Compounds with ALK inhibitory activity, and their production methods and uses

Abstract

The present application relates to the technical field of medicinal chemistry, specifically to a compound having ALK inhibitory activity and a production method and use thereof. [Solution] The compound with ALK inhibitory activity provided in the present application is an ALK inhibitor for treating diseases that respond to inhibition of ALK kinase, and can be used to treat ALK-positive related diseases, such as tumors and cancers, and has broad application prospects.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from a Chinese patent application filed on May 12, 2021, with application number 202110515421.8, entitled "Compounds with ALK inhibitory activity and their preparation methods and uses," the entire contents of which are incorporated herein by reference. [Technical Field]

[0002] The present application relates to the field of medicinal chemistry, and more particularly to compounds having ALK inhibitory activity, as well as methods for producing and uses thereof. [Background technology]

[0003] Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that belongs to the insulin receptor superfamily and shares high homology with leukocyte tyrosine kinases. ALK was first discovered in 1994 in the form of the NPM1-ALK fusion gene in anaplastic large-cell lymphoma (ALCL). The ALK gene, located on human chromosome 2p23, encodes a 1620-amino acid polypeptide, which undergoes post-translational modification to generate the mature ALK protein of 200–220 kDa. ALK consists of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain consisting of 1030 amino acids. ALK is highly conserved across species, and ALK, expressed in the adult brain, is thought to play an important role in nervous system development and function. ALK is also expressed in the small intestine, testis, prostate, and colon, but is not expressed in normal lymphoid tissues, lungs, or other tissues.

[0004] ALK can activate multiple intracellular signaling pathways, including phospholipase Cγ, JAK kinase, signal transducer and activator of transcription-3 (STAT3), phosphatidylinositol 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK), which are involved in regulating cell growth, transformation, and anti-apoptotic cell death. ALK gene recombination, mutation, or amplification has been observed in multiple tumor types. To date, 21 different genes have been identified as translocated with ALK. Different ALK fusion proteins may activate different signaling pathways, resulting in different proliferation rates, invasiveness, and tumorigenic potential of cancer cells.

[0005] Traditionally, ALK fusion protein, ALK gene overexpression, and ALK gene mutation have been identified in a large number of human diseases, including tumors and cancers, such as melanoma, neuroblastoma, glioblastoma, rhabdomyosarcoma, astrocytoma, Ewing's sarcoma, retinoblastoma, anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumor (IMT), diffuse large B-cell lymphoma (DLBCL), non-small cell lung cancer (NSCLC), renal medullary carcinoma (RMC), renal cell carcinoma (RCC), breast cancer, colon cancer, ovarian serous carcinoma (SOC), and esophageal squamous cell carcinoma (ESCC).

[0006] Due to the association of ALK with tumors and cancers, there is an increasing demand for ALK inhibitors to treat diseases that respond to inhibition of ALK kinase. In light of this, the present application provides compounds having ALK inhibitory activity, as well as methods for producing and using the same. Summary of the Invention [Problem to be solved by the invention]

[0007] Based on common knowledge in the art, the various preferred conditions described above can be arbitrarily combined without departing from the spirit and scope of protection of the present application. [Means for solving the problem]

[0008] To solve the above problems, the present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. TIFF0007752700000001.tif48170 (wherein R1 is selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a C3-C6 cycloalkane group, a substituted or unsubstituted aryl group or heterocyclic aryl group, and a halogen atom; R2 is selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a cyano group, and a halogen atom, and the substituent of the C1-C4 alkyl group is selected from a C3-C6 cycloalkane group, a halogen atom, and a cyano group; R3 is selected from a heterocyclic aryl group, an aryl group, and a substituted or unsubstituted 5- to 7-membered heterocycle, wherein the 5- to 7-membered heterocycle contains 1 to 3 heteroatoms each independently selected from N, P, O, and S; In the present application, the heterocyclic aryl group includes, but is not limited to, a pyridyl group, a pyrazidinyl group, an indolyl group, an azaindolyl group, an indazolyl group, a benzoimidazolyl group, a benzofuryl group, a thienyl group, a furyl group, an imidazolyl group, a benzothienyl group, a benzisoxazolyl group, a benzoxazolyl group, a benzopyrazolyl group, a benzothiazolyl group, a benzothiadiazoyl group, a benzotriazolyl group, an adenyl group, an isoxazolyl group, an oxazolyl group, a pyrazolyl group, a pyrrolyl group, a thiazolyl group, a thiadiazoyl group, a triazolyl group, a pyrimidinyl group, and a pyrazinyl group. R4 and R5 are each independently selected from hydrogen, a substituted or unsubstituted saturated C1-C4 alkyl group, and a substituted or unsubstituted unsaturated C1-C4 alkyl group.

[0009] In one preferred embodiment, the compound or a pharmaceutically acceptable salt thereof is R1 is selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, and a C3-C6 cycloalkane group; R2 is selected from hydrogen, an unsubstituted C1-C4 alkyl group, a cyano group, and a halogen atom; R3 is selected from a substituted or unsubstituted 5- to 7-membered heterocycle, wherein the 5- to 7-membered heterocycle contains 1 to 3 heteroatoms each independently selected from N, P, O, and S; R4 and R5 are each independently selected from hydrogen and an unsubstituted saturated C1-C4 alkyl group.

[0010] In one preferred embodiment, the compound or a pharmaceutically acceptable salt thereof is R1 is hydrogen, a methyl group, an ethyl group, a propyl group, Selected from TIFF0007752700000002.tif12170, R2 is selected from the group consisting of methyl, ethyl, propyl, cyano, Cl, Br, and F; R3 is selected from a substituted or unsubstituted six-membered heterocycle, wherein the six-membered heterocycle contains 1 to 3 N heteroatoms; R4 and R5 are each independently selected from hydrogen, a methyl group, an ethyl group, and a propyl group.

[0011] In one preferred embodiment, the compound or a pharmaceutically acceptable salt thereof is R1 is hydrogen, a methyl group, Selected from TIFF0007752700000003.tif11170, R2 is selected from the group consisting of methyl, ethyl, cyano, Cl, Br, and F; R3 is TIFF0007752700000004.tif13170, wherein R6, R7, and R8 are each independently selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkane group, a substituted or unsubstituted 4- to 7-membered heterocycle, a cyano group, a halogen atom, and a nitrogen-containing alkyl group, and the 4- to 7-membered heterocycle each independently contains 1 to 3 heteroatoms selected from N, P, O, and S; R4 and R5 are each independently selected from methyl groups.

[0012] In one preferred embodiment, in the compound or a pharmaceutically acceptable salt thereof, R6, R7, and R8 each independently represent hydrogen, a methyl group, an ethyl group, a cyano group, a dimethylamino group, a diethylamino group, Selected from TIFF0007752700000005.tif16170.

[0013] In one preferred embodiment, the compound or a pharmaceutically acceptable salt thereof is R1 is hydrogen, Selected from TIFF0007752700000006.tif11170, R2 is selected from an ethyl group, a cyano group, and Cl; R3 is Selected from TIFF0007752700000007.tif72170.

[0014] In one preferred embodiment, the compound or a pharmaceutically acceptable salt thereof, the compound represented by formula (I), is Selected from TIFF0007752700000008.tif236170TIFF0007752700000009.tif239170TIFF0007752700000010.tif77170.

[0015] According to a second aspect of the present application, there is provided a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0016] According to a third aspect of the present application, there is provided a use of the pharmaceutical composition in the manufacture of a medicament for inhibiting ALK activity.

[0017] According to a fourth aspect of the present application, there is provided a use of said pharmaceutical composition for the treatment of ALK-positive related tumors and cancers.

[0018] According to a fifth aspect of the present application, there is provided a method for producing the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, which comprises at least a step of adding a carbonate to a methanol solution of the compound represented by formula (II) and reacting the compound with stirring, The compound represented by the formula (II) is as follows: TIFF0007752700000011.tif39170 (wherein R'2 is selected from an ethyl group, a cyano group, Cl, Br, and F; R'3 is TIFF0007752700000012.tif13170, wherein R6, R7, and R8 are each independently selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkane group, a substituted or unsubstituted 4- to 7-membered heterocycle, a cyano group, a halogen atom, and a nitrogen-containing alkyl group, and the 4- to 7-membered heterocycle each independently contains 1 to 3 heteroatoms selected from N, P, O, and S; R4 and R'4 represent the same group; R5 and R'5 represent the same group.

[0019] According to a sixth aspect of the present application, there is provided a method for producing the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, comprising at least the steps of adding a compound represented by formula (III) and a carbonate salt to acetonitrile and methanol, and reacting the compound with stirring, The compound represented by formula (III) is as follows: TIFF0007752700000013.tif39170R''3 is Selected from TIFF0007752700000014.tif19170, R and R represent the same group; R5 and R''5 represent the same group.

[0020] According to a seventh aspect of the present application, there is provided a method for producing the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, comprising at least a step of adding tetrabutylammonium fluoride to a tetrahydrofuran solution of the compound represented by formula (IV) and reacting the compound with stirring, The compound represented by formula (IV) is as follows: TIFF0007752700000015.tif39170 The above R'''3 is Selected from TIFF0007752700000016.tif24170.

[0021] According to an eighth aspect of the present application, there is provided a method for producing the compound represented by formula (V) or a pharmaceutically acceptable salt thereof, the method comprising at least the steps of adding potassium phosphate, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, and tris(dibenzylideneacetone)dipalladium to an acetonitrile solution of the compound represented by formula (V) and an alkyl alkyne, and reacting the compound with stirring under an inert gas atmosphere; The compound represented by formula (V) is as follows: TIFF0007752700000017.tif48170 The alkyl alkyne is selected from the group consisting of ethynylcyclopropane, propynyl, ethynylcyclobutane, and butyne. [Effects of the Invention]

[0022] The compounds having ALK inhibitory activity and the methods for producing and using the same provided in the present application have the following beneficial effects: (1) The series of compounds provided in the present application exhibit significantly superior ALK kinase inhibitory activity and ALK gene fusion cell proliferation inhibitory activity compared to the reference compounds. (2) The ALK inhibitor provided in the present application can be used to treat ALK-positive related diseases, such as ALK-mutated anaplastic large cell lymphoma, diffuse large B-cell lymphoma, inflammatory myofibroblastic tumor, renal cell carcinoma, breast cancer, colon cancer, thyroid cancer, glioblastoma, non-small cell lung cancer, especially brain metastatic non-small cell lung cancer, and recurrent ALK-positive non-small cell lung cancer, thereby overcoming drug resistance to commercially available drugs and having broad application prospects. (3) The manufacturing method provided in the present application does not require any special reaction, is easy to operate and control in both the laboratory and industrial stages, and is clean, ecological, and safe. DETAILED DESCRIPTION OF THE INVENTION

[0023] For purposes of the following detailed description, it should be understood that the present specification may employ various alternative variations and process sequences unless otherwise indicated. Furthermore, unless otherwise indicated in any operating examples or where otherwise indicated, all numbers expressing quantities of ingredients used in the specification and claims, for example, should be understood to be modified in all instances by the term "about." Accordingly, unless expressly indicated otherwise, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending on the desired performance obtained herein. At the very least, no attempt is made to limit the application of this principle to the scope of the claims, and each numerical parameter should be construed by applying ordinary rounding techniques in light of, at least, the number of reported significant digits.

[0024] According to a first aspect of the present application, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt thereof: TIFF0007752700000018.tif48170 (wherein R1 is selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a C3-C6 cycloalkane group, a substituted or unsubstituted aryl group or heterocyclic aryl group, and a halogen atom; R2 is selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a cyano group, and a halogen atom, and the substituent of the C1-C4 alkyl group is selected from a C3-C6 cycloalkane group, a halogen atom, and a cyano group; R3 is selected from a heterocyclic aryl group, an aryl group, and a substituted or unsubstituted 5- to 7-membered heterocycle, wherein the 5- to 7-membered heterocycle contains 1 to 3 heteroatoms each independently selected from N, P, O, and S, and the heterocyclic aryl group is selected from a pyridyl group, a pyrazidinyl group, an indolyl group, an azaindolyl group, an indazolyl group, a benzoimidazolyl group, a benzofuryl group, a thienyl group, a furyl group, an imidazolyl group, a benzothienyl group, a benzisoxazolyl group, a benzoxazolyl group, a benzopyrazolyl group, a benzothiazolyl group, a benzothiadiazoyl group, a benzotriazolyl group, an adenine group, an isoxazolyl group, an oxazolyl group, a pyrazolyl group, a pyrrolyl group, a thiazolyl group, a thiadiazoyl group, a triazolyl group, a pyrimidinyl group, and a pyrazinyl group; R4 and R5 are each independently selected from hydrogen, a substituted or unsubstituted saturated C1-C4 alkyl group, and a substituted or unsubstituted unsaturated C1-C4 alkyl group.

[0025] In some preferred embodiments, the compound or a pharmaceutically acceptable salt thereof is R1 is selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, and a C3-C6 cycloalkane group; R2 is selected from hydrogen, an unsubstituted C1-C4 alkyl group, a cyano group, and a halogen atom; R3 is selected from a substituted or unsubstituted 5- to 7-membered heterocycle, wherein the 5- to 7-membered heterocycle contains 1 to 3 heteroatoms each independently selected from N, P, O, and S; R4 and R5 are each independently selected from hydrogen and an unsubstituted saturated C1-C4 alkyl group.

[0026] In some preferred embodiments, the compound or a pharmaceutically acceptable salt thereof is R1 is hydrogen, a methyl group, an ethyl group, a propyl group, Selected from TIFF0007752700000019.tif12170, R2 is selected from the group consisting of methyl, ethyl, propyl, cyano, Cl, Br, and F; R3 is selected from a substituted or unsubstituted six-membered heterocycle, wherein the six-membered heterocycle contains 1 to 3 N heteroatoms; R4 and R5 are each independently selected from hydrogen, a methyl group, an ethyl group, and a propyl group.

[0027] In some preferred embodiments, the compound or a pharmaceutically acceptable salt thereof is R1 is hydrogen, a methyl group, Selected from TIFF0007752700000020.tif20170, R2 is selected from the group consisting of methyl, ethyl, cyano, Cl, Br, and F; R3 is TIFF0007752700000021.tif13170, wherein R6, R7, and R8 are each independently selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkane group, a substituted or unsubstituted 4- to 7-membered heterocycle, a cyano group, a halogen atom, and a nitrogen-containing alkyl group, and the 4- to 7-membered heterocycle contains 1 to 3 heteroatoms independently selected from N, P, O, and S; R4 and R5 are each independently selected from methyl groups.

[0028] In some preferred embodiments, the compound or a pharmaceutically acceptable salt thereof is R6, R7, and R8 each independently represent a hydrogen atom, a methyl group, an ethyl group, a cyano group, a dimethylamino group, a diethylamino group, Selected from TIFF0007752700000022.tif16170.

[0029] In some preferred embodiments, the compound or a pharmaceutically acceptable salt thereof is R1 is hydrogen, Selected from TIFF0007752700000023.tif20170, R2 is selected from an ethyl group, a cyano group, and Cl; R3 is Selected from TIFF0007752700000024.tif72170.

[0030] In some preferred embodiments, the compound or a pharmaceutically acceptable salt thereof, which is represented by formula (I), is Selected from TIFF0007752700000025.tif237170TIFF0007752700000026.tif239170TIFF0007752700000027.tif78170.

[0031] According to a second aspect of the present application, there is provided a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0032] According to a third aspect of the present application, there is provided a use of the pharmaceutical composition in the manufacture of a medicament for inhibiting ALK activity.

[0033] According to a fourth aspect of the present application, there is provided a use of said pharmaceutical composition for treating ALK-positive related tumors and cancers.

