CN113544129B - Tricyclic compound preparation method and application thereof in medicine field - Google Patents

Tricyclic compound preparation method and application thereof in medicine field Download PDF

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CN113544129B
CN113544129B CN202080018606.1A CN202080018606A CN113544129B CN 113544129 B CN113544129 B CN 113544129B CN 202080018606 A CN202080018606 A CN 202080018606A CN 113544129 B CN113544129 B CN 113544129B
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dimethyl
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triazol
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CN113544129A (en
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许忻
张瑱
覃华
武琦梅
王影
臧成旭
张雨云
秦成刚
周晓波
郭凤英
王艺瑾
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Zhejiang Huahai Pharmaceutical Co Ltd
Shanghai Synergy Pharmaceutical Sciences Co Ltd
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Zhejiang Huahai Pharmaceutical Co Ltd
Shanghai Synergy Pharmaceutical Sciences Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

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Abstract

Provides a tricyclic small molecule compound, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof in medicine. The compounds are useful as inhibitors of bromodomain protein 4 (BRD 4) for the prevention and/or treatment of diseases associated with BRD4, such as malignant tumors and the like.

Description

Tricyclic compound preparation method and application thereof in medicine field
Technical Field
The invention belongs to the field of medicines, and relates to a tricyclic small molecular compound, a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound in medicine.
Background
Malignant tumors are diseases which seriously threaten human health, and the morbidity and mortality of the malignant tumors are always on the rising trend in recent years, so that the malignant tumors become serious health problems facing the world. The occurrence and development of tumors are a multi-factor and multi-stage evolution process, and involve mutation and epigenetic change of various genes. Epigenetic refers to a genetic phenomenon in which the expression level and function of a gene are altered without altering the DNA sequence of the gene, and a heritable phenotype is produced.
Post-translational modifications of histones are important in epigenetic regulation. Methylation and acetylation at histone tail lysine residues are the most predominant modes of histone modification, where histone acetylation can precisely regulate chromatin structure and function in cells. Bromodomains and super terminal structure (bromodomain and extraterminal domain, BET) family proteins can bind acetylated histones or nonhistones, exerting gene transcriptional regulatory functions associated with cell growth and cell cycle. The BET protein family is a subclass of the bromodomain protein superfamily, characterized by the N-terminal end comprising 2 conserved bromodomain (BD 1 and BD 2) and the C-terminal end comprising a ET (extraterminal) domain. The family includes 4 members, BRD2, BRD3, BRD4 and BRDT, respectively. BRD2, BRD3, BRD4 are widely expressed in all body cells, BRDT is expressed only in testis tissue. BRD4 regulates expression of target genes by recruiting different transcription factors, such as Mediator, positive transcription elongation factor b (p-TEFb), thereby playing an important role in regulating cell cycle progression, transcription, inflammation, etc.
Studies have shown that BRD4 abnormalities are associated with a number of diseases. Translocation of the BRD4 gene into the testosterone Nucleoprotein (NUT) locus produces BRD4-NUT fusion proteins, which in turn result in c-Myc over-expression, promoting the formation of NUT midline cancer. BRD4 also plays an important role in many hematological tumors, and bromodomain protein BRD4 recruits p-TEFb by recognizing acetylated lysine on histone, and phosphorylates RNA polymerase II, ultimately leading to downstream gene expression, such as oncogene c-Myc gene, etc., whose abnormal expression can lead to the occurrence of diseases such as cancer, including acute myelolymphoma, acute lymphoblastic leukemia, lymphoma and multiple myeloma.
The BRD4 small molecule inhibitor can interfere the specific combination of BRDs structural domain and acetylated lysine, regulate and control the transcription of downstream related target genes, and further regulate downstream signal channels, thereby playing a role in treating diseases such as cancer and inflammation. Selective inhibitors that have been disclosed include WO2011054553、WO2013097052、WO2013158952、WO2014165127、WO2014206345、WO2016077378、WO2015081189、WO2016044067、WO2017177955 and WO2018137655, among others. JQ1 is the most widely known such drug, JQ1 being an inhibitor of BET family protein BRD 4. As early as 2010, filippakopoulos et al reported in journal of nature that JQ1 exhibited antitumor properties on some specific cell and mouse models. JQ1 is currently widely used as a chemical probe to study the physiological function of BET protein and its relationship to disease. A series of BRD4 inhibitor patents have been disclosed, but there is still a need to develop new BRD4 inhibitors to meet the market demand.
The BRD4 inhibitor has good application prospect in the medicine industry, no medicament is marketed at present, and in order to achieve the aim of better therapeutic effect and meet market demands, we hope to develop the BRD4 inhibitor with better activity and lower toxicity.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), or a tautomer, a meso, a racemate, an enantiomer, a diastereomer and a mixture thereof, and pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, metabolites and isotopic derivatives thereof,
Wherein 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 -heterocycloalkylene, benzene ring, heteroaromatic ring, wherein the heterocycloalkylene is 4-6 membered heterocycloalkylene, when the heteroatom on the heterocycloalkylene is nitrogen, the hydrogen on the nitrogen can be substituted by-C 1-3 alkyl, - (CH 2)n-C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, R 0 is preferably T 1 is-C 1-3 alkyl, -CH 2-C3-6 cycloalkyl, T 2 is-O, -S, -NH, -N-CH 3;
R 1 is-H, a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring; r 1 is further-H, phenyl, a 5-6 membered heteroaromatic ring, wherein said phenyl or 5-6 membered heteroaromatic ring may be substituted with: halogen, -OH, -C 1-3 alkyl, -O-C 1-4 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl;
r 1 can be
R 2 is-H, halogen, -C 1-3 alkyl, -C 2-3 alkylene, -C (O) OH-C (O) O-C 1-3 alkyl, - (CH 2)n-C3-6 cycloalkyl, - (CH 2)n -heterocycloalkylene, -OR a、-NRaRb),Wherein said-C 1-3 alkyl, -C 2-3 alkylene or heteroalkyl may be substituted with: -OH, -C 1-3 alkyl, -C 5-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-3 alkyl substituted 4-6 membered heterocyclyl, 5-10 membered heteroaryl, -O-C 1-4 alkyl, -NH 2, halogen or cyano;
R a and R b are each 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、-C2-3 alkylene-O-C 1-3 alkyl;
R a and R b either form together with the nitrogen atom to which they are attached a 4-6 membered heterocycloalkyl which is unsubstituted or substituted by a T group, T being-C 1-4 alkyl, -OH, 4-6 membered heterocyclyl which is substituted by R x7;
R x1、Rx2、Rx3、Rx4、Rx5、Rx6 is independently-H, -OH, halogen, -C 1-3 alkyl, -C 2-3 alkylene; r x1、Rx2、Rx3、Rx4、Rx5、Rx6 is further preferably-H, -CH 3;
R x7 is-H, -C 1-3 alkyl, -C 2-3 alkylene, or C 3-6 cycloalkyl; r x7 is further preferably-H, -CH 3、CH2CH3、CH(CH3)2, cyclopropane;
R y、Rz is independently-H, -C 1-3 alkyl, -C 2-3 alkylene; r y、Rz is further preferably-H, -CH 3;
R 2 is further preferably halogen, -C 1-3 alkyl, -C 2-3 alkylene, -C (O) OH, -C (O) O-C 1-3 alkyl, -C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, -NR aRb, Wherein said-C 1-3 alkyl, -C 2-3 alkylene or 4-6 membered heterocycloalkylene may be substituted with: -OH, -C 1-3 alkyl, -C 5-6 cycloalkyl, 4-6 membered heterocyclyl, C 1-3 alkyl substituted 4-6 membered heterocyclyl, -O-C 1-4 alkyl;
R 2 is specifically-F, -Cl, -COOH, -NR aRb, Wherein-NR aRb is -NH2、-N(CH3)2、-N(CH3)-(CH2)2-NH-CH3、-N(CH3)-(CH2)2-NH-CH2CH3、-N(CH2CH3)-(CH2)2-NH-CH3、
R 3 is a 5-6 membered heteroaryl, which heteroaryl may be substituted with C 1-3 alkyl; r 3 can be
R 4 is-H, halogen, -O-C 1-3 alkyl, -S-C 1-3 alkyl-OC (O) -C 1-3 alkyl, -C (O) O-C 1-3 alkyl; r 4 is specifically selected from the group consisting of-H, -Cl, -F, -O-C 1-3 alkyl-S-C 1-3 alkyl, -OC (O) -C 1-3 alkyl, -C (O) O-C 1-3 alkyl;
R 5 is-C 3-6 cycloalkyl; r 5 may specifically be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
R 6 and R 7 are each independently hydroxy or-C 1-3 alkyl; r 6 and R 7 are further preferably hydroxy or methyl; r 8 is-H, -C 1-3 alkyl, -C 3-6 cycloalkyl;
Of the general formula The structure is also denoted 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、-C1-3 alkylene-O-C 1-3 alkyl; r 9 and R 10 are further preferably-H, -OH, -C 1-3 alkyl, -C 1-3 alkylene-OH-C 1-3 subunit-NH-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl;
R 9 can be-H, -OH;
R 10 may specifically be-CH 2-O-C1-3 alkyl;
r 11 is-C 1-3 alkyl;
n is 0, 1 or 2.
According to the invention, the compound shown in the general formula (I) and pharmaceutically acceptable salts thereof are 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) -1H benzo [ d ] imidazol-4-yl) benzhydrol;
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) -5H pyrido [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-methylpiperidin-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- (oxetan-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) -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' ] bipyridinyl;
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' ] bipyridinyl;
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' ] bipyridinyl-7-amine;
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' ] bipyridinyl;
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' ] bipyridinyl;
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' ] bipyridinyl-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' ] bipyridinyl-7-yl) -4-methylpiperidinyl-4-ol;
2- (3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (methylsulfanyl) -5- (phenyl (tetrahydro-2H-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' ] bipyridinyl;
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' ] bipyridinyl;
(2-cyclopropyl-5- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1H-benzo [ d ] imidazol-7-yl) bis (pyridin-2-yl) methanol;
(2-cyclopropyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1H-benzo [ d ] imidazol-4-yl) (tetrahydrofuran-2-yl) methanolic hydrochloride;
(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;
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;
(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-dihydrobenzofuran-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 (thiazol-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' ] bipyridinyl;
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-methylnaphthalen-1-yl) -1H-benzo [ 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-4 yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thiophen [2',3':4,5] pyrrol [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-isopropyl 7-methyl 3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -5H-pyridinyl [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' ] bipyridinyl;
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' ] bipyridinyl-7-yl) amino) ethyl) -1, 3-dimethylpiperazin-2-one;
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' ] bipyridinyl-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' ] bipyridinyl;
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' ] bipyridinyl;
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' ] bipyridinyl-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' ] bipyridinyl;
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' ] bipyridinyl;
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' ] bipyridinyl;
7- (4- (1-cyclopropylpiperidin-4-yl) piperazin-1-yl) -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' ] bipyridinyl;
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' ] bipyridinyl;
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) -1, 10-dihydro-cyclopenta [ g ] pyrido [3,2-b ] indol-3 (2H) -one;
10-chloro-3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8, 9-dihydro-cyclopenta [ f ] pyrido [3,2-b ] indol-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 ] indol-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) propan-2-ol;
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;
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;
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;
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' ] bipyridinyl-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-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 compounds of formula I may be prepared by the following scheme,
Scheme 1: when Ar is
The synthetic route is as follows:
wherein Ar 1 is a group consisting of,
Is that
The compound (I-1) is coupled with corresponding arylboronic acid (I-2) through Suzuki under the conditions of heating, alkalinity and the existence of a catalyst to obtain a compound of a general formula (I-3), wherein reagents of alkaline conditions provided under the conditions are preferably potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium fluoride and the like; the catalyst is preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate, tetraphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium and the like; the compound (I-3) is subjected to intramolecular cyclization under the catalysis of phosphine reagents to obtain a compound (I-4), wherein the phosphine reagents are preferably 1, 2-bis (diphenylphosphine) ethane (DPPE), triphenylphosphine and the like; carrying out Mitsunobu reaction on the compound (I-4) and corresponding alcohol to obtain a compound (I-6); the compound (I-6) is Still coupled with a corresponding tin reagent under the catalysis of palladium to obtain the compound (I), and the catalyst used is preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate, tetraphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium and the like; after the compound I is obtained, the functional group on the aromatic ring is further converted to obtain a specific target series compound.
In the case of scheme 2, the method comprises,
Ar isIn the time-course of which the first and second contact surfaces,
Reacting the compound (II-1) with a halogenating reagent to obtain a compound (II-2) of the general formula, wherein the halogenating reagent is preferably NBS, NCS, NIS, liquid bromine and the like; the compound (II-2) reacts with a reducing agent to obtain a compound (II-3) of the general formula, wherein the reducing agent is preferably stannous chloride, reduced iron powder, zinc powder and the like; condensing the compound (II-3) with corresponding acyl chloride or carboxylic acid to obtain a compound (II-4); intramolecular ring closure of the compound (II-4) under an acidic condition to obtain a compound (II-5); the compound (II-5) is Still coupled with a tin reagent under the catalysis of palladium to obtain a compound (II-6), and the catalyst is preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate, tetraphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium and the like; reacting the compound (II-6) with an aryl format reagent or an aryl lithium salt to obtain a compound (I);
In the case of scheme 3, the method comprises,
Ar isIn the time-course of which the first and second contact surfaces,
Reacting the compound (III-1) with a halogenating reagent to obtain a compound (III-2) of the general formula, wherein the halogenating reagent is preferably NBS, NCS, NIS; the compound (III-2) reacts with a reducing agent to obtain a compound (III-3), wherein the reducing agent is preferably stannous chloride, reduced iron powder, zinc powder and the like; condensing the compound (III-3) with corresponding acyl chloride or carboxylic acid to obtain a compound (III-4); intramolecular ring closure of the compound (III-4) under an acidic condition to obtain a compound (III-5); the compound (III-5) is Still coupled with a tin reagent under the catalysis of palladium to obtain a compound (III-6), and the catalyst is preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate, tetraphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium and the like; the compound (III-6) reacts with a reducing agent to obtain a compound (III-7) with the general formula, wherein the reducing agent is preferably stannous chloride, reduced iron powder, zinc powder and the like; reacting the compound (III-7) with sodium nitrite and sodium halide under an acidic condition to obtain a compound (III-8); coupling the compound (III-8) with arylboronic acid or arylboronic acid ester Suzuki under heating in the presence of an alkaline catalyst to obtain a compound of the general formula (I), wherein the alkaline reagent is preferably potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium fluoride or the like; the catalyst is preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate, tetraphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium and the like;
in the case of scheme 4, the method comprises,
Ar isIn the time-course of which the first and second contact surfaces,
Buchwald-Hartwig coupling of the compound (III-8) with an amine in the presence of a catalyst in the presence of a heating, alkaline, or alkaline condition to give a compound of the general formula (I), the alkaline condition provided under this condition being preferably selected from the group consisting of potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium fluoride, sodium t-butoxide, potassium t-butoxide, etc.; the catalyst is preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate, tetraphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium and the like;
In the case of scheme 5 of the present invention,
Ar isIn the time-course of which the first and second contact surfaces,
Reacting the compound (II-5) with di-tert-butyl dicarbonate to obtain a compound (IV-1); the compound (IV-1) is reduced to the compound (IV-2) by a reducing agent, preferably diisobutylaluminum hydride; reacting the compound (IV-2) with the corresponding ether under the conditions of triethylboron and tert-butyl peroxide to obtain a compound (IV-3); oxidizing the compound (IV-3) by an oxidizing agent to obtain a compound (IV-4), wherein the oxidizing agent is preferably active manganese dioxide, dess-martin oxidizing agent, pyridinium Dichromate (PDC) and the like; the compound (IV-4) is Still coupled with a tin reagent under the catalysis of palladium to obtain a compound (IV-5), and the catalyst is preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate, tetraphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium and the like; the compound (IV-5) is reacted with an aryl lithium salt or an aryl format reagent to give the compound of formula (I).
The pharmaceutically acceptable salts of the present invention refer to inorganic basic salts such as sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, ammonium salt, quaternary ammonium salt or aluminum salt; organic base salts such as lysine, arginine, diethylamine, triethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, dibenzylamine, piperidine and other pharmaceutically acceptable organic amine salts.
When at least one salifiable nitrogen atom is contained in the molecule of the compound of the present invention, it can be converted into the corresponding salt by reaction with the corresponding organic or inorganic acid in an organic solvent such as acetonitrile, 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, glucuronic acid, naphthalenesulfonic acid, glutaric acid, acetic acid, trifluoroacetic acid, malic acid, fumaric acid, salicylic acid, 4-aminosalicylic acid, lactic acid, palmitate, stearic acid, lauric acid, cinnamic acid, alginic acid, ascorbate, and typical inorganic acids are nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid.
When the compounds of the invention have one or more asymmetric carbon atoms, they can exist in the following form: optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, racemates or mixtures of racemates. All possible isomers, stereoisomers and mixtures thereof of the compounds 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 as described above or a tautomer, mesomer, racemate, enantiomer, diastereomer, and mixtures thereof, and pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, metabolites, isotopic derivatives thereof, and optionally one or more pharmaceutically acceptable carriers and/or diluents.
The pharmaceutical compositions provided herein may be prepared in any form, such as granules, powders, tablets, coated tablets, capsules, pills, syrups, drops, solutions, suspensions and emulsions, or sustained release formulations of the active ingredient, wherein examples of the capsules include hard or soft gelatin capsules, and the granules and powders may be in non-effervescent or effervescent form.
The pharmaceutical compositions of the present invention may further comprise one or more pharmaceutically or physiologically acceptable carriers, which will be suitably formulated for administration. For example, the pharmaceutically or physiologically acceptable carrier may be saline, hot-pressed water, ringer's solution, buffered saline, dextrose, maltodextrin, glycerol, ethanol, and mixtures thereof. The pharmaceutical compositions of the present invention may also include pharmaceutically or physiologically acceptable additives such as diluents, lubricants, binders, glidants, disintegrants, sweeteners, flavoring agents, wetting agents, dispersing agents, surfactants, solvents, coating agents, foaming agents, or fragrances.
Examples of diluents that may be used include, but are not limited to, lactose, sucrose, starch, kaolin, salts, mannitol, and dicalcium phosphate; examples of lubricants include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid; examples of binders include, but are not limited to, microcrystalline cellulose, gum tragacanth, dextrose solution, acacia syrup, gelatin solution, sucrose and starch paste; examples of glidants include, but are not limited to, colloidal silicon dioxide; examples of disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose; 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 flavors; examples of flavoring agents include, but are not limited to, natural flavoring agents extracted from plants, 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 monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
The pharmaceutical compositions of the present invention may be administered according to conventional methods by a variety of routes including oral, intravenous, intra-arterial, intraperitoneal, intrathoracic, transdermal, nasal, inhalation, rectal, ocular and subcutaneous introduction.
Pharmaceutically acceptable carriers optionally added to the pharmaceutical composition of the invention are: water, alcohol, honey, mannitol, sorbitol, dextrin, lactose, caramel, gelatin, calcium sulfate, magnesium stearate, talcum powder, kaolin, glycerol, tween, agar, calcium carbonate, calcium bicarbonate, surfactant, cyclodextrin and derivatives thereof, phospholipids, phosphates, starches and derivatives thereof, silicon derivatives, celluloses and derivatives thereof, pyrrolidone, polyethylene glycol, acrylic resins, phthalate esters, acrylic copolymers and trimellitates.
Pharmacological experiments prove that the compound or the pharmaceutical composition provided by the invention can treat tumors through BRD4, wherein the tumors are lymphoma, melanoma, glioma, gastrointestinal stromal tumor, prostate cancer, breast cancer, ovarian cancer, bladder cancer, lung cancer, rectal cancer, skin cancer, epithelial cell cancer, nasopharyngeal carcinoma, bone cancer, esophageal cancer or leukemia.
The compounds provided by the present invention are generally administered in a dosage range of about 0.001mg/Kg to 1000mg/Kg, preferably about 0.01mg/Kg to 100mg/Kg, more preferably about 0.1 to 20mg/Kg per day, with the dosage range of the pharmaceutical composition being calculated as the amount of the above-mentioned compound contained therein.
The invention also relates to the use of a compound according to the invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, and mixtures thereof, and pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, metabolites, isotopic derivatives thereof, or a pharmaceutical composition according to the invention for the manufacture of a medicament for the prevention and/or treatment of BRD4 mediated related diseases.
The BRD4 mediated related diseases include tumors.
The tumors are acute myelolymphoma, acute lymphoblastic leukemia, lymphoma and multiple myeloma.
The present invention also relates to a method for preventing and/or treating tumors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the invention, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to the invention.
The invention also relates to the use of the compounds according to the invention and their pharmaceutically acceptable salts or stereoisomers or of the pharmaceutical compositions according to the invention for the prophylaxis 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
First step N-methoxy-N-methyl-2- (tetrahydro-2H-pyran-4-yl) acetamide (1 j)
Tetrahydropyrane-4-acetic acid 1i (10.0 g,69.4 mmol) was dissolved in 30ml DCM, CDI (12.39 g,76.4 mmol) was added at 0deg.C, and after half an hour stirring dimethylhydroxylamine dihydrochloride (7.48 g,76.4 mmol) and DIPEA (15 mL,138.8 mmol) were added. Stir at room temperature overnight. TLC monitored the reaction, and the system was washed successively with 1M NaOH (aq) (50 ml x 2), citric acid (50 ml x 2), and saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give N-methoxy-N-methyl-2- (tetrahydro-2H-pyran-4-yl) acetamide 1j (9.0 g), a yellow oily liquid, 69% yield, without further purification.
Second step 1-phenyl-2- (tetrahydro-2H-pyran-4-yl) ethyl-1-one (1 k)
N-methoxy-N-methyl-2- (tetrahydropyran-4-yl) acetamide 1j (9.0 g,48 mmol) was placed in a 100ml three-necked flask. Sealing, adding 40ml anhydrous THF under nitrogen protection, stirring, cooling to-70deg.C, and dripping phenyl lithium (2M in THF,24ml,48mmol). The system color gradually deepens. Stirring at-70 ℃ for 2 hours, and quenching the reaction by NH 4Cl(sat.). Ethyl acetate (100 ml) and water (100 ml) were separated, the organic phase was washed with anhydrous saturated brine, dried over anhydrous sodium sulfate, filtered, spin-dried, and separated by column chromatography, and PE/ea=100/10 eluted to give 1-phenyl-2- (tetrahydropyran-4-yl) ethyl-1-one 1k (4.0 g), a white solid, yield 41%.
