium bromide (1mL, 2.5mmol) was added dropwise, and the reaction was stirred at room temperature for 2 hours. Flash was passed through the column (DCM/MeOH0 ~10%) to obtain the title compound 48 (4mg, 0.008mmol) with a yield of 3.3%.

LCMS(ESI-MS)m/z:493.3[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.52(d,J=4.9Hz,2H), 8.23(d,J=1.8Hz,1H), 7.76(d,J=1.9Hz,1H), 7.74 (d,J=1.7Hz,2H), 7.32(dd,J=7.4,4.9Hz,2H), 7.26–7.17(m,3H), 6.65–6.61(m,1H),5.21(s,1H), 4.19 (s, 3H), 3.84 (s, 3H), 2.11 (s, 3H), 1.20 (s, 6H).

Example 49: 8-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-3-methyl-10-(phenyl(tetrahydro-2H-pyran- 4-yl)methyl)-1,2,3,10-tetrahydrocyclopenta[g]pyrido[3,2-b]indol-3-ol

The first step 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one ( 49b)

The 5-bromo-2,3-dihydro-1H-inden-1-one 49a (10.0g, 47.4mmol), 4,4,4',4',5,5,5',5'-octamethyl 2,2'-linked (1,3,2-dioxaborolane) (13.2g, 52.1mmol), potassium acetate (7.05g, 70.5mmol) dissolved in 150ml of dioxane, under nitrogen protection Pd(DPPF)Cl ₂ (3.4 g, 4.7 mmol) was added, and the reaction was carried out at 100° C. for 5 hours. TLC monitoring, the raw material reaction is complete, add water, extract with EA, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, and purify by Flash column to obtain methyl 4-(5-bromo-3-nitropyridin-2-yl)benzoic acid Ester 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one 49b (8.9 g, 34.4 mmol), the yield is 72.7%.

LCMS(ESI-MS)m/z:259.1[M+H] ⁺ .

The second step 5-(5-bromo-3-nitropyridin-2-yl)-2,3-dihydro-1H-inden-1-one (49c)

Combine methyl 4-(5-bromo-3-nitropyridin-2-yl)benzoate 49b (8.9g, 34.4mmol) and 2,5-dibromo-3-nitropyridine (9.7g, 34.4mmol) Dissolve in 200ml THF, add potassium phosphate (21.9g, 103.2mmol), H ₂ O (40ml), add Pd(DPPF)Cl ₂ (2.56g, 3.5mmol) under nitrogen protection, and stir at 80°C for 4 hours. TLC monitoring, the raw material reaction is complete, add water, extract with EA, wash with saturated aqueous sodium chloride solution, dry with anhydrous sodium sulfate, and purify by Flash column to obtain 5-(5-bromo-3-nitropyridin-2-yl)-2, 3-Dihydro-1H-inden-1-one 49c (5.1g, 15.3mmol), the yield was 44.5%.

¹ H NMR (400MHz, CDCl ₃ ) δ 8.95 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H), 7.88-7.80 (m, 1H), 7.66 (dt, J = 1.8, 0.9 Hz, 1H), 7.50 (ddt, J = 7.8, 1.4, 0.7 Hz, 1H), 3.24–3.20 (m, 2H), 2.78–2.75 (m, 2H).

The third step 8-bromo-1,10-dihydrocyclopenta[g]pyrido[3,2-b]indole-3(2H)-one(49d)

Dissolve 49c (5.0g, 15.0mmol) in 40ml of o-dichlorobenzene, add triethyl phosphite (7.5g, 45mmol), under nitrogen protection, and stir for 2 hours at 145°C. TLC monitoring shows that the reaction of the raw materials is complete and precipitates out after cooling. The solid was filtered and washed with DCM to obtain 8-bromo-1,10-dihydrocyclopenta[g]pyrido[3,2-b]indole-3(2H)-one 49d (2.4g, 7.7 mmol), the yield is 51.6%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.30 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 8.1Hz,1H), 7.52(d,J=8.1Hz,1H), 3.40–3.34(m,2H), 2.83–2.72(m,2H).

The fourth step 8-bromo-10-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,10-dihydrocyclopenta[g]pyrido[3,2- b)Indole-3(2H)-one (49e)

49d (1.5g, 5.0mmol) and phenyl (tetrahydro-2H-pyran-4-yl) methanol Int1 (2.8g, 15mmol) were dissolved in 60ml of anhydrous DCM, and tributylphosphine (3.1g, 15mmol), nitrogen protection, stirring under ice bath conditions for 0.5 hours, adding TMAD (2.6g, 15mmol), slowly warming to room temperature for 6 hours, TLC monitoring, raw material reaction is complete, directly mixed with silica gel sample, Flash column purification, 8-bromide -10-(Phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,10-dihydrocyclopenta[g]pyrido[3,2-b]indole-3 (2H)-ketone 49e (630mg, 1.32mmol), yield 26.5%.

LCMS(ESI-MS)m/z:477.0[M+H] ⁺ .

¹ H NMR(400MHz, CDCl ₃ )δ8.58(dd,J=3.7,1.8Hz,1H), 8.39(d,J=8.1Hz,1H), 7.87(d,J=1.8Hz,1H), 7.78 (d,J=8.0Hz,1H),7.46(d,J=7.5Hz,2H),7.42-7.27(m,3H),5.90(d,J=11.0Hz,1H),4.06(dd,J= 15.6, 5.8 Hz, 1H), 3.82 (dd, J = 11.7, 4.4 Hz, 1H), 3.73 (d, J = 6.5 Hz, 2H), 3.56 (q, J = 10.4, 9.0 Hz, 1H), 3.39- 3.30 (m, 1H), 3.06 (d, J = 11.4 Hz, 1H), 2.93 (t, J = 5.7 Hz, 2H), 2.10 (d, J = 13.5 Hz, 1H), 1.58 (qd, J = 11.9 ,4.2Hz,1H),1.38-1.30(m,1H),0.81(d,J=13.5Hz,1H).

Step 5 8-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-10-(phenyl(tetrahydro-2H-pyran-4-yl)methyl )-1,10-Dihydrocyclopenta[g]pyrido[3,2-b]indole-3(2H)-one (49f)

Dissolve 49e (430mg, 0.9mmol) in 10mL DMF, add CuI (34.2mg, 0.18mmol), Int1 (694.8mg, 1.8mmol), Pd(dba)2 (103.5mg, 0.18mmol), tricyclohexylphosphine (50.4mg, 0.18mmol), nitrogen protection, heating at 105℃ for 2 hours, TLC monitoring, raw material reaction is complete, adding water, EA extraction, saturated sodium chloride washing, anhydrous sodium sulfate drying, Flash column purification, 8-(1 ,4-Dimethyl-1H-1,2,3-triazol-5-yl)-10-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,10-bis Hydrocyclopenta[g]pyrido[3,2-b]indole-3(2H)-one 49f (400mg, 0.81mmol), yield 90.5%.

LCMS(ESI-MS)m/z:492.3[M+H] ⁺ .

The sixth step 8-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3-methyl-10-(phenyl(tetrahydro-2H-pyran-4 -Yl)methyl)-1,2,3,10-tetrahydrocyclopenta[g]pyrido[3,2-b]indol-3-ol (49)

Dissolve 49f (530mg, 1.1mmol) in 5ml anhydrous THF, add CH3MgBr (3M in THF, 3ml, 9mmol), stir the reaction at room temperature for 4 hours, TLC monitoring, the reaction of the raw materials is complete, quenched with water, extracted with EA, saturated NaCl Wash with aqueous solution, dry with anhydrous sodium sulfate, and purify by Flash column to obtain 8-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3-methyl-10-(benzene Group (tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,10-tetrahydrocyclopenta[g]pyrido[3,2-b]indole-3- Alcohol 49 (210mg, 0.41mmol), yield 37.2%, pale yellow solid.

LCMS(ESI-MS)m/z:508.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.48 (t, J = 1.5Hz, 1H), 8.20-8.08 (m, 2H), 7.64 (dt, J = 9.2, 3.1 Hz, 2H), 7.41- 7.30 (m, 3H), 7.26 (td, J = 7.1, 1.6 Hz, 1H), 5.85 (d, J = 11.1 Hz, 1H), 5.20 (s, 1H), 3.90 (d, J = 5.2 Hz, 4H ),3.78–3.64(m,2H),3.61–3.16(m,7H),2.35(t,J=6.9Hz,2H),2.21(d,J=5.0Hz,3H),1.84(d,J= 13.2Hz, 1H), 1.56 (d, J=2.9Hz, 3H).

Example 50: (2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazol-7-yl )Bis(thiazol-2-yl)methanol

Using a synthetic method similar to that of Example 37, the title product 41 was obtained.

LCMS(ESI-MS) m/z: 450.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.76-7.65 (m, 4H), 7.33 (dd, J = 12.8, 3.2 Hz, 2H), 3.84 (s, 3H), 2.59 (s, 1H), 2.12 ( d, J = 18.5 Hz, 3H), 1.43 (d, J = 8.0 Hz, 4H).

Example 51: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro- 2H-pyran-4-yl)ethyl)-7-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-5H-pyrrolo[2,3-b:4 ,5-b']dipyridine

Using a synthetic method similar to that of Example 28, the title product 51 was obtained.

LCMS(ESI-MS)m/z:652.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.36 (d, J = 1.8 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.97-7.85 (m, 2H), 7.34-7.17 ( m, 2H), 7.04 (dd, J = 10.6, 8.1 Hz, 1H), 6.82 (d, J = 8.9 Hz, 1H), 6.47 (d, J = 9.0 Hz, 1H), 3.86 (s, 3H), 3.74 (d, J = 11.0 Hz, 1H), 3.65 (t, J = 4.9 Hz, 5H), 3.02 (d, J = 10.5 Hz, 1H), 2.81 (d, J = 11.7 Hz, 3H), 2.57 ( s, 4H), 2.15 (d, J = 7.0 Hz, 7H), 1.98 (d, J = 8.5 Hz, 1H), 1.89 (s, 2H), 1.73 (d, J = 12.0 Hz, 2H), 1.49- 1.32(m,3H),1.22(m,5H).

Example 52: 2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(pyridin-4-yl)-1H-benzene And [d]imidazole

Using a synthetic method similar to that of Example 40, the title product 52 was obtained.

LCMS (ESI-MS) m/z: 331.2 [M+H] ⁺ _.

Example 53: 2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(2-methylnaphthalene-1-yl) -1H-Benzo[d]imidazole

Using a synthetic method similar to that of Example 40, the title product 53 was obtained.

LCMS(ESI-MS)m/z:394.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.04 (s, 1H), 7.92 (t, J = 13.4 Hz, 2H), 7.64 (s, 1H), 7.57-7.49 (m, 1H), 7.42 ( d, J = 7.7 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.97 (s, 1H), 3.94 (s, 3H), 2.23 ( s,3H),2.19-1.96(m,4H),0.98(d,J=9.0Hz,4H).

Example 54: 5-(2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazole-7 -Base)-6-methylquinoline

Using a synthetic method similar to that of Example 40, the title product 54 was obtained.

LCMS (ESI-MS) m/z: 395.2 [M+H] ⁺ .

¹ H NMR(400MHz, MeOD)δ8.77(s,1H), 8.06(d,J=8.7Hz,1H),7.86-7.71(m,2H),7.65(s,1H),7.39(s,1H) ), 7.09(s,1H),4.01(s,3H),2.30(d,J=8.3Hz,6H),2.03(s,1H),1.17-0.99(m,4H).

Example 55: 2-(6-(3,5-Dimethylisoxazol-4yl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-4H-thiophene [2',3':4,5] Pyrrole[3,2-b]pyridin-2-yl)propan-2-ol

The first step is 5-(5-bromo-3-nitropyridin-2-yl)thiophene-2-carboxylic acid methyl ester (55a)

Add 1a (15.2g, 53.8mmol), 5-boronic acid thiophene-2-carboxylic acid methyl ester 55e (10.0g, 53.8mmol), Pd(dppf)Cl ₂ (1.97g, 2.69mmol) and 54mL phosphoric acid in a single-mouth flask. Potassium solution (3M) and 100 mL tetrahydrofuran. Under nitrogen protection, react at 80°C for 3 hours. The solvent was spin-dried, the obtained solid was dissolved in DCM, filtered to remove insolubles, the organic phase was spin-dried, and dissolved in EA. After adding PE, the solid precipitated out and filtered out to be the crude product of target compound 55a. The crude product was separated by column and DCM/ MeOH=20/1 (V/V) eluted to obtain target compound 55a (3.85g) as a yellow solid with a yield of 21%.

LCMS(ESI-MS)m/z:343[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.98(s,1H),8.80(s,1H),7.73-7.74(d,J=4.0Hz,1H),7.28-7.29(d,J=4.0 Hz, 1H), 3.82 (s, 3H).

Step 2 6-Bromo-4H-thiophene[2',3':4,5]pyrrole[3,2-b]pyridine-2-carboxylic acid methyl ester (55b)

Add 55a (1.25 g, 3.64 mmol), triethyl phosphite (2.72 g, 16.4 mmol), and 6 mL of dichlorobenzene into a 20 mL microwave tube, and react at 150° C. for 3 h under nitrogen protection. After cooling, a solid precipitated and was filtered out to be 55b (280 mg), a yellow solid, with a yield of 25%. It was used directly in the next step without further purification.

LCMS(ESI-MS)m/z:311.1&313.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.95 (s, 1H), 8.45 (s, 1H), 8.18 (s, 1H), 7.92 (s, 1H), 3.85 (s, 3H).

The third step 6-(3,5-dimethylisoxazol-4-yl)-4H-thiophene[2',3':4,5]pyrrole[3,2-b]pyridine-2-carboxylic acid methyl Ester (55c)

Add 55b (280mg, 0.80mmol), 3,5-dimethylisoxazol-4-yl borate 55f (222mg, 0.99mmol), 0.9mL of 3M potassium phosphate solution and 5mL of tetrahydrofuran into a 50mL single-mouth flask. After nitrogen replacement, Pd(dppf)Cl ₂ (66 mg, 0.09 mmol) was added. Under nitrogen protection, react at 85°C for 5 hours. Let stand, separate the water layer, spin-dry the organic phase, add dichloromethane to make a slurry, and precipitate a yellow solid. The solid was filtered out to be 55c (380mg), the crude product, without further purification, it was used directly in the next step.

LCMS(ESI-MS)m/z:328[M+H] ⁺ .

The fourth step 6-(3,5-dimethylisoxazol-4-yl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-4H-thiophene[2' ,3':4,5]pyrrole[3,2-b]pyridine-2-carboxylic acid methyl ester (55d)

Dissolve 55c (275mg, 0.84mmol), phenyl-4-tetrahydropyranmethanol (179mg, 0.93mmol), triphenylphosphonium (440mg, 1.68mmol) in anhydrous 15mL THF, add DIAD( 340mg, 1.68mmol), after the addition, stir overnight at room temperature. The reaction solution was directly prepared and separated, and developed with PE/EA=2/1 (V/V) to obtain 55d (150mg), a yellow oily liquid, with a yield of 42%.

LCMS(ESI-MS)m/z:502.1[M+H] ⁺ .

