CN109206360B - Carbazole amide derivative or salt thereof, and preparation method and application thereof - Google Patents

Carbazole amide derivative or salt thereof, and preparation method and application thereof Download PDF

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CN109206360B
CN109206360B CN201810700432.1A CN201810700432A CN109206360B CN 109206360 B CN109206360 B CN 109206360B CN 201810700432 A CN201810700432 A CN 201810700432A CN 109206360 B CN109206360 B CN 109206360B
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王永辉
黄亚飞
郁明诚
谢琼
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Fudan University
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Abstract

The invention discloses a novel carbazole amide derivative with ROR gamma t activity regulation function shown in a general formula I or a salt thereof, a preparation method thereof, and application of the carbazole amide derivative or the salt thereof in preparation of a medicament for treating ROR gamma t related diseases. The experimental result shows that the carbazole amide derivatives or the salts thereof can effectively regulate the activity of ROR gamma t protein receptors, thereby regulating the differentiation of Th17 cells and the generation of IL-17, and further serve as therapeutic drugs for treating related diseases mediated by ROR gamma t, and are particularly suitable for treating related diseases such as multiple sclerosis, rheumatoid arthritis, collagen-induced arthritis, psoriasis, inflammatory bowel disease, encephalomyelitis, clone diseases, asthma, various cancers and the like.

Description

Carbazole amide derivative or salt thereof, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of chemical medicines, and relates to a novel carbazole amide derivative with ROR gamma t regulation activity and a preparation method thereof, and also relates to application of the compound in treating ROR gamma t related diseases.
Background
Retinoic acid receptor-Related Orphan Receptors (RORs), also known as NF1R, are members of the nuclear receptor superfamily of ligand-dependent transcription factors. The RORs subfamily mainly includes three members, ROR α, ROR β and ROR γ. ROR γ exists in two distinct subtypes: ROR γ 1 and ROR γ t (also referred to as ROR γ 2), in which ROR γ 1 is distributed in skeletal muscle, thymus, testis, pancreas, prostate, heart, liver, and the like, and ROR γ t is expressed only in some immune cells.
Littman et al first reported ROR γ t for initial CD4+Differentiation of T cells into Th17 cells is essential. During the differentiation process of antigen-stimulated Thp cells to Th17 cells, ROR gamma t is induced and expressed under the action of cytokines such as IL-6, IL-21 and TGF-beta. The ability of Thp cells isolated from ROR γ t-deficient mice to differentiate into the Th17 cell line was significantly reduced. These all indicate that ROR γ t is a key regulator for promoting differentiation of Th17 cells.
Th17 cells are one of the helper T cells, and produce IL-17 and other proinflammatory cytokines. Th17 cells play a key role in many mouse models of autoimmune disease, such as Experimental Allergic Encephalomyelitis (EAE) and collagen-induced arthritis (CIA) animal models. Furthermore, increased IL-17 levels are detectable in some human autoimmune diseases, including Rheumatoid Arthritis (RA), Multiple Sclerosis (MS), Psoriasis (Psoriasis) and Inflammatory Bowel Disease (IBD). The number of Th17 cells found in both tissues and peripheral blood samples from patients with autoimmune disease is increased. Therefore, the Th17 cell or its produced cytokine IL-17 is closely related to the pathogenesis of inflammation and autoimmune diseases.
The monoclonal antibody Cosentyx (Secukinumab/AIN457) developed by Nowa, which is used to treat psoriasis by specifically blocking IL-17, was approved by the FDA to be marketed in 1 month 2015, and is the first drug acting on IL-17 in the psoriasis-treating drug market. This also underscores the importance of the IL-17 signaling pathway in inflammatory diseases and demonstrates the potential for treating inflammatory diseases by affecting the IL-17 signaling pathway through ROR γ t inhibitors.
Therefore, ROR gamma t can be used as a new target of drugs for treating autoimmune diseases, and the search for ROR gamma t small molecule modulators and the application of ROR gamma t small molecule modulators in the treatment of ROR gamma t mediated inflammation and autoimmune diseases have important significance.
The tumor immunotherapy is to enhance the anti-tumor immunity of the tumor microenvironment by mobilizing the immune system of the body, thereby controlling and killing tumor cells, and the target of the tumor immunotherapy is the immune system of the human body and not directly aiming at the tumor. Tumor immunotherapy has attracted much attention in recent years and is the focus of the field of tumor therapy. It has been reported that strong antitumor activity has been demonstrated in the treatment of some tumor types such as melanoma, non-small cell lung cancer, etc., and tumor immunotherapy mab drugs have been approved by FDA in the united states for marketing. Because of its excellent curative effect and innovation, immunotherapy for tumor is the most important scientific breakthrough in year 2013 as judged by the "Science" journal. The tumor immunotherapy is expected to become an innovation in the field of tumor therapy after operations, chemotherapy, radiotherapy and targeted therapy.
It has been found that Th17 cells are widely present in tumor tissues, however, there is no knowledge about the function of Th17 in tumor tissues. In 2009, professor "Immunity" in the president of article "mainly analyzed that Th17 cells could promote cytotoxic T cell activation to exert tumor immune function, and it was found that mice deficient in IL-17A were more likely to develop lung melanoma (a cancer, if T cell therapy was applied to mice, treatment with T cells secreting IL-17A could effectively prevent tumor development, more importantly, Th17 cells showed stronger therapeutic effect than Th1 cells with the aid of IL-17A, and surprisingly, treatment with Th17 cells could also effectively activate tumor-specific CD8+T cells of, among others, CD8+T cells are anti-tumorEssential cells of tumor, research shows that Th17 cell can collect dendritic cell into tumor tissue and make CD8 alpha+Dendritic cells accumulate in tumor tissue. In addition, Th17 cells activated the tumor tissue chemokine CCL 20. Overall, Th17 cells were effective in promoting tumor-specific CD8+T cell activity, these new findings broaden the field of vision for tumor immunotherapy. ROR γ t is expressed in certain immune cells. Research reports that Th17 cells specifically express ROR gamma t, and activation of ROR gamma t can promote differentiation of Th17 cells and produce proinflammatory cytokine IL-17. Thus, it is theorized that Th17 cell differentiation could be increased by activating ROR γ t, thereby promoting tumor-specific CD8+T cell activity, and tumor immunity.
On day 9/6 of 2015, Celgene agreed with Lycera on T cell drugs against cancer with 8250 ante + 2250 ten thousand recent payments. In 2 months of 2015, the Lycera announces that a large amount of evidence is obtained, which indicates that the oral ROR gamma agonist can improve the efficacy of T cells, increase the production of IL-17 and promote the activation of Tc cells, so that the immune response to cancer cells is stimulated, and the effect of killing tumor cells for a long time is achieved; in 2017, in 1 month, the medicine formally enters a first-stage clinical experiment; this cooperation fully demonstrates the great potential of ROR γ t agonists for tumor immunotherapy.
Therefore, ROR γ t can be used as a potential target of tumor immunotherapy, and it is of great significance to search for small-molecule ROR γ t agonists and use the agonists in virology infection and cancer treatment.
Disclosure of Invention
The invention provides a novel carbazole amide derivative with a general formula I and pharmaceutically acceptable salts thereof:
Figure BDA0001714564360000031
wherein:
a represents phenyl, heteroaryl, aliphatic heterocyclic group or aliphatic cycloalkyl;
b represents phenyl or heteroaryl;
R1optionally selected from hydrogen, halogen, cyano, C1-C6Alkyl, halogen substituted C1-C6Alkyl radical, C3-C6Cycloalkyl-substituted C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Oxygen or azacycloalkyl, C3-C6Oxygen or azacycloalkyl substituted C1-C6Alkyl radical, C1-C6Alkoxy, halogen substituted C1-C6Alkoxy radical, C3-C8Cycloalkoxy, halogen-substituted C3-C8Cycloalkoxy, C3-C8Heterocyclic alkoxy radical, C1-C3Alkoxy-substituted C1-C3Alkyl, heterocyclyl, heterocyclyloxy, C2-C6Alkenyl, - (CH)2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2；
R2Optionally selected from hydrogen, halogen, cyano, C1-C6Alkyl, halogen substituted C1-C6Alkyl radical, C3-C6Cycloalkyl-substituted C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Oxygen or azacycloalkyl, C1-C6Alkoxy, halogen substituted C1-C6Alkoxy radical, C1-C3Alkoxy-substituted C1-C3Alkyl radical, C2-C6Alkenyl, - (CH)2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2；
R3Selected from hydrogen, C1-C6Alkyl, halogen substituted C1-C6Alkyl radical, C3-C6Cycloalkyl-substituted C1-C3Alkyl radical, C3-C6Oxygen or azacycloalkyl substituted C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Oxygen or azacycloalkyl, phenyl substituted C1-C3Alkyl, substituted phenyl substituted C1-C3Alkyl, heteroaryl substituted C1-C3Alkyl, substituted heteroaryl substituted C1-C3An alkyl group;
R4selected from hydrogen, C1-C3Alkyl, halogen substituted C1-C3Alkyl radical, C3-C6Cycloalkyl-substituted C1-C3Alkyl radical, C3-C6Oxygen or azacycloalkyl substituted C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Oxygen or azacycloalkyl;
R5、R6each independently selected from hydrogen, hydroxy, halogen, cyano, C1-C3Alkyl, hydroxy or C1-C3Alkoxy-substituted C1-C3Alkyl, halogen substituted C1-C3Alkyl radical, C1-C3Alkoxy, halogen substituted C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C3-C6Oxygen or azacycloalkyl, and R5、R6Can also be connected to form C3-C6A ring;
R7optionally selected from hydrogen, halogen, cyano, C1-C6Alkyl, halogen substituted C1-C6Alkyl radical, C3-C6Cycloalkyl-substituted C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Oxygen or azacycloalkyl, C1-C6Alkoxy, halogen substituted C1-C6Alkoxy radical, C1-C3Alkoxy-substituted C1-C3Alkyl, heterocyclyl, heterocyclyloxy, C2-C6Alkenyl, - (CH)2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2；
Y is selected from the group consisting of a covalent bond, -NRa-、-O-、-CRa1Ra2-、-C(O)NRa-；
R8Selected from hydroxy, C1-C6Alkyl, halogen substituted C1-C6Alkyl, hydroxy or C1-C3Alkoxy-substituted C1-C3Alkyl radical, C2-C6Alkenyl, - (CH)2)nNRa1Ra2、-NHC(O)CH3；
Z is selected from O, NRa；
Ra、Ra1、Ra2Each independently selected from hydrogen, C1-C3Alkyl or halogen substituted C1-C3An alkyl group;
m, r, t, n and s are independently selected from any integer value of 0-2.
In some preferred embodiments, Y is a covalent bond, s is 1 and R is6Is H.
In some preferred embodiments, B is phenyl or a six-membered (or five-membered) heteroaryl, and R is4Is H, r is 0, and Z is O or NH.
In some preferred embodiments, R7Optionally selected from hydrogen, halogen, cyano, hydroxy, C1-C6An alkyl group.
In some preferred embodiments, R8Is selected from C1-C3Alkyl, -NHCH3、-NH2、-NHC(O)CH3。
In some more preferred embodiments, the carbazole amide derivative or the pharmaceutically acceptable salt thereof has the structure of formula I-a:
Figure BDA0001714564360000041
wherein:
a represents phenyl, heteroaryl, aliphatic heterocyclic group or aliphatic cycloalkyl;
b represents phenyl or a six-membered (or five-membered) heteroaryl;
R1optionally selected from hydrogen, halogen, cyano, C1-C6Alkyl, halogen substituted C1-C6Alkyl radical, C3-C6Cycloalkyl-substituted C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Oxygen or azacycloalkyl, C3-C6Oxygen or azacycloalkyl substituted C1-C6Alkyl radical, C1-C6Alkoxy, halogen substituted C1-C6Alkoxy radical, C3-C8Cycloalkoxy, halogen-substituted C3-C8Cycloalkoxy, C3-C8Heterocyclic alkoxy radical, C1-C3Alkoxy-substituted C1-C3Alkyl, heterocyclyl, heterocyclyloxy, C2-C6Alkenyl, - (CH)2)nOH、-C(O)Ra、-(CH2)nNRa1Ra2、-(CH2)nC(O)ORa、-C(O)NRa1Ra2；
R3Selected from hydrogen, C1-C6Alkyl, halogen substituted C1-C6Alkyl radical, C3-C6Cycloalkyl-substituted C1-C3Alkyl radical, C3-C6Oxygen or azacycloalkyl substituted C1-C3Alkyl radical, C3-C6Cycloalkyl, C3-C6Oxygen or azacycloalkyl, phenyl substituted C1-C3Alkyl, substituted phenyl substituted C1-C3Alkyl, heteroaryl substituted C1-C3Alkyl, substituted heteroaryl substituted C1-C3An alkyl group;
R5selected from hydrogen, hydroxy, halogen, cyano, C1-C3Alkyl, hydroxy or C1-C3Alkoxy-substituted C1-C3Alkyl, halogen substituted C1-C3Alkyl radical, C1-C3Alkoxy, halogen substituted C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C3-C6Oxygen or azacycloalkyl;
R7optionally selected from hydrogen, halogen, cyano, hydroxy, C1-C6An alkyl group;
R8is selected from C1-C3Alkyl, -NHCH3、-NH2、-NHC(O)CH3；
Z is selected from O, NH;
Ra、Ra1、Ra2each independently selected from hydrogen and C1-C3Alkyl or halogen substituted C1-C3An alkyl group;
m, n, t are each independently selected from any integer value of 0 to 2.
Most preferably, the carbazole amide derivatives or salts thereof provided by the present invention include, but are not limited to, the following specific compound examples:
Figure BDA0001714564360000051
Figure BDA0001714564360000061
the present invention also provides a method of preparing a compound of the invention, comprising the following synthetic scheme:
synthesis scheme 1:
Figure BDA0001714564360000062
the formula I-1 reacts with the formula I-2 under the action of palladium acetate to obtain a formula I-3, the formula I-3 is subjected to ring closure under the action of palladium acetate and acetic acid to obtain a formula I-4, the formula I-4 reacts with halogenated hydrocarbon to obtain a formula I-5, the formula I-5 is hydrolyzed under the action of alkali to obtain a formula I-6, and the formula I-6 is condensed with benzylamine to obtain a formula I-a.
Synthesis scheme 2:
Figure BDA0001714564360000071
the formula I-1 reacts with the formula I-2 under the action of palladium acetate to obtain the formula I-3, the formula I-3 is subjected to ring closure under the action of palladium acetate and acetic acid to obtain the formula I-4, the formula I-4 is hydrolyzed to obtain the formula I-7, the formula I-7 is condensed with benzylamine to obtain the formula I-8, and the formula I-8 reacts with halogenated hydrocarbon to obtain the formula I-b.
Unless otherwise indicated, the groups, terms, and meanings described in the above synthetic schemes are the same as those in the compounds of formula I.
The above synthetic schemes are only examples of the preparation methods of the compounds of the present invention, and the skilled person can synthesize the compounds of the present invention by similar methods based on the above synthetic schemes according to the well-known techniques in the art.
The term "compound" as used herein includes all stereoisomers, geometric isomers, tautomers and isotopes.
The "compounds" of the present invention may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the invention containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The "compound" of the present invention also includes tautomeric forms. Tautomeric forms result from the exchange of one single bond with an adjacent double bond and the concomitant migration of one proton.
The invention also includes all isotopic atoms, whether in the intermediate or final compound. Isotopic atoms include those having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.
In the present invention, the terms used have the following meanings, unless otherwise specified:
the term "halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
The term "cyano" refers to — CN.
The term "hydroxy" refers to-OH.
The term "carboxyl" refers to-COOH.
The term "alkyl" denotes a straight or branched chain saturated hydrocarbon group consisting of carbon and hydrogen atoms, such as C1-C20Alkyl, preferably C1-C6Alkyl groups such as methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylhexyl and the like. The alkyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxy, aryl, heteroaryl, amino, halo, sulfonyl, sulfinyl, phosphoryl.
The term "cycloalkyl" refers to a monocyclic, fused, spiro or bridged ring all carbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, spiro [3.4] octane, bicyclo [3.1.1] hexane.
The term "heterocycloalkyl" refers to a monocyclic or fused ring containing 1 or more heteroatoms of N, O or S. Typically a 5-6 membered heterocyclic group containing 1 or more heteroatoms of N, O or S, such as piperazino, morpholino, piperidino, pyrrolidinyl and derivatives thereof.
The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, typically having 6 to 14 carbon atoms, preferably having 6 to 12 carbon atoms, and most preferably having 6 carbon atoms. Aryl groups may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxy, aryl, aralkyl, amino, halo, sulfonyl, sulfinyl, phosphoryl. Examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "heteroaryl" refers to a monocyclic or fused ring of 5-12 ring atoms containing 1-4 ring atoms selected from N, O, S, the remaining ring atoms being C, and having a fully conjugated pi-electron system including, but not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, tetrahydropyrrolyl. Heteroaryl groups may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkoxy, aryl, aralkyl, amino, halo, hydroxy, cyano, nitro, carbonyl, and heteroalicyclic.
By "treatment" is meant any treatment of a disease in a mammal, including: (1) preventing disease, i.e., the symptoms that cause clinical disease do not develop; (2) inhibiting disease, i.e., arresting the development of clinical symptoms; (3) alleviating the disease, i.e., causing regression of clinical symptoms.
The invention also provides a pharmaceutical composition, which comprises the compound or the pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.
"pharmaceutical composition" as used herein, refers to a formulation of one or more compounds of the present invention or salts thereof with a carrier generally accepted in the art for delivery of biologically active compounds to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate delivery of the drug to an organism.
The term "pharmaceutically acceptable carrier" refers to a substance that is co-administered with, and facilitates the administration of, an active ingredient, including, but not limited to, any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is acceptable for use in humans or animals (e.g., livestock) as permitted by the national food and drug administration. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
The pharmaceutical composition can be prepared into solid, semisolid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, pastes, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.
The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
The route of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof includes, but is not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral.
For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient. For example, for pharmaceutical compositions intended for oral administration, tablets may be obtained in the following manner: the active ingredient is combined with one or more solid carriers, the resulting mixture is granulated if necessary, and processed into a mixture or granules, if necessary with the addition of small amounts of excipients, to form tablets or tablet cores. The core may be combined with an optional enteric coating material and processed into a coated dosage form more readily absorbed by an organism (e.g., a human).
The invention also provides a compound or a pharmaceutically acceptable salt thereof or an application thereof in preparing a ROR gamma t receptor modulator.
The invention also provides the application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof as a ROR gamma t receptor modulator in the preparation of medicines for treating or preventing ROR gamma t related diseases.
Preferably, the disease related to the ROR γ t receptor is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, collagen-induced arthritis, psoriasis, inflammatory bowel disease, encephalomyelitis, crohn's disease, asthma, and various cancers. The cancer is preferably prostate cancer, melanoma, non-small cell lung cancer, etc.
The invention provides a carbazole amide compound with structural characteristics of a general formula I. Researches show that the compounds can effectively regulate ROR gamma t protein receptors, thereby regulating the differentiation of Th17 cells and regulating the generation of IL-17, and can be used as therapeutic drugs for treating ROR gamma t-mediated inflammation-related diseases.
Detailed Description
The following are specific examples of the present invention and further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
In the preparation method of the target compound, the column chromatography adopts silica gel (300-400 meshes) produced by Ningsan Sun drying agent GmbH; thin layer chromatography using GF254(0.25 mm); nuclear magnetic resonance chromatography (NMR) was measured using a Varian-400 nuclear magnetic resonance spectrometer; LC/MS Using an Agilent technology ESI 6120 LC/MS spectrometer.
In addition, all operations involving easily oxidizable or hydrolyzable raw materials were carried out under nitrogen protection. Unless otherwise indicated, the starting materials used in the present invention are all commercially available starting materials and can be used without further purification.
Example 1:9-ethyl-N- (4- (ethylsulfonyl) phenyl) -9H-carbazole-3-carboxamide
9-ethyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000101
Intermediate 1: synthesis of 9-ethyl-9H-carbazole-3-carboxylic acid
Step 1: synthesis of methyl 4-phenylaminobenzoate
To a 25mL microwave tube were added aniline (1.82g, 19.5mmol), methyl 4-bromobenzoate (3.5g, 16.28mmol), potassium carbonate (6.72g, 49.4 m)mol), rac-BINAP (506mg, 0.81mmol), palladium acetate (218mg, 0.97mmol), toluene (10mL), microwave heated at 130 ℃ for 2 hours, after the reaction was completed, ethyl acetate was added for dilution, celite was filtered, the solvent was spin-dried under reduced pressure, silica gel column separation (petroleum ether: ethyl acetate 10:1-5:1) gave 3.5g of product as a yellow solid in 94.6% yield.1H NMR(400MHz，CDCl3)δ7.92(d，J＝8.5Hz，2H)，7.34(t，J＝7.7Hz，2H)，7.17(d，J＝7.7Hz，2H)，7.07(t，J＝7.3Hz，1H)，6.99(d，J＝8.6Hz，2H)，6.08(s，1H)，3.88(s，3H).MS(ESI)m/z:228.1(MH+).
Step 2: synthesis of methyl 9H-carbazole-3-carboxylate
Methyl 4-phenylaminobenzoate (1.97g, 8.67mmol), palladium acetate (2.14g, 9.56mmol) and acetic acid (10mL) were charged into a 100mL single-neck flask, and the mixture was heated at 120 ℃ for 1 hour to react, after which time the acetic acid was removed under reduced pressure, and the crude product was dissolved in ethyl acetate and stirred, and isolated on a silica gel column to give 1.5g of a yellow solid product in 76.9% yield. MS (ESI) M/z 248.0(M +23).
And step 3: synthesis of 9-ethyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with methyl 9H-carbazole-3-carboxylate (700mg, 3.11mmol) and anhydrous N, N-dimethylformamide (10mL), stirred in an ice bath for 5 minutes, then added with NaH (245mg, 6.22mmol, 60%), reacted at room temperature for 30 minutes, and then added dropwise with ethyl bromide (678mg, 6.22mmol) under cooling in an ice bath, reacted at room temperature for 3 hours, after TLC detection, the starting material had reacted. The reaction was quenched with water, ethyl acetate (3X 20mL), water (5X 20mL), saturated sodium chloride, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was spun off under reduced pressure to give 700mg of a yellow solid in 88.9% yield.