Third step 1-phenyl-2- (tetrahydropyran-4-yl) ethyl-1-ol (1 g)
Phenyl-4-tetrahydropyran methanone 1k (4.0 g,19.6 mmol) was dissolved in 40ml methanol and sodium borohydride (1.12 g,29.4 mmol) was added in portions at 0 ℃. After addition, stirring for 1 hour at room temperature, adding water quench (20 ml), extracting with EA (50 ml x 3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, column separation, PE/ea=90/10 elution, obtaining 1-phenyl-2- - (tetrahydropyran-4-yl) ethyl-1-ol 1g (2.2 g), white solid, yield 55%.
1H NMR(400MHz,CDCl3)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).
Fourth step methyl 4- (5-bromo-3-nitropyridin-2-yl) benzoate (1 c)
2, 5-Dibromo-3-nitropyridine 1a (5.0 g,17.7 mmol), 4-methoxycarbonylphenylboronic acid (3.19 g,17.7 mmol), K 3PO4 (3.0M, 18 ml) were dissolved in 60ml THF, pd (dppf) Cl 2 (1.30 g, 730 mmol) was added under nitrogen and reacted at 80℃for 3 hours. EA (100 ml) was separated from water (100 ml), the organic phase was dried, filtered, separated by column, and PE/EA=2/1 eluted to give methyl 4- (5-bromo-3-nitropyridin-2-yl) benzoate 1c (3.15 g), a white solid, yield 53%.
LCMS(ESI-MS)m/z：337.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.83(s,1H),8.02-8.04(d,J＝8.0Hz,2H),7.64-7.66(d,J＝8.0Hz,2H),3.85(s,3H).
Fifth step methyl 3-bromo-5H-pyrido [3,2-b ] indole-7-carboxylate (1 d)
Methyl 4- (5-bromo-3-nitropyridin-2-yl) benzoate 1c (200 mg,0.59 mmol) and DPPE (295 mg,0.74 mmol) were dissolved in 3ml o-dichlorobenzene and reacted at 180℃for 4 hours. The precipitated solid was filtered off at room temperature and the filter cake was washed with DCM to give methyl 3-bromo-5H-pyrido [3,2-b ] indole-7-carboxylate 1d (90 mg), an off-white solid in 50% yield.
LCMS(ESI-MS)m/z：305.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.80(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).
Sixth step methyl 3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -5H-pyrido [3,2-b ] indole-7-carboxylate (1 f)
3-Bromo-5H-pyrido [3,2-b ] indole-7-carboxylic acid methyl ester 1d (90 mg,0.30 mmol) and 1, 4-dimethyl-5- (tributylstannyl) -1H-1,2, 3-triazole 1e (126 mg,0.33 mmol) were dissolved in 5ml DMF, cuI (10 mg,0.045 mmol), pd (PPh 3)4 (35 mg,0.03 mmol) and 60mg TEA (0.6 mmol) were added sequentially, reacted under nitrogen atmosphere at 90℃for 3 hours, filtered through celite, and the DMF was dried by spin-drying, and the resultant was slurried with DCM, filtered to give a solid, 3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -5H-pyrido [3,2-b ] indole-7-carboxylic acid methyl ester 1f (24 mg), yellow solid, yield 25%.
LCMS(ESI-MS)m/z：322.1[M+H]+.
1H NMR(400MHz,DMSO-d6)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).
Seventh step methyl 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-carboxylate (1H)
1F (107 mg,0.33 mmol), 1g (136 mg,0.66 mmol) and triphenylphosphine (173 mg,0.66 mmol) were dissolved in 5mL dry THF and DIAD (133 mg,0.66 mmol) was added. Stirring overnight at room temperature, spin-drying the reaction, TLC preparation separation, DCM/meoh=20/1 development to give the title compound 1h (55 mg), off-white solid, 33% yield.
LCMS(ESI-MS)m/z：510.0[M+H]+.
Eighth step 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 (1)
1H (700 mg,1.37 mmol) was dissolved in 15mL dry THF and 6.9mL methyl magnesium bromide (2M in THF) was added with an ice salt bath (-10 ℃). After the addition, stirring overnight at room temperature, adding saturated aqueous ammonium chloride solution to quench the reaction, and filtering off solids. The filtrate was diluted with 50mL dichloromethane, washed with water (50 mL x 2), the organic phase dried over anhydrous magnesium sulfate, filtered, dried, column separated, and eluted with DCM/meoh=20/1 to give crude 400mg. The product was slurried with an appropriate amount of THF to give 1 (101 mg) as a white solid in 14% yield.
LCMS(ESI-MS)m/z：510.3[M+H]+.
1H NMR(400MHz,CDCl3)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-triazol-5-yl) -5H-pyrido [3,2-b ] indol-7-yl) propan-2-ol
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 (2 a)
1F (150 mg,0.47 mmol), 2b (129 mg,0.93 mmol) and triphenylphosphine (245 mg,0.93 mmol) were dissolved in 9mL dry THF and DIAD (188 mg,0.93 mmol) was added. Stirring overnight at room temperature, spin-drying the reaction, TLC preparation separated, DCM/meoh=20/1 development to give the title compound 2a (120 mg), an off-white solid, 56% yield.
LCMS(ESI-MS)m/z：438.1[M+H]+.
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)
2A (120 mg,0.27 mmol) was dissolved in 10mL dry THF, and 5.0mL methyl magnesium bromide (2M in THF) was added under an ice-salt bath (-10 ℃). After the addition, stirring overnight at room temperature, adding saturated aqueous ammonium chloride solution to quench the reaction, and filtering off solids. The filtrate was diluted with 30mL dichloromethane, washed with water (30 mL x 2), the organic phase dried over anhydrous magnesium sulfate, filtered, dried, column separated, DCM/meoh=20/1 eluting to give crude 140mg. The product was slurried with an appropriate amount of THF to give 2 (80 mg) as a white solid in 67% yield.
LCMS(ESI-MS)m/z：438.2[M+H]+.
1H NMR(400MHz,CDCl3)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
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 (3 a)
1F (200 mg,0.62 mmol), 3b (105 mg,1.24 mmol) and triphenylphosphine (325 mg,1.24 mmol) were dissolved in 10mL dry THF and DIAD (250 mg,1.24 mmol) was added. Stirring overnight at room temperature, spin-drying the reaction, TLC preparation separated, DCM/meoh=20/1 development to give the title compound 3a (146 mg), an off-white solid, 61% yield.
LCMS(ESI-MS)m/z：388.1[M+H]+.
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)
3A (146 mg,0.38 mmol) was dissolved in 10mL dry THF and 8.0mL methyl magnesium bromide (2 Min THF) was added with an ice salt bath (-10 ℃). After the addition, stirring overnight at room temperature, adding saturated aqueous ammonium chloride solution to quench the reaction, and filtering off solids. The filtrate was diluted with 30mL dichloromethane, washed with water (30 mL x 2), the organic phase dried over anhydrous magnesium sulfate, filtered, dried, column separated, and eluted with DCM/meoh=20/1 to give 130mg of crude product. The product was slurried with an appropriate amount of MeOH to collect 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 (50 mg), as a white solid, yield 34%.
LCMS(ESI-MS)m/z：388.1[M+H]+.
1H NMR(400MHz,CDCl3)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-Acetyloxy-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
First step methyl 3-bromo-5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -5H-pyrido [3,2-b ] indole-7-carboxylate (4 a)
Methyl 3-bromo-5-hydropyridine [3,2-b ] indole-7-carboxylate 1d (2.0 g,6.5 mmol) and phenyl (tetrahydro-2H-pyran-4-yl) methanol Int1 (2.5 g,13 mmol) were dissolved in 50ml THF, triphenylphosphine (3.4 g,13 mmol) was added, stirred under ice bath for 0.5H, DIAD (2.6 g,13 mmol) was added, slowly warmed to room temperature for 6H, TLC was monitored, the starting material was complete, the reaction was directly stirred on silica gel, flash column purified to give methyl 3-bromo-5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -5H-pyrido [3,2-b ] indole-7-carboxylate 4a (1.1 g,2.3 mmol) in 35.3% yield.
LCMS(ESI-MS)m/z：479.1[M+H]+.
1H NMR(400MHz,CDCl3)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＝11.0Hz,1H),4.01(s,4H),3.85(dd,J＝11.6,3.6Hz,1H),3.55(td,J＝11.6,2.0Hz,1H),3.37(td,J＝11.6,2.0Hz,1H),3.12(dt,J＝11.6,3.6Hz,1H),1.98(d,J＝13.5Hz,1H),1.68-1.50(m,1H),1.46-1.29(m,1H),1.02(d,J＝13.4Hz,1H).
Second step 3-bromo-7- (methoxycarbonyl) -5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -5H-pyrido [3,2-b ] indole 1-oxide (4 b)
4A (1.1 g,2.3 mmol) was dissolved in 20mL DCM and mCPBA (793.5 mg,4.6 mmol) was added under ice-bath conditions. Stirring overnight at room temperature, TLC monitoring, complete reaction of starting material, washing reaction solution with 1M aqueous NaOH solution, saturated aqueous sodium bisulphite solution, flash column purification to give 4b (930 mg,1.87 mmol), yield 81.6%.
1H NMR(400MHz,CDCl3)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＝11.9,2.1Hz,1H),3.38(td,J＝12.0,2.1Hz,1H),3.12(dt,J＝11.3,3.6Hz,1H),1.66-1.52(m,1H),1.37(qd,J＝12.1,4.2Hz,1H),1.05-0.97(m,1H).
Third step 2-Acetyloxy-3-bromo-5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -5H-pyrido [3,2-b ] indole-7-carboxylic acid methyl ester (4 c)
4B (780 mg,1.52 mmol) was dissolved in 5mL acetic anhydride and heated to reflux for 2 hours at 145℃and TLC monitoring was performed, the starting material was reacted completely, water was added, saturated aqueous sodium bicarbonate solution was used for washing, saturated aqueous sodium chloride solution was used for washing, dried over anhydrous sodium sulfate, spin-dried, flash column purification was performed, and 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) was obtained in 63.1% yield.
LCMS(ESI-MS)m/z：538.0[M+H]+.
1H NMR(400MHz,CDCl3)δ8.41(s,1H),832(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＝11.4Hz,1H),4.01(s,3H),3.86(d,J＝11.7Hz,1H),3.55(dd,J＝12.9,10.7Hz,1H),3.43-3.31(m,1H),3.10(q,J＝11.3Hz,1H),2.44(s,3H),1.70-1.51(m,1H),1.45-1.31(m,1H),1.05(d,J＝13.4Hz,1H).
Fourth step 2-Acetyloxy-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)
4C (200 mg,0.37 mmol) was dissolved in 5mL DMF and CuI (7.6 mg,0.04 mmol), 1e (157.5 mg,0.4 mmol), pd (PPh 3)4 (42.7 mg,0.4 mmol), nitrogen protected, heated to 95℃for 4 hours, monitored by TLC, the starting material was complete, water was added, the EA extracted, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the Flash column purified to give 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) as a pale yellow solid.
LCMS(ESI-MS)m/z：554.2[M+H]+.
1H NMR(400MHz,CDCl3)δ8.48(s,1H),842-8.34(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＝11.2Hz,1H),3.55(d,J＝17.2Hz,3H),3.33(t,J＝11.8Hz,1H),3.08(d,J＝11.2Hz,1H),2.05(d,J＝2.4Hz,6H),1.68-1.52(m,1H),1.42(d,J＝12.8Hz,1H),1.24(td,J＝7.3,1.9Hz,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
First step 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 (5)
4 (180 Mg,0.32 mmol) was dissolved in 5ml anhydrous THF, CH3MgBr (1M in THF,2mL,2mmol) was added, the reaction was stirred at room temperature for 4 hours, TLC was monitored, the reaction of the starting material was complete, water quenching was added, EA extraction, washing with saturated aqueous NaCl solution, drying over anhydrous sodium sulfate, flash column purification gave 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 5 (68 mg,0.13 mmol) as a pale yellow solid.
LCMS(ESI-MS)m/z：512.3[M+H]+.
1H NMR(400MHz,CDCl3)δ8.04(d,J＝8.4Hz,1H),7.92-7.86(m,1H),7.67(s,1H),7.42-7.27(m,5H),7.26(d,J＝1.1Hz,1H),5.49(d,J＝10.3Hz,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＝3.9Hz,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) -1H-benzo [ d ] imidazol-4-yl) benzhydrol
First step methyl 2-amino-5-bromo-3-nitrobenzoate (6 b)
Compound 6a (1.5 g,7.653 mmol) was dissolved in acetic acid (20 mL), bromine (3.26 g,19.1 mmol) was slowly added dropwise, the reaction was stirred at room temperature for 2 hours, the acetic acid was dried by spinning, then petroleum ether was added for beating, filtration, petroleum ether washing, and air drying gave the title compound 6b (1.2 g,4.36 mmol) in 57% yield.
LCMS(ESI-MS)m/z：277[M+H]+
Second step 2, 3-diamino-5-bromobenzoic acid methyl ester (6 c)
Compound 6b (1.2 g,4.36 mmol) was dissolved in ethanol (40 mL) and tetrahydrofuran (10 mL), then ammonium chloride (2.31 g,43.6 mmol) and zinc powder (2.83 g,43.6 mmol) were added, heated under reflux for 20 hours, filtered, washed with ethyl acetate, dried by spin-drying, then saturated sodium bicarbonate solution was added, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated and then purified by plate chromatography to give the title compound 6c (0.6 g,2.448 mmol) in 56% yield.
LCMS(ESI-MS)m/z：247[M+H]+.
Third step methyl 2-amino-5-bromo-3- (cyclopropanecarboxamido) benzoate (6 d)
Compound 6c (0.6 g,2.4 mmol) was dissolved in dichloromethane (10 mL), triethylamine (0.495 g,4.9 mmol) was added followed by dropwise addition of cyclopropanecarbonyl chloride (0.254 g,2.4 mmol), and after stirring at room temperature for 2h, the reaction was completed. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was dried over saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 6d (0.58 g,1.853 mmol) in 75% yield.
LCMS(ESI-MS)m/z：313[M+H]+.
Fourth step 6-bromo-2-cyclopropyl-1H-benzo [ d ] imidazole-4-carboxylic acid methyl ester (6 e)
Compound 6d (580 mg,1.966 mmol) was dissolved in acetic acid (4 mL) and stirred under microwave heating at 150deg.C under argon for 1h. After cooling, the mixture was dried by spinning, extracted three times with methylene chloride, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated, and then the title compound 6e (350 mg,1.19 mmol) was purified by plate chromatography to give a yield of 64%.
LCMS(ESI-MS)m/z：297[M+H]+.
Fifth step 2-cyclopropyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1H-benzo [ d ] imidazole-4-carboxylic acid methyl ester (6 f)
Compound 6e (300 mg,1.02 mmol), compound 1a (1161 mg,3.02 mmol) and Tetratriphenylphosphine palladium (230 mg,0.2 mmol) were dissolved in 1, 4-dioxane (5 mL), and stirred under argon at 150℃under microwave heating, after the reaction was completed, the reaction solution was extracted three times with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 6f (120 mg,0.38 mmol) as a layer purification product in 38% yield.
LCMS(ESI-MS)m/z：312[M+H]+.
Sixth step (2-cyclopropyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1H-benzo [ d ] imidazol-4-yl) diphenylmethanol (6)
Compound 6f (120 mg,0.38 mmol) was dissolved in dry tetrahydrofuran (5 mL), phenyl lithium (1.9 mL,1.9 mmol) was added at-78C, and after the addition was completed, the reaction was warmed to room temperature and allowed to react for 24 h. The reaction solution was washed with water, extracted three times with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 6 (7 mg,0.016 mmol) in 5% yield.
LCMS(ESI-MS)m/z：436[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),7.46(m,2H),7.26(d,J＝9.8Hz,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-pyran-4-yl) methyl) -5H-pyrido [3,2-b ] indol-7-yl) propan-2-ol
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-oxide (7 a)
4B (990 mg,2.0 mmol) was dissolved in 20mL DMF, cuI (38.0 mg,0.2 mmol), 1e (849.2 mg,2.2 mmol), pd (PPh 3)4 (231.1 mg,0.2 mmol), nitrogen protection, heating at 95℃for 4 hours, TLC monitoring, complete reaction of starting material, addition of water, EA extraction, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, flash column purification to give 7a (930 mg,1.82 mmol), yield 90.9%.
LCMS(ESI-MS)m/z：512.2[M+H]+.
1H NMR(400MHz,CDCl3)δ8.48(s,1H),842-8.34(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).
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 (7 b)
7A (300 mg,0.58 mmol) was dissolved in 5mL toluene, pyridine (176.3 mg,2.32 mmol), phosphorus oxychloride (177.8 mg,1.16 mmol) was added, the reaction was heated at 80℃for 4 hours under nitrogen protection, TLC monitoring, the starting material was complete, the solvent was spun dry, flash column purified to give 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 7b (173 mg,0.32 mmol), yield 56.2%.
LCMS(ESI-MS)m/z：530.2[M+H]+.
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)
7B (173 mg,0.32 mmol) was dissolved in 5ml anhydrous THF, CH3MgBr (1M in THF,2ml,2mmol) was added, stirred at room temperature for 4 hours, TLC was monitored, the starting material was complete, quenched with water, extracted with EA, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, and Flash column purified to give 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 (43 mg,0.08 mmol), yield 25% white solid.
LCMS(ESI-MS)m/z：530.4[M+H]+.
1H NMR(400MHz,CDCl3)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-pyran-4-yl) methyl) -5H-pyrido [3,2-b ] indol-7-yl) propan-2-ol
First step 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 (8 a)
7A (300 mg,0.58 mmol) was dissolved in 5mL toluene, pyridine (176.3 mg,2.32 mmol), phosphorus oxychloride (177.8 mg,1.16 mmol) was added, nitrogen protection, heating at 80℃for 4 hours, TLC monitoring, complete reaction of starting material, spin-drying of solvent, flash column purification to give 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 (40 mg,0.07 mmol), yield 13.0%.
LCMS(ESI-MS)m/z：530.23[M+H]+.
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)
8A (40 mg,0.07 mmol) was dissolved in 5ml anhydrous THF, CH 3 MgBr (1M in THF,1ml,1mmol) was added, the reaction was stirred at room temperature for 4 hours, TLC was monitored, the starting material was complete, quenched with water, EA extracted, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, and Flash column purified to give 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 (9 mg) as a white solid.
LCMS(ESI-MS)m/z：530.4[M+H]+.
1H NMR(400MHz,CDCl3)δ8.35(d,J＝8.3Hz,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＝2.0Hz,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-dimethyl-1H-1, 2, 3-triazol-5-yl) -5H-pyrido [3,2-b ] indol-7-yl) propan-2-ol
The title product 9 was obtained by a similar synthetic method to example 1.
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
First step methyl 3-bromo-5- (tetrahydrofuran-3-yl) -5H-pyrido [3,2-b ] indole-7-carboxylate (10 a)
Compound 1d (2 g,6.56 mmol), 10b (0.866 g,9.84 mmol), PPh 3 (3.44 g,13.12 mmol) and dry THF (30 mL) were added sequentially to a dry three-neck flask, nitrogen was purged, DIAD (2.64 g,13.12 mmol) was added dropwise to the reaction solution under ice-salt bath conditions, and after the dropwise addition was completed, the mixture was allowed to spontaneously warm to room temperature and stirred overnight. EA/water (30 mL/30 mL) was added, the mixture was stirred for 5 minutes, the liquid was separated, the aqueous phase was extracted with EA (20 ml×3), the organic phases were combined and washed with saturated brine (20 ml×3), dried and stirred, and purified by column chromatography (EA/pe=0% -100%) to give the title compound 10a (350 mg,0.936 mmol), a white solid, yield 14.2%.
LCMS(ESI-MS)m/z：377.1[M+H]+.
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 (10 b)
Compound 10a (250 mg,0.667 mmol), tetrakis triphenylphosphine palladium (77 mg,0.0667 mmol), cuI (25 mg,0.1333 mmol), dry DMF (10 mL), TEA (202 mg,2.0 mmol) and compound 1e (516 mg,1.333 mmol) were added sequentially to a dry three-neck flask, nitrogen-protected, and the oil bath heated to 100deg.C and stirred for 4h. After cooling to room temperature, saturated aqueous KF (5 mL) was added and stirred for 30 min, EA/water (30 mL/20 mE) was added, the mixture was stirred for 5min and separated, the aqueous phase was extracted with EA (15 ml×3), the organic phases were combined and washed with saturated brine (20 ml×3), dried and stirred, and purified by column chromatography (MeOH/dcm=0% -20%) to give the title compound 10b (200 mg,0.511 mmol), a white solid, yield 76.7%.
LCMS(ESI-MS)m/z：392.3[M+H]+.
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)
Compound 10b (180 mg,0.460 mmol) was dissolved in 30ml dry THF under nitrogen, stirred for 10min in ice-water bath, meMgBr (4.6 mL, 1M/THF) was added dropwise to the flask via syringe, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH 4 Cl (10 mL) in ice bath, the solids filtered off, the filtrate extracted with EA (30 ml×3), the organic phases combined and washed with saturated brine (15 ml×3), dried over anhydrous magnesium sulfate, concentrated and stirred, and purified by column chromatography (MeOH/dcm=0% -10%) to give the title compound 10 (75 mg,0.192 mmol), a white solid, 41.7% yield.
LCMS(ESI-MS)m/z：392[M+H]+.
1H 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＝9.8,5.3Hz,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-pyrido [3,2-b ] indol-5-yl) tetrahydro-2H-pyran-3-ol
First step 3, 7-dioxabicyclo [4.1.0] heptane (11 b)
Compound 11a (500 mg,5.95 mmol) was dissolved in methylene chloride (10.0 mL), m-CPBA (1.13 g,6.54 mmol) was added, stirred at room temperature for 4h, the disappearance of the starting material was found, quenched with aqueous sodium thiosulfate solution, extracted three times with methylene chloride, the organic phase was washed with sodium bicarbonate water, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 11b (290 mg,2.89 mmol) in 48.7% yield.
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 (11 c)
Compound 11b (270 mg,2.7 mmol) and 1f (284 mg,1.0 mmol) were dissolved in DMF (5.0 mL), cesium carbonate (1.02 g,3.4 mmol) was added and stirred under nitrogen at 110deg.C for 8h. After cooling, the mixture was dried by spinning, extracted three times with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and then purified by chromatography to give compound 11c (200 mg,0.49 mmol) in 49% yield.
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 (11 d)
Compound 11c (200 mg,0.49 mmol) was dissolved in methanol (2.0 mL), TMSCHN2 (5 mL) was added and stirred overnight at room temperature, after completion of the reaction, the organic phase was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and then purified by plate chromatography to give compound 11d (50 mg,0.118 mmol) in 24% yield.