[0034] In the present application, a pharmaceutical composition prepared using a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient can be used to treat ALK-positive related tumors and cancers, including, but not limited to, melanoma, neuroblastoma, glioblastoma, rhabdomyosarcoma, astrocytoma, Ewing's sarcoma, retinoblastoma, anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumor (IMT), diffuse large B-cell lymphoma (DLBCL), non-small cell lung cancer (NSCLC), renal medullary carcinoma (RMC), renal cell carcinoma (RCC), breast cancer, colon cancer, ovarian serous carcinoma (SOC), and esophageal squamous cell carcinoma (ESCC).

[0035] The compounds provided herein exist in the form of pharmaceutically acceptable salts, and in pharmaceutical applications, the salts of the compounds provided herein refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid / anion salts or base / cation salts. Pharmaceutically acceptable acid / anion salts generally exist in the form of a basic nitrogen protonated with an inorganic or organic acid.

[0036] Typical organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, isethionic, besylic, oxalic, pamoic, 2-naphthalenesulfonic, paratoluenesulfonic, cyclohexylsulfamic, salicylic, saccharinic, or trifluoroacetic acid. Pharmaceutically acceptable base / cation salts include, but are not limited to, aluminum, calcium, procaine hydrochloride, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc salts.

[0037] According to a fifth aspect of the present application, there is provided a method for producing a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the method comprising at least a step of adding a carbonate to a methanol solution of the compound represented by formula (II) and reacting the compound with stirring, wherein the compound represented by formula (II) is as follows: TIFF0007752700000028.tif39170 (wherein R'2 is selected from an ethyl group, a cyano group, Cl, Br, and F; R'3 is TIFF0007752700000029.tif13170, wherein R6, R7, and R8 are each independently selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkane group, a substituted or unsubstituted 4- to 7-membered heterocycle, a cyano group, a halogen atom, and a nitrogen-containing alkyl group, and the 4- to 7-membered heterocycle each independently contains 1 to 3 heteroatoms selected from N, P, O, and S; R4 and R'4 represent the same group; R5 and R'5 represent the same group.

[0038] According to a sixth aspect of the present application, there is provided a method for producing the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, the method comprising at least the steps of adding a compound represented by formula (III) and a carbonate salt to acetonitrile and methanol, and reacting the compound with stirring, The compound represented by formula (III) is as follows: TIFF0007752700000030.tif39170R''3 is Selected from TIFF0007752700000031.tif19170, R and R represent the same group; R5 and R''5 represent the same group.

[0039] According to a seventh aspect of the present application, there is provided a method for producing the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising at least the steps of adding tetrabutylammonium fluoride to a tetrahydrofuran solution of the compound represented by formula (IV) and reacting the compound with stirring, The compound represented by formula (IV) is as follows: TIFF0007752700000032.tif48170 The above R'''3 is Selected from TIFF0007752700000033.tif24170.

[0040] According to an eighth aspect of the present application, there is provided a method for producing the compound represented by formula (V) or a pharmaceutically acceptable salt thereof, the method comprising at least the steps of adding potassium phosphate, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, and tris(dibenzylideneacetone)dipalladium to an acetonitrile solution of the compound represented by formula (V) and an alkyl alkyne, and reacting the compound with stirring under an inert gas atmosphere; The compound represented by formula (V) is as follows: TIFF0007752700000034.tif56170 The alkyl alkyne is selected from the group consisting of ethynylcyclopropane, propynyl, ethynylcyclobutane, and butyne.

[0041] The technical aspects of the present application will be described in detail below with reference to the following examples, but the present application is not limited to the scope of the described examples. In the following examples, experimental methods without specific conditions are selected according to conventional methods and conditions or product instructions. All reagents and raw materials used in the present application are commercially available products.

[0042] Example 1: 9-Ethyl-3-ethynyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (E1) TIFF0007752700000035.tif129170

[0043] tert-Butyl 4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate TIFF0007752700000036.tif16170 To a solution of 3-(t-butoxy)-3-oxopropanoic acid (20.0 g, 124.8 mmol) in N,N-dimethylacetamide (100 mL) were added triethylamine (52.6 mL, 378.4 mmol) and magnesium chloride (8.24 g, 86.6 mmol). The reaction was allowed to proceed with stirring at room temperature for 2 hours. Carbonyldiimidazole (14.7 g, 90.6 mmol) was added to a solution of 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid (25.0 g, 78.6 mmol) in dichloroethane (100 mL) and the mixture was stirred at room temperature for 1 hour. The resulting solution was added dropwise to the above solution, heated to 70 °C, and stirred for 5 hours. Complete reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate (500 mL) and water (500 mL), and the organic phase was separated. It was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ester:ethyl acetate = 40:1) to obtain a colorless oily substance, tert-butyl 4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate (28.7 g, 87.8% yield). MS (ESI) m / z: 415.1 (MH)-;

[0044] tert-Butyl 4-(4-ethyl-3-(4-morpholinopiperidin-1-yl)phenyl)-4-methyl-3-oxopentanoate TIFF0007752700000037.tif28170 To a solution of tert-butyl 4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate (20.0 g, 48.0 mmol) and 4-(piperidinebutan-4-yl)morpholinyl (12.3 g, 72.2 mmol) in dichloroethane (400 mL) was added 1,3-bis-(2,6-diisopropylphenyl)-oxadiazolyl-2-alkylene(allyl)palladium chloride (2.0 g, 3.50 mmol) and sodium bis(trimethylsilyl)amide (144 mL, 288 mmol). The mixture was heated to 60 °C and stirred for 3 h. The reaction was complete as determined by thin-layer chromatography. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate (2 × 200 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ester:ethyl acetate = 1:2) to give a light brown oily substance, tert-butyl 4-(4-ethyl-3-(4-morpholinopiperidin-1-yl)phenyl)-4-methyl-3-oxopentanoate (14.8 g, 67.4% yield). MS (ESI) m / z: 459.3 (M+H). + ;

[0045] 2-(2-(2-(4-ethyl-3-(4-morpholinopiperidin-1-yl)phenyl)propan-2-yl)-6-iodo-1H-indole-3-carboxylate t-butyl ester TIFF0007752700000038.tif30170 To a solution of tert-butyl 4-(4-ethyl-3-(4-morpholinopiperidin-1-yl)phenyl)-4-methyl-3-oxopentanoate (10.0 g, 21.8 mmol) and 1-fluoro-4-iodo-2-nitrobenzene (7.3 g, 27.3 mmol) in DMF (200 mL) was added cesium carbonate (21.3 g, 65.4 mmol). The reaction was heated to 35 °C and stirred for 8 hours. The reaction was monitored for completeness by LCMS. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration gave the intermediate. The intermediate was dissolved in tetrahydrofuran (60 mL) and water (30 mL), and sodium sulfite (20.0 g, 109 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with water (300 mL) and filtered. The resulting residue was dissolved in a mixture of dichloromethane and methanol (v / v = 10 / 1, 100 mL). p-Toluenesulfonic acid (3.7 g, 21.8 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was monitored for completeness by LCMS. The reaction mixture was concentrated, diluted with water (200 mL), and extracted with ethyl acetate (2 × 300 mL). The combined organic phases were washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the resulting crude product was purified by silica gel column chromatography (petroleum ester:ethyl acetate=1:1) to give a white solid: tert-butyl 2-(2-(2-(4-ethyl-3-(4-morpholinopiperidin-1-yl)phenyl)propan-2-yl)-6-iodo-1H-indole-3-carboxylate (10.7 g, 70.1% yield). MS (ESI) m / z: 658.4 (M+H). + ;

[0046] Sodium 2-(2-(2-(4-ethyl-3-(4-morpholinopiperidin-1-yl)phenyl)propan-2-yl)-6-iodo-1H-indole-3-carboxylate TIFF0007752700000039.tif301700°C To a solution of t-butyl 2-(2-(2-(4-ethyl-3-(4-morpholinopiperidin-1-yl)phenyl)propan-2-yl)-6-iodo-1H-indole-3-carboxylate (16.0 g, 24.3 mmol) in trifluoroethyl alcohol (120 mL) was added chlorotrimethylsilane (9.23 mL, 73.0 mmol) at 700°C. The reaction was stirred at 0°C for 2 hours. LCMS showed 70% conversion of the desired compound. The reaction was quenched with saturated aqueous sodium carbonate (100 mL). 2×200 The mixture was extracted with 1 mL of 2-(2-(2-(4-ethyl-3-(4-morpholinopiperidin-1-yl)phenyl)propan-2-yl)-6-iodo-1H-indole-3-carboxylate). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give crude sodium 2-(2-(2-(4-ethyl-3-(4-morpholinopiperidin-1-yl)phenyl)propan-2-yl)-6-iodo-1H-indole-3-carboxylate) (15.4 g) as a pale yellow solid. MS (ESI) m / z: 602.2 (M+H). + ;

[0047] 9-Ethyl-3-iodo-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000040.tif33170To a solution of sodium 2-(2-(2-(4-ethyl-3-(4-morpholinopiperidin-1-yl)phenyl)propan-2-yl)-6-iodo-1H-indole-3-carboxylate (15.4 g, 24.7 mmol) in N,N-dimethylacetamide (240 mL) were added diisopropylethylamine (32 mL, 193.1 mmol) and acetic anhydride (7.2 mL, 76.4 mmol). The mixture was heated to 90°C and stirred for 1 hour. The reaction was monitored for completeness by LCMS. The reaction mixture was diluted with water (200 mL). The mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic phase was diluted with water (300 mL) and saturated brine (300 mL). The residue was washed with 1 mL of ethyl acetate and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give a light brown solid, 9-ethyl-3-iodo-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (6.7 g, two-step yield 47.5%). 1H NMR (400 MHz, CDCl3): δ 12.23 (s, 1H), 8.02 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.83(s, 1H), 7. 52 (d, J= 8.4 Hz, 1H), 7.32 (s, 1H), 3.60 (m, 4H), 3.21~3.19 (m, 2H), 2.78~2.67 (m, 4H), 2.55~2.45 (m, 4H), 2.31~2.29 (m, 1H), 1.92~1.89 (m, 2H), 1.72 (s, 6H), 1.63~1.58 (m, 2H), 1.27 (t, 3H).

[0048] 9-Ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 9-ethyl-3-iodo-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (98 mg, 0.17 mmol) and ethynyltrimethylsilane (1.67 g, 17.0 mmol) in DMF (10 mL) was added copper iodide (32 mg, 0.17 mmol), diisopropylethylamine (44 mg, 0.37 mmol), and tetrakistriphenylphosphinepalladium (9 mg). The mixture was stirred at 100 °C for 2 h under argon gas protection. The reaction was monitored for completeness by LCMS. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 9-ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (300 mg). The crude product was used directly in the next step without further purification. MS (ESI) m / z: 552.3 (M−H)−;

[0049] 9-Ethyl-3-ethynyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 9-ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (300 mg) in methanol (30 mL) was added potassium carbonate (200 mg). The mixture was stirred at room temperature overnight. The reaction was monitored for completeness by LCMS. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. Purification by prep-HPLC gave a white solid, 9-ethyl-3-ethynyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (8 mg, two-step yield 9.9%). 1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.28 (s, 1H), 7.58 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.15(s, 1H), 3.79~3.79 (m, 4H), 3.32~3.29 (m, 2H), 3.08 (s, 1H), 2.79~2.66 (m, 8H), 2.40~2.39 (m, 1H), 2.03~2.00 (m, 2H), 1.76 (m, 8H), 1.33 (t, 3H).

[0050] Example 2: 9-Ethyl-3-ethynyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (E2) TIFF0007752700000043.tif122170

[0051] 7-Methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one TIFF0007752700000044.tif14170 Under nitrogen gas protection in an ice-water bath, a solution of 7-methoxy-3,4-dihydronaphthalen-2(1H)-one (200 g, 1136 mmol) in tetrahydrofuran (1 L) was added dropwise with 50% aqueous potassium hydroxide (400 mL), followed by the dropwise addition of methyl iodide (403 g, 2840 mmol). The reaction was stirred at room temperature for 3 hours. Completeness was monitored by LCMS. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude 7-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (300 g, 100% yield). 1H NMR (400 MHz, DMSO) δ 7.11 (t, J = 7.3 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 6.77 (dd, J = 8.3, 2.6 Hz, 1H), 3.73 (d, J = 11.7 Hz, 3H), 2.98 (t, J = 6.8 Hz, 2H), 2.63 - 2.57 (m, 2H), 1.37 - 1.29 (m, 6H).

[0052] 6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one To a solution of 7-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (200 g, 980 mmol) in DMF (1500 mL) was added N-bromosuccinimide (192 g, 1078 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was confirmed to be complete by thin-layer chromatography. The reaction mixture was poured into ice-water (1 L). The mixture was extracted with ethyl acetate (3 × 800 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was recrystallized to give 6-bromo-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (200 g, 60.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.43 (s, 1H), 7.05 (s, 1H), 3.86 (s, 3H), 2.98 (t, J = 6.9 Hz, 2H), 2.68 - 2.53 (m, 2H), 1.37 (s, 6H).

[0053] 7-Methoxy-1,1-dimethyl-6-vinyl-3,4-dihydronaphthalen-2(1H)-one To a solution of 6-bromo-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (33.0 g, 11.7 mmol) in dioxane (50 mL) was added potassium trifluoro(vinyl)borate (2.36 g, 17.6 mmol) and potassium fluoride (1.36 g, 23.40 mmol). After degassing the mixture three times with nitrogen, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (955 mg, 1.2 mmol) was added. The mixture was degassed three times with nitrogen. The mixture was heated at 100 °C overnight. The reaction was monitored for completeness by LCMS. The reaction was filtered, and the filter cake was washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure until dry. The crude product was purified by silica gel column chromatography (petroleum ester: ethyl acetate = 20:1 to 6:1) to obtain an ochre solid, 7-methoxy-1,1-dimethyl-6-vinyl-3,4-dihydronaphthalen-2(1H)-one (2.54 g, yield 94%).

[0054] 6-Ethyl-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one Palladium on carbon (10%, 500 mg) was added to a solution of 7-methoxy-1,1-dimethyl-6-vinyl-3,4-dihydronaphthalen-2(1H)-one (2.54 g, 11.0 mmol) in ethyl acetate (50 mL). The mixture was degassed under vacuum with hydrogen gas three times. The reaction mixture was stirred at room temperature overnight. After filtration, the filtrate was concentrated under reduced pressure to give a pale yellow solid, 6-ethyl-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (2.46 g, 97% yield). MS (ESI) m / z: 233.2 (M+H). +

[0055] 3-Bromo-9-ethyl-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole 3-Bromophenylhydrazine hydrochloride (2.20 g, 9.8 mmol) was added to a solution of 6-ethyl-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (2.27 g, 9.8 mmol) in acetic acid (25 mL). The reaction was heated to 125 °C and stirred for 6 hours. LCMS indicated complete reaction. The reaction was concentrated to dryness to give 3-bromo-9-ethyl-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole (3.90 g, crude). MS (ESI) m / z: 384.0 (M+H). + ;

[0056] 3-Bromo-9-ethyl-8-methoxy-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000049.tif221703-Bromo-9-ethyl-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole (3.76 g, 9.8 mmol) was dissolved in tetrahydrofuran (40 mL) and water (4 mL). The mixture was stirred at room temperature for 10 minutes. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (3.35 g, 14.8 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction was monitored for completeness by LCMS. The mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed successively with sodium hydroxide (0.5 M), brine (0.5 M), and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography to obtain an ochre solid, 3-bromo-9-ethyl-8-methoxy-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (2.10 g, crude product).

