Benzocycloalkyl derivatives, processes for their preparation and their use

Abstract

The present application relates to a kind of benzocyclo derivatives, its preparation method and the pharmaceutical composition containing the derivative in medicine application. Specifically, the present application relates to a kind of benzocyclo derivatives shown in general formula (I), its preparation method and its pharmaceutically acceptable salt, and they are used as therapeutic agent, especially as RAC1 inhibitor, wherein the definition of each substituent in general formula (I) is the same as the definition in the specification.

Description

TECHNICAL FIELD

[0001] The present application relates to a benzocyclo derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and use of the derivative as a therapeutic agent, particularly as an RAC1 inhibitor. BACKGROUND

[0002] The RAC subfamily consists of RAC1, RAC2, RAC3 and RAC1b (a splice mutant of RAC1), RAC1 is widely distributed in various tissues, RAC2 is limited to blood cells, and RAC3 is mainly expressed in neurons. RAC1 is an important intracellular signal transduction molecule, which is closely related to the occurrence and development of malignant tumors.

[0003] The basic biological function of RAC1 is to bind and hydrolyze guanosine acid, and has two binding states, one is the activated state of binding GTP, and the other is the inactivated state of binding GDP, and can cycle between the two states. Its activity is mainly regulated by GEFs, GAPs and Rho GDI. It is the conversion of the two active forms that makes RAC1 play a "molecular switch" role in cell proliferation, differentiation and apoptosis, cell movement and adhesion, and transcription factor regulation, and is an important intracellular signal transduction molecule.

[0004] RAC1 protein has not been found to have a mutant in most invasive tumors in humans, but overactivity and high expression have been found. Abnormal increase of RAC1 expression has been reported in gastric cancer, colon cancer, breast cancer, lung cancer, testicular cell cancer, pancreatic cancer, head and neck tumors, ovarian cancer, etc.

[0005] At the same time, RAC1 target has a clear genetic confirmation. RAC1 inhibitors have obvious advantages for melanoma with RAC1 P29S mutation. At present, there is no available targeted therapy drug for melanoma with RAC1 P29S mutation in the world, and this driver mutation is the third largest melanoma mutation after BRAF and NRAS mutations, accounting for as high as 9%, making RAC1 inhibitors have broad market prospects.

[0006] There is no drug on the market that selectively targets RAC1. In 2021, Roche announced CDC42, RAC1 modulators (i.e. inhibitors and agonists) and their use for treating diseases, including cancers (solid tumors such as medulloblastoma, ovarian, breast, head and neck, testicular, prostate, etc. and hematological malignancies such as cell lymphoma, etc.) and diseases in which the activation of Rho GTPases plays a key role (Menkes disease, rheumatoid arthritis, atherosclerosis, diabetes (type I), Huntington's disease and Alzheimer's disease, etc.). Currently, this project is just in clinical phase I. As a relatively advanced research direction, RAC1 inhibitors are likely to become another breakthrough in the "undruggable" target direction after KRAS, bringing major opportunities and great challenges to pharmaceutical research and development. SUMMARY

[0007] The present application provides a compound represented by general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0008]

[0009] wherein:

[0010] R A is selected from a hydrogen atom, C1-C6 alkyl, hydroxyl, halogen, cyano, C1-C6 haloalkyl or C1-C6 alkoxy;

[0011] R 2 , R 3 are each independently selected from a group G or a hydrogen atom, provided that when R 2 is a group G, R 3 is a hydrogen atom; when R 2 is a hydrogen atom, R 3 is a group G, the group G is

[0012] ring A is selected from C6-C 10 aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl or 3-10 membered heterocyclyl;

[0013] ring B is selected from C6-C 10 aryl, 5-10 membered heteroaryl or 6-14 membered fused ring;

[0014] X is selected from O, S(O) r or NR a ;

[0015] R a is selected from a hydrogen atom or C1-C6 alkyl;

[0016] L 1 , L 2Each is independently selected from C1-C7 alkylene groups, wherein one or more methylene groups in the alkylene group are optionally separated by one or more O, S(O) groups. r C(O) or NR b What it replaces;

[0017] R b Selected from hydrogen atoms or C1-C6 alkyl groups;

[0018] W is selected from a bond or a 3-10 membered heterocyclic group, wherein the heterocyclic group is optionally further substituted by one or more substituents selected from C1-C6 alkyl, hydroxyl, cyano, halogen or C1-C6 alkoxy.