Fifth step 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 (50 mg,0.12 mmol) was dissolved in THF (2.0 mL), methyl magnesium bromide (0.4 mL,1.2 mmol) was added under ice-bath, and after stirring overnight at room temperature, the reaction was completed. The reaction solution was washed with water, extracted three times with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 11 (21.0 mg,0.05 mmol) in a yield of 42%.
LCMS(ESI-MS)m/z：422.1[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝7.0Hz,1H),2.28(d,J＝4.0Hz,3H),2.04(d,J＝12.3Hz,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 pyrido [3,2-b ] indol-5-yl ] tetrahydrofuran-3-ol
The title product 12 was obtained by a similar synthetic method to example 11.
LCMS(ESI-MS)m/z：408.2[M+H]+.
1H 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＝8.3,1.4Hz,1H),5.31(s,1H),4.67(d,J＝3.4Hz,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
The title product 13 was obtained by a similar synthetic method to example 1.
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
First step 1- (pyridin-2-yl) -2- (tetrahydro-2H-pyran-4-yl) ethan-1-one (14 b)
A250 mL three-necked flask was taken, and compound 14a (5.06 g,32.04 mmol), N2 protection, THF (50 mL) was added, cooled to-65℃and N-butyllithium/N-hexane (15 mL,37.39mmol, 2.5M) was added dropwise and stirred at low temperature for 2h. Compound 1j (5 g,26.7 mmol) was dissolved in 10mL of HF and added dropwise to the reaction mixture, which was allowed to slowly warm to room temperature, and then allowed to warm to 60℃for 2h. TLC showed that there was a new point, the reaction solution was quenched with saturated aqueous ammonium chloride, extracted with EA, dried over anhydrous sodium sulfate, concentrated, and purified by Flash column to give compound 14b (3.2 g,15.6 mmol) as a pale yellow oil in 48.65% yield.
Second step 1- (pyridin-2-yl) -2- (tetrahydro-2H-pyran-4-yl) ethan-1-ol (14 c)
A single vial of 250mL was taken, compound 14b (3.2 mg,15.59 mmol), meOH (60 mL), an ice bath, and NaBH 4 (1.18 g,31.18 mmol) was added in small portions and allowed to react at 25℃for 16h. TLC monitoring shows complete reaction of starting materials with new points. The reaction mixture was concentrated in water to remove MeOH, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration to give compound 14c (3.2 g,15.44 mmol) as a pale yellow solid in 99% yield.
Using a synthesis similar to example 1, substituting 1j for 14c, the title product 14 was obtained in 3% yield.
LCMS(ESI-MS)m/z：511.4[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝11.9Hz,1H),3.67(d,J＝11.1Hz,1H),2.99(td,J＝11.2,10.2,2.9Hz,2H),2.62(d,J＝6.8Hz,2H),2.24(s,3H),1.83(d,J＝12.6Hz,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
The title product 15 was obtained by a similar synthetic method to example 1.
LCMS(ESI-MS)m/z：540.4[M+H]+.
1H NMR(400MHz,DMSO-d6)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-pyridinyl [3,2-b ] indole-5, 7-dicarboxylic acid ester
The title product 16 was obtained by a similar synthetic method to example 1.
LCMS(ESI-MS)m/z：408.2[M+H]+.
1H NMR(400MHz,CDCl3)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＝6.4Hz,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
The title product 17 was obtained by a similar synthetic method to example 14.
LCMS(ESI-MS)m/z：528.4[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝8.3,1.3Hz,1H),7.36-7.22(m,2H),7.07(ddd,J＝10.8,8.0,1.3Hz,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
The title product 18 was obtained by a similar synthetic method to example 14.
LCMS(ESI-MS)m/z：540[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝1.7Hz,1H),8.14-8.06(m,2H),7.86(d,J＝7.3Hz,2H),7.40(dd,J＝8.3,1.3Hz,1H),7.25(t,J＝7.7Hz,1H),7.03-6.97(m,1H),6.89(d,J＝8.1Hz,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
The title product 15 was obtained by a similar synthetic method to example 1.
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
The title product 20 was obtained by a similar synthetic method to example 1.
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-dimethyl-1H-1, 2, 3-triazol-5-yl) -5H-pyrido [3,2-b ] indol-7-yl) propan-2-ol
The title product 21 was obtained by a similar synthetic method to example 1.
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-dimethyl-1H-1, 2, 3-triazol-5-yl) -5H-pyrido [3,2-b ] indol-7-yl) propan-2-ol
The title product 22 was obtained by a similar synthetic method to example 1.
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
First step tert-butyl 4- (2- (methoxy (methyl) amino) -2-carbonylethyl) piperidine-1-carboxylate (23 b)
Compound 23a (4.86 g,20 mmol) and 23h (2.91 g,30 mmol) were dissolved in DCM (100 mL), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.76 mg,30 mmol), 1-hydroxybenzotriazole (4.05 g,30 mmol) and triethylamine (8.08 g,80 mmol) were added and after 24h at room temperature the reaction was completed. The reaction solution was washed with water, extracted three times with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 23b (4 g,13.98 mmol) in a yield of 70%.
LCMS(ESI-MS)m/z：309.3[M+Na]+.
Second step tert-butyl 4- (2- (3-fluorophenyl) -2-carbonylethyl) piperidine-1-carboxylate (23 c)
23B (4 g,13.98 mmol) was dissolved in 50mL dry THF, dry ice bath (-78 ℃ C.) and 35mL M-fluorophenylmagnesium bromide (1M in THF) was added. After the addition, stirring overnight at room temperature, adding saturated aqueous ammonium chloride solution to quench the reaction, and filtering off solids. The filtrate was diluted with 100mL dichloromethane, washed with water (50 mL x 2), the organic phase dried over anhydrous magnesium sulfate, filtered, dried by spin-on, and purified by column chromatography to give the title compound 23c (3 g,9.34 mmol) in 66% yield.
LCMS(ESI-MS)m/z：344.2(M+Na)+.
Third step tert-butyl 4- (2- (3-fluorophenyl-2-hydroxyethyl) piperidine-1-carboxylate (23 d)
Compound 23c (1.7 g,5.29 mmol) was dissolved in methanol (40 mL), sodium borohydride (0.2 g,15.88 mmol) was added, then stirred overnight at room temperature, acetic acid was added to quench the reaction, then dried by spinning, water was added and extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give the title compound 23d (1.5 g,4.643 mmol), yield 87%
LCMS(ESI-MS)m/z：346.3[M+Na]+.
Fourth step 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 (23 e)
Compound 23d (1 g,3.095 mmol) and 1f (497 mg,1.547 mmol) were dissolved in dry tetrahydrofuran (30 mL), triphenylphosphine (81mg, 3.095mmol and DIAD (625 mg,3.095 mmol) were added, stirred under argon for 14h at room temperature, dried by spin-drying, extracted three times with ethyl acetate after adding water, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give the title compound 23e (700 mg,1.182 mmol) in 72% yield
LCMS(ESI-MS)m/z：627.5[M+H]+.
Fifth step tert-butyl 4 (2- (3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -7- (2-hydroxypropan-2-yl) -5H pyrido [3,2-b ] indol-5-yl ] -2- (3-fluorophenyl) ethyl ] piperidine-1-carboxylic acid ester (23 f)
Compound 23e (700 mg,1.182 mmol) was dissolved in 20mL dry THF, dry ice bath (-78 ℃ C.) and 8mL methyl magnesium bromide (2M in THF) was added. After the addition, stirring overnight at room temperature, adding saturated aqueous ammonium chloride solution to quench the reaction, and filtering off solids. The filtrate was diluted with 50mL dichloromethane, washed with water (50 mL x 2), the organic phase dried over anhydrous magnesium sulfate, filtered, dried, and separated by preparative TLC, DCM/meoh=10/1, to give the crude target product 23f (350 mg,0.559 mmol) in 50% yield.
LCMS(ESI-MS)m/z：627.5[M+H]+.
Sixth step 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 (23 g)
Compound 23f (350 mg,0.559 mmol) was dissolved in DCM (5.0 mL), TFA (5 mL) was added and the reaction was stirred at room temperature for 2h after completion. The reaction mixture was dried by spinning, neutralized with saturated potassium carbonate, filtered, and concentrated to give 23g (280 mg,0.531 mmol) of the title compound in 95% yield.
LCMS(ESI-MS)m/z：527.5[M+H]+.
Seventh step 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)
23G (90 mg,0.1711 mmol) of the compound was dissolved in methylene chloride (5 mL), acetic acid (10 mg,0.1711 mmol) and formaldehyde (36 mg,1.2 mmol) were added, and after stirring at room temperature for 30 minutes, sodium borohydride (109 mg,0.5133 mmol) was added, and after stirring at room temperature for 13 hours, the reaction was completed. The reaction solution was quenched with water, extracted three times with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, followed by purification by plate chromatography to give the title compound 23 (13 mg,0.024 mmol) in 14% yield.
LCMS(ESI-MS)m/z：541.4[M+H]+.
1H 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＝14.6Hz,1H),1.62(d,J＝6.8Hz,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- (oxetan-3-yl) piperidin-4-yl) ethyl) -5H-pyrido [3,2-b ] indol-7-yl) propan-2-ol
The title product 24 was obtained by a similar synthetic method to example 23.
LCMS(ESI-MS)m/z：583.5[M+H]+.
1H 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＝14.4Hz,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
The title product 25 was obtained by a similar synthetic method to example 23.
LCMS(ESI-MS)m/z：581.1[M+H]+.
1H NMR(400MHz,MeOD)δ8.55(d,J＝1.6Hz,1H),8.36(d,J＝8.3Hz,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＝11.2,4.9Hz,1H),3.92(s,3H),3.53(dd,J＝41.5,12.8Hz,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
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)
4 (150 Mg,0.27 mmol) was dissolved in 3ml MeOH, 3ml H 2 O, potassium carbonate (372.6 mg,2.7 mmol) was added and the reaction stirred at room temperature for 4 hours, monitored by TLC, the starting material was complete, 3M hydrochloric acid was brought to pH < 7, the solvent was spun dry, and HPLC preparation was performed to give 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) as a 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' ] bipyridinyl
First step 5-bromo-6 '-chloro-3-nitro-2, 3' -bipyridine (27 b)
Compound 27a (5.0 g,21 mmol) compound 1a (4.9 g,17 mmol), potassium phosphate (13 g,63 mmol), THF (50 ml) was added Pd (dppf) Cl2 (1.4 g,2 mmol) and refluxed at 80℃for 4h. Cooling, adding water, extracting by EA, washing once by saturated sodium chloride water solution, concentrating, and passing through a Flash column to obtain the compound 27b (1.2 g,3.8 mmol) with the yield of 22%.
Second step 3-bromo-7-chloro-5H-pyrrolo [3,2-B:4,5-C' ] bipyridinyl (27C)
Compound 27b (3 g,9.5 mmol), DPPE (4.5 g,11.4 mmol) was added to dichlorobenzene (40 ml), heated to 180℃under reflux for 6h, cooled, filtered, washed with DCM, and the filter cake slurried with DCM, filtered to give compound 27c (1.1 g,3.9 mmol) in 41% yield.
Third step 7-chloro-3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -5H-pyrido [3,2-b ] indole (27 d)
Compound 27c (1.1 g,3.9 mmol), compound 5 (3 g,7.7 mmol), tetraphenylpalladium phosphate (0.45 g,0.39 mmol), copper iodide (38 mg,0.2 mmol), TEA (1.1 g,11.7 mmol) were dissolved in DMF (20 ml) and heated to 90℃for 6h. Concentration through the Flash column gave compound 27d (400 mg,1.34 mmol) in 34% yield.
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' ] bipyridinyl (27)
Compound 27d (100 mg,0.33 mol), compound 27e (79 mg,0.33 mmol), triphenylphosphine (172 mg,0.66 mmol) DIAD (133 mg,0.66 mmol) was added DCM (5 ml) and stirred overnight at room temperature. Passing through a Flash column gives compound 27 (20 mg,0.04 mmol) in 12% yield.
LCMS(ESI-MS)m/z：517.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.66-8.55(m,2H),8.06(d,J＝1.8Hz,1H),7.83-7.74(m,1H),7.42(d,J＝8.1Hz,1H),7.28-7.16(m,1H),7.02-6.92(m,1H),6.86(d,J＝8.2Hz,1H),6.55(dd,J＝10.5,5.3Hz,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＝13.0Hz,1H),2.15(s,3H),2.00(s,1H),1.38(d,J＝9.2Hz,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' ] bipyridinyl
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' ] bipyridinyl (28)
Compound 27 (100 mg,0.19 mmol), tetrahydropyrrole (28 mg,0.386 mmol), cesium carbonate (190 mg,0.58 mmol) was dissolved in DMF (10 ml) and reacted at 150℃for 78h. Cooling, adding water, extracting with EA, washing with saturated sodium chloride water solution once, concentrating, and passing 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' ] bipyridinyl-7-amine
The title product 29 was obtained by a similar synthetic method to example 28.
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' ] bipyridinyl
The title product 30 was obtained by a similar synthetic method to example 28.
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' ] bipyridinyl
The title product 31 was obtained by a similar synthetic method to example 27.
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' ] bipyridinyl-7-yl) -N1, N2-dimethylethane-1, 2-diamine
The title product 32 was obtained by a similar synthetic method to example 28.
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' ] bipyridinyl-7-yl) -4-methylpiperidin-4-ol
The title product 33 was obtained by a similar synthetic method to example 28.
LCMS(ESI-MS)m/z：584.5[M+H]+.
Example 34:2- (3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (methylsulfanyl) -5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -5H-pyrido [3,2-b ] indol-7-yl) propan-2-ol
First step methyl 3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (methylsulfanyl) -5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -5H-pyrido [3,2-b ] indole-7-carboxylate (34 a)
7G (150 mg,0.28 mmol) was dissolved in 5ml anhydrous DMF, sodium methyl mercaptan (72 mg,1.04 mmol) was added, the reaction was monitored by TLC at 90℃for 1 hour, methyl iodide (198.6 mg,1.4 mmol) was added, the reaction was monitored by LC-MS at room temperature for 2 hours, the reaction was complete, water was added, EA extraction, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, flash column purification gave 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 (130 mg,0.24 mmol), yield 85.6%.
LCMS(ESI-MS)m/z：542.4[M+H]+.
Second step 2- (3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (methylsulfanyl) -5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -5H-pyrido [3,2-b ] indol-7-yl) propan-2-ol (34)
34A (130 mg,0.24 mmol) was dissolved in 5ml anhydrous THF, CH3MgBr (1M in THF,2ml,2mmol) was added, the reaction was stirred at room temperature for 4 hours, TLC was monitored, the starting material was complete, quenched with water, EA extracted, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, flash column purified, 2- (3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (methylsulfanyl) -5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -5H-pyrido [3,2-b ] indol-7-yl) propan-2-ol 34 (35 mg,0.06 mmol), yield 26.9% pale yellow solid.
LCMS(ESI-MS)m/z：542.4[M+H]+.
1H NMR(400MHz,CDCl3)δ8.45-8.35(m,1H),8.32(d,J＝6.4Hz,1H),7.70-7.60(m,1H),7.53(dd,J＝12.0,7.5Hz,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＝12.4Hz,4H),1.78-1.72(m,2H),1.59(d,J＝2.7Hz,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' ] bipyridinyl
The title product 35 was obtained by a similar synthetic method to example 31.
LCMS(ESI-MS)m/z：487.2[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝12.1Hz,1H),1.42(d,J＝10.7Hz,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' ] bipyridinyl
First step 5-bromo-2 '-chloro-3-nitro-2, 4' -bipyridine (36 b)
4, 5-Dibromo-3-nitropyridine 1a (10.0 g,35.5 mmol), 36a (6.1 g,39.0 mmol), K 3PO4 (3.0M, 35.3 ml) were dissolved in 100ml THF, pd (DPPF) Cl 2 (2.6 g,3.55 mmol) was added under nitrogen and reacted at 80℃for 3 hours. EA (100 ml) was separated from water (100 ml), the organic phase was dried, filtered, separated by column, and PE/EA=2/1 eluted to give 5-bromo-2 '-chloro-3-nitro-2, 4' -bipyridine 36b (6.5 g), a white solid, 59.1% yield.
LCMS(ESI-MS)m/z：316[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝1.6,0.7Hz,1H),7.55(dd,J＝5.1,1.5Hz,1H).
Second step 3-bromo-6-chloro-5H-pyrrolo [3,2-B:5,4-C' ] bipyridinyl (36C)
5-Bromo-2 '-chloro-3-nitro-2, 4' -bipyridine 36b (4.0 g,12.7 mmol) and DPPE (6.0 g,15.2 mmol) were mixed in 40mL o-dichlorobenzene and reacted at 180℃for 4 hours. The reaction mixture was cooled to room temperature, distilled under pressure to remove dichlorobenzene, dissolved in DCM, and stirred with DCM: passing the MeOH through a column to obtain 3-bromo-6-chloro-5H-pyrrolo [3,2-B:5,4-C' ] bipyridinyl 36C (1.0 g), white solid, yield 28%.
LCMS(ESI-MS)m/z：283.9[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.32(s,1H),8.64(d,J＝2.0Hz,1H),8.21(d,J＝5.2Hz,1H),8.16(d,J＝2.1Hz,1H),8.10(dd,J＝5.2,0.7Hz,1H).
Step three 3-bromo-6-chloro-5- (1-phenyl-2- (tetrahydro-2H-pyran-4-yl) ethyl) -5H-pyrrolo [3,2-B:5,4-C' ] bipyridinyl (36 d)
36C (240 mg,0.85 mmol) and 1g (210.2 mg,1.02 mmol) triphenylphosphine (445.9 mg,1.7 mmol) were dissolved in 20mL dry THF and DIAD (343.7 mg,1.7 mmol) was added. Stirring overnight at room temperature, spin-drying the reaction, TLC preparation separation, DCM/meoh=20/1 development to give the target compound 3-bromo-6-chloro-5- (1-phenyl-2- (tetrahydro-2H-pyran-4-yl) ethyl) -5H-pyrrolo [3,2-B:5,4-C' ] bipyridinyl (36 d) (280 mg), as an off-white solid in 70% yield.
LCMS(ESI-MS)m/z：322.1[M+H]+.
1H NMR(400MHz,CDCl3)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),
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' ] bipyridinyl (36)
To a single vial was added 3-bromo-6-chloro-5- (1-phenyl-2- (tetrahydro-2H-pyran-4-yl) ethyl) -5H-pyrrolo [3,2-B:5,4-C '] bipyridinyl 36d (180 mg,0.4 mmol) and Int-1 (170.4 mg,0.44 mmol) were then added sequentially with CuI (11.4 mg,0.06 mmol), pd (PPh 3)4 (46.2 mg,0.04 mmol) and 110.9ul TEA (0.8 mmol) under nitrogen atmosphere at 90℃for 3 hours, filtered through celite, dried with spin-on DMF, and passed through the column to give 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-pyrrolo [3,2-b:5,4-C' ] bipyridine (36) (55 mg) as a white solid in 33% yield.
LCMS(ESI-MS)m/z：487.3[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝12.3,5.7Hz,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
First step (2-cyclopropyl-5- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1H-benzo [ d ] imidazol-7-yl) di (pyridin-2-yl) methanol (37)
2-Bromopyridine (660 mg,4.18 mmol) was placed in a dry three-necked flask, replaced with argon, 4ml of anhydrous THF was added, n-butyllithium (1.67 ml,4.18 mmol) was added dropwise at-78℃and stirred for 30min, compound 6f (130 mg,0.418 mmol) was dissolved in 2ml of anhydrous THF, added dropwise to the reaction solution and stirred for 1h at-78 ℃. 30ml of water was added dropwise thereto under ice-bath, then 60ml of EA was added for extraction, and the organic phase was dried after washing with saturated brine, purified by column chromatography with stirring, and eluted with pure methanol to give the title compound 37 (53 mg,0.121 mmol) in 29% yield.
LCMS(ESI-MS)m/z：438.1[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝1.5Hz,1H),3.83(s,3H),2.57(tq,J＝12.3,7.3,6.1Hz,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) methanolic hydrochloride
Step 1- (tert-butyl) 4 -methyl-6-bromo-2-cyclopropyl-1H-benzo [ d ] imidazole-1, 4-dicarboxylic acid ester (38 b)
Compound 6e (4.5 g,15.25 mmol) was dissolved in DCM (100 ml), and (Boc) 2O(5.0g,22.88mmol),Et3 N (4.6 g,45.75 mmol) and DMAP (93 mg,0.7625 mmol) were added sequentially with stirring at room temperature, then stirred at room temperature for three hours, 100ml of water was added, stirred for 5min to separate the aqueous phase, extracted with DCM (50 ml x 2), the organic phases combined, washed once with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and concentrated over column (EA/PE=0% -30%) to give the desired product 38b (5.2 g,13.20 mmol) as a white solid in 86.5% yield.
LCMS(ESI-MS)m/z：395.2[M+H]+.
Second step 6-bromo-2-cyclopropyl-4-formyl-1H-benzo [ d ] imidazole-1-carboxylic acid tert-butyl ester (38 c)
Morpholines (925 mg,10.63 mmol) were dissolved in dry THF (50 ml), DIBAL-H (6.75 ml,10.12 mmol) was added dropwise to the solution under nitrogen protection in ice bath, and stirred at 0deg.C for 3H. Raw material 38b (2 g,5.06 mmol) was dissolved in THF (2 ml), slowly added dropwise to the reaction solution, stirring was continued for 10min after the addition was completed, DIBAL-H (3.75 ml,5.57 mmol) was slowly added dropwise to the reaction solution, and stirring was continued for 20min after the addition was completed. The reaction was quenched by slowly dropping dilute hydrochloric acid (1 n,5 ml) into the reaction solution, adding EA (30 ml) and aqueous citric acid (50 ml) and stirring for 10min, separating the solution, extracting the aqueous phase with EA (30 ml x 2), combining the organic phases, washing twice with saturated aqueous NaCl, drying over anhydrous sodium sulfate, concentrating the mixture over column (EA/pe=0% -20%) to give the desired product 38c (1.3 g,3.56 mmol), a white solid, yield 70.4%.
LCMS(ESI-MS)m/z：365.1[M+H]+.
Third step 6-bromo-2-cyclopropyl-4- (hydroxy (tetrahydrofuran-2-yl) methyl) -1H-benzo [ d ] imidazole-1-carboxylic acid tert-butyl ester (38 d)
Compound 38c (1.3 g,3.57 mmol) was dissolved in dry THF (35 ml), et 3 B (35.7 g,35.7 mmol) was added dropwise to the reaction solution under ice-bath conditions, after stirring was continued for 10min after addition, t-BuOOH (3.57 ml,21.42 mmol) was added dropwise to the reaction solution, stirring was continued for 10min, the ice bath was removed, and stirring was continued for 20min at room temperature. The reaction was quenched by dropwise addition of aqueous ammonia (4 ml), continued stirring for 5min with 15ml of water, extracted with EA (20 ml x 3), combined organic phases, washed once with saturated aqueous NaCl, dried over anhydrous sodium sulfate, concentrated over column (EA/pe=0% -30%) to give the desired product 38d (900 mg,2.06 mmol), yellow oil, yield 57.7%.