[0057] 3-Bromo-9-ethyl-8-hydroxy-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000050.tif221703-Bromo-9-ethyl-8-methoxy-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazole-11-ketone (2.10 g, 5.3 mmol) and pyridine hydrochloride (30 g) were heated to 170 °C and stirred for 13 hours. The reaction was monitored for completeness by LCMS. The reaction mixture was cooled to room temperature and poured into ice water (100 mL). Extraction was performed with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography to give a brown solid, 3-bromo-9-ethyl-8-hydroxy-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (1.32 g, 65% yield). MS(ESI) m / z: 385.1 (M+H). + ;

[0058] 3-Bromo-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate TIFF0007752700000051.tif231 3-Bromo-9-ethyl-8-hydroxy-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazole-11-ketone (1.26 g, 3.3 mmol) was added to a solution of pyridine (30 mL) at 700 °C. After stirring at 0 °C for 10 minutes, trifluoromethanesulfonic anhydride (2.7 g, 9.6 mmol) was added dropwise. The reaction was stirred at room temperature for 1 hour. The reaction was monitored for completeness by LCMS. The reaction was quenched by the addition of water (100 mL). The mixture was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ester:toluene = 8:1 to 2:1) to give a brown solid, 3-bromo-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (816 mg, 48% yield). MS (ESI) m / z: 528.0 (M+H). + ;

[0059] 3-Bromo-9-ethyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000052.tif281701-Methylpiperazine (2.33 g, 23.3 mmol) was dissolved in N-methylpyrrolidone (6 mL). The mixture was stirred at 150°C for 10 minutes. 3-Bromo-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (600 mg, 1.16 mmol) was added. The mixture was stirred at 150°C for 6 hours. The reaction was monitored for completeness by LCMS. The reaction was cooled to room temperature and quenched by the addition of water (30 mL). The reaction mixture was filtered to obtain a brown solid, 3-bromo-9-ethyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (630 mg, crude product). MS (ESI) m / z: 466.1 (M+H). + ;

[0060] 9-Ethyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000053.tif281703-Bromo9-ethyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (200 mg, 0.43 mmol) in acetonitrile (10 mL) was added with ethynyltrimethylsilane (2.10 g, 21.50 mmol) and potassium phosphate (137 mg, 0.65 mmol). After purging with nitrogen gas three times, tris(dibenzylideneacetone)dipalladium (79 mg, 0.09 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (82 mg, 0.17 mmol) were added. After purging with nitrogen three times, the mixture was heated to 90 °C and stirred overnight. The mixture was filtered, and the filter cake was washed with a mixed solvent of dichloromethane and methanol (v / v = 10 / 1, 50 mL). The filtrate was concentrated under reduced pressure until no water remained. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to obtain a brown solid, 9-ethyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (100 mg, 43% yield). MS (ESI) m / z: 484.3 (M+H). + ;

[0061] 9-Ethyl-3-ethynyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazole-11 ketone To a solution of 9-ethyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (183 mg, 0.38 mmol) in methanol (10 mL) was added potassium carbonate (143 mg, 1.01 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored for completeness by LCMS. The mixture was quenched with water (30 mL) and extracted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to obtain a brown solid, 9-ethyl-3-ethynyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (57.67 mg, 55% yield). 1H NMR (400 MHz, DMSO-d6): δ12.61 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.04 (s, 1H), 7.61 (s, 1H), 7.35 (s, 1H), 7.32 (d, J=8.0 Hz, 1H), 4.15 (s, 1H), 3.17 (d, J=4.8Hz, 4H), 3.02 (s,4H), 2.74-2.61 (m, 5H), 2.33 (s, 3H), 1.75 (s, 6H), 1.29-1.23 (m,5H).

[0062] Example 3: 3-ethynyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (E3) TIFF0007752700000055.tif62170

[0063] 3-Bromo-8-(4-cyclopropylpiperazin-1-yl)-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000056.tif301701-Cyclopropylpiperazine (2.5 g, 19.5 mmol) was dissolved in N-methylpyrrolidone (4 mL) and heated to 150 °C and stirred for 10 min. 3-Bromo-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (500 mg, 0.98 mmol) was added. The mixture was stirred at 150 °C for 5 h. The reaction was monitored for completeness by LCMS. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to give a brown solid, 3-bromo-8-(4-cyclopropylpiperazin-1-yl)-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (280 mg, 58% yield). MS (ESI) m / z: 492.1 (M+H)+

[0064] 8-(4-cyclopropylpiperazin-1-yl)-9-ethyl-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000057.tif301703-Bromo-8-(4-cyclopropylpiperazin-1-yl)-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (180 mg, 0.37 mmol) in acetonitrile (10 mL) was added with ethynyltrimethylsilane (1.1 g, 11.24 mmol) and potassium phosphate (157 mg, 0.74 mmol). The mixture was purged with nitrogen and degassed under vacuum three times. Tris(dibenzylideneacetone)dipalladium (68 mg, 0.07 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (71 mg, 0.15 mmol) were added. The mixture was purged with nitrogen and degassed under vacuum three times. The mixture was heated to 90 °C and stirred overnight. The mixture was filtered, and the filter cake was washed with a mixture of dichloromethane and methanol (v / v = 10 / 1, 50 mL). The filtrate was concentrated under reduced pressure until no water remained. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to give a brown solid: 8-(4-cyclopropylpiperazin-1-yl)-9-ethyl-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (40 mg, 21% yield). MS (ESI) m / z: 510.2 (M+H). + ;

[0065] 8-(4-cyclopropylpiperazin-1-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 8-(4-cyclopropylpiperazin-1-yl)-9-ethyl-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (40 mg, 0.08 mmol) in methanol (3 mL) was added potassium carbonate (54 mg, 0.39 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was monitored for completeness by LCMS. The mixture was quenched with water (30 mL). The mixture was extracted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to obtain a white solid, 8-(4-cyclopropylpiperazin-1-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (4.93 mg, 14% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.35 (s, 1H), 8.15 (d, J=4.4 Hz, 1H), 8.05 (s, 1H), 7.60 (s, 1H), 7.35-7.31 (m, 2H), 4.11 (s, 1H), 3.39 (s,2H), 2.98 (s,4H), 2.79 (s,2H), 2.76 (q, J=11.2 Hz,3H), 2.55 (s,1H), 1.73 (s, 6H), 1.30 (t, J=14.8 Hz, 3H), 0.53-0.39 (m, 3H).

[0066] Example 4: 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (E4) TIFF0007752700000059.tif71170

[0067] 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-3-bromo-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000060.tif311703-Bromo-9-ethyl-6,6-dimethyl-8-(4-oxopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (230 mg, 0.49 mmol) in dichloromethane (20 mL) was added with acetic acid (5 drops) and azetidinyl (280 mg, 4.9 mmol). The reaction was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (312 mg, 1.47 mmol) was added. The reaction was heated to 60 °C and stirred for 3 hours. The reaction was monitored for completeness by LCMS. The reaction was quenched with saturated ammonium chloride (30 mL). The mixture was extracted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 3 × 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated until dry. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 60:1 to 15:1) to give a yellow solid: 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-3-bromo-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (290 mg, crude product). MS (ESI) m / z: 506.1 (M+H). + ;

[0068] 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000061.tif311708-(4-(azetidinyl-1-yl)piperidin-1-yl)-3-bromo-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (230 mg, 0.46 mmol) in acetonitrile (10 mL) was added ethynyltrimethylsilane (1.34 g, 13.66 mmol) and potassium phosphate (193 mg, 0.91 mmol). The mixture was degassed three times under nitrogen / vacuum. Tris(dibenzylideneacetone)dipalladium (83 mg, 0.09 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (86 mg, 0.18 mmol) were added. The mixture was degassed three times again. The mixture was heated to 90 °C and stirred overnight. The mixture was filtered, and the filter cake was washed with a mixture of dichloromethane and methanol (v / v = 10 / 1, 50 mL). The filtrate was concentrated under reduced pressure until no water remained. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to obtain a brown solid: 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (200 mg, 83% yield). MS (ESI) m / z: 524.3 (M+H). + ;

[0069] 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (200 mg, 0.38 mmol) in methanol (30 mL) was added potassium carbonate (263 mg, 1.91 mmol). The reaction was stirred at room temperature overnight. The reaction was monitored for completeness by LCMS. The reaction was quenched by the addition of water (30 mL). The mixture was extracted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to obtain a yellow solid, 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (57.67 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6): δ12.35 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.03 (s, 1H), 7.59 (s, 1H), 7.33 (t, J=8.0 Hz,2H), 4.13 (s, 1H), 3.34 (s,2H), 3.16 (d, J=12.0 Hz, 2H), 2.77-2.65 (m, 5H), 2.01(s, 2H), 1.81 (d, J=10.4 Hz, 2H), 1.73 (s, 6H), 1.41-1.15(m, 7H).

[0070] Example 5: 9-Ethyl-3-acetylene-6,6-dimethyl-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (E5) TIFF0007752700000063.tif113170

[0071] 3-Bromo-9-ethyl-6,6-dimethyl-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000064.tif311703-Bromo-9-ethyl-6,6-dimethyl-8-(4-oxopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (200 mg, 0.43 mmol) in dichloroethane (20 mL) was added pyrrolidine (306 mg, 4.3 mmol) and acetic acid (5 drops). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (273 mg, 1.29 mmol) was added. The mixture was heated to 60 °C and stirred for 3 hours. The reaction was monitored for completeness by LCMS. The mixture was quenched with saturated ammonium chloride (30 mL). The mixture was extracted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 3 × 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 60:1 to 15:1) to give a yellow solid: 3-bromo-9-ethyl-6,6-dimethyl-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (260 mg, crude product). MS (ESI) m / z: 520.2 (M+H). + ;

[0072] 9-Ethyl-6,6-dimethyl-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000065.tif311703-Bromo-9-ethyl-6,6-dimethyl-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (216 mg, 0.42 mmol) in acetonitrile (10 mL) was added ethynyltrimethylsilane (1200 mg, 12.48 mmol) and potassium phosphate (178 mg, 0.84 mmol). The mixture was degassed three times under nitrogen gas / vacuum. Tris(dibenzylideneacetone)dipalladium (77 mg, 0.08 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (80 mg, 0.17 mmol) were added. The mixture was degassed three times again. The mixture was heated to 90 °C and stirred overnight. The mixture was filtered, and the filter cake was washed with a mixture of dichloromethane and methanol (v / v = 10 / 1, 50 mL). The filtrate was concentrated under reduced pressure until no water remained. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to give a brown solid, 9-ethyl-6,6-dimethyl-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (216 mg, 95% yield). MS (ESI) m / z: 538.3 (M+H). + ;

[0073] 9-Ethyl-3-ethynyl-6,6-dimethyl-8-(4-(pyrrolidinyl-1-yl)piperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 9-ethyl-6,6-dimethyl-8-(4-(pyrrolidinyl-1-yl)piperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (216 mg, 0.38 mmol) in methanol (30 mL) was added potassium carbonate (352 mg, 1.91 mmol). The reaction was stirred at room temperature overnight. Complete reaction was monitored by LCMS. The mixture was quenched with water (30 mL) and extracted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to obtain a yellow solid, 9-ethyl-3-ethynyl-6,6-dimethyl-8-(4-(pyrrolidinyl-1-yl)piperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (37.94 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.41 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.04 (s, 1H), 7.60 (s, 1H), 7.34-7.31 (m, 2H), 4.12 (s,1H), 3.25 (d, J=11.6 Hz,3H), 3.18 (d, J=4.8 Hz, 1H), 2.78-2.70 (m, 6H), 2.11 (s, 2H), 1.86 (s, 6H), 1.74 (s, 6H), 1.33-1.23 (m,4H).

[0074] Example 6: 8-(4-(dimethylamino)piperidin-1-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (E6) TIFF0007752700000067.tif71170

[0075] 3-Bromo-8-(4-(dimethylamino)piperidin-1-yl)-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000068.tif31170 Under nitrogen gas protection, N,N-dimethylpiperidin-4-amine (2.49 g, 19.37 mmol) was dissolved in N-methylpyrrolidone (30 mL). After heating to 150 °C and stirring for 5 minutes, 3-bromo-9-ethyl-6,6-dimethyl-11-oxy-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (500 mg, 0.97 mmol) was added. The reaction was stirred at 150 °C for 3 hours. The reaction was monitored for completeness by LCMS. The reaction mixture was cooled to room temperature and poured into water (100 mL). Extraction was performed with ethyl acetate (2 × 30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until dry. The crude product was purified by silica gel column chromatography (petroleum ester:ethyl acetate = 3:1) to give a white solid, 3-bromo-8-(4-(dimethylamino)piperidin-1-yl)-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (210 mg, 43.8% yield). MS (ESI) m / z: 496.0 (M+H). + ;

[0076] 9-Ethyl-6,6-dimethyl-8-(4-(methylamino)piperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000069.tif28170 Under nitrogen gas protection, a solution of 3-bromo-8-(4-(dimethylamino)piperidin-1-yl)-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (118 mg, 0.24 mmol) and ethynyltrimethylsilane (235 mg, 2.39 mmol) in acetonitrile (18 mL) was added with tris(dibenzylideneacetone)dipalladium (44 mg, 0.05 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (46 mg, 0.10 mmol), and potassium phosphate (203 mg, 0.95 mmol). The mixture was heated to 90 °C and stirred for 6 hours. The reaction was monitored for completeness by LCMS. The reaction mixture was filtered, and the filter cake was washed with dichloromethane and methanol. The filtrate was concentrated under reduced pressure until no water remained, and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a yellow solid: 9-ethyl-6,6-dimethyl-8-(4-(methylamino)piperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (75 mg, 61.4% yield). MS (ESI) m / z: 512.4 (M+H). + ;

[0077] 8-(4-(dimethylamino)piperidin-1-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 9-ethyl-6,6-dimethyl-8-(4-(methylamino)piperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazole-11-ketone (75 mg, 0.15 mmol) in methanol (10 mL) was added potassium carbonate (102 mg, 0.73 mmol). The reaction was stirred at room temperature for 3 hours. Complete reaction was monitored by LCMS. The reaction mixture was poured into ice water (120 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give a yellow solid, 8-(4-(dimethylamino)piperidin-1-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (12 mg, 0.03 mmol, 18.6% yield). 1H NMR (400 MHz, DMSO-d6):δ 12.83 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.63 (s, 1H), 7.35 (m, 1H), 7.31 (dd, J = 16.0, 8.0 Hz, 1H), 4.11 (s, 1H), 3.23 (m, 6H), 2.79 (t, J = 10.9 Hz, 4H), 2.71 (dd, J = 15.0, 7.6 Hz, 4H), 2.10 - 2.01 (m, 4H), 2.00 - 1.94 (m, 2H), 1.75 (s, 6H), 1.34 - 1.25 (m, 3H).

[0078] Example 7: 9-Ethyl-3-(3-hydroxypropyl-1-ynyl-1-yl)-6,6-dimethyl-8-(piperazin-1-yl)-5H-benzo[b]carbazol-11(6H)-one (E7) TIFF0007752700000071.tif95170

[0079] t-Butyl 4-(3-bromo-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate TIFF0007752700000072.tif231703-Bromo-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (1 g, 1.94 mmol) in N-methylpyrrolidone (5 mL) was added with tert-butyl piperazine-1-formate (3.6 g, 19.4 mmol). The mixture was stirred at 150 °C overnight. After cooling to room temperature, the reaction mixture was poured into ice water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ester:ethyl acetate = 2:1) to obtain the target product, tert-butyl 4-(3-bromo-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate (280 mg, 26.8% yield), as a yellow solid. MS (ESI) m / z: 552.1 (M+H). + ;

[0080] t-Butyl 4-(9-ethyl-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(3-bromo-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate (280 mg, 0.51 mmol) in acetonitrile (5 mL) was added tris(dibenzylideneacetone)dipalladium (45 mg, 0.05 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (47 mg, 0.1 mmol), potassium phosphate (318 mg, 1.5 mmol), and trimethylsilylacetylene (490 mg, 5 mmol). The mixture was heated to 90 °C under argon gas protection and stirred for 3 h. The reaction was monitored for completeness by LCMS. The reaction mixture was diluted with water and extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 0-50%) to give a yellow solid, tert-butyl 4-(9-ethyl-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate (120 mg, 64% yield). MS (ESI) m / z: 470.1 (M+H). + ;

[0081] t-Butyl 4-(9-ethyl-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(9-ethyl-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate (180 mg, 0.32 mmol) in methanol (5 mL) was added potassium carbonate (318 mg, 1.5 mmol). The reaction was stirred at 25 °C for 2 hours. Complete reaction was monitored by LCMS. The reaction mixture was diluted with water and extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ester:ethyl acetate = 2:1) to give a yellow solid, tert-butyl 4-(9-ethyl-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate (100 mg, 89% yield). MS(ESI) m / z: 498.1 (M+H). + ;

[0082] 9-Ethyl-3-ethynyl-6,6-dimethyl-8-(piperazin-1-yl)-5H-benzo[b]carbazol-11(6H)-one TIFF0007752700000075.tif201704-(9-Ethyl-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate tert-Butyl ester (100 mg, 0.20 mmol) was added to 1,1,1,3,3,3-hexafluoro-2-propanol (5 mL). The reaction mixture was microwaved at 120 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by prep-HPLC to give a yellow solid, 9-ethyl-3-ethynyl-6,6-dimethyl-8-(piperazin-1-yl)-5H-benzo[b]carbazol-11(6H)-one (4 mg, 6% yield). 1H NMR (400 MHz, CD3OD) δ8.22 - 8.20 (m, 2H), 7.59 (s, 1H), 7.41-7.38 (d, J = 12 Hz, 1H), 7.36-7.33 (m, 2H),4.95 (s, 1H), 3.47-3.42 (m, 6H), 3.29-3.23 (m, 2H), 2.83-2.79 (m, 2H),1.79 (s, 6H), 1.37-1.33 (m, 3H).