Step 5 2-(6-(3,5-Dimethylisoxazol-4-yl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-4H-thiophene [2',3':4,5]pyrrole[3,2-b]pyridin-2-yl)propan-2-ol (55)

55d (150 mg, 0.30 mmol) was dissolved in 10 mL of anhydrous THF, and methylmagnesium bromide (3M 2-methyltetrahydrofuran solution, 2 mL) was added at 0°C. After the addition, stir overnight at room temperature. The reaction was quenched with saturated ammonium chloride, diluted with dichloromethane and filtered, the organic phase was spin-dried, the residue was prepared and separated, and developed with DCM/MeOH=20/1 (V/V) to obtain the target compound 55 (40mg) as a yellow solid. The yield was 27%.

LCMS(ESI-MS)m/z:502.1[M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δ8.57(s,1H), 8.43(s,1H), 7.62-7.67(m,3H), 7.20-7.32(m,3H), 5.64-5.67(d ,J=11.2Hz,1H),3.72-3.85(m,2H),3.38-3.43(m,1H),3.24-3.32(m,2H),2.45(s,3H),2.28(s,3H), 1.61 (s, 3H), 1.60 (s, 3H), 1.23-1.47 (m, 4H), 1.12-1.15 (m, 1H).

Example 56: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H- Pyran-4-yl)methyl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol

Using a synthetic method similar to that of Example 55, the title product 56 was obtained.

LCMS(ESI-MS) m/z: 499.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.22(dd,J=4.8,1.7Hz,2H), 7.60(d,J=7.1Hz,2H), 7.29(t,J=7.4Hz,2H) ,7.21(t,J=7.3Hz,1H),6.45(s,1H),5.42(d,J=11.2Hz,1H),5.33(s,1H),4.23(s,3H),3.99(s, 3H), 3.83 (dd, J = 17.3, 13.3 Hz, 2H), 3.42 (m, 2H), 3.07 (dd, J = 12.8, 8.1 Hz, 1H), 2.28 (s, 3H), 1.64 (d, J =5.6Hz,6H),1.35(m,4H).

Example 57: 6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran- 4-yl)methyl)-2-(prop-1-en-2-yl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b] Pyridine

The first step 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4 -Yl)methyl)-2-(prop-1-en-2-yl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridine (57)

Dissolve 56 (100 mg) in 10 mL of THF, and add NaOH (40 mg) at 0°C. After the addition, stir overnight at room temperature. Water (40 mL) was added, dichloromethane was added for extraction, the organic phase was spin-dried, the residue was prepared and separated, and developed with DCM/MeOH=20/1 (V/V) to obtain target compound 57 (20 mg) with a yield of 21%.

LCMS(ESI-MS)m/z:481.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.53(s,1H), 8.40(d,J=1.4Hz,1H), 7.65(d,J=7.2Hz,2H), 7.31(t,J= 7.4Hz, 2H), 7.23 (t, J = 7.3Hz, 1H), 6.85 (s, 1H), 5.53 (d, J = 11.3 Hz, 1H), 5.43 (s, 1H), 5.36 (s, 1H) ,4.09(s,3H),4.02(s,3H),3.83(dd,J=25.1,11.1Hz,2H), 3.40(qd,J=11.4,3.7Hz,2H), 3.15(m,1H), 2.30 (s, 3H), 2.24 (s, 3H), 1.34 (dd, J = 10.0, 5.8 Hz, 4H).

Example 58: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-4H-furo[2',3': 4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol

Using a synthetic method similar to that of Example 55, the title product 58 was obtained.

LCMS(ESI-MS)m/z:486.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ8.34(s,1H),7.66(s,1H),7.32(t,J=4.2Hz,5H),6.75(s,1H),5.09(d,J= 10.7Hz, 1H), 4.03 (m, 2H), 3.93 (s, 3H), 3.49 (m, 2H), 2.81 (s, 1H), 2.32 (s, 4H), 1.79 (s, 5H), 1.66 ( s, 1H), 1.48 (m, 4H).

Example 59: 2-Cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-ethyl-N-phenyl-N-( Tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-amine

The first step 2-bromo-4-iodo-6-nitroaniline (59b)

Methyl acetoacetate 59a (24.0 g, 110.4 mmol) was dissolved in a solution of acetic acid (50 mL), and then N-iodosuccinimide (NIS) (29.8 g, 132.5 mmol) was added. After the addition, heat to 50°C to react for 16h. Add 150mL of water, stir for 15min, filter, wash twice with petroleum ether, collect the solid, and spin to dry to obtain 2-bromo-4-iodo-6-nitroaniline 59b (37.0g), yellow solid, yield 97.9% .

LCMS(ESI-MS) m/z: 343.1[M+H] ⁺ .

The second step 3-bromo-5-iodo-1,2-diphenylamine (59c)

Put compound 59b (10g, 29.0mmol) in a single-neck flask, dissolve it with 120mL of THF, add Fe (9.0g, 145mmol), NH ₄ Cl (21.1g, 396mmol), and finally add EtOH/H ₂ O (120mL /60mL), heated to 90°C and refluxed for 2h. After the reaction, filter and concentrate the filtrate to obtain 3-bromo-5-iodo-1,2-diphenylamine 59c (9.0 g) as a white solid with a yield of 99%.

LCMS(ESI-MS)m/z:315.1[M+H] ⁺ .

The third step N-(2-amino-6-bromo-4-iodophenyl)cyclopropylformamide (59d)

Compound 59c (11.0g, 35.2mmol) was dissolved in 80mL THF, replaced with nitrogen, under ice-water bath conditions, Et ₃ N (10.2mL, 70.4mmol) was added, and cyclopropylformyl chloride (5.5g, 52.8mmol) was added dropwise ). Stir at room temperature overnight. Add water, EA extraction, drying, spin-drying through the column to obtain the target compound 59d (10.0g), the yield is 63%.

LCMS(ESI-MS)m/z:380.9[M+H] ⁺

The fourth step 4-bromo-2-cyclopropyl-6-iodo-1H-benzo[d]imidazole (59e)

To a 80 mL formic acid solution in which compound 59d (10.0 g, 26.2 mmol) was dissolved, it was heated to 120° C. and refluxed for 4 h. The reaction solution was spin-dried, sampled, and separated and removed by column to obtain 4-bromo-2-cyclopropyl-6-iodo-1H-benzo[d]imidazole 59e (4.6g) with a yield of 48%.

LCMS(ESI-MS) m/z: 364.9[M+H] ⁺ .

The fifth step 4-bromo-2-cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazole (59f )

Dissolve 59e (4.6g, 12.6mmol) in 10mL of anhydrous DMF, then add 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (5.3g, 13.8mmol), CuI (360mg, 1.89mmol), TEA (3.6mL, 25.2mmol) after adding Pd(PPh ₃ ) ₄ (1.4g, 1.26mmol) after nitrogen replacement, nitrogen replacement, heating to 95℃ for 7h . Spin to dry DMF, mix the sample, and pass through the column to obtain 4-bromo-2-cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H- The yield of benzo[d]imidazole 59f (2.0g) was 48.8%.

LCMS(ESI-MS)m/z:332[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.51-7.41 (m, 1H), 7.24 (d, J = 1.5Hz, 1H), 3.93 (s, 3H), 2.30 (s, 3H), 1.94 (d, J = 12.6Hz, 1H), 1.34-1.13 (m, 5H).

The sixth step 4-bromo-2-cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-ethyl-1H-benzo[ d) Imidazole (59g)

Dissolve 59f (1.0 g, 3.0 mmol) in 5 mL of anhydrous tetrahydrofuran, add iodoethane (701.8 mg, 4.5 mmol), NaH (240 mg, 6.0 mmol), and react at room temperature overnight. Rotate the solution to dryness, mix the sample, and pass the column to obtain 4-bromo-2-cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1- The yield of 59 g (1.0 g) of ethyl-1H-benzo[d]imidazole was 92.6%.

LCMS(ESI-MS)m/z:359.9[M+H] ⁺ .

The seventh step 2-cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-ethyl-N-phenyl-N-(tetra Hydrogen-2H-pyran-4-yl)-1H-benzo[d]imidazol-4-amine (59)

Add 59g(200mg, 0.56mmol), 59h(148mg, 0.84mmol), Pd2(dba)3(51mg, 0.056mmol, 0.1eq), XPhos(53mg, 0.112mmol, 0.2eq), Sodium t-amylate (123mg, 1.12mmol, 2.0eq), then add 10mL of anhydrous DME. After the addition, under nitrogen protection, react at 110°C for 2 hours. LCMS monitors the reaction. The solvent was spin-dried, the residue was dissolved in dichloromethane, TLC preparation and separation, DCM/MeOH=(20/1, V/V) development. The main product obtained is 59 (30 mg), a white solid, with a yield of 12%.

LCMS(ESI-MS)m/z:457.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 7.28-7.32 (m, 2H), 7.07-7.11 (t, J = 8.0 Hz, 1H), 6.97-6.99 (d, J = 8.0 Hz, 2H), 6.69 ( s,1H),6.04(s,1H),5.44(m,1H),4.26-4.28(m,2H),3.96-4.00(m,2H),3.78(s,3H),3.53-3.59(t, J = 11.6Hz, 2H), 2.21 (s, 3H), 1.97-2.02 (m, 3H), 1.55-1.65 (m, 2H), 1.44-1.48 (t, J = 7.2Hz, 3H), 1.01-1.23 (m,4H).

Example 60: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-4H-thieno[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol

Using a synthetic method similar to that of Example 55, the title product 60 was obtained.

LCMS(ESI-MS)m/z:502.1[M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ ) δ8.57(s,1H), 8.43(s,1H), 7.62-7.67(m,3H), 7.20-7.32(m,3H), 5.64-5.67(d ,J=11.2Hz,1H),3.73-3.86(m,2H),3.39-3.43(m,1H),3.26-3.29(m,2H),2.45(s,3H),2.27(s,3H), 1.61 (s, 3H), 1.60 (s, 3H), 1.39-1.44 (m, 2H), 1.26-1.36 (m, 2H), 1.09-1.14 (m, 1H).

Example 61: 7-(aziridin-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetra Hydrogen-2H-pyran-4-yl)methyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridine

The first step 2-((3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)amino)ethane-1-ol (61b)

61a (320mg, 0.67mmol) and ethanolamine (3mL) were added to the sealed tube and reacted at 120°C for 2 hours. After the reaction is complete, pour into 10 mL of water and stir for 30 min. The yellow solid was filtered out to be 10072a (309mg), the yield was 75%.

LCMS(ESI-MS)m/z:498.4[M+H] ⁺ .

The second step N-(2-chloroethyl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H -Pyran-4-yl)methyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-amine (61c)

61b (80 mg, 0.16 mmol) was dissolved in 15 mL of dichloromethane, 38 mg of thionyl chloride was added, and the mixture was stirred at room temperature overnight. Spin dry the solvent, which is 10072b, and use it directly in the next step.

LCMS(ESI-MS) m/z: 516.4[M+H] ⁺ .

The third step 7-(aziridin-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro -2H-pyran-4-yl)methyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridine(61)

Dissolve 61c (40mg, 0.078mmol) in 5mL DMF, add DIPEA (40mg, 0.32mmol), and react at 110°C for 4 hours. The reaction is monitored by LCMS. Reverse phase preparation and separation gave compound 61 (10 mg) as an off-white solid.

LCMS(ESI-MS) m/z: 480.3[M+H] ⁺ .

¹ H NMR (400MHz, MeOD) δ8.68 (d, J = 9.2Hz, 1H), 8.55 (s, 1H), 8.05 (s, 1H), 7.69-7.71 (m, 2H), 7.33-7.45 (m ,3H),6.90(d,J＝9.2Hz,1H),5.97(d,J＝11.2Hz,1H),5.31-5.42(m,2H),4.29(t,J＝8.4Hz,2H),3.97 –4.00(m,1H),3.85-3.80(m,4H),3.59(t,J=10.8Hz,1H),3.32-3.35(m,2H),2.11(s,3H),2.00-2.05(m ,1H), 1.53-1.69 (m, 2H), 0.84-0.89 (m, 1H).

Example 62: 4-(2-((3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyridine) (Pyran-4-yl)methyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)amino)ethyl)-1,3-dimethylpiperazine -2-one

The first step 2-(2-(2-methyl-3-carbonylpiperazin-1-yl)ethyl)isoindole-1,3-dione (62b)

Dissolve 3-methylpiperazin-2-one 23936-11-0 (5.0g, 43.9mmol), 574-98-1 (11.2g, 43.9mmol) in DMF (15mL), add DIPEA (11.3g, 87.8mmol). After the addition, stir at 110°C for 16 hours. After spinning off DMF, add 50 mL of ethyl acetate, separate the layers, wash the organic phase with citric acid (sat) (50 ml*2), and dry with anhydrous sodium sulfate. Filtration, spin-drying, column separation, DCM/MeOH=20/1 elution, 62b, 8.0g, yellow liquid, yield 64%.

LCMS(ESI-MS)m/z:288.2[M+H] ⁺ .

The second step 2-(2-(2,4-dimethyl-3-carbonylpiperazin-1-yl)ethyl)isoindole-1,3-dione (62c)

Compound 10073a (850mg, 2.96mmol) was dissolved in 10mL DMF, NaH (60% in Oil, 180mg, 4.44mmol) was added at 0°C, and stirred at this temperature for 1 hour. Add methyl iodide (505mg, 3.55mmol), after addition, stir overnight at room temperature. After the reaction was quenched, it was spin-dried and separated by column, eluted with DCM/MeOH=20/1 to obtain compound 62c (956 mg) as a brown oily liquid with a yield of 83%.

The third step 4-(2-aminoethyl)-1,3-dimethylpiperazin-2-one (62d)

Compound 62c (956 mg, 3.17 mmol) was dissolved in 1.5 mL of ethanol, and hydrazine hydrate (80%, 254 mg, 6.35 mmol) was added in batches. Stir at room temperature overnight. The precipitated white solid was filtered, filtered off, and washed with a small amount of ethanol. Combine the ethanol phases, spin dry, add acetonitrile until no solids are precipitated, filter, remove the acetonitrile solution, and spin dry. Add dichloromethane to the residue, let it stand for 10 min, and filter out the solid. The dichloromethane phase is spin-dried to give 10073c. Without further purification, about 550mg of 62d is obtained as a yellow oily liquid with a yield of 100%.

The fourth step 4-(2-((3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran) -4-yl)methyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)amino)ethyl)-1,3-dimethylpiperazine- 2-ketone (62)

In a 10mL microwave tube, add 62e (160mg, 0.34mmol), 62d (crude, 250mg), and dissolve it with 5mL NMP, and react in microwave at 170°C for 3 hours. LCMS monitors the reaction. Reversed phase preparation and separation, the target compound 10073, 40 mg, pale yellow solid, yield 15%.

LCMS(ESI-MS)m/z:473.3[M+H] ⁺ .

¹ H NMR(400MHz,MeOD)δ8.46(s,1H), 8.28–8.32(m,2H), 7.67-7.69(m,2H), 7.27–7.38(m,3H), 6.72(d,J= 8.8Hz,1H), 5.98(d,J=6.4Hz,1H), 3.97–4.13(m,6H), 3.72–3.88(m,2H), 3.38–3.68(m,8H), 2.99(s,3H) ), 2.28 (s, 3H), 1.82-1.86 (m, 1H), 1.50-1.60 (m, 4H), 1.20-1.44 (m, 4H).

Example 63: N1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-( Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)-N1-ethyl-N2-methyl Ethane-1,2-diamine

Using a synthesis method similar to that of Example 62, the title product 63 was prepared.