And 4, step 4: synthesis of 9-ethyl-9H-carbazole-3-carboxylic acid
A25 mL single-neck bottle is added with 9-ethyl-9H-carbazole-3-methyl formate (690mg, 2.72mmol), lithium hydroxide (344mg, 8.18mmol), ethanol (5mL), water (1mL), heated at 80 ℃ for reaction for 3 hours, TLC detects that the raw materials are reacted, 2N hydrochloric acid is used for adjusting the pH to 3, white solid is separated out, filtration is carried out, and the obtained solid is dried in vacuum to obtain 590mg of white solid product with the yield of 80.4%. MS (ESI) m/z 240.1(MH +).
Intermediate 2: synthesis of 4- (ethylsulfonyl) benzylamine
Step 1: synthesis of 4- (ethylsulfonyl) benzonitrile
To a 100mL single-neck flask were added 4-cyanobenzenesulfonyl chloride (1g, 4.97mmol), water (15mL), sodium bicarbonate (835mg, 9.94mmol), sodium sulfite (689mg, 5.47mmol), and the reaction mixture was stirred at 70 ℃ for 4 hours, and the solvent was removed by evaporation under reduced pressure. The crude product was dissolved again in N, N-dimethylformamide (20mL), ethyl iodide (1.2mL) was added, and the reaction mixture was stirred at 70 ℃ for 4 hours. After cooling to room temperature, water (30mL) and ethyl acetate (3 × 30mL) were added for extraction, the organic layers were combined, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to give a crude product, which was separated with a silica gel column (ethyl acetate: petroleum ether ═ 1:4-1:2) to give 630mg of a yellow solid product with a yield of 65.0%.1H NMR(400MHz，CDCl3)δ8.04(d，J＝8.5Hz，2H)，7.89(d，J＝8.6Hz，2H)，3.16(q，J＝7.4Hz，2H)，1.30(t，J＝7.4Hz，3H).
Step 2: synthesis of 4- (ethylsulfonyl) benzylamine
To a 25mL single-necked flask was added 4- (ethylsulfonyl) benzonitrile (630mg, 3.23mmol), methanol (10mL), Pd/C (100mg, 10%). The reaction solution was stirred at room temperature for 1 hour under hydrogen atmosphere, filtered through celite, and the solvent was spin-dried to give 500mg of a white solid product with a yield of 77.9%.1H NMR(400MHz，CDCl3)δ7.86(d，J＝8.3Hz，2H)，7.53(d，J＝8.2Hz，2H)，3.99(s，2H)，3.10(d，J＝7.4Hz，2H)，1.27(t，J＝7.4Hz，3H).
Synthesis of compound 9-ethyl-N- (4- (ethylsulfonyl) phenyl) -9H-carbazole-3-formamide
9-Ethyl-9H-carbazole-3-carboxylic acid (66mg, 0.26mmol), 2- (7-azo) was added to a single-neck flaskBenzotriazines Azole)-N，N，N′，N′-TetramethylureaHexafluorophosphate (102mg, 0.26mmol), N, N-diisopropylethylamine (65mg, 0.52mmol 1), 4- (ethylsulfonyl) benzylamine (50mg, 0.26mmol), dichloromethane (2mL) and stirred at room temperature for 10 h. After the reaction is finished, ethyl acetate is added for dilution, saturated sodium chloride solution and water are used for washing in sequence, and the organic phase is dried by anhydrous sodium sulfate. The organic solvent was removed by distillation under the reduced pressure, and the 9-ethyl-N- (4- (ethylsulfonyl) phenyl) -9H-carbazole-3-carboxamide was obtained in a yield of 71mg by separation with a silica gel column.1H NMR(400MHz，CD3OD)δ8.70(s，1H)，8.15(d，J＝7.7Hz，1H)，8.03(d，J＝8.7Hz，1H)，7.89(d，J＝8.3Hz，2H)，7.66(d，J＝8.2Hz，2H)，7.61–7.54(m，2H)，7.50(t，J＝7.6Hz，1H)，7.26(t，J＝7.3Hz，1H)，4.75(s，2H)，4.47(q，J＝7.1Hz，2H)，3.19(q，J＝7.4Hz，2H)，1.42(t，J＝7.2Hz，3H)，1.20(t，J＝7.4Hz，3H).MS(ESI)m/z:421.1(MH+).
Example 2:9-Ethyl-N- (4-ethylsulfonyl) benzyl) -2, 3, 4, 9-tetrahydro-1H-carbazole-6-carboxamide(9-ethyl-N-(4-(ethylsulfonyl)benzyl)-2，3，4，9-tetrahydro-1H-carbazole-6-carboxamide)
Figure BDA0001714564360000121
Step 1: synthesis of 2, 3, 4, 9-tetrahydro-1H-carbazole-6-carboxylic acid
A25 mL single neck flask was charged with 4-hydrazinobenzoic acid (1g, 6.6mmol), cyclohexanone (647mg, 6.6mmol), 1, 4-dioxane (10mL), concentrated hydrochloric acid (5mL), and reacted at 120 ℃ under reflux overnight with the formation of a large amount of solid, which was filtered, stirred in water (10mL) for 30 minutes and filtered again, and the solid was dried under vacuum to give 1.13g of a brown solid product in 80.1% yield. MS (ESI) m/z 216.1 (MH)+).
Step 2: synthesis of N- (4- (ethylsulfonyl) benzyl) -2, 3, 4, 9-tetrahydro-1H-carbazole-6-carboxamide
To a 25mL single vial was added 2, 3, 4, 9-tetrahydro-1H-carbazole-6-carboxylic acid (169mg, 0.78mmol), 4- (ethylsulfonyl) benzylamine (130mg, 0.65mmol), HATU (296mg, 0.78mmol), N, N-diisopropylethylamine (302mg, 2.34mmol), dichloromethane (5mL), N, N-dimethylformamide (1mL), reacted overnight at room temperature, and the starting materials were reacted by TLC. Dichloromethane (20mL) was added, the mixture was washed with saturated ammonium chloride (30mL), and the organic layer was spin-dried to give 230mg of crude product, which was used directly in the next reaction.
And step 3: synthesis of 9-ethyl-N- (4- (ethylsulfonyl) benzyl) -2, 3, 4, 9-tetrahydro-1H-carbazole-6-carboxamide
N- (4- (ethylsulfonyl) benzyl) -2, 3, 4, 9-tetrahydro-1H-carbazole-6-carboxamide (130mg, 0.33mmol), anhydrous N, N-dimethylformamide (3mL) was added to a 25mL single vial, stirred in ice bath for 5 minutes, then NaH (26mg, 0.66mmol, 60%) was added, reacted at room temperature for 30 minutes, and then iodoethane (103mg, 0.66mmol) was added dropwise in ice bath, reacted at room temperature for 3 hours, and the starting material was reacted by TLC. The reaction was quenched with water, and then washed with ethyl acetate (3 × 20mL), water (5 × 20mL), saturated sodium chloride, dried over anhydrous sodium sulfate for the organic layer, filtered, and the solvent was dried under reduced pressure, and separated with silica gel column (dichloromethane: methanol ═ 100:1) to obtain 80mg of a yellow solid with a yield of 74.7%.1HNMR(400MHz，CD3OD)δ8.02(s，1H)，7.85(d，J＝8.1Hz，2H)，7.65(d，J＝8.6Hz，1H)，7.61(d，J＝8.1Hz，2H)，7.35(d，J＝8.6Hz，1H)，4.68(s，2H)，4.16–4.10(m，2H)，3.17(q，J＝7.4Hz，2H)，2.73(d，J＝6.1Hz，4H)，1.95(d，J＝5.5Hz，2H)，1.87(d，J＝5.2Hz，2H)，1.28(t，J＝7.1Hz，3H)，1.19(t，J＝7.4Hz，3H).MS(ESI)m/z:425.0(MH+).
Example 3:n- (4- (ethylsulfone) benzyl) -9H-carbazole-3-carboxamide
N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000122
Step 1: synthesis of methyl 4- (phenylamino) benzoate
To a 25mL microwave tube under argon protection was added aniline (1.82g, 19.53mmol), methyl 4-bromobenzoate (3.5g, 16.28mmol), palladium acetate (218mg, 0.97mmol), rac-BINAP (506mg, 0.81mmol), potassium carbonate (6.72g, 48.62mmol), toluene (10 mL). The reaction is carried out for 2 hours under the condition of microwave 160 ℃, and the temperature is cooled to room temperature. After the reaction was completed, the solvent was dried by spin-drying under reduced pressure, diluted with dichloromethane and filtered. After the organic phase was spin-dried, water (15mL) was added, extracted with ethyl acetate (3X 30mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to give the crude product. Column chromatography gave 3.32g of a light brown solid in 89.7% yield. MS (ESI) m/z 228.1(MH +).
Step 2: synthesis of methyl 9-hydrocarbazole-3-carboxylate
Methyl 4- (phenylamino) benzoate (3.32g, 15.58mmol), palladium acetate (3.84g, 17.1mmol), and acetic acid (50mL) were charged in a 100mL eggplant-shaped bottle under an argon atmosphere. The reaction was carried out at 130 ℃ for 2 hours with stirring. After completion of the reaction, the solvent was dried under reduced pressure and diluted with methanol (40 mL). Filtering with diatomite. After the organic phase was spin-dried, water (15mL) was added, extracted with ethyl acetate (3X 30mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to give the crude product. Column chromatography gave 2.23g of a light brown solid in 63.6% yield MS (ESI) m/z 226.1(MH +).
And step 3: synthesis of 9-hydrocarbazole-3-carboxylic acid:
a25 mL eggplant-shaped bottle was charged with a mixture of methyl 9-hydrocarbazole-3-carboxylate (50mg, 0.22mmol), solid potassium hydroxide (37mg, 0.67mmol), and ethanol (2 mL)/water (0.5 mL). The reaction was carried out at 100 ℃ for 2 hours with stirring. After completion of the reaction, ethanol was removed by evaporation under reduced pressure, water (2mL) was added thereto, and 2N hydrochloric acid was added dropwise to the reaction mixture to adjust the pH of the reaction mixture to 2, whereby a solid was precipitated. Vacuum filtering to obtain white solid, eluting with small amount of water, dissolving in methanol (10mL), and vacuum drying to obtain white solid 28mg with yield of 60.8%. MS (ESI) M/z 210.0(M-1), 212.0 (MH)+) And 4, step 4: synthesis of N- (4- (ethylsulfone) benzyl) -9H-carbazole-3-carboxamide
To a 25mL eggplant-shaped bottle, 9-hydrocarbazole-3-carboxylic acid (27mg, 0.128mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (55mg, 0.147mmol), N, N-diisopropylethylamine (25mg, 0.147mmol), 4- (ethylsulfonyl) benzylamine (29.3mg, 0.147mmol), and dichloromethane (5mL) were added. The reaction was carried out for 2 hours under stirring at room temperature. After the reaction was completed, the reaction solution was spin-dried under reduced pressure, extracted with ethyl acetate (3 × 5mL), and the organic phase was washed with saturated sodium chloride (3 × 5mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain a crude product. Column chromatography (petroleum ether: ethyl acetate 1:1) afforded 19mg of a white solid in 38.1% yield.1H NMR(400MHz，CD3OD)δ8.68(d，J＝1.2Hz，1H)，8.12(d，J＝7.8Hz，1H)，7.96(d，J＝8.5，1.7Hz，1H)，7.89(d，J＝8.3Hz，2H)，7.67(d，J＝8.3Hz，2H)，7.52–7.46(m，2H)，7.42(t，J＝7.7Hz，1H)，7.22(t，J＝7.4Hz，1H)，4.74(s，2H)，3.19(q，J＝7.4Hz，2H)，1.20(t，J＝7.4Hz，3H).MS(ESI)m/z:390.9(M-1)，MS(ESI)m/z:393.0(MH+)。
Example 4:n- (4- (ethylsulfone) benzyl) -9-methyl-9H-carbazole-3-carboxamide
N-(4-(ethylsulfonyl)benzyl)-9-methyl-9H-carbazole-3-carboxamide
Figure BDA0001714564360000141
Step 1: synthesis of methyl 9-methylcarbazole-3-carboxylate
In a 25mL eggplant-shaped bottle, 9-hydrocarbazole-3-carboxylic acid methyl ester (200mg, 0.89mmol), sodium hydride (64mg, 2.67mmol) and N, N-dimethylformamide (3mL) were added under ice-cooling, and after the addition, the ice-cooling was removed and the mixture was stirred for 30 minutes. After 30 minutes, methyl iodide (380 mg/248. mu.L, 2.67mmol) was added dropwise and reacted for 3 hours. After the reaction was complete, the neutralization was quenched by addition of saturated ammonium chloride solution (15 mL). Extraction was performed with ethyl acetate (3X 30mL), and the organic phase was washed with water (5X 10mL), saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to give the crude product. The crude product was isolated by column chromatography (petroleum ether: ethyl acetate 10:1) to give 80mg of a white solid in 39.6% yield.
Step 2: synthesis of 9-methylcarbazole-3-carboxylic acid
A25 mL round bottom flask was charged with a mixture of 9-methylcarbazole-3-carboxylic acid methyl ester (80mg, 0.335mmol), potassium hydroxide solid (56mg, 1.005mmol), and ethanol (3 mL)/water (0.75 mL). The reaction was stirred for 1 hour under heating at 100 ℃. After the reaction was completed, ethanol was removed by evaporation under reduced pressure, water was added to the reaction mixture to 2mL, and 2N hydrochloric acid was added dropwise to the reaction mixture until the pH of the reaction mixture became 2, whereby precipitation of a solid was observed. Suction filtration under reduced pressure gave a white solid, which was rinsed with a small amount of water, dissolved in methanol (5mL), and spin-dried under reduced pressure to give 65mg of a white solid in 86.2% yield.
And step 3: synthesis of N- (4- (ethylsulfone) benzyl) -9-methyl-9H-carbazole-3-formamide
To a 25mL eggplant-shaped bottle, 9-methylcarbazole-3-carboxylic acid (65mg, 0.29mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (130mg, 0.33mmol), N, N-diisopropylethylamine (65mg, 0.33mmol), (4- (ethylsulfonyl) phenyl) methylamine (65.7mg, 0.33mmol), and dichloromethane (5mL) were added. The reaction is carried out for 2 hours under the stirring at normal temperature, and the reactants are reacted completely. After completion of the reaction, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate 1:1) afforded 12mg of a white solid in 10.2% yield.1H NMR(400MHz，CD3OD)δ8.70(s，1H)，8.15(d，J＝7.7Hz，1H)，8.04(d，J＝8.6，1.7Hz，1H)，7.89(d，J＝8.4Hz，2H)，7.67(d，J＝8.4Hz，2H)，7.57(t，J＝7.9Hz，2H)，7.51(t，J＝7.9Hz，1H)，7.27(t，J＝6.7Hz，1H)，4.75(s，2H)，3.92(s，3H)，3.20(q，J＝7.4Hz，2H)，1.21(t，J＝7.4Hz，3H).MS(ESI)m/z:404.8(M-1)，407.0(MH+).
Example 5:n- (4- (ethylsulfone) benzyl) -9-N-propyl-9H-carbazole-3-carboxamide
N-(4-(ethylsulfonyl)benzyl)-9-propyl-9H-carbazole-3-carboxamide
Figure BDA0001714564360000142
Step 1: synthesis of 9-propylcarbazole:
carbazole (500mg, 3.0mmol), sodium hydride (144mg, 6mmol) and N, N-dimethylformamide (8mL) were added to a 25mL eggplant-shaped bottle under ice-bath, and after the addition was completed, the ice-bath was removed and the mixture was stirred at room temperature for 30 minutes. After 30 minutes, bromopropane (726 mg/538. mu.l, 6mmol) was added dropwise and reacted for 3 hours. After the reaction was complete, the neutralization was quenched by addition of saturated ammonium chloride solution (15 mL). Extraction was performed with ethyl acetate (3X 30mL), and the organic phase was washed with water (5X 10mL), saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to give the crude product. Column chromatography (petroleum ether: ethyl acetate: 10:1) gave 386mg of a white solid in 61.6% yield.
Step 2: synthesis of 9-propyl-3-carbazole formaldehyde:
into a 25mL eggplant-shaped bottle, 9-propylcarbazole (386mg, 1.85mmol), phosphorus oxychloride (558mg/339.6mL, 3.70mmol), and N, N-dimethylformamide (8mL) were added under ice-bath. The reaction was stirred for 4 hours under heating at 80 ℃. TLC detects that the reaction is complete. And cooling to room temperature. After the reaction, ice water and 20% sodium hydroxide aqueous solution were added to adjust the pH to be alkaline, and dichloromethane was extracted. Column chromatography (petroleum ether: ethyl acetate: 10:1) gave 180mg of a white solid in 41.1% yield ms (esi) m/z:238.1(MH +).
And step 3: synthesis of 9-propyl-3-carbazolformic acid:
to a 25mL eggplant-shaped bottle were added 9-propyl-3-carbazinecarbaldehyde (180mg, 0.76mmol), an aqueous potassium permanganate solution (168mg in 3mL of water), and anhydrous magnesium sulfate (180mg, 1.52 mmol). The reaction is carried out for 2 hours under the stirring at normal temperature, and the reactants are reacted completely. After completion of the reaction, 1N hydrochloric acid solution was added to adjust pH to 2, and the mixture was extracted with ethyl acetate (3 × 5mL), and the organic phase was washed with saturated sodium chloride (3 × 5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to obtain a crude product. Column chromatography (petroleum ether: ethyl acetate 1:1) gave 120mg of a white solid in 62.4% yield MS (ESI) M/z 251.9(M-1)
And 4, step 4: synthesis of N- (4- (ethylsulfone) benzyl) -9-N-propyl-9H-carbazole-3-carboxamide:
to a 25mL eggplant-shaped bottle, 9-propyl-3-carbazolcarboxylic acid (120mg, 0.47mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (207mg, 0.55mmol), N, N-diisopropylethylamine (70.4mg, 0.55mmol), 4- (ethylsulfonyl) benzylamine (108.5mg, 0.55mmol), and dichloromethane (5mL) were added. The reaction was carried out overnight under stirring at room temperature, and the reaction was complete. After completion of the reaction, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate 1:1) gave 2mg of a white solid in yield12.7％.1H NMR(400MHz，CD3OD)δ8.67(d，J＝1.5Hz，1H)，8.09(d，J＝7.8Hz，1H)，7.99(dd，J＝8.6，1.8Hz，1H)，7.83(d，J＝8.4Hz，2H)，7.61(d，J＝8.4Hz，2H)，7.54–7.41(m，3H)，7.24–7.17(t，J＝8.0Hz，1H)，4.71(s，2H)，4.29(t，J＝7.1Hz，2H)，3.13(q，J＝7.4Hz，2H)，1.84(q，J＝7.4Hz，2H)，1.16(t，J＝7.4Hz，3H)，0.89(t，J＝7.4Hz，3H).MS(ESI)m/z:432.9(M-1)，435.0(MH+).
Example 6:n- (4- (ethylsulfone) benzyl) -9-isopropyl-9H-carbazole-3-carboxamide
N-(4-(ethylsulfonyl)benzyl)-9-isopropyl-9H-carbazole-3-carboxamide
Figure BDA0001714564360000161
Step 1: synthesis of 9-isopropylcarbazole-3-methyl formate
In an ice bath, 9-hydrocarbazole-3-carboxylic acid methyl ester (300mg, 1.33mmol), sodium hydride (96mg, 4mmol) and N, N-dimethylformamide (3mL) were added to a 25mL eggplant-shaped flask, and after the addition, the ice bath was removed and the mixture was stirred for 30 minutes. After 30 minutes, bromoisopropane (488 mg/373. mu.L, 4mmol) was added dropwise and reacted overnight. Monitoring overnight, generating new points and more raw materials, and adding 400 mu L of bromoisopropane. After 5 hours, the reaction was completed by TLC detection (developer: petroleum ether: ethyl acetate: 5:1) using methyl 9-hydrocarbazole-3-carboxylate as a control.
After the reaction was complete, the neutralization was quenched by addition of saturated ammonium chloride solution (15 mL). Extraction was performed with ethyl acetate (3X 30mL), and the organic phase was washed with water (5X 10mL), saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to give the crude product. Column chromatography (petroleum ether: ethyl acetate: 10:1) afforded 120mg of a white solid in 54.0% yield.
Step 2: synthesis of 9-isopropylcarbazole-3-carboxylic acid
A25 mL round bottom flask was charged with a mixture of 9-isopropylcarbazole-3-carboxylic acid methyl ester (120mg, 0.45mmol), potassium hydroxide solid (75.5mg, 1.005mmol), and ethanol (3 mL)/water (0.75 mL). The reaction was carried out at 100 ℃ for 1 hour with stirring. After the reaction was completed, ethanol was removed by evaporation under reduced pressure, water was further added to the reaction solution to 2mL, and 2N hydrochloric acid was added dropwise to the reaction solution until the pH of the reaction solution became 2, whereby precipitation of a solid was observed. The white solid was obtained by suction filtration under reduced pressure, rinsed with a little water, dissolved in methanol (5mL) and spin-dried under reduced pressure to give 110mg of white solid with a yield of 96.6%.
And step 3: synthesis of N- (4- (ethylsulfone) benzyl) -9-isopropyl-9H-carbazole-3-formamide
To a 25mL eggplant-shaped bottle were added 9-isopropylcarbazole-3-carboxylic acid (110mg, 0.43mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (196mg, 0.49mmol), N, N-diisopropylethylamine (98.5mg, 0.49mmol), (4- (ethylsulfonyl) phenyl) methylamine (100mg, 0.49mmol), and methylene chloride (5 mL). After completion of the reaction, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate: 1) afforded 68mg of a white solid in 35.4% yield.1H NMR(400MHz，CD3OD)δ8.70(d，J＝1.6Hz，1H)，8.15(d，J＝7.8Hz，1H)，8.00(d，J＝8.7，1.8Hz，1H)，7.89(d，J＝8.3Hz，2H)，7.67(t，J＝9.0Hz，4H)，7.47(t，J＝7.3Hz，1H)，7.24(t，J＝7.5Hz，1H)，5.18–5.08(m，1H)，4.74(s，2H)，3.19(q，J＝7.4Hz，2H)，1.71(d，J＝7.0Hz，6H)，1.20(t，J＝7.4Hz，3H).MS(ESI)m/z:446.8(M-1)，448.9(MH+).