[0083] Example 8: 9-Ethyl-3-ethynyl-6,6-dimethyl-8-(piperidin-4-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (E8) TIFF0007752700000076.tif120170

[0084] 3-Ethyl-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate To a solution of 6-ethyl-7-hydroxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (3.2 g, 14.66 mmol) in dichloromethane (50 mL) was added pyridine (11.60 g, 146.59 mmol). Trifluoromethanesulfonic anhydride (20.68 g, 73.30 mmol) was added dropwise at 0 °C under argon gas protection. The reaction was stirred at room temperature for 4 hours and quenched with water. The resulting mixture was washed with saturated brine (3 × 100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography (petroleum ester:ethyl acetate = 20:1) to give a yellow solid, 3-ethyl-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (3.6 g, 70% yield). 1H NMR (400 MHz, CDCl3): δ 7.16 (s, 1H), 7.14 (s, 1H), 3.10 (t, J = 6.8 Hz, 2H), 2.75–2.67 (m, 4H), 1.42 (s, 6H), 1.27 (t, J = 7.6 Hz, 3H).

[0085] t-Butyl 4-(3-ethyl-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate To a suspension of 3-ethyl-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (3.6 g, 10.28 mmol) in dioxane (40 mL) and water (4 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (6.35 g, 20.55 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (752 mg, 1.03 mmol), and potassium carbonate (4.26 g, 30.83 mmol). The resulting mixture was degassed with argon gas three times. The reaction was heated at reflux overnight. After the reaction was completed, ethyl acetate (50 mL) was added, and the resulting suspension was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ester:ethyl acetate=15:1) to give a pale yellow solid, tert-butyl 4-(3-ethyl-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4.8 g, 100% yield). 1H NMR (400 MHz, CDCl3): δ 7.02 (s, 1H), 7.00 (s, 1H), 5.55 (s, 1H), 4.03 (s, 2H), 3.63 (t, J = 5.2 Hz, 2H), 3.07 (t, J = 6.4 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H), 2.61 (q, J = 7.2 Hz, 2H), 2.34 (s, 2H), 1.51 (s, 9H), 1.42 (s, 6H), 1.20 (t, J = 7.6 Hz, 3H).

[0086] t-Butyl 4-(3-ethyl-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)piperidine-1-formate Palladium on carbon (10%, 500 mg) was added to a solution of tert-butyl 4-(3-ethyl-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4.8 g, 12.52 mmol) in ethyl acetate (50 mL). The resulting mixture was degassed three times with hydrogen gas. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow solid, tert-butyl 4-(3-ethyl-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)piperidine-1-formate (4.7 g, 97% yield). MS (ESI) m / z: 286.2 (M-100+H). + ;

[0087] 3-Bromo-9-ethyl-6,6-dimethyl-8-(piperidin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole To a solution of 4-(3-ethyl-8,8-dimethyl-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)piperidine-1-tert-butyl formate (14.0 g, 39.16 mmol) in acetic acid (150 mL) was added (3-bromophenyl)hydrazine (7.32 g, 39.16 mmol). The mixture was stirred at 125 °C for 6 h. The reaction mixture was concentrated, and the residue was poured into water. The pH was adjusted to 9 with saturated sodium bicarbonate. Filtration and washing of the filter cake with water and solvent (petroleum ester:ethyl acetate = 10:1) gave a yellow solid, 3-bromo-9-ethyl-6,6-dimethyl-8-(piperidin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole (11.2 g, 70% yield). MS (ESI) m / z: 437.4 (M+1). + ;

[0088] t-Butyl 4-(3-bromo-9-ethyl-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidine-1-formate To a solution of 3-bromo-9-ethyl-6,6-dimethyl-8-(piperidin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole (11.2 g, 25.61 mmol) and triethylamine (5.18 g, 51.21 mmol) in dichloromethane (120 mL) was added di-tert-butyl dicarbonate (6.71 g, 30.73 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give tert-butyl 4-(3-bromo-9-ethyl-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidine-1-formate (14.5 g, crude product). The crude product was used in the next step without further purification.

[0089] 4-(3-bromo-9-ethyl-6,6-dimethyl-11-oxy-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidine-1-formate t-butyl ester TIFF0007752700000082.tif211704-(3-Bromo-9-ethyl-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidine-1-t-butylformate (14.5 g, 26.98 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.12 g, 26.98 mmol) were added to tetrahydrofuran (150 mL) and water (15 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran solvent. The mixture was washed with ethyl acetate (150 mL) and saturated brine (3 × 150 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography (dichloromethane:methanol=20:1) to give a yellow solid product, tert-butyl 4-(3-bromo-9-ethyl-6,6-dimethyl-11-oxy-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidine-1-formate (3.6 g, two-step yield: 25%). 1H NMR (400 MHz, CDCl3): δ 9.61 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.23 ​​(s, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.43~7.41 (m, 2H), 4.35~4.33 (m, 2H), 3.06~2.99 (m, 1H), 2.89 (t, J = 11.6 Hz, 2H), 2.82 (q, J = 7.2 Hz, 2H), 1.84~1.78 (m, 8H), 1.71~1.66 (m, 2H), 1.54 (s, 9H), 1.28 (t, J = 7.6 Hz, 3H).

[0090] 4-(9-ethyl-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidine-1-formic acid TIFF0007752700000083.tif221704-(3-bromo-9-ethyl-6,6-dimethyl-11-oxy-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidine-1-t-butylformate (200 mg, 0.36 mmol), ethynyltrimethylsilane (356 mg, 3.63 mmol), and potassium carbonate (154 mg, 0.74 mmol) in acetonitrile (8 mL) were added with 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (35 mg, 0.07 mmol) and tris(dibenzylideneacetone)dipalladium (33 mg, 0.04 mmol). The resulting mixture was degassed three times with argon gas. The reaction mixture was stirred at 90 °C overnight. A mixed solvent of dichloromethane and methanol (v / v = 10 / 1, 30 mL) was added and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a yellow solid product, 4-(9-ethyl-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidine-1-formic acid (130 mg, 63% yield). MS (ESI) m / z: 569.2 (M+H).+ ;

[0091] 9-Ethyl-3-ethynyl-6,6-dimethyl-8-(piperidin-4-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000084.tif211704-(9-Ethyl-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidine-1-formic acid (130 mg, 0.23 mmol) was added to 1,1,1,3,3,3-hexafluoro-2-propanol (10 mL). The mixture was stirred in a sealed tube at 100°C for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with methanol (5 mL). Potassium carbonate (64 mg, 0.46 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the crude product was purified by prep-TLC (dichloromethane:methanol=10:1) to give a white solid product, 9-ethyl-3-ethynyl-6,6-dimethyl-8-(piperidin-4-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (30.62 mg, 34% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.50 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.62 (s, 1H), 7.61 (s, 1H), 7.34 (dd, J = 8.0, 1.2 Hz, 1H), 4.12 (s, 1H), 3.36 ~ 3.20(m, 2H), 3.22~3.15 (m, 1H), 3.07~3.02 (m, 2H), 2.82 (q, J = 7.6 Hz, 2H), 2.09~2.01 (m, 2H), 1.85~1.82 (m, 2H), 1.75 (s, 6H), 1.24 (t, J = 7.6 Hz, 3H).

[0092] Example 9: 9-Ethyl-3-ethynyl-6,6-dimethyl-8-(1-methylpiperidin-4-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (E9) TIFF0007752700000085.tif96170

[0093] 3-Bromo-9-ethyl-6,6-dimethyl-8-(piperidin-4-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000086.tif281704-(3-bromo-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidine-1-t-butyl ether (2.0 g, 3.63 mmol) in dioxane (15 mL) was added to a solution of 4N hydrochloric acid in dioxane (15 mL). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the crude hydrochloride salt (1.8 g). The crude product was dissolved in water (30 mL) and basified to pH 9 with 1N aqueous sodium hydroxide solution. The mixture was filtered to give a yellow solid: 3-bromo-9-ethyl-6,6-dimethyl-8-(piperidin-4-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (1.46 g, 89% yield). MS(ESI)m / z:453.1(M+H) + ;

[0094] 3-Bromo-9-ethyl-6,6-dimethyl-8-(1-methylpiperidin-4-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000087.tif281703-Bromo-9-ethyl-6,6-dimethyl-8-(piperidin-4-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (400 mg, 0.89 mL) in dichloroethane (4 mL) and DMF (4 mL) was added with 37% aqueous formaldehyde (1 mL), anhydrous magnesium sulfate (1.0 g), and acetic acid (53 mg, 0.89 mmol). The mixture was stirred at room temperature for 3 hours. Sodium borohydride acetate (376 mg, 1.76 mmol) was added. The mixture was heated to 60 °C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL), washed with water (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was washed with petroleum esters:ethyl acetate = 10:1 to give a yellow solid, 3-bromo-9-ethyl-6,6-dimethyl-8-(1-methylpiperidin-4-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (310 mg, 75% yield). MS (ESI) m / z: 467.1 (M+H). + ;

[0095] 9-Ethyl-6,6-dimethyl-8-(1-methylpiperidin-4-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000088.tif211703-Bromo-9-ethyl-6,6-dimethyl-8-(1-methylpiperidin-4-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (200 mg, 0.43 mmol), potassium phosphate (183 mg, 0.86 mmol), and ethynyltrimethylsilane (422 mg, 4.30 mmol) in acetonitrile (8 mL) were added with 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (41 mg, 0.09 mmol) and tris(dibenzylideneacetone)dipalladium (39 mg, 0.04 mmol). The resulting mixture was degassed three times with argon gas. The mixture was heated to 90 °C and stirred overnight. The reaction mixture was diluted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 30 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give a yellow solid: 9-ethyl-6,6-dimethyl-8-(1-methylpiperidin-4-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (120 mg, 58% yield). MS(ESI) m / z: 483.2 (M+H). + ;

[0096] 9-Ethyl-3-ethynyl-6,6-dimethyl-8-(1-methylpiperidin-4-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000089.tif281709-Ethyl-6,6-dimethyl-8-(1-methylpiperidin-4-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (120 mg, 0.25 mmol) and potassium carbonate (69 mg, 0.50 mmol) were added to a solution of methanol (5 mL) and stirred overnight. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by Prep-TLC (dichloromethane:methanol=10:1) and then by Prep-HPLC (0.1% ammonium bicarbonate / water / acetonitrile) to give a white solid, 9-ethyl-3-ethynyl-6,6-dimethyl-8-(1-methylpiperidin-4-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (17.73 mg, yield 17%). 1H NMR (400 MHz, DMSO-d6): δ 12.44 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.34 (dd, J = 8.0, 1.2 Hz, 1H), 4.12 (s, 1H), 3.20 ~ 3.13(m, 2H), 2.96~2.94 (m, 1H), 2.80 (q, J = 7.6 Hz, 2H), 2.51~2.49 (m, 5H), 2.05~2.02 (m, 2H), 1.80~1.75 (m, 8H), 1.25 (t, J = 7.6 Hz, 3H).

[0097] Example 10: 8-(1-Cyclopropylpiperidin-4-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (E10) TIFF0007752700000090.tif71170

[0098] 3-Bromo-8-(1-cyclopropylpiperidin-4-yl)-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000091.tif281703-Bromo-9-ethyl-6,6-dimethyl-8-(piperidin-4-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (650 mg, 1.44 mmol) and (1-ethyloxycyclopropoxy)trimethylsilyl (1.0 g, 5.74 mmol) in 1,2-dichloroethane (5 mL) and N,N-dimethylformamide (8 mL) were added with acetic acid (86 mg, 1.44 mmol). After stirring at room temperature for 6 hours, sodium cyanotrihydroborate (181 mg, 2.88 mmol) was added. The mixture was stirred at 60 °C overnight. The reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give a yellow solid, 3-bromo-8-(1-cyclopropylpiperidin-4-yl)-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (240 mg, 34% yield). MS (ESI) m / z: 493.2 (M+H). + ;

[0099] 8-(1-cyclopropylpiperidin-4-yl)-9-ethyl-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000092.tif221703-Bromo-8-(1-cyclopropylpiperidin-4-yl)-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (140 mg, 0.28 mmol), ethynyltrimethylsilane (280 mg, 2.85 mmol), and potassium phosphate (121 mg, 0.57 mmol) in acetonitrile (5 mL) were added with 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (21 mg, 0.06 mmol) and tris(dibenzylideneacetone)dipalladium (26 mg, 0.03 mmol). The resulting mixture was degassed three times with argon gas. The reaction mixture was heated to 90 °C and stirred overnight. The reaction mixture was diluted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 30 mL) and filtered. The filtrate was concentrated under reduced pressure until the water content was gone. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give a yellow solid: 8-(1-cyclopropylpiperidin-4-yl)-9-ethyl-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (55 mg, 38% yield). MS (ESI) m / z: 509.6 (M+H). + ;

[0100] 8-(1-cyclopropylpiperidin-4-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000093.tif221708-(1-Cyclopropylpiperidin-4-yl)-9-ethyl-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (55 mg, 0.11 mmol) and potassium carbonate (30 mg, 0.22 mmol) were added to methanol (3 mL) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure until no water remained, and the crude product was purified by prep-TLC (dichloromethane:methanol=10:1) and then by prep-HPLC (0.1% ammonium bicarbonate / water / acetonitrile) to give a white solid, 8-(1-cyclopropylpiperidin-4-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (4.38 mg, yield 9.2%). 1H NMR (400 MHz, DMSO-d6): δ 12.31 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 4.12 (s, 1H), 3.10 (d, J = 11.2 Hz, 2H), 2.86~2.67 (m, 3H), 2.35~2.29 (m, 2H), 1.84~1.66 (m, 11H), 1.22 (t, J = 7.6 Hz, 3H), 0.48~0.45 (m, 2H), 0.35~0.31 (m, 2H).