LCMS(ESI-MS) m/z: 571.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 8.32--8.34 (m, 2H), 8.11 (s, 1H), 7.70-7.73 (m, 1H), 7.48 (m, 1H), 7.10--7.15 (m, 1H) ), 6.97–7.02(m,1H), 8.60–8.62(d,J=8.0Hz,1H), 6.49(m,1H), 3.95(S,3H), 3.95(m,2H), 3.25(s, 3H), 3.20 (m, 1H), 2.96 (m, 1H), 2.72 (m, 1H), 2.28-2.32 (m, 4H), 1.93-1.97 (m, 1H), 1.47 (m, 4H), 1.40 (s,3H),1.12(t,3H),0.83-0.89(m,2H).

Example 64: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro- 2H-pyran-4-yl)ethyl)-7-(4-isopropylpiperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5-b']bipyridine

Using a synthetic method similar to that of Example 62, the title product 64 was prepared.

LCMS(ESI-MS)m/z:597.2[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.36(d,J=1.8Hz,1H), 8.21(d,J=8.8Hz,1H), 7.95(d,J=1.8Hz,1H), 7.90 (td,J=7.8,1.8Hz,1H), 7.29(m,1H), 7.21(td,J=7.6,1.3Hz,1H), 7.04(m,1H), 6.82(d,J=8.9Hz, 1H), 6.48 (dd, J = 10.6, 5.1 Hz, 1H), 3.86 (s, 3H), 3.75 (d, J = 10.7 Hz, 1H), 3.66 (m, 5H), 3.03 (m, 2H), 2.84(m,1H), 2.65-2.68(m,1H), 2.53(m,4H), 2.29-2.20(m,1H), 2.17(s,3H), 1.98(m,1H), 1.38(m, 1H),1.25(s,3H),0.97(d,J=6.5Hz,6H).

Example 65: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro- 2H-pyran-4-yl)ethyl)-7-(4-(1-isopropylpiperidin-4-yl)piperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5-b']dipyridine

Using a synthesis method similar to that of Example 62, the title product 65 was prepared.

LCMS(ESI-MS) m/z: 680.3[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.36(d,J=1.7Hz,1H), 8.21(d,J=8.8Hz,1H), 7.96-7.86(m,2H), 7.28(dd, J=7.6,5.2Hz,1H), 7.21(dd,J=8.1,6.8Hz,1H), 7.07–7.00(m,1H), 6.82(d,J=8.9Hz,1H), 6.47(dd,J = 10.5, 5.0 Hz, 1H), 3.78–3.58 (m, 6H), 3.13 (s, 1H), 3.03 (d, J = 10.7 Hz, 2H), 2.78 (d, J = 11.6 Hz, 3H), 2.64 –2.54(m,4H),2.16(s,3H),2.02(q,J=14.0,12.6Hz,4H),1.73(d,J=11.5Hz,2H),1.31(d,J=47.6Hz, 6H),0.91(d,J=6.5Hz,6H).

Example 66: 4-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-( Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b: 4,5-b']bispyridin-7-yl)morpholine

Using a synthetic method similar to that of Example 62, the title product 66 was prepared.

LCMS(ESI-MS)m/z:556.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.38 (d, J = 1.7 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.99 (s, 1H), 7.90 (td, J = 7.8,1.7Hz,1H),7.33-7.25(m,1H),7.21(td,J=7.5,1.3Hz,1H),7.04(m,1H),6.83(d,J=8.8Hz,1H), 6.48(dd,J=10.6,5.1Hz,1H), 3.87(s,3H), 3.77–3.69(m,5H), 3.60-3.67(m,4H), 3.00-3.05(m,2H), 2.83( t, J = 12.3 Hz, 1H), 2.30–2.21 (m, 1H), 2.17 (s, 3H), 1.97 (d, J = 9.2 Hz, 1H), 1.45–1.35 (m, 1H), 1.22-1.18 (m,4H).

Example 67: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-7-(4-(1-ethylpiperidin-4-yl)piperazine -1-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b: 4 ,5-b']bispyridine

Using a synthetic method similar to that of Example 62, the title product 67 was obtained.

LCMS(ESI-MS) m/z: 666.4[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.36(d,J=1.7Hz,1H), 8.21(d,J=8.8Hz,1H), 7.97-7.85(m,2H), 7.34-7.25( m, 1H), 7.21 (td, J = 7.5, 1.3 Hz, 1H), 7.04 (m, 1H), 6.82 (d, J = 8.9 Hz, 1H), 6.47 (dd, J = 10.6, 4.9 Hz, 1H) ), 3.75 (d, J = 10.7 Hz, 1H), 3.67 (d, J = 9.0 Hz, 2H), 3.13 (s, 1H), 3.03 (d, J = 10.6 Hz, 2H), 2.87 (d, J =11.0Hz,4H),2.56-2.59(m,5H),2.23-2.26(m,3H),2.16(s,3H),1.95-1.98(m,1H),1.84-1.69(m,4H), 1.46–1.35(m,4H),1.22-1.23(m,6H),0.95(t,J=7.2Hz,3H).

Example 68: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro- 2H-pyran-4-yl)ethyl)-7-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5-b']bispyridine

Using a synthetic method similar to that of Example 62, the title product 68 was prepared.

LCMS(ESI-MS) m/z: 639.3[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.36(d,J=1.7Hz,1H), 8.21(d,J=8.8Hz,1H), 7.98–7.93(m,1H), 7.90(td, J = 7.8, 1.8 Hz, 1H), 7.29 (tdd, J = 7.5, 5.2, 1.8 Hz, 1H), 7.21 (td, J = 7.5, 1.3 Hz, 1H), 7.04 (ddd, J = 10.7, 8.1, 1.3Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.48 (dd, J = 10.7, 5.0 Hz, 1H), 3.86 (s, 4H), 3.75 (d, J = 10.6 Hz, 1H) , 3.67 (d, J = 10.6Hz, 4H), 3.28–3.19 (m, 2H), 3.03 (q, J = 10.2Hz, 2H), 2.84 (t, J = 12.3Hz, 1H), 2.58 (s, 4H), 2.40(s, 1H), 2.28–2.20(m, 1H), 2.17(s, 3H), 1.98(d, J=9.5Hz, 1H), 1.76–1.64(m, 2H), 1.40(d ,J=13.0Hz,3H), 1.30–1.20(m,3H).

Example 69: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro- 2H-pyran-4-yl)ethyl)-7-(4-methylpiperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5-b']bipyridine

Using a synthesis method similar to that of Example 62, the title product 69 was prepared.

LCMS(ESI-MS) m/z: 569.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.40 (d, J = 1.7Hz, 1H), 8.25 (d, J = 8.8Hz, 1H), 7.94-7.98 (m, 2H), 7.32 (tdd, J = 7.3, 5.2, 1.7 Hz, 1H), 7.24 (td, J = 7.6, 1.3 Hz, 1H), 7.07-7.09 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.52 (dd ,J＝10.7,5.0Hz,1H),3.89(s,3H),3.78(d,J＝10.7Hz,1H),3.75–3.65(m,4H),3.14–2.98(m,2H),2.86( t, J = 12.3 Hz, 1H), 2.45 (d, J = 5.2 Hz, 4H), 2.28 (d, J = 5.8 Hz, 1H), 2.24 (s, 3H), 2.20 (s, 3H), 2.01 ( d,J=9.3Hz,1H), 1.48–1.36(m,1H), 1.29(s,3H), 1.22(s,1H).

Example 70: 7-(4-(1-cyclopropylpiperidin-4-yl)piperazin-1-yl)-3-(1,4-dimethyl-1H-1,2,3-tri Azol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b: 4,5-b']bispyridine

Using a synthesis method similar to that of Example 62, the title product 70 was prepared.

LCMS(ESI-MS) m/z: 678.6[M+H] ⁺ .

¹ H NMR(600MHz,DMSO-d ₆ )δ8.53–8.31(m,2H), 8.10(s,1H), 7.96(td,J=7.8,1.8Hz,1H), 7.39–7.23(m,2H) ), 7.13-6.96 (m, 2H), 6.53 (dd, J = 10.6, 5.3 Hz, 1H), 3.90 (s, 3H), 3.60-3.45 (m, 6H), 3.18-3.21 (m, 2H), 3.09-3.13(m,4H), 2.91–2.74(m,2H), 2.38–2.30(m,2H),2.21(s,3H), 2.00–1.96(m,3H), 1.46–1.39(m,1H) ), 1.26-1.29 (m, 9H), 0.98-0.99 (m, 2H), 0.82-0.85 (m, 2H).

Example 71: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro- 2H-pyran-4-yl)ethyl)-7-(4-(1-methylpiperazin-4-yl)piperidin-1-yl)-5H-pyrrolo[2,3-b: 4 ,5-b']dipyridine

Using a synthetic method similar to that of Example 62, the title product 71 was prepared.

LCLCMS(ESI-MS)m/z:652.6[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.36 (d, J = 1.8 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.97-7.85 (m, 2H), 7.34-7.17 ( m, 2H), 7.04 (dd, J = 10.6, 8.1 Hz, 1H), 6.82 (d, J = 8.9 Hz, 1H), 6.43-6.51 (m, 1H), 3.86 (s, 3H), 3.74 (d ,J=11.0Hz,1H),3.64-3.67(m,5H),3.00-3.03(m,1H),2.74-2.83(m,3H),2.50-2.57(m,4H),2.14-2.30(m ,7H),1.98-1.89(m,3H),1.71-1.73(m,2H),1.49-1.32(m,3H),1.22(m,5H).

Example 72: 2-(4-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-(phenyl(tetrahydro-2H-pyridine) (Pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)phenyl)propyl-2-ol

The first step is methyl 4-(6-bromo-1H-imidazo[4,5-b]pyridin-2-yl)benzoate (72c)

To a solution of methyl 4-formylbenzoate (8.2g, 50mmol) and 5-bromopyridine-2,3-diamine (9.4g, 50mmol) in DMF (200mL) was added Na ₂ S ₂ O ₇ (11.1g , 50mmol), heated to 130°C for 5 hours, cooled to room temperature, diluted with EA (2L), washed with water (1.0L*5), dried with Na2SO4, filtered, concentrated, Flash column (PE/EA 0-100%) Compound 72c (8.6 g, 24.4 mmol) was obtained with a yield of 51.8%.

LCMS(ESI-MS) m/z: 333.9[M+H] ⁺ .

The second step 4-(6-bromo-1-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)benzene Methyl formate (72d)

A solution of 72c (2g, 6mmol) and phenyl(tetrahydro-2H-pyran-4-yl)methanol (1.3g, 6.6mmol) in THF (50mL) was cooled to 0°C, and triphenylphosphonium (1.9g , 7.2mmol), stir for 15 minutes, add DIAD (1.5g, 7.2mmol) dropwise, continue to stir for 1 hour, raise to room temperature and stir overnight. Flash column chromatography purification (PE/EA 0-100%) yielded 72d (400mg, 0.79mmol) with a yield of 13.1%.

LCMS(ESI-MS)m/z:508.2[M+H] ⁺ .

The third step 4-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl benzoate (72e)

Under nitrogen, compound 72d (400mg, 0.79mmol), 1,4-dimethyl-5-(tributyltinyl)-1H-1,2,3-triazole (600mg, 1.55mmol) and four (three A solution of phenylphosphorus) palladium (100mg, 0.08mmol) in DMF (10mL) was heated to 100°C for 2 hours. After cooling, it was diluted with ethyl acetate (100mL), washed with water (100mL*3), dried with Na2SO4, filtered, and concentrated. Flash column (PE/EA 0-100%) to obtain compound 72e (280 mg, 0.54 mmol) with a yield of 67.9%.

LCMS(ESI-MS)m/z:523.3[M+H] ⁺ .

The fourth step 2-(4-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-(phenyl(tetrahydro-2H-pyran) -4-yl)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)phenyl)propyl-2-ol (72)

Under nitrogen, the THF (10mL) solution of compound 72e (280mg, 0.54mmol) was cooled to 0°C, methylmagnesium bromide (1mL, 2.5mmol) was added dropwise, and the reaction was stirred at room temperature for 2 hours. Flash was passed through the column (PE/EA 0-100%) to obtain the title compound 72 (80 mg, 0.15 mmol) with a yield of 28.6%.

LCMS(ESI-MS) m/z: 523.4[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.60(d,J=2.0Hz,1H), 8.33(d,J=2.0Hz,1H), 7.75(d,J=8.4Hz,2H), 7.69 –7.60(m,2H),7.56(d,J=8.4Hz,2H),7.35(d,J=7.7Hz,2H),7.33-7.28(m,1H), 5.25(s,1H), 5.12( d, J = 11.1Hz, 1H), 4.01 (s, 3H), 3.77 (d, J = 11.0 Hz, 2H), 3.72–3.62 (m, 1H), 3.30–3.05 (m, 2H), 2.30 (s ,3H),1.54(s,6H),1.30-0.95(m,4H).

Example 73: 2-(4-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-3-(phenyl(tetrahydro-2H-pyridine) (Pyran-4-yl)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)propyl-2-ol

The first step 4-(6-Bromo-3-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzene Methyl formate (73b)

A solution of 73a (2g, 6mmol) and phenyl(tetrahydro-2H-pyran-4-yl)methanol (1.3g, 6.6mmol) in THF (50mL) was cooled to 0°C, and triphenylphosphonium (1.9g , 7.2mmol), stir for 15 minutes, add DIAD (1.5g, 7.2mmol) dropwise, continue to stir for 1 hour, raise to room temperature and stir overnight. Flash column chromatography purification (PE/EA 0-100%) to obtain 73b (300 mg, 0.59 mmol) with a yield of 9.8%.

LCMS(ESI-MS)m/z:508.2[M+H] ⁺ .

The second step 4-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl benzoate (73c)

Under nitrogen, compound 73b (300mg, 0.59mmol), 1,4-dimethyl-5-(tributyltinyl)-1H-1,2,3-triazole (450mg, 1.17mmol) and four (three Phenylphosphorus) palladium (100mg, 0.08mmol) in DMF (10mL) solution was heated to 100°C for 2 hours, cooled and diluted with ethyl acetate (100mL), washed with water (100mL*3), dried over Na ₂ SO ₄ , filtered , Concentration, Flash column (PE/EA 0-100%) to obtain compound 73c (190 mg, 0.36 mmol) with a yield of 61.4%.

LCMS(ESI-MS)m/z:523.5[M+H] ⁺ .

The third step 2-(4-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3-(phenyl(tetrahydro-2H-pyran) -4-yl)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)propyl-2-ol (73)

Under nitrogen, a solution of compound 73c (190mg, 0.54mmol) in THF (10mL) was cooled to 0°C, methylmagnesium bromide (1mL, 2.5mmol) was added dropwise, and the reaction was stirred at room temperature for 2 hours. Flash was passed through the column (DCM/MeOH0 ~10%) to obtain the title compound 73 (40 mg, 0.077 mmol) with a yield of 21.1%.

LCMS(ESI-MS) m/z: 523.4[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.69(d,J=1.5Hz,1H), 8.39(d,J=8.4Hz,2H), 8.33(d,J=1.3Hz,1H), 7.89 –7.85(m,2H),7.64(d,J=8.4Hz,2H),7.42(t,J=7.3Hz,2H),7.36(d,J=7.3Hz,1H), 6.28(d,J= 11.6Hz, 1H), 5.12 (s, 1H), 3.98 (s, 3H), 3.92-3.80 (m, 2H), 3.46-3.35 (m, 2H), 3.28 (dd, J = 11.5, 2.6 Hz, 1H ), 2.24(s, 3H), 1.49(s, 6H), 1.43-1.21(m, 4H).