[0019] R 1 Whether identical or different, each is independently selected from C1-C6 alkyl, halogen, nitro, hydroxyl, amino, cyano, carboxyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic, C6-C 10 Aryl or 5-10-membered heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further composed of one or more groups selected from C1-C6 alkyl, halogen, nitro, cyano, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic, C6-C 10 aryl, 5-10 heteroaryl, =O, -OR 5 -C(O)R 5 -C(O)OR 5 -NHC(O)R 5 -NHC(O)OR 5 -NR 6 R 7 -C(O)NR 6 R 7 -CH2NHC(O)OR 5 -CH2NR 6 R 7 or -S(O) r R 5 The substituents are replaced by the substituents.

[0020] Alternatively, two R atoms connected to the same carbon atom 1 Together with the carbon atom it is attached to, it forms a -C(=O)-;

[0021] R 4 Whether the same or different, each is independently selected from C1-C6 alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic, C3-C 10 cycloalkyl, -OR 5 -C(O)R 5 -C(O)OR5 -NR 6 R 7 or -NR 6 C(O)R 7 , wherein said alkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally further substituted with one or more R F substituents;

[0022] R F are the same or different, each being independently selected from the group consisting of C1-C6alkyl, halogen, nitro, cyano, C2-C6alkenyl, C2-C6alkynyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C6-C 10 aryl, 5-10 membered heteroaryl, -OR 5 , -C(O)R 5 , -C(O)OR 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7 , -C(O)NR 6 R 7 , -CH2NHC(O)OR 5 , -CH2NR 6 R 7 or -S(O) r R 5 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of C1-C6alkyl, halogen, nitro, cyano, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C6-C 10 aryl, 5-10 membered heteroaryl, =O, -OR 5 , -C(O)R 5 , -C(O)OR 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7 , -C(O)NR 6 R 7 , -C(=NH)NR 6 R 7 , -CH2NHC(O)OR 5 , -CH2NR 6 R 7 or -S(O) r R 5 ,

[0023] or, two R groups attached to the same carbon atom are combined to form a =CR F , together with the carbon atom to which they are attached, form a -C(=O)-;

[0024] R 5 is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group, a C3-C 10 cycloalkyl group, a 3-10 membered heterocyclyl group, a C6-C 10 aryl group, or a 5-10 membered heteroaryl group; wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of a deuterium atom, a hydroxyl group, a halogen, a nitro group, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a C1-C6 hydroxyalkyl group, a C3-C 10 cycloalkyl group, a 3-10 membered heterocyclyl group, a C6-C 10 aryl group, a 5-10 membered heteroaryl group, =O, -C(O)R 8 , -C(O)OR 8 , -OC(O)R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -SO2NR 9 R 10 , or -NR 9 C(O)R 10 ;

[0025] R 6 and R 7 are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C 10 cycloalkyl group, a 3-10 membered heterocyclyl group, a C6-C 10 aryl group, or a 5-10 membered heteroaryl group; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a C1-C6 hydroxyalkyl group, a C3-C 10 cycloalkyl group, a 3-10 membered heterocyclyl group, a C6-C 10 aryl group, a 5-10 membered heteroaryl group, =O, -C(O)R 8 , -C(O)OR 8 , -OC(O)R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -SO2NR 9 R 10 , or -NR9 C(O)R 10 The substituents are replaced;

[0026] Or, R 6 and R 7 The atoms bonded to them together form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O). r Furthermore, the 4- to 8-membered heterocyclic group may optionally be further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic, C6-C 10 Aryl, 5-10 heteroaryl, =O, -C(O)R 8 -C(O)OR 8 -OC(O)R 8 -NR 9 R 10 -C(O)NR 9 R 10 -SO2NR 9 R 10 or -NR 9 C(O)R 10 The substituents are replaced;

[0027] R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, C1-C6 alkyl groups, amino groups, and C3-C4 atoms. 10 Cycloalkyl, 3-10 membered heterocyclic, C6-C 10 Aryl or 5-10-membered heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic, C6-C 10 Substituted by aryl, 5-10 heteroaryl, carboxyl or carboxylic acid ester groups;

[0028] r is selected from 0, 1, or 2;

[0029] m is selected from 0, 1, 2, or 3;

[0030] n is selected from 0, 1, 2, 3 or 4.