[0101] Example 11: 8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (E11) TIFF0007752700000094.tif107170

[0102] 3-Bromo-8-t-butyl-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000095.tif301703-Bromo-9-ethyl-6,6-dimethyl-8-(4-oxopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (200 mg, 0.43 mmol) and 1-cyclopropylpiperazine (543 mg, 4.30 mmol) in 1,2-dichloroethane (30 mL) were added with acetic acid (26 mg, 0.43 mmol). The mixture was stirred at room temperature for 1 h. Sodium hydrogen boroacetate (212 mg, 1.29 mmol) was then added. The mixture was heated to 60 °C and stirred for 3 h. The reaction was monitored for completeness by LCMS. The reaction mixture was cooled to room temperature and poured into ice water (200 mL). The mixture was extracted with dichloromethane (2 × 40 mL). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a yellow solid: 3-bromo-8-t-butyl-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (153 mg, 61.8% yield). MS (ESI) m / z: 575.2 (M+H). + ;

[0103] 8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000096.tif321703-Bromo-8-t-butyl-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (153 mg, 0.26 mmol), ethynyltrimethylsilane (522 mg, 5.32 mmol), and potassium phosphate (141 mg, 0.66 mmol) in acetonitrile (15 mL) were added with 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (51 mg, 0.11 mmol) and tris(dibenzylideneacetone)dipalladium (49 mg, 0.05 mmol). The mixture was heated to 90 °C and stirred for 6 h. The reaction was monitored for completeness by LCMS. The reaction mixture was filtered, and the filter cake was washed with dichloromethane and methanol. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a yellow solid: 8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (40 mg, 25.4% yield). MS(ESI) m / z: 593.5 (M+H). + ;

[0104] 8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (40 mg, 0.07 mmol) in methanol (10 mL) was added potassium carbonate (48 mg, 0.35 mmol). The reaction was stirred at room temperature for 3 h. Complete reaction was monitored by LCMS. The reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give a yellow solid, 8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-9-ethyl-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (14 mg, yield 39.8%). 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.15 (d, J = 8.1 Hz, 1H), 8.03 (s, 1H), 7.58 (s, 1H), 7.31 (dd, J = 7.3, 2.1 Hz, 2H), 4.11 (s, 1H), 3.20 (d, J = 11.4 Hz, 2H), 2.72 (dt, J = 15.0, 9.5 Hz, 5H), 2.65 - 2.52 (m, 4H), 2.47 - 2.21 (m, 4H), 1.88 (d, J = 10.3 Hz, 2H), 1.72 (s, 6H), 1.69- 1.51 (m, 3H), 1.27 (t, J = 7.5 Hz, 3H), 0.40 (d, J = 4.5 Hz, 2H), 0.28 (s, 2H).

[0105] Example 12: 3-ethynyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxy-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (E12) TIFF0007752700000098.tif122170

[0106] 3-Methoxy-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile TIFF0007752700000099.tif201706-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (100 g, 355 mmol) and zinc cyanide (84 g, 710 mmol) in DMF (1 L) and water (50 mL) were mixed with tetrakistriphenylphosphinepalladium (41 g, 35.5 mmol). The mixture was purged with nitrogen three times. The mixture was heated to 120 °C and stirred overnight. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-methoxy-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (49.4 g, 61.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (s, 1H), 7.18 (s, 1H), 3.94 (s, 3H), 3.07 - 2.92 (m, 2H), 2.60 (dd, J = 13.6, 6.9 Hz, 2H), 1.39 (s, 6H).

[0107] 3-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000100.tif211703-Methoxy-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (60 g, 262 mmol) and 3-bromophenylhydrazine hydrochloride (60 g, 288 mmol) were added to acetic acid (1.2 L). The mixture was heated to 125 °C under nitrogen gas protection and reacted for 6 hours. Water (1.2 L) was added to dilute the mixture, and the mixture was stirred. A pale red solid precipitated. The crude product (100 g, 100% yield) was obtained by filtration. The crude product was used directly in the next step.

[0108] 3-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000101.tif231703-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (150 g, 394 mmol) in tetrahydrofuran (1.5 L) and water (150 mL) was mixed with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (100 g, 440 mmol). The mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (500 mL) was added. Extraction with ethyl acetate (2 × 500 mL) was carried out, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (74 g, 48.2% yield), which was used crude in the next step.

[0109] 3-Bromo-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000102.tif221703-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (150 g, 380 mmol) and pyridine hydrochloride (750 g, 6466 mmol) were heated to 170 °C and reacted for 16 hours. The mixture was diluted with ice water (800 mL) and extracted with ethyl acetate (3 × 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give an off-white solid, 3-bromo-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (145 g, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 12.24 (s, 1H), 8.32 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 1.2 Hz, 1H), 7.60 (s, 1H), 7.38 (dd, J = 8.3, 1.3 Hz, 1H), 1.75 (s, 6H).

[0110] 3-Bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate TIFF0007752700000103.tif22170In an ice-water bath, trifluoromethanesulfonic anhydride (111 g, 395 mmol) was added dropwise to a solution of 3-bromo-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (150 g, 395 mmol) and pyridine (125 g, 1580 mmol) in dichloromethane (1 L).The reaction was allowed to proceed with stirring at room temperature for 3 hours. The reaction was quenched by adding ice water, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ester:ethyl acetate=2:1) ​​to give a pale yellow solid, 3-bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (88 g, yield 43.5%). 1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.73 (s, 1H), 8.41 (d, J = 13.0 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 1.5 Hz, 1H), 7.44 (dt, J = 16.6, 8.3 Hz, 1H), 1.82 (s, 6H).

[0111] 3-Bromo-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000104.tif331703-Bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (250 mg, 0.49 mmol) and 4-(piperidinebutan-4-yl)morpholinyl (1.66 g, 9.74 mmol) were added to N-methylpyrrolidone (5 mL). The mixture was heated to 120 °C under argon gas protection and stirred for 4 h. The mixture was diluted with ethyl acetate (30 mL), washed with saturated brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give a yellow solid, 3-bromo-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (220 mg, 85% yield). MS (ESI) m / z: 533.0 (M+H). + ;

[0112] 6,6-Dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000105.tif231703-Bromo-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (200 mg, 0.39 mmol), potassium phosphate (123 mg, 0.58 mmol), and ethynyltrimethylsilane (378 mg, 3.85 mmol) were added to acetonitrile (10 mL). After purging with argon gas three times, tris(dibenzylideneacetone)dipalladium (35 mg, 0.04 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (37 mg, 0.08 mmol) were added. The air was purged with argon gas three times. The mixture was heated to 90 °C and stirred overnight. The reaction mixture was diluted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 30 mL), filtered, and the filtrate was concentrated under reduced pressure until the water content was gone. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid: 6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (200 mg, 97% yield). MS(ESI) m / z: 551.2 (M+1). + .

[0113] 3-ethynyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile To a solution of 6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (180 mg, 0.34 mmol) in methanol (10 mL) was added potassium carbonate (139 mg, 1.01 mmol). The mixture was stirred at room temperature overnight. The solvent methanol was removed by concentration under reduced pressure. The residue was diluted with dichloromethane (30 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-TLC (dichloromethane:methanol = 15:1) to give a pale yellow solid, 3-ethynyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (25 mg, 16% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.55 (s, 1H), 8.33 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.34 (dd, J = 8.0, 1.2 Hz, 1H), 4.14 (s, 1H), 3.84 (d, J = 12.4 Hz, 2H), 3.60 (t, J = 4.0 Hz, 4H), 3.33~3.26 (m, 4H), 3.01 (t, J = 11.6 Hz, 2H), 2.50~2.40 (m, 1H), 1.97 (d, J = 11.6 Hz, 2H), 1.78 (s, 6H), 1.64~1.55 (m, 2H).

[0114] Example 13: 3-ethynyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (E13) TIFF0007752700000107.tif71170

[0115] 3-Bromo-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000108.tif281701 3-Bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (500 mg, 0.98 mmol) and 1-methylpiperazine (1.95 g, 19.5 mmol) were added to a solution of N-methylpyrrolidone (4 mL) at 20 °C. The mixture was heated to 120 °C and stirred for 5 h. LCMS indicated complete reaction. After cooling to room temperature, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until dry. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to give a brown solid, 3-bromo-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (357 mg, 78% yield). MS (ESI) m / z: 463.0 (M+H). + .

[0116] 6,6-Dimethyl-8-(4-methylpiperazin-1-yl)-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000109.tif281703-Bromo-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-11-oxy-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (200 mg, 0.43 mmol), ethynyltrimethylsilane (850 mg, 6.39 mmol), and potassium phosphate (183 mg, 0.86 mmol) were dissolved in acetonitrile (10 mL). The mixture was purged with nitrogen gas three times. Tris(dibenzylideneacetone)dipalladium (79 mg, 0.09 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (82 mg, 0.17 mmol) were added. The mixture was purged with nitrogen gas three times. The mixture was heated to 90 °C and stirred overnight. The mixture was filtered, and the filter cake was washed with a mixture of dichloromethane and methanol (v / v = 10 / 1, 50 mL). The filtrate was concentrated under reduced pressure until no water remained. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to obtain a brown solid, 6,6-dimethyl-8-(4-methylpiperazin-1-yl)-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (183 mg, 88% yield). MS (ESI) m / z: 481.2 (M+H). + .

[0117] 3-ethynyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000110.tif281706,6-Dimethyl-8-(4-methylpiperazin-1-yl)-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (183 mg, 0.38 mmol) and potassium carbonate (263 mg, 1.91 mmol) were added to a mixture of acetonitrile (20 mL) and methanol (3 mL). The mixture was stirred at room temperature overnight. The reaction was monitored for completeness by LCMS. The mixture was quenched with water (30 mL). The mixture was extracted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until dry. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to obtain a yellow solid, 3-ethynyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (86.21 mg, 55% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.44 (s, 1H), 8.35 (s, 1H), 8.15 (d, J=8.0 Hz, 1H),7.60 (s, 1H), 7.42(s, 1H), 7.35(q, J=4.6 Hz, 1H), 4.14(s, 2H), 3.41(t, J=8.8 Hz, 4H), 2.55 (s,4H), 2.28 (s,3H), 1.78 (s, 6H).

[0118] Example 14: 3-ethynyl-6,6-dimethyl-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (E14) TIFF0007752700000111.tif73170

[0119] 3-Bromo-6,6-dimethyl-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000112.tif32170 3-Bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (500 mg, 0.98 mmol) and 4-(pyrrolidin-1-yl)piperidine (3.0 g, 19.5 mmol) were dissolved in N-methylpyrrolidone (4 mL). The reaction was stirred at 120 °C for 5 h under nitrogen gas protection. LCMS showed complete reaction. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until dry. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to give a white solid: 3-bromo-6,6-dimethyl-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (165 mg, 33% yield). MS (ESI) m / z: 517.1 (M+H). + .

[0120] 6,6-Dimethyl-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000113.tif321703-Bromo-6,6-dimethyl-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (165 mg, 0.32 mmol), ethynyltrimethylsilane (628 mg, 6.39 mmol), and potassium phosphate (204 mg, 0.96 mmol) were dissolved in acetonitrile (10 mL). After purging with nitrogen gas three times, tris(dibenzylideneacetone)dipalladium (59 mg, 0.06 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (61 mg, 0.13 mmol) were added. The atmosphere was purged with nitrogen gas three times. The mixture was heated to 85°C and stirred for 10 hours. The mixture was filtered, and the filter cake was washed with a mixture of dichloromethane and methanol (v / v = 10 / 1, 50 mL). The filtrate was concentrated under reduced pressure until the water content was gone. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to give a brown solid, 6,6-dimethyl-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (110 mg, 66% yield). MS (ESI) m / z: 535.3 (M+H). + .

[0121] 3-ethynyl-6,6-dimethyl-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000114.tif321706,6-Dimethyl-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (110 mg, 0.21 mmol) and potassium carbonate (138 mg, 1.03 mmol) were added to acetonitrile (15 mL) and methanol (5 mL). The mixture was stirred at room temperature overnight. The reaction was monitored for completeness by LCMS. The mixture was quenched with water (30 mL). The mixture was extracted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until dry. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to obtain a pale yellow solid, 3-ethynyl-6,6-dimethyl-11-oxo-8-(4-(pyrrolidin-1-yl)piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (53.61 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.60 (s, 1H), 8.34 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.42 (s, 1H), 7.29 (q, J=4.6 Hz, 1H), 4.22(s, 1H), 3.83 (d, J=11.2 Hz, 2H), 3.08 (t, J=11.4Hz, 3H), 2.10 (s,2H), 1.91 (s, 2H), 1.79 (s, 6H), 1.35-1.23 (m, 8H).

[0122] Example 15: 8-(4-(Dimethylamino)piperidin-1-yl)-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (E15) TIFF0007752700000115.tif71170

[0123] 3-Bromo-8-(4-(dimethylamino)piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile N,N-Dimethylpiperidin-4-amine (148.2 g, 1160 mmol) was added to N-methylpyrrolidone (800 mL) and heated to 120 °C and stirred for 5 minutes. 3-Bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (88 g, 232 mmol) was added. The reaction was stirred at 120 °C for 5 hours under nitrogen gas protection. The reaction was monitored for completeness by LCMS. The reaction was cooled to room temperature and poured into methanol (8.0 L). Stirring and filtration gave a yellow solid, 3-bromo-8-(4-(dimethylamino)piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (61 g, 124.5 mmol, 72.4% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.33 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.39 (dd, J = 7.2, 2.5 Hz, 2H), 4.10 (q, J = 5.1 Hz, 1H), 3.81 (d, J = 12.3 Hz, 2H), 3.01 (t, J = 11.5 Hz, 2H), 2.23 (s, 6H), 1.92 (d, J = 10.8 Hz, 2H), 1.77 (s, 6H), 1.58 (dd, J = 20.5, 11.0 Hz, 2H).

[0124] 8-(4-(dimethylamino)piperidin-1-yl)-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile To a solution of 3-bromo-8-(4-(dimethylamino)piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (10 g, 20.4 mmol) and ethynyltrimethylsilane (20 g, 204 mmol) in acetonitrile (150 mL) was added tris(dibenzylideneacetone)dipalladium (918 mg, 1.02 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (946 mg, 8.16 mmol), and potassium phosphate (26 g, 122.4 mol). The mixture was heated to 90 °C under nitrogen gas protection and stirred for 6 hours. The reaction was monitored for completeness by LCMS. The reaction mixture was cooled to room temperature. The cake was filtered, and the filter cake was washed with dichloromethane and methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give a yellow solid, 8-(4-(dimethylamino)piperidin-1-yl)-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (43 g, yield 68.04%).

[0125] 8-(4-(dimethylamino)piperidin-1-yl)-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile To a solution of 8-(4-(dimethylamino)piperidin-1-yl)-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (43 g, 84.6 mmol) in tetrahydrofuran (200 mL) was added tetrabutylammonium fluoride (22.1 g, 84.6 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was monitored for completeness by LCMS. The reaction mixture was poured into ice water (150 mL) and extracted with ethyl acetate (2 × 300 mL). The organic phases were combined, washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) and then recrystallized to give a pale yellow solid, 8-(4-(dimethylamino)piperidin-1-yl)-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (20.062 g, 54.4% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.33 (s, 1H), 8.16 - 8.10 (m, 1H), 7.60 (s, 1H), 7.39 (s, 1H), 7.33 (dd, J = 8.1, 1.3 Hz, 1H), 4.13 (s, 1H), 3.80 (d, J = 0.01). 12.5 Hz, 2H), 3.00 (t, J = 11.3 Hz, 2H), 2.35 - 2.25 (m, 1H), 2.22 (s, 6H), 1.91 (d, J = 11.0 Hz, 2H), 1.77 (s, 6H), 1.64 - 1.51 (m, 2H).

[0126] Example 16: 3-ethynyl-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (E16) TIFF0007752700000119.tif72170

[0127] 3-Bromo-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000120.tif37170 3-Bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (500 mg, 0.97 mmol) in N-methylpyrrolidone (6 mL) was added with 1-methyl-4-(piperidin-4-yl)piperazine (1.79 g, 9.7 mmol). The mixture was heated to 150 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, quenched with ice water (30 mL), and extracted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until dry. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to give a white solid: 3-bromo-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (273 mg, 53% yield). MS (ESI) m / z: 532, 534 (M+H). + .