Example 74: 8-(3,5-Dimethylisoxazol-4-yl)-10-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl) )Ethyl)-3-methyl-1,2,3,10-tetrahydrocyclopenta[g]pyrido[3,2-b]indol-3-ol

The first step 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indene-1- Ketone (74b)

Take a 500mL single-mouth flask, add compound 74a (30g, 0.14mmol), borate (54g, 1.5mmol), potassium acetate (40g.3.0mmol), pd(pddf)cl2 (5g.0.07mmol), and dissolve with tetrahydrofuran, N2 gas protection, react for one hour at 80 degrees. After the post-treatment, the solid was filtered out, and the sample was directly mixed through the Flash column to obtain about 30 g of compound 74b with a yield of 83%.

The second step 5-(5-bromo-3-nitropyridin-2-yl)-2,3-dihydro-1H-inden-1-one (74c)

Take a 500mL single-mouth flask, add compound 74b (30g, 0.12mmol), 3-nitro, 2,5-dibromopyridine (32g, 0.12mmol), potassium phosphate (48g.0.34mmol), pd(pddf)cl2(5g , 0.07mmol), dissolved with dioxane, protected by N ₂ gas, reacted at 100 degrees for one hour. After the post-treatment, the solid was filtered out, and the sample was directly mixed through the Flash column to obtain 18 g of compound 74c with a yield of 78%.

LCMS(ESI-MS)m/z:332.0[M+H] ⁺ .

The third step 8-bromo-1,10-dihydrocyclopenta[g]pyrido[3,2-b]indole-3(2H)-one (74d)

Take a 100ml single-mouth bottle, take compound 74c (2g.0.006mmol), triethyl phosphite (3g.0.18mmol), dissolve it with 10ml dichlorobenzene, react at 140°C for 2 hours, filter, and wash with DCM to obtain 74d 1g. Used directly in the next step.

LCMS(ESI-MS)m/z:301.9[M+H] ⁺ .

The fourth step 8-bromo-10-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-1,10dihydrocyclopenta[g] Pyrido[3,2-b]indole-3-(2H)-one (74e)

Take a 50ml three-necked flask, under anhydrous and oxygen-free conditions, add compound 74d (1g.0.003mmol), compound 7 (1.5g, 0.006mmol).TMAD (600mg.0.006mmol), Bu3P (700mg.0.006mmol), Dissolved in DCM, reacted overnight, washed, and passed through the column to obtain compound 74e.

LCMS(ESI-MS)m/z:506.1[M+H] ⁺ .

The fifth step 8-bromo-10-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-methyl1,2,3,10 Tetrahydrocyclopenta[g]pyrido[3,2-b]indol-3-ol (74f)

Take a 50mL three-necked flask, add compound 74e (500mg, 1mmol), dissolve it in anhydrous DCM (50ml), add methylmagnesium bromide (13ml, 10mmol) under a dry ice bath, and react overnight. It is determined that the raw material has reacted completely and there are new points. generate. The reaction solution was quenched with ammonium chloride, extracted with DCM, dried over anhydrous sodium sulfate, and passed through the column compound 74f.

LCMS(ESI-MS)m/z:522.2[M+H] ⁺ .

Step 6 8-(3,5-Dimethylisoxazol-4-yl)-10-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl Yl)-3-methyl-1,2,3-,10-tetrahydrocyclopenta[g]pyrido[3,2-b]indol-3-ol (74)

Take a 50mL single-mouth bottle, add compound 74f (70mg.0.13mmol), borate (207mg.0.53mmol), CSF (52mg, 0.53mmol). PD(DBA) (12mg, 0.02mmol), use 1.4-dioxane The ring was dissolved, and the mixture was stirred and refluxed at 100°C under N2 protection for 1 hour. LCMS monitoring showed that the reaction was complete, and the target compound 74 (15 mg) was obtained as a white solid after passing through a Flash column.

LCMS(ESI-MS) m/z: 540.4[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )δ8.41(s,2H),7.58(s,1H),7.41(d,J=7.7Hz,1H), 7.30(d,J=7.7Hz,2H), 7.16 –7.00(m,2H),6.57(t,J=7.6Hz,1H),3.84-3.82(m,2H),3.48-3.46(m,1H),3.35-3.30(m,1H),3.15-3.13 (m, 2H), 2.40-2.30 (m, 7H), 2.19 (s, 3H), 1.91-1.88 (m, 1H), 1.42-1.40 (m, 2H), 1.33-1.30 (m, 2H), 1.23 -1.20(m,3H).

Example 75: 8-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-fluoro-10-(phenyl(tetrahydro-2H-pyran-4 -Yl)methyl)-1,10-dihydrocyclopenta[g]pyrido[3,2-b]indole-3(2H)-one

The first step 7-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H- Inden-1-one (81b)

Compound 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one 81a (5g, 21.834mmol) dual pinacol borate (11.091g, 43.668mmol), [1,1 '-Bis(diphenylphosphino)ferrocene]palladium dichloride (1.596g, 2.1834mmol), potassium acetate (6.419g, 65.502mmol) were dissolved in 1,4-dioxane (150mL). Under argon protection, react at 100°C for 3h. After the reaction, the solvent was spinned to dryness, water was added and extracted 3 times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and column chromatography was purified to obtain the title compound 81b (3.9 g, 14.13 mmol) with a yield of 64.7%.

LCMS(ESI-MS)m/z:195.2[M+H] ⁺ .

The second step 5-(5-bromo-3-nitropyridin-2-yl)-7-fluoro-2,3-dihydro-1H-inden-1-one (81c)

Compound 81b (3.6g, 13.043mmol), compound 2,5-dibromo-3-nitropyridine (3.665g, 13.043mmol), [1,1'-bis(diphenylphosphino)ferrocene] two Palladium chloride (953mg, 1.3043mmol) and potassium phosphate (8.295g, 39.129mmol) were dissolved in N,N-dimethylformamide (50mL), protected with argon, and reacted at 50°C for 5h. Post-treatment: spin-dry part of the solvent, add water and extract 3 times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and purify by column chromatography to obtain the title compound 81c (2g, 5.698mmol) with a yield of 43%.

LCMS(ESI-MS)m/z:351.1[M+H] ⁺ .

The third step 8-bromo-4-fluoro-1,10-dihydrocyclopenta[g]pyrido[3,2-b]indole-3(2H)-one(81d)

Compound 83c (2.5 g, 7.122 mmol) was dissolved in o-dichlorobenzene (20 mL), triethyl phosphite (3.547 g, 21.366 mmol) was added, and the reaction was heated at 140° C. for 5 h. After the reaction was completed, it was cooled to room temperature, and the product was precipitated. The solvent was filtered and washed with ethyl acetate to obtain the title compound 81d (580 mg, 1.81 mmol) with a yield of 25%.

LCMS(ESI-MS)m/z:321.1[M+H] ⁺ .

The fourth step 8-bromo-4-fluoro-10-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,10-dihydrocyclopenta[g]pyrido[ 3,2-b)indole-3(2H)-one(81e)

Compound 81d (580mg, 1.818mmol) and phenyl(tetrahydro-2H-pyran-4-yl)methanol (1047mg, 5.454mmol) were added to a three-neck flask, replaced with argon, and dissolved in dichloromethane (30mL). Add triphenylphosphine (1101mg, 5.454mmol), then add N,N,N',N'-tetramethylazodicarbonamide (938mg, 5.454mmol), stir at room temperature for 12h. Water was added and extracted with dichloromethane three times, the organic phase was dried with anhydrous sodium sulfate, and purified by column chromatography to obtain the title compound 81e (78 mg, 0.158 mmol), the yield was 8.7%.

LCMS(ESI-MS) m/z: 459.2[M+H] ⁺ .

The fifth step 8-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-fluoro-10-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-1,10-dihydrocyclopenta[g]pyrido[3,2-b]indole-3(2H)-one(81)

Compound 81e (78mg, 0.158mmol), 1,4-Dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (183mg, 0.474mmol), tris(dibenzylideneacetone) ) Dipalladium (15mg, 0.0158mmol) and tricyclohexylphosphine (9mg, 0.0316mmol), potassium fluoride (96mg, 0.632mmol) dissolved in 1,4-dioxane (6mL), argon protection, 100 React at ℃ for 1h. Cool to room temperature, add water and extract twice with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and purify by column chromatography to obtain the title compound 10081 (26 mg, 0.051 mmol), yield 32.5%.

LCMS(ESI-MS) m/z: 510.4[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.58(d,J=1.6Hz,1H), 8.24(d,J=1.7Hz,1H), 7.94(d,J=9.0Hz,1H), 7.66 (d,J=7.6Hz,2H),7.32-7.24(m,3H),5.86(d,J=11.3Hz,1H), 3.89(s,3H), 3.85–3.70(m,3H), 3.49- 3.46 (m, 2H), 3.22-3.26 (m, 1H), 2.89-2.87 (m, 2H), 2.18 (s, 3H), 1.80-1.78 (m, 1H), 1.48-1.43 (m, 3H), 0.87-0.90(m,1H).

Example 76: 10-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4 -(Yl)methyl)-8,9-dihydrocyclopenta[f]pyrido[3,2-b]indole-7(5H)-one

The first step (3-bromo-2-chlorophenyl)methanol (76b)

Compound 3-bromo-2-chlorobenzoic acid 76a (50 g, 212.7 mmol) was dissolved in tetrahydrofuran (80 mL), and borane/tetrahydrofuran complex 1M solution (640 mL, 640 mmol) was slowly added under ice-water bath and stirred at room temperature for 5 h. The reaction was quenched by adding water, extracted with ethyl acetate 3 times, dried with anhydrous sodium sulfate, and concentrated to obtain the title compound 76b (445.1 g, 204.2 mmol), yield 96%.

Step 2 3-bromo-2-chlorobenzaldehyde (76c)

Compound (3-bromo-2-chlorophenyl)methanol 76b (45.1g, 204.2mmol) solution was added to dichloromethane (100mL), and manganese dioxide (87.6g, 1.01mol) was added and stirred at room temperature for 12h. The reaction was completely filtered to remove manganese dioxide, dried dichloromethane, water was added and extracted with ethyl acetate 3 times, the organic phase was dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title compound 76c (43.8 g, 200.1 mmol) with a yield of 98%.

The third step 3-(3-bromo-2-chlorophenyl)propionic acid (76d)

Triethylamine (24.2g, 240.1mmol) was added to formic acid (27.6g, 600.3mmol) under ice bath, and stirred at room temperature for 30min. Compound 3-bromo-2-chlorobenzaldehyde 76c (43.8g, 200.1mmol) and compound 2,2-dimethyl-1,3-dioxane-4,6-dione (28.8g, 200.1mmol), Dissolve in 150mL of N,N-dimethylformamide, add it to the reaction flask, and react at 100°C for 6h. After the reaction is complete, adjust the pH to 2 with dilute hydrochloric acid solution, extract twice with dichloromethane, wash the organic phase twice with sodium hydroxide solution, and adjust the pH to 2 with dilute hydrochloric acid solution. The product is precipitated and filtered to obtain the title compound 76d (47.3g, 180.1mmol) The yield was 90%.

Step 4 3-(3-Bromo-2-chlorophenyl)propionyl chloride (76e)

Compound 3-(3-bromo-2-chlorophenyl)propionic acid 83d (47.3g, 180.1mmol) was dissolved in dichloromethane (50mL), thionyl chloride (42.8g, 360.2mmol) was added and heated at 50℃ and stirred 2h. The solvent was spin-dried to obtain the title compound 76e (50.5 g, 180.1 mmol) with a yield of 100%.

Step 5 5-Bromo-4-chloro-2,3-dihydro-1H-inden-1-one (76f)

The compound aluminum trichloride (71.8g, 540.3mmol) was dissolved in dichloromethane (200mL), and the compound 3-(3-bromo-2-chlorophenyl)propionyl chloride 76e (50.5g, 180.1mmol) was dissolved in dichloromethane. Methane (50 mL) was slowly added dropwise to the aluminum trichloride solution under ice bath. The reaction was stirred at room temperature for 3h. Dilute hydrochloric acid solution was added to make the pH weakly acidic, extracted with dichloromethane three times, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain the title compound 76f (20.2g, 82.4mmol), yield 45.7%.

The sixth step 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H- Indan-1-one (76g)

Compound 5-bromo-4-chloro-2,3-dihydro-1H-inden-1-one 76f (20.2g, 82.4mmol) and double pinacol borate (41.7g, 164.4mmol), [1 ,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6g, 8.2mmol), potassium acetate (16.1g, 164.4mmol) dissolved in 1,4-dioxane (150mL) . Under argon protection, react at 100°C for 3h. After the reaction, the solvent was spin-dried, water was added and extracted 3 times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 76 g (21.6 g, 73.9 mmol) of the title compound with a yield of 89.7%.

Step 7 5-(5-Bromo-3-nitropyridin-2-yl)-4-chloro-2,3-dihydro-1H-inden-1-one (76h)

The compound 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indene- 1-ketone 76g (21.6g, 73.9mmol), compound 2,5-dibromo-3-nitropyridine (20.8g, 73.9mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (5.4g, 7.39mmol) and potassium phosphate (148.1mmol) were dissolved in N,N-dimethylformamide (150mL), protected with argon, and reacted at 50°C for 5h. Post-treatment: spin-dry part of the solvent, add water and extract 3 times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and purify by column chromatography to obtain the title compound 76h (9.2 g, 25.1 mmol) with a yield of 33%.

LCMS(ESI-MS) m/z: 366.9[M+H] ⁺ .

Step 8 3-Bromo-10-chloro-8,9-dihydrocyclopenta[f]pyrido[3,2-b]indole-7(5H)-one(76i)

Compound 5-(5-bromo-3-nitropyridin-2-yl)-4-chloro-2,3-dihydro-1H-inden-1-one 76h (9.2g, 25.1mmol) dissolved in o-dichloro To benzene (40 mL), triethyl phosphite (12.4 g, 76.8 mmol) was added, and the reaction was heated at 140° C. for 5 h. After the reaction was completed, it was cooled to room temperature, and the product was precipitated. The solvent was filtered and washed with ethyl acetate to obtain the title compound 76i (1.8 g, 5.3 mmol) with a yield of 21.1%.

LCMS(ESI-MS) m/z: 335.0[M+H] ⁺ .

Step 9 3-Bromo-10-chloro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-8,9-dihydrocyclopenta[f]pyrido[ 3,2-b)indole-7(5H)-one (76j)

The compound 3-bromo-10-chloro-8,9-dihydrocyclopenta[f]pyrido[3,2-b]indole-7(5H)-one 83i (1.8g, 5.3mmol) and The compound phenyl(tetrahydro-2H-pyran-4-yl)methanol (2.1g, 10.6mmol) was added to a three-necked flask, replaced with argon, dissolved with dichloromethane (50mL), and added triphenylphosphine (3.2 g, 15.9mmol), then add N,N,N',N'-tetramethylazodicarbonamide (2.7g, 15.9mmol), and stir at room temperature for 12h. Water was added and extracted with dichloromethane three times, the organic phase was dried with anhydrous sodium sulfate, and purified by column chromatography to obtain the title compound 76j (0.6 g, 1.2 mmol), yield 22.6%.