LCMS(ESI-MS)m/z：437.2[M+H]+.
Fourth step 2-cyclopropyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (hydroxy (tetrahydrofuran-2-yl) methyl) -1H-benzo [ d ] t-butyl ester ] imidazole-1-carboxylic acid tert-butyl ester (38 f)
Compound 38d(200mg,0.4577mmol),38e(354mg,0.915mmol),Pd2(dba)3(42mg,0.0458mmol),CsF(278mg,1.83mmol) and Cy 3 P (26 mg,0.0915 mmol) were added to a microwave tube, solvent dioxane (10 ml) was added to dissolve, the tube was sealed after nitrogen substitution, and the mixture was heated to 110℃in an oil bath and stirred for 3 hours, cooled to room temperature and then directly concentrated and stirred, and purified by column chromatography (EA/PE=0%: 100%) to give the title compound 38f (140 mg,0.309 mmol) in 67.5% yield.
LCMS(ESI-MS)m/z：454.4[M+H]+.
Fifth step (2-cyclopropyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1H-benzo [ d ] imidazol-4-yl) (tetrahydrofuran-2-yl) methanolic hydrochloride (38)
Compound 38f (60 mg,0.132 mmol) was added to a 10ml single-port flask, dissolved in DCM (4 ml), HCl/MeOH (1.32 ml,5.29 mmol) was added dropwise to the reaction, stirred at room temperature for 4h after the dropwise addition, the solvent was removed by concentration, and dried under vacuum to give the title compound 10038 (51 mg,0.132 mmol) as a white solid in 100% yield after lyophilization with water.
LCMS(ESI-MS)m/z：354.2[M+H]+.
1H 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＝1.8Hz,3H),3.87-3.77(m,1H),3.72(dt,J＝11.2,6.9Hz,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
First step 6-bromo-2-cyclopropyl-4- (tetrahydrofuran-2-carbonyl) -1H-benzo [ d ] imidazole-1-carboxylic acid tert-butyl ester (39 a)
Compound 38d (400 mg,0.915 mmol) was dissolved in DCM (30 ml), dess-Martin reagent (552 mg,1.373 mmol) was added and stirred at room temperature for 2h, saturated Na 2S2SO3 solution (10 ml) was added, the mixture was stirred for 10min and the liquid separated, the aqueous phase was extracted with DCM (10 ml x 2), the organic phases combined, saturated aqueous NaHCO 3 washed once, dried over anhydrous sodium sulfate, concentrated over column (EA/PE=0% -20%) to give the desired product 39a (250 mg, 0.514 mmol) as a pale yellow solid in 62.8% yield. LCMS (ESI-MS) m/z:435.2[ M+H ] +.
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-carboxylic acid (39 b)
Compound 39a(200mg,0.460mmol),1e(356mg,0.920mmol),Pd2(dba)3(42mg,0.046mmol),CsF(280mg,1.84mmol) and Cy 3 P (26 mg,0.092 mmol) were added to a microwave tube, solvent dioxane (10 ml) was added to dissolve, the tube was sealed after nitrogen substitution, and the mixture was heated to 110℃in an oil bath and stirred for 3 hours, cooled to room temperature and then directly concentrated and stirred, and purified by column chromatography (EA/PE=0%: 100%) to give the title compound 39b (60 mg,0.133 mmol) in 28.9% yield.
LCMS(ESI-MS)m/z：352.2[M-100]+.
Step three (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)
2-Bromopyridine (203 mg, 1.284 mmol) was dissolved in dry THF (2 ml), nitrogen-blanketed, and n-BuLi (0.51 ml, 2.5M) was added dropwise to the solution at-78deg.C, followed by stirring for 30min. Raw material 39b (58 mg,0.1286 mmol) was dissolved in THF (0.5 ml), slowly added dropwise to the reaction solution, stirring was continued for 10min after the addition was completed, DIBAL-H (3.75 ml,5.57 mmol) was slowly added dropwise to the reaction solution, and stirring was continued for 30min after the addition was completed. The reaction was quenched by slow dropwise addition to the reaction solution with saturated aqueous ammonium chloride, the solution was separated, the aqueous phase was extracted with EA (5 ml x 2), the organic phases were combined, washed once with saturated aqueous NaCl, dried over anhydrous sodium sulfate, and concentrated over column (MeOD/dcm=0% -10%) to give the desired product 10038 (30 mg,0.070 mmol), a white solid, yield 54.3%.
LCMS(ESI-MS)m/z：431.3[M+H]+.
1H 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
First step 4-bromo-2, 6-dinitroaniline (40 b)
Compound 40a (15 g,81.9 mmol) and 300ml of acetic acid were added to a 500ml single-necked flask, br 2 (7.5 ml,122.8 mmol) was slowly added dropwise under ice bath, and the mixture was allowed to warm to room temperature and stirred overnight. At the end of the reaction, 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 give the title compound 40b (17 g,64.8 mmol) in 79.2% yield.
LCMS(ESI-MS)m/z：262.2[M+H]+.
Second step 5-bromo-3-nitrobenzene-1, 2-diamine (40 c)
Compound 40b (5 g,19 mmol) was dissolved in 200ml ethanol and 60ml THF, zn powder (12.4 g,190 mmol) was added under ice-bath, NH 4 Cl (10 g,190 mmol) was added, and stirred at 70℃for 3h. After cooling, the black insoluble matter was filtered off, the solvent was evaporated, EA and saturated sodium bicarbonate solution were added to wash for 2 times, and the organic phase was further washed with saturated brine, dried to give a concentrated preshrunk sample, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give the title compound 40c (3.5 g,15 mmol), yield 79%.
LCMS(ESI-MS)m/z：232.1[M+H]+.
Third step N- (2-amino-5-bromo-3-nitrophenol) cyclopropanecarboxamide (40 d)
Compound 40c (1.2 g,5.17 mmol) was dissolved in DCM 100ml, triethylamine (1.1 g,10.34 mmol) was added, cyclopropylcarbonyl chloride (537 mg,5.17 mmol) was added dropwise to the solution in ice water, and the mixture was allowed to warm to room temperature overnight. The layers were separated after quenching with water and DCM was dried and column chromatographed to give the title compound 40d (1 g,3.33 mmol) in 64% yield.
LCMS(ESI-MS)m/z：300.1[M+H]+.
Fourth step 5-bromo-2-cyclopropyl-7-nitro-1H-benzo [ d ] imidazole (40 e)
Compound 40d (1.5 g,5 mmol) was dissolved in 10ml of acetic acid, and after nitrogen substitution, reacted under microwaves at 150℃for 1 hour. After cooling, acetic acid was evaporated to dryness, EA was added, the mixture was washed with a saturated sodium hydrogencarbonate solution, and the organic phase was washed with a saturated brine. Dry preshrunk column chromatography (petroleum ether: ethyl acetate=2:1) gave the title compound 40e (560 mg,2.02 mmol) in 40.4% yield.
LCMS(ESI-MS)m/z：282.1[M+H]+.
Fifth step 2-cyclopropyl-5- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -7-nitro-1H-benzo [ d ] imidazole (40 g)
Compound 40e (570 mg,2.02 mmol), 1e (1.95 g,5.05 mmol), tetrakis triphenylphosphine palladium (251 mg,0.202 mmol), cuI (76 mg,0.404 mmol), triethylamine (408 mg,4.04 mmol) were added to a 20ml microwave tube, 1,4-Dioxane 8ml was added, and after Ar2 displacement, the reaction was carried out at 150℃for 1h. After cooling, EA was added for dilution, and after washing twice, the organic phase was dried and concentrated preshrunk-column chromatographed, eluting with pure EA to give the title compound 40g (500 mg,1.67 mmol) in 83% yield.
LCMS(ESI-MS)m/z：299.1[M+H]+.
Sixth step 2-cyclopropyl-5- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1H-benzo [ d ] imidazol-7-amine (40H)
40G (1.2 g,4.01 mmol) of the compound and 300mg of palladium on carbon were dissolved in 50ml of EA, replaced with hydrogen gas three times and stirred overnight at room temperature. After the reaction, palladium on carbon was filtered off and the filter cake was washed with EA. The title compound was obtained after concentration for 40h (1.0 g,2.67 mmol) in 93% yield.
LCMS(ESI-MS)m/z：269.1[M+H]+.
Seventh step 2-cyclopropyl-5- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -7-iodo-1H-benzo [ d ] imidazole (40 i)
Compound 40h (100 mg,0.373 mmol), p-toluenesulfonic acid (283 mg,1.49 mmol) were dissolved in 10ml acetonitrile and 5ml water, stirred at-5℃for 10min, KI (155 mg,0.934 mmol) and NaNO 2 (51 mg,0.74 mmol) were dissolved in 5ml water, and added dropwise to the reaction mixture, followed by reaction at-5℃for 1.5h. Water and EA were added to extract, and the organic phase was washed with saturated brine, dried and purified by column chromatography (methanol: dichloromethane=1:10) to give the title compound 40i (60 mg,0.158 mmol) in 42.4% yield.
LCMS(ESI-MS)m/z：380.2[M+H]+.
Eighth step 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 (40)
Compound 40i (100 mg,0.264 mmol), compound 40j (60 mg,0.264 mmol), pd (dppf) Cl 2 (20 mg,0.0264 mmol), potassium carbonate (92 mg,0.66 mmol), water 1ml, 1,4-Dioxane4ml were added to a microwave tube and replaced with argon. The reaction is carried out for 1h at 120 ℃. Water and EA were added for extraction, and column chromatography (methanol: dichloromethane=1:20) was used to elute the title compound 40 (11 mg, mmol) in 12% yield.
LCMS(ESI-MS)m/z：348.2[M+H]+.
1H 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
The title product 41 was obtained by a similar synthetic method to example 39.
LCMS(ESI-MS)m/z：445.5[M+H]+.
1H NMR(400MHz,MeOD)δ8.06(s,1H),7.89(d,J＝8.0Hz,1H),7.68(s,1H),7.61(d,J＝1.4Hz,1H),7.51(s,1H),5.23(s,1H),3.95(s,4H),3.82(q,J＝6.6Hz,1H),2.72(s,3H),2.62(td,J＝8.6,4.4Hz,1H),2.24(s,3H),1.97-1.78(m,J＝6.9Hz,4H),1.50(dd,J＝8.5,5.9Hz,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
Synthesis of the Compound 2- (allyloxy) benzaldehyde (42 b) in the first step
Compound 42a (20.0 g,164 mmol), bromopropene (22.0 g,180 mmol) and potassium carbonate (34.0 g,246 mmol) were dissolved in acetonitrile (200 mL), and the system was warmed to reflux for 3 hours. The reaction was monitored by TLC, the reaction solution was cooled to room temperature and poured into water, extracted 2 times with ethyl acetate, the organic phases were combined, washed with water, dried and concentrated to give 42b crude (20.0 g).
Synthesis of 2- (allyloxy) benzamide oxime as the second Compound (42 c)
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 3 times with ethyl acetate, and the combined organic phases were washed with water, dried and concentrated to give 42c crude (20.0 g).
1H NMR(400MHz,CDCl3)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).
Synthesis of third step Compound 3a, 4-dihydro-3H-chromene [4,3-c ] isoxazole (42 d)
Compound 42c (20.0 g,113 mmol) and catalytic amount of triethylamine (114 mg,1.13 mmol) were dissolved in dichloromethane (1200 mL), the system was cooled to 0-5deg.C, 4% sodium hypochlorite solution (1200 mL) was slowly added dropwise, and the temperature was controlled at 0-5deg.C and stirred for 2 hours. TLC detection, the reaction solution was poured into water and split. The aqueous phase was extracted twice with dichloromethane, the organic phases combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give 42d crude (12.0 g).
LCMS(ESI-MS)m/z：176.2[M+H]+.
1H NMR(400MHz,CDCl3)δ7.78(d,1H,J＝7.6Hz),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).
Synthesis of the fourth Compound 3- (hydroxymethyl) chroman-4-one (42 e)
Compound 42d (12.0 g,68.4 mmol) and boric acid (8.41 g,137 mmol) were dissolved in a mixture of methanol and water (120 mL, v/v=5/1) in a hydrogenation flask, nitrogen was purged 3 times, and Raney nickel (12.0 g) was added. Hydrogen was introduced and replaced 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 give crude 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).
Synthesis of Compound 3- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) chroman-4-one in the fifth step (42 f)
Compound 42e (6.0 g,33.7 mmol) and tetrahydropyran (11.2 g,135 mmol) were dissolved in dichloromethane (60 mL), and catalytic amounts of p-toluene sulfonic acid (580 mg,3.37 mmol) were added and stirred at room temperature for 2 hours. The aqueous phase was added and extracted twice with dichloromethane, the organic phases combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give 42f crude (8.0 g).
Synthesis of the sixth Compound 3- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) chroman-4-ol (42 g)
Compound 42f (8.0 g,30.5 mmol) was dissolved in methanol (80 mL), the temperature of the system was lowered to 0-5℃and sodium borohydride (1.2 g,30.5 mmol) was added in portions and the reaction was allowed to stand for 1 hour. A saturated ammonium chloride solution is dropwise added into the system, the mixture is extracted twice by ethyl acetate, the organic phases are combined, washed by water, dried by adding anhydrous sodium sulfate, filtered and concentrated to obtain a crude product E10_14, and 42g of pure product (4.0 g,15.3 mmol) is obtained by column chromatography, wherein the yield is 50%.
LCMS(ESI-MS)m/z：247.3[M-OH]+.
Synthesis of the Compound 4- (benzyloxy) -3- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) chromane in the seventh step (42H)
42G (4.0 g,15.2 mmol) of the compound was dissolved in a mixed solution of tetrahydrofuran and dimethylformamide (60 mL, v/v=5/1), the temperature of the system was lowered to 0-5 ℃, sodium hydride (308 mg,15.2 mmol) was added in portions, and the mixture was kept for 1 hour. Benzyl bromide (2.6 g,15.2 mmol) was added dropwise to the system, and the reaction was continued for 2 hours with a constant temperature. The reaction solution was poured into ice water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give a 42h crude product (5.0 g).
Synthesis of Compound (4- (benzyloxy) chroman-3-yl) methanol (42 i) in the eighth step
The compound (42 h) (5.0 g,14.1 mmol) was dissolved in methanol (50 mL), the system was cooled to 0-5℃and a catalytic amount of pyridinium p-toluenesulfonate (355 mg,1.41 mmol) was added and slowly warmed to room temperature and stirred for 4 hours. The reaction solution was poured into water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give crude E10_16, which was purified by column chromatography to give 42i (2.4 g,8.89 mmol) in 63% yield.
LCMS(ESI-MS)m/z：293.3[M+Na]+.
Synthesis of Compound 4- (benzyloxy) -3- (methoxymethyl) chroman (42 j) in the ninth step
Compound 42i (2.4 g,8.89 mmol) was dissolved in tetrahydrofuran (60 mL), the system was cooled to 0-5℃and sodium hydride (356 mg,8.89 mmol) was added in portions and incubated for 1 hour. Methyl iodide (1.3 g,8.89 mmol) was added dropwise to the system, and the reaction was carried out at room temperature for 2 hours with slow temperature rise. The reaction solution was poured into ice water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give crude E10_17, which was purified by column chromatography to give 42j (2.0 g,7.11 mmol) in 80% yield.
LCMS(ESI-MS)m/z：307.2[M+Na]+.
1H NMR(400MHz,CDCl3)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).
Tenth step Synthesis of 3- (methoxymethyl) chroman-4-ol (42 k)
Compound 42j (500 mg,1.76 mmol) was dissolved in methanol (10 mL) in a hydrogenation flask, replaced with nitrogen 3 times, 10% palladium on carbon (50 mg) was added, replaced with hydrogen 3 times, and stirred at room temperature overnight. Three reactions are added in parallel, palladium carbon is removed by combining filtration after the reaction is finished, a filter cake is washed by methanol, a filtrate is concentrated to obtain a crude product, and the crude product is subjected to column chromatography to obtain a 42k pure product (750 mg,1.32 mmol) with the yield of 75%.
LCMS(ESI-MS)m/z：177.1[M-17]+.
Eleventh step 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 (42 & 43)
Using a synthesis similar to example 1, substituting 42k for 1g gave the title products 42 and 43 in 17% yield. 42 (20 mg,0.042 mmol), 42 (40 mg,0.081 mmol) in 17% yield.
42：LCMS(ESI-MS)m/z：498.1[M+H]+.
1H NMR(400MHz,DMSO--d6)δ8.38-8.40(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]+.
1H NMR(400MHz,DMSO-d6)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: synthesis of 2- (3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -5- (2- (2-methoxyethyl) -2, 3-dihydrobenzofuran-3-yl) -5H-pyrido [3,2-b ] indol-7-yl) propan-2-ol
Synthesis of methyl 4-methoxybutyrate as Compound (44 h) in the first step
44A (50.0 g,0.58 mol), trimethyl orthoformate (117.0 g,1.1 mol) and MeOH (200 mL) were added sequentially to the flask, and concentrated sulfuric acid (5 mL) was added dropwise with stirring at room temperature. The system was warmed to reflux overnight and monitored by TLC. The reaction solution was cooled to room temperature, poured into water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give 44b as a pure product (27 g,0.2 mol) in a yield of 35.2%.
1H NMR(400MHz,CDCl3)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).
Synthesis of 4-methoxybutyric acid, the Compound of the second step (44 c)
Compound 44b (27.0 g,0.2 mol) was dissolved in methanol/water (250 mL/50 mL) and LiOH.H2O (12.9 g,0.3 mol) was added. The reaction system was stirred at room temperature for 2 hours. The reaction was checked by TLC, 1M hydrochloric acid solution was added dropwise to ph=3-4, extracted twice with ethyl acetate, the organic phases combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give 44c as pure product (18 g,0.15 mol) in 75% yield.
1H NMR(400MHz,CDCl3)δ3.47-3.42(m，2H)，3.34(s，3H)，2.48-2.44(m，2H)，1.94-1.87(m，2H).
Synthesis of the third Compound N, 4-dimethoxy-N-methylbutanamide (44 d)
Compound 44c (18 g,0.15 mol) was dissolved in methylene chloride (180 mL) and HOBt (31.1 g,0.23 mol), EDCI (43.9 g,0.23 mol), TEA (46.2 g,0.46 mol) and dimethylamine hydrochloride (17.8 g,0.18 mol) were added sequentially. The reaction system was stirred at room temperature for 4 hours. TLC detection reaction, reaction liquid water washing, saturated saline water washing, adding anhydrous sodium sulfate for drying, filtering and concentrating to obtain a 44d crude product, and column chromatography to obtain a 44d pure product (12 g,74.5 mmol) with a yield of 48.6%.
LCMS(ESI-MS)m/z：162.0[M+H]+.
1H NMR(400MHz,CDCl3)δ3.68(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).
Synthesis of 4-methoxy-1- (2-methoxyphenyl) butan-1-one as Compound in the fourth step (44 f)
Compound 44e (5 g,26.7 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) and nitrogen replaced 3 times. The temperature of the system was reduced to-70℃and n-BuLi (11.8 mL,29.4 mmol) was slowly added dropwise. After stirring the system at-70℃for 1 hour, 44d (6.5 g,40.1 mmol) was added dropwise. Four reactions were added in parallel, stirred for 2 hours at-70 ℃, detected by TLC, quenched by dropwise addition of saturated ammonium chloride solution, extracted twice with ethyl acetate, the organic phases combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give crude 44f, which was purified by column chromatography (16 g,76.9 mmol) in 72% yield.
LCMS(ESI-MS)m/z：209.2[M+H]+.
1H NMR(400MHz,CDCl3)δ7.68-7.66(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).
Synthesis of the Compound 2-bromo-4-methoxy-1- (2-methoxyphenyl) butan-1-one in the fifth step (44 g)
Compound 44f (16 g,76.9 mmol) was dissolved in dichloromethane (320 mL). The temperature of the system was lowered to 0℃and bromine (12.2 g,76.9 mmol) was slowly added dropwise thereto and stirred at room temperature for 0.5 hours. TLC detection, reaction solution washing with water, drying with anhydrous sodium sulfate, filtering and concentrating to obtain E11-7 crude product, column chromatography to obtain 44g pure product (20 g,69.7 mmol) with a yield of 91%.
LCMS(ESI-MS)m/z：287.2[M+H]+.
1H NMR(400MHz,CDCl3)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).
Synthesis of the Compound 2-bromo-1- (2-hydroxyphenyl) -4-methoxybutan-1-one in the sixth step (44 h)
Compound 44f (20 g,69.7 mmol) was dissolved in dichloromethane (400 mL), the temperature of the system was lowered to-10℃and boron tribromide (10 mL) was slowly added dropwise and stirred at-10℃for 10 minutes. TLC detection was carried out, the reaction solution was poured into ice water, extracted twice with dichloromethane, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give crude E11-8, which was purified by column chromatography (6 g,22.1 mmol) for 44h in 31.6% yield.
1H NMR(400MHz,CDCl3)δ11.91(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).
Synthesis of the Compound 2- (2-methoxyethyl) benzofuran-3 (2H) -one in seventh step (44 i)
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, extracted 2 times with ethyl acetate, the organic phases were combined, washed with water, dried and concentrated to give crude 44i, which was purified by column chromatography (2 g,10.4 mmol) in 47.6% yield.
1H NMR(400MHz,CDCl3)δ7.68-7.58(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).
Synthesis of the eighth Compound 2- (2-methoxyethyl) -2, 3-dihydrobenzofuran-3-ol (44 j)
Compound 44i (2 g,10.4 mmol) was dissolved in methanol (40 mL), the system was cooled to 0deg.C, sodium borohydride (0.4 g,10.4 mmol) was added, and stirred at 0deg.C for 1 hour. The reaction was monitored by TLC, the reaction mixture was extracted with water, the organic phases were combined, washed with water, dried and concentrated to give crude 44j, which was chromatographed on thin layer to give 44j (1.5 g,7.7 mmol) in 75% yield.
1H NMR(400MHz,CDCl3)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).
Synthesis of the ninth Compound 2- (3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -5- (2- (2-methoxyethyl) -2, 3-dihydrobenzofuran-3-yl) -5H-pyrido [3,2-b ] indol-7-yl) propan-2-ol (44 & 45)
Using a synthesis similar to example 1, substituting 1g for 42j gives the title products 44 and 45, and purifying by perp-HPLC gives 44 (30 mg,0.06 mmol), 45 (30 mg,0.06 mmol) in 10% yield.