[0128] 6,6-Dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000121.tif301703-Bromo-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (273 mg, 0.48 mmol), ethynyltrimethylsilane (946 mg, 9.63 mmol), and potassium phosphate (307 mg, 1.44 mmol) were dissolved in acetonitrile (30 mL). The mixture was purged with nitrogen gas three times. Tris(dibenzylideneacetone)dipalladium (88 mg, 0.096 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (92 mg, 0.19 mmol) were added. The mixture was purged with nitrogen gas three times. The mixture was heated to 90 °C and stirred for 6 hours. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The mixture was filtered, and the filter cake was washed with a mixture of dichloromethane and methanol (v / v = 10 / 1, 50 mL). The filtrate was extracted with dichloromethane:methanol (10:1, 3 × 50 mL). The organic phase was separated, washed with saturated brine (30 mL), and concentrated until the water content was zero. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to give a yellow solid, 6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (90 mg, 32% yield). MS (ESI) m / z: 564 (M+H). + .

[0129] 3-ethynyl-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000122.tif311706,6-Dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (90 mg, 0.17 mmol) and potassium carbonate (110 mg, 0.84 mmol) were added to acetonitrile (10 mL) and methanol (10 mL). The reaction was allowed to proceed with stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure until no water remained, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain a white solid, 3-ethynyl-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (29.85 mg, yield 38%). 1H NMR (400 MHz, DMSO-d6) δ12.43 (s, 1H), 8.33 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.34 (t, J = 2.4 Hz, 1H), 7.32(s, 2H), 4.12 (s,1H),3.80 (d, J = 12.0 Hz, 2H), 3. 01 (m, 2H), 2.98 (t, J = 11.7 Hz, 2H), 2.66 (m, 4H), 2.49 (m, 2H), 2.05 (m, 2H), 2.17 (s, 3H), 1.78 (s, 6H), 1.27 (m, 2H).

[0130] Example 17: 8-(4-Cyclopropylpiperazin-1-yl)-3-ethynyl-6,6-dimethyl-11-oxy-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (E17) TIFF0007752700000123.tif71170

[0131] 3-Bromo-8-(4-cyclopropylpiperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000124.tif301701-Cyclopropylpiperazine (2.5 g, 19.5 mmol) and 3-bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (500 mg, 0.98 mmol) were added to N-methylpyrrolidone (10 mL). The mixture was stirred at 120 °C for 5 h. The reaction was monitored for completeness by LCMS. The mixture was quenched with water (30 mL) and extracted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until dry. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to give a white solid, 3-bromo-8-(4-cyclopropylpiperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (329 mg, 69% yield). MS (ESI) m / z: 489.1 (M+H). + .

[0132] 8-(4-Cyclopropylpiperazin-1-yl)-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000125.tif301703-Bromo-8-(4-cyclopropylpiperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (329 mg, 0.67 mmol), ethynyltrimethylsilane (1324 mg, 13.48 mmol), and potassium phosphate (284 mg, 1.34 mmol) were dissolved in acetonitrile (10 mL). The mixture was degassed three times with nitrogen gas / vacuum, and then tris(dibenzylideneacetone)dipalladium (123 mg, 0.13 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (128 mg, 0.27 mmol) were added. The mixture was degassed three times with nitrogen gas. The mixture was heated to 85 °C and stirred for 10 h. The mixture was filtered, and the filter cake was washed with a mixed solvent of dichloromethane and methanol (v / v = 10 / 1, 50 mL). The filtrate was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until the filtrate was free of water. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to obtain a brown solid, 8-(4-cyclopropylpiperazin-1-yl)-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (426 mg). MS (ESI) m / z: 507.1 (M+H). + .

[0133] 8-(4-Cyclopropylpiperazin-1-yl)-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000126.tif301708-(4-Cyclopropylpiperazin-1-yl)-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (426 mg, 0.84 mmol) and potassium carbonate (464 mg, 3.36 mmol) were added to acetonitrile (15 mL) and methanol (5 mL). The reaction was stirred at room temperature for 6 hours. The reaction was monitored for completeness by LCMS. The mixture was quenched with water (30 mL) and extracted with a mixture of dichloromethane and methanol (v / v = 10 / 1, 3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until dry. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 30:1) to obtain a pale yellow solid, 8-(4-cyclopropylpiperazin-1-yl)-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (48 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 8.35 (s, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.41 (s, 1H), 7.35 (d, J=8.0Hz, 1H), 4.14 (s, 1H), 2.76 (s, 4H), 2.70 (s, 2H), 2.20 (t, J=8.0 Hz, 1H), 1.94-1.86 (m, 2H), 1.78 (s, 6H), 0.48 (s, 2H), 0.38(s, 2H).

[0134] Example 18: 8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (E18) TIFF0007752700000127.tif38170E18 JPEG0007752700000128.jpg59170

[0135] 3-Bromo-6,6-dimethyl-11-oxy-8-(1,4-dioxy-8-aza[4.5]decan-8-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000129.tif22170 3-Bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (1.2 g, 2.34 mmol) in N-methylpyrrolidone (10 mL) was added with 1,4-dioxo-8-azaspiro[4.5]decane (1.7 g, 11.70 mmol). The reaction was heated to 140 °C and stirred overnight. The reaction was monitored for completeness by LCMS. The mixture was diluted with ethyl acetate (200 mL) and water (200 mL). The organic phase was separated, washed with saturated brine (2 × 200 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure until no water remained. The crude product was purified by silica gel column chromatography (petroleum ester:ethyl acetate=5:1) to obtain a yellow solid, 3-bromo-6,6-dimethyl-11-oxy-8-(1,4-dioxy-8-aza[4.5]decan-8-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (350 mg, yield 29.7%).

[0136] 3-Bromo-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000130.tif211703-Bromo-6,6-dimethyl-11-oxy-8-(1,4-dioxy-8-aza[4.5]decan-8-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (350 mg, 0.69 mmol) in tetrahydrofuran (10 mL) was added to aqueous sulfuric acid (10%, 5 mL). The mixture was heated to 50 °C and stirred overnight. The reaction was monitored for completeness by LCMS. The mixture was diluted with ethyl acetate (200 mL) and water (200 mL). The organic phase was washed with saturated brine (2 × 200 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ester:ethyl acetate=1:1) to give a yellow solid, 3-bromo-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (250 mg, yield 78.6%).

[0137] 3-Bromo-8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000131.tif291703-Bromo-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (250 mg, 0.54 mmol) in 1,2-dichloroethane (10 mL) was added with 1-cyclopropylpiperazine (204 mg, 1.62 mmol). After stirring at room temperature for 2 hours, sodium borohydride acetate (420 mg, 2 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was monitored for completeness by LCMS. The reaction mixture was diluted with ethyl acetate (200 mL) and water (200 mL). The organic phase was washed with saturated brine (2 × 200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give a yellow solid, 3-bromo-8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (220 mg, yield 71.4%).

[0138] 8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000132.tif301703-Bromo-8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (220 mg, 0.39 mmol), ethynyltrimethylsilane (172 mg, 1.76 mmol), and potassium phosphate (250 mg, 1.2 mmol) in acetonitrile (10 mL) were added tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (38 mg, 0.08 mmol). The mixture was purged with nitrogen three times and heated to 70 °C and stirred overnight. The reaction was monitored for completeness by LCMS. The reaction mixture was diluted with dichloromethane (200 mL) and water (200 mL), and the organic phase was washed with saturated brine (2 × 200 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford a brown solid: 8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (90 mg, 39.1% yield).

[0139] 8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000133.tif331708-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (220 mg, 0.39 mmol) in tetrahydrofuran (10 mL) was added to a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 1 mL). The mixture was stirred overnight at room temperature under nitrogen gas protection. The reaction was monitored for completeness by LCMS. The reaction mixture was diluted with dichloromethane (200 mL) and water (200 mL). The organic phase was washed with saturated brine (2 × 200 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give a pale yellow solid: 8-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (10.03 mg, yield 5.0%). 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 8.36 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.06 (s, 1H), 3.89 (d, J = 12.0 Hz, 2H), 3.10 (s, 1H), 2.98 (t, J = 11.7 Hz, 2H), 2.66 (d, J = 23.6 Hz, 7H), 2.49 (s, 1H), 2.05 (s, 1H), 2.00 (s, 2H), 1.78 (s, 6H), 1.61 (s, 1H), 1.27 (d, J = 9.9 Hz, 2H), 0.44 (d, J = 11.4 Hz, 3H).

[0140] Example 19: 9-Chloro-3-ethynyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (E19) TIFF0007752700000134.tif120170

[0141] 6-chloro-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one N-Chlorosuccinimide (15.8 g, 118 mmol) was added to a solution of 7-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (22 g, 108 mmol) in acetonitrile (500 mL). The mixture was heated to 80 °C and stirred for 1 h. The reaction mixture was cooled to room temperature, poured into water (1000 mL), and extracted with ethyl acetate (2 × 300 mL). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 6-chloro-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (21 g, 81% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.11 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 2.6 Hz, 1H), 6.77 (dd, J = 8.3, 2.6 Hz, 1H), 3.75 (s, 3H), 3.01 - 2.94 (m, 2H), 2.59 (dd, J = 7.5, 6.2 Hz, 2H), 1.34 (s, 6H).

[0142] 3-Bromo-9-chloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole TIFF0007752700000136.tif211706-Chloro-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one (23.9 g, 100 mmol) and (3-bromophenyl)hydrazine hydrochloride (22.4 g, 100 mmol) were dissolved in acetic acid (400 mL). The mixture was heated to 120 °C and stirred for 8 hours. The mixture was cooled to room temperature and filtered. The filter cake was washed with water to give a brown solid, 3-bromo-9-chloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole (25 g, 64.2% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 7.80 (d, J = 0.7 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.39 (s, 1H), 7.35 (dd, J = 8.1, 1.4 Hz, 1H), 7.30 (s, 1H), 4.02 (s, 2H), 3.92 (s, 3H), 1.70 (s, 6H).

[0143] 3-Bromo-9-chloro-8-methoxy-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000137.tif22170 3-Bromo-9-chloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole (500 mg, 1.28 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (467 mg, 2.06 mmol) were dissolved in tetrahydrofuran (9 mL) and water (1 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give a red solid, 3-bromo-9-chloro-8-methoxy-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (300 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.62 (dd, J = 8.1, 1.2 Hz, 1H), 7.53 (s, 1H), 4.05 (s, 3H), 1.82 (s, 6H).

[0144] 3-Bromo-9-chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000138.tif221703-Bromo-9-chloro-8-methoxy-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (5 g, 12.3 mmol) and pyridine hydrochloride (28.6 g, 247 mmol) were added to a reaction flask. The mixture was heated to 170 °C and stirred for 13 hours. LCMS showed complete reaction. The reaction was quenched with ice water (500 mL). The mixture was extracted with ethyl acetate (3 × 150 mL), and the combined organic phases were washed with saturated brine (2 × 100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure until no water remained, to give a brown solid, 3-bromo-9-chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (4.1 g, crude product). 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 11.08 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 7.61 (dd, J = 8.1, 1.2 Hz, 1H), 7.31 (s, 1H), 1.73 (s, 6H).

[0145] 3-Bromo-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate TIFF0007752700000139.tif221703-Bromo-9-chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (810 mg, 2.0 mmol), triethylamine (606 mg, 6.0 mmol), and N,N-dimethylpyridine (24 mg, 0.2 mmol) were dissolved in dichloromethane (20 mL). The mixture was stirred at 0 °C for 10 min. Trifluoromethanesulfonic anhydride (846 mg, 3.0 mmol) was added dropwise. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with water (50 mL), extracted with ethyl acetate (3 × 30 mL), and washed with saturated brine (30 mL). The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a yellow oily substance, 3-bromo-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (650 mg, yield 62.5%). 1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.38 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 7.67 (dd, J = 8.1, 1.2 Hz, 1H), 1.81 (s, 6H).

[0146] 3-Bromo-9-chloro-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000140.tif281703-Bromo-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (240 mg, 0.46 mmol) and 1-methylpiperazine (69 mg, 0.69 mmol) were added to N-methylpyrrolidone (5 mL). The mixture was heated to 120 °C and stirred for 2 h. The reaction was monitored for completeness by LCMS. The reaction mixture was poured into ice water (150 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-TLC to give 3-bromo-9-chloro-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (165 mg, 76% yield) as a brown oil. MS(ESI) m / z: 472.1 (M+H). + .

[0147] 9-chloro-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 3-bromo-9-chloro-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (100 mg, 0.18 mmol), ethynyltrimethylsilane (176 mg, 1.8 mmol), and potassium phosphate (114 mg, 0.54 mmol) in acetonitrile (5 mL) was added tris(dibenzylideneacetone)dipalladium (16 mg, 0.018 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (9 mg, 0.018 mmol). The mixture was heated to 80 °C under nitrogen gas protection and stirred for 18 h. The reaction mixture was cooled and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a yellow oil, 9-chloro-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (84 mg, 81% yield). MS(ESI) m / z: 490.2 (M+H). + .

[0148] 9-chloro-3-ethynyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000142.tif241709-Chloro-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (84 mg, 0.17 mmol) and potassium carbonate (235 mg, 1.7 mmol) were added to methanol (5 mL). The mixture was heated to 30 °C under nitrogen gas protection and stirred for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by prep-HPLC to give a white solid, 9-chloro-3-ethynyl-6,6-dimethyl-8-(4-methylpiperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (23.55 mg, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 8.1 Hz, 1H), 8.08 (s, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 7.33 (dd, J = 8.1, 1.3 Hz, 1H), 4.12 (s, 1H), 3.17 (s, 4H), 2.51 (s, 4H), 2.26 (s, 3H), 1.76 (s, 6H).

[0149] Example 20: 9-chloro-8-(4-cyclopropylpiperazin-1-yl)-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (E20) TIFF0007752700000143.tif80170

[0150] 3-Bromo-9-chloro-8-(4-cyclopropylpiperazin-1-yl)-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000144.tif301703-Bromo-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (300 mg, 0.57 mmol) and 1-cyclopropylpiperazine (1.44 g, 11.4 mmol) were added to N-methylpyrrolidone (3 mL). The mixture was heated to 120°C and stirred for 16 hours. The reaction mixture was cooled to room temperature. The filtrate was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a yellow solid, 3-bromo-9-chloro-8-(4-cyclopropylpiperazin-1-yl)-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (90 mg, 31% yield). MS(ESI) m / z: 498.1 (M+H). + .

[0151] 9-chloro-8-(4-cyclopropylpiperazin-1-yl)-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 3-bromo-9-chloro-8-(4-cyclopropylpiperazin-1-yl)-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (75 mg, 0.15 mmol), ethynyltrimethylsilane (294 mg, 3 mmol), and potassium phosphate (95.4 mg, 0.45 mmol) in acetonitrile (8.0 mL) was added tris(dibenzylideneacetone)dipalladium (16 mg, 0.018 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (9 mg, 0.018 mmol). The mixture was heated to 80 °C under nitrogen gas protection and stirred for 18 h. The reaction mixture was cooled and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a yellow solid: 9-chloro-8-(4-cyclopropylpiperazin-1-yl)-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (37 mg, 47% yield). MS(ESI) m / z: 516.2 (M+H). + .

[0152] 9-chloro-8-(4-cyclopropylpiperazin-1-yl)-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000146.tif301709-Chloro-8-(4-cyclopropylpiperazin-1-yl)-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (37 mg, 0.07 mmol) and potassium carbonate (60 mg, 0.43 mmol) were added to methanol (20 mL). The mixture was heated to 30 °C under nitrogen gas protection and stirred for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC to give a white solid, 9-chloro-8-(4-cyclopropylpiperazin-1-yl)-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (7 mg, 22% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H), 7.60 (s, 1H), 7.42(s, 1H), 7.28 (dd, J = 1.2, 6.8 Hz, 1H), 4.11 (s, 1H), 3.12 (br, 4H), 2.74 (br, 4H), 1.74 (s, 6H). 0.46 (br, 2H), 0.35(br, 2H).