Example 7:n- (4- (ethylsulfone) benzyl) -9-isobutyl-9H-carbazole-3-carboxamide
N-(4-(ethylsulfonyl)benzyl)-9-isobutyl-9H-carbazole-3-carboxamide
Figure BDA0001714564360000171
Step 1: synthesis of 9-isobutylcarbazole-3-methyl formate
In a 25mL eggplant-shaped bottle, 9-hydrocarbazole-3-carboxylic acid methyl ester (300mg, 1.33mmol), sodium hydride (64mg, 2.67mmol) and N, N-dimethylformamide (3mL) were added under ice-cooling, and after the addition, the ice-cooling was removed and the mixture was stirred for 30 minutes. After 30 min, bromoisobutane (370mg/293 μ L, 2.67mmol) was added dropwise and reacted overnight. After 4 hours of reaction, the reaction was completed by TLC.
After the reaction was complete, the neutralization was quenched by addition of saturated ammonium chloride solution (15 mL). Extraction was performed with ethyl acetate (3X 30mL), and the organic phase was washed with water (5X 10mL), saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to give the crude product. Column chromatography (petroleum ether: ethyl acetate: 10:1) afforded 170mg of a white solid in 45.5% yield.
Step 2: synthesis of 9-isobutylcarbazole-3-carboxylic acid:
a25 mL round bottom flask was charged with a mixture of methyl 9-isobutylcarbazole-3-carboxylate (170mg, 0.60mmol), solid potassium hydroxide (100.8mg, 1.8mmol), and ethanol (3 mL)/water (0.75 mL). The reaction was carried out at 100 ℃ for 2 hours with stirring. The reaction was complete by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature, ethanol was removed under reduced pressure, water was added to the reaction mixture to 5mL, and 2N hydrochloric acid was added dropwise to the reaction mixture until the pH of the reaction mixture became 2, whereby a solid was precipitated. Suction filtration under reduced pressure gave a white solid which was rinsed with a small amount of water, dissolved in methanol (5mL) and spin-dried under reduced pressure to give 114mg of a white solid with a yield of 71.2%.
And step 3: synthesis of N- (4- (ethylsulfone) benzyl) -9-isobutyl-9H-carbazole-3-carboxamide
To a 25mL eggplant-shaped bottle, 9-isobutylcarbazole-3-carboxylic acid (114mg, 0.43mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (186mg, 0.49mmol), N, N-diisopropylethylamine (64mg, 0.49mmol), 4- (ethanesulfonyl) benzylamine (98mg, 0.49mmol), and dichloromethane (5mL) were added. After completion of the reaction, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate 1:1) gave 39mg of a white solid in 20.2% yield.1H NMR(400MHz，CD3OD)δ8.64(d，J＝1.5Hz，1H)，8.09(d，J＝7.8Hz，1H)，7.95(d，J＝8.7，1.8Hz，1H)，7.82(d，J＝8.4Hz，2H)，7.60(d，J＝8.3Hz，2H)，7.50(t，J＝7.6Hz，2H)，7.42(t，J＝7.6Hz，1H)，7.19(t，J＝7.4Hz，1H)，4.68(s，2H)，4.15(d，J＝7.5Hz，2H)，3.12(d，J＝7.4Hz，2H)，2.30(m，1H)，1.14(t，J＝7.4Hz，3H)，0.90(d，J＝6.7Hz，6H).MS(ESI)m/z:446.8(M-1)，448.9(MH+).
Example 8:9-cyclopropylmethyl-N- (4- (ethylsulfonyl) benzene) -9H-carbazole-3-carboxamide
9-(cyclopropylmethyl)-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000181
Step 1: synthesis of 9-cyclopropyl methyl carbazole-3-methyl formate
In a 25mL eggplant-shaped bottle, 9-hydrocarbazole-3-carboxylic acid methyl ester (200mg, 0.89mmol), sodium hydride (64mg, 2.67mmol) and N, N-dimethylformamide (3mL) were added under ice-cooling, and after the addition, the ice-cooling was removed and the mixture was stirred at room temperature for 30 minutes. After 30 minutes, bromomethylcyclopropane (360 mg/259. mu.L, 2.67mmol) was added dropwise, and the reaction was carried out at room temperature for 10 hours,
after the reaction was complete, saturated ammonium chloride solution (15mL) was added to quench and neutralize. Extraction was performed with ethyl acetate (3X 30mL), and the organic phase was washed with water (5X 10mL), saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to give the crude product. Column chromatography (petroleum ether: ethyl acetate: 10:1) afforded 110mg of a white solid in 44.3% yield.
Step 2: synthesis of 9-cyclopropyl methyl carbazole-3-carboxylic acid
A25 mL round bottom flask was charged with a mixture of 9-cyclopropylmethylcarbazole-3-carboxylic acid methyl ester (170mg, 0.60mmol), potassium hydroxide solid (100.8mg, 1.8mmol), and ethanol (3 mL)/water (0.75 mL). The reaction was carried out at 100 ℃ for 2 hours with stirring. The reaction was complete by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature, ethanol was removed under reduced pressure, water was added to the reaction mixture to 5mL, and 2N hydrochloric acid was added dropwise to the reaction mixture until the pH of the reaction mixture became 2, whereby a solid was precipitated. Suction filtration under reduced pressure gave a white solid, which was rinsed with a small amount of water, dissolved in methanol (5mL), and spin-dried under reduced pressure to give 64mg of a white solid with a yield of 40.3%.
And step 3: synthesis of 9- (cyclopropylmethyl) -N- (4- (ethylsulfonyl) benzene) -9H-carbazole-3-carboxamide
To a 25mL eggplant-shaped bottle, 9-cyclopropylmethylcarbazole-3-carboxylic acid (64mg, 0.24mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (107mg, 0.28mmol), N, N-diisopropylethylamine (36mg, 0.28mmol), 4- (ethylsulfonyl) benzylamine (48mg, 0.28mmol), and methylene chloride (5mL) were added. After completion of the reaction, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate: 1) afforded 41mg of a white solid in 38.3% yield.1H NMR(400MHz，CD3OD)δ8.70(d，J＝1.3Hz，1H)，8.14(d，J＝7.7Hz，1H)，8.02(d，J＝8.6，1.7Hz，1H)，7.88(d，J＝8.3Hz，2H)，7.66(d，J＝8.3Hz，2H)，7.59(t，J＝8.3Hz，2H)，7.49(t，J＝7.7Hz，1H)，7.25(t，J＝7.5Hz，1H)，4.74(s，2H)，4.33(d，J＝6.6Hz，2H)，3.18(q，J＝7.4Hz，2H)，1.20(t，J＝7.4Hz，3H)，0.52(m，2H)，0.45(m，2H).MS(ESI)m/z:445.0(M-1)，447.0(MH+).
Example 9:9- (cyclobutylmethyl) -N- (4- (ethylsulfonyl) benzene) -9H-carbazole-3-carboxamide
9-(cyclobutylmethyl)-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000191
Step 1: synthesis of 9-cyclobutylmethylcarbazole-3-carboxylic acid methyl ester
Under ice bath, 9-hydrocarbazole-3-carboxylic acid methyl ester (300mg, 1.33mmol), sodium hydride (96mg, 4mmol) and N, N-dimethylformamide (3mL) were added to a 25mL eggplant-shaped bottle, and after the addition, the ice bath was removed and the mixture was stirred at room temperature for 30 minutes. After 30 minutes, bromomethylcyclobutane (596mg/450 μ L, 4mmol) was added dropwise and reacted for 3 hours, TLC detected that the reaction was not complete, 100(μ L) bromomethylcyclobutane was added and stirring was continued for 10 hours, and the reaction was complete. After the reaction was complete, the neutralization was quenched by addition of saturated ammonium chloride solution (15 mL). Extraction was performed with ethyl acetate (3X 30mL), and the organic phase was washed with water (5X 10mL), saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to give the crude product. Column chromatography (petroleum ether: ethyl acetate: 10:1) afforded 100mg of a white solid in 25.7% yield.
Step 2: synthesis of 9-cyclobutylmethylcarbazole-3-carboxylic acid methyl ester
A25 mL eggplant-shaped bottle was charged with a mixed solution of methyl 9-cyclobutylmethylcarbazole-3-carboxylate (100mg, 0.34mmol), solid potassium hydroxide (100.8mg, 1.02mmol), and ethanol (3 mL)/water (0.75 mL). The reaction was carried out at 100 ℃ for 2 hours with stirring. TLC (developing solvent: dichloromethane: methanol ═ 7: 1) and the reaction was complete. After the reaction was completed, it was cooled to room temperature. Ethanol was removed by rotation under reduced pressure, and a solution was added to 5mL, and 2N hydrochloric acid was added dropwise to the reaction solution until the pH of the reaction solution became 2, whereby a solid was precipitated. Suction filtration under reduced pressure gave a white solid which was rinsed with a small amount of water, dissolved in methanol (5mL) and spin-dried under reduced pressure to give 70mg of a white solid in 73.8% yield.
And step 3: synthesis of 9- (cyclobutylmethyl) -N- (4- (ethylsulfonyl) benzene) -9H-carbazole-3-carboxamide
To a 25mL eggplant-shaped bottle, 9-cyclobutylmethylcarbazole-3-carboxylic acid methyl ester (70mg, 0.25mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (110mg, 0.29mmol), N, N-diisopropylethylamine (37mg, 0.29mmol), 4- (ethylsulfonyl) benzylamine (58mg, 0.29mmol), and dichloromethane (5mL) were added. The reaction was stirred at room temperature for 11 hours and the reaction was complete as detected by TLC. After completion of the reaction, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate: 1) afforded 67mg of a white solid in 58.3% yield.1H NMR(400MHz，CD3OD)δ8.70(s，1H)，8.15(d，J＝7.8Hz，1H)，8.02(d，J＝8.6Hz，1H)，7.90(d，J＝8.2Hz，2H)，7.67(d，J＝8.2Hz，2H)，7.60(d，J＝14.2，8.4Hz，2H)，7.49(t，J＝7.6Hz，1H)，7.26(t，J＝7.4Hz，1H)，4.76(d，J＝4.5Hz，2H)，4.44(d，J＝6.9Hz，2H)，3.20(q，J＝7.4Hz，2H)，2.97(d，J＝7.0Hz，1H)，1.99(m，3H)，1.90(m，3H)，1.21(t，J＝7.4Hz，3H).MS(ESI)m/z:461.0(MH+).
Example 10:9-benzyl-N- (4- (ethylsulfone) benzyl) -9H-carbazole-3-carboxamide
9-benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000201
Step 1: synthesis of 9-benzylcarbazole-3-methyl formate
In a 25mL eggplant-shaped bottle, 9-hydrocarbazole-3-carboxylic acid methyl ester (300mg, 1.33mmol), sodium hydride (96mg, 4mmol) and N, N-dimethylformamide (3mL) were added under ice-cooling, and after the addition, the ice-cooling was removed and the mixture was stirred at room temperature for 30 minutes. At the same time, benzyl bromide (684.16 mg/475. mu.L, 4mmol) was diluted with N, N-dimethylformamide (1 mL). After 30 minutes, diluted benzyl bromide/N, N-dimethylformamide solution was added dropwise and reacted overnight. After completion of the reaction, a saturated ammonium chloride solution (15mL) was added, extraction was performed with ethyl acetate (3X 30mL), and the organic phase was washed with water (5X 10mL), saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate: 10:1) gave 170mg of yellow viscous liquid in 40.5% yield ms (esi) m/z:316.1(MH +). step 2: synthesis of 9-benzylcarbazole-3-carboxylic acid
A25 mL eggplant-shaped bottle was charged with a mixture of methyl 9-benzylcarbazole-3-carboxylate (170mg, 0.549mmol), solid potassium hydroxide (90.7mg, 1.62mmol), and ethanol (6 mL)/water (1.5 mL). The reaction was carried out at 100 ℃ for 2 hours with stirring. After the reaction was completed, ethanol was removed by evaporation under reduced pressure, water was added to the reaction mixture to 5mL, and 2N hydrochloric acid was added dropwise to the reaction mixture until the pH of the reaction mixture became 2, whereby a large amount of solid was precipitated. Suction filtration under reduced pressure gave a white solid, which was rinsed with a small amount of water, dissolved in methanol (10mL), and spin-dried under reduced pressure to give 136mg of a white solid, 83.7% yield MS (ESI) M/z 302.1(MH +), 300.1(M-1)
And step 3: synthesis of 9-benzyl-N- (4- (ethylsulfone) benzyl) -9H-carbazole-3-formamide
To a 25mL eggplant-shaped bottle, 9-benzylcarbazole-3-carboxylic acid (136mg, 0.45mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (198mg, 0.52mmol), N, N-diisopropylethylamine (67mg, 0.52mmol), 4- (ethylsulfonyl) benzylamine (103mg, 0.52mmol), and dichloromethane (5mL) were added. The reaction was carried out for 3 hours under stirring at room temperature. After completion of the reaction, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate: 1) afforded 158mg of a white solid in 72.8% yield.1H NMR(400MHz，CD3OD)δ8.74(s，1H)，8.19(d，J＝8.2Hz，1H)，7.99(d，J＝8.6Hz，1H)，7.89(d，J＝8.2Hz，2H)，7.67(d，J＝8.2Hz，2H)，7.56(d，J＝8.7Hz，1H)，7.51(t，J＝9.0Hz，2H)，7.46(d，J＝8.2Hz，1H)，7.29(d，J＝7.4Hz，1H)，7.24(d，J＝7.8Hz，2H)，7.14(d，J＝6.9Hz，2H)，5.66(s，2H)，4.75(s，2H)，3.19(q，J＝7.2Hz，2H)，1.20(t，J＝7.4Hz，3H).MS(ESI)m/z:480.8(M-1)，483.0(MH+).
Example 11:(9-cyclohexylmethyl) - (4- (ethylsulfonyl) benzene) -9H-carbazole-3-carboxamide
9-(cyclohexylmethyl)-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000211
Step 1: synthesis of 9-cyclohexyl methyl carbazole-3-methyl formate
In a 25mL eggplant-shaped bottle, 9-hydrocarbazole-3-carboxylic acid methyl ester (200mg, 0.89mmol), sodium hydride (64mg, 2.67mmol) and N, N-dimethylformamide (3mL) were added under ice-cooling, and after the addition, the ice-cooling was removed and the mixture was stirred for 30 minutes. After 30 min, bromomethylcyclohexane (472 mg/372. mu.L, 2.67mmol) was added dropwise and reacted for 2h, TLC detected incomplete reaction, stirring was continued for 2h and the reaction was completed. After the reaction was complete, the neutralization was quenched by addition of saturated ammonium chloride solution (15 mL). Extraction was performed with ethyl acetate (3X 30mL), and the organic phase was washed with water (5X 10mL), saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to give the crude product. Column chromatography (petroleum ether: ethyl acetate: 10:1) afforded 156mg of a white solid in 54.6% yield.
Step 2: synthesis of 9-cyclohexylmethylcarbazole-3-carboxylic acid:
a25 mL round bottom flask was charged with a mixture of methyl 9-cyclohexylmethylcarbazole-3-carboxylate (130mg, 0.4mmol), solid potassium hydroxide (68mg, 1.2mmol), and ethanol (4 mL)/water (1 mL). The reaction was carried out at 100 ℃ for 2 hours with stirring.
After the reaction was completed, ethanol was removed by evaporation under reduced pressure, water was further added to the reaction solution to 5mL, and 2N hydrochloric acid was added dropwise to the reaction solution until the pH of the reaction solution became 2, whereby a large amount of solid was precipitated. Suction filtration under reduced pressure gave a white solid which was rinsed with a small amount of water, dissolved in methanol (10mL) and spin-dried under reduced pressure to give 125mg of a white solid with a 100% yield.
And step 3: synthesis of (9-cyclohexylmethyl) - (4- (ethylsulfonyl) benzene) -9H-carbazole-3-carboxamide
9-Cyclohexylmethylcarbazole-3-carboxylic acid (125mg, 0.41mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (178mg, 0.47mmol), N, N-diisopropylethylamine (60mg, 0.47mmol), 4- (ethylsulfonyl) benzylamine (93mg, 0.47mmol), and methylene chloride (5mL) were added to a 25mL eggplant-shaped bottle. After the reaction was completed, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate 1:1) afforded 16mg of a white solid in 8.0% yield.1H NMR(400MHz，CDCl3)δ8.61(s，1H)，8.12(d，J＝7.7Hz，1H)，7.94(d，J＝8.6Hz，1H)，7.87(d，J＝8.1Hz，2H)，7.59(d，J＝8.2Hz，2H)，7.51(t，J＝7.5Hz，1H)，7.43(d，J＝10.7Hz，2H)，7.29(d，J＝7.6Hz，1H)，6.76(s，1H)，4.82(d，J＝5.7Hz，2H)，4.14(d，J＝7.3Hz，2H)，3.10(q，J＝7.4Hz，2H)，2.00(m，1H)，1.66(m，10H)，1.28(t，J＝7.4Hz，3H).MS(ESI)m/z:486.9(M-1)，MS(ESI)m/z:489.3(MH+).
Example 12:9-ethyl-N- (4- (ethylsulfonyl) benzyl) -6-methyl-9H-carbazole-3-carboxamide
(9-ethyl-N-(4-(ethylsulfonyl)benzyl)-6-methyl-9H-carbazole-3-carboxamide)
Figure BDA0001714564360000221
Step 1: synthesis of methyl 4- ((4-methylphenyl) amino) benzoate
To a 25mL microwave tube was added 4-methylaniline (1.07g, 10mmol), methyl 4-bromobenzoate (2.58g, 12mmol), potassium carbonate (1.66g, 12mmol), rac-BINAP (310mg, 0.5mmol), palladium acetate (130mg, 0.6mmol), toluene (5mL), and the reaction was heated at 120 ℃ by microwave for 2 hours, after completion of the reaction, diluted with ethyl acetate, filtered through celite, the solvent was spin-dried under reduced pressure, and the product was isolated on a silica gel column (petroleum ether: ethyl acetate 10:1) to give 1.45g of a yellow solid product in 68.4% yield.1H NMR(400MHz，DMSO)δ8.64(s，1H)，7.75(d，J＝8.8Hz，2H)，7.12(d，J＝8.2Hz，2H)，7.06(d，J＝8.4Hz，2H)，6.96(d，J＝8.8Hz，2H)，3.75(s，3H)，2.24(s，3H).MS(ESI)m/z:242.1(MH+).
Step 2: synthesis of 6-methyl-9H-carbazole-3-methyl formate
Methyl 4- ((4-methylphenyl) amino) benzoate (600mg, 3mmol), palladium acetate (555mg, 3.3mmol) and acetic acid (30mL) were added to a 100mL single-neck flask, and the mixture was heated at 120 ℃ for 2 hours, after completion of the reaction, the acetic acid was dried under reduced pressure, and the crude product was dissolved in ethyl acetate and separated by silica gel column (petroleum ether: ethyl acetate ═ 10:1) to obtain 180mg of a yellow solid product with a yield of 30.2%%.1H NMR(400MHz，CDCl3)δ8.78(s，1H)，8.22(s，1H)，8.11(d，J＝8.6Hz，1H)，7.92(s，1H)，7.41(d，J＝8.5Hz，1H)，7.35(d，J＝8.2Hz，1H)，7.28(d，J＝8.2Hz，1H)，3.97(s，3H)，2.54(s，4H).
And step 3: synthesis of 6-methyl-9-ethyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with methyl 6-methyl-9H-carbazole-3-carboxylate (180mg, 0.75mmol) and anhydrous N, N-dimethylformamide (5mL), stirred in an ice bath for 5 minutes, then added with NaH (90mg, 2.56mmol, 60%), reacted at room temperature for 30 minutes, and then added dropwise with ethyl bromide (279mg, 2.56mmol) while cooling, reacted at room temperature for 3 hours, after which the starting material was reacted by TLC. The reaction was quenched with water, ethyl acetate (3X 20mL), washed with water (5X 20mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate of the organic layer, filtered, and the solvent was dried under reduced pressure to give 200mg of crude product, which was used directly in the next reaction.
And 4, step 4: synthesis of 6-methyl-9-ethyl-9H-carbazole-3-carboxylic acid
6-methyl-9-ethyl-9H-carbazole-3-methyl formate (200mg, 0.75mmol), lithium hydroxide (94mg, 2.25mmol), ethanol (5mL), water (1mL) were added to a 25mL single-neck flask, the reaction was carried out at 90 ℃ for 2 hours, the starting materials were reacted by TLC, the pH was adjusted to 3 with 2N hydrochloric acid, a white solid precipitated, filtered, and dried under vacuum to give 180mg of a white solid product, with a yield of 94.7% in two steps. MS (ESI) m/z 254.1(MH +).