[0031] In a preferred embodiment of the present application, a compound of general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof is a compound of general formula (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

[0032]

[0033]

[0034] wherein: ring A, ring B, X, W, R 1 , R A , R 4 , L 1 , L 2 , m and n are as defined in general formula (I).

[0035] In a preferred embodiment of the present application, a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof is wherein X is -S-, -O- or -NH-.

[0036] In a preferred embodiment of the present application, a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof is wherein L 1 , L 2 are each independently selected from a bond or a C1-C7 alkylene group, wherein one or more methylene groups of said alkylene group are optionally replaced by one or more O, S(O) r , C(O) or NR b ;

[0037] r is selected from 0, 1 or 2;

[0038] R b is selected from a hydrogen atom or a methyl group.

[0039] In a preferred embodiment of the present application, a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof is wherein W is a bond or

[0040] In a preferred embodiment of the present application, a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof is wherein is selected from -(CH2)6NH- or

[0041] In a preferred embodiment of the present application, a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of

[0042]

[0043] In a preferred embodiment of the present application, a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of C1-C6 alkyl or 3-10 membered heterocyclyl; wherein said alkyl or heterocyclyl is optionally further substituted with one or more halogen. 10 aryl, wherein said alkyl or aryl is optionally further substituted with one or more halogen;

[0044] or, two R 1 , attached to the same carbon atom, together with the carbon atom to which they are attached form a -C(=O)-.

[0045] In a preferred embodiment of the present application, a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of

[0046]

[0047] In a preferred embodiment of the present application, a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein ring B is

[0048] In a preferred embodiment of the present application, a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of C1-C6 alkyl or 3-10 membered heterocyclyl; wherein said alkyl or heterocyclyl is optionally further substituted with one or more halogen.

[0049] In a preferred embodiment of the present application, a compound of general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of

[0050] In a preferred embodiment of the present application, a compound of general formula (I) is selected from the group consisting of:

[0051]

[0052]

[0053]

[0054] Or its stereoisomers, tautomers, or medicinal salts.

[0055] Note: If there is a difference between the drawn structure and the given name of the structure, the drawn structure will be given greater weight.

[0056] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

[0057] The present invention provides the use of a compound of general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a RAC1 inhibitor.

[0058] The present invention also provides the use of a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating diseases mediated by RAC1 mutations, wherein the diseases mediated by RAC1 mutations are selected from cancer, Menx disease, rheumatoid arthritis, atherosclerosis, diabetes (type I), Huntington's disease and Alzheimer's disease, wherein the cancers are selected from melanoma, gastric cancer, colon cancer, breast cancer, lung cancer, testicular cell carcinoma, pancreatic cancer, head and neck tumors, ovarian cancer, medulloblastoma, prostate cancer and B-cell lymphoma, preferably melanoma.

[0059] This invention provides the use of a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating cancer, Menx disease, rheumatoid arthritis, atherosclerosis, diabetes (type I), Huntington's disease and Alzheimer's disease, wherein the cancer is selected from melanoma, gastric cancer, colon cancer, breast cancer, lung cancer, testicular cell cancer, pancreatic cancer, head and neck tumors, ovarian cancer, medulloblastoma, prostate cancer and B-cell lymphoma, preferably melanoma.

[0060] DETAILED DESCRIPTION

[0061] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0062] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20straight-chain or branched aliphatic hydrocarbon group, preferably C1-C 10 alkyl, more preferably C1-C6alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. Alkyl groups can be substituted or unsubstituted.

[0063] "alkylene" refers to an alkyl group as defined above consisting of two carbon atoms and a single bond between them, preferably C1-C7alkylene. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, and the like. Alkylene groups can be substituted or unsubstituted. 20 straight-chain or branched aliphatic hydrocarbon group, preferably C1-C 10 alkylene, more preferably C1-C7alkylene. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, and the like. Alkylene groups can be substituted or unsubstituted.

[0064] "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups can be optionally substituted or unsubstituted.

[0065] "alkenylene" refers to an alkylene group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably C2-C7alkenylene. Examples of alkenylene groups include -CH=CH-, -CH2CH=CHCH2-, -CH=CH-CH=CH-, -(CH2)2CH=CH(CH2)3-, and the like. Alkenylene groups can be optionally substituted or unsubstituted. "Alkynyl" refers to an aliphatic hydrocarbon group containing one carbon-carbon triple bond, which can be straight-chain or branched. Preferred is C2-C 10 alkynyl, more preferably C2-C6alkynyl, most preferably C2-C4alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.