LCMS(ESI-MS) m/z: 509.2[M+H] ⁺ .

The tenth step 10-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-8,9-dihydrocyclopenta[f]pyrido[3,2-b]indole-7(5H)-one(76)

The compound 3-bromo-10-chloro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-8,9-dihydrocyclopenta[f]pyrido[3, 2-b]Indole-7(5H)-one 76j (0.6g, 1.2mmol), compound 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (0.9g, 2.4mmol), tris(dibenzylideneacetone)dipalladium (107mg, 0.12mmol) and tricyclohexylphosphine (66mg, 0.24mmol) were dissolved in 1,4-dioxane (20mL), Under argon protection, react at 100°C for 3h. Cool to room temperature, add water and extract twice with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and purify by column chromatography to obtain the title compound 76 (160 mg, 0.3 mmol), yield 25%.

LCMS(ESI-MS)m/z:526.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.66 (s, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 7.43 (s, 1H), 7.41 (s, 1H), 7.35 to 7.34 ( m,3H), 5.59(d,J=11.6Hz,1H),4.05-4.03(m,1H),3.90(s,3H),3.83-3.80(m,1H),3.57–3.49(m,1H) ,3.39–3.34(m,2H),3.10-3.12(m,1H),2.92-2.90(m,2H),2.31(s,3H),2.04–1.99(m,1H),1.63-1.60(m, 2H), 1.39-1.36 (m, 2H).

Example 77: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl Base)-5,7,8,9-tetrahydrocyclopenta[f]pyrido[3,2-b]indole

The first step 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl )-5,7,8,9-Tetrahydrocyclopenta[f]pyrido[3,2-b]indole(77)

Compound 10-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl) Methyl)-8,9-dihydrocyclopenta[f]pyrido[3,2-b]indole-7(5H)-one 10083 (50mg, 0.095mmol) dissolved in dichloromethane (10mL ), hydrogen replacement, stirring at room temperature for 48h. The palladium-carbon was removed by filtration, concentrated and purified by thin layer chromatography to obtain the title compound 77 (5.8 mg, 0.012 mmol) with a yield of 12.6%.

LCMS(ESI-MS)m/z:478.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 8.38 (s, 1H), 8.28 (s, 1H), 7.55-7.53 (m, 2H), 7.41-7.43 (m, 2H), 7.35-7.26 (m, 3H) ), 5.48 (d, J = 10.6 Hz, 1H), 4.03-4.02 (m, 1H), 3.85 (s, 3H), 3.81-3.83 (m, 1H), 3.52-3.50 (m, 1H), 3.32 ( s,1H),3.12-3.10(m,6H),2.26(s,3H),2.21-2.25(m,2H),2.03-1.98(m,1H),1.57-1.59(m,2H),1.00- 1.05(m,1H).

Example 78: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl Yl)-5,7,8,9-tetrahydrocyclopenta[f]pyrido[3,2-b]indole-7-ol

The first step 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl )-5,7,8,9-tetrahydrocyclopenta[f]pyrido[3,2-b]indole-7-ol(78)

Compound 10-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl) Methyl)-8,9-dihydrocyclopenta[f]pyrido[3,2-b]indole-7(5H)-one 10083 (50mg, 0.095mmol) dissolved in dichloromethane (10mL ), hydrogen replacement, stirring at room temperature for 48h. The palladium-carbon was removed by filtration, concentrated and purified by thin layer chromatography to obtain the title compound 10087 (10.2 mg, 0.021 mmol) with a yield of 22.1%.

LCMS(ESI-MS)m/z:494.4[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.46(d,J=1.5Hz,1H), 8.36(s,1H), 8.03-8.01(m,2H), 7.65-7.60(m,2H), 7.30–7.19(m,3H), 5.80–5.73(m,1H), 5.45(s,1H), 5.21-5.19(m,1H), 3.97(s,3H), 3.88-3.85(m,1H), 3.72-3.68(m,1H),3.46-3.56(m,2H),3.06-3.02(m,1H),2.88-2.70(m,1H),2.46-2.56(m,1H),2.30(s,3H) ), 1.91-1.88 (m, 1H), 1.67-1.60 (m, 1H), 1.56-1.53 (m, 1H), 1.28-1.26 (m, 1H), 1.00-0.95 (m, 1H).

Example 79: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-fluorophenyl)(tetrahydro-2H- Pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl) Propane-2-ol

The first step (4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanone (79b)

Compound 79a (4.0 g, 23.1 mmol) was dissolved in 20 mL of anhydrous THF, and p-fluorophenyl magnesium bromide (25.4 mL, 25.4 mmol) was added at -5°C. After the addition, stir at room temperature for 16 hours. The reaction was quenched with saturated ammonium chloride solution, layered with EA/H2O, the organic phase was collected, dried, filtered, spin-dried solvent, column separation, PE/EA=4/1(V/V) eluted to obtain the target compound 79b( 2.0g), white solid, yield 43%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.03-8.06 (m, 2H), 7.29-7.34 (m, 2H), 3.82-3.86 (m, 2H), 3.61--3.66 (m, 1H), 3.42 -3.48(m,2H),1.48-1.46(m,4H)

The second step (4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (79c)

79b (2.0 g, 9.6 mmol) was dissolved in 10 mL of methanol, cooled to 0° C., sodium borohydride (401 mg, 10.6 mmol) was added, and the reaction was completed at room temperature for 2 hours. Column separation, PE/EA=1/1 (V/V) elution, to obtain the target compound 79c (1.57g), a colorless oil, the yield is 79%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.25-7.30(m,2H), 7.06-7.12(m,2H), 5.20-5.22(d,J=4.4Hz,1H), 4.21-4.23(m ,1H), 3.78–3.83(m,1H), 3.71–3.75(m,1H), 3.08–3.09(m,2H), 1.56–1.66(m,2H), 1.00-1.26(m,3H).

The third step is methyl 6-bromo-4-((4-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrrolo[ 2',3':4,5]pyrrolo[3,2-b]pyridine-2-carboxylate (79e)

Compound 79d (308mg, 1.23mmol), 79c (260mg, 1.23mmol), (Bu)3P (745mg, 3.69mmol) were dissolved in 10mL of anhydrous THF, the system was yellow and clear. At room temperature, TMSD (635 mg, 3.69 mmol) in 10 mL of THF was added. During the addition, the system gradually became turbid, and continued stirring at room temperature overnight. The white solid was removed by filtration, the filtrate was separated by column, and DCM/MeOH=96/4 (V/V) was eluted to obtain the target compound 79e (290 mg) as a white solid with a yield of 46%.

LCMS(ESI-MS)m/z:500[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.68(s,1H),8.40(s,1H),7.68–7.71(m,2H),7.33(s,1H),7.18(t,J=9.2 Hz, 2H), 5.47 - 5.50 (m, 1H), 4.30 (s, 3H), 3.90 (s, 3H), 1.10 - 1.30 (m, 6H), 0.74 - 0.88 (m, 3H).

Step 4 Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-fluorophenyl)(tetrahydro-2H-pyran) -4-yl)methyl)-1-methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridine-2-carboxylate ( 79f)

Add 79e (250mg, 0.5mmol), tin reagent (195mg, 0.5mmol), PCY3 (28mg, 0.1mmol), Pd2(dba)3 (96mg, 0.1mmol), CuI (9.5mg, 0.05mmol) in the single-mouth bottle in sequence And 5 mL of anhydrous DMF, react at 115°C for 8 hours. The DMF was spin-dried and eluted with DCM/MeOH=20/1 to obtain the target compound 79f (110 mg) as a brown oil with a yield of 43%.

LCMS(ESI-MS) m/z: 517.4[M+H] ⁺ .

Step 5 Methyl 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-fluorophenyl)(tetrahydro-2H-pyran) -4-yl)methyl)-1-methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridine-2-carboxylate ( 79)

Compound 79e (110 mg, 0.21 mmol) was dissolved in 5 mL dry THF, and MeMgBr (3.0M, 1.0 mL) was added. After the addition, the mixture was stirred at room temperature overnight, and the solvent was evaporated to dryness. The preparation and separation were carried out twice. DCM/MeOH=20/1 developed to obtain 79 (7mg) as a white solid with a yield of 6.4%.

LCMS(ESI-MS) m/z: 517.4[M+H] ⁺ .

¹ H NMR (400MHz, MeOD) δ 8.16 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.53–7.57 (m, 2H), 6.98–7.02 (m, 2H) ), 6.44(s, 1H), 5.30–5.33(d, J = 11.2Hz, 1H), 4.32(s, 3H), 3.99(s, 3H), 3.91–3.96(m, 1H), 3.45–3.54( m, 2H), 3.00--3.04 (m, 1H), 2.29 (s, 3H), 1.76 (s, 6H), 1.28 - 1.60 (m, 6H)

Example 80: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(1-phenyl-2-( Tetrahydro-2H-pyran-4-yl)ethyl)-1,4-dihydropyrrolo[2',3': 4,5]pyrrolo[3,2-b]pyridin-2-yl) Propan-2-ol

Using a synthetic method similar to that of Example 79, the target compound 80 was prepared.

LCMS(ESI-MS) m/z: 513.4[M+H] ⁺ .

¹ H NMR (400MHz, MeOD) δ 8.16 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.34-7.13 (m, 5H), 6.20 (s, 1H), 5.83(dd,J=10.6,5.2Hz,1H),4.33(s,3H),3.91(s,3H),3.80-3.84(m,2H),3.12-3.24(m,2H),2.63-2.70( m, 1H), 2.24 (s, 2H), 2.19-2.23 (m, 2H), 1.81-1.79 (m, 1H), 1.70 (s, 3H), 1.68 (s, 3H), 1.58-1.60 (m, 1H),1.46-1.33(m,3H).

Example 81: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((2-fluorophenyl)(tetrahydro-2H- Pyran-4-yl)methyl)-1-methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl) Propan-2-ol

Using a synthetic method similar to that of Example 79, the target compound 81 was prepared.

LCMS(ESI-MS) m/z: 517.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 8.18 (d, J = 1.8 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.53-7.39 (m, 1H), 7.19-7.16 (m, 1H), 7.08–6.95 (m, 2H), 6.18 (s, 1H), 5.43 (d, J = 11.2 Hz, 1H), 4.34 (s, 3H), 4.04–3.83 (m, 5H), 3.36 to 3.46 (m, 2H), 2.79-2.90 (m, 1H), 2.35 (br s, 1H), 2.30 (s, 3H), 1.78 (s, 3H), 1.77 (s, 3H), 1.59-1.62 (m, 1H), 1.40-1.44 (m, 2H), 1.18-1.23 (m, 1H).

Example 82: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(1-(2-fluorophenyl)-2-( Tetrahydro-2H-pyran-4-yl)ethyl)-1-methyl-1,4-dihydropyrrolo[2',3': 4,5]pyrrolo[3,2-b]pyridine -2-yl)propan-2-ol

Using a synthetic method similar to that of Example 79, the target compound 82 was prepared.

LCMS(ESI-MS)m/z:531.4[M+H] ⁺ .

¹ H NMR (400MHz, MeOD) δ 8.17 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.45 (td, J = 7.7, 1.8 Hz, 1H), 7.22 7.24(m,1H),7.12–7.00(m,2H),6.22(s,1H), 6.09(dd,J=10.4,5.2Hz,1H),4.31(s,3H),3.95(s,3H) ,3.80-3.83(m,2H), 3.23–3.12(m,2H), 2.77–2.68(m,1H), 2.26(s,3H), 2.23–2.15(m,1H), 1.81(d,J= 11.9Hz, 1H), 1.70 (s, 3H), 1.69 (s, 3H), 1.62-1.29 (m, 5H).

Example 83: N1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-( Tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)-N1-ethyl-N2-methyl Ethane-1,2-diamine

Using a synthetic method similar to that of Example 79, the target compound 83 was prepared.

LCMS(ESI-MS) m/z: 518.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.50 (d, J = 1.6 Hz, 1H), 8.46 (d, J = 4.8 Hz, 1H), 8.27 (d, J = 1.6 Hz, 1H), 8.21 (s,1H),7.97(t,J=6.0Hz,1H),6.32(s,1H),5.80(d,J=11.2Hz,1H),5.30(s,1H),4.21(s,3H) ,4.01(s,3H),3.84(m,1H),3.77-3.80(m,1H),3.45(m,2H),3.15(m,1H),2.30(s,3H),1.62(s,3H) ), 1.59(s, 3H), 1.37-1.44(m, 3H), 1.14-1.17(m, 1H).

Example 84: 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(pyridin-2-yl (tetrahydro -2H-pyran-4-yl)methyl)-1,4-dihydropyrrolo[2',3': 4,5]pyrrolo[3,2-b]pyridin-2-yl)propan- 2-alcohol

Using a synthetic method similar to that of Example 79, the target compound 84 was prepared.

LCMS(ESI-MS)m/z:500.4[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.58(dd,J=5.0,1.8Hz,1H), 8.29(s,1H), 8.24(d,J=1.7Hz,1H), 7.74(td, J = 7.7, 1.9 Hz, 1H), 7.56 (dd, J = 7.8, 1.1 Hz, 1H), 7.27 (m, 1H), 6.33 (s, 1H), 5.55 (d, J = 10.9 Hz, 1H), 5.30(s,1H),4.21(s,3H),4.01(s,3H),3.84-3.74(m,2H),3.25-3.13(m,2H),2.29(s,3H),1.61(s, 3H), 1.59 (s, 3H), 1.46 - 1.20 (m, 4H), 1.10 (m, 1H).

Example 85: 2-(6-(3,5-dimethylpyridin-4-yl)-4-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4- (Yl)ethyl)-1-methyl-1,4-dihydropyrrolo[2',3': 4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol

Using a synthetic method similar to that of Example 79, the target compound 85 was prepared.

LCMS(ESI-MS)m/z:531.5[M+H] ⁺ .

¹ H NMR (400MHz, MeOD) δ 8.09 (d, J = 1.8 Hz, 1H), 7.71 (t, J = 1.2 Hz, 1H), 7.41 (td, J = 7.8, 1.8 Hz, 1H), 7.28- 7.21(m,1H),7.10–7.00(m,2H), 6.21(s,1H), 6.06(dd,J=10.5,5.2Hz,1H), 4.30(s,3H), 3.82(d,J= 10.6Hz, 2H), 3.25--3.13(m, 2H), 2.77--2.67(m, 1H), 2.39(s, 3H), 2.22(s, 4H), 1.80(m, 1H), 1.70(s, 3H) ), 1.69(s, 3H), 1.57(m, 1H), 1.51-1.32(m, 4H).

Biological activity test

Experiment 1: In vitro enzyme activity determination of the compound

1. Experimental purpose and method

The purpose of this experiment is to test the binding strength of the compound of the present invention to Bromodomain-containing protein 4 (BRD4) protein, and to evaluate the in vitro activity of the compound according to the IC50.

2. Experimental protocol

2.1 Preparation of experimental compounds

The compound 1-85 and JQ1 used in this experiment were dissolved in dimethyl sulfoxide (DMSO) to prepare a mother liquor of 10 millimoles per liter (mM). The highest concentration during the test is 1 micromole per liter (μM), diluted by 5 times, a total of 7 concentration gradients, set up multiple wells.