And 5: synthesis of 9-ethyl-N- (4- (ethylsulfonyl) benzyl) -6-methyl-9H-carbazole-3-carboxamide
To a 25mL single vial was added 6-methyl-9-ethyl-9H-carbazole-3-carboxylic acid (65mg, 0.26mmol), 4- (ethylsulfonyl) benzylamine (61mg, 0.31mmol), HATU (117mg, 0.31mmol), N, N-diisopropylethylamine (100mg, 0.78mmol), dichloromethane (2mL), reacted overnight at room temperature, and the starting material was reacted by TLC. Dichloromethane (20mL) and saturated ammonium chloride (30mL) were added and washed, the organic layer was spin-dried to give the crude product, which was separated on a silica gel column (petroleum ether: ethyl acetate ═ 2:1-1:1) to give 77mg of the product as a white solid in 69.4% yield.1H NMR(400MHz，CDCl3)δ8.62(s，1H)，7.96(dd，J＝8.6，1.3Hz，1H)，7.87(s，1H)，7.74(d，J＝8.2Hz，2H)，7.48(d，J＝8.2Hz，2H)，7.35(d，J＝8.6Hz，1H)，7.32–7.27(m，3H)，4.74(d，J＝5.9Hz，2H)，4.32(q，J＝7.2Hz，2H)，3.05(q，J＝7.4Hz，2H)，2.49(s，3H)，1.39(t，J＝7.2Hz，3H)，1.24(d，J＝7.4Hz，4H).MS(ESI)m/z:435.2(MH+)。
Example 13:9-Ethyl-N- (4- (ethylsulfonyl) benzyl) -6-methoxy-9H-carbazole-3-carboxamide
(9-ethyl-N-(4-(ethylsulfonyl)benzyl)-6-methoxy-9H-carbazole-3-carboxamide)
Figure BDA0001714564360000231
Step 1: synthesis of methyl 4- ((4-methoxyphenyl) amino) benzoate
To a 25mL microwave tube was added 4-methoxyaniline (1.23g, 10mmol), methyl 4-bromobenzoate (2.58g, 12mmol), potassium carbonate (1.66g, 12mmol), rac-BINAP (310mg, 0.5mmol), palladium acetate (130mg, 0.6mmol), toluene (10mL), and the mixture was heated at 120 ℃ by microwave for 1 hour, after completion of the reaction, diluted with ethyl acetate, filtered through celite, the solvent was spin-dried under reduced pressure, and separated on a silica gel column (petroleum ether: ethyl acetate: 10:1-5:1) to give 1.3g of a yellow solid product in 50.6% yield.1H NMR(400MHz，DMSO)δ8.51(s，1H)，7.72(d，J＝8.7Hz，2H)，7.10(d，J＝8.8Hz，2H)，6.91(d，J＝8.9Hz，2H)，6.85(d，J＝8.8Hz，2H)，3.74(s，3H)，3.72(s，3H).
Step 2: synthesis of 6-methoxy-9H-carbazole-3-methyl formate
Methyl 4- ((4-methoxyphenyl) amino) benzoate (512mg, 2mmol), palladium acetate (444mg, 4.4mmol) and acetic acid (30mL) were charged into a 100mL single-neck flask, and the mixture was heated at 120 ℃ for 2 hours, after completion of the reaction, the acetic acid was rotary-dried under reduced pressure, and the crude product was dissolved in ethyl acetate and separated by silica gel column (petroleum ether: ethyl acetate ═ 10:1) to obtain 210mg of a yellow solid product with a yield of 41.3%.1H NMR(400MHz，CDCl3)δ8.78(s，1H)，8.19(s，1H)，8.11(dd，J＝8.5，1.5Hz，1H)，7.60(d，J＝2.3Hz，1H)，7.41(d，J＝8.5Hz，1H)，7.36(d，J＝8.8Hz，1H)，7.10(dd，J＝8.8，2.5Hz，1H)，3.97(s，3H)，3.94(s，3H).
And step 3: synthesis of 6-methoxy-9-ethyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with methyl 6-methoxy-9H-carbazole-3-carboxylate (210mg, 0.82mmol) and anhydrous N, N-dimethylformamide (5mL), stirred in an ice bath for 5 minutes, then added with NaH (99mg, 2.47mmol, 60%), reacted at room temperature for 30 minutes, then added dropwise with ethyl bromide (269mg, 2.47mmol) while cooling, reacted at room temperature for 3 hours, and the starting material was reacted by TLC. The reaction was quenched with water, ethyl acetate (3X 20mL), washed with water (5X 20mL), washed with saturated sodium chloride, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure to give 120mg of crude product, which was used directly in the next reaction.
And 4, step 4: synthesis of 6-methoxy-9-ethyl-9H-carbazole-3-carboxylic acid
6-methoxy-9-ethyl-9H-carbazole-3-carboxylic acid methyl ester (120mg, 0.42mmol), lithium hydroxide (53mg, 1.26mmol), ethanol (5mL), water (1mL) were added to a 25mL single-neck flask, the reaction was carried out at 90 ℃ for 2 hours, the starting materials were reacted by TLC, the pH was adjusted to 3 with 2N hydrochloric acid, a white solid precipitated, filtered, and dried in vacuo to give 110mg of a white solid product, with a yield of 49.7% in two steps. MS (ESI) m/z 270.1(MH +).
And 5:synthesis of 9-ethyl-N- (4- (ethylsulfonyl) benzyl) -6-methoxy-9H-carbazole-3-carboxamide
To a 25mL single vial was added 6-methoxy-9-ethyl-9H-carbazole-3-carboxylic acid (100mg, 0.37mmol), 4- (ethylsulfonyl) benzylamine (89mg, 0.45mmol), HATU (171mg, 0.45mmol), N, N-diisopropylethylamine (143mg, 1.11mmol), dichloromethane (5mL), reacted overnight at room temperature, and the starting material was reacted by TLC. Dichloromethane (20mL) and saturated ammonium chloride (30mL) were added and washed, the organic layer was spin-dried to give the crude product, which was separated on a silica gel column (petroleum ether: ethyl acetate ═ 1:1-1:2) to give 140mg of the product as a white solid in 83.8% yield.1H NMR(400MHz，CDCl3)δ8.59(s，1H)，7.92(d，J＝8.5Hz，1H)，7.85–7.76(m，2H)，7.59(d，J＝2.3Hz，1H)，7.53(t，J＝9.3Hz，2H)，7.37(d，J＝8.3Hz，1H)，7.33(d，J＝9.0Hz，1H)，7.14(dd，J＝8.8，2.4Hz，1H)，4.78(t，J＝5.8Hz，2H)，4.34(dd，J＝13.5，6.5Hz，2H)，3.90(q，J＝7.1Hz，2H)，3.08(q，J＝7.3Hz，2H)，1.41(t，J＝7.1Hz，3H)，1.26(t，J＝7.3Hz，3H).MS(ESI)m/z:451.2(MH+)。
Example 14:9-ethyl-N- (4- (ethylsulfonyl) benzyl) -6-fluoro-9H-carbazole-3-carboxamide
(9-ethyl-N-(4-(ethylsulfonyl)benzyl)-6-fluoro-9H-carbazole-3-carboxamide)
Figure BDA0001714564360000241
Step 1: synthesis of methyl 4- ((4-fluorophenyl) amino) benzoate
To a 25mL microwave tube were added 4-fluoroaniline (1.18g, 10mmol), methyl 4-bromobenzoate (2.58g, 12mmol), potassium carbonate (1.66g, 12mmol), rac-BINAP (310mg, 0.5mmol), palladium acetate (130mg, 0.6mmol), toluene (10mL), and the reaction was heated at 120 ℃ by microwave for 1 hour, after completion of the reaction, diluted with ethyl acetate, filtered through celite, the solvent was spin-dried under reduced pressure, and separated by a silica gel column (petroleum ether: ethyl acetate: 10:1-5:1) to give 1.0g of a yellow solid product in 41.7% yield. MS (ESI) m/z 253.0(MH +).
Step 2: synthesis of 6-fluoro-9H-carbazole-3-methyl formate
Methyl 4- ((4-fluorophenyl) amino) benzoate (600mg, 2.45mmol), palladium acetate (603mg, 2.69mmol) and acetic acid (5mL) were added to a 100mL single-neck flask, and the mixture was heated at 120 ℃ for 2 hours to complete the reaction, the acetic acid was dried under reduced pressure, and the crude product was dissolved in ethyl acetate and separated by silica gel column (petroleum ether: ethyl acetate: 10:1-5:1) to obtain 350mg of a yellow solid product with a yield of 58.8%.1H NMR(400MHz，CDCL3)δ8.76(s，1H)，8.30(s，1H)，8.14(d，J＝8.6Hz，1H)，7.77(dd，J＝8.6，2.0Hz，1H)，7.43(d，J＝8.6Hz，1H)，7.38(dd，J＝8.8，4.2Hz，1H)，7.20(td，J＝9.0，2.3Hz，1H)，3.98(s，3H).
And step 3: synthesis of 6-fluoro-9-ethyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with methyl 6-fluoro-9H-carbazole-3-carboxylate (200mg, 0.82mmol) and anhydrous N, N-dimethylformamide (5mL), stirred in an ice bath for 5 minutes, then added with NaH (99mg, 2.47mmol, 60%), reacted at room temperature for 30 minutes, and then dropwise added with ethyl bromide (269mg, 2.47mmol) while cooling, reacted at room temperature for 3 hours, after which the starting material was reacted by TLC. The reaction was quenched with water, extracted with ethyl acetate (3X 20mL), washed with water (5 extract)20mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate of the organic layer, filtered, and the solvent was dried under reduced pressure to give 220mg of crude product, which was used directly in the next reaction.1H NMR(400MHz，CDCl3)δ8.77(s，1H)，8.18(dd，J＝8.7，1.6Hz，1H)，7.79(dd，J＝8.7，2.5Hz，1H)，7.42–7.38(m，1H)，7.35(dd，J＝8.9，4.2Hz，1H)，7.23(dd，J＝8.9，2.5Hz，1H)，4.37(t，J＝7.2Hz，2H)，3.97(s，3H)，1.45(t，J＝7.2Hz，3H).
And 4, step 4: synthesis of 6-fluoro-9-ethyl-9H-carbazole-3-carboxylic acid
6-fluoro-9-ethyl-9H-carbazole-3-carboxylic acid methyl ester (200mg, 0.74mmol), lithium hydroxide (93mg, 2.21mmol), ethanol (5mL), water (1mL) are added into a 25mL single-neck flask, the mixture reacts for 1 hour at 90 ℃, the raw materials are detected by TLC to be reacted completely, the pH is adjusted to 3 by using 2N hydrochloric acid, white solid is separated out, the mixture is filtered and dried in vacuum, the white solid product 160mg is obtained, and the yield of the two steps is 43.2%. MS (ESI) m/z 258.1(MH +).
And 5: synthesis of 9-ethyl-N- (4- (ethylsulfonyl) benzyl) -6-fluoro-9H-carbazole-3-carboxamide
To a 25mL single vial was added 6-fluoro-9-ethyl-9H-carbazole-3-carboxylic acid (80mg, 0.31mmol), 4- (ethylsulfonyl) benzylamine (74mg, 0.37mmol), HATU (141mg, 0.37mmol), N, N-diisopropylethylamine (120mg, 0.93mmol), dichloromethane (5mL), reacted overnight at room temperature, and the starting material was reacted by TLC. Dichloromethane (20mL) and saturated ammonium chloride (30mL) were added and washed, the organic layer was spin-dried to give the crude product, which was separated on a silica gel column (petroleum ether: ethyl acetate ═ 1:1-1:2) to give 53mg of the product as a white solid in 83.8% yield.1H NMR(400MHz，CDCl3)δ8.56(s，1H)，7.97(d，J＝8.7Hz，1H)，7.87(d，J＝8.2Hz，2H)，7.77(dd，J＝8.6，2.4Hz，1H)，7.58(d，J＝8.2Hz，2H)，7.43(d，J＝8.5Hz，1H)，7.36(dd，J＝8.8，4.1Hz，1H)，7.25–7.22(m，1H)，4.82(d，J＝5.7Hz，2H)，4.37(t，J＝7.2Hz，2H)，3.10(q，J＝7.4Hz，2H)，1.44(t，J＝7.2Hz，3H)，1.27(t，J＝7.5Hz，3H).MS(ESI)m/z:439.0(MH+)。
Example 15:6-chloro-9-ethyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-carboxamide
(6-chloro-9-ethyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide)
Figure BDA0001714564360000251
Step 1: synthesis of methyl 4- ((4-chlorophenyl) amino) benzoate
To a 25mL microwave tube were added 4-chloroaniline (500mg, 3.9mmol), methyl 4-bromobenzoate (1.01g, 4.68mmol), potassium carbonate (1.6g, 11.7mmol), rac-BINAP (121mg, 0.20mmol), palladium acetate (52mg, 0.23mmol), toluene (10mL), and the reaction was heated at 130 ℃ for 1.5 hours under microwave, after completion of the reaction, diluted with ethyl acetate, filtered through celite, the solvent was spin-dried under reduced pressure, and the silica gel column was separated (petroleum ether: ethyl acetate 4:1) to give 700mg of a yellow solid product in 68.4% yield.1H NMR(400MHz，CDCl3)δ7.92(d，J＝8.7Hz，2H)，7.29(d，J＝8.7Hz，2H)，7.10(d，J＝8.7Hz，2H)，6.96(d，J＝8.7Hz，2H)，3.88(s，3H).MS(ESI)m/z:262.0(MH+).
Step 2: synthesis of 6-chloro-9H-carbazole-3-methyl formate
A100 mL single-neck flask was charged with methyl 4- ((4-chlorophenyl) amino) benzoate (200mg, 0.76mmol), palladium acetate (188mg, 0.84mmol), and acetic acid (5mL), and the mixture was heated at 130 ℃ for 1 hour, after the reaction was completed, the acetic acid was dried under reduced pressure, and the crude product was dissolved in ethyl acetate, stirred, and subjected to silica gel column separation (petroleum ether: ethyl acetate: 4:1) to obtain 160mg of a yellow solid product with a yield of 82.4%%.1H NMR(400MHz，DMSO)δ11.85(s，1H)，8.85(s，1H)，8.40(d，J＝1.8Hz，1H)，8.03(dd，J＝8.6，1.6Hz，1H)，7.55(t，J＝8.6Hz，2H)，7.44(dd，J＝8.6，2.1Hz，1H)，3.87(s，3H).MS(ESI)m/z:257.9(M-1).
And step 3: synthesis of 6-chloro-9-ethyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with 6-chloro-9H-carbazole-3-carboxylic acid methyl ester (150mg, 0.58mmol) and anhydrous N, N-dimethylformamide (3mL), stirred in ice bath for 5 minutes, then added with NaH (69mg, 1.73mmol, 60%), reacted at room temperature for 30 minutes, then added dropwise with ethyl bromide (189mg, 1.73mmol) while cooling, reacted at room temperature for 3 hours, and the starting material was reacted by TLC. The reaction was quenched with water, extracted with ethyl acetate (3 × 20mL), washed with water (5 × 20mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate of the organic layer, filtered, and the solvent was dried under reduced pressure to give a crude product, which was isolated on silica gel column (petroleum ether: ethyl acetate 10:1) to give 65mg of yellow solid with a yield of 39.4%.
And 4, step 4: synthesis of 6-chloro-9-ethyl-9H-carbazole-3-carboxylic acid
6-chloro-9-ethyl-9H-carbazole-3-carboxylic acid methyl ester (65mg, 0.23mmol), lithium hydroxide (28mg, 0.69mmol), ethanol (5mL), water (1mL) are added into a 25mL single-neck flask, the mixture reacts for 3 hours at 90 ℃, the raw materials are detected by TLC to be reacted completely, the pH is adjusted to 3 by using 2N hydrochloric acid, white solid is separated out, the mixture is filtered and dried in vacuum, and the white solid product 60mg is obtained, and the yield is 96.7%.
And 5: synthesis of 6-chloro-9-ethyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-carboxamide
A25 mL single vial was charged with 6-chloro-9-ethyl-9H-carbazole-3-carboxylic acid (60mg, 0.22mmol), 4- (ethylsulfonyl) benzylamine (52mg, 0.26mmol), HATU (99mg, 0.26mmol), N, N-diisopropylethylamine (85mg, 0.66mmol), dichloromethane (2mL), N, N-dimethylformamide (2mL) and reacted overnight at room temperature with TLC detection of the starting material. Dichloromethane (20mL) and saturated ammonium chloride (30mL) were added and the solvent was washed with the organic layer to give a crude product, which was separated by silica gel column (petroleum ether: ethyl acetate 1:1-1:2) to give 70mg of a white solid product in 77.8% yield.1H NMR(400MHz，DMSO)δ9.11(t，J＝5.9Hz，1H)，8.80(s，1H)，8.26(d，J＝1.9Hz，1H)，8.09–8.02(m，1H)，7.84(d，J＝8.3Hz，2H)，7.70(dd，J＝8.7，3.3Hz，2H)，7.61(d，J＝8.3Hz，2H)，7.50(dd，J＝8.7，2.0Hz，1H)，4.63(d，J＝5.8Hz，2H)，4.47(q，J＝6.9Hz，2H)，3.24(t，J＝7.4Hz，2H)，1.29(t，J＝7.1Hz，3H)，1.07(t，J＝7.4Hz，3H).MS(ESI)m/z:454.9(MH+).
Example 16:6-cyano-9-ethyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-carboxamide
(6-cyano-9-ethyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide)
Figure BDA0001714564360000271
Step 1: synthesis of methyl 4- ((4-cyanophenyl) amino) benzoate
To a 25mL microwave tube under argon protection was added 4-cyanoaniline (566mg, 4.80mmol), methyl 4-bromobenzoate (1g, 4.67mmol), palladium acetate (52mg, 0.23mmol), rac-BINAP (506mg, 0.81mmol), cesium carbonate (6.72g, 48.62mmol), and toluene (10 mL). The reaction is carried out for 3 hours under the condition of microwave 160 ℃, and then the reaction is cooled to room temperature. After the reaction was completed, the solvent was spin-dried under reduced pressure, diluted with dichloromethane and filtered. After the organic phase was spin dried, water (15mL) was added, extracted with ethyl acetate (30mL X3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin dried under reduced pressure to give the crude product. Column chromatography (mobile phase: petroleum ether: ethyl acetate: 5:1) gave 400mg of a white solid in 34.0% yield ms (esi) M/z 253.1(MH +), 251.0(M-1)
And 2, step: synthesis of 6-cyano-9-hydrocarbazole-3-carboxylic acid methyl ester
Methyl 4- ((4-cyanophenyl) amino) benzoate (360mg, 1.43mmol), palladium acetate (350mg, 1.57mmol), and acetic acid (8mL) were charged in a 100mL eggplant-shaped bottle under an argon atmosphere. The reaction was carried out at 130 ℃ for 45 minutes with stirring. After completion of the reaction, the solvent was dried under reduced pressure and diluted with methanol (40 mL). The suspension was filtered through celite. After the organic phase was spin-dried, water (15mL) was added, extracted with ethyl acetate (3X 30mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to give the crude product. Column chromatography gave 70mg of a yellow solid in 19.7% yield MS (ESI) M/z 251.1(MH +), 248.9(M-1).
And step 3: synthesis of 6-cyano-9-ethylcarbazole-3-methyl formate
Under ice bath, 6-cyano-9-hydrocarbazole-3-carboxylic acid methyl ester (70mg, 0.28mmol), sodium hydride (20.3mg, 0.85mmol) and N, N-dimethylformamide (2mL) were added to a 25mL eggplant-shaped bottle, reacted at room temperature for 30 minutes, and then bromoethane (31mg, 0.28mmol) was added dropwise under ice bath, and after the addition, the ice bath was removed and the mixture was stirred for 30 minutes. After the reaction was complete, saturated ammonium chloride solution (5mL) was added to quench neutralization. Extraction with ethyl acetate (3X 10mL) and washing of the organic phase with water (5X 10mL), saturated sodium chloride, drying over anhydrous sodium sulfate, filtration and spin-drying under reduced pressure gave the crude product. Column chromatography (eluent: petroleum ether: ethyl acetate 7: 1) gave 80mg of a white solid in 100% yield ms (esi) m/z 279.1(MH +).
And 4, step 4: synthesis of 6-cyano-9-ethylcarbazole-3-carboxylic acid
A25 mL round bottom flask was charged with a mixture of 6-cyano-9-ethylcarbazole-3-carboxylic acid methyl ester (80mg, 0.29mmol), 20% sodium hydroxide solution (173. mu.L), and ethanol (3 mL)/water (0.75 mL). The reaction was carried out at 50 ℃ for 2 hours with stirring. After the reaction was completed, ethanol was removed by evaporation under reduced pressure, water was added to the reaction mixture to 5mL, and 2N hydrochloric acid was added dropwise to the reaction mixture until the pH of the reaction mixture became 2, whereby precipitation of a solid was observed. Suction filtration under reduced pressure gave a white solid, which was rinsed with a small amount of water, dissolved in methanol (10mL), and spin-dried under reduced pressure to give 36mg of a white solid, 47% yield MS (ESI) M/z:263.0(M-1), 265.1(MH +).
And 5: synthesis of 6-cyano-9-ethyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-carboxamide
To a 25mL eggplant-shaped bottle, 6-cyano-9-ethylcarbazole-3-carboxylic acid (36mg, 0.14mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (60mg, 0.16mmol), N, N-diisopropylethylamine (20mg, 0.16mmol), 4- (ethylsulfonyl) benzylamine (31mg, 0.16mmol), and dichloromethane (3mL) were added. After the reaction was completed, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride water (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Preparative plate separation (developing solvent: petroleum ether: ethyl acetate ═ 1:1) afforded 3mg of a white solid in 4.8% yield.1H NMR(400MHz，CDCl3)δ8.63(s，1H)，8.40(s，1H)，8.08(t，J＝8.1Hz，2H)，7.87(d，J＝8.2Hz，2H)，7.75(d，J＝8.7Hz，1H)，7.59(d，J＝8.3Hz，2H)，7.50(t，J＝8.1Hz，2H)，6.90(s，1H)，4.83(d，J＝5.9Hz，2H)，4.43(q，J＝7.4Hz，2H)，3.10(q，J＝7.4Hz，2H)，1.48(t，J＝7.4Hz，3H)，1.28(t，J＝7.4Hz，3H).MS(ESI)m/z:443.9(M-1)，446.2(MH+).
Example 17:5-Ethyl-N- (4- (ethylsulfonyl) benzyl) -5H-pyrido [3, 2-b]Indole-8-carboxamides
(5-ethyl-N-(4-(ethylsulfonyl)benzyl)-5H-pyrido[3，2-b]indole-8-carboxamide)
Figure BDA0001714564360000281
Step 1: synthesis of ethyl 4- ((2-chloropyridin-3-yl) amino) benzoate
Add 2-chloro-3-iodopyridine (1g, 4.2mmol), ethyl 4-aminobenzoate (830mg, 5mmol), palladium acetate (56mg, 0.25mmol), cesium carbonate (4.1g, 12.6mmol), rac-BINAP (130mg, 0.21mmol), toluene (15mL), Nitrogen bubbling for 5 min to the microwave tube, and then react for 1.5 h at 140 ℃. Washed with saturated ammonium chloride (20mL), and the solvent was evaporated under reduced pressure. Silica gel column separation (petroleum ether: ethyl acetate ═ 5:1-4:1) gave 260mg of a colorless oil, 22.6% yield.1H NMR(400MHz，CDCl3)δ8.05–7.93(m，3H)，7.69(d，J＝7.9Hz，1H)，7.18(dd，J＝8.0，4.6Hz，1H)，7.12(d，J＝8.7Hz，2H)，6.35(s，1H)，4.35(t，J＝7.1Hz，2H)，1.38(t，J＝7.1Hz，3H).