[0066] "Alkynylene" refers to an alkylene group as defined above containing at least one carbon-carbon triple bond, preferably C2-C7alkynylene. Examples of alkynylene groups include -C≡C-, -CH2C≡CCH2-, -CH2C≡C(CH2)2-, -CH2C≡C(CH2)3-, -CH2C≡C(CH2)4-, and the like. Alkynylene groups can be optionally substituted or unsubstituted.

[0067] "Cycloalkyl" refers to saturated or partially saturated monocyclic, fused ring, bridged ring, and spirocyclic carbocyclic rings. Preferably C3-Ci8cycloalkyl, more preferably C3-C8cycloalkyl, most preferably C3-C6cycloalkyl. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, preferably cyclopropyl, cyclohexenyl, cyclohexyl, and cycloheptyl. 10 Cycloalkyl, more preferably C3-C8cycloalkyl, most preferably C3-C6cycloalkyl. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, preferably cyclopropyl, cyclohexenyl, Cycloalkyl can be substituted or unsubstituted.

[0068] "Spiroalkyl" refers to a polycyclic group of 5 to 18 members, two or more cyclic structures sharing one carbon atom between the rings (referred to as a spiro atom), and the rings can contain one or more double bonds, but no ring has a fully conjugated system of π electrons. Preferably 6 to 14 members, more preferably 7 to 10 members. Spiroalkyl groups are classified as mono-, bi-, or polycycloalkyl groups depending on the number of spiro atoms shared between the rings, preferably mono- and bi-cycloalkyl groups, preferably 4 / 5, 4 / 6, 5 / 5, or 5 / 6 members. Non-limiting examples of "spiroalkyl" groups include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0069] "Fused cycloalkyl" refers to a fully carbon polycyclic group of 5 to 18 members, two or more cyclic structures sharing a pair of carbon atoms between the rings, one or more rings can contain one or more double bonds, but no ring has a fully conjugated system of π electrons, preferably 6 to 12 members, more preferably 7 to 10 members. Fused cycloalkyl groups are classified as bi-, tri-, tetra-, or polycycloalkyl groups depending on the number of rings, preferably bi- or tri-cycloalkyl groups, more preferably 5 / 5 or 5 / 6 bi-cycloalkyl groups. Non-limiting examples of "fused cycloalkyl" groups include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decalinyl, or tetradecahydrophenanthryl.

[0070] "Bicyclic ring alkyl" refers to a 5- to 18-membered, all-carbon polycyclic ring group containing two or more cyclic structures that share two non-adjacent carbon atoms with each other, one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron aromatic system, preferably 6- to 12-membered, more preferably 7- to 10-membered. Bicyclic ring alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic, based on the number of rings comprising the ring system. Non-limiting examples of "bicyclic ring alkyl" groups include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.

[0071] "Heterocyclyl," "heterocycle," or "heterocyclic" are used interchangeably herein and refer to non-aromatic heterocyclic groups in which one or more of the ring atoms is a heteroatom such as oxygen, nitrogen, sulfur, and the like, including mono-, bi-, poly-, fused-, and spiro- rings.

[0072] Examples of "monocyclic heterocyclyl" groups include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, piperazinyl, hexahydropyrimidinyl,

[0073] Monocyclic heterocyclyl groups can be substituted or unsubstituted.

[0074] "Spiroheterocyclyl" refers to a 5- to 18-membered, polycyclic ring group containing two or more cyclic structures that share a single atom between the rings, one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) r wherein r is selected from 0, 1, or 2, and the remaining ring atoms are carbon. Spirocycloalkyl groups are classified as mono-, bi-, or polycyclic, preferably mono- and bi- spiroheterocyclyl, based on the number of rings sharing a single atom between the rings. More preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monosprioheterocyclyl. Non-limiting examples of "spiroheterocyclyl" groups include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0075]

[0076] Spiroheterocyclyl groups can be substituted or unsubstituted.

[0077] "Condensed heterocyclyl" refers to a polycyclic group containing two or more cyclic structures that share one pair of atoms in common, one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) r ranging from 6 to 14 members, more preferably from 7 to 10 members. Depending on the number of rings making up the ring system, condensed heterocyclyl groups can be bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic or tricyclic, more preferably 5- membered / 5-membered or 5-membered / 6-membered bicyclic condensed heterocyclyl groups. Non-limiting examples of "condensed heterocyclyl" groups include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-lH-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][l,4]dioxine.