LCMS(ESI-MS)m/z：498.2[M+H]+.
44：1H NMR(400MHz,DMSO-d6)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).
45：1H NMR(400MHz,DMSO-d6)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).
Examples 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)
First step N-methoxy-N-methyltetrahydrofuran-3-carboxamide (46 b)
46A (10.0 g,86.2 mmol) was dissolved in 200mL of dichloromethane, CDI (20.95 g,129.3 mmol) was added at 0deg.C, and then stirred for 1 hour at room temperature. Dihydroxylamine hydrochloride (12.67 g,129.3 mmol) and DIPEA (22.07 g,172.4 mmol) were added. After the addition, the mixture was stirred at room temperature overnight.
The reaction system was washed with saturated citric acid, sodium bicarbonate, brine in this order, and the organic phase was collected, dried, filtered, spin-dried, and then subjected to column separation PE/ea=4/1 elution and iodine development to give the objective compound 46b (9.8 g), a colorless oil, in 66% yield.
Second step pyridin-2-yl magnesium bromide (46 d)
1088C (5.0 g,31.6 mmol) was dissolved in 10mL of anhydrous tetrahydrofuran at room temperature, and i-PrMgCl (3.0M, 11.6mL,34.8mmol,1.1 eq) was added dropwise. After the addition, the mixture was stirred at room temperature for 3 hours. The system is brownish black for standby.
Third step pyridin-2-yl (tetrahydrofuran-3-yl) methanol (46 e)
Compound 46b (5.0 g,31.6 mmol) was dissolved in 18mL of anhydrous tetrahydrofuran, and 46d (31.6 mmol) prepared above was added dropwise at room temperature. After the completion of the dropping, stirring was continued at room temperature overnight. After quenching the reaction with saturated ammonium chloride, it was diluted with EA, washed with water, the organic phase was collected, dried, filtered, and column separated, and PE/ea=4/1 eluted to give the target compound 46e (3.4 g), a pale yellow liquid, in 61% yield.
LCMS(ESI-MS)m/z：178.1[M+H]+.
Fourth step pyridin-2-yl (tetrahydrofuran-3-yl) methanol (46 f)
46E (1.0 g,5.65 mmol) was dissolved in 5mL of methanol and sodium borohydride (257 mg,6.78 mmol) was added at 0deg.C. After the addition, the mixture was stirred at room temperature for 2 hours. After the reaction, the system was spun-dried, EA/H2O was separated, the organic phase was collected, dried, and filtered to give the target compound 46f (575 mg), a yellow liquid.
LCMS(ESI-MS)m/z：180.2[M+H]+.
Fifth step 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-carboxylic acid ester (46 h)
In a 50mL single-necked flask, 46g (230 mg,0.75 mmol), 46f (147 mg,0.82 mmol), CMBP (cas: 157141-27-0, 271mg,1.125 mmol) and 8mL o-dichlorobenzene were successively added, and reacted at 150℃for 4 hours. LCMS monitored the reaction. After the reaction was completed, the sample was applied by wet method, and PE/EA=4/1 was eluted to give 46h (286 mg), a yellow solid, yield 76%. (TLC shows two more mixtures of the same molecular weight, retention time on LCMS is essentially identical.)
LCMS(ESI-MS)m/z：469.2[M+H]+.
Sixth step 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-carboxylic acid ester (46 j)
In a 100mL single-port flask, 46h (320 mg,0.64 mmol), tin reagent (300 mg,0.78 mmol), cuI (11.4 mg,0.06 mmol), PCy3 (35.8 mg,1.28 mmol), pd2 (dba) 3 (117 mg,1.28 mmol), and 8mL DMF under nitrogen were added in this order and reacted at 100℃for 3 hours. LCMS monitored the reaction. Spin-dry DMF, dissolve with DCM/meoh=1/1, isolate the suspension by TLC prep, DCM/meoh=20/1 develop to give 46j (200 mg), yellow solid in 60% yield.
LCMS(ESI-MS)m/z：518.4[M+H]+.
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 (200 mg,0.39 mmol) was dissolved in 20mL anhydrous tetrahydrofuran, cooled to 0deg.C, methyl magnesium bromide (1.0M, 3.9mL,10 eq) was added, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride solution, the solid was filtered off, the organic phase was dried by spinning, the residue was dissolved in dichloromethane, TLC was separated, DCM/meoh=20/1 was developed to give 46 (30 mg, white solid, TLC showed a larger spot of Rf), 47 (14 mg, white solid, TLC showed a smaller spot of Rf) and the yield was 22%.
LCMS(ESI-MS)m/z：486.4[M+H]+.
46：1H NMR(400MHz,DMSO-d6)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).
47：1H NMR(400MHz,DMSO-d6)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
First step 5-bromo-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (48 a)
1-Methyl-1H-pyrrole-2-carboxylic acid methyl ester (10 g,71.9 mmol) was dissolved in dichloromethane (200 mL), N-bromosuccinimide (12.8 g,71.9 mmol) was added in ice bath and stirred overnight at room temperature. Flash column chromatography purification (PE/EA 0-10%) gave 48a (7.6 g,34.9 mmol) in 48.5% yield.
1H NMR(400MHz,DMSO-d6)δ6.88(d，J＝4.2Hz，1H)，6.30(d，J＝4.2Hz，1H)，3.82(s，3H)，3.71(s，3H).
Second step 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylic acid methyl ester (48 b)
A solution of compound 48a (7.6 g,34.9 mmol), bis (pinacolato) diboron (10.6 g,41.7 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride (2.5 g,3.4 mmol) and potassium acetate (6.8 g,6.9 mmol) in N, N-dimethylformamide (100 mL) was heated to 100deg.C under nitrogen and reacted for 2 hours, cooled, diluted with ethyl acetate (800 mL), washed with water (500 mL. Times.5), dried over Na2SO4, filtered and concentrated to give crude compound 48b (11.8 g,44.5 mmol).
LCMS(ESI-MS)m/z：266.2[M+H]+.
Third step 5- (5-bromo-3-nitropyridin-2-yl) -1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (48 c)
A mixed solution of 48b (11.8 g,44.5 mmol), 2, 5-dibromo-3-nitropyridine (14.1 g,50 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride (3.3 g,4.5 mmol), and potassium phosphate (18.9 g,89.0 mmol) in 1, 4-dioxane (100 mL) and water (5 mL) was heated to 100deg.C under nitrogen and stirred for 2 hours, cooled, diluted with ethyl acetate (600 mL), washed with water (400 mL. Times.3), dried over Na 2SO4, filtered, concentrated, and Flash passed over a column (PE/EA 0-10%) to give 48c (6.6 g,19.4 mmol) as the title compound in 43.6% yield.
LCMS(ESI-MS)m/z：340.1[M+H]+.
Fourth step 6-bromo-1-methyl-1, 4-dihydropyrrolo [2',3':4,5] pyrrolo [3,2-b ] pyridine-2-carboxylic acid methyl ester (48 d)
A solution of compound 48c (6.6 g,19.4 mmol) and triethyl phosphite (10.0 g,60.2 mmol) in dichlorobenzene (100 mL) was heated to 160deg.C and stirred for 4 hours, cooled to room temperature, filtered, and the filter cake was washed with dichloromethane and dried to give the title compound 48d (1.4 g,4.5 mmol) in 23.2% yield.
LCMS(ESI-MS)m/z：308.1[M+H]+.
Fifth step 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 (48 e)
A solution of compound 90d (300 mg,0.97 mmol), 1, 4-dimethyl-5- (tributylstannyl) -1H-1,2, 3-triazole (600 mg,1.55 mmol) and tetrakis (triphenylphosphine) palladium (100 mg,0.08 mmol) in DMF (10 mL) was heated to 100deg.C under nitrogen and reacted for 2 hours, cooled and diluted with ethyl acetate (100 mL), washed with water (100 mL. Times.3), dried over Na2SO4, filtered, concentrated and Flash column passed (PE/EA 0-100%) to give compound 90e (280 mg,0.86 mmol) in 88.7% yield.
LCMS(ESI-MS)m/z：325.2[M+H]+.
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 (48 f)
A solution of compound 90e (280 mg,0.86 mmol), 2' - (bromomethylene) bipyridine (320 mg,1.28 mmol) and potassium carbonate (250 mg,1.81 mmol) in N, N-dimethylformamide (10 mL) was heated to 50deg.C under nitrogen, cooled, diluted with ethyl acetate (100 mL), washed with water (50 mL. Times.5), dried over Na 2SO4, filtered, concentrated, and Flash passed over column (DCM/MeOH 0-10%) to afford the title compound 90f (120 mg,0.24 mmol) in 28.2% yield.
LCMS(ESI-MS)m/z：493.4[M+H]+.
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)
A solution of compound 90f (120 mg,0.24 mmol) in THF (10 mL) was cooled to 0deg.C under nitrogen, methyl magnesium bromide (1 mL,2.5 mmol) was added dropwise and the reaction stirred at room temperature for 2h, flash column chromatography (DCM/MeOH 0-10%) afforded the title compound 48 (4 mg,0.008 mmol) in 3.3% yield.
LCMS(ESI-MS)m/z：493.3[M+H]+.
1H NMR(400MHz,DMSO-d6)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
First step 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-one (49 b)
5-Bromo-2, 3-dihydro-1H-inden-1-one 49a (10.0 g,47.4 mmol), 4',5, 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborolane) (13.2 g,52.1 mmol), potassium acetate (7.05 g,70.5 mmol) was dissolved in 150ml dioxane, pd (DPPF) Cl 2 (3.4 g,4.7 mmol) was added under nitrogen and reacted at 100℃for 5 hours. TLC monitoring of the starting material reacted completely, water addition, EA extraction, washing with saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, flash column purification, obtaining methyl 4- (5-bromo-3-nitropyridin-2-yl) benzoate 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-one 49b (8.9 g,34.4 mmol), yield 72.7%.
LCMS(ESI-MS)m/z：259.1[M+H]+.
Second step 5- (5-bromo-3-nitropyridin-2-yl) -2, 3-dihydro-1H-inden-1-one (49 c)
Methyl 4- (5-bromo-3-nitropyridin-2-yl) benzoate 49b (8.9 g,34.4 mmol) and 2, 5-dibromo-3-nitropyridine (9.7 g,34.4 mmol) were dissolved in 200ml THF, potassium phosphate (21.9 g,103.2 mmol) was added, H 2 O (40 ml), pd (DPPF) Cl 2 (2.56 g,3.5 mmol) was added under nitrogen and the reaction stirred at 80℃for 4 hours. TLC monitoring of the starting material reacted completely, water addition, EA extraction, washing with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, flash column purification, obtaining 5- (5-bromo-3-nitropyridin-2-yl) -2, 3-dihydro-1H-inden-1-one 49c (5.1 g,15.3 mmol), yield 44.5%.
1H NMR(400MHz,CDCl3)δ8.95(d,J＝2.0Hz,1H),8.38(d,J＝2.1Hz,1H),7.88-7.80(m,1H),7.66(dt,J＝1.8,0.9Hz,1H),7.50(ddt,J＝7.8,1.4,0.7Hz,1H),3.24-3.20(m,2H),2.78-2.75(m,2H).
Third step 8-bromo-1, 10-dihydro-cyclopenta [ g ] pyrido [3,2-b ] indol-3 (2H) -one (49 d)
49C (5.0 g,15.0 mmol) was dissolved in 40ml o-dichlorobenzene, triethylphosphite (7.5 g,45 mmol) was added, nitrogen protected, stirred at 145 ℃ for 2 hours, monitored by TLC, the starting material reacted completely, cooled to precipitate a solid, filtered and washed with DCM to give 8-bromo-1, 10-dihydro-cyclopenta [ g ] pyrido [3,2-b ] indol-3 (2H) -one 49d (2.4 g,7.7 mmol), in 51.6% yield.
1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),8.62(d,J＝2.0Hz,1H),8.27(d,J＝2.0Hz,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).
Fourth step 8-bromo-10- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 10-dihydro-cyclopenta [ g ] pyrido [3,2-b ] indol-3 (2H) -one (49 e)
49D (1.5 g,5.0 mmol) and phenyl (tetrahydro-2H-pyran-4-yl) methanol Int1 (2.8 g,15 mmol) were dissolved in 60ml anhydrous DCM, tributylphosphine (3.1 g,15 mmol) was added, stirring under ice-bath conditions for 0.5H, TMAD (2.6 g,15 mmol) was added, reaction was slowly warmed to room temperature for 6H, TLC monitored, starting material reacted completely, direct silica gel stirring, flash column purification, 8-bromo-10- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 10-dihydro cyclopenta [ g ] pyrido [3,2-b ] indol-3 (2H) -one 49e (630 mg,1.32 mmol) was added, yield 26.5%.
LCMS(ESI-MS)m/z：477.0[M+H]+.
1H NMR(400MHz,CDCl3)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＝15.6,5.8Hz,1H),3.82(dd,J＝11.7,4.4Hz,1H),3.73(d,J＝6.5Hz,2H),3.56(q,J＝10.4,9.0Hz,1H),3.39-3.30(m,1H),3.06(d,J＝11.4Hz,1H),2.93(t,J＝5.7Hz,2H),2.10(d,J＝13.5Hz,1H),1.58(qd,J＝11.9,4.2Hz,1H),1.38-1.30(m,1H),0.81(d,J＝13.5Hz,1H).
Fifth step 8- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -10- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 10-dihydro-cyclopenta [ g ] pyrido [3,2-b ] indol-3 (2H) -one (49 f)
49E (430 mg,0.9 mmol) was dissolved in 10mL DMF, cuI (34.2 mg,0.18 mmol), int1 (694.8 mg,1.8 mmol), pd (dba) 2 (103.5 mg,0.18 mmol), tricyclohexylphosphine (50.4 mg,0.18 mmol), nitrogen protection, heating at 105℃for 2 hours, TLC monitoring, complete reaction of starting material, addition of water, EA extraction, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, flash column purification, 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 ] indol-3 (2H) -one 49f (400 mg,0.81 mmol), yield 90.5%.
LCMS(ESI-MS)m/z：492.3[M+H]+.
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)
49F (530 mg,1.1 mmol) was dissolved in 5ml anhydrous THF, CH3MgBr (3M in THF,3ml,9mmol) was added, stirred at room temperature for 4 hours, TLC was monitored, the starting material was complete, quenched with water, extracted with EA, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, and Flash column purified to give 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 (210 mg,0.41 mmol), yield 37.2% as a pale yellow solid.
LCMS(ESI-MS)m/z：508.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.48(t,J＝1.5Hz,1H),8.20-8.08(m,2H),7.64(dt,J＝9.2,3.1Hz,2H),7.41-7.30(m,3H),7.26(td,J＝7.1,1.6Hz,1H),5.85(d,J＝11.1Hz,1H),5.20(s,1H),3.90(d,J＝5.2Hz,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
The title product 41 was obtained by a similar synthetic method to example 37.
LCMS(ESI-MS)m/z：450.2[M+H]+.
1H NMR(400MHz,CDCl3)δ7.76-7.65(m,4H),7.33(dd,J＝12.8,3.2Hz,2H),3.84(s,3H),2.59(s,1H),2.12(d,J＝18.5Hz,3H),1.43(d,J＝8.0Hz,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' ] bipyridinyl
The title product 51 was obtained by a similar synthetic method to example 28.
LCMS(ESI-MS)m/z：652.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.36(d,J＝1.8Hz,1H),8.21(d,J＝8.8Hz,1H),7.97-7.85(m,2H),7.34-7.17(m,2H),7.04(dd,J＝10.6,8.1Hz,1H),6.82(d,J＝8.9Hz,1H),6.47(d,J＝9.0Hz,1H),3.86(s,3H),3.74(d,J＝11.0Hz,1H),3.65(t,J＝4.9Hz,5H),3.02(d,J＝10.5Hz,1H),2.81(d,J＝11.7Hz,3H),2.57(s,4H),2.15(d,J＝7.0Hz,7H),1.98(d,J＝8.5Hz,1H),1.89(s,2H),1.73(d,J＝12.0Hz,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-benzo [ d ] imidazole
The title product 52 was obtained by a similar synthetic method to example 40.
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-methylnaphthalen-1-yl) -1H-benzo [ d ] imidazole
The title product 53 was obtained by a similar synthetic method to example 40.
LCMS(ESI-MS)m/z：394.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),7.92(t,J＝13.4Hz,2H),7.64(s,1H),7.57-7.49(m,1H),7.42(d,J＝7.7Hz,1H),7.34(t,J＝7.9Hz,1H),7.21(d,J＝8.5Hz,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 ] imidazol-7-yl) -6-methylquinoline
The title product 54 was obtained by a similar synthetic method to example 40.
LCMS(ESI-MS)m/z：395.2[M+H]+。
1H 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-4 yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thiophen [2',3':4,5] pyrrol [3,2-b ] pyridin-2-yl) propan-2-ol
First step 5- (5-bromo-3-nitropyridin-2-yl) thiophene-2-carboxylic acid methyl ester (55 a)
1A (15.2 g,53.8 mmol), 5-boronic acid thiophene-2-carboxylic acid methyl ester 55e (10.0 g,53.8 mmol), pd (dppf) Cl 2 (1.97 g,2.69 mmol) and 54mL of potassium phosphate solution (3M) and 100mL of tetrahydrofuran were added sequentially to a single flask. The reaction was carried out at 80℃for 3 hours under nitrogen protection. The solvent was dried by spinning, the resulting solid was dissolved with DCM, the insoluble material was removed by filtration, the organic phase was spun dry, dissolved with EA, and PE was added to precipitate the solid, which was filtered off to give crude product of the target compound 55a, which was separated by column, and DCM/meoh=20/1 (V/V) was eluted to give the target compound 55a (3.85 g), as a yellow solid, yield 21%.
LCMS(ESI-MS)m/z：343[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.80(s,1H),7.73-7.74(d,J＝4.0Hz,1H),7.28-7.29(d,J＝4.0Hz,1H),3.82(s,3H).
Second step 6-bromo-4H-thiophene [2',3':4,5] pyrrole [3,2-b ] pyridine-2-carboxylic acid methyl ester (55 b)
55A (1.25 g,3.64 mmol) and triethyl phosphite (2.72 g,16.4 mmol) were added to a 20mL microwave tube and reacted for 3 hours at 150℃under nitrogen with 6mL dichlorobenzene. After cooling, a solid precipitated, which was filtered off, as 55b (280 mg), as a yellow solid in 25% yield. No further purification was carried out and used directly in the next step.
LCMS(ESI-MS)m/z：311.1&313.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.95(s，1H)，8.45(s，1H)，8.18(s，1H)，7.92(s，1H)，3.85(s，3H).
Step three 6- (3, 5-dimethylisoxazol-4-yl) -4H-thiophene [2',3':4,5] pyrrole [3,2-b ] pyridine-2-carboxylic acid methyl ester (55 c)
To a 50mL single-necked flask was added 55b (280 mg,0.80 mmol), 3, 5-dimethylisoxazol-4-ylborate 55f (222 mg,0.99 mmol), 0.9mL of a 3M potassium phosphate solution and 5mL of tetrahydrofuran. After nitrogen displacement, pd (dppf) Cl 2 (66 mg,0.09 mmol) was added. The reaction was carried out at 85℃for 5 hours under nitrogen protection. Standing, separating out a water layer, spin-drying an organic phase, adding dichloromethane, pulping, and separating out a yellow solid. The solid was filtered off, 55c (380 mg), crude, without further purification, and used directly in the next step.
LCMS(ESI-MS)m/z：328[M+H]+.
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 (55 d)
55C (275 mg,0.84 mmol) phenyl-4-tetrahydropyran methanol (178 mg,0.93 mmol) and triphenylphosphine (440 mg,1.68 mmol) were dissolved in anhydrous 15mL THF, DIAD (340 mg,1.68 mmol) was added at 0deg.C and the addition was completed and stirred overnight at room temperature. The reaction mixture was directly isolated and PE/EA=2/1 (V/V) was developed to give 55d (150 mg) as a yellow oily liquid in 42% yield.
LCMS(ESI-MS)m/z：502.1[M+H]+.
Fifth step 2- (6- (3, 5-dimethylisoxazol-4-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thiophen [2',3':4,5] pyrrolo [3,2-b ] pyridin-2-yl) propan-2-ol (55)
55D (150 mg,0.30 mmol) was dissolved in 10mL anhydrous THF and methyl magnesium bromide (3M in 2-methyltetrahydrofuran, 2 mL) was added at 0deg.C. After the addition, the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride, diluted with dichloromethane, filtered, the organic phase was dried by spin-drying, the residue was prepared and isolated, DCM/meoh=20/1 (V/V) and the title compound 55 (40 mg) was obtained as a yellow solid in 27% yield.
LCMS(ESI-MS)m/z：502.1[M+H]+.
1H NMR(400MHz,DMSO-d6)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
The title product 56 was obtained by a similar synthetic method to example 55.
LCMS(ESI-MS)m/z：499.1[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝17.3,13.3Hz,2H),3.42(m,2H),3.07(dd,J＝12.8,8.1Hz,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 ] pyridines
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)
56 (100 Mg) was dissolved in 10mL of HF and NaOH (40 mg) was added at 0deg.C. After the addition, the mixture was stirred at room temperature overnight. Water (40 mL) was added, dichloromethane was added to extract, the organic phase was dried, the residue was prepared and separated, DCM/MeOH=20/1 (V/V) was developed to give the title compound 57 (20 mg), yield 21%.
LCMS(ESI-MS)m/z：481.1[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝11.3Hz,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＝10.0,5.8Hz,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
The title product 58 was obtained by a similar synthetic method to example 55.
LCMS(ESI-MS)m/z：486.1[M+H]+.
1H NMR(400MHz,CDCl3)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
First step 2-bromo-4-iodo-6-nitroaniline (59 b)
Methyl acetoacetate 59a (24.0 g,110.4 mmol) was dissolved in a solution of acetic acid (50 mL) followed by N-iodosuccinimide (NIS) (29.8 g,132.5 mmol). After the addition, the mixture was heated to 50℃and reacted for 16 hours. 150mL of water was added, stirred for 15min, filtered, washed twice with petroleum ether, the solid was collected and spun-dried to give 2-bromo-4-iodo-6-nitroaniline 59b (37.0 g), a yellow solid, yield 97.9%.
LCMS(ESI-MS)m/z：343.1[M+H]+.
Second step 3-bromo-5-iodo-1, 2-diphenylamine (59 c)
Compound 59b (10 g,29.0 mmol) was placed in a single vial, dissolved in 120mL of THF, added with Fe (9.0 g,145 mmol), NH 4 Cl (21.1 g, 390 mmol), and finally EtOH/H 2 O (120 mL/60 mL) and heated to 90℃under reflux for 2H. After the reaction, the mixture was filtered and the filtrate was concentrated to give 3-bromo-5-iodo-1, 2-diphenylamine 59c (9.0 g) as a white solid in 99% yield.