Step 2: synthesis of ethyl 5H-pyrido [3, 2-b ] indole-8-carboxylate
Add Ethyl 4- ((2-Chloropyridin-3-yl) aminobenzoate (400mg, 1.45mmol), sodium acetate trihydrate (247mg, 3.63mmol), PdCl to the microwave tube2(PPh3)2(105mg, 0.15mmol), N, N-dimethylacetamide (10mL), nitrogen bubbling was carried out for 5 minutes, and then the reaction was carried out by microwave at 140 ℃ for 1.5 hours. After the reaction, water (20mL) was added, ethyl acetate (3 × 10mL) was extracted, the organic layers were combined, washed with saturated sodium chloride (3 × 20mL), and the solvent was evaporated under reduced pressure to give a crude product, which was separated by a silica gel column (petroleum ether: ethyl acetate: 4:1-2:1) to give 220mg of a yellow solid, with a yield of 63.9%.1H NMR(400MHz，CDCl3)δ9.12(s，1H)，8.98(s，1H)，8.62(dd，J＝4.7，1.1Hz，1H)，8.23(dd，J＝8.6，1.6Hz，1H)，7.78(dd，J＝8.2，1.1Hz，1H)，7.48(d，J＝8.6Hz，1H)，7.37(dd，J＝8.2，4.7Hz，1H)，4.39(q，J＝7.1Hz，2H)，1.43–1.36(m，3H).
And step 3: synthesis of ethyl 5-ethyl-5H-pyrido [3, 2-b ] indole-8-carboxylate
To a 25mL single neck flask was added 5H-pyrido [3, 2-b ] indole-8-carboxylic acid ethyl ester (220mg, 0.97mmol), anhydrous N, N-dimethylformamide (5mL), stirred in an ice bath for 5 minutes, then NaH (116mg, 12.9mmol, 60%) was added, reacted at room temperature for 30 minutes, and then bromoethane (316mg, 2.9mmol) was added dropwise while cooling, reacted at room temperature for 2 hours, and the starting material was reacted by TLC. The reaction was quenched with water, extracted with ethyl acetate (3X 20mL), washed with water (5X 20mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate of the organic layer, filtered, and the solvent was dried under reduced pressure to give the crude product, which was used directly in the next reaction.
And 4, step 4: synthesis of 5-ethyl-5H-pyrido [3, 2-b ] indole-8-carboxylic acid
A25 mL single-neck flask was charged with 5-ethyl-5H-pyrido [3, 2-b ] indole-8-carboxylic acid ethyl ester, lithium hydroxide (112mg, 2.76mmol), ethanol (5mL), water (1mL), heated at 90 ℃ for 2 hours, TLC checked that the starting material had reacted, adjusted to pH 3 with 2N hydrochloric acid to precipitate a white solid, filtered, and dried under vacuum to give 150mg of the product as a white solid in 68.2% yield over two steps. MS (ESI) m/z 241.1(MH +).
And 5: synthesis of 5-ethyl-N- (4- (ethylsulfonyl) benzyl) -5H-pyrido [3, 2-b ] indole-8-carboxamide
Add 5-Ethyl-5H-pyrido [3, 2-b ] to a 25mL single neck flask]Indole-8-carboxylic acid (100mg, 0.29mmol), 4- (ethylsulfonyl) benzylamine (70mg, 0.35mmol), HATU (133mg, 0.35mmol), N, N-diisopropylethylamine (112mg, 0.87mmol), dichloromethane (5mL), N, N-dimethylformamide (1mL) reacted overnight at room temperature, and the starting material was reacted by TLC. Dichloromethane (20mL) and saturated ammonium chloride (30mL) were added and the organic layer was spin-dried to give the crude product, which was separated on a silica gel column (petroleum ether: ethyl acetate ═ 2:1) to give the product as a white solid, 40mg, 22.8% yield.1H NMR(400MHz，CDCl3)δ8.79(s，1H)，8.54(d，J＝4.6Hz，1H)，8.23(dd，J＝8.7，1.7Hz，1H)，7.85(d，J＝8.3Hz，2H)，7.76(d，J＝8.3Hz，1H)，7.56(d，J＝8.2Hz，2H)，7.53(d，J＝8.7Hz，1H)，7.42(dd，J＝8.3，4.7Hz，1H)，7.15(s，1H)，4.78(d，J＝5.9Hz，2H)，4.40(q，J＝7.3Hz，3H)，3.10(q，J＝7.4Hz，3H)，1.46(t，J＝7.2Hz，3H)，1.28(d，J＝7.4Hz，4H).MS(ESI)m/z:422.2(MH+)。
Example 18:9-Ethyl-N- ((5- (ethylsulfonyl) pyridin-2-yl) methyl) -9H-carbazole-3-carboxamide
(9-ethyl-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-9H-carbazole-3-carboxamide)
Figure BDA0001714564360000301
Step 1: synthesis of 5- (ethylsulfanyl) -2-pyridinecarbonitrile
To a 50mL single-neck flask was added 5-bromo-2-pyridinecarbonitrile (940mg, 5.14mmol), ethanethiol (505mg, 6.01mmol), potassium carbonate (981mg, 7.11mmol), NMP (10 mL). The reaction was stirred at room temperature overnight. Water (20mL) was added, extracted with ethyl acetate (3X 30mL) and the organic layer was spin dried to give 900mg of the product 5- (ethylsulfanyl) -2-pyridinecarbonitrile in 100% yield. MS (ESI) m/z 165.1(MH +).
Step 2: synthesis of 5- (ethylsulfonyl) -2-pyridinecarbonitrile
To a 25mL single vial was added 5- (ethylthio) -2-pyridinecarbonitrile (800mg, 4.88mmol), dichloromethane (20mL), and stirred in ice for 10 minutes, mCPBA (1.84g, 10.7mmol) was added to the reaction mixture in portions, followed by reaction at room temperature overnight, washing with 2N sodium carbonate solution, spin-drying of the organic layer, and separation with silica gel column (petroleum ether: ethyl acetate ═ 2:1-1:1) to obtain 900mg, yield 90.0%.1H NMR(400MHz，CDCl3)δ9.18(d，J＝1.2Hz，1H)，8.37(dd，J＝8.0，1.8Hz，1H)，7.93(d，J＝8.0Hz，1H)，3.21(q，J＝7.4Hz，2H)，1.34(t，J＝7.4Hz，3H).MS(ESI)m/z:197.1(MH+).
And step 3: synthesis of (5- (ethylsulfonyl) -pyridin-2-yl) methylamine
To a 25mL single-necked flask was added 5- (ethylsulfonyl) -2-pyridinecarbonitrile (200mg, 1mmol), methanol (10mL), Pd/C (100mg, 10%). The reaction mixture was stirred at room temperature for 30 minutes under hydrogen atmosphere, filtered through celite, and the solvent was spin-dried to give 110mg of a white solid product with a yield of 53.9%. MS (ESI) m/z 201.1(MH +).
And 4, step 4: synthesis of 9-ethyl-N- ((5- (ethylsulfonyl) pyridin-2-yl) methyl) -9H-carbazole-3-carboxamide
The procedure is as for example 1, 9-ethyl-9H-carbazole-3-carboxylic acid (80mg, 0.33mmol), 5-ethylsulfonyl-2-pyridinemethanamine (82mg, 0.37mmol), HATU (141mg, 0.37mmol), N, N-diisopropylethylamine (129mg, 0.99mmol), dichloromethane (5 mL). The product was obtained as a white solid, 24mg, 17.0% yield.1H NMR(400MHz,CD3OD3)δ8.99(d,J＝1.7Hz,1H),8.73(d,J＝1.1Hz,1H),8.26(dd,J＝8.3,2.2Hz,1H),8.15(d,J＝7.8Hz,1H),8.05(dd,J＝8.6,1.6Hz,1H),7.68(d,J＝8.3Hz,1H),7.61–7.53(m,2H),7.50(t,J＝7.6Hz,1H),7.25(t,J＝7.4Hz,1H),4.85(s,2H),4.46(q,J＝7.1Hz,2H),3.26(t,J＝7.4Hz,2H),1.41(t,J＝7.2Hz,3H),1.24(t,J＝7.4Hz,3H).MS(ESI)m/z:423.1(MH+).
Example 19:9-ethyl-N- (4- (methylsulfonyl) benzyl) -9H-carbazole-3-carboxamide
(9-ethyl-N-(4-(methylsulfonyl)benzyl)-9H-carbazole-3-carboxamide)
Figure BDA0001714564360000311
A25 mL single-neck flask was charged with 9-ethyl-9H-carbazole-3-carboxylic acid (80mg, 0.33mmol), 4-methylsulfobenzylamine (82mg, 0.37mmol), HATU (141mg, 0.37mmol), N, N-diisopropylethylamine (129mg, 0.99mmol), dichloromethane (5mL), reacted overnight at room temperature, and the starting material was reacted by TLC. Dichloromethane (20mL) and saturated ammonium chloride (30mL) were added and washed, the organic layer was spin-dried to give the crude product, which was separated on a silica gel column (petroleum ether: ethyl acetate ═ 2:1-1:1) to give 66mg of the product as a white solid in 48.5% yield.1H NMR(400MHz，DMSO)δ9.15(t，J＝5.8Hz，1H)，8.75(s，1H)，8.17(d，J＝7.7Hz，1H)，8.07–8.00(m，1H)，7.88(d，J＝8.3Hz，2H)，7.70–7.62(m，2H)，7.60(d，J＝8.3Hz，2H)，7.49(t，J＝7.7Hz，1H)，7.24(t，J＝7.4Hz，1H)，4.62(d，J＝5.8Hz，2H)，4.47(q，J＝7.0Hz，2H)，3.17(s，3H)，1.31(t，J＝7.1Hz，3H).MS(ESI)m/z:407.0(MH+).
Example 20-Ethyl-N- (4- (propylsulfonyl) benzyl) -9H-carbazole-3-carboxamide
9-ethyl-N-(4-(propylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000312
Step 1: synthesis of 4- (propylsulfonyl) benzonitrile
To a 100(mL) single-neck flask were added 4-cyanobenzenesulfonyl chloride (1g, 4.97mmol), water (15mL), sodium bicarbonate (835mg, 9.94mmol), sodium sulfite (689mg, 5.47mmol), and the reaction mixture was stirred at 70 ℃ for 4 hours, and the solvent was removed by evaporation under reduced pressure. The crude product was dissolved in N, N-dimethylformamide (20mL) again, iodopropane (1.1mL) was added, and the reaction mixture was stirred at 70 ℃ for 4 hours. After cooling to room temperature, water (30mL) and ethyl acetate (3 × 30mL) were added for extraction, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to give a crude product, which was separated by a silica gel column (ethyl acetate: petroleum ether: 1:4-1:2) to give 520mg of a yellow solid product with a yield of 50.1%.
Step 2: synthesis of 4- (propylsulfonyl) benzylamine
To a 25mL single-neck flask were added 4- (propylsulfonyl) benzonitrile (520mg, 2.49mmol), methanol (10mL), palladium on carbon (100mg, 10%). The reaction solution was stirred at room temperature for 2 hours under a hydrogen atmosphere, filtered through celite, the solvent was spun off, and column chromatography was performed (petroleum ether: ethyl acetate 1:1) to give 120mg of a white solid as a product with a yield of 22.6%.
And step 3: synthesis of 9-ethyl-N- (4- (propylsulfonyl) benzyl) -9H-carbazole-3-carboxamide
To a 25mL eggplant-shaped bottle was added 4- (propylsulfonyl) benzylamine (100mg, 0.47mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (178mg, 0).47mmol), N, N-diisopropylethylamine (60mg, 0.47mmol), 9-ethyl-9 h-carbazole-3-carboxylic acid (98mg, 0.41mmol), dichloromethane (5 mL). After the reaction was completed, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate 1:1) gave 82mg of a white solid in 40.2% yield.1H NMR(400MHz，CDCl3)δ8.63(s，1H)，8.12(d，J＝7.8Hz，1H)，7.97(d，J＝8.6Hz，1H)，7.82(d，J＝8.1Hz，2H)，7.55(d，J＝8.2Hz，2H)，7.51(d，J＝7.9Hz，1H)，7.47–7.40(t，J＝7.9Hz，2H)，7.28(d，J＝7.3Hz，1H)，6.93(s，1H)，4.80(d，J＝5.6Hz，2H)，4.38(t，J＝7.2Hz，2H)，3.08–3.00(m，2H)，1.72(t，J＝7.9Hz，2H)，1.45(t，J＝7.2Hz，3H)，0.97(t，J＝7.4Hz，3H).MS(ESI)m/z:432.9(M-1)，435.2(MH+).
Example 21:9-ethyl-N- (4- (N-methylsulfamoyl) benzoyl) -9H-carbazole-3-carboxamide
(9-ethyl-N-(4-(N-methylsulfamoyl)benzyl)-9H-carbazole-3-carboxamide)
Figure BDA0001714564360000321
Step 1: synthesis of 4- (aminomethyl) -N-methylbenzenesulfonamide
A50 mL eggplant-shaped bottle was charged with an aqueous methylamine solution (15mL, 25% w/v) and acetone (5mL), and 4-cyanobenzenesulfonyl chloride (1g, 4.96mmol) was added in portions at room temperature and stirred for 2 hours. After the reaction, water was added for dilution, extraction was performed 3 times with ethyl acetate, and the organic phases were combined, spin-dried, and dried to obtain 1g of a white solid, which was used directly in the next step. MS (ESI) m/z 197.1(MH +).
Step 2: synthesis of 4- (aminomethyl) -N-methylbenzenesulfonamide
Raney nickel (250mg), 4-cyano-N-methylbenzenesulfonamide (250mg), methanol (3mL), 28% ammonia (12 drops), and tetrahydrofuran (24 drops) were put into a 25mL eggplant-shaped bottle, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction was complete, the organic solvent was filtered and spun dry under reduced pressure to give a viscous liquid (120mg, 47% yield MS (ESI) m/z:201.1(MH +).
And step 3: synthesis of 9-ethyl-N- (4- (N-methylsulfamoyl) benzoyl) -9H-carbazole-3-carboxamide
The procedure is as in example 1, 9-ethyl-9H-carbazole-3-carboxylic acid (52mg, 0.22mmol), 4- (aminomethyl) -N-methylbenzenesulfonamide (36mg, 0.18mmol), HATU (84mg, 0.22mmol), N, N-diisopropylethylamine (70mg, 0.54mmol) in dichloromethane (4 mL). 44mg of white solid product is obtained, yield 31.2%.1H NMR(400MHz，DMSO)δ9.12(t，J＝6.0Hz，1H)，8.76(s，1H)，8.17(d，J＝7.7Hz，1H)，8.04(d，J＝8.6Hz，1H)，7.73(d，J＝8.2Hz，2H)，7.70–7.62(m，2H)，7.55(d，J＝8.1Hz，2H)，7.49(t，J＝7.7Hz，1H)，7.40(q，J＝4.8Hz，1H)，7.24(t，J＝7.5Hz，1H)，4.60(d，J＝5.8Hz，2H)，4.47(q，J＝6.9Hz，2H)，2.37(d，J＝5.0Hz，3H)，1.31(t，J＝7.0Hz，3H).MS(ESI)m/z:422.1(MH+).
Example 22:9- (cyclopropylmethyl) -N- (4- (methylsulfonyl) benzyl) -9H-carbazole-3-carboxamide
(9-(cyclopropylmethyl)-N-(4-(methylsulfonyl)benzyl)-9H-carbazole-3-carboxamide)
Figure BDA0001714564360000331
A25 mL single vial was charged with 9- (cyclopropylmethyl) -9H-carbazole-3-carboxylic acid (80mg, 0.30mmol), 4-methylsulphonylbenzyamine (74mg, 0.33mmol), HATU (125mg, 0.33mmol), N, N-diisopropylethylamine (116mg, 0.90mmol), dichloromethane (5mL), reacted overnight at room temperature, and the starting material was reacted by TLC. Dichloromethane (20mL) and saturated ammonium chloride (30mL) were added and washed, the organic layer was spin-dried to give the crude product, which was separated on a silica gel column (petroleum ether: ethyl acetate ═ 2:1-1:1) to give 75mg of the product as a white solid in 57.7% yield.1H NMR(400MHz，CDCl3)δ8.61(s，1H)，8.12(d，J＝7.7Hz，1H)，7.95(d，J＝8.4Hz，1H)，7.91(d，J＝8.2Hz，2H)，7.59(d，J＝8.2Hz，2H)，7.55–7.49(m，1H)，7.49–7.42(m，2H)，7.29(d，J＝6.9Hz，1H)，6.82(s，1H)，4.81(d，J＝5.8Hz，2H)，4.26(d，J＝6.5Hz，2H)，3.04(s，3H)，1.33(s，2H)，0.56(d，J＝7.7Hz，2H)，0.41(d，J＝5.2Hz，2H).MS(ESI)m/z:433.0(MH+).
Example 23:9- (cyclopropylmethyl) -N- ((5- (ethylsulfonyl) pyridin-2-yl) methyl) -9H-carbazole-3- Carboxamides
(9-(cyclopropylmethyl)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-9H-carbazole-3-carboxamide)
Figure BDA0001714564360000332
The procedure is as for example 1, 9- (cyclopropylmethyl) -9H-carbazole-3-carboxylic acid (80mg, 0.30mmol), 5-ethylsulfonyl-2-pyridinemethanamine (66mg, 0.33mmol), HATU (125mg, 0.33mmol), N, N-diisopropylethylamine (116mg, 0.90mmol), dichloromethane (5 mL). 10mg of white solid are obtained, yield 17.4%.1H NMR(400MHz，CD3OD)δ8.98(s，1H)，8.72(s，1H)，8.24(d，J＝8.2Hz，1H)，8.14(d，J＝7.7Hz，1H)，8.03(d，J＝8.5Hz，1H)，7.68(d，J＝8.2Hz，1H)，7.62–7.53(m，2H)，7.49(d，J＝7.3Hz，1H)，7.25(t，J＝7.4Hz，1H)，4.84(s，2H)，4.31(d，J＝6.5Hz，2H)，3.26(dd，J＝14.9，7.5Hz，2H)，1.34(d，J＝7.0Hz，1H)，1.22(d，J＝7.4Hz，4H)，0.51(d，J＝7.8Hz，2H)，0.43(d，J＝4.5Hz，2H).MS(ESI)m/z:448.0(MH+).
Example 24:9- (cyclopropylmethyl) -N- (4- (N-methylsulfamoyl) benzoyl) -9H-carbazole-3-carboxylic acid Amines as pesticides(9-(cyclopropylmethyl)-N-(4-(N-methylsulfamoyl)benzyl)-9H-carbazole-3-carboxamide)
Figure BDA0001714564360000341
The procedure is as in example 1, 9- (cyclopropylmethyl) -9H-carbazole-3-carboxylic acid (58mg, 0.22mmol), 4- (aminomethyl) -N-methylbenzenesulfonamide (36mg, 0.18mmol)l), HATU (84mg, 0.22mmol), N, N-diisopropylethylamine (70mg, 0.54mmol), dichloromethane (4 mL). 39mg of a white solid was obtained, yield 28.9%.1H NMR(400MHz，DMSO)δ9.13(s，1H)，8.76(s，1H)，8.17(d，J＝7.9Hz，1H)，8.03(d，J＝8.6Hz，1H)，7.72(dd，J＝16.9，8.6Hz，4H)，7.56(d，J＝8.3Hz，2H)，7.49(t，J＝7.6Hz，1H)，7.41(d，J＝5.0Hz，1H)，7.25(t，J＝7.4Hz，1H)，4.61(d，J＝5.9Hz，2H)，4.36(d，J＝6.8Hz，2H)，2.38(d，J＝5.0Hz，3H)，1.29(s，2H)，0.44(d，J＝7.5Hz，4H).MS(ESI)m/z:448.0(MH+).
Example 25:n- (4- (ethylsulfonyl) benzyl) -9-phenethyl-9H-carbazole-3-carboxamide
(N-(4-(ethylsulfonyl)benzyl)-9-phenethyl-9H-carbazole-3-carboxamide)
Figure BDA0001714564360000342
Step 1: synthesis of 9-phenethyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with methyl 9H-carbazole-3-carboxylate (300mg, 1.33mmol) and anhydrous N, N-dimethylformamide (10mL), stirred in an ice bath for 5 minutes, then added with NaH (160mg, 4mmol, 60%), reacted at room temperature for 30 minutes, then added dropwise with (2-bromoethyl) benzene (736mg, 4mmol) while cooling on ice, reacted at room temperature for 3 hours, and the starting material was reacted by TLC. The reaction was quenched with water, ethyl acetate (3X 20mL), washed with water (5X 20mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate of the organic layer, filtered, and the solvent was dried under reduced pressure to give 140mg of a yellow solid with a yield of 32.0%.
Step 2: synthesis of 9-phenethyl-9H-carbazole-3-formic acid
A25 mL single-neck bottle is added with 9-phenethyl-9H-carbazole-3-methyl formate (140mg, 0.43mmol), potassium hydroxide (72mg, 1.29mmol), ethanol (4mL), water (1mL), and the mixture reacts for 1 hour at 80 ℃, the TLC detection raw material is reacted, 2N hydrochloric acid is used for adjusting the pH to 3, white solid is separated out, the filtration and the vacuum drying are carried out, and then 100mg of white solid product is obtained, and the yield is 75.6%.