2.2 Experimental process

Homogeneous time-resolved fluorescence (HTRF) assay was used to determine the binding strength of the compound to Bromodomain-containing protein 4 (BRD4) protein. Transfer the prepared compound and dimethyl sulfoxide (DMSO) to a 384-well plate (PerkinElmer, OptiPlate-384), and then add BRD4(1,2)(49-460) (purchased from BPS) ( The final concentration is 5 nanomoles per liter (nM)), centrifuge to mix, and then add protein and GL-16 (H4(1-20)K5/8/12/16AC) (synthesized by Gil Biochemical (Shanghai) Co., Ltd.) The peptide (final concentration of 5 nanomolar per liter (nM)) initiates the reaction (total reaction volume is 10 microliters (μL)). Place the 384-well plate in an incubator at 23°C for 60 minutes, and then add Anti-GST-EU ³⁺ Cryptate (purchased from Cisbio, 0.25 nanomole per liter (nM)), and SA-XL-665 (purchased from Cisbio) , 0.625 nanomole per liter (nM)) to stop the reaction. After incubating for another 2 hours in the incubator, read the fluorescence value (340 nanometers (nm) excitation on Envision (purchased from PerkinElmer)), and detect 665 nanometers (nm) and 615 nanometers (nm). Emission light, the ratio of the two is the binding signal of the enzyme), and the IC50 value of the compound is calculated using the Prism 5 software (GraphPad Prism 5).

2.3 Test results and conclusions

The results show that the IC50 of the compound of the present invention is better than JQ1, showing stronger activity, indicating that the compound of the present invention can effectively bind the Bromodomain-containing protein 4 (BRD4) protein at the level of in vitro biochemical experiments. Therefore, the compound of the present invention can become an effective therapeutic drug for tumors. The results are shown in Table 1.

Table 1. Experimental results of biological activity of compound BRD4

Experiment two, the compound of the present invention analyzes the proliferation of human myeloid monocytic leukemia cells (MV-4-11 cells)

1. Experimental purpose and method

(CTG))法测量本发明化合物对人髓性单核细胞白血病细胞(MV-4-11细胞)的体外抗增殖作用。 This experiment uses the luminescence method to detect cell viability (

(CTG)) method to measure the in vitro anti-proliferation effect of the compound of the present invention on human myeloid monocytic leukemia cells (MV-4-11 cells).

2. Experimental protocol

2.1 Cell culture

Human myeloid monocytic leukemia cells (MV-4-11 cells) were ordered from the cell bank of the Chinese Academy of Sciences, using IMDM (Kangning, 26917008) plus 10% fetal bovine serum (Gibco, 10817010) and 1% penicillin/streptomycin Double antibody (Corning, 30002297) was cultured and observed under a microscope to confirm that the cells were in good condition. Transfer the cells to a 15 milliliter (mL) centrifuge tube, centrifuge at 1000 revolutions per minute (rpm) for 5 minutes, discard the supernatant, and add to the complete culture Base, pipette into a single cell suspension and place it in a 37°C, 5% CO ₂ incubator (Thermo Scientific).

2.2 Compound preparation and compound board preparation

The compound 1-60 and JQ1 used in this experiment were dissolved in dimethyl sulfoxide (DMSO) to prepare a mother liquor of 10 millimoles per liter (mM). The highest concentration during the test was 1 micromole per liter (μM), and 3 Multiple dilutions, a total of 9 concentration gradients, set up multiple wells.

2.3 Experimental process

Day 1: Cell plating

Take the above cell suspension and use a cell counter to count the cells, adjust the cell suspension to the required cell density with complete medium and then inoculate it into a 96-well plate, 90 microliters (μL) per well to make the cell number 10,000/well , Set the T0 plate, add 90 microliters (μL) of complete medium to the blank control, and place it in a 37°C, 5% CO ₂ incubator (Invitrogen) overnight.

Day 2: T0 board reading

Add 10 microliters (μL) of medium containing solvent to each well for CTG analysis, melt the CTG reagent (Promag, G7573) and equilibrate the cell plate to room temperature for 30 minutes, add 50 microliters (μL) of CTG solution to each well , Vibrate on an orbital shaker for 2 minutes to lyse the cells, place the cell plate at room temperature for 10 minutes to stabilize the luminescence signal, and read the luminescence value with Envision (purchased from PerkinElmer).

Day 2: Add the drug to be tested

The mother liquor is diluted 1000 times with the culture medium to obtain a 1000X solution. Dilute 3 times to obtain a compound plate. Add 10 microliters (μL) of the drug solution to each well. The maximum concentration during the test is 1 micromole per liter (μM), which is 3 times Dilution, a total of 9 concentration gradients, set up multiple wells. Cell culture was performed for 72 hours (h) at 37°C, 5% CO ₂ , and 95% humidity.

Day 5: Reading the test board (72 hours of drug treatment)

Melt CTG reagent (Promag, G7573) and equilibrate the cell plate to room temperature for 30 minutes, add 50 microliters (μL) of CTG solution to each well, shake on an orbital shaker for 2 minutes to lyse the cells, and place the cell plate at room temperature The luminescence signal was stabilized for 10 minutes, and the luminescence value was read with Envision (purchased from PerkinElmer).

2.4 Data processing and statistics

The cell survival rate is calculated by the formula: V _sample /V _{vehicle control} ×100%. Where V _sample is the reading of the drug treatment group, and V _{vehicle control} is the average value of the solvent control group. Using GraphPad Prism 5 software, a non-linear regression model was used to draw an S-type dose-survival curve and calculate the IC50 value.

2.5 Test results and conclusions

The results showed that the half inhibitory concentration (IC50) of JQ1 on the proliferation of human myeloid monocytic leukemia cells (MV-4-11 cells) was 186 nanomoles per liter (nM). The proliferation of leukemia cells (MV-4-11 cells) has a strong inhibitory effect, and the inhibitory activity is better than JQ1. The results are shown in Table 2.

Experiment 3. The compound of the present invention analyzes the proliferation of human B-cell lymphoma cells (SU-DHL-6 cells)

1. Experimental purpose and method

(CTG))法测量本发明化合物对人B细胞淋巴瘤细胞(SU-DHL-6细胞)的体外抗增殖作用。 This experiment uses the luminescence method to detect cell viability (

(CTG)) method to measure the in vitro anti-proliferation effect of the compounds of the present invention on human B-cell lymphoma cells (SU-DHL-6 cells).

2. Experimental program

2.1 Cell culture

Human B-cell lymphoma cells (SU-DHL-6 cells) were ordered from Nanjing Kebai Biotechnology Co., Ltd., using RPMI 1640 (Corning, 35417005) plus 10% fetal bovine serum (Gibco, 10817010) and 1% penicillin/chain Incubate the antimycin antibody (Kangning, 30002297), observe under a microscope to confirm that the cells are in good condition, transfer the cells to a 15 milliliter (mL) centrifuge tube, centrifuge at 1,000 revolutions per minute (rpm) for 5 minutes, discard the supernatant, and add Complete the medium, pipet into a single cell suspension, and place it in a 37°C, 5% CO ₂ incubator (Thermo Fisher).

2.2 Compound preparation and compound board preparation

Compound 1-85 and JQ1 used in this experiment were dissolved in dimethyl sulfoxide (DMSO) to prepare a mother liquor of 10 millimoles per liter (mM). The highest concentration in the test was 1 micromole per liter (μM), and Double dilution, a total of 9 concentration gradients, set up multiple wells.

2.3 Experimental process

Day 1: Cell plating

Take the above-mentioned cell suspension and use a cell counter to count the cells. Adjust the cell suspension to the required cell density with complete medium and then inoculate it into a 96-well plate. 90 microliters (μL) per well to make the number of cells 5000/well , Set the T0 plate, add 90 microliters (μL) of complete medium to the blank control, and place it in a 37°C, 5% CO ₂ incubator (Invitrogen) overnight.

Day 2: T0 board reading

Add 10 microliters (μL) of medium containing solvent to each well for CTG analysis, melt the CTG reagent (Promag, G7573) and equilibrate the cell plate to room temperature for 30 minutes, add 50 microliters (μL) of CTG solution to each well , Vibrate on an orbital shaker for 2 minutes to lyse the cells, place the cell plate at room temperature for 10 minutes to stabilize the luminescence signal, and read the luminescence value with Envision (purchased from PerkinElmer).

Day 2: Add the drug to be tested

The mother liquor is diluted 1000 times with the culture medium to obtain a 1000X solution. Dilute 3 times to obtain a compound plate. Add 10 microliters (μL) of the drug solution to each well. The maximum concentration during the test is 1 micromole per liter (μM), which is 3 times Dilution, a total of 9 concentration gradients, set up multiple wells. Cell culture was performed for 72 hours (h) at 37°C, 5% CO ₂ , and 95% humidity.

Day 5: Reading the test board (72 hours of drug treatment)

Melt CTG reagent (Promag, G7573) and equilibrate the cell plate to room temperature for 30 minutes, add 50 microliters (μL) of CTG solution to each well, shake on an orbital shaker for 2 minutes to lyse the cells, and place the cell plate at room temperature The luminescence signal was stabilized for 10 minutes, and the luminescence value was read with Envision (purchased from PerkinElmer).

2.4 Data processing and statistics

The cell survival rate is calculated by the formula: V _sample /V _{vehicle control} ×100%. Where V _sample is the reading of the drug treatment group, and V _{vehicle control} is the average value of the solvent control group. Using GraphPad Prism 5 software, a non-linear regression model was used to draw an S-type dose-survival curve and calculate the IC50 value.

2.5 Test results and conclusions

The results showed that the half-inhibitory concentration (IC50) of JQ1 in inhibiting the proliferation of human B-cell lymphoma cells (SU-DHL-6 cells) was 189 nanomolar per liter (nM). SU-DHL-6 cells) have a strong inhibitory effect on proliferation, and the inhibitory activity is better than that of JQ1. The results are shown in Table 2.

Experiment 4. The compound of the present invention analyzes the proliferation of human myeloma cells (MM.1S cells)

1. Experimental purpose and method

(CTG))法测量本发明化合物对人骨髓瘤细胞(MM.1S细胞)的体外抗增殖作用。 This experiment uses the luminescence method to detect cell viability (

(CTG)) method to measure the in vitro anti-proliferation effect of the compound of the present invention on human myeloma cells (MM.1S cells).

2. Experimental protocol

2.1 Cell culture

Human myeloma cells (MM.1S cells) were ordered from Nanjing Kebai Biotechnology Co., Ltd., using RPMI1640 (Kangning, 35417005) plus 10% fetal bovine serum (Gibco, 10817010) and 1% penicillin/streptomycin double antibody ( Corning, 30002297) culture, observe under a microscope, confirm that the cells are in good condition, transfer the cells to a 15 milliliter (mL) centrifuge tube, centrifuge at 1000 revolutions per minute (rpm) for 5 minutes, discard the supernatant, add complete medium, and blow Make a single cell suspension and place it in a 37°C, 5% CO ₂ incubator (Invitrogen).

2.2 Compound preparation and compound board preparation

The compound 1-60 and JQ1 used in this experiment were dissolved in dimethyl sulfoxide (DMSO) to prepare a mother liquor of 10 millimoles per liter (mM). The highest concentration during the test was 1 micromole per liter (μM), and 3 Multiple dilutions, a total of 9 concentration gradients, set up multiple wells.

2.3 Experimental process

Day 1: Cell plating

Take the above cell suspension and use a cell counter to count the cells, adjust the cell suspension to the required cell density with complete medium and then inoculate it into a 96-well plate, 90 microliters (μL) per well to make the cell number 10,000/well , Set the T0 plate, add 90 microliters (μL) of complete medium to the blank control, and place it in a 37°C, 5% CO ₂ incubator (Invitrogen) overnight.

Day 2: T0 board reading

Add 10 microliters (μL) of medium containing solvent to each well and perform CTG analysis. Thaw the CTG reagent (Promega, G7573) and equilibrate the cell plate to room temperature for 30 minutes. Add 50 microliters (μL) of CTG solution to each well , Vibrate on an orbital shaker for 2 minutes to lyse the cells, place the cell plate at room temperature for 10 minutes to stabilize the luminescence signal, and read the luminescence value with Envision (purchased from PerkinElmer).

Day 2: Add the drug to be tested

The mother liquor is diluted 1000 times with the culture medium to obtain a 1000X solution. Dilute 3 times to obtain a compound plate. Add 10 microliters (μL) of the drug solution to each well. The maximum concentration during the test is 1 micromole per liter (μM), which is 3 times Dilution, a total of 9 concentration gradients, set up multiple wells. Cell culture was performed for 72 hours (h) at 37°C, 5% CO ₂ , and 95% humidity.

Day 5: Reading the test board (72 hours of drug treatment)

Melt CTG reagent (Promag, G7573) and equilibrate the cell plate to room temperature for 30 minutes, add 50 microliters (μL) of CTG solution to each well, shake on an orbital shaker for 2 minutes to lyse the cells, and place the cell plate at room temperature The luminescence signal was stabilized for 10 minutes, and the luminescence value was read with Envision (purchased from PerkinElmer).

2.4 Data processing and statistics

The cell survival rate is calculated by the formula: V _sample /V _{vehicle control} ×100%. Where V _sample is the reading of the drug treatment group, and V _{vehicle control} is the average value of the solvent control group. Using GraphPad Prism 5 software, a non-linear regression model was used to draw an S-type dose-survival curve and calculate the IC50 value.

2.5 Test results and conclusions

The results showed that the half inhibitory concentration (IC50) of JQ1 on the proliferation of human myeloma cells (MM.1S cells) was 200 nanomolar per liter (nM). Strong inhibitory effect, the inhibitory activity is better than JQ1. The results are shown in Table 2.

Table 2. Inhibitory effects of compounds on cell proliferation

Experiment 5. Pharmacokinetics experiment of the compound of the present invention in rats

1. Summary

Male Sprague Dawley (SD) rats weighing 200-300g and 8 weeks old were used as experimental animals. Liquid chromatography-mass spectrometry/mass spectrometry (LC/MS/MS) technology was used to determine intragastric administration Example 3 compound, Example 5 compound, Example 9 compound, Example 17 compound, Example 18 compound, Example 19 compound, Example 21 compound, Example 22 compound, Example 23 compound, Example 24 compound, Example 27 compound, Example 28 compound, Example 29 compound, Example 30 compound, Example 31 compound, Example 32 compound, Example 33 compound, Example 34 compound, Example 36 compound, Example 38 compound, The concentration of the drug in the plasma at different times after the compound of Example 40, the compound of Example 41, the compound of Example 43, the compound of Example 45, the compound of Example 50, the compound of Example 51, the compound of Example 54 and the compound of Example 58. Study the pharmacokinetic behavior of the compound of the present invention in rats and evaluate its pharmacokinetic characteristics.

2. Experimental program

2.1 Experimental compounds

Determination of Example 3 Compound, Example 5 Compound, Example 9 Compound, Example 17 Compound, Example 18 Compound, Example 19 Compound, Example 21 Compound, Example 22 Compound, Example 23 Compound, and Example 24 Compound , Example 27 compound, Example 28 compound, Example 29 compound, Example 30 compound, Example 31 compound, Example 32 compound, Example 33 compound, Example 34 compound, Example 36 compound, Example 38 compound , Example 40 compound, Example 41 compound, Example 43 compound, Example 45 compound, Example 50 compound, Example 51 compound, Example 54 compound, and Example 58 compound.

2.2 Compound preparation

Weigh a certain amount of the compound and dissolve it in dimethyl sulfoxide (DMSO)/polyethylene glycol 300/physiological saline=5/20/75 to prepare a uniform solution.