LCMS(ESI-MS)m/z：315.1[M+H]+.
Third step N- (2-amino-6-bromo-4-iodophenyl) cyclopropylcarboxamide (59 d)
Compound 59c (11.0 g,35.2 mmol) was dissolved in 80mL of HF, purged with nitrogen, and Et 3 N (10.2 mL,70.4 mmol) was added under ice-water bath and cyclopropylcarbonyl chloride (5.5 g,52.8 mmol) was added dropwise. Stir at room temperature overnight. Adding water, extracting by EA, drying, spin-drying and passing through a column to obtain the target compound 59d (10.0 g) with the yield of 63%.
LCMS(ESI-MS)m/z：380.9[M+H]+
Fourth step 4-bromo-2-cyclopropyl-6-iodo-1H-benzo [ d ] imidazole (59 e)
To a solution of compound 59d (10.0 g,26.2 mmol) in 80mL formic acid was heated to 120deg.C and refluxed for 4h. The reaction solution was dried by spinning, stirred, and separated by column to give 4-bromo-2-cyclopropyl-6-iodo-1H-benzo [ d ] imidazole 59e (4.6 g) in 48% yield.
LCMS(ESI-MS)m/z：364.9[M+H]+.
Fifth step 4-bromo-2-cyclopropyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1H-benzo [ d ] imidazole (59 f)
59E (4.6 g,12.6 mmol) was dissolved in 10mL anhydrous DMF, then 1, 4-dimethyl-5- (tributylstannyl) -1H-1,2, 3-triazole (5.3 g,13.8 mmol), cuI (360 mg,1.89 mmol), TEA (3.6 mL,25.2 mmol) were added, pd (PPh 3)4 (1.4 g,1.26 mmol) was added after nitrogen substitution, and the mixture was heated to 95℃for 7H.
LCMS(ESI-MS)m/z：332[M+H]+.
1H NMR(400MHz,CDCl3)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).
Sixth step 4-bromo-2-cyclopropyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1-ethyl-1H-benzo [ d ] imidazole (59 g)
59F (1.0 g,3.0 mmol) was dissolved in 5mL anhydrous tetrahydrofuran, iodoethane (701.8 mg,4.5 mmol), naH (240 mg,6.0 mmol) and reacted overnight at room temperature. Spin-drying the solution, mixing the sample, and passing the mixture through a column to obtain 59g (1.0 g) of 4-bromo-2-cyclopropyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -1-ethyl-1H-benzo [ d ] imidazole with a yield of 92.6%.
LCMS(ESI-MS)m/z：359.9[M+H]+.
Seventh step 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 (59)
To a 50mL single port flask was added 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), followed by 10mL of anhydrous DME. After the addition, the reaction is carried out for 2 hours at 110 ℃ under the protection of nitrogen. LCMS monitored the reaction. The solvent was dried, the residue was dissolved in dichloromethane, separated by TLC preparation, and developed with DCM/meoh= (20/1, V/V). The main product was obtained as 59 (30 mg), white solid in 12% yield.
LCMS(ESI-MS)m/z：457.2[M+H]+.
1H NMR(400MHz,CDCl3)δ7.28-7.32(m,2H),7.07-7.11(t,J＝8.0Hz,1H),6.97-6.99(d,J＝8.0Hz,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
The title product 60 was obtained by a similar synthetic method to example 55.
LCMS(ESI-MS)m/z：502.1[M+H]+.
1H NMR(400MHz,DMSO-d6)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 (tetrahydro-2H-pyran-4-yl) methyl) -5H-pyrrolo [2,3-b:4,5-b' ] bipyridinyl
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' ] bipyridinyl-7-yl) amino) ethan-1-ol (61 b)
To the tube was added 61a (320 mg,0.67 mmol), ethanolamine (3 mL), and the mixture was reacted at 120℃for 2 hours. After the reaction, the mixture was poured into 10mL of water and stirred for 30min. The yellow solid was filtered off as 10072a (309 mg) in 75% yield.
LCMS(ESI-MS)m/z：498.4[M+H]+.
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' ] bipyridinyl-7-amine (61 c)
61B (80 mg,0.16 mmol) was dissolved in 15mL of dichloromethane, 38mg of thionyl chloride was added and stirred at room temperature overnight. The solvent was spun dry, 10072b, and used directly in the next step.
LCMS(ESI-MS)m/z：516.4[M+H]+.
Step three 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' ] bipyridinyl (61)
61C (40 mg,0.078 mmol) was dissolved in 5mL of MF, DIPEA (40 mg,0.32 mmol) was added and reacted at 110℃for 4 hours, and LCMS monitored. The isolation was carried out in reverse phase to give compound 61 (10 mg) as an off-white solid.
LCMS(ESI-MS)m/z：480.3[M+H]+.
1H 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-pyran-4-yl) methyl) -5H-pyrrolo [2,3-b:4,5-b' ] bipyridinyl-7-yl) amino) ethyl) -1, 3-dimethylpiperazin-2-one
First step 2- (2- (2-methyl-3-carbonylpiperazin-1-yl) ethyl) isoindoline-1, 3-dione (62 b)
3-Methylpiperazin-2-one 23936-11-0 (5.0 g,43.9 mmol) was dissolved 574-98-1 (11.2 g,43.9 mmol) in DMF (15 mL) and DIPEA (11.3 g,87.8 mmol) was added. After the addition, stirring was carried out at 110℃for 16 hours. After removal of DMF by spin, 50mL ethyl acetate was added and the layers separated, the organic phase was washed with citric acid (sat) (50 mL x 2) and dried over anhydrous sodium sulfate. Filtration, spin-drying, column separation, DCM/meoh=20/1 elution gave 62b,8.0g, yellow liquid in 64% yield.
LCMS(ESI-MS)m/z：288.2[M+H]+.
Second step 2- (2, 4-dimethyl-3-carbonylpiperazin-1-yl) ethyl) isoindoline-1, 3-dione (62 c)
Compound 10073a (850 mg,2.96 mmol) was dissolved in 10mL DMF, naH (60%in Oil,180mg,4.44mmol) was added at 0deg.C and stirred at this temperature for 1 hour. Methyl iodide (505 mg,3.55 mmol) was added, and the mixture was stirred overnight at room temperature. After quenching the reaction, it was dried, the column separated, and DCM/meoh=20/1 eluted to give compound 62c (956 mg) as a brown oily liquid in 83% yield.
Third step 4- (2-aminoethyl) -1, 3-dimethylpiperazin-2-one (62 d)
Compound 62c (956 mg,3.17 mmol) was dissolved in 1.5mL of ethanol and hydrazine hydrate (80%, 254mg,6.35 mmol) was batchwise used. Stir at room temperature overnight. The white solid precipitated was filtered off, filtered off and washed with a small amount of ethanol. And combining ethanol phases, spin-drying, adding acetonitrile until no solid is separated out, filtering, and spin-drying the acetonitrile solution of the mobile phone. The residue was taken up in dichloromethane, left to stand for 10min, the solid was filtered off, and the dichloromethane phase was spun-dried to give 10073c, which was not further purified, 62d about 550mg, as a yellow oily liquid, 100% yield.
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' ] bipyridinyl-7-yl) amino) ethyl) -1, 3-dimethylpiperazin-2-one (62)
62E (160 mg,0.34 mmol), 62d (crude, 250 mg) were added to a 10mL microwave tube, dissolved in 5mLNMP, and reacted at 170℃for 3 hours with microwaves. LCMS monitored the reaction. Reverse phase preparation and separation to obtain the target compound 10073, 40mg, pale yellow solid with 15% yield.
LCMS(ESI-MS)m/z：473.3[M+H]+.
1H 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' ] bipyridinyl-7-yl) -N1-ethyl-N2-methylethane-1, 2-diamine
The title product 63 was obtained by a similar synthetic method to example 62.
LCMS(ESI-MS)m/z：571.5[M+H]+.
1H NMR(400MHz,CDCl3)δ8.32-8.34(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' ] bipyridinyl
The title product 64 was obtained by a similar synthetic method to example 62.
LCMS(ESI-MS)m/z：597.2[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝10.6,5.1Hz,1H),3.86(s,3H),3.75(d,J＝10.7Hz,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' ] bipyridinyl
Using a method of synthesis similar to example 62, the title product 65 was obtained.
LCMS(ESI-MS)m/z：680.3[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝10.5,5.0Hz,1H),3.78-3.58(m,6H),3.13(s,1H),3.03(d,J＝10.7Hz,2H),2.78(d,J＝11.6Hz,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' ] bipyridinyl-7-yl) morpholine
The title product 66 was obtained by a similar synthetic method to example 62.
LCMS(ESI-MS)m/z：556.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.38(d,J＝1.7Hz,1H),8.26(d,J＝8.8Hz,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＝12.3Hz,1H),2.30-2.21(m,1H),2.17(s,3H),1.97(d,J＝9.2Hz,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) piperazin-1-yl) -5- (1- (2-fluorophenyl) -2- (tetrahydro-2H-pyran-4-yl) ethyl) -5H-pyrrolo [2,3-b:4,5-b' ] bipyridinyl
The title product 67 was obtained by a similar synthetic method to example 62.
LCMS(ESI-MS)m/z：666.4[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝7.5,1.3Hz,1H),7.04(m,1H),6.82(d,J＝8.9Hz,1H),6.47(dd,J＝10.6,4.9Hz,1H),3.75(d,J＝10.7Hz,1H),3.67(d,J＝9.0Hz,2H),3.13(s,1H),3.03(d,J＝10.6Hz,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' ] bipyridinyl
The title product 68 was obtained by a similar synthetic method to example 62.
LCMS(ESI-MS)m/z：639.3[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.36(d,J＝1.7Hz,1H),8.21(d,J＝8.8Hz,1H),7.98-7.93(m,1H),7.90(td,J＝7.8,1.8Hz,1H),7.29(tdd,J＝7.5,5.2,1.8Hz,1H),7.21(td,J＝7.5,1.3Hz,1H),7.04(ddd,J＝10.7,8.1,1.3Hz,1H),6.82(d,J＝8.8Hz,1H),6.48(dd,J＝10.7,5.0Hz,1H),3.86(s,4H),3.75(d,J＝10.6Hz,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' ] bipyridinyl
The title product 69 was obtained by a similar synthetic method to example 62.
LCMS(ESI-MS)m/z：569.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.40(d,J＝1.7Hz,1H),8.25(d,J＝8.8Hz,1H),7.94-7.98(m,2H),7.32(tdd,J＝7.3,5.2,1.7Hz,1H),7.24(td,J＝7.6,1.3Hz,1H),7.07-7.09(m,1H),6.87(d,J＝8.8Hz,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＝12.3Hz,1H),2.45(d,J＝5.2Hz,4H),2.28(d,J＝5.8Hz,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-triazol-5-yl) -5- (1- (2-fluorophenyl) -2- (tetrahydro-2H-pyran-4-yl) ethyl) -5H-pyrrolo [2,3-b:4,5-b' ] bipyridinyl
The title product 70 was obtained by a similar synthetic method to example 62.
LCMS(ESI-MS)m/z：678.6[M+H]+.
1H NMR(600MHz,DMSO-d6)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＝10.6,5.3Hz,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' ] bipyridinyl
Using a method of synthesis similar to example 62, the title product 71 was obtained.
LCLCMS(ESI-MS)m/z：652.6[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.36(d,J＝1.8Hz,1H),8.21(d,J＝8.8Hz,1H),7.97-7.85(m,2H),7.34-7.17(m,2H),7.04(dd,J＝10.6,8.1Hz,1H),6.82(d,J＝8.9Hz,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-pyran-4-yl) methyl) -1H-imidazo [4,5-b ] pyridin-2-yl) phenyl) propyl-2-ol
First step methyl 4- (6-bromo-1H-imidazo [4,5-b ] pyridin-2-yl) benzoate (72 c)
To a solution of methyl 4-formylbenzoate (8.2 g,50 mmol) and 5-bromopyridine-2, 3-diamine (9.4 g,50 mmol) in DMF (200 mL) was added Na 2S2O7 (11.1 g,50 mmol), heated to 130℃for 5h, cooled to room temperature, diluted with EA (2L), washed with water (1.0 L.5), dried over Na2SO4, filtered, concentrated, flash over column (PE/EA 0-100%) to give compound 72c (8.6 g,24.4 mmol) in 51.8% yield.
LCMS(ESI-MS)m/z：333.9[M+H]+.
Second step methyl 4- (6-bromo-1- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1H-imidazo [4,5-b ] pyridin-2-yl) benzoate (72 d)
A solution of 72c (2 g,6 mmol) and phenyl (tetrahydro-2H-pyran-4-yl) methanol (1.3 g,6.6 mmol) in THF (50 mL) was cooled to 0deg.C, triphenylphosphine (1.9 g,7.2 mmol) was added and stirred for 15 min, DIAD (1.5 g,7.2 mmol) was added dropwise and stirring continued for 1H, and the mixture was allowed to warm to room temperature and stirred overnight. Flash column chromatography purification (PE/EA 0-100%) gave 72d (400 mg,0.79 mmol) in 13.1% yield.
LCMS(ESI-MS)m/z：508.2[M+H]+.
Third step methyl 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) benzoate (72 e)
A solution of compound 72d (400 mg,0.79 mmol), 1, 4-dimethyl-5- (tributylstannyl) -1H-1,2, 3-triazole (600 mg,1.55 mmol) and tetrakis (triphenylphosphine) palladium (100 mg,0.08 mmol) in DMF (10 mL) was heated to 100deg.C under nitrogen and reacted for 2 hours, cooled and diluted with ethyl acetate (100 mL), washed with water (100 mL. Times.3), dried over Na2SO4, filtered, concentrated and Flash passed through a column (PE/EA 0-100%) to give compound 72e (280 mg,0.54 mmol) in 67.9% yield.
LCMS(ESI-MS)m/z：523.3[M+H]+.
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)
A solution of compound 72e (280 mg,0.54 mmol) in THF (10 mL) was cooled to 0deg.C under nitrogen, methyl magnesium bromide (1 mL,2.5 mmol) was added dropwise and the reaction was stirred at room temperature for 2 hours, flash column chromatography (PE/EA 0-100%) afforded the title compound 72 (80 mg,0.15 mmol) in 28.6% yield.
LCMS(ESI-MS)m/z：523.4[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝11.0Hz,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-pyran-4-yl) methyl) -3H-imidazo [4,5-b ] pyridin-2-yl) phenyl) propyl-2-ol
First step methyl 4- (6-bromo-3- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -3H-imidazo [4,5-b ] pyridin-2-yl) benzoate (73 b)
A solution of 73a (2 g,6 mmol) and phenyl (tetrahydro-2H-pyran-4-yl) methanol (1.3 g,6.6 mmol) in THF (50 mL) was cooled to 0deg.C, triphenylphosphine (1.9 g,7.2 mmol) was added and stirred for 15 min, DIAD (1.5 g,7.2 mmol) was added dropwise and stirring continued for 1H, and the mixture was allowed to warm to room temperature and stirred overnight. Flash column chromatography purification (PE/EA 0-100%) gave 73b (300 mg,0.59 mmol) in 9.8% yield.
LCMS(ESI-MS)m/z：508.2[M+H]+.
Second step methyl 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) benzoate (73 c)
A solution of compound 73b (300 mg,0.59 mmol), 1, 4-dimethyl-5- (tributylstannyl) -1H-1,2, 3-triazole (450 mg,1.17 mmol) and tetrakis (triphenylphosphine) palladium (100 mg,0.08 mmol) in DMF (10 mL) was heated to 100deg.C under nitrogen and reacted for 2 hours, cooled and diluted with ethyl acetate (100 mL), washed with water (100 mL. Times.3), dried over Na 2SO4, filtered, concentrated and Flash passed through a column (PE/EA 0-100%) to give compound 73c (190 mg,0.36 mmol) in 61.4% yield.
LCMS(ESI-MS)m/z：523.5[M+H]+.
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)
A solution of compound 73c (190 mg,0.54 mmol) in THF (10 mL) was cooled to 0deg.C and methylmagnesium bromide (1 mL,2.5 mmol) was added dropwise and the reaction stirred at room temperature for 2h, flash column chromatography (DCM/MeOH 0-10%) afforded the title compound 73 (40 mg,0.077 mmol) in 21.1% yield.
LCMS(ESI-MS)m/z：523.4[M+H]+.
1H NMR(400MHz,DMSO-d6)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＝11.5,2.6Hz,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
First step 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-one (74 b)
A500 mL single-port bottle was charged with compound 74a (30 g,0.14 mmol), boric acid ester (54 g,1.5 mmol), potassium acetate (40 g, 3.0 mmol), pd (pddf) cl2 (5 g, 0.07 mmol), dissolved in tetrahydrofuran, and reacted at 80℃for one hour under N2 gas. The post-treatment was carried out to filter out the solid, and the mixture was directly stirred on a Flash column to obtain about 30g of compound 74b in 83% yield.
Second step 5- (5-bromo-3-nitropyridin-2-yl) -2, 3-dihydro-1H-inden-1-one (74 c)
A500 mL single-port flask was used, and compound 74b (30 g,0.12 mmol), 3-nitro, 2, 5-dibromopyridine (32 g,0.12 mmol), potassium phosphate (48 g, 0.34 mmol), pd (pddf) cl2 (5 g,0.07 mmol) was dissolved in dioxane and N 2 gas-shielded and reacted at 100℃for one hour. The solid was filtered off after working up, and the mixture was directly stirred on a Flash column to give 18g of compound 74, 78% yield.
LCMS(ESI-MS)m/z：332.0[M+H]+.
Third step 8-bromo-1, 10-dihydro-cyclopenta [ g ] pyrido [3,2-b ] indol-3 (2H) -one (74 d)
100Ml of a single-necked flask was taken, and compound 74c (2 g.0.006mmol), triethyl phosphite (3 g.0.18 mmol) was taken and dissolved in 10ml of dichlorobenzene and reacted at 140℃for 2 hours, filtered and washed with DCM to obtain 74d 1g which was directly used in the next step.
LCMS(ESI-MS)m/z：301.9[M+H]+.
Fourth step 8-bromo-10- (1- (2-fluorophenyl) -2- (tetrahydro-2H-pyran-4-yl) ethyl) -1, 10-dihydro-cyclopenta [ g ] pyrido [3,2-b ] indol-3- (2H) -one (74 e)
50Ml of a three-necked flask was taken, and under anhydrous and anaerobic conditions, compound 74d (1 g.0.003mmol), compound 7 (1.5 g, 0.006mmol). TMAD (600 mg.0.006mmol) and Bu3P (700 mg.0.006mmol) were sequentially added, dissolved with DCM, reacted overnight, and washed, followed by passing through the column to give compound 74e.
LCMS(ESI-MS)m/z：506.1[M+H]+.
Fifth step 8-bromo-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 (74 f)
A50 mL three-necked flask was taken, and compound 74e (500 mg,1 mmol) was added thereto, dissolved in anhydrous DCM (50 mL), and methylmagnesium bromide (13 mL,10 mmol) was added under dry ice bath to react overnight. The reaction was quenched with ammonium chloride, extracted with DCM, dried over anhydrous sodium sulfate and passed over column compound 74f.
LCMS(ESI-MS)m/z：522.2[M+H]+.
Sixth step 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 (74)
A50 mL single-port bottle was charged with 74f (70 mg.0.13 mmol), borate (207 mg.0.53 mmol), CSF (52 mg,0.53 mmol) PD (DBA) (12 mg,0.02 mmol), dissolved in 1.4-dioxane, and N2-protected under stirring at 100deg.C for 1h. LCMS monitored completion of reaction and passing through Flash column gave the title compound 74 (15 mg) as a white solid.
LCMS(ESI-MS)m/z：540.4[M+H]+.
1H NMR(400MHz,CDCl3)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-dihydro-cyclopenta [ g ] pyrido [3,2-b ] indol-3 (2H) -one
First step 7-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-one (81 b)
The compound 5-bromo-7-fluoro-2, 3-dihydro-1H-inden-1-one 81a (5 g, 21.284 mmol) bis-pinacolato borate (11.091 g,43.668 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (1.596 g,2.1834 mmol), potassium acetate (6.319 g,65.502 mmol) was dissolved in 1, 4-dioxane (150 mL). And (3) under the protection of argon, reacting for 3 hours at 100 ℃. After the completion of the reaction, the solvent was dried by spinning, water was added and extracted 3 times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound 81b (3.9 g,14.13 mmol) in a yield of 64.7%.
LCMS(ESI-MS)m/z：195.2[M+H]+.
Second step 5- (5-bromo-3-nitropyridin-2-yl) -7-fluoro-2, 3-dihydro-1H-inden-1-one (81 c)
Compound 81b (3.6 g,13.043 mmol), compound 2, 5-dibromo-3-nitropyridine (3.6615 g,13.043 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (953 mg,1.3043 mmol) and potassium phosphate (8.245 g,39.129 mmol) were dissolved in N, N-dimethylformamide (50 mL) and reacted at 50℃under argon for 5h. Post-treatment: part of the solvent was dried, water was added and extracted 3 times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound 81c (2 g,5.698 mmol) in 43% yield.
LCMS(ESI-MS)m/z：351.1[M+H]+.
Third step 8-bromo-4-fluoro-1, 10-dihydro-cyclopenta [ g ] pyrido [3,2-b ] indol-3 (2H) -one (81 d)
Compound 83c (2.5 g,7.122 mmol) was dissolved in o-dichlorobenzene (20 mL), and triethyl phosphite (3.547 g,21.366 mmol) was added thereto and reacted at 140℃for 5 hours. After the reaction was cooled to room temperature, the product was precipitated, filtered and the solvent was removed by washing with ethyl acetate to give the title compound 81d (580 mg,1.81 mmol) in 25% yield.
LCMS(ESI-MS)m/z：321.1[M+H]+.
Fourth step 8-bromo-4-fluoro-10- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -1, 10-dihydro-cyclopenta [ g ] pyrido [3,2-b ] indol-3 (2H) -one (81 e)
Compound 81d (580 mg, 1.814 mmol) and phenyl (tetrahydro-2H-pyran-4-yl) methanol (1047 mg,5.454 mmol) are added to a three-necked flask, replaced with argon, dissolved in dichloromethane (30 mL), triphenylphosphine (1101 mg,5.454 mmol) is added, and then N, N, N ', N' -tetramethyl azodicarboxamide (938 mg,5.454 mmol) is added and stirred at ambient temperature for 12H. Water was added and extracted 3 times with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and purified by column chromatography to give the title compound 81e (78 mg,0.158 mmol) in 8.7% yield.
LCMS(ESI-MS)m/z：459.2[M+H]+.