And step 3: synthesis of N- (4- (ethylsulfonyl) benzyl) -9-phenethyl-9H-carbazole-3-formamide
Into a 25mL single-necked flask was added 9-phenethyl-9H-carbazole-3-carboxylic acid (100mg, 0.32mmol), 2- (7-azo)Benzene and its derivatives Triazole)-N，N，N′，N′-TetramethylureaHexafluorophosphate (138mg, 0.36mmol), N, N-diisopropylethylamine (47mg, 0.36mmol 1), 4- (ethylsulfonyl) benzylamine (73mg, 0.36mmol), dichloromethane (5mL) and stirred at room temperature for 10 h. After the reaction, the mixture was diluted with ethyl acetate, washed with a saturated sodium chloride solution and water in this order, and the organic phase was dried over anhydrous sodium sulfate. The organic solvent was removed by distillation under the reduced pressure, and 90mg of 9-phenethyl-N- (4- (ethylsulfonyl) phenyl) -9H-carbazole-3-amide was obtained by separation with a silica gel column, with a yield of 57.2%.1H NMR(400MHz，CDCl3)δ8.59(s，1H)，8.12(d，J＝7.9Hz，1H)，7.87(d，J＝8.2Hz，3H)，7.59(d，J＝8.0Hz，2H)，7.48(t，J＝7.6Hz，1H)，7.36(d，J＝8.1Hz，1H)，7.31–7.26(m，2H)，7.21(t，J＝7.6Hz，3H)，7.11(d，J＝6.3Hz，2H)，6.73(brs，1H)，4.81(d，J＝5.7Hz，2H)，4.54(t，J＝7.4Hz，2H)，3.21–3.01(m，4H)，1.27(t，J＝7.5Hz，3H).
Example 26: n- (4- (ethylsulfonyl) benzyl) -9- (4- (trifluoromethyl) phenethyl) -9H-carbazole-3-amide
N-(4-(ethylsulfonyl)benzyl)-9-(4-(trifluoromethyl)phenethyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000351
Step 1: synthesis of methyl 9- (4- (trifluoromethyl) phenethyl) carbazole-3-carboxylate
In a 25mL eggplant-shaped bottle, methyl 9-hydrocarbazole-3-carboxylate (150mg, 0.67mmol), cesium carbonate (261mg, 0.8mmol), N, N-dimethylformamide (10mL), potassium iodide (11mg, 0.078mmol) were added under ice-cooling, and after the addition, the ice-cooling was removed and stirring was carried out for 30 minutes. After 30 minutes, 4- (trifluoromethyl) phenethyl bromide (261 mg/174. mu.L, 0.8mmol) was added dropwise, reaction was carried out for 9 hours, and TLC detection (developing solvent: petroleum ether: ethyl acetate: 10:1) was carried out to complete the reaction. After the reaction was complete, water (20mL) was added to quench neutralization. Extraction was performed with ethyl acetate (3X 10mL), and the organic phase was washed with water (5X 10mL), saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to give the crude product. Column chromatography (petroleum ether: ethyl acetate: 20:1) gave 32mg of a colorless oily liquid, in 12.0% yield.
Step 2: synthesis of 9- (4- (trifluoromethyl) phenethyl) carbazole-3-formic acid
A25 mL round bottom flask was charged with a mixture of methyl 9- (4- (trifluoromethyl) phenethyl) carbazole-3-carboxylate (32mg, 0.08mmol), solid lithium hydroxide monohydrate (9.67mg, 0.24mmol), and ethanol (2 mL)/water (0.5 mL). The reaction was carried out at 60 ℃ for 3 hours with stirring. After the reaction was completed, ethanol was removed by evaporation under reduced pressure, water was added to the reaction mixture to 5mL, and 2N hydrochloric acid was added dropwise to the reaction mixture until the pH of the reaction mixture became 3, whereby a large amount of solid was precipitated. Extraction was carried out with ethyl acetate (3X 10mL), and the organic phase was washed with water (5X 10mL), saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to give the crude product, which was suction-filtered under reduced pressure to give 17mg of a yellow oil in 56.2% yield.
Synthesis of compound N- (4- (ethylsulfonyl) benzyl) -9- (4- (trifluoromethyl) phenethyl) -9H-carbazole-3-amide
To a 25mL eggplant-shaped bottle were added 9- (4- (trifluoromethyl) phenethyl) carbazole-3-carboxylic acid (17mg, 0.045mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (21mg, 0.054mmol), N, N-diisopropylethylamine (21mg, 0.054mmol), (4- (ethylsulfonyl) phenyl) methylamine (11mg, 0.054mmol), and dichloromethane (2 mL). After the reaction was completed, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Preparative plate separation (petroleum ether: ethyl acetate ═ 1:2) afforded 15mg of a white solid in 59.0% yield.1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.10(d,J＝7.7Hz,1H),7.87(d,J＝7.7Hz,1H),7.81(d,J＝8.0Hz,2H),7.54(d,J＝8.0Hz,2H),7.44(d,J＝7.8Hz,3H),7.29(d,J＝8.1Hz,2H),7.20(d,J＝8.1Hz,1H),7.16(d,J＝7.8Hz,2H),6.96(brs,1H),4.79(d,J＝5.0Hz,2H),4.55(t,J＝6.8Hz,2H),3.19(t,J＝6.8Hz,2H),3.09(q,J＝7.5Hz,2H),1.27(d,J＝7.5Hz,3H).
Example 27: 9- (2-trifluoromethyl) benzyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
9-(2-trifluoromethyl)benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000361
Step 1: synthesis of 9- (2-trifluoromethyl) benzyl-9H-carbazole-3-methyl formate
To a 25mL single-neck flask was added methyl 9H-carbazole-3-carboxylate (100mg, 0.44mmol), anhydrous N, N-dimethylformamide (3mL), stirred in an ice bath for 5 minutes, and then added sodium hydride (53.8mg, 1.32mmol, 60%) and reacted at room temperature for 30 minutes. After 30 minutes, 2- (trifluoromethyl) benzyl bromide (0.2mL, 1.32mmol) was added dropwise with ice-cooling and the reaction was carried out at room temperature for 1 hour, after which the starting material was reacted by TLC. The reaction was quenched with water, extracted with ethyl acetate (3 × 10mL), washed with saturated sodium chloride, the organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was removed by evaporation under reduced pressure, and column chromatography (petroleum ether: ethyl acetate 5:1) gave 100mg of crude product in 59.3% yield.
Step 2: synthesis of 9- (2-trifluoromethyl) benzyl-9H-carbazole-3-formic acid
Adding 9- (2-trifluoromethyl) benzyl-9H-carbazole-3-methyl formate (100mg, 0.26mmol), potassium hydroxide (43.68mg, 0.78mmol) and water (1mL) into a 25mL single-neck flask, adding ethanol until the solid is completely dissolved, heating at 90 ℃ for reaction for 1 hour, detecting that the raw material is completely reacted by TLC, evaporating the ethanol at 65 ℃ under reduced pressure, adjusting the pH to 3 by using 2N hydrochloric acid, separating out the solid, performing suction filtration to obtain the solid, dissolving the solid in ethyl acetate (5mL), and evaporating the solvent under reduced pressure to obtain a solid product 130 mg. MS-ESI (m/z): 370[ M + H]+.
Synthesis of compound 9- (2-trifluoromethyl) benzyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
To a 25mL single-necked flask was added 9- (2-trifluoromethyl) benzyl-9H-carbazole-3-carboxylic acid (130mg, 0.35mmol), 2- (7-azo)Benzotriazole)-N，N，N′，N′-TetramethylureaHexafluorophosphate (149mg, 0.392mmol), N, N-diisopropylethylamine 10d, (4- (ethylsulfonyl) phenyl) methylamine (78mg, 0.392mmol), and dichloromethane (4mL) were stirred at room temperature overnight. After the reaction, the reaction solution was spin-dried, washed once with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. The organic solvent was removed by distillation under the reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate 1:2) gave 104mg of a white solid in 54% yield.1H-NMR(400MHz,CDCl3)δ8.69(s,1H),8.19(d,J＝7.5Hz,1H),7.90(d,J＝7.5Hz,1H),7.88(d,J＝7.9Hz,2H),7.77(d,J＝7.6Hz,1H),7.59(d,J＝7.9Hz,2H),7.48(t,J＝7.8Hz,1H),7.35(s,1H),7.32(t,J＝7.7Hz,3H),7.23(d,J＝7.3Hz,1H),6.79(s,1H),6.50(d,J＝7.4Hz,1H),5.75(s,2H),4.83(s,2H),3.11(q,J＝7.5Hz,2H),1.27(t,J＝7.5Hz,3H).
Example 28: 9- (3-trifluoromethyl) benzyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
9-(3-trifluoromethyl)benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000371
Step 1: synthesis of 9- (3-trifluoromethyl) benzyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with 9H-carbazole-3-carboxylic acid methyl ester (50mg, 0.22mmol), anhydrous N, N-dimethylformamide (3mL), stirred in ice bath for 5 minutes, then added with sodium hydride (26.4mg, 0.66mmol, 60%), reacted at room temperature for 30 minutes, then added dropwise with 3- (trifluoromethyl) benzyl bromide (0.1mL, 0.66mmol) under cooling in ice bath, reacted at room temperature for 1 hour, and the starting material was reacted by TLC. The reaction was quenched with water, extracted with ethyl acetate (3 × 10mL), washed with saturated sodium chloride, the organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was removed by evaporation under reduced pressure, and column chromatography was performed (petroleum ether: ethyl acetate 5:1) to obtain 203mg of a crude product.
Step 2: synthesis of 9- (2-trifluoromethyl) benzyl-9H-carbazole-3-formic acid
Add 9- (3-Trifluoromethane) to a 25mL single-neck flaskMethyl) benzyl-9H-carbazole-3-carboxylate (203mg, 0.53mmol), potassium hydroxide (89.04mg, 1.59mmol), water (1mL), ethanol is added until the solid is completely dissolved, the mixture is heated at 90 ℃ for reaction for 1 hour, TLC detects that the raw material has reacted completely, ethanol is distilled off under reduced pressure at 65 ℃, 2N hydrochloric acid is used for adjusting the pH value to 3, the solid is separated out, the solid is obtained by suction filtration, ethyl acetate (5mL) is dissolved, the solvent is distilled off under reduced pressure, and 155mg of a solid product is obtained, and the yield is 79.3%. MS-ESI (m/z): 370[ M + H]+.
Synthesis of compound 9- (3-trifluoromethyl) benzyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
Into a 25mL single-necked flask was added 9- (3-trifluoromethyl) benzyl-9H-carbazole-3-carboxylic acid (155mg, 0.42mmol), 2- (7-azo)Benzotriazole)-N，N，N′，N′-TetramethylureaHexafluorophosphate (178.6mg, 0.47mmol), N, N-diisopropylethylamine 10d, (4- (ethylsulfonyl) phenyl) methylamine (93.53mg, 0.47mmol), and dichloromethane (4mL) were stirred at room temperature overnight. After completion of the reaction, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate: 1:2) gave 83.5mg of a white solid in 36% yield.1H-NMR:(400MHz,CDCl3)δ8.66(s,1H),8.01(d,J＝7.7Hz,1H),7.90(d,J＝8.6Hz,1H),7.80(t,J＝5.9Hz,1H),7.65(s,1H),7.63(s,1H),7.40(d,J＝8.4Hz,3H),7.36(d,J＝7.8Hz,1H),7.23(s,1H),7.22(s,1H),7.20(d,J＝2.9Hz,1H),7.17(d,J＝7.4Hz,1H),7.05(d,J＝7.7Hz,1H),5.44(s,2H),4.65(d,J＝5.8Hz,2H),2.96(q,J＝7.4Hz,2H),1.12(t,J＝7.4Hz,3H).
Example 29: 9- (4-trifluoromethyl) benzyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
9-(4-trifluoromethyl)benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000381
Step 1: synthesis of 9- (4-trifluoromethyl) benzyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with 9H-carbazole-3-carboxylic acid methyl ester (50mg, 0.22mmol), anhydrous N, N-dimethylformamide (3mL), stirred in ice bath for 5 minutes, then added with sodium hydride (26.4mg, 0.66mmol, 60%), reacted at room temperature for 30 minutes, and then added dropwise with cooling in ice bath with 4- (trifluoromethyl) benzyl bromide (0.1mL, 0.66mmol), reacted at room temperature for 1 hour, and the starting material was reacted by TLC. The reaction was quenched with water, extracted with ethyl acetate (3 × 10mL), washed with saturated sodium chloride, the organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was removed by evaporation under reduced pressure, and column chromatography (petroleum ether: ethyl acetate 5:1) was performed to obtain 170mg of a crude product.
Step 2: synthesis of 9- (4-trifluoromethyl) benzyl-9H-carbazole-3-formic acid
Adding 9- (4-trifluoromethyl) benzyl-9H-carbazole-3-methyl formate (170mg, 0.44mmol), potassium hydroxide (73.92mg, 1.32mmol), water (1mL) and ethanol into a 25mL single-neck flask until the solid is completely dissolved, heating to 90 ℃ for reaction for 1 hour, detecting that the raw material is completely reacted by TLC, evaporating the ethanol at 65 ℃ under reduced pressure, adjusting the pH to 3 by using 2N hydrochloric acid, separating out the solid, performing suction filtration to obtain the solid, dissolving the solid in ethyl acetate (5mL), and evaporating the solvent under reduced pressure to obtain a solid product 79mg, wherein the yield is 45.5%. MS-ESI (m/z): 370[ M + H ] +.
Synthesis of compound 9- (4-trifluoromethyl) benzyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
To a 25mL single-necked flask was added 9- (4-trifluoromethyl) benzyl-9H-carbazole-3-carboxylic acid (74mg, 0.2mmol), 2- (7-azobenzotriazol) -N, N' -tetramethylurea hexafluorophosphate (85.12mg, 0.224mmol), N-diisopropylethylamine 10d, (4- (ethylsulfonyl) phenyl) methylamine (44.576mg, 0.224mmol), and dichloromethane (4mL), and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate: 1:2) afforded 47mg of solid, 43% yield.1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.17(d,J＝8.0Hz,1H),7.92(d,J＝8.6Hz,1H),7.87(d,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,2H),7.52(d,J＝8.5Hz,2H),7.48(d,J＝7.3Hz,1H),7.35(d,J＝8.5Hz,2H),7.32(d,J＝7.3Hz,1H),7.20(d,J＝7.9Hz,2H),6.78(brs,1H),5.60(s,2H),4.82(d,J＝5.6Hz,2H),3.10(q,J＝7.4Hz,2H),1.28(t,J＝7.4Hz,3H).
Example 30:9- (2-isopropoxy) benzyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
9-(2-isopropoxy)benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000391
Step 1: synthesis of 2- (isopropoxy) benzyl alcohol
2-hydroxybenzyl alcohol (2g, 16.12mmol), ethanol (12mL), and potassium carbonate (6.68g, 48.39mmol) were added to a 50mL eggplant-shaped bottle, heated to 65 ℃ for 10min, and then bromoisopropane (2.86mL, 30.65mmol) was added thereto, followed by further reaction, condensation and reflux overnight. TLC (petroleum ether: ethyl acetate 3:1) monitored and the reaction was complete. The diatomite is filtered by suction and steamed by rotation to obtain 2.78g of orange-red oily liquid as a crude product.
Step 2: synthesis of 2- (isopropoxy) benzyl bromide
2- (Isopropoxy) benzyl alcohol (2.7mg,16.27mmol) was added to a 50mL eggplant-shaped bottle, methylene chloride (20mL) and phosphorus tribromide (1.16mL,12.20mmol) were added under ice-cooling, and after the addition, the ice-cooling was removed, and the color of the system was lightened. After 2h of reaction, TLC (petroleum ether: ethyl acetate 3:1) monitored for complete reaction, saturated sodium bicarbonate solution was quenched to colorless, extracted with dichloromethane (3 × 10mL), saturated brine (3 × 40mL), and dried by spinning to give 4g of crude pale orange oily liquid. MS-ESI (m/z): 230[ M + H [ ]]+.
And step 3: synthesis of 9- (2-isopropoxy) benzyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with methyl 9H-carbazole-3-carboxylate (50mg, 0.22mmol) and anhydrous N, N-dimethylformamide (3mL), stirred in ice bath for 5 minutes, then charged with sodium hydride (26.4mg, 0.66mmol, 60%), reacted at room temperature for 30 minutes, then 2- (isopropoxy) benzyl bromide (151.14mg, 0.66mmol) was added dropwise with cooling in ice bath, reacted at room temperature for 1 hour, and the starting material was reacted by TLC. The reaction was quenched with water, extracted with ethyl acetate (3 × 10mL), washed with saturated sodium chloride, the organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was removed by evaporation under reduced pressure, and column chromatography (petroleum ether: ethyl acetate 5:1) was performed to obtain 156.7mg of a colorless liquid.
And 4, step 4: synthesis of 9- (2-isopropoxy) benzyl-9H-carbazole-3-carboxylic acid
Adding 9- (2-isopropoxy) benzyl-9H-carbazole-3-methyl formate (156.7mg, 0.42mmol), potassium hydroxide (70.56mg, 1.26mmol), water (1mL) and ethanol into a 25mL single-neck flask until the solid is completely dissolved, heating at 90 ℃ for reaction for 1 hour, detecting that the raw material is completely reacted by TLC, evaporating the ethanol at 65 ℃ under reduced pressure, adjusting the pH to 3 by using 2N hydrochloric acid, separating out a solid, performing suction filtration to obtain a solid, dissolving the solid in ethyl acetate, and evaporating the solvent under reduced pressure to obtain a solid product 188.4 mg. MS-ESI (m/z): 360[ M + H ]]+.
Synthesis of compound 9- (2-isopropoxy) benzyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
To a 25mL single-neck flask was added 9- (2-isopropoxy) benzyl-9H-carbazole-3-carboxylic acid (188.4mg, 0.525mmol), 2- (7-azobenzotriazol) -N, N' -tetramethylurea hexafluorophosphate (223mg, 0.588mmol), N-diisopropylethylamine 20d, (4- (ethylsulfonyl) phenyl) methylamine (117mg, 0.588mmol), dichloromethane (4mL), and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate: 1:2) afforded 147.4mg of a white solid in 51% yield.1H-NMR:(400MHz,CDCl3)δ8.53(s,1H),8.04(d,J＝6.9Hz,1H),7.48(d,J＝8.1Hz,2H),7.35(s,1H),7.31(s,1H),7.07(s,1H),6.81(d,J＝7.9Hz,1H),6.63(s,1H),6.56(t,J＝7.4Hz,1H),6.47(t,J＝7.4Hz,1H),5.42(s,2H),4.71(s,2H),4.50-4.60(m,1H),2.99(q,J＝7.4Hz,2H),1.24-1.28(m,6H),1.16(t,J＝7.4Hz,3H).
Example 31:9- (3-isopropoxy) benzyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
9-(3-isopropoxy)benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000401
Step 1: synthesis of 3- (isopropoxy) toluene
To a 50mL eggplant-shaped bottle was added 3-methylphenol (0.97mL, 9.26mmol), ethanol (12mL), and potassium carbonate (3.83g, 27.78mmol), and the mixture was heated to 60 ℃ for 10min, followed by addition of bromoisopropane (1.65mL, 17.6mmol), followed by further reaction, reflux condensation, and overnight. TLC (petroleum ether: ethyl acetate: 9:1) monitoring, complete reaction, suction filtration by using kieselguhr and rotary evaporation to obtain 1.36g of a crude product, namely an orange-red oily liquid. MS-ESI (m/z): 151[ M + H ] +
Step 2: synthesis of 3- (isopropoxy) benzyl bromide
3- (isopropoxy) toluene (500mg, 3.33mmol) was added to a 50mL eggplant-shaped bottle, dissolved in 8mL carbon tetrachloride, azobisisobutyronitrile (119.7mg, 0.73mmol) was added, N-bromosuccinimide (712mg, 4mmol) was added in portions, and the mixture was heated to 90 ℃ and then refluxed by condensation. After 6 hours of reaction, TLC (petroleum ether: ethyl acetate: 2mL:1 drop) was monitored, the reaction was completed, the mixture was filtered with celite, the solid was dissolved in dichloromethane, and rotary evaporation was carried out at 70 ℃ to obtain 1.046g of a crude pale yellow oily liquid. MS-ESI (m/z): 230[ M + H [ ]]+.
And step 3: synthesis of 9- (3-isopropoxy) benzyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with methyl 9H-carbazole-3-carboxylate (30mg, 0.13mmol) and anhydrous N, N-dimethylformamide (3mL), stirred in ice bath for 5 minutes, then added with sodium hydride (15.6mg, 0.39mmol, 60%) and reacted at room temperature for 30 minutes, and then dropwise added with 3- (isopropoxy) benzyl bromide (89.31mg, 0.39mmol) under cooling in ice bath and reacted at room temperature for 1 hour, and the reaction was completed. The reaction was quenched with water, extracted with ethyl acetate (3X 10mL), washed with saturated sodium chloride, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 100mg of crude product.
Step 6: synthesis of 9- (3-isopropoxy) benzyl-9H-carbazole-3-carboxylic acid
To a 25mL single-neck flask was added 9- (3-isopropoxy) benzyl-9H-carbazole-3-carboxylic acid methyl ester (100mg, 0.26mmol), potassium hydroxide (43.68 m)g, 0.78mmol), water (1mL), ethanol is added until the solid is completely dissolved, the mixture is heated at 90 ℃ for reaction for 1 hour, TLC detects that the raw material has reacted completely, ethanol is distilled off under reduced pressure at 65 ℃, 2N hydrochloric acid is used for adjusting the pH value to 3, solid is separated out, solid is obtained by suction filtration, ethyl acetate (5mL) is dissolved, the solvent is distilled off under reduced pressure, and the solid product is obtained by 61mg, wherein the yield is 65.4%. MS-ESI (m/z): 360[ M + H ]]+.