[0078] "Bridge heterocyclyl" refers to a polycyclic group containing two or more cyclic structures that share two non-adjacent atoms in common, one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) r ranging from 6 to 14 members, more preferably from 7 to 10 members. Depending on the number of rings making up the ring system, bridge heterocyclyl groups can be bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridge heterocyclyl" groups include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl;

[0079] Bridge heterocyclyl groups can be substituted or unsubstituted.

[0080] "Aryl" refers to a carbocyclic aromatic ring system containing one or two rings, wherein the rings can be connected together in a condensed fashion. The term "aryl" includes mono- or bicyclic aromatic groups such as the aromatic groups of phenyl, naphthyl, tetrahydronaphthyl. Preferably, aryl is C6-C 10 Aryl, more preferably aryl is phenyl and naphthyl, most preferably phenyl. Aryl groups can be substituted or unsubstituted.

[0081] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indolyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indolyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isoxazolyl], pyridinoneyl, etc. The heteroaryl group can be substituted or unsubstituted.

[0082] A "fused ring" refers to a polycyclic group in which two or more ring structures share a pair of atoms, wherein at least one ring has a fully conjugated π electron aromatic system, and one or more rings may contain one or more double bonds, but at least one ring does not have a fully conjugated π electron aromatic system, wherein the ring atoms are selected from 0, or one or more selected from nitrogen, oxygen, or S(O). r (where r is selected from 0, 1, or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably comprises a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably, it is 6 to 14 quinary, more preferably 8 to 10 quinary. Examples of "fused rings" include, but are not limited to:

[0083]

[0084] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0085] "Hydroxyalkyl" refers to an alkyl group that is substituted with a hydroxyl group.

[0086] "Halogenated alkyl" refers to alkyl groups that have been substituted with halogens.

[0087] "Hydroxy" refers to the -OH group.

[0088] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0089] "Amino" refers to -NH2.

[0090] “Cyano” refers to -CN.

[0091] "Nitro" refers to -NO2.

[0092] "Benzyl" means -CH2-phenyl.

[0093] "DMSO" means dimethyl sulfoxide.

[0094] "HATU" means 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0095] "TFA" means trifluoroacetic acid

[0096] "FA" means formic acid

[0097] "CH3CN" means acetonitrile

[0098] "Leaving group", or leaving group, is an atom or functional group that departs from a larger molecule in a chemical reaction, and is a term used in nucleophilic substitution and elimination reactions. In nucleophilic substitution reactions, the reactant that is attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. Groups that can readily accept electrons and bear a negative charge well are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the more readily the leaving group departs from other molecules. This is because the smaller the pKa of the conjugate acid, the greater the tendency of the corresponding leaving group to exist as an anion (or a neutral leaving group) without bonding to other atoms. Common leaving groups include, but are not limited to, halogen, methylsulfonyl, -OTs, or -OH.

[0099] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of the group are independently of each other replaced by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by a person skilled in the art without undue effort, as to whether a substitution is possible or not. For example, an amino group with a free hydrogen or a hydroxyl group can not be stable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond.

[0100] "Substituted" or "substitution" as used in the present specification, unless otherwise specified, means that a group can be substituted with one or more substituents.

[0101] "Pharmaceutically acceptable salts" means certain salts of the above compounds which retain the biological activity of the free compounds and which are suitable for medical use. Pharmaceutically acceptable salts of the compounds of general formula (I), (II), (III) can be metal salts, ammonium salts with suitable acids.

[0102] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or physiologically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism, while minimizing any adverse effects.

[0103] Methods of synthesizing the compounds of the invention

[0104] To achieve the objectives of the present application, the present application adopts the following technical solutions:

[0105] The method for preparing the compounds of the general formula (III) includes:

[0106] Method 1:

[0107]

[0108] The compound of the general formula (IIIA) and the compound of the general formula (IIIB) are subjected to reductive amination reaction under the action of a basic reagent, and optionally further removed from the protecting group to obtain the compound of the general formula (III);

[0109] Wherein:

[0110] L 2 is -L 3 -CH2-NH-;

[0111] L 3 is selected from a bond or -C1-C5 alkylene, wherein one or more methylene groups in the alkylene are optionally further replaced by one or more O, S(O) r , C(O) or NR b ;

[0112] R b is selected from a hydrogen atom or a methyl group;

[0113] r is selected from 0, 1 or 2;

[0114] ring A, ring B, X, W, R 1 , R A , R 4 , L 1 , L 2 , m and n are defined as described in the general formula (III).