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-dihydro-cyclopenta [ g ] pyrido [3,2-b ] indol-3 (2H) -one (81)
Compound 81e (78 mg,0.158 mmol), 1, 4-dimethyl-5- (tributylstannyl) -1H-1,2, 3-triazole (183 mg,0.474 mmol), tris (dibenzylideneacetone) dipalladium (15 mg,0.0158 mmol) and tricyclohexylphosphine (9 mg,0.0316 mmol), potassium fluoride (96 mg,0.632 mmol) were dissolved in 1, 4-dioxane (6 mL), protected with argon, and reacted at 100℃for 1H. Cooling to room temperature, adding water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and purifying by column chromatography to obtain the title compound 10081 (26 mg,0.051 mmol) in 32.5% yield.
LCMS(ESI-MS)m/z：510.4[M+H]+.
1H NMR(400MHz,DMSO-d6)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-dihydro-cyclopenta [ f ] pyrido [3,2-b ] indol-7 (5H) -one
First step (3-bromo-2-chlorophenyl) methanol (76 b)
Compound 3-bromo-2-chlorobenzoic acid 76a (50 g,212.7 mmol) was dissolved in tetrahydrofuran (80 mL), and a solution of borane/tetrahydrofuran complex 1M (640 mL,640 mmol) was slowly added in an ice-water bath and stirred at room temperature for 5h. The reaction was quenched with water, extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give the title compound 76b (445.1 g,204.2 mmol) in 96% yield.
Second step 3-bromo-2-chlorobenzaldehyde (76 c)
To a solution of compound (3-bromo-2-chlorophenyl) methanol 76b (45.1 g,204.2 mmol) in methylene chloride (100 mL) was added manganese dioxide (87.6 g,1.01 mol) and stirred at room temperature for 12h. After the reaction was completely filtered to remove manganese dioxide and dried dichloromethane, water was added and extracted 3 times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound 76c (43.8 g,200.1 mmol) in 98% yield.
Third step 3- (3-bromo-2-chlorophenyl) propionic acid (76 d)
Triethylamine (24.2 g,240.1 mmol) was added to formic acid (27.6 g,600.3 mmol) under ice bath and stirred at room temperature for 30min. Compound 3-bromo-2-chlorobenzaldehyde 76c (43.8 g,200.1 mmol) and compound 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (28.8 g,200.1 mmol) were dissolved in 150mL of N, N-dimethylformamide, added to a reaction flask, and reacted at 100℃for 6 hours. After completion of the reaction, pH was adjusted to 2 with a dilute hydrochloric acid solution, extracted twice with methylene chloride, the organic phase was washed twice with a sodium hydroxide solution, pH was adjusted to 2 with a dilute hydrochloric acid solution, and the product was precipitated and filtered to give the title compound 76d (47.3 g,180.1 mmol) in 90% yield.
Fourth step 3- (3-bromo-2-chlorophenyl) propionyl chloride (76 e)
Compound 3- (3-bromo-2-chlorophenyl) propionic acid 83d (47.3 g,180.1 mmol) was dissolved in dichloromethane (50 mL), and thionyl chloride (42.8 g,360.2 mmol) was added and heated at 50deg.C and stirred for 2h. The solvent was dried to give the title compound 76e (50.5 g,180.1 mmol) in 100% yield.
Fifth step 5-bromo-4-chloro-2, 3-dihydro-1H-inden-1-one (76 f)
The compound aluminum trichloride (71.8 g,540.3 mmol) was dissolved in methylene chloride (200 mL), and the compound 3- (3-bromo-2-chlorophenyl) propionyl chloride 76e (50.5 g,180.1 mmol) was dissolved in methylene chloride (50 mL) and slowly added dropwise to the aluminum trichloride solution under ice bath. Stirring and reacting for 3h at normal temperature. The diluted hydrochloric acid solution was added to make pH weakly acidic, extracted 3 times with methylene chloride, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give the title compound 76f (20.2 g,82.4 mmol) in a yield of 45.7%.
Sixth step 4-chloro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-one (76 g)
The compound 5-bromo-4-chloro-2, 3-dihydro-1H-inden-1-one 76f (20.2 g,82.4 mmol) and bis-pinacolato borate (41.7 g,164.4 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (6 g,8.2 mmol), potassium acetate (16.1 g,164.4 mmol) were dissolved in 1, 4-dioxane (150 mL). And (3) under the protection of argon, reacting for 3 hours at 100 ℃. After the completion of the reaction, the solvent was dried by spinning, water was added and extracted 3 times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and purified by column chromatography to give 76g (21.6 g,73.9 mmol) of the title compound in 89.7% yield.
Seventh step 5- (5-bromo-3-nitropyridin-2-yl) -4-chloro-2, 3-dihydro-1H-inden-1-one (76H)
The compound 4-chloro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-one 76g (21.6 g,73.9 mmol), the compound 2, 5-dibromo-3-nitropyridine (20.8 g,73.9 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (5.4 g,7.39 mmol) and potassium phosphate (148.1 mmol) were dissolved in N, N-dimethylformamide (150 mL), protected with argon and reacted at 50℃for 5H. Post-treatment: part of the solvent was dried by spinning, water was added and extracted 3 times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the title compound was purified by column chromatography for 76h (9.2 g,25.1 mmol) in 33% yield.
LCMS(ESI-MS)m/z：366.9[M+H]+.
Eighth step 3-bromo-10-chloro-8, 9-dihydro-cyclopenta [ f ] pyrido [3,2-b ] indol-7 (5H) -one (76 i)
The compound 5- (5-bromo-3-nitropyridin-2-yl) -4-chloro-2, 3-dihydro-1H-inden-1-one 76H (9.2 g,25.1 mmol) was dissolved in o-dichlorobenzene (40 mL), triethylphosphite (12.4 g,76.8 mmol) was added and reacted at 140℃for 5H. After completion of the reaction, cooled to room temperature, the product precipitated, filtered and the solvent was removed by washing with ethyl acetate to give the title compound 76i (1.8 g,5.3 mmol) in 21.1% yield.
LCMS(ESI-MS)m/z：335.0[M+H]+.
Ninth step 3-bromo-10-chloro-5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8, 9-dihydro-cyclopenta [ f ] pyrido [3,2-b ] indol-7 (5H) -one (76 j)
The compound 3-bromo-10-chloro-8, 9-dihydro-cyclopenta [ f ] pyrido [3,2-b ] indol-7 (5H) -one 83i (1.8 g,5.3 mmol) and the compound phenyl (tetrahydro-2H-pyran-4-yl) methanol (2.1 g,10.6 mmol) are added to a three-necked flask, replaced with argon, dissolved in dichloromethane (50 mL), triphenylphosphine (3.2 g,15.9 mmol) and then N, N, N ', N' -tetramethyl azodicarboxamide (2.7 g,15.9 mmol) are added and stirred at ambient temperature for 12H. Water was added and extracted 3 times with dichloromethane, the organic phase was dried over anhydrous sodium sulfate and purified by column chromatography to give the title compound 76j (0.6 g,1.2 mmol) in 22.6% yield.
LCMS(ESI-MS)m/z：509.2[M+H]+.
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-dihydro-cyclopenta [ f ] pyrido [3,2-b ] indol-7 (5H) -one (76)
The compound 3-bromo-10-chloro-5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8, 9-dihydro-cyclopenta [ f ] pyrido [3,2-b ] indol-7 (5H) -one 76j (0.6 g,1.2 mmol), the compound 1, 4-dimethyl-5- (tributylstannyl) -1H-1,2, 3-triazole (0.9 g,2.4 mmol), tris (dibenzylideneacetone) dipalladium (107 mg,0.12 mmol) and tricyclohexylphosphine (66 mg,0.24 mmol) were dissolved in 1, 4-dioxane (20 mL), protected by argon, and reacted at 100℃for 3H. Cooling to room temperature, adding water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and purifying by column chromatography to obtain the title compound 76 (160 mg,0.3 mmol) in 25% yield.
LCMS(ESI-MS)m/z：526.3[M+H]+.
1H NMR(400MHz,CDCl3)δ8.66(s,1H),8.07(s,1H),7.67(s,1H),7.43(s,1H),7.41(s,1H),7.35-7.34(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) -5,7,8, 9-tetrahydrocyclopenta [ f ] pyrido [3,2-b ] indole
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)
The compound 10-chloro-3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8, 9-dihydro-cyclopenta [ f ] pyrido [3,2-b ] indol-7 (5H) -one 10083 (50 mg,0.095 mmol) was dissolved in dichloromethane (10 mL), replaced with hydrogen and stirred at ambient temperature for 48H. Palladium on carbon was removed by filtration, and after concentration, the resultant was purified by thin layer chromatography to give the title compound 77 (5.8 mg,0.012 mmol) in a yield of 12.6%.
LCMS(ESI-MS)m/z：478.4[M+H]+.
1H NMR(400MHz,CDCl3)δ8.38(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＝10.6Hz,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) -5,7,8, 9-tetrahydrocyclopenta [ f ] pyrido [3,2-b ] indol-7-ol
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 ] indol-7-ol (78)
The compound 10-chloro-3- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -5- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8, 9-dihydro-cyclopenta [ f ] pyrido [3,2-b ] indol-7 (5H) -one 10083 (50 mg,0.095 mmol) was dissolved in dichloromethane (10 mL), replaced with hydrogen and stirred at ambient temperature for 48H. Palladium on carbon was removed by filtration, concentrated and purified by thin layer chromatography to give the title compound 10087 (10.2 mg,0.021 mmol) in 22.1% yield.
LCMS(ESI-MS)m/z：494.4[M+H]+.
1H NMR(400MHz,DMSO-d6)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) propan-2-ol
First step (4-fluorophenyl) (tetrahydro-2H-pyran-4-yl) methanone (79 b)
Compound 79a (4.0 g,23.1 mmol) is dissolved in 20mL dry THF and p-fluorophenylmagnesium bromide (25.4 mL,25.4 mmol) is added at-5 ℃. After the addition, the mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated ammonium chloride solution, the EA/H2O was separated, the organic phase was collected, dried, filtered, the solvent was spin-dried, and the column was separated, and PE/ea=4/1 (V/V) was eluted to give the target compound 79b (2.0 g), a white solid, yield 43%.
1H NMR(400MHz,DMSO-d6)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).
Second step (4-fluorophenyl) (tetrahydro-2H-pyran-4-yl) methanol (79 c)
79B (2.0 g,9.6 mmol) in 10mL of methanol, cooled to 0deg.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 gave the title compound 79c (1.57 g), colorless oil, yield 79%.
1H NMR(400MHz,DMSO-d6)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).
Third step 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-carboxylic acid ester (79 e)
Compound 79d (308 mg,1.23 mmol), 79c (260 mg,1.23 mmol), (Bu) 3P (745 mg,3.69 mmol) is dissolved in 10mL dry THF and the system is clear yellow. TMSD (635 mg,3.69 mmol) in 10mL THF was added at room temperature. During the addition, the system was gradually cloudy and stirring was continued at room temperature overnight. The white solid was removed by filtration, and the filtrate was separated by column chromatography eluting with DCM/meoh=96/4 (V/V) to give the title compound 79e (290 mg), a white solid in 46% yield.
LCMS(ESI-MS)m/z：500[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.40(s,1H),7.68-7.71(m,2H),7.33(s,1H),7.18(t,J＝9.2Hz,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).
Fourth step 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-carboxylic acid ester (79 f)
79E (250 mg,0.5 mmol), tin reagent (195 mg,0.5 mmol), PCY3 (28 mg,0.1 mmol), pd2 (dba) 3 (96 mg,0.1 mmol), cuI (9.5 mg,0.05 mmol) and 5mL anhydrous DMF were added sequentially to a single-port flask and reacted at 115℃for 8 hours. Spin-dry DMF, DCM/meoh=20/1, afforded the title compound 79f (110 mg), brown oil, 43% yield.
LCMS(ESI-MS)m/z：517.4[M+H]+.
Fifth step 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-carboxylic acid ester (79)
Compound 79e (110 mg,0.21 mmol) is dissolved in 5mL dry THF and MeMgBr (3.0M, 1.0 mL) is added. After addition, stirring overnight at room temperature, spin-drying the solvent, preparation separation twice, DCM/meoh=20/1 development gave 79 (7 mg), a white solid, yield 6.4%.
LCMS(ESI-MS)m/z：517.4[M+H]+.
1H NMR(400MHz,MeOD)δ8.16(d,J＝1.6Hz,1H),8.01(d,J＝1.6Hz,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
The title compound 80 was obtained by a synthesis method similar to that of example 79.
LCMS(ESI-MS)m/z：513.4[M+H]+.
1H NMR(400MHz,MeOD)δ8.16(d,J＝1.8Hz,1H),7.86(d,J＝1.8Hz,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
The title compound 81 was obtained by a synthesis method similar to that of example 79.
LCMS(ESI-MS)m/z：517.4[M+H]+.
1H NMR(400MHz,CDCl3)δ8.18(d,J＝1.8Hz,1H),7.56(d,J＝1.8Hz,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＝11.2Hz,1H),4.34(s,3H),4.04-3.83(m,5H),3.36-3.46(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 ] pyridin-2-yl) propan-2-ol
The title compound 82 was obtained by a synthesis method similar to that of example 79.
LCMS(ESI-MS)m/z：531.4[M+H]+.
1H NMR(400MHz,MeOD)δ8.17(d,J＝1.8Hz,1H),7.87(d,J＝1.8Hz,1H),7.45(td,J＝7.7,1.8Hz,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' ] bipyridinyl-7-yl) -N1-ethyl-N2-methylethane-1, 2-diamine
The title compound 83 was obtained by a synthesis method similar to that of example 79.
LCMS(ESI-MS)m/z：518.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝1.6Hz,1H),8.46(d,J＝4.8Hz,1H),8.27(d,J＝1.6Hz,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-ol
The title compound 84 was obtained by a synthesis method similar to that of example 79.
LCMS(ESI-MS)m/z：500.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.58(dd,J＝5.0,1.8Hz,1H),8.29(s,1H),8.24(d,J＝1.7Hz,1H),7.74(td,J＝7.7,1.9Hz,1H),7.56(dd,J＝7.8,1.1Hz,1H),7.27(m,1H),6.33(s,1H),5.55(d,J＝10.9Hz,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
The title compound 85 was obtained by a synthesis method similar to that of example 79.
LCMS(ESI-MS)m/z：531.5[M+H]+.
1H NMR(400MHz,MeOD)δ8.09(d,J＝1.8Hz,1H),7.71(t,J＝12Hz,1H),7.41(td,J＝7.8,1.8Hz,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 assay
Experiment one, in vitro enzymatic Activity determination of Compounds
1. Purpose of experiment and method
The purpose of this experiment was to test the binding strength of the compounds of the invention to Bromodomain protein 4 (Bromodomain-containing protein, (BRD 4)) protein and to evaluate the in vitro activity of the compounds according to the semi-inhibitory concentration (IC 50).
2. Experimental protocol
2.1 Preparation of Compounds for experiments
Compounds 1-85 and JQ1 used in this experiment were dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 millimoles per liter (mM) stock solution. The highest concentration at the time of testing was 1 micromolar per liter (μm), diluted 5-fold, and 7 concentration gradients were set up in duplicate wells.
2.2 Experimental procedure
The binding strength of the compounds to Bromodomain protein 4 (Bromodomain-containing protein, (BRD 4)) protein was determined using a Homogeneous Time Resolved Fluorescence (HTRF) assay. The formulated compound and dimethyl sulfoxide (DMSO) were transferred to 384 well plates (Perkin Elmer, optiPlate-384), BRD4 (1, 2) (49-460) (purchased at BPS) (final concentration 5 nanomoles per liter (nM)), centrifuged and mixed well, and protein and GL-16 (H4 (1-20) K5/8/12/16 AC) (synthesized by Jil Biochemical Co., ltd.) were added (final concentration 5 nanomoles per liter (nM)) to initiate the reaction (total reaction volume 10. Mu.L)). 384-well plates were placed in an incubator at 23℃for 60 minutes, then the reaction was stopped by adding Anti-GST-EU 3+ Cryptate (purchased from Cisbio,0.25 nanomoles per liter (nM)), and SA-XL-665 (purchased from Cisbio,0.625 nanomoles per liter (nM)). After a further incubation in the incubator for 2 hours, the fluorescence values (340 nanometers (nm) excitation, detection of 665 nm to 615 nm emissions, the ratio of which is the enzyme binding signal) were read on an Envision (purchased from PerkinElmer) and the half-inhibitory concentration (IC 50) values of the compound were calculated using prism 5 software (GRAPHPAD PRISM).
2.3 Test results and conclusions
The results show that the compound IC50 of the invention is superior to JQ1, and shows stronger activity, which shows that the compound of the invention can effectively bind to Bromodomain protein 4 (Bromodomain-containing protein, (BRD 4)) protein in an in vitro biochemical experiment level, so that the compound of the invention can become an effective therapeutic drug for tumors, and the results are shown in Table 1.
TABLE 1 biological Activity results of Compound BRD4 experiments
Experiment II proliferation assay of the Compounds of the invention on human myelomonocytic leukemia cells (MV-4-11 cells)
1. Purpose of experiment and method
Cell viability detection by luminescence method for the experiment(CTG)) method the in vitro antiproliferative effect of the compounds of the invention on human myelomonocytic leukemia cells (MV-4-11 cells) was measured.
2. Experimental protocol
2.1 Cell culture
Human myelogenous monocytic leukemia cells (MV-4-11 cells) were ordered in the China academy of sciences cell bank, cultured using IMDM (Corning, 26917008) plus 10% fetal bovine serum (Gibco, 10817010) and 1% penicillin/streptomycin diaantibody (Corning, 30002297), observed under a microscope, to confirm good cell status, transferred to a 15 milliliter (mL) centrifuge tube, centrifuged at 1000 revolutions per minute (rpm) for 5 minutes, the supernatant was discarded, added to complete medium, blown into a single cell suspension, and placed in a 37℃5% CO 2 incubator (Simer fly) for culture.
2.2 Preparation of Compounds and preparation of Compound Board
Compounds 1-60 and JQ1 used in this experiment were dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 millimoles per liter (mM) stock solution, and the highest concentration at the time of testing was 1 micromole per liter (μM), diluted 3-fold, and a total of 9 concentration gradients were set up for multiplexing.
2.3 Experimental procedure
The first day: cell plating
Cell counting was performed on the above cell suspension using a cell counter, the cell suspension was adjusted to a desired cell density with complete medium and then inoculated into 96-well plates, 90 microliters (μl) per well was made to be 10000 per well, T0 plates were set, and a blank was added with 90 microliters (μl) of complete medium and placed in a 5% co 2 incubator (zemoeid) at 37 ℃ overnight.
The following day: t0 plate read value
After adding 10. Mu.L of medium containing a solvent to each well, CTG analysis was performed, CTG reagent (Promega, G7573) was thawed and cell plates were equilibrated to room temperature for 30 minutes, 50. Mu.L of CTG solution was added to each well, cells were lysed by shaking on an orbital shaker for 2 minutes, cell plates were left at room temperature for 10 minutes to stabilize luminescence signals, and luminescence values were read using Envision (purchased from Perkinelmer).
The following day: adding the medicine to be tested
The mother solution was diluted 1000-fold with medium to give 1000X solution, 3-fold dilution to give compound plate, 10. Mu.L of drug solution was added per well to give the highest concentration at test of 1. Mu.M per liter, 3-fold dilution was used, and multiple wells were set up with 9 concentration gradients. The cells were incubated at 37℃under 5% CO 2 and 95% humidity for 72 hours (h).
Fifth day: test plate reading (drug treatment 72 hours)
The CTG reagent (pluromill, G7573) was thawed and the cell plates were equilibrated to room temperature for 30 minutes, 50 microliters (μl) of CTG solution was added to each well, the cells were lysed by shaking on an orbital shaker for 2 minutes, the cell plates were left at room temperature for 10 minutes to stabilize the luminescence signal, and the luminescence values were read using Envision (purchased from PerkinElmer).
2.4 Data processing and statistics
Cell viability was expressed as: v sample/Vvehicle control x 100% calculation. Where V sample is the reading of the drug-treated group and V vehicle control is the average of the solvent control group. Using prism 5 (GRAPHPAD PRISM) software, an S-type dose-survival curve was plotted using a nonlinear regression model and half-inhibitory concentration (IC 50) values were calculated.
2.5 Test results and conclusions
The results show that the half inhibition concentration (IC 50) of JQ1 on proliferation inhibition of human myelomonocytic leukemia cells (MV-4-11 cells) is 186 nanomoles per liter (nM), and the compound of the example has stronger inhibition effect on proliferation of the human myelomonocytic leukemia cells (MV-4-11 cells) and better inhibition activity than JQ1. The results are shown in Table 2.
Experiment III proliferation assay of the Compounds of the invention on human B cell lymphoma cells (SU-DHL-6 cells)
1. Purpose of experiment and method
Cell viability detection by luminescence method for the experiment(CTG)) method the in vitro antiproliferative effect of the compounds of the invention on human B-cell lymphoma cells (SU-DHL-6 cells) was measured.
2. Experimental protocol
2.1 Cell culture
Human B cell lymphoma cells (SU-DHL-6 cells) were ordered in Nanjing, bai Biotechnology Co., ltd, cultured using RPMI 1640 (Corning, 35417005) plus 10% fetal bovine serum (Gibco, 10817010) and 1% penicillin/streptomycin diab (Corning, 30002297), observed under a microscope, to confirm that the cell status was good, the cells were transferred to a 15 milliliter (mL) centrifuge tube, centrifuged at 1000 revolutions per minute (rpm) for 5 minutes, the supernatant was discarded, complete medium was added, blown into a single cell suspension, and incubated in a 5% CO 2 incubator (Simer's fly) at 37 ℃.
2.2 Preparation of Compounds and preparation of Compound Board
Compounds 1-85 and JQ1 used in this experiment were dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 millimoles per liter (mM) stock solution, and the highest concentration at the time of testing was 1 micromole per liter (μM), diluted 3-fold, and a total of 9 concentration gradients were set up for multiplexing.
2.3 Experimental procedure
The first day: cell plating
Cell counting was performed on the above cell suspension using a cell counter, the cell suspension was adjusted to a desired cell density using a complete medium and then inoculated into 96-well plates, 90 microliters (μl) per well was set to 5000 cells/well, T0 plates were set, a blank was added to 90 microliters (μl) of complete medium, and the mixture was placed in a 5% co 2 incubator (zemoeid) at 37 ℃ overnight.
The following day: t0 plate read value
After adding 10. Mu.L of medium containing a solvent to each well, CTG analysis was performed, CTG reagent (Promega, G7573) was thawed and cell plates were equilibrated to room temperature for 30 minutes, 50. Mu.L of CTG solution was added to each well, cells were lysed by shaking on an orbital shaker for 2 minutes, cell plates were left at room temperature for 10 minutes to stabilize luminescence signals, and luminescence values were read using Envision (purchased from Perkinelmer).