Synthesis of compound 9- (3-isopropoxy) benzyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
To a 25mL single-necked flask was added 9- (3-isopropoxy) benzyl-9H-carbazole-3-carboxylic acid (61mg, 0.17mmol), 2- (7-azo)Benzotriazole)-N，N，N′，N′-TetramethylureaHexafluorophosphate (72.2mg, 0.19mmol), N, N-diisopropylethylamine 20d, (4- (ethylsulfonyl) phenyl) methylamine (37.81mg, 0.19mmol), dichloromethane (4mL), stirred at room temperature overnight. After completion of the reaction, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate: 1:2) gave 45mg of a colorless oily liquid, 48% yield.1H-NMR:(400MHz,CDCl3)δ8.70(s,1H),8.11(d,J＝7.6Hz,1H),7.94(d,J＝8.4Hz,1H),7.73(d,J＝7.9Hz,2H),7.47(d,J＝7.6Hz,3H),7.40(s,1H),7.36(t,J＝7.6Hz,2H),7.16(t,J＝7.8Hz,1H),6.76(d,J＝8.0Hz,1H),6.66(d,J＝7.4Hz,1H),6.64(s,1H),5.45(s,2H),4.74(s,2H),3.06(q,J＝7.1Hz,2H),1.24(d,J＝6.0Hz,9H).
Example 32:9- (4-isopropoxy) benzyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
9-(4-isopropoxy)benzyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000411
Step 1: synthesis of 4- (isopropoxy) benzyl alcohol
Adding 4-hydroxybenzyl alcohol (1g, 8mmol), ethanol (12mL), and potassium carbonate (3.3g, 24mmol) into a 50mL eggplant-shaped bottle, heating to 65 deg.C for 10min, and adding bromineIsopropane (1.43mL, 15.2mmol) was removed and the reaction was continued, condensed to reflux, overnight. TLC (PE: EA is 3:1) monitoring, complete reaction, suction filtration of diatomite, rotary evaporation and obtaining 1.34g of crude orange-red oily liquid. MS-ESI (m/z): 167[ M + H ]]+.
Step 2: synthesis of 4- (isopropoxy) benzyl bromide
A50 mL eggplant-shaped bottle was charged with 4- (isopropoxy) benzyl alcohol (500mg, 3mmol), and methylene chloride (6mL) and phosphorus tribromide (0.2mL, 2.25mmol) were added in an ice bath, and after the addition, the ice bath was removed, whereby the color of the system became lighter. After 2h of reaction, TLC (PE: EA ═ 3:1) was monitored and the reaction was complete. The saturated sodium bicarbonate solution is quenched until the solution is colorless, the diatomite is filtered in a suction way, the solid is dissolved in dichloromethane and is evaporated in a rotary manner at 70 ℃, and the crude product, namely 614.3mg of light orange oily liquid is obtained, and the yield is 89.4%. MS-ESI (m/z): 230[ M + H [ ]]+.
And step 3: synthesis of 9- (4-isopropoxy) benzyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with methyl 9H-carbazole-3-carboxylate (50mg, 0.22mmol) and anhydrous N, N-dimethylformamide (3mL), stirred in ice bath for 5 minutes, then charged with sodium hydride (26.4mg, 0.66mmol, 60%), reacted at room temperature for 30 minutes, and 4- (isopropoxy) benzyl bromide (151.14mg, 0.66mmol) was added dropwise under cooling in ice bath, reacted at room temperature for 1 hour, and the starting material was reacted by TLC. The reaction was quenched with water, extracted with ethyl acetate (3X 10mL), washed with saturated sodium chloride, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 188mg of the crude product.
And 4, step 4: synthesis of 9- (4-isopropoxy) benzyl-9H-carbazole-3-carboxylic acid
Adding 9- (4-isopropoxy) benzyl-9H-carbazole-3-methyl formate (188mg, 0.5mmol), potassium hydroxide (84mg, 1.5mmol), water (1mL) into a 25mL single-neck bottle, adding ethanol until the solid is completely dissolved, heating at 90 ℃ for reaction for 1 hour, detecting that the raw material is completely reacted by TLC, evaporating the ethanol at 65 ℃ under reduced pressure, adjusting the pH to 3 by using 2N hydrochloric acid, separating out the solid, performing suction filtration to obtain the solid, dissolving ethyl acetate, and evaporating the solvent under reduced pressure to obtain a solid product 136.9mg, wherein the yield is 76.3%. MS-ESI (m/z): 360[ M + H ]]+.
Synthesis of compound 9- (4-isopropoxy) benzyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
To a 25mL single neck flask was added 9- (4-isopropoxy) benzyl-9H-carbazole-3-carboxylic acid (136.9mg, 0.38mmol), 2- (7-azobenzotriazol) -N, N' -tetramethylurea hexafluorophosphate (163.4mg, 0.43mmol), N-diisopropylethylamine 20d, (4- (ethylsulfonyl) phenyl) methylamine (85.57mg, 0.43mmol), dichloromethane (4mL), and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was dried under reduced pressure, extracted with ethyl acetate (3X5mL), and the organic phase was washed with saturated sodium chloride (3X5mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give a crude product. Column chromatography (petroleum ether: ethyl acetate: 1:2) gave 118mg of a colorless oily liquid, 56% yield.1H-NMR:(400MHz,CDCl3)δ8.65(d,J＝7.4Hz,1H),8.14(t,J＝7.7Hz,1H),7.91(t,J＝7.9Hz,1H),7.84(t,J＝8.0Hz,2H),7.56(t,J＝7.8Hz,2H),7.48(d,J＝7.4Hz,1H),7.41(q,J＝7.7Hz,2H),7.31(t,J＝7.3Hz,1H),7.04(t,J＝8.0Hz,2H),6.94(d,J＝6.2Hz,1H),6.76(t,J＝8.1Hz,2H),5.46(d,J＝7.6Hz,2H),4.42-4.50(m,1H),3.08(q,J＝7.2Hz,2H),1.27(d,J＝6.1Hz,9H).
Example 33: 9-ethyl-N- (4- (ethylsulfonyl) benzyl) -6- (trifluoromethoxy) -9H-carbazole-3-amide
9-ethyl-N-(4-(ethylsulfonyl)benzyl)-6-(trifluoromethoxy)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000421
Step 1: synthesis of methyl 4- ((4-trifluoromethoxyphenyl) amino) benzoate
To a 25mL microwave tube was added 4-trifluoromethoxyaniline (2.3g, 13mmol), methyl 4-bromobenzoate (3.44g, 16mmol), potassium carbonate (2.21g, 16mmol), rac-BINAP (405mg, 0.65mmol), palladium acetate (290mg, 1.3mmol), toluene (10mL), and the reaction was heated at microwave 130 ℃ for 1 hour, after completion of the reaction, diluted with ethyl acetate (10mL), filtered through celite, the solvent was spin-dried under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate: 20:1-10:1) to give 870mg of a purple solid product in 21.5% yield.1H NMR(400MHz，CDCl3)δ7.93(d,J＝8.6Hz,2H),7.18(d,J＝1.8Hz,4H),6.99(d,J＝8.7Hz,2H),3.88(s,3H).MS-ESI(m/z):312.1[M+H]+ step 2: synthesis of 6-trifluoromethoxy-9H-carbazole-3-methyl formate
Methyl 4- ((4-trifluoromethoxyphenyl) amino) benzoate (550mg, 1.8mmol), palladium acetate (450mg, 2mmol), acetic acid (20mL) were added to a 50mL single-neck flask, and the mixture was heated at 120 ℃ for 2 hours, after completion of the reaction, the acetic acid was dried under reduced pressure, and dissolved in ethyl acetate (10mL), and the product was isolated by column chromatography (petroleum ether: ethyl acetate ═ 10:1) as a yellow solid, 330mg, with a yield of 60.4%.1H NMR(400MHz，CDCl3)δ8.80(s,1H),8.42(s,1H),8.17(d,J＝8.4Hz,1H),7.98(s,1H),7.48–7.43(m,2H),7.34(d,J＝8.9Hz,1H),3.98(d,J＝1.4Hz,3H).MS-ESI(m/z):310.1[M+H]+
And step 3: synthesis of 6-trifluoromethoxy-9-ethyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with 6-trifluoromethoxy-9H-carbazole-3-carboxylic acid methyl ester (200mg, 0.65mmol), anhydrous N, N-dimethylformamide (5mL), stirred in ice bath for 5 minutes, then added with sodium hydride (40mg, 1mmol, 60%), reacted at room temperature for 30 minutes, and then dropwise added with ethyl bromide (110mg, 1mmol) in ice bath, reacted at room temperature for 3 hours, and the starting material was reacted by TLC. The reaction was quenched with water, and then washed with ethyl acetate (3 × 20mL), water (5 × 20mL), saturated sodium chloride, dried over anhydrous sodium sulfate for the organic layer, filtered, the solvent was dried under reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 10:1) gave 116mg of a yellow solid product in 53.2% yield.
And 4, step 4: synthesis of 6-trifluoromethoxy-9-ethyl-9H-carbazole-3-carboxylic acid
6-trifluoromethoxy-9-ethyl-9H-carbazole-3-methyl formate (116mg, 0.34mmol), lithium hydroxide (45mg, 1.07mmol), ethanol (5mL), water (1mL) were added to a 25mL single-neck flask, the reaction was carried out at 90 ℃ for 2 hours, the starting materials were detected by TLC to have reacted, the pH was adjusted to 3 with 2N hydrochloric acid, a white solid precipitated, and the product was filtered, vacuum dried to obtain 102mg of a white solid, with a yield of 91.8%.
Synthesis of compound 9-ethyl-N- (4- (ethylsulfonyl) benzyl) -6- (trifluoromethoxy) -9H-carbazole-3-amide
Adding 6-trifluoromethoxy-one into a 25mL single-port bottle9-Ethyl-9H-carbazole-3-carboxylic acid (102mg, 0.32mmol), (4- (ethylsulfonyl) phenyl) methylamine (78mg, 0.39mmol), 2- (7-oxide benzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (150mg, 0.39mmol), N, N-diisopropylethylamine (124mg, 0.96mmol), dichloromethane (5mL), reacted overnight at room temperature, and TLC detected that the starting materials were reacted. Dichloromethane (20mL) and saturated ammonium chloride (30mL) were added and the organic layer was spin-dried to give the crude product, which was separated by column chromatography (petroleum ether: ethyl acetate: 1-1:1.5) to give 75mg of the product as a white solid in 47.1% yield.1H NMR(400MHz，CDCl3)δ8.60(s,1H),8.02(d,J＝8.8Hz,1H),7.98(s,1H),7.86(d,J＝7.9Hz,2H),7.58(d,J＝7.9Hz,2H),7.47(d,J＝8.5Hz,1H),7.43(d,J＝8.6Hz,1H),7.39(d,J＝9.2Hz,1H),6.86(s,1H),4.83(d,J＝6.1Hz,2H),4.44–4.37(q,J＝7.2Hz,2H),3.11(q,J＝7.4Hz,2H),1.46(t,J＝7.4Hz,3H),1.28(t,J＝8.4Hz,3H).MS-ESI(m/z):505.1[M+H]+。
Example 34:9-ethyl-N- (4- (ethylsulfonyl) benzyl) -6-isopropoxy-9H-carbazole-3-amide
9-ethyl-N-(4-(ethylsulfonyl)benzyl)-6-isopropoxy-9H-carbazole-3-carboxamide
Figure BDA0001714564360000441
Step 1: synthesis of 4-isopropoxynitrobenzene
A50 mL single-neck flask was charged with p-nitrophenol (1g, 7.2mmol), 2-bromopropane (1.33mg, 10.8mmol), potassium carbonate (1.49g, 10.8mmol), and N, N-dimethylformamide (10mL), and the reaction was heated at 120 ℃ for 1 hour to complete the reaction. Ethyl acetate (3 × 20mL), water (5 × 20mL), saturated sodium chloride, and the organic layer were dried over anhydrous sodium sulfate, filtered, and the solvent was dried by spin-drying under reduced pressure, and column chromatography (petroleum ether: ethyl acetate: 100:1-50:1) gave 1.2g of a solid product with a yield of 96.2%.1H NMR(400MHz，CDCl3)δ8.19(dd,J＝9.2,2.4Hz,2H),6.92(dd,J＝9.2,2.4Hz,2H),4.66(d,J＝6.2Hz,1H),1.39(dd,J＝6.2,2.2Hz,6H).
And 2, step: synthesis of 4-isopropoxy aniline
A50 mL single-neck flask was charged with 4-isopropoxynitrobenzene (1.2g, 6.6mmol), stannous dichloride dihydrate (4.5g, 20mmol), concentrated hydrochloric acid (0.5mL), ethanol (15mL), and heated at 60 ℃ for 10 hours to complete the reaction. Ethyl acetate (3 × 20mL), washed with saturated sodium chloride, and the organic layer dried over anhydrous sodium sulfate, filtered, the solvent was spin-dried under reduced pressure, and column chromatography was performed (petroleum ether: ethyl acetate: 20:1) to obtain 670mg of a solid product with a yield of 66.9%.
And step 3: synthesis of methyl 4- ((4-isopropoxyphenyl) amino) benzoate
To a 25mL microwave tube was added 4-isopropoxyaniline (670mg, 4.4mmol), methyl 4-bromobenzoate (1.14g, 5.3mmol), potassium carbonate (730mg, 5.3mmol), rac-BINAP (137mg, 0.22mmol), palladium acetate (100mg, 0.44mmol), toluene (10mL), and the reaction was heated at microwave 130 ℃ for 1 hour, after completion of the reaction, the mixture was diluted with ethyl acetate, filtered through celite, the solvent was spin-dried under reduced pressure, and column chromatography was performed (petroleum ether: ethyl acetate: 20:1-10:1) to give 420mg of a purple solid product, 33.2% yield. MS-ESI (M/z) 286.2[ M + H ] +
And 4, step 4: synthesis of 6-isopropoxy-9H-carbazole-3-methyl formate
Methyl 4- ((4-isopropoxyphenyl) amino) benzoate (420mg, 1.5mmol), palladium acetate (360mg, 1.6mmol), acetic acid (20mL) were added to a 50mL single-neck flask, and the mixture was heated at 120 ℃ for reaction for 3 hours, after the reaction was completed, the acetic acid was dried under reduced pressure, and dissolved in ethyl acetate (5mL), and the product was separated by column chromatography (petroleum ether: ethyl acetate: 10:1) to give 170mg of a yellow solid product, with a yield of 40.7%.1H NMR(400MHz，CDCl3)δ8.76(s,1H),8.25(s,1H),8.10(d,J＝8.6Hz,1H),7.62(s,1H),7.40(d,J＝8.6Hz,1H),7.35(d,J＝8.8Hz,1H),7.08(d,J＝8.7Hz,1H),4.61(d,J＝6.4Hz,1H),3.97(s,3H),1.40(d,J＝6.1Hz,6H).MS-ESI(m/z):284.2[M+H]+
And 5: synthesis of 6-isopropoxy-9-ethyl-9H-carbazole-3-methyl formate
A25 mL single vial was charged with 6-isopropoxy-9H-carbazole-3-carboxylic acid methyl ester (170mg, 0.6mmol), anhydrous N, N-dimethylformamide (5mL), stirred in ice bath for 5 minutes, then added with sodium hydride (72mg, 1.8mmol, 60%), reacted at room temperature for 30 minutes, and then dropwise added with ethyl bromide (196mg, 1.8mmol) while cooling on ice, reacted at room temperature for 3 hours, and the starting material was reacted by TLC. The reaction was quenched with water, ethyl acetate (3X 20mL), washed with water (5X 20mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate of the organic layer, filtered, and the solvent was dried under reduced pressure to give 190mg of crude product, which was used directly in the next reaction.
Step 6: synthesis of 6-isopropoxy-9-ethyl-9H-carbazole-3-carboxylic acid
6-isopropoxy-9-ethyl-9H-carbazole-3-carboxylic acid methyl ester (190mg, 0.6mmol), lithium hydroxide (76mg, 1.8mmol), ethanol (5mL), water (1mL) were added to a 25mL single-neck flask, the reaction was carried out at 90 ℃ for 2 hours, the starting materials were reacted by TLC, the pH was adjusted to 3 with 2N hydrochloric acid, a white solid precipitated, filtered, and vacuum-dried to give 164mg of a white solid product, 91.9% yield in two steps. MS-ESI (M/z) 298.2[ M + H ] +.
Synthesis of compound 9-ethyl-N- (4- (ethylsulfonyl) benzyl) -6-isopropoxy-9H-carbazole-3-amide
A25 mL single vial was charged with 6-isopropoxy-9-ethyl-9H-carbazole-3-carboxylic acid (164mg, 0.55mmol), (4- (ethanesulfonyl) phenyl) methylamine (132mg, 0.66mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (252mg, 0.66mmol), N, N-diisopropylethylamine (210mg, 1.65mmol), dichloromethane (5mL), reacted at room temperature for 2 hours, TLC detection of the completion of the reaction. Dichloromethane (20mL) and saturated ammonium chloride (30mL) were added and washed, the organic layer was spin-dried to give the crude product, which was separated by column chromatography (petroleum ether: ethyl acetate 1:1) to give 200mg of a white solid product, 75.8% yield.1H NMR(400MHz，CDCl3)δ8.58(d,J＝1.8Hz,1H),7.93(dd,J＝8.6,1.8Hz,1H),7.84(d,J＝8.1Hz,2H),7.63(d,J＝2.5Hz,1H),7.57(d,J＝8.0Hz,2H),7.38(d,J＝8.6Hz,1H),7.33(d,J＝8.8Hz,1H),6.92(s,1H),4.80(d,J＝5.3Hz,2H),4.54-4.64(m,1H),4.35(q,J＝7.4Hz,2H),3.09(q,J＝7.4Hz,2H),1.43(t,J＝3.2Hz,3H),1.38(d,J＝5.9Hz,6H),1.4(t,J＝3.3Hz,3H).MS-ESI(m/z):479.4[M+H]+。
Example 35: 6-cyclopentanyloxy 9-ethyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
6-cyclopentyloxy-9-ethyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000451
Step 1: synthesis of 4-cyclopentanyloxy nitrobenzene
A50 mL single-neck flask was charged with p-nitrophenol (3g, 21.6mmol), 1-bromocyclopentane (4.82g, 32.3mmol), potassium carbonate (4.47g, 32.3mmol), and N, N-dimethylformamide (10mL), and the reaction was heated at 120 ℃ for 1 hour to complete the reaction. Ethyl acetate (3 × 20mL), water (5 × 20mL), saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, the solvent was dried by spin-drying under reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 10:1) gave 4.4g of a solid product with a yield of 98.5%.1H NMR(400MHz，CDCl3)δ8.22–8.13(m,2H),6.91(d,J＝9.0Hz,2H),4.85(dd,J＝6.1,2.9Hz,1H),1.97–1.64(m,8H).
Step 2: synthesis of 4-cyclopentanyloxyaniline
A50 mL single-neck flask was charged with 4-cyclopentyloxynitrobenzene (2g, 9.7mmol), stannous dichloride dihydrate (6.5g, 29mmol), concentrated hydrochloric acid (0.5mL), ethanol (15mL), and heated at 60 ℃ for 5 hours to complete the reaction. Ethyl acetate (3 × 20mL), washed with saturated sodium chloride, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was dried by spin-drying under reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 20:1) gave 1.6g of a solid product with a yield of 62.5%.
And step 3: synthesis of methyl 4- ((4-cyclopentyloxyphenyl) amino) benzoate
To a 25mL microwave tube was added 4-isopentyloxyaniline (1.6g, 9mmol), methyl 4-bromobenzoate (2.32g, 10.8mmol), potassium carbonate (1.49g, 10.8mmol), rac-BINAP (280mg, 0.45mmol), palladium acetate (202mg, 0.9mmol), toluene (10mL), heated at microwave 130 ℃ for 1 hour, after the reaction was completed, diluted with ethyl acetate, filtered through celite, the solvent was spin-dried under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate: 20:1-10:1) to give 690mg of a solid product in 24.6% yield.
And 4, step 4: synthesis of 6-cyclopentanyloxy-9H-carbazole-3-methyl formate
Add 4- ((4-Cyclopentyloxyphenyl) Ammonia to 50mL Single-necked flaskMethyl benzoate (690mg, 2.22mmol), palladium acetate (548mg, 2.44mmol), acetic acid (20mL), heating at 120 ℃ for reaction for 3 hours, after the reaction is finished, spinning off the acetic acid under reduced pressure, dissolving in ethyl acetate (10mL), and performing column chromatography (petroleum ether: ethyl acetate 3:1) was isolated as a solid product 330mg, 48.1% yield.1H NMR(400MHz，CDCl3)δ8.76(s,1H),8.21(s,1H),8.10(d,J＝8.5Hz,1H),7.58(d,J＝2.3Hz,1H),7.40(d,J＝8.6Hz,1H),7.34(d,J＝8.6Hz,1H),7.08–7.04(m,1H),4.88(s,1H),3.97(s,3H),2.09–1.83(m,8H).MS-ESI(m/z):310.2[M+H]+
And 5: synthesis of 6-cyclopentanyloxy-9-ethyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with 6-cyclopentanyloxy-9H-carbazole-3-carboxylic acid methyl ester (200mg, 0.65mmol), anhydrous N, N-dimethylformamide (5mL), stirred in an ice bath for 5 minutes, then added with sodium hydride (78mg, 1.95mmol, 60%), reacted at room temperature for 30 minutes, and then dropwise added with ethyl bromide (212mg, 1.95mmol) while cooling, reacted at room temperature for 3 hours, and the starting material was reacted by TLC. The reaction was quenched with water, and then washed with ethyl acetate (3 × 20mL), water (5 × 20mL), saturated sodium chloride, dried over anhydrous sodium sulfate for the organic layer, filtered, the solvent was dried under reduced pressure, and column chromatography was performed (petroleum ether: ethyl acetate ═ 10:1) to obtain 214mg of a solid product with a yield of 98.0%. MS-ESI (M/z) 338.4[ M + H ] +
Step 6: synthesis of 6-cyclopentanyloxy-9-ethyl-9H-carbazole-3-carboxylic acid
6-cyclopentanyloxy-9-ethyl-9H-carbazole-3-carboxylic acid methyl ester (214mg, 0.63mmol), lithium hydroxide (80mg, 1.9mmol), ethanol (5mL), water (1mL) were added to a 25mL single-neck flask, and the reaction was carried out at 90 ℃ for 2 hours, after the reaction of the starting materials was detected by TLC, the pH was adjusted to 3 with 2N hydrochloric acid, a white solid precipitated, and the solid product was obtained by filtration, vacuum drying, 146mg, and a yield of 71.2%. MS-ESI (M/z) 324.3[ M + H ] +.