[0115] Method 2:

[0116]

[0117] The compound of the general formula (IIA) and the compound of the general formula (IIB) are subjected to substitution reaction under the action of a basic reagent, and optionally further subjected to deprotection reaction to obtain the compound of the general formula (II).

[0118] wherein:

[0119] X 1 is a leaving group, preferably halogen;

[0120] ring A, ring B, X, W, R 1 , R A , R 4 , L 1 , L 2 , m and n are as defined in general formula (II). DETAILED DESCRIPTION

[0121] The present application is further described in connection with the following examples, which are not meant to limit the scope of the present application.

[0122] Examples

[0123] The examples below give the preparation of representative compounds of formula (I) and related structural identification data. It must be understood that the examples below are intended to illustrate the present application and not to limit it. 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are expressed in ppm using tetramethylsilane as internal standard (0.00 ppm). 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are expressed in ppm using tetramethylsilane as internal standard (0.00 ppm).

[0124] Mass spectra were recorded on a LC / MS instrument, using ESI or APCI ionization.

[0125] Thin layer chromatography silica gel plates were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used in thin layer chromatography (TLC) had a thickness of 0.15 mm to 0.2 mm. The silica gel plates used in thin layer chromatography for product purification had a thickness of 0.4 mm to 0.5 mm.

[0126] Column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0127] In the following examples, all temperatures are in degrees Celsius, unless otherwise indicated, and all starting materials and reagents are commercially available or synthesized according to known procedures, and used without further purification, unless otherwise indicated. The commercial suppliers include, but not limited to, Shanghai Hao Hong Biological Medicine Science and Technology Co., Ltd., Shanghai Shao Yuan Reagent Co., Ltd., Shanghai Bide Medicine Science and Technology Co., Ltd., San Chemical Technology (Shanghai) Co., Ltd., and Shanghai Lingkai Medicine Science and Technology Co., Ltd., etc. MeOD: deuterated methanol.

[0128] CDCl3: deuterated chloroform.

[0129] DMSO-d6: deuterated dimethyl sulfoxide.

[0130] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1 L.

[0131] In the examples, unless otherwise specified, the solution in the reaction refers to an aqueous solution.

[0132] The eluent system of column chromatography and thin layer chromatography is selected from the following systems: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate system; D: dichloromethane and ethanol system, wherein the volume ratio of the solvents is different according to the polarity of the compound, and a small amount of acidic or basic reagent can also be added, such as acetic acid or triethylamine, etc.

[0133] Room temperature: 20-30°C.

[0134] Example 1

[0135] 4-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)-7-(trifluoromethyl)naphthalen-2-ol

[0136] 4-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)-7-(trifluoromethyl)naphthalen-2-ol

[0137]

[0138] First step

[0139] 2,2-dimethyl-5-(2-(3-(trifluoromethyl)phenyl)acetyl)-1,3-dioxane-4,6-dione

[0140] 2,2-dimethyl-5-(2-(3-(trifluoromethyl)phenyl)acetyl)-1,3-dioxane-4,6-dione

[0141] 2-(3-(trifluoromethyl)phenyl)acetyl chloride 1a (980 mg, 4.40 mmol, commercial) and pyridine (1.39 g, 17.61 mmol) were dissolved in dichloromethane (20 mL). 2,2-dimethyl-1,3-dioxane-4,6-dione 1b (761.44 mg, 5.28 mmol, commercial) was added at 0 °C, and stirred at 25 °C for 3 hours. After the reaction was completed, the reaction mixture was washed with 5% hydrochloric acid (5 mL), then washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain 2,2-dimethyl-5-(2-(3-(trifluoromethyl)phenyl)acetyl)-1,3-dioxane-4,6-dione 1c (740 mg), yield 50.89%.

[0142] Second step

[0143] tert-butyl 3-oxo-4-(3-(trifluoromethyl)phenyl)butanoate

[0144] 3-oxo-4-(3-(trifluoromethyl)phenyl)butanoic acid tert-butyl ester

[0145] 2,2-dimethyl-5-(2-(3-(trifluoromethyl)phenyl)acetyl)-1,3-dioxane-4,6-dione 1c (1.0 g, 3.03 mmol) was added to tert-butyl alcohol (20 mL) and stirred at 90 °C for 2 hours. After the reaction was completed, it was dried by evaporation, and the residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl 3-oxo-4-(3-(trifluoromethyl)phenyl)butanoate 1d (766 mg), yield 83.69%.