The following day: adding the medicine to be tested
The mother solution was diluted 1000-fold with medium to give 1000X solution, 3-fold dilution to give compound plate, 10. Mu.L of drug solution was added per well to give the highest concentration at test of 1. Mu.M per liter, 3-fold dilution was used, and multiple wells were set up with 9 concentration gradients. The cells were incubated at 37℃under 5% CO 2 and 95% humidity for 72 hours (h).
Fifth day: test plate reading (drug treatment 72 hours)
The CTG reagent (pluromill, G7573) was thawed and the cell plates were equilibrated to room temperature for 30 minutes, 50 microliters (μl) of CTG solution was added to each well, the cells were lysed by shaking on an orbital shaker for 2 minutes, the cell plates were left at room temperature for 10 minutes to stabilize the luminescence signal, and the luminescence values were read using Envision (purchased from PerkinElmer).
2.4 Data processing and statistics
Cell viability was expressed as: v sample/Vvehicle control x 100% calculation. Where V sample is the reading of the drug-treated group and V vehicle control is the average of the solvent control group. Using prism 5 (GRAPHPAD PRISM) software, an S-type dose-survival curve was plotted using a nonlinear regression model and half-inhibitory concentration (IC 50) values were calculated.
2.5 Test results and conclusions
The results show that the JQ1 has a half inhibition concentration (IC 50) of 189 nanomoles per liter (nM) on proliferation of human B cell lymphoma cells (SU-DHL-6 cells), and the compound of the example has a strong inhibition effect on proliferation of human B cell lymphoma cells (SU-DHL-6 cells), and the inhibition activity is superior to that of JQ1. The results are shown in Table 2.
Experiment IV proliferation assay of the Compounds of the invention on human myeloma cells (MM.1S cells)
1. Purpose of experiment and method
Cell viability detection by luminescence method for the experiment(CTG)) method the in vitro antiproliferative effect of the compounds of the invention on human myeloma cells (mm.1s cells) was measured.
2. Experimental protocol
2.1 Cell culture
Human myeloma cells (mm.1 s cells) were ordered in the kyaniraceae, herborist, inc, and cultured using RPMI1640 (corning, 35417005) plus 10% fetal bovine serum (Gibco, 10817010) and 1% penicillin/streptomycin diaantibody (corning, 30002297), and observed under a microscope to confirm that the cells were in good condition, transferred to 15 milliliter (mL) centrifuge tubes, centrifuged at 1000 revolutions per minute (rpm) for 5 minutes, the supernatant was discarded, complete medium was added, and the suspension was blown into single cell suspensions and incubated in a 5% co 2 incubator (zemer).
2.2 Preparation of Compounds and preparation of Compound Board
Compounds 1-60 and JQ1 used in this experiment were dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 millimoles per liter (mM) stock solution, and the highest concentration at the time of testing was 1 micromole per liter (μM), diluted 3-fold, and a total of 9 concentration gradients were set up for multiplexing.
2.3 Experimental procedure
The first day: cell plating
Cell counting was performed on the above cell suspension using a cell counter, the cell suspension was adjusted to a desired cell density with complete medium and then inoculated into 96-well plates, 90 microliters (μl) per well was made to be 10000 per well, T0 plates were set, and a blank was added with 90 microliters (μl) of complete medium and placed in a 5% co 2 incubator (zemoeid) at 37 ℃ overnight.
The following day: t0 plate read value
After adding 10. Mu.L of medium containing a solvent to each well, CTG analysis was performed, CTG reagent (Promega, G7573) was thawed and cell plates were equilibrated to room temperature for 30 minutes, 50. Mu.L of CTG solution was added to each well, cells were lysed by shaking on an orbital shaker for 2 minutes, cell plates were left at room temperature for 10 minutes to stabilize luminescence signals, and luminescence values were read using Envision (purchased from Perkinelmer).
The following day: adding the medicine to be tested
The mother solution was diluted 1000-fold with medium to give 1000X solution, 3-fold dilution to give compound plate, 10. Mu.L of drug solution was added per well to give the highest concentration at test of 1. Mu.M per liter, 3-fold dilution was used, and multiple wells were set up with 9 concentration gradients. The cells were incubated at 37℃under 5% CO 2 and 95% humidity for 72 hours (h).
Fifth day: test plate reading (drug treatment 72 hours)
The CTG reagent (pluromill, G7573) was thawed and the cell plates were equilibrated to room temperature for 30 minutes, 50 microliters (μl) of CTG solution was added to each well, the cells were lysed by shaking on an orbital shaker for 2 minutes, the cell plates were left at room temperature for 10 minutes to stabilize the luminescence signal, and the luminescence values were read using Envision (purchased from PerkinElmer).
2.4 Data processing and statistics
Cell viability was expressed as: v sample/Vvehicle control x 100% calculation. Where V sample is the reading of the drug-treated group and V vehicle control is the average of the solvent control group. Using prism 5 (GRAPHPAD PRISM) software, an S-type dose-survival curve was plotted using a nonlinear regression model and half-inhibitory concentration (IC 50) values were calculated.
2.5 Test results and conclusions
The results show that the half inhibition concentration (IC 50) of JQ1 on proliferation inhibition of human myeloma cells (MM.1S cells) is 200 nanomoles per liter (nM), and the compound of the embodiment has a strong inhibition effect on proliferation of human myeloma cells (MM.1S cells), and the inhibition activity is superior to JQ1. The results are shown in Table 2.
TABLE 2 inhibition of cell proliferation by Compounds
Experiment five, pharmacokinetic experiments of the Compounds of the invention in rats
1. Summary
The drug concentrations in plasma were varied by measuring the concentrations of the compounds of example 3, example 5, example 9, example 17, example 18, example 19, example 21, example 22, example 23, example 24, example 27, example 28, example 29, example 30, example 31, example 32, example 33, example 34, example 36, example 38, example 40, example 41, example 43, example 45, example 50, example 51, example 54, example 58, and by gavage administration using liquid chromatography-mass spectrometry (LC/MS) techniques in rats weighing 200-300g and 8 weeks old, as experimental animals. The pharmacokinetic behavior of the compound of the invention in rats was studied and its pharmacokinetic profile was evaluated.
2. Experimental protocol
2.1 Compounds for experiments
The compound of example 3, example 5, example 9, example 17, example 18, example 19, example 21, example 22, example 23, example 24, example 27, example 28, example 29, example 30, example 31, example 32, example 33, example 34, example 36, example 38, example 40, example 41, example 43, example 45, example 50, example 51, example 54, example 58 were measured.
2.2 Formulation of Compounds
A certain amount of the compound was weighed and dissolved in dimethyl sulfoxide (DMSO)/polyethylene glycol 300/physiological saline=5/20/75 to prepare a uniform solution.
2.3 Plasma collection and processing
Rats were given the above compound intravenously and orally at a dose of 1 milligram per kilogram (mg/kg), 0.2 milliliter (ml) was collected from the orbit 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 hours after administration, and plasma was isolated by centrifugation at 6000 rpm for 10 minutes at-80 ℃ in an anticoagulant tube.
2.4 Experimental results and conclusions
The pharmacokinetic parameters of the compounds of the invention following 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 six, efficacy experiments of the Compounds of examples 5, 18, 22, 29, 31, 41, 54 of the invention in the model of human myelomonocytic leukemia cells (MV-4-11 cells) mouse transplantation tumor
1. Summary
Results of drug effects on tumors in mice after the compound of example 5, the compound of example 18, the compound of example 22, the compound of example 29, the compound of example 31, the compound of example 41 and the compound of example 54 were administered to the transplanted tumor mice by gavage were measured using 8-week-old female immunodeficiency mice (Balb/c Nude) weighing 16g to 18g as experimental animals. The effect of the inventive compounds on tumor growth was investigated.
2. Experimental protocol
2.1 Compounds for experiments
Example 5, example 18, example 22, example 29, example 31, example 41, example 54.
2.2 Formulation of Compounds
A certain amount of the compound was weighed and dissolved in dimethyl sulfoxide (DMSO)/polyethylene glycol 300/physiological saline=5/20/75 to prepare a uniform solution.
2.3 Cultivation of cells
Human myelogenous monocytic leukemia cells (MV-4-11 cells) were ordered in the China academy of sciences cell bank, cultured using IMDM (Corning, 26917008) plus 10% fetal bovine serum (Gibco, 10817010) and 1% penicillin/streptomycin diaantibody (Corning, 30002297), observed under a microscope, to confirm good cell status, transferred to a 15 milliliter (mL) centrifuge tube, centrifuged at 1000 revolutions per minute (rpm) for 5 minutes, the supernatant was discarded, added to complete medium, blown into a single cell suspension, and placed in a 37℃5% CO 2 incubator (Simer fly) for culture.
2.4 Experimental procedure
Human myelomonocytic leukemia cells (MV-4-11 cells) in logarithmic growth phase were centrifuged and mixed with Matrigel (corning, 8274014) and transplanted subcutaneously on the right back of female immunodeficient mice (Balb/c Nude), each mouse was inoculated with 5X 10 6 cells and 100 microliter (μl) in volume, after inoculation, the mice were randomly divided into 9 groups according to tumor size balance, 6 in vivo efficacy experiments were performed in each group, the positive control group was JQ1, and the negative control group was given an equal amount of vehicle. The specific design is shown in Table 4.
TABLE 4 in vivo efficacy experiment of Compounds
2.5 Experimental results and conclusions
The inhibition of tumor growth by JQ1 was only 50.00% at 50 milligrams per kilogram (mg/kg), and the inhibition of tumor growth by the compounds of examples 5, 18, 22, 29, 31, 41, 54 at 1.0 milligrams per kilogram (mg/kg) reached 98.12%, 101.75%, 97.63%, 103.25%, 95.17%, 94.65% and 94.02%, respectively, indicating that the compounds of examples 5, 18, 22, 29, 31, 41, 54 of the present invention had a greater tumor growth inhibition in human myelogenous monocytic leukemia cell (MV-4-11 cell) xenograft models than JQ 1.
Experiment seven, efficacy experiments of the Compounds of examples 9, 19, 24, 30, 33, 45, 50, 58 of the invention in a model of human myeloma cell (MM.1S cell) mouse transplantation tumor
1. Summary
Results of drug effects on tumors in mice after administration of the compounds of example 9, example 19, example 24, example 30, example 33, example 45, example 50, and example 58 by gavage were measured using 8-week-old female combined severe immunodeficiency (SCID) mice weighing 18g to 20g as experimental animals. The effect of the inventive compounds on tumor growth was investigated.
2. Experimental protocol
2.1 Compounds for experiments
Example 9, example 19, example 24, example 30, example 33, example 45, example 50, example 58.
2.2 Formulation of Compounds
A certain amount of the compound was weighed and dissolved in dimethyl sulfoxide (DMSO)/polyethylene glycol 300/physiological saline=5/20/75 to prepare a uniform solution.
2.3 Cultivation of cells
Human myeloma cells (mm.1 s cells) were ordered in the kyaniraceae, herborist, inc, and cultured using RPMI1640 (corning, 35417005) plus 10% fetal bovine serum (Gibco, 10817010) and 1% penicillin/streptomycin diaantibody (corning, 30002297), and observed under a microscope to confirm that the cells were in good condition, transferred to 15 milliliter (mL) centrifuge tubes, centrifuged at 1000 revolutions per minute (rpm) for 5 minutes, the supernatant was discarded, complete medium was added, and the suspension was blown into single cell suspensions and incubated in a 5% co 2 incubator (zemer).
2.4 Experimental procedure
Human myeloma cells (mm.1 s cells) in log phase were centrifuged and mixed with Matrigel (corning, 8274014) under aseptic conditions and transplanted under the back right side of combined severe immunodeficiency (SCID) mice, each mouse was inoculated with 1 x 10 7 cells, 100 μl (μl) in volume, and after inoculation, the mice were randomly divided into 10 groups according to tumor size balance, 6 in vivo efficacy experiments were performed, the positive control group was JQ1, and the negative control group was given an equal amount of vehicle. The specific design is shown in Table 5.
TABLE 5 in vivo efficacy experiment of Compounds
2.5 Experimental results and conclusions
The inhibition rate of JQ1 on tumor growth was 46.00% at 50 milligrams per kilogram (mg/kg), and the inhibition rates of the compounds of examples 9, 19, 24, 30, 33, 45, 50, 58 on tumor growth were 109.97%, 93.16%, 102.18%, 95.72%, 92.18%, 98.71%, 96.79% and 96.88% at 1.5 milligrams per kilogram (mg/kg), respectively, indicating that the compounds of examples 9, 19, 24, 30, 33, 45, 50, 58 of the present invention have a stronger tumor growth inhibition effect than JQ1 in human myeloma cell (MM.1S cell) xenograft models.
Experiment eight, drug efficacy experiments of Compounds of examples 3, 17, 27, 34, 38, 43, 51 of the invention in human colon cancer cell (RKO cell) mouse transplantation tumor model
1. Summary
Results of drug effects on tumors in mice after 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 administered to the transplanted tumor mice by gavage were measured using 8-week-old female immunodeficiency mice (Balb/c Nude) weighing 16g to 18g as experimental animals. The effect of the inventive compounds on tumor growth was investigated.
2. Experimental protocol
2.1 Compounds for experiments
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 Formulation of Compounds
A certain amount of the compound was weighed and dissolved in dimethyl sulfoxide (DMSO)/polyethylene glycol 300/physiological saline=5/20/75 to prepare a uniform solution.
2.3 Cultivation of cells
Human colon cancer cells (RKO cells) were ordered in Nanjac Bai Biotechnology Co., ltd, cultured using MEM (Corning, 06419006) plus 10% fetal bovine serum (Gibco, 10817010), 1% penicillin/streptomycin diabody (Corning, 30002297) and 1 millimole per liter (mM) of sodium pyruvate (Corning, 03118009), and observed under a microscope to confirm that the cells were well conditioned, the cells were transferred to a 15 milliliter (mL) centrifuge tube, centrifuged at 1000 revolutions per minute (rpm) for 5 minutes, the supernatant was discarded, complete medium was added, and blown into a single cell suspension, and cultured in a 5% CO 2 incubator (Xiefei) at 37 ℃.
2.4 Experimental procedure
Human colon cancer cells (RKO cells) in logarithmic growth phase were digested and mixed with Matrigel (Matrigel) (corning, 8274014) under aseptic conditions and transplanted under the skin on the back right side of female immunodeficiency mice (Balb/c Nude), each mouse was inoculated with 2X 10 6 cells and 100 microliter (μl) in volume, after inoculation, the mice were randomly divided into 9 groups according to tumor size balance, 6 in vivo efficacy experiments were performed in each group, the positive control group was JQ1, and the negative control group was given an equal amount of vehicle. The specific design is shown in Table 6.
TABLE 6 in vivo efficacy experiment of Compounds
2.5 Experimental results and conclusions
The results of the inhibition of tumor growth by JQ1 at a concentration of 50 milligrams per kilogram (mg/kg) were 43.24%, and the inhibition of tumor growth by the compounds of examples 3, 17, 27, 34, 38, 43, 51 at a concentration of 1.5 milligrams per kilogram (mg/kg) was 86.51%, 81.24%, 83.62%, 88.83%, 90.01%, 89.33% and 84.29%, respectively, indicating that the compounds of examples 3, 17, 27, 34, 38, 43, 51 of the present invention had a greater tumor growth inhibition than JQ1 in human colon cancer cell (RKO cell) xenograft models.

Claims (12)

1. A compound represented by the general formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Scheme 1:
Wherein Ar is
X is a carbon atom; y is-H;
R 0 is- (CH 2)n -heterocycloalkyl), and the heterocycloalkyl is 4-6 membered heterocycloalkyl;
r 1 is a substituted or unsubstituted benzene ring, which may be substituted with: halogen;
R 2 is-C 1-3 alkyl, -C (O) OH, wherein said-C 1-3 alkyl may be substituted with: -OH;
R 3 is a 5-6 membered heteroaryl, which heteroaryl may be substituted with C 1-3 alkyl;
R 6 and R 7 are each independently hydroxy or-C 1-3 alkyl;
n is 0, 1 or 2;
Scheme 2:
Wherein Ar is
X is a carbon atom; y is-H;
R 0 is- (CH 2)n -heterocycloalkyl), and the heterocycloalkyl is 4-6 membered heterocycloalkyl;
R 1 is an unsubstituted benzene ring;
R 2 is-C 1-3 alkyl, said-C 1-3 alkyl being substituted by: -OH;
R 3 is
N is 0, 1 or 2;
Scheme 3:
Wherein Ar is
X is a carbon atom; y is-H;
R 0 is- (CH 2)n -heterocycloalkylene), Wherein the heterocycloalkane is a 4-6 membered heterocycloalkane; r 1 is an unsubstituted 5-6 membered heteroaromatic ring; r 2 is-C 1-3 alkyl, said-C 1-3 alkyl being substituted by: -OH; n is 0,1 or 2;
Or R 0 is- (CH 2)n -heterocycloalkyl, the heterocycloalkyl is 4-6 membered heterocycloalkyl, R 1 is unsubstituted benzene ring, R 2 is-C 2-3 alkylene, n is 0, 1 or 2;
Or R 0 is- (CH 2)n -heterocycloalkyl) and the heterocycloalkyl is 4-6 membered heterocycloalkyl, R 1 is substituted benzene ring which can be substituted by halogen, R 2 is-C 1-3 alkyl and the-C 1-3 alkyl can be substituted by-OH, n is 0, 1 or 2;
Or R 0 is- (CH 2)n -heterocycloalkyl), the heterocycloalkyl is 4-6 membered heterocycloalkyl, R 1 is unsubstituted benzene ring, R 2 is-C 1-3 alkyl, the-C 1-3 alkyl can be substituted by-OH, n is 1 or 2;
R 3 is a 5-6 membered heteroaryl, which heteroaryl may be substituted with C 1-3 alkyl;
R 8 is-C 1-3 alkyl;
scheme 4:
Wherein Ar is
X is a carbon atom; y is-H;
R 0 is- (CH 2)n -heterocycloalkyl), and the heterocycloalkyl is 4-6 membered heterocycloalkyl;
R 1 is an unsubstituted benzene ring;
R 2 is-C 1-3 alkyl, said-C 1-3 alkyl being substituted by: -OH;
R 3 is a 5-6 membered heteroaryl, which heteroaryl may be substituted with C 1-3 alkyl;
R 6 is hydroxy;
n is 0, 1 or 2.
2. A compound according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
For scheme 1:
R 3 is a 5-6 membered nitrogen containing heteroaryl, which heteroaryl may be substituted with C 1-3 alkyl;
For scheme 3:
R 0 is- (CH 2)n -heterocycloalkylene), Wherein the heterocycloalkane is a 4-6 membered heterocycloalkane; r 1 is a 5-6 membered heteroaromatic ring; r 2 is-C 1-3 alkyl, said-C 1-3 alkyl being substituted by: -OH; n is 0, 1 or 2;
Or R 0 is- (CH 2)n -heterocycloalkyl) and the heterocycloalkyl is 4-6 membered heterocycloalkyl, R 1 is phenyl optionally substituted with halogen, R 2 is-C 1-3 alkyl, and-C 1-3 alkyl is optionally substituted with-OH, n is 0, 1 or 2;
R 3 is a 5-6 membered nitrogen containing heteroaryl, which heteroaryl may be substituted with C 1-3 alkyl;
For scheme 4:
r 1 is phenyl;
R 2 is-C 1-3 alkyl, said-C 1-3 alkyl being substituted by: -OH;
R 3 is a 5-6 membered nitrogen containing heteroaryl, which heteroaryl may be substituted with C 1-3 alkyl.
3. A compound according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
For scheme 1:
R 0 is
R 1 is
R 2 is-COOH,
R 3 is
R 6 and R 7 are each independently hydroxy or methyl;
For scheme 2:
R 0 is
R 1 is
R 2 is
R 3 is
For scheme 3:
R 0 is R 1 isR 2 isOr R 0 isR 1 isR 2 is
Or R 0 isR 1 is R 2 is
Or R 0 isR 1 isR 2 is
R 3 is
R 8 is-C 1-3 alkyl;
For scheme 4:
R 0 is
R 1 is
R 2 is
R 3 is
R 6 is hydroxy.
4. A compound according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, and mixtures thereof, and pharmaceutically acceptable salts thereof, wherein said compound is:
5. A process for preparing a compound of the general formula (I) as defined in any one of claims 1 to 4, which is prepared by the following scheme,
Scheme 1-3: ar isThe synthetic route is as follows:
Wherein Ar 1 is
Is that
Carrying out Suzuki coupling on the compound I-1 and the corresponding aryl boric acid I-2 under the conditions of heating, alkalinity and the existence of a catalyst to obtain a compound with a general formula I-3; the compound I-3 is subjected to intramolecular cyclization under the catalysis of a phosphine reagent to obtain a compound I-4; carrying out Mitsunobu reaction on the compound I-4 and corresponding alcohol to obtain a compound I-6; the compound I-6 is Still coupled with a corresponding tin reagent under palladium catalysis to obtain a compound (I); after the compound (I) is obtained, the functional group on the aromatic ring is further converted to obtain a specific target series compound.
6. The process for producing a compound according to claim 5, wherein in the step of obtaining the compound I-3, the reagent providing alkaline conditions is selected from the group consisting of potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium fluoride.
7. A process for preparing a compound according to claim 5, wherein in the step of obtaining compound I-3, the catalyst is selected from the group consisting of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium.
8. The process for preparing a compound according to claim 5, wherein in the step of obtaining the compound I-4, the phosphine reagent is selected from the group consisting of 1, 2-bis (diphenylphosphine) ethane (DPPE), triphenylphosphine.
9. A process for preparing a compound according to claim 5, wherein in the step of obtaining the compound (I), the catalyst is selected from the group consisting of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium.
10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-4, or a tautomer, mesomer, racemate, enantiomer, diastereomer, and mixtures thereof, and pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable carriers and/or diluents.
11. Use of a compound according to any one of claims 1-4, or a tautomer, mesomer, racemate, enantiomer, diastereomer, and mixtures thereof, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 10, in the manufacture of a medicament for the prevention and/or treatment of BRD4 mediated related diseases, which BRD4 mediated related diseases are lymphomas or myelomas.
12. Use of a compound according to any one of claims 1-4, or a tautomer, mesomer, racemate, enantiomer, diastereomer, and mixtures thereof, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 10, in the manufacture of a medicament for the prevention and/or treatment of BRD4 mediated related diseases, which BRD4 mediated related diseases are acute myelolymphoma or acute lymphoblastic leukemia.
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