Synthesis of compound 6-cyclopentanyloxy-9-ethyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-carboxamide
To a 25mL single neck flask was added 6-cyclopentanyloxy-9-ethyl-9H-carbazole-3-carboxylic acid (146mg, 0.45mmol), (4- (ethanesulfonyl) phenyl) methylamine (108mg, 0.54mmol), 2- (7-oxybenzotriazole) -N, N',n' -tetramethyluronium hexafluorophosphate (206mg, 0.54mmol), N, N-diisopropylethylamine (172mg, 1.35mmol), and dichloromethane (5mL) were reacted at room temperature for 2 hours, and the starting material was reacted by TLC. Dichloromethane (20mL) and saturated ammonium chloride (30mL) were added and washed, the organic layer was spin-dried to give the crude product, which was separated by column chromatography (petroleum ether: ethyl acetate 1:1) to give 200mg of a white solid product, 47.1% yield.1H NMR(400MHz，CDCl3)δ8.59(s,1H),7.89(d,J＝23.4Hz,3H),7.59(s,3H),7.36(dd,J＝15.4,8.0Hz,2H),7.13(d,J＝8.4Hz,1H),6.83(s,1H),4.86(s,1H),4.82(s,2H),4.36(s,2H),3.11(s,2H),2.08–1.77(m,8H),1.61(s,3H),1.43(s,3H).MS-ESI(m/z):505.3[M+H]+。
Example 36: 6-dimethylaminomethyl-9-ethyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-carboxamide
6-((dimethylamino)methyl)-9-ethyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000471
Step 1: synthesis of methyl 4- ((4-methylphenyl) amino) benzoate
To a 25mL microwave tube were added 4-methylaniline (500mg, 4.7mmol), methyl 4-bromobenzoate (1.2g, 5.6mmol), potassium carbonate (0.77g, 5.6mmol), rac-BINAP (143mg, 0.23mmol), palladium acetate (105mg, 0.47mmol), toluene (10mL), heated at microwave 130 ℃ for 1 hour, after the reaction was completed, diluted with ethyl acetate, filtered through celite, the solvent was spin-dried under reduced pressure, and column chromatography (petroleum ether: ethyl acetate: 20:1) gave 724mg of a solid product in 64.3% yield.
Step 2: synthesis of 6-methyl-9H-carbazole-3-methyl formate
Methyl 4- ((4-methylphenyl) amino) benzoate (724mg, 3.0mmol), palladium acetate (740mg, 3.3mmol) and acetic acid (20mL) were added to a 50mL single-neck flask, the mixture was heated at 120 ℃ for 2 hours, after the reaction was completed, the acetic acid was dried under reduced pressure and dissolved in ethyl acetate (10mL), and the product was isolated by column chromatography (petroleum ether: ethyl acetate: 10:1) to give 610mg of a yellow solid product in 62.5% yield.
And step 3: synthesis of 6-methyl-9-ethyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with 6-methyl-9H-carbazole-3-carboxylic acid methyl ester (610mg, 2.55mmol) and anhydrous N, N-dimethylformamide (5mL), stirred in ice bath for 5 minutes, then added with NaH (152mg, 3.8mmol, 60%), reacted at room temperature for 30 minutes, and then added dropwise with ethyl bromide (413mg, 3.8mmol) while cooling at ice, reacted at room temperature for 3 hours, after which the starting material was reacted by TLC. The reaction was quenched with water, and then washed with ethyl acetate (3 × 20mL), water (5 × 20mL), saturated sodium chloride, dried over anhydrous sodium sulfate for the organic layer, filtered, the solvent was dried under reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 10:1) gave 330mg of a yellow solid product, in 36.6% yield.
And 4, step 4: synthesis of 6-bromomethyl-9-ethyl-9H-carbazole-3-methyl formate
Adding 6-methyl-9-ethyl-9H-carbazole-3-methyl formate (220mg, 0.37mmol), N-bromosuccinimide (80mg, 0.45mmol), azobisisobutyronitrile (6mg, 0.04mmol), carbon tetrachloride (2mL) into a 25mL single-neck bottle, reacting for 2 hours at 90 ℃ under the protection of nitrogen, detecting that the raw materials have reacted by TLC, and performing rotary drying on the solvent under reduced pressure to obtain a crude product which is directly used for the next reaction.
And 5: synthesis of 6-dimethylaminomethyl-9-ethyl-9H-carbazole-3-methyl formate
A25 mL single vial was charged with 6-bromomethyl-9-ethyl-9H-carbazole-3-carboxylic acid methyl ester (102mg, 0.32mmol), dimethylamine (78mg, 0.39mmol), dichloromethane (150mg, 0.39mmol)) and reacted at room temperature for 2 hours, after which the starting material was reacted by TLC. The solvent is dried by rotary drying under reduced pressure to obtain a crude product which is directly used for the next reaction. MS-ESI (M/z) 311.4[ M + H ] +
Step 6: synthesis of 6-dimethylaminomethyl-9-ethyl-9H-carbazole-3-carboxylic acid
6-dimethylaminomethyl-9-ethyl-9H-carbazole-3-carboxylic acid methyl ester (200mg, 0.65mmol), potassium hydroxide (53mg, 1.26mmol), ethanol (5mL), water (2 drops) were added to a 25mL single-neck flask and reacted at 90 ℃ for 2 hours, after which the starting material was reacted by TLC. The solvent is dried by rotary drying under reduced pressure to obtain a crude product which is directly used for the next reaction. MS-ESI (M/z) 297.4[ M + H ] +
Synthesis of compound 6-dimethylaminomethyl-9-ethyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
A25 mL single-neck flask was charged with 6-dimethylaminomethyl-9-ethyl-9H-carbazole-3-carboxylic acid (100mg, 0.37mmol), 4-ethylsulfonylbenzylamine (89mg, 0.45mmol), HATU (171mg, 0.45mmol), N, N-diisopropylethylamine (143mg, 1.11mmol), dichloromethane (5mL), reacted overnight at room temperature, and TLC detected that the starting material had reacted. Dichloromethane (20mL) and saturated ammonium chloride (30mL) were added and washed, the organic layer was spin dried to give the crude product, which was separated by column chromatography (petroleum ether: ethyl acetate: 1-1:2) to give 140mg of white solid product in 83.8% yield.1H NMR(400MHz，CDCl3)δ8.67(s,1H),8.43(s,1H),8.11(d,J＝8.6Hz,1H),7.87(d,J＝7.7Hz,2H),7.70(d,J＝8.4Hz,1H),7.61(d,J＝7.9Hz,2H),7.48(d,J＝8.2Hz,2H),4.82(s,2H),4.41(d,J＝7.5Hz,2H),4.33(s,2H),3.13–3.08(m,2H),2.78(s,6H),1.47(d,J＝7.1Hz,3H),1.30(d,J＝8.1Hz,3H).
Example 37: 6-cyclohexanyloxy 9-ethyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-amide
6-(cyclohexyloxy)-9-ethyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide
Figure BDA0001714564360000481
Step 1: synthesis of 4-cyclohexanyloxy nitrobenzene
A50 mL single-neck flask was charged with 1-hydroxycyclohexane (1.5g, 14.98mmol), N, N-dimethylformamide (20mL), stirred for 5 minutes in an ice bath, and reacted for 30 minutes at room temperature with sodium hydride (900mg, 22.46mmol, 60%) in an ice bath. P-nitrofluorobenzene (2.59g, 17.97mmol) was added dropwise in an ice bath, and the reaction was completed at room temperature for 3 hours. Ethyl acetate (3 × 20mL), water (5 × 20mL), saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, the solvent was dried under reduced pressure, and column chromatography (petroleum ether: ethyl acetate 40:1) gave 1.8g of a red liquid product, 54.3% yield.
Step 2: synthesis of 4-cyclohexylalkoxyaniline
A25 mL single-neck flask was charged with 4-cyclohexyloxynitrobenzene (570mg, 2.58mmol), palladium on carbon hydrogenation catalyst, concentrated hydrochloric acid (5 drops), and methanol (5mL) and reacted at room temperature for 1 hour. Filtration and spin-drying of the solvent under reduced pressure gave 264.5mg of a brown solid product, 53.7% yield, which was used directly in the next reaction.
And step 3: synthesis of methyl 4- ((4-cyclohexyloxyphenyl) amino) benzoate
To a 25mL microwave tube was added 4-cyclohexylalkoxyaniline (264.5mg, 1.38mmol), methyl 4-bromobenzoate (356.1mg, 1.66mmol), potassium carbonate (571.32mg, 4.14mmol), rac-BINAP (42.96mg, 0.069mmol), palladium acetate (15.49mg, 0.069mmol), toluene (10mL), and the mixture was heated at 130 ℃ under microwave for 1 hour, after the reaction was completed, diluted with ethyl acetate, filtered through celite, the solvent was dried under reduced pressure, and column chromatography (petroleum ether: ethyl acetate 20:1-10:1) gave 254mg of a white solid product in 56.6% yield. MS-ESI (M/z) 326.3[ M + H ] +.
And 4, step 4: synthesis of 6-cyclohexylalkoxy-9H-carbazole-3-methyl formate
Adding methyl 4- ((4-cyclohexyloxyphenyl) amino) benzoate (117mg, 0.36mmol), palladium acetate (89mg, 0.40mmol) and acetic acid (3mL) into a 50mL single-neck bottle, heating at 120 ℃ for reaction for 9 hours, dissolving the reaction product in ethyl acetate (4mL), and separating by column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain 64mg of a solid product with the yield of 54.7 percent. MS-ESI (M/z) 324.2[ M + H ] +.
And 5: synthesis of 6-cyclohexylalkoxy-9-ethyl-9H-carbazole-3-methyl formate
A25 mL single-neck flask was charged with 6-cyclohexylalkoxy-9H-carbazole-3-carboxylic acid methyl ester (62.1mg, 0.19mmol), anhydrous N, N-dimethylformamide (5mL), stirred in ice bath for 5 minutes, then added with sodium hydride (23mg, 0.58mmol, 60%), reacted at room temperature for 30 minutes, and then added dropwise with iodoethane (90mg, 0.58mmol) while cooling on ice, reacted at room temperature for 3 hours, and the starting material was reacted by TLC. The reaction was quenched with water, and then washed with ethyl acetate (3 × 20mL), water (5 × 20mL), saturated sodium chloride, dried over anhydrous sodium sulfate for the organic layer, filtered, the solvent was dried under reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 10:1) was performed to obtain 55mg of a solid product with a yield of 83.4%.
Step 6: synthesis of 6-cyclohexylalkoxy-9-ethyl-9H-carbazole-3-carboxylic acid
6-cyclohexylalkoxy-9-ethyl-9H-carbazole-3-methyl formate (55mg, 0.16mmol), potassium hydroxide (26.88mg, 0.48mmol), ethanol (4mL), water (1mL) are added into a 25mL single-neck flask, the mixture reacts for 2 hours at 90 ℃, TLC detects that the raw materials have reacted completely, 2N hydrochloric acid is used for adjusting the pH to 3, white solid is separated out, the mixture is filtered, and vacuum drying is carried out to obtain 62.1mg of a solid product. MS-ESI (M/z) 338.4[ M + H ] +.
Synthesis of compound 6-cyclohexylalkoxy-9-ethyl-N- (4- (ethylsulfonyl) benzyl) -9H-carbazole-3-formamide
A25 mL single vial was charged with 6-cyclohexyloxy-9-ethyl-9H-carbazole-3-carboxylic acid (55mg, 0.16mmol), (4- (ethylsulfonyl) phenyl) methylamine (39mg, 0.20mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (74mg, 0.20mmol), N, N-diisopropylethylamine (23mg, 0.20mmol), dichloromethane (3mL), reacted at room temperature for 2 hours, TLC detected that the starting material had reacted. Dichloromethane (20mL) and saturated ammonium chloride (10mL) were added and washed, the organic layer was spin-dried to give a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate 1:1) to give 26mg of a white solid product, yield 31.3%, MS-ESI (m/z): 519. 2[ M + H]+.1H NMR(400MHz,CDCl3)δ8.61(s,1H),7.94(d,J＝8.5Hz,1H),7.74(d,J＝7.8Hz,2H),7.64(s,1H),7.49(d,J＝7.8Hz,2H),7.33(d,J＝9.9Hz,1H),7.30(d,J＝9.9Hz,1H),7.25(brs,1H),7.14(d,J＝8.5Hz,1H),4.75(d,J＝5.5Hz,2H),4.31(q,J＝7.2Hz,2H),4.31-4.22(m,1H),3.06(q,J＝7.2Hz,2H),2.02(s,2H),1.80(s,2H),1.62–1.52(m,3H),1.41(d,J＝7.0Hz,2H),1.38(d,J＝7.0Hz,2H),1.35(d,J＝7.3Hz,2H),1.23(t,J＝7.4Hz,3H).
Example 38: in vitro assay of compounds for inhibitory activity on ROR γ receptor (FRET method):
the inhibitory activity of a compound on ROR gamma protein receptors was determined using Fluorescence Resonance Energy Transfer (FRET) assay on a portion of the compounds of the invention. The inhibitory activity employs half inhibition rate (IC)50) This index is used to express.
The experimental method comprises the following steps:
preparation of ROR gamma basic buffer solution
100mL of base buffer was prepared, 10mL of LDTT was added, and the mixture was mixed well for use.
2. Preparation of Compound solutions
The compounds were diluted 3-fold for 10 concentrations at 7.5mM each.
3 preparation of protein solution mixture
a. A solution of 40nM B-ROR γ LBD and 20nM SA-APC was prepared, mixed well, incubated at room temperature for 15 minutes, then added 400nM biotin, mixed well, and incubated at room temperature for 10 minutes.
b. A40 nM solution of Bioin-SRC1 and 10nM solution of SA-eu were prepared, mixed well, incubated for 15 minutes at room temperature, then 200nM biotin was added, mixed well, and incubated for 10 minutes at room temperature.
c. Mixing the two mixed solutions 1:1 and incubated at room temperature for 5 minutes.
d. Add 0.1. mu.M surrogate agonist N- (2-chloro-6-fluorophenyl) -N- ((20-methoxy- [1, 10-biphenyl) to 384-well plates per well]-4-substituted) methyl) benzenesulfonamide, 25 μ LB-ROR γ LBD/SA-APC and Bioin-SRC1/SA-eu mixture and test compound, centrifuged at 1000rpm for 1 min and incubated at room temperature for 1 h. Reading data on an Envision microplate detector, and calculating IC50The value is obtained. The measurement results are shown in the table I.
Table one example compound ROR γ inhibitory Activity assay results
Figure BDA0001714564360000501
·IC50The value is the average of at least two independent tests
+ + + denotes IC50Less than or equal to 500 nM; + means 500nM<IC50Less than or equal to 5000 nM; + denotes IC50In the range of 5000nM<IC50≤50000nM。
The experimental results are as follows: most of the compounds of the invention have good inhibitory activity on ROR gamma protein receptors.
Example 39:in vitro determination of agonistic activity of compounds at the ROR gamma receptor (Dual FRET method)
The partial compound of the invention adopts fluorescence resonance energy transferA dual FRET assay to determine the agonistic activity of a compound at the ROR γ protein receptor. The agonistic activity employs half the activation rate (EC)50) And the maximum activation (%) index.
The experimental method comprises the following steps:
preparation of ROR gamma basic buffer solution
100mL of base buffer was prepared, 10mL of DTT was added, and mixed well for use.
2. Preparation of Compound solutions
The compounds were diluted 3-fold for 10 concentrations at 7.5mM each.
3. Preparation of protein solution mixture
a. A solution of 40nM B-ROR γ LBD and 20nM SA-APC was prepared, mixed well, incubated at room temperature for 15 minutes, then added 400nM biotin, mixed well, and incubated at room temperature for 10 minutes.
b. A40 nM solution of Bioin-SRC1 and 10nM solution of SA-eu were prepared, mixed well, incubated for 15 minutes at room temperature, then 200nM biotin was added, mixed well, and incubated for 10 minutes at room temperature.
c. Mixing the two mixed solutions 1:1 and incubated at room temperature for 5 minutes.
d. 25 μ L B-ROR γ LBD/SA-APC and Bioin-SRC1/SA-eu mixture and test compound were added to each well of 384-well plates, centrifuged at 1000rpm for 1 minute, and incubated at room temperature for 1 hour. Reading data on an Envision microplate detector, and calculating EC50Value and maximum activation (%). The measurement results are shown in Table II.
TABLE II example compounds ROR gamma agonist Activity assay
Figure BDA0001714564360000511
+ + represents EC50<10 nM; + means 10nM < EC50<100 nM; + represents 100 nM. ltoreq.EC50<5000 nM. + + + + indicates a maximum activation (%) > 100; the + represents that the maximum activation rate (%) < 100
The experimental results are as follows: the compound tested by the invention has better activation capability on ROR gamma protein receptor.
Example 40: in vitro assay compounds for IL-17 inhibition of EL4 cells:
the experimental method comprises the following steps: culturing mouse lymphoma EL4 cells transfected with ROR gamma t plasmid at 37 deg.C under 5% carbon dioxide, adding compound, and analyzing IL-17 alpha generation efficiency after 24 hr; adding 50ng/mL PMA and 500ng/mL ionomycin to stimulate for 4 hours before collecting cells, and detecting the proportion of IL-17 by using methods of intracellular staining and flow cytometry; analyzing Cell survival rate by Live/Dead Cell Dye (Invitrogen) staining method, determining whether drug is toxic to cells, determining inhibition rate of compound on IL-17 production of EL4 cells at different concentrations, and calculating IC50The value is obtained. The measurement results are shown in Table III. .
Epitrial EL4 cellular IL-17 inhibition assay
Figure BDA0001714564360000521
+ + + denotes 1. mu.M.ltoreq.IC50<2 mu M; + represents 2. mu.M.ltoreq.IC50<3 mu M; + denotes IC50≥3μM。
The experimental results: the partial compound of the invention has better capability of inhibiting IL-17 production of EL4 cells.
Example 41:experiment for determining single concentration point inhibition rate of mouse Th17 cell differentiation
The experimental method comprises the following steps: isolation of mouse spleen CD4+T cells and differentiated the cells to Th 17. CD4+T cells were cultured in an environment of anti-CD3 (0.25. mu.g/mL), anti-CD28 (1. mu.g/mL), anti-IL4 (2. mu.g/mL), anti-IFN-. gamma. (2. mu.g/mL), TGF-. beta. (5ng/mL), IL6(20ng/mL) while adding a compound at a concentration of 0.3. mu.M, and analyzed for Th17 differentiation efficiency after 96 hours. Cells were harvested by adding 50ng/mL PMA and 500ng/mL ionomycin for 4 hours and the IL-17 ratio was measured by intracellular staining and flow cytometry. Meanwhile, the survival rate of cells is analyzed by a Live/Dead Cell Dye (Invitrogen) staining method, whether the drug is toxic to the cells is judged, and the inhibition of the IL-17 generation capacity of Th17 cells by the compound is measured at the concentration of 0.3 mu MAnd (5) preparing the rate. The test results show that the compound of the invention has better capability of inhibiting the differentiation of Th17 cells and the generation of IL-17 (shown in the fourth table).
TABLE IV experiment result of single concentration point inhibition rate determination of mouse Th17 cell differentiation
Figure BDA0001714564360000522
++ represents an inhibition > 40%; + represents an inhibition of between 20% and 40%; + means an inhibition of < 20%.
The experimental results are as follows: the partial compound of the invention has better capability of inhibiting IL-17 production of Th17 cells.
Example 42:mouse liver microsome metabolic stability experiment
The incubation system comprises microsome, cofactor and PBS, the reaction is started by pre-incubation for 3min at 37 ℃, and the substrate is added. Samples were taken at 0, 1, 5, 10, 15, 20, 30, 60min from the start of the reaction and appropriate stoppers were added to stop the reaction. Sample treatment (n ═ 3): adding appropriate internal standards, vortexing, centrifuging at high speed, taking supernatant, and detecting a substrate by adopting HPLC-MS/MS. The peak area at the time point of 0min was taken as 100%. The peak areas at other time points were converted to percent residual, the natural logarithm of the percent residual at each time point was plotted against incubation time, the slope (-k) was calculated by linear regression, and the intrinsic Clearance (CL) was followedint) CL was calculated as (k × volume of incubation solution)/mass of liver microsomesint(mL·min-1·mg-1) And compound half-life (T)1/2Min). The results are shown in Table five.
TABLE V results of the mouse liver microsome metabolic stability experiment
Figure BDA0001714564360000531

Claims (6)

1. Carbazole amide derivatives represented by general formula (I-A) or pharmaceutically acceptable salts thereof,
Figure FDA0003504635710000011
wherein:
a represents a phenyl or pyridine ring;
b represents a phenyl or pyridine ring;
R1optionally selected from hydrogen, halogen, cyano, C1-C6Alkyl, halogen substituted C1-C6Alkyl radical, C3-C6Cycloalkyl-substituted C1-C6Alkyl radical, C3-C6Cycloalkyl, C1-C6Alkoxy, halogen substituted C1-C6An alkoxy group;
R3selected from hydrogen, C1-C6Alkyl, halogen substituted C1-C6Alkyl radical, C3-C6Cycloalkyl-substituted C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Oxygen or azacycloalkyl, phenyl substituted C1-C3An alkyl group;
R5selected from hydrogen;
R7selected from hydrogen;
R8is selected from C1-C6Alkyl, -NHCH3、-NH2、-NHC(O)CH3；
Z is selected from O;
m is 1;
t is 0.
2. The carbazole amide-based derivative according to claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:
Figure FDA0003504635710000012
Figure FDA0003504635710000021
。
3. a pharmaceutical composition as ROR γ t receptor modulator comprising a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, as active ingredient, in association with one or more pharmaceutically acceptable carriers.
4. Use of a compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a ROR γ t receptor modulator.
5. Use of a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease associated with the roryt receptor.
6. Use according to claim 5, characterized in that: the disease is selected from multiple sclerosis, rheumatoid arthritis, collagen-induced arthritis, psoriasis, inflammatory bowel disease and encephalomyelitis.
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