2.3 Plasma collection and processing

The compound was administered intravenously or orally to rats at a dose of 1 milligram per kilogram (mg/kg), and blood was collected from the orbit at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 hours after administration. 0.2 Milliliters (ml), as for the anticoagulation tube, centrifuge at 6000 rpm at 4°C for 10 minutes to separate plasma, and store at -80°C.

2.4 Experimental results and conclusions

The pharmacokinetic parameters of the compound of the present invention after administration are shown in Table 3 below. As shown in Table 3, the compounds of the present invention have better metabolic characteristics and better bioavailability.

Table 3. Pharmacokinetic parameters of the compounds of the invention

Experiment 6. Pharmacodynamic experiment of the compounds of Examples 5, 18, 22, 29, 31, 41, and 54 of the present invention in human myeloid monocytic leukemia cells (MV-4-11 cells) mouse transplantation tumor model

1. Summary

Using 8-week-old female immunodeficiency mice (Balb/c Nude) weighing 16g-18g as experimental animals, the compounds of Example 5, Example 18, Example 22, Example 29, and Example 31 were tested. The results of the pharmacodynamics of the compound of Example 41 and the compound of Example 54 on the tumor of mice after intragastric administration of the compound of Example 54. Explore the effect of the compound of the invention on tumor growth.

2. Experimental program

2.1 Experimental compounds

Example 5 compound, Example 18 compound, Example 22 compound, Example 29 compound, Example 31 compound, Example 41 compound, and Example 54 compound.

2.2 Compound preparation

Weigh a certain amount of the compound and dissolve it in dimethyl sulfoxide (DMSO)/polyethylene glycol 300/physiological saline=5/20/75 to prepare a uniform solution.

2.3 Cell culture

Human myeloid monocytic leukemia cells (MV-4-11 cells) were ordered from the cell bank of the Chinese Academy of Sciences, using IMDM (Kangning, 26917008) plus 10% fetal bovine serum (Gibco, 10817010) and 1% penicillin/streptomycin Double antibody (Corning, 30002297) was cultured and observed under a microscope to confirm that the cells were in good condition. Transfer the cells to a 15 milliliter (mL) centrifuge tube, centrifuge at 1000 revolutions per minute (rpm) for 5 minutes, discard the supernatant, and add to the complete culture Base, pipette into a single cell suspension and place it in a 37°C, 5% CO ₂ incubator (Thermo Scientific).

2.4 Experimental process

Under sterile conditions, the logarithmic growth phase of human myeloid monocytic leukemia cells (MV-4-11 cells) were centrifuged and mixed with Matrigel (Corning, 8274014) and then transplanted into female immunodeficiency mice (Balb /c Nude) Subcutaneously on the right side of the back, each mouse is inoculated with 5*10 ⁶ cells, with a volume of 100 microliters (μL). After the inoculation, the mice are randomly divided into 9 groups according to the tumor size, and each group has 6 mice in vivo In the efficacy test, the positive control group is JQ1, and the negative control group is given the same amount of solvent. The specific design is shown in Table 4.

Table 4. In vivo efficacy experiment of the compound

2.5 Experimental results and conclusions

JQ1 inhibited tumor growth by only 50.00% at a concentration of 50 milligrams per kilogram (mg/kg). The compounds of Examples 5, 18, 22, 29, 31, 41, and 54 were at 1.0 milligram per kilogram (mg/kg). ), the tumor growth inhibition rate reached 98.12%, 101.75%, 97.63%, 103.25%, 95.17%, 94.65% and 94.02% respectively, indicating that Examples 5, 18, 22, 29, 31, 41 of the present invention The 54 compound has a stronger tumor growth inhibitory effect than JQ1 in a xenograft model of human myeloid monocytic leukemia cells (MV-4-11 cells).

Experiment 7. Pharmacodynamic experiment of the compounds of Examples 9, 19, 24, 30, 33, 45, 50, and 58 of the present invention in a mouse transplanted tumor model of human myeloma cells (MM.1S cells)

1. Summary

Using 8-week-old female combined severe immunodeficiency (SCID) mice weighing 18g-20g as experimental animals, the compounds of Example 9, Example 19, Example 24, Example 30, and Example 33 were tested. The effect of the compound of Example 45, the compound of Example 50, and the compound of Example 58 on mouse tumors after intragastric administration. Explore the effect of the compound of the invention on tumor growth.

2. Experimental program

2.1 Experimental compounds

Example 9 compound, Example 19 compound, Example 24 compound, Example 30 compound, Example 33 compound, Example 45 compound, Example 50 compound, and Example 58 compound.

2.2 Compound preparation

Weigh a certain amount of the compound and dissolve it in dimethyl sulfoxide (DMSO)/polyethylene glycol 300/physiological saline=5/20/75 to prepare a uniform solution.

2.3 Cell culture

Human myeloma cells (MM.1S cells) were ordered from Nanjing Kebai Biotechnology Co., Ltd., using RPMI1640 (Kangning, 35417005) plus 10% fetal bovine serum (Gibco, 10817010) and 1% penicillin/streptomycin double antibody ( Corning, 30002297) culture, observe under a microscope, confirm that the cells are in good condition, transfer the cells to a 15 milliliter (mL) centrifuge tube, centrifuge at 1000 revolutions per minute (rpm) for 5 minutes, discard the supernatant, add complete medium, and blow Make a single cell suspension and place it in a 37°C, 5% CO ₂ incubator (Invitrogen).

2.4 Experimental process

Under aseptic conditions, human myeloma cells (MM.1S cells) in the logarithmic growth phase were centrifuged and mixed with Matrigel (Corning, 8274014) and transplanted on the right side of the back of combined severe immunodeficiency (SCID) mice subcutaneously, each mouse was inoculated with 1 * ¹⁰⁷ cells, volume of 100 microliters ([mu] l), after inoculation, the mice were randomized based on tumor size equalization divided into 10 groups, each group in vivo efficacy experiment 6, the positive control group For JQ1, the negative control group gave the same amount of solvent. The specific design is shown in Table 5.

Table 5. In vivo efficacy experiment of the compound

2.5 Experimental results and conclusions

JQ1 inhibits tumor growth at a concentration of 50 milligrams per kilogram (mg/kg) of 46.00%. Examples 9, 19, 24, 30, 33, 45, 50, and 58 compounds at 1.5 milligrams per kilogram (mg/kg) /kg), the tumor growth inhibition rates were 109.97%, 93.16%, 102.18%, 95.72%, 92.18%, 98.71%, 96.79% and 96.88%, respectively, indicating that Examples 9,19,24, Compounds 30, 33, 45, 50, and 58 have stronger tumor growth inhibitory effects than JQ1 in a xenograft model of human myeloma cells (MM.1S cells).

Experiment 8. Pharmacodynamic experiment of the compounds of Examples 3, 17, 27, 34, 38, 43, 51 of the present invention in the transplanted tumor model of human colon cancer cells (RKO cells)

1. Summary

Taking 8-week-old female immunodeficiency mice (Balb/c Nude) weighing 16g-18g as experimental animals, the compound of Example 3, the compound of Example 17, the compound of Example 27, the compound of Example 34, and the compound of Example 38 were determined. The results of the pharmacodynamics of the compound of Example 43 and the compound of Example 51 on tumors of mice after intragastric administration of the transplanted tumor mice. Explore the effect of the compound of the invention on tumor growth.

2. Experimental program

2.1 Experimental compounds

The compound of Example 3, the compound of Example 17, the compound of Example 27, the compound of Example 34, the compound of Example 38, the compound of Example 43, and the compound of Example 51 were measured.

2.2 Compound preparation

Weigh a certain amount of the compound and dissolve it in dimethyl sulfoxide (DMSO)/polyethylene glycol 300/physiological saline=5/20/75 to prepare a uniform solution.

2.3 Cell culture

Human colon cancer cells (RKO cells) were ordered from Nanjing Kebai Biotechnology Co., Ltd., using MEM (Corning, 06419006) plus 10% fetal bovine serum (Gibco, 10817010), 1% penicillin/streptomycin double antibody (Corning, 30002297) and 1 millimole per liter (mM) sodium pyruvate (Corning, 03118009). Observe under a microscope to confirm that the cells are in good condition. Transfer the cells to a 15 milliliter (mL) centrifuge tube at 1000 revolutions per minute (rpm). ) Centrifuge for 5 minutes, discard the supernatant, add complete medium, pipette to form a single cell suspension, and place it in a 37°C, 5% CO ₂ incubator (Invitrogen).

2.4 Experimental process

Under aseptic conditions, human colon cancer cells (RKO cells) in the logarithmic growth phase were digested and mixed with Matrigel (Corning, 8274014) and then transplanted into the right subcutaneous back of female immunodeficiency mice (Balb/c Nude) , Each mouse was inoculated with 2*10 ⁶ cells with a volume of 100 microliters (μL). After the inoculation, the mice were randomly divided into 9 groups according to the tumor size. Each group of 6 mice was tested in vivo. The positive control group was JQ1, the negative control group was given the same amount of solvent. The specific design is shown in Table 6.

Table 6. In vivo efficacy experiment of compounds

2.5 Experimental results and conclusions

JQ1 has a 43.24% inhibitory effect on tumor growth at a concentration of 50 milligrams per kilogram (mg/kg). Examples 3, 17, 27, 34, 38, 43, 51 compounds at 1.5 milligrams per kilogram (mg/kg) ), the tumor growth inhibition rate reached 86.51%, 81.24%, 83.62%, 88.83%, 90.01%, 89.33% and 84.29% respectively, indicating that Examples 3, 17, 27, 34, 38, 43 of the present invention Compound 51 has stronger tumor growth inhibitory effect than JQ1 in human colon cancer cell (RKO cell) xenograft model.

Claims (11)

A compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, and mixtures thereof, and Pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, metabolites, isotopic derivatives,

Where Ar is

X is a nitrogen atom or a carbon atom; Y is -H or -OH; When Ar is

When, X is a carbon atom; When Ar is

When, X is a nitrogen atom or a carbon atom; R ⁰ is -(CH ₂ ) _n -heterocycloalkane, benzene ring, heteroaromatic ring, wherein the heterocycloalkane is 4-6 membered heterocycloalkane, and when the heteroatom on the heterocycloalkane is nitrogen, the nitrogen The hydrogen on can also be substituted by the following substituents: -C _1-3 alkyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl; R ¹ is -H, a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring; R ² is -H, halogen, -C _1-3 alkyl, -C _2-3 alkenyl, -C(O)OH, -C(O)OC _1-3 alkyl, -(CH ₂ ) _n- C _3-6 cycloalkyl, -(CH ₂ ) _n -heterocycloalkane, -OR ^a R ^b , -NR ^a R ^b ,

The -C _1-3 alkyl, -C _2-3 alkenyl or heterocycloalkane may be substituted by the following groups: -OH, -C _1-3 alkyl, -C _5-6 cycloalkyl, 4-6 membered heterocyclic group, 4-6 membered heterocyclic group substituted with C _1-3 alkyl, 5-10 membered heteroaryl, -OC _1-4 alkyl, -NH ₂ , halogen or cyano; R ^a and R ^b are independently hydrogen, -C _1-3 alkyl, -C _1-4 alkylene-OH, -C _2-3 alkylene-NH-C _1-3 alkyl, -C _2-3 alkylene-N-(C _1-3 alkyl) ₂ , -C _2-3 alkylene-OC _1-3 alkyl; R ^a and R ^b or together with the nitrogen atom to which they are attached form a 3-6 membered heterocycloalkyl group that is unsubstituted or substituted by a T group, and T is -C _1-4 alkyl, -OH, and R _x7 substituted 4-6 membered heterocyclic group; R _x1 , R _x2 , R _x3 , R _x4 , R _x5 , and R _x6 are each independently -H, -OH, halogen, -C _1-3 alkyl, and -C _2-3 alkenyl; R _x7 is -H, -C _1-3 alkyl, -C _2-3 alkenyl, C _3-6 cycloalkyl; R _y and R _z are each independently -H, -C _1-3 alkyl, and -C _2-3 alkenyl; R ³ is a 5-6 membered heteroaryl group, and the heteroaryl group may be substituted by a C _1-3 alkyl group; R ⁴ is -H, halogen, -OC _1-3 alkyl, -SC _1-3 alkyl, -OC(O)-C _1-3 alkyl, -C(O)OC _1-3 alkyl; R ⁵ is -C _3-6 cycloalkyl; R ⁶ and R ⁷ are each independently a hydroxyl group or a -C _1-3 alkyl group; R ⁸ is -H, -C _1-3 alkyl, -C _3-6 cycloalkyl; In the general formula

The structure is also expressed as

R ⁹ and R ¹⁰ are each independently -H, -OH, halogen, -C _1-3 alkyl, -C _1-3 alkylene-OH, -C _1-3 alkylene-NH-C _{1- 3} alkyl, -C _1-3 alkylene-N-(C _1-3 alkyl) ₂ , -C _1-3 alkylene-OC _1-3 alkyl; R ¹¹ is -C _1-3 alkyl; n is 0, 1, or 2. The compound according to claim 1 or its tautomers, mesosomes, racemates, enantiomers, diastereomers, and mixtures thereof, and pharmaceutically acceptable salts thereof , Polymorphs, solvates, prodrugs, metabolites, isotopic derivatives, characterized in that: R ¹ is -H, phenyl, 5-6 membered heteroaromatic ring, wherein the phenyl or 5-6 membered heteroaromatic ring can be substituted by the following groups: halogen, -OH, -C _1-3 alkyl , -OC _1-4 alkyl, -C _1-3 alkylene-OC _1-3 alkyl; R ² is halogen, -C _1-3 alkyl, -C _2-3 alkenyl, -C(O)OH, -C(O)OC _1-3 alkyl, -C _3-6 cycloalkyl, 4 -6 membered heterocycloalkane, -NR ^a R ^b ,

The -C _1-3 alkyl, -C _2-3 alkenyl or 4-6 membered heterocycloalkane can be substituted by the following groups: -OH, -C _1-3 alkyl, -C _5-6 Cycloalkyl, 4-6 membered heterocyclic group, C _1-3 alkyl substituted 4-6 membered heterocyclic group, -OC _1-4 alkyl; R _x1 , R _x2 , R _x3 , R _x4 , R _x5 , and R _x6 are independently -H and -CH _{3 respectively} ; R _x7 is -H, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , cyclopropanyl; R _y and R _z are independently -H and -CH ₃ ; R ³ is a 5-6 membered nitrogen-containing heteroaryl group, the heteroaryl group may be substituted by a C _1-3 alkyl group; In the general formula

The structure is also expressed as

R ⁹ and R ¹⁰ are independently -H, -OH, -C _1-3 alkyl, -C _1-3 alkylene-OH, -C _1-3 alkylene-NH-C _1-3 alkane Group, -C _1-3 alkylene-OC _1-3 alkyl. The compound according to claim 1 or 2 or its tautomers, mesoisomers, racemates, enantiomers, diastereomers, and mixtures thereof, and pharmaceutically acceptable Salts, polymorphs, solvates, prodrugs, metabolites, and isotopic derivatives are characterized in that: R ⁰ is