[0153] Example 21: 9-chloro-8-(4-(dimethylamino)piperidin-1-yl)-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (E21) TIFF0007752700000147.tif72170

[0154] 3-Bromo-9-chloro-8-(4-(dimethylamino)piperidin-1-yl)-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000148.tif311703-Bromo-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo-[b]carbazol-8-yl trifluoromethanesulfonate (500 mg, 0.96 mmol) and N,N-dimethylpiperidin-4-amine (2.4 g, 19.2 mmol) were added to N-methylpyrrolidone (5 mL). The mixture was heated to 120 °C and stirred for 16 h. After cooling to room temperature, the reaction mixture was purified by prep-HPLC (acetonitrile / water / 0.1% trifluoroacetic acid) to give a brown solid, 3-bromo-9-chloro-8-(4-(dimethylamino)piperidin-1-yl)-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (200 mg, 42% yield). MS(ESI)m / z:500.1(M+1) + .

[0155] 9-chloro-8-(4-(dimethylamino)piperidin-1-yl)-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 3-bromo-9-chloro-8-(4-(dimethylamino)piperidin-1-yl)-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (100 mg, 0.2 mmol), ethynyltrimethylsilane (392 mg, 4 mmol), and potassium phosphate (127.2 mg, 0.6 mmol) in acetonitrile (8.0 mL) was added tris(dibenzylideneacetone)dipalladium (36.6 mg, 0.04 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (38.08 mg, 0.08 mmol). The mixture was heated to 80 °C under nitrogen gas protection and stirred for 18 h. The reaction mixture was cooled and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a brown solid: 9-chloro-8-(4-(dimethylamino)piperidin-1-yl)-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (47 mg, 45% yield). MS (ESI) m / z: 518.2 (M+1). + .

[0156] 9-chloro-8-(4-(dimethylamino)piperidin-1-yl)-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000150.tif311709-Chloro-8-(4-(dimethylamino)piperidin-1-yl)-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (47 mg, 0.09 mmol) and potassium carbonate (125 mg, 0.9 mmol) were added to methanol (5 mL). The mixture was stirred at room temperature for 2 hours. After filtration, the filtrate was concentrated under reduced pressure to remove the solvent, and the crude product was purified by prep-HPLC to give a white solid: 9-chloro-8-(4-(dimethylamino)piperidin-1-yl)-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (12.3 mg, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.46(s, 1H), 8.23 ​​(s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H), 7.61 (s, 1H), 7.42(s, 1H), 7.33 (dd, J = 1.2, 6.8 Hz, 1H), 4.13 (s, 1H), 2.81 (t, J = 12.0 Hz, 2H), 2.45-2.40 (m, 1H), 2.30 (s, 6H), 1.94-1.91(m, 2H), 1.75 (s, 6H). 1.65-1.60 (m, 2H).

[0157] Example 22: 9-Chloro-3-ethynyl-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (E22) TIFF0007752700000151.tif72170

[0158] 3-Bromo-9-chloro-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000152.tif331703-Bromo-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (1.2 g, 2.3 mmol), 1-(1-methylpiperidin-4-yl)piperazine hydrochloride (504 mg, 22.9 mmol), and sodium bicarbonate (2.4 g, 22.9 mmol) were added to N-methylpyrrolidone (20 mL). The mixture was heated to 120 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give 3-bromo-9-chloro-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (205 mg, 17% yield) as a brown oil. MS (ESI) m / z: 555.1 (M+H). + .

[0159] 9-chloro-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 3-bromo-9-chloro-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (100 mg, 0.18 mmol), ethynyltrimethylsilane (176 mg, 1.8 mmol), and potassium phosphate (114 mg, 0.54 mmol) in acetonitrile (5 mL) was added tris(dibenzylideneacetone)dipalladium (16 mg, 0.018 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (9 mg, 0.018 mmol). The mixture was heated to 80 °C under nitrogen gas protection and stirred for 18 hours. The reaction mixture was filtered. The filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give a yellow oily substance, 9-chloro-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (65 mg, 63% yield). MS(ESI) m / z: 573.3 (M+H). + .

[0160] 9-chloro-3-ethynyl-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000154.tif311709-Chloro-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (65 mg, 0.11 mmol) and potassium carbonate (152 mg, 1.1 mmol) were added to methanol (5 mL). The reaction was stirred at 30°C for 2 hours under nitrogen gas protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure until no water remained. The crude product was purified by prep-HPLC to give a white solid product, 9-chloro-3-ethynyl-6,6-dimethyl-8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (8.17 mg, 15% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 8.0 Hz, 1H), 8.08 (s, 1H), 7.60 (s, 1H), 7.41 (s, 1H), 7.32 (d, J = 8.6 Hz, 1H), 4.10 (s, 1H), 3.50 (s, 4H), 2.85 - 2.65 (m, 4H), 2.33 (s, 4H), 2.15 (s, 3H), 1.90 (d, J = 11.6 Hz, 2H), 1.75 (s, 6H), 1.60 (d, J = 12.4 Hz, 3H).

[0161] Example 23: 9-Chloro-3-ethynyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (E23) TIFF0007752700000155.tif79170

[0162] 3-Bromo-9-chloro-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000156.tif331703-Bromo-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (300 mg, 0.57 mmol) and 4-(piperidin-4-yl)morpholinyl (1.94 g, 11.4 mmol) were added to N-methylpyrrolidone (3 mL). The mixture was heated to 120 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and purified by C18 column chromatography to give a yellow solid, 3-bromo-9-chloro-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazole-11 ketone (100 mg, 32% yield). MS(ESI)m / z:542.1(M+H) + .

[0163] 9-chloro-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 3-bromo-9-chloro-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (100 mg, 0.18 mmol), ethynyltrimethylsilane (353 mg, 3.6 mmol), and potassium phosphate (127.2 mg, 0.6 mmol) in acetonitrile (8.0 mL) was added tris(dibenzylideneacetone)dipalladium (32.9 mg, 0.036 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (34.3 mg, 0.072 mmL). The reaction was stirred at 80 °C for 18 hours under nitrogen gas protection. The reaction mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a brown solid, 9-chloro-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (40 mg, 39% yield). MS (ESI) m / z: 560.2 (M+H). + .

[0164] 9-chloro-8-(4-cyclopropylpiperazin-1-yl)-3-(3-hydroxypropyl-1-ynyl-1-yl)-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000158.tif301709-Chloro-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (40 mg, 0.07 mmol) and potassium carbonate (60 mg, 0.43 mmol) were added to methanol (20 mL). The mixture was stirred at room temperature for 2 hours. After filtration, the filtrate was concentrated under reduced pressure until dry. The crude product was purified by prep-HPLC to give a white solid: 9-chloro-8-(4-cyclopropylpiperazin-1-yl)-3-(3-hydroxypropyl-1-ynyl-1-yl)-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (4.0 mg, 11% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.45(s, 1H), 8.31 (s, 1H), 8.13 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.60 (s, 1H), 7.42(s, 1H), 7.32 (dd, J = 1.2, 6.8 Hz, 1H), 4.13 (s, 1H), 3.60-3.40 (m, 7H), 2.84-2.78 (m, 2H), 2.38-2.32 (m, 2H), 1.94-1.91 (m, 2H),1.77 (s, 6H). 1.62-1.52 (m, 2H).

[0165] Example 24: 9-Chloro-3-ethynyl-6,6-dimethyl-8-(piperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (E24) TIFF0007752700000159.tif107170

[0166] t-Butyl 4-(3-bromo-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate TIFF0007752700000160.tif281703-Bromo-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (500 mg, 0.96 mmol) and tert-butyl piperazine-1-carboxylate (3.56 g, 19 mmol) were added to N-methylpyrrolidone (5 mL). The mixture was heated to 120 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was purified by prep-HPLC to yield a white solid: tert-butyl 4-(3-bromo-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate (200 mg, 37% yield). MS(ESI)m / z:558.1(M+H) + .

[0167] t-Butyl 4-(9-chloro-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(3-bromo-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate (100 mg, 0.18 mmol), ethynyltrimethylsilane (352.8 mg, 3.6 mmol), and potassium phosphate (95.4 mg, 0.45 mmol) in acetonitrile (8.0 mL) was added tris(dibenzylideneacetone)dipalladium (27.5 mg, 0.03 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (28.6 mg, 0.06 mmL). The mixture was stirred at 80 °C under nitrogen gas protection for 18 hours. The reaction mixture was filtered. The filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a yellow solid, t-butyl 4-(9-chloro-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate (70 mg, 68% yield). MS (ESI) m / z: 576.2 (M+1). + .

[0168] t-Butyl 4-(9-chloro-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate t-Butyl 4-(9-chloro-6,6-dimethyl-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate (70 mg, 0.07 mmol) and potassium carbonate (60 mg, 0.43 mmol) were added to methanol (20 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure until dry. The crude product was purified by prep-HPLC to give t-butyl 4-(9-chloro-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate (30 mg, 41% yield) as a white solid. MS(ESI)m / z:504.2(M+H) + .

[0169] 9-Chloro-3-ethynyl-6,6-dimethyl-8-(piperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one t-Butyl 4-(9-chloro-3-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazine-1-carboxylate (30 mg, 0.059 mmol) was added to 1,1,1,3,3,3-hexafluoropropan-2-ol (2.0 mL). The mixture was heated to 120 °C and stirred for 16 hours. The reaction mixture was concentrated to remove the solvent, and the crude product was purified by prep-HPLC (acetonitrile / water / 0.1% formic acid) to give a white solid, 9-chloro-3-ethynyl-6,6-dimethyl-8-(piperazin-1-yl)-5,6-dihydro-11H-benzo[b]carbazole-11 ketone (7.1 mg, 29% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.28 (s, 1H), 8.14 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.60 (s, 1H), 7.41(s, 1H), 7.32 (dd, J = 1.2, 6.8 Hz, 1H), 4.13 (s, 1H), 3.10 (br, 4H), 2.90 (br, 4H), 1.76 (s, 6H).

[0170] Example 25: 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-9-chloro-3-ethynyl-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (E25) TIFF0007752700000164.tif107170

[0171] 3-Bromo-9-chloro-6,6-dimethyl-8-(1,4-dioxo-8-azaspiro[4.5]decan-8-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000165.tif301703-Bromo-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (600 mg, 1.15 mmol) and 1,4-dioxo-8-azaspiro[4.5]decane (3.3 g, 23 mmol) were dissolved in N-methylpyrrolidone (5 mL). The mixture was heated to 120 °C and stirred for 3 days. The reaction mixture was cooled to room temperature and purified by prep-HPLC to give a white solid: 3-bromo-9-chloro-6,6-dimethyl-8-(1,4-dioxo-8-azaspiro[4.5]decan-8-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (200 mg, 34% yield). MS(ESI) m / z: 515.1 (M+H). + .

[0172] 3-Bromo-9-chloro-6,6-dimethyl-8-(4-oxopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000166.tif281703-Bromo-9-chloro-6,6-dimethyl-8-(1,4-dioxo-8-azaspiro[4.5]decan-8-yl)-5,6-dihydro-11H-benzo[b]carbazole-11-ketone (200 mg, 0.39 mmol) in acetone (20 mL) was added to 4-methylbesylic acid (133 mg, 0.78 mmol) and water (3 mL). The mixture was heated to reflux and stirred for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate (25 mL), washed with saturated aqueous sodium bicarbonate (2 × 10 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to give a white solid, 3-bromo-9-chloro-6,6-dimethyl-8-(4-oxopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (130 mg, 31% yield). MS (ESI) m / z: 471.1 (M+H). + .

[0173] 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-3-bromo-9-chloro-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000167.tif301703-Bromo-9-chloro-6,6-dimethyl-8-(4-oxopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (130 mg, 0.27 mmol), azetidinyl azetidinyl (47 mg, 0.81 mmol), and anhydrous magnesium sulfate (50 mg, 0.42 mmol) in 1,2-dichloroethane (5 mL) were added with acetic acid (5 drops). The mixture was stirred at room temperature for 2 hours. Sodium borohydride acetate (114.5 mg, 0.54 mmol) was added. The mixture was heated to 50°C and stirred for 2 hours. The reaction mixture was cooled to room temperature and quenched with methanol. The solvent was removed by concentration under reduced pressure, and the crude product was purified by prep-HPLC to give a yellow solid: 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-3-bromo-9-chloro-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (100 mg, 71% yield). MS(ESI) m / z: 512.1 (M+H). + .

[0174] 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-9-chloro-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-3-bromo-9-chloro-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (50 mg, 0.10 mmol), ethynyltrimethylsilane (196 mg, 2 mmol), and potassium phosphate (42.4 mg, 0.2 mmol) in acetonitrile (5 mL) was added tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (19 mg, 0.04 mmL). The mixture was stirred at 80 °C for 18 hours under nitrogen gas protection. The reaction mixture was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure until no water remained. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a brown solid: 8-(4-(azetidinyl-1-yl)piperidin-1-yl)-9-chloro-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (40 mg, 77% yield). MS (ESI) m / z: 530.3 (M+H). + .

[0175] 9-chloro-8-(4-cyclopropylpiperazin-1-yl)-3-(3-hydroxypropyl-1-ynyl-1-yl)-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one TIFF0007752700000169.tif301708-(4-(azetidinyl-1-yl)piperidin-1-yl)-9-chloro-6,6-dimethyl-3-((trimethylsilyl)ethynyl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (40 mg, 0.075 mmol) and potassium carbonate (60 mg, 0.43 mmol) were dissolved in methanol (20 mL) and stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure until no water remained. The crude product was purified by Prep-HPLC to give a brown solid, 9-chloro-8-(4-cyclopropylpiperazin-1-yl)-3-(3-hydroxypropyl-1-ynyl-1-yl)-6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one (9.2 mg, yield 27%). 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 10.21 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 7.61 (s, 1H), 7.44 (s, 1H), 7.33 (dd, J =1.6, 6.4 Hz, 1H), 4.21-4.01 (m, 5H), 3.59-3.50 (m, 2H), 2.83 (t, J=14.0 Hz, 2H), 2.40-2.32 (m 1H), 2.21-2.02 (m, 2H), 1.75 (s, 6H), 1.60-1.48 (m, 2H).

[0176] Example 26: 3-(Cyclopropylethynyl)-9-ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (E26) TIFF0007752700000170.tif79170

[0177] 3-(cyclopropylethynyl)-9-ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 9-ethyl-3-iodo-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (98 mg, 0.17 mmol) and ethynylcyclopropane (2.0 mL, dissolved in 70% toluene) in acetonitrile (10 mL) was added potassium phosphate (42 mg, 0.20 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (20 mg, 0.04 mmol), and tris(dibenzylideneacetone)dipalladium (20 mg, 0.02 mmol). The mixture was stirred under argon gas protection at 90 °C for 1 h and monitored for completeness by LCMS. The reaction mixture was diluted with water and extracted with ethyl acetate (2 × 100 mL). The combined organic phases were washed with water (100 mL), saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC to give an off-white solid: 3-(cyclopropylethynyl)-9-ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (22 mg, 27.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.28 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.46 (s, 1H), 7.32 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 3.61~3.60 (m, 4H), 3.22~3.19 (m, 2H), 2.78~2.64 (m, 6H), 2.56~2.50 (m, 2H), 2.33~2.31 (m, 1H), 1.93~1.90 (m, 2H), 1.71 (s, 6H), 1.64~1.60 (m, 3H), 1.27 (t, J=6.0 Hz, 3H), 0.90~0.88 (m, 2H), 0.76~0.75 (m, 1H).