T ¹ is -C _1-3 alkyl, -CH ₂ -C _3-6 cycloalkyl,

T ² is -O, -S, -NH, -N-CH ₃ ; R ¹ is

R ² is -F, -Cl, -COOH, -NR ^a R ^b ,

Where -NR ^a R ^b is -NH ₂ , -N(CH ₃ ) ₂ , -N(CH ₃ )-(CH ₂ ) ₂ -NH-CH ₃ , -N(CH ₃ )-(CH ₂ ) _2- NH-CH ₂ CH ₃ , -N(CH ₂ CH ₃ )-(CH ₂ ) ₂ -NH-CH ₃ ,

R ³ is

R ⁴ is -H, -Cl, -F, -OC _1-3 alkyl, -SC _1-3 alkyl, -OC(O)-C _1-3 alkyl, -C(O)OC _1-3 alkyl; R ⁵ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R ⁶ and R ⁷ are each independently a hydroxyl group or a methyl group; R ⁸ is -H, -C _1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; In the general formula

The structure is also expressed as

R ⁹ is -H, -OH; R ¹⁰ is -CH ₂ -OC _1-3 alkyl. The compound of claim 1, wherein the compound is: 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-phenyl-2-(tetrahydro-2H-pyran-4 -Yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(5-(2,3-Dihydro-1H-inden-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H -Pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(5-(Cyclopent-3-en-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyrido[ 3,2-b]indol-7-yl)propan-2-ol; 2-Acetoxy-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl )Methyl)-5H-pyrido[3,2-b]indole-7-carboxylic acid methyl ester; 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-7-(2-hydroxypropan-2-yl)-5-(phenyl(tetrahydro-2H -Pyran-4-yl)methyl)-1,5-dihydro-2H-pyrido[3,2-b]indol-2-one; (2-Cyclopropyl-6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1Hbenzo(d)imidazol-4-yl)diphenylmethanol ； 2-(4-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(2-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(5-(1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-dimethyl-1H -1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(tetrahydrofuran-3-yl)-5H-pyrido[3,2-b ]Indol-7-yl)propan-2-ol; 4-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-7-(2-hydroxypropan-2-yl)-5H-pyrido[3, 2-b]indol-5-yl)tetrahydro-2H-pyran-3-ol; 4-(3-(1,4-Dimethyl-1H-,1,2,3-triazol-5-yl)-7-(2-hydroxypropan-2-yl)-5Hpyrido[3, 2-b]indol-5-yl]tetrahydrofuran-3-ol; 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(4-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(pyridin-2-yl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(4-methoxyphenyl)-2-(tetrahydro -2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2-(tetrahydro -2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(3-methoxyphenyl)-2-(tetrahydro -2H-pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(3-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(5-(1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-dimethyl-1H -1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(5-(1-(2,3-Difluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-dimethyl-1H -1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(3-fluorophenyl)-2-(1-methyl Piperidin-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(3-fluorophenyl)-2-(1-(oxa Butyl-3-yl)piperidin-4-yl)ethyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(5-(2-(1-(cyclopropylmethyl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)-3-(1,4-dimethyl- 1H-1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-2-carbonyl-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl Group)-2,5-dihydro-1H-pyrido[3,2-b]indole-7-carboxylic acid; 7-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2-(tetrahydro -2H-pyran-4-yl)ethyl)-5H-pyrrolo[3,2-b:4,5-c']dipyridine; 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2-(tetrahydro-2H-pyridine (Pyran-4-yl)ethyl)-7-(pyrrolidin-1-yl)-5H-pyrrolo[3,2-b:4,5-c']dipyridine; 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methoxyphenyl)-2-(tetrahydro-2H-pyridine (Pyran-4-yl)ethyl)-N,N-dimethyl-5H-pyrrolo[3,2-b:4,5-c']dipyridin-7-amine; 7-(azetidine-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-methyl Oxyphenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[3,2-b:4,5-c']dipyridine; 7-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro- 2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridine; N1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)-N1,N2-dimethylethane-1, 2-diamine; 1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)-4-methylpiperidin-4-ol; 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(methylthio)-5-(phenyl(tetrahydro-2H-pyridine) (Pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 7-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-phenyl-2-(tetrahydro-2H-pyran- 4-yl)ethyl)-5H-pyrrolo[3,2-b: 4,5-C']dipyridine; 6-chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-phenyl-2-(tetrahydro-2H-pyran- 4-yl)ethyl)-5H-pyrrolo[3,2-b: 5,4-C']dipyridine; (2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo(d)imidazol-7-yl)bis(pyridine -2-yl)methanol; (2-Cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo(d)imidazol-4-yl)(tetrahydrofuran- 2-base) methanol hydrochloride; (2-Cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo(d)imidazol-4-yl)(pyridine- 2-yl)(tetrahydrofuran-2-yl)methanol; 2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(3,5-dimethyl-1H-pyrazole-4 -Base) -1H-benzo[d]imidazole; (2-Cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo(d)imidazol-4-yl)(6- Methylpyridin-2-yl)(tetrahydrofuran-2-yl)methanol; 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(3-(methoxymethyl)chroman-4-yl)- 5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 2-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(2-(2-methoxyethyl)-2,3-di Hydrobenzofuran-3-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 8-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-3-methyl-10-(phenyl(tetrahydro-2H-pyran-4-yl) (Methyl)-1,2,3,10-tetrahydrocyclopenta[g]pyrido[3,2-b]indol-3-ol; (2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo(d)imidazol-7-yl)bis(thiazole -2-yl)methanol; 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran -4-yl)ethyl)-7-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-5H-pyrrolo[2,3-b:4,5-b ']Dipyridine; 2-Cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(pyridin-4-yl)-1H-benzo[d] Imidazole 2-cyclopropyl-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-(2-methylnaphthalene-1-yl)-1H-benzene And [d]imidazole; 5-(2-Cyclopropyl-5-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazol-7-yl)- 6-methylquinoline; 2-(6-(3,5-Dimethylisoxazol-4yl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-4H-thiophene[2', 3': 4,5] pyrrole[3,2-b]pyridin-2-yl)propan-2-ol; 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4 -Yl)methyl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol; 6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl) Methyl)-2-(prop-1-en-2-yl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridine; 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl )-4H-furo[2',3': 4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol; 2-cyclopropyl-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-ethyl-N-phenyl-N-(tetrahydro-2H -Pyran-4-yl)-1H-benzo[d]imidazol-4-amine; 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl )-4H-thieno[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol; 2-(5-(1-(2,4-Dichlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(1,4-dimethyl-1H -1,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol; 5-isopropyl7-methyl 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5H-pyridyl[3,2-b]indole- 5,7-dicarboxylic acid ester; 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(pyridin-2-yl(tetrahydrofuran-3-yl) (Methyl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol; 2-(4-(Bis(pyridin-2-yl)methyl)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl -1,4-Dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propyl-2-ol; 7-(aziridin-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H- Pyran-4-yl)methyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridine; 4-(2-((3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)amino)ethyl)-1,3-dimethylpiperazin-2-one ； N1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)-N1-ethyl-N2-methylethane- 1,2-diamine; 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran -4-yl)ethyl)-7-(4-isopropylpiperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5-b']bipyridine; 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran -4-yl)ethyl)-7-(4-(1-isopropylpiperidin-4-yl)piperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5- b']Bipyridine; 4-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b: 4,5-b']bispyridin-7-yl)morpholine; 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-7-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl )-5-(1-(2-Fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b: 4,5-b ']Bipyridine; 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran -4-yl)ethyl)-7-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5- b']Bipyridine; 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran -4-yl)ethyl)-7-(4-methylpiperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5-b']bipyridine; 7-(4-(1-Cyclopropylpiperidin-4-yl)piperazin-1-yl)-3-(1,4-dimethyl-1H-1,2,3-triazole-5- Yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b: 4,5- b']Bipyridine; 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran -4-yl)ethyl)-7-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-5H-pyrrolo[2,3-b: 4,5-b ']Dipyridine; 2-(4-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)phenyl)propyl-2-ol; 2-(4-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-3-(phenyl(tetrahydro-2H-pyran-4- (Yl)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)propyl-2-ol; 8-(3,5-Dimethylisoxazol-4-yl)-10-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl) -3-Methyl-1,2,3,10-tetrahydrocyclopenta[g]pyrido[3,2-b]indol-3-ol; 8-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-fluoro-10-(phenyl(tetrahydro-2H-pyran-4-yl)methyl基)-1,10-dihydrocyclopenta[g]pyrido[3,2-b]indole-3(2H)-one; 10-Chloro-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl基)-8,9-dihydrocyclopenta[f]pyrido[3,2-b]indole-7(5H)-one; 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5 ,7,8,9-tetrahydrocyclopenta[f]pyrido[3,2-b]indole; 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5 ,7,8,9-tetrahydrocyclopenta[f]pyrido[3,2-b]indole-7-ol; 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((4-fluorophenyl)(tetrahydro-2H-pyran-4 -Yl)methyl)-1-methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propane-2- alcohol; 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(1-phenyl-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2- alcohol; 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-((2-fluorophenyl)(tetrahydro-2H-pyran-4 -Yl)methyl)-1-methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2- alcohol; 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-4-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-1-methyl-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl ) Propan-2-ol; N1-(3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-(1-(2-fluorophenyl)-2-(tetrahydro-2H -Pyran-4-yl)ethyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridin-7-yl)-N1-ethyl-N2-methylethane- 1,2-diamine; 2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(pyridin-2-yl(tetrahydro-2H-pyridine (Pyran-4-yl)methyl)-1,4-dihydropyrrolo[2',3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol; 2-(6-(3,5-dimethylpyridin-4-yl)-4-(1-(2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl )-1-Methyl-1,4-dihydropyrrolo[2':3':4,5]pyrrolo[3,2-b]pyridin-2-yl)propan-2-ol. A method for preparing the compound represented by the general formula I as defined in any one of claims 1-4, the compound represented by the general formula I is prepared by the following scheme, Scheme 1: Ar is

When, the synthetic route is as follows:

Where Ar ¹ is,

for

Compound (I-1) is coupled with the corresponding arylboronic acid (I-2) Suzuki in the presence of heating, basicity, and catalyst to obtain the compound of general formula (I-3), which provides basicity The reagents of the conditions are preferably potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium fluoride, etc.; the catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, acetic acid Palladium, tetratriphenylphosphine palladium, tris(dibenzylideneacetone) dipalladium, etc.; compound (I-3) undergoes intramolecular cyclization under the catalysis of a phosphine reagent to obtain compound (I-4), and the phosphine reagent is preferably 1 , 2-bis(diphenylphosphine)ethane (DPPE), triphenylphosphine, etc.; compound (I-4) reacts with the corresponding alcohol by Mitsunobu to obtain compound (I-6); compound (I-6) in palladium Catalyzed by Still coupling with the corresponding tin reagent to obtain compound (I), the catalyst used is preferably [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, palladium acetate, tetratriphenyl Phosphine palladium, tris(dibenzylideneacetone) dipalladium, etc.; after obtaining compound I, the functional group on the aromatic ring is further converted to obtain a specific target series compound; Scenario 2, Ar is

Time,

Compound (II-1) reacts with halogenating reagent to obtain compound of general formula (II-2). The halogenating reagent is preferably NBS, NCS, NIS, liquid bromine, etc.; compound (II-2) reacts with reducing agent to obtain compound of general formula (II -3), the reducing agent used is preferably stannous chloride, reduced iron powder, zinc powder, etc.; compound (II-3) is condensed with the corresponding acid chloride or carboxylic acid to obtain compound (II-4); compound (II-4) Under acidic conditions, compound (II-5) is obtained by intramolecular ring closure; compound (II-5) is Still coupled with tin reagent under palladium catalysis to obtain compound (II-6). The catalyst used is preferably [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride, palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, etc.; compound (II-6) and aryl format reagent Or the aryl lithium salt reacts to obtain compound (I); Option 3. Ar is

Compound (III-1) reacts with halogenating reagent to obtain compound (III-2) of general formula, and the halogenating reagent used is preferably NBS, NCS, NIS, etc.; compound (III-2) reacts with reducing agent to obtain compound of general formula (III-3) The reducing agent used is preferably stannous chloride, reduced iron powder, zinc powder, etc.; compound (III-3) is condensed with the corresponding acid chloride or carboxylic acid to obtain compound (III-4); compound (III-4) is under acidic conditions Compound (III-5) is obtained by closing the intramolecular ring; Compound (III-5) is Still coupled with tin reagent under palladium catalysis to obtain Compound (III-6). The catalyst used is preferably [1,1'-bis(二) Phenylphosphino)ferrocene]palladium dichloride, palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, etc.; compound (III-6) reacts with a reducing agent to obtain a compound of general formula (III-7), the reducing agent used is preferably stannous chloride, reduced iron powder, zinc powder, etc.; compound (III-7) reacts with sodium nitrite and sodium halide under acidic conditions to obtain compound (III-8); Compound (III-8) is coupled with aryl boronic acid or aryl boronic acid ester Suzuki in the presence of heating, alkaline, and catalyst to obtain the compound of general formula (I), which provides reagents for alkaline conditions Preferably potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium fluoride, etc.; the catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, palladium acetate, Triphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, etc.; Option 4. Ar is

Compound (III-8) is subjected to Buchwald-Hartwig coupling with an amine under heating, alkaline, and presence of a catalyst to obtain a compound of general formula (I). The reagent for alkaline conditions provided under this condition is preferably potassium carbonate, Cesium carbonate, potassium hydroxide, sodium hydroxide, cesium fluoride, sodium tert-butoxide, potassium tert-butoxide, etc.; the catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride , Palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, etc.; Option 5. Ar is

Compound (II-5) is reacted with di-tert-butyl dicarbonate to obtain compound (IV-1); compound (IV-1) is reduced to compound (IV-2) by a reducing agent, and the reducing agent used is preferably diisobutyl aluminum hydride Compound (IV-2) reacts with the corresponding ether under the conditions of triethyl boron and tert-butanol to obtain compound (IV-3); compound (IV-3) is oxidized with oxidizing agent to obtain compound (IV-4), The oxidant used is preferably active manganese dioxide, Dess-martin oxidant, pyridinium dichromate (PDC), etc.; compound (IV-4) is still coupled with tin reagent under palladium catalysis to obtain compound (IV-5). The catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, etc.; compound (IV -5) React with aryl lithium salt or aryl grating reagent to obtain the compound of general formula (I). A pharmaceutical composition, characterized by comprising a therapeutically effective amount of the compound according to any one of claims 1 to 4 or its tautomer, mesosome, racemate, or enantiomer , Diastereomers, and mixtures thereof, and pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, metabolites, isotopic derivatives, and optionally one or more pharmaceutically acceptable Accepted carrier and/or diluent. The compound according to any one of claims 1-4 or its tautomer, meso, racemate, enantiomer, diastereomer, and mixtures thereof, and The pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, metabolites, isotopic derivatives thereof, or the pharmaceutical composition according to claim 6 are prepared for the prevention and/or treatment of BRD4-mediated related Use in medicine for diseases. The use according to claim 7, wherein the related diseases mediated by BRD4 include tumors. The use according to claim 8, wherein the tumor is acute myeloid lymphoma, acute lymphocytic leukemia, lymphoma and various myeloma. A method for preventing and/or treating tumors, the method comprising administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1 to 4 and a pharmaceutically acceptable salt or stereo Isomer or the pharmaceutical composition according to claim 6. The compound according to any one of claims 1 to 4 and a pharmaceutically acceptable salt or stereoisomer thereof or the pharmaceutical composition according to claim 6 are used for the prevention and/or treatment of tumors.