[0178] Example 27: 9-Ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-3-(propan-1-ynyl-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (E27) TIFF0007752700000172.tif86170

[0179] 9-Ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-3-(propan-1-yl-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one To a solution of 9-ethyl-3-iodo-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (50 mg, 0.08 mmol) and propynyl ether (3 mL, 4% DMF) in acetonitrile (10 mL) was added potassium phosphate (20 mg, 0.10 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (10 mg, 0.02 mmol), and tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mmol). The reaction was stirred under argon gas protection at 60 °C for 1 h and monitored for completeness by LCMS. The reaction mixture was diluted with water and extracted with ethyl acetate (2 × 50 mL). The combined organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC to give an off-white solid: 9-ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-3-(propan-1-yl-1-yl)-5,6-dihydro-11H-benzo[b]carbazol-11-one (8.0 mg, 18.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.22 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.48 (s, 1H), 7.32 (s, 1H), 7.23 (d, J=6.8 Hz, 1H), 3.65~3.60 (m, 4H), 3.24~3.19 (m, 2H), 2.79~2.76 (m, 4H), 2.73~2.69 (m, 4H), 2.35~2.32 (m, 1H), 2.07 (s, 1H), 1.92~1.90 (m, 2H), 1.72 (s, 6H), 1.61~1.56 (m, 2H), 1.27 (t, J=6.0 Hz, 3H).

[0180] Example 28: 3-ethynyl-6,6-dimethyl-8-(4-(methylamino)piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (E28) TIFF0007752700000174.tif98170

[0181] 3-Bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate TIFF0007752700000175.tif241703-Bromo-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (15 g, 39.5 mmol) and pyridine (12.5 g, 158 mmol) were added to dichloromethane (200 mL) and cooled to 0-10°C. Trifluoromethanesulfonic anhydride (44.6 g, 158 mmol) was added dropwise and the mixture was allowed to react at room temperature for 3 hours. The reaction mixture was thoroughly extracted with dichloromethane and water. The mixture was concentrated and spun onto a column (petroleum ether:ethyl acetate = 2:1). 3-Bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (9.0 g, 17.5 mmol, 44.4% yield) was obtained as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.73 (s, 1H), 8.41 (d, J = 13.0 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 1.5 Hz, 1H), 7.44 (dt, J = 16.6, 8.3 Hz, 1H), 1.82 (s, 6H).

[0182] t-Butyl(1-(3-bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)carbamate methyl Methylpiperidinyl t-butylcarbamate (18.7 g, 87.5 mmol) was stirred in N-methylpyrrolidone (50 mL) at room temperature. 3-Bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl trifluoromethanesulfonate (9.0 g, 17.5 mmol) was added at 120 °C. The resulting mixture was stirred at 120 °C for 5 h under a nitrogen atmosphere. The reaction was monitored for completeness by LCMS. The reaction was cooled to room temperature, poured into water (500 mL), filtered, and washed with MeOH. After drying, a yellow solid product, methyl t-butyl(1-(3-bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)carbamate (8.2 g, 14.2 mmol, 81.2% yield), was obtained.

[0183] 3-Bromo-6,6-dimethyl-8-(4-(methylamino)piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile Methyl t-butyl(1-(3-bromo-9-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-4-yl)carbamate (8.2 g, 14.2 mmol) was added to a solution of 4 M dioxane-HCl (250 mL). The resulting mixture was stirred at room temperature for 16 hours and then concentrated to dryness to give a yellow solid, 3-bromo-6,6-dimethyl-8-(4-(methylamino)piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (8.2 g, 17.2 mmol, 100% yield).

[0184] 6,6-Dimethyl-8-(4-(methylamino)piperidin-1-yl)-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile To a solution of 3-bromo-6,6-dimethyl-8-(4-(methylamino)piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (8.2 g, 17.2 mmol) in acetonitrile (250 mL) and DMF (50 mL) was added ethynyltrimethylsilane (16.9 g, 172 mmol). Pd(dba) (1.58 mg, 1.72 mmol), X-phos (1.64 g, 3.44 mmol), and potassium phosphate tribasic (21.9 g, 103.2 mol) were added under a nitrogen atmosphere. The resulting mixture was heated to 90 °C and stirred for 16 h. After monitoring the complete reaction by LCMS, the reaction mixture was filtered, washed with a mixture of dichloromethane and methanol, and the solution was concentrated and purified by column chromatography (methanol dissolved in dichloromethane: 0-25%) to give a yellow solid, 6,6-dimethyl-8-(4-(methylamino)piperidin-1-yl)-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (7.1 g, 14.4 mmol, 83.7% yield).

[0185] 3-ethynyl-6,6-dimethyl-8-(4-(methylamino)piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile TIFF0007752700000179.tif281706,6-Dimethyl-8-(4-(methylamino)piperidin-1-yl)-11-oxo-3-((trimethylsilyl)ethynyl)-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (7.1 g, 14.4 mmol) was added to a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 144 mL, 14.4 mmol) and stirred at room temperature for 2 h. The reaction was monitored for completeness by LCMS. The reaction mixture was poured into ice water (150 mL) and extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (methanol in dichloromethane: 0-25%) to give a crude product, which was then purified by preparative HPLC (NH3.HO) to give a pale yellow solid, 3-ethynyl-6,6-dimethyl-8-(4-(methylamino)piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-carbonitrile (2.0 g, 4.73 mmol, 32.8% yield). HPLC: 254 nm: 98.76%, 214 nm: 99.00%. 1H NMR (400 MHz, DMSO) δ 12.33 (s, 1H), 8.33 (s, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H), 7.39 (s, 1H), 7.33 (dd, J = 8.1, 1.3 Hz, 1H), 4.13 (s, 1H), 3.72 (d, J = 12.6 Hz, 2H), 3.07 (t, J = 10.6 Hz, 2H), 2.54 (s, 1H), 2.32 (s, 3H), 1.97 (d, J = 10.6 Hz, 2H), 1.77 (s, 6H), 1.44 (dd, J = 20.0, 9.6 Hz, 2H).

[0186] Biological evaluation 1. ALK kinase inhibition test The inhibitory activity of the compounds of the present application against ALK kinase was measured in an in vitro test, and the activity can be expressed as an IC value. The half-maximal inhibitory concentration (IC value) of a compound (the compound concentration required to inhibit enzyme activity at a certain concentration by 50%) was calculated by mixing different test compounds with a certain amount of kinase and a specific substrate and then measuring the reaction.

[0187] The specific experimental procedure is as follows: Test compounds were prepared in DMSO to a 10 mM stock solution, aliquoted and stored at -20°C. Just before use, they were thawed and diluted to 1 mM with DMSO. They were then diluted 40-fold with 1x kinase buffer (50 mM 4-hydroxyethylpiperazineethanesulfonic acid pH 7.0, 0.02% NaN3, 0.01% BSA, 0.1 mM orthovanadate, 5 mM MgCl2, 1 mM DTT, and 37.5 nM supplemented enzyme buffer). Four μL of the diluted test compound solution and 2 μL of 0.4 ng / well ALK kinase solution (Thermo Scientific) were sequentially added to the reaction wells. After 10 min of incubation at room temperature, 4 μL of 0.7 μM biotin-labeled tyrosine kinase substrate and 5 μM ATP solution were added to initiate the kinase reaction. After the reaction was completed, 5 μL of 43.75 nM streptavidin-labeled XL665 was added, and immediately after mixing, 5 μL of 0.04 nM europium-labeled tyrosine kinase antibody detection solution was added. After 1 h of reaction at room temperature, the fluorescence signal (320 nm excitation, 665 nm, 615 nm emission) was detected using a SpectraMax i3x instrument. Finally, the inhibition rate of the test compound against ALK kinase activity was calculated according to the following formula: Emission coefficient (ER) = 665 nm emitted optical signal / 615 nm emitted optical signal Inhibition rate % = (ERv-ERs) / (ERv-ERb) × 100% ERs: ER of sample treatment group ERv: ER in the vehicle control group ERb: ER of blank control group The IC50 values ​​were calculated by performing IC50 curve fitting using the software Graphpad Prism 6, and the calculation results are shown in Table 1.

[0188] As is evident from the data in Table 1, the compounds provided herein have significant inhibitory effects on ALK kinase activity.

[0189] Here, kinase buffer is a translation of Kinase Buffer, 4-Hydroxyethylpiperazineethanesulfonic acid is HEPES, Orthovanadate is the translation of orthovanadate, Supplementary enzyme buffer is SEB translation, Biotin-labeled tyrosine kinase substrate is TK-biotin substrate, Streptavidin-labeled XL665 is Streptavidin-XL665. Europium-labeled tyrosine kinase antibody is TK antibody europium cryptate.

[0190] 2. ALK gene fusion cell growth inhibition test Hereinafter, the growth inhibitory activity of the compounds of the present application against ALK gene fusion highly expressing human anaplastic large cell lymphoma cells Karpas 299 was measured by an in vitro test, and the activity can be expressed as an IC50 value.

[0191] The specific experimental procedure is as follows: Logarithmic growth phase human anaplastic large cell lymphoma cells, Karpas 299, were harvested and adjusted to the appropriate concentration. The appropriate concentration of cells was seeded into a 96-well culture plate, with 100 μL of cell suspension added per well. The 96-well culture plate was placed in a 37°C, 5% CO2 incubator overnight. Test compounds were prepared in DMSO to a 10 mM stock solution, and then serially diluted 4-fold with DMSO, starting with 10 mM, to obtain nine test compound concentrations. The test compounds were diluted with culture medium to 5 times the corresponding final working concentration. 25 μL / well of the diluted test compounds were added to the appropriate cell wells according to the compound layout, and incubated at 37°C, 5% CO2 incubator for 72 hours. After 72 hours, 10 μL of CCK-8 was added to the cell culture medium. The culture medium was aspirated, and freshly prepared CCK-8 detection solution was added. The cells were then incubated for 1-4 hours in a 37°C incubator. After gentle shaking, the absorbance was measured at 450 nm using a SpectraMax i3X Microplate Reader, with the absorbance at 650 nm used as a reference. Finally, the inhibitory rate of the test compound against the proliferation of human anaplastic large cell lymphoma Karpas 299 cells was calculated according to the following formula: Cell proliferation inhibition rate % = [(Av - As) / (As - Ab)] x 100% As: absorbance of sample-treated cells (sample-treated group) (cells + CCK-8 + test compound). Av: absorbance of solvent-treated cells (solvent control group) (cells + CCK-8 + DMSO). Ab: Absorbance of cell-free blank control (medium + CCK-8 + DMSO) The IC50 values ​​were calculated by performing IC50 curve fitting using the software Graphpad Prism 6, and the calculation results are shown in Table 1.

[0192] As is clear from the data in Table 1, the compounds provided in the present application have significant growth inhibitory activity against human anaplastic large cell lymphoma cells Karpas 299.

[0193] [Table 1] TIFF0007752700000181.tif228170TIFF0007752700000182.tif231170TIFF0007752700000183.tif239170TIFF0007752700000184.tif69170

[0194] The above examples are preferred embodiments of the present application, but the embodiments of the present application are not limited to the above examples. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principles of the present application should be considered as equivalent substitution methods, and should all be protected within the scope of the claims of the present invention.

[0195] Industrial Applicability The present application provides compounds with ALK inhibitory activity, as well as methods for preparing and using the same. The compounds with ALK inhibitory activity provided in the present application are ALK inhibitors for treating diseases that respond to ALK kinase inhibition, and can be used to treat ALK-positive related diseases, such as tumors and cancers, and have broad clinical application prospects.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (In the formula, R １ is selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a C3-C6 cycloalkane group, a substituted or unsubstituted aryl group or heterocyclic aryl group, and a halogen atom; R ２ is selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a cyano group, and a halogen atom, and the substituent of the C1-C4 alkyl group is selected from a C3-C6 cycloalkane group, a halogen atom, and a cyano group; R ３ is selected from a heterocyclic aryl group, an aryl group, and a substituted or unsubstituted 5- to 7-membered heterocycle, wherein the 5- to 7-membered heterocycle contains 1 to 3 heteroatoms each independently selected from N, P, O, and S; R ４ , R ５ are each independently selected from hydrogen, a substituted or unsubstituted saturated C1-C4 alkyl group, and a substituted or unsubstituted unsaturated C1-C4 alkyl group.

2. R １ is selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, and a C3-C6 cycloalkane group; R ２ is selected from hydrogen, an unsubstituted C1-C4 alkyl group, a cyano group, and a halogen atom; R ３ is selected from a substituted or unsubstituted 5- to 7-membered heterocycle, wherein the 5- to 7-membered heterocycle contains 1 to 3 heteroatoms each independently selected from N, P, O, and S; R ４ , R ５ and each independently is selected from hydrogen and an unsubstituted saturated C1-C4 alkyl group, or a pharmaceutically acceptable salt thereof.

3. R １ is hydrogen, methyl group, ethyl group, propyl group, is selected from R ２ is selected from a methyl group, an ethyl group, a propyl group, a cyano group, Cl, Br, and F; R ３ is selected from a substituted or unsubstituted six-membered heterocycle, wherein said six-membered heterocycle contains 1 to 3 N heteroatoms; R ４ , R ５ and R are each independently selected from hydrogen, a methyl group, an ethyl group, and a propyl group, or a pharmaceutically acceptable salt thereof.

4. R １ is a hydrogen, a methyl group, is selected from R ２ is selected from a methyl group, an ethyl group, a cyano group, Cl, Br, and F; R ３ teeth, wherein R ６ , R ７ , R ８ are each independently selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkane group, a substituted or unsubstituted 4- to 7-membered heterocycle, a cyano group, a halogen atom, and a nitrogen-containing alkyl group, and the 4- to 7-membered heterocycle contains 1 to 3 heteroatoms each independently selected from N, P, O, and S; R ４ , R ５ and each independently is selected from a methyl group, or a pharmaceutically acceptable salt thereof.

5. The R ６ , R ７ , R ８ each independently represents a hydrogen atom, a methyl group, an ethyl group, a cyano group, a dimethylamino group, a diethylamino group, 5. The compound according to claim 4, wherein the compound is selected from the group consisting of:

6. R １ is hydrogen, is selected from R ２ is selected from an ethyl group, a cyano group, and Cl; R ３ teeth, The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

7. The compound of formula (I) is The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

8. A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

9. 10. Use of the pharmaceutical composition of claim 8 in the manufacture of a medicament for inhibiting ALK activity.

10. 10. Use of the pharmaceutical composition of claim 8 in the manufacture of a medicament for treating ALK-positive related tumors and cancers.

11. 8. A method for producing the compound or a pharmaceutically acceptable salt thereof according to claim 7, characterized in that it comprises at least a step of adding a carbonate to a methanol solution of a compound represented by formula (II) and reacting with stirring, wherein the compound represented by formula (II) is as follows: (In the formula, R' ２ is selected from an ethyl group, a cyano group, Cl, Br, and F; R' ３ teeth, wherein R ６ , R ７ , R ８ are each independently selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkane group, a substituted or unsubstituted 4- to 7-membered heterocycle, a cyano group, a halogen atom, and a nitrogen-containing alkyl group, and the 4- to 7-membered heterocycle contains 1 to 3 heteroatoms each independently selected from N, P, O, and S; R ４ and R' ４ represent the same group, R ５ and R' ５ represent the same group.)

12. 8. A method for producing the compound or a pharmaceutically acceptable salt thereof according to claim 7, comprising at least a step of adding a compound represented by formula (III) and a carbonate to acetonitrile and methanol and reacting them with stirring, wherein the compound represented by formula (III) is as follows: (R'' ３ teeth, is selected from R ４ and R'' ４ represent the same group, R ５ and R'' ５ represent the same group.)

13. 8. A method for producing the compound or a pharmaceutically acceptable salt thereof according to claim 7, characterized in that the method comprises at least a step of adding tetrabutylammonium fluoride to a tetrahydrofuran solution of a compound represented by formula (IV) and reacting the resulting mixture with stirring, wherein the compound represented by formula (IV) is as follows: (The above R''' ３ teeth, is selected from

14. 8. A method for producing the compound or a pharmaceutically acceptable salt thereof according to claim 7, comprising at least the steps of adding potassium phosphate, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, and tris(dibenzylideneacetone)dipalladium to an acetonitrile solution of a compound represented by formula (V) and an alkyl alkyne, and reacting them with stirring under an inert gas atmosphere, wherein the alkyl alkyne is selected from ethynylcyclopropane, propynyl, ethynylcyclobutane, and butyne, and the compound represented by formula (V) is as follows:

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