[0146] MS m / z (ESI): 247.0 [M-55]

[0147] Third step

[0148] 3-oxo-4-(3-(trifluoromethyl)phenyl)butanoic acid

[0149] 3-oxo-4-(3-(trifluoromethyl)phenyl)butanoic acid

[0150] tert-Butyl 3-oxo-4-(3-(trifluoromethyl)phenyl)butanoate 1d (21.0 g, 69.47 mmol) was added to trifluoroacetic acid (40 mL) and dichloromethane (200 mL). The reaction was carried out at 25 °C for 16 hours. After the reaction was completed, it was rotary evaporated and the residue was separated and purified by silica gel column chromatography (eluent: system A) to obtain 3-oxo-4-(3-(trifluoromethyl)phenyl)butanoic acid 1e (13.4 g) with a yield of 78.35%.

[0151] MS m / z (ESI): 247.0 [M+1]

[0152] Fourth step

[0153] 6-(trifluoromethyl)naphthalene-1,3-diol

[0154] 6-(trifluoromethyl)naphthalene-1,3-diol

[0155] 3-oxo-4-(3-(trifluoromethyl)phenyl)butanoic acid 1e (11.4 g, 46.31 mmol) was added to triflic acid (220 mL) and the reaction was carried out at 25 °C for 16 hours. After the reaction was completed, water (50 mL) was added to the mixture, which was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: system A) to obtain 6-(trifluoromethyl)naphthalene-1,3-diol 1f (10.0 g) with a yield of 53.00%.

[0156] MS m / z (ESI): 229.0 [M+1]

[0157] Fifth step

[0158] 3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-ol

[0159] 3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-ol

[0160] To a solution of 6-(trifluoromethyl)naphthalen-1,3-diol 1f (3.0 g, 7.36 mmol), N,N- diisopropylethylamine (3.81 g, 29.45 mmol) in dichloromethane (60 mL) was added methoxy methyl hypobromite (920.08 mg, 7.36 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: system A) to give 3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-ol 1g (1.23 g, 61.37% yield).

[0161] MS m / z (ESI): 273.1 [M+1]

[0162] Sixth step

[0163] 3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-yltrifluoromethanesulfonate

[0164] 3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-yltrifluoromethanesulfonate

[0165] To a solution of 3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-ol 1g (630 mg, 2.31 mmol), N,N-diisopropylethylamine (1.20 g, 9.26 mmol) in dichloromethane (15 mL) was added trifluoromethanesulfonic anhydride (979.43 mg, 3.47 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: system A) to give 3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-yl trifluoromethanesulfonate 1h (320 mg, 34.20% yield).

[0166] Seventh step

[0167] 6-((3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-yl)thio)hexan-1-ol

[0168] 6-((3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-yl)thio)hexan-1-ol

[0169] Into a flask, 3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-yl trifluoromethanesulfonic anhydride 1h (380 mg, 939.94 pmol), 6-mercapto-1-ol 1i (189.27 mg, 1.41 mmol), tris(dibenzylideneacetone)dipalladium (172.14 mg, 187.99 pmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (217.55 mg, 375.98 pmol), potassium acetate (184.50 mg, 1.88 mmol) were added into dioxane (6 mL). After being purged with argon, the mixture was stirred at 90 °C for 4 h. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. The residue was separated and purified by column chromatography on silica gel (eluent: A system) to give 6-((3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-yl)thio)hexan-1-ol 1j (490 mg, crude).

[0170] MS m / z (ESI): 389.2 [M+1]

[0171] Eighth step

[0172] 6-((3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-yl)thio)hexanal

[0173] 6-((3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-yl)thio)hexanal

[0174] Into a flask, 6-((3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-yl)thio)hexan-1-ol 1j (50 mg, 128.72 pmol), Dess-Martin oxidant (81.89 mg, 193.08 pmol) were added into dichloromethane (2 mL). After being stirred at 25 °C for 2 h, the mixture was concentrated under reduced pressure. The residue was separated and purified by column chromatography on silica gel (eluent: A system) to give 6-((3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-yl)thio)hexanal 1k (52 mg), which was used directly in the next step.

[0175] MS m / z (ESI): No mass.

[0176] Ninth step

[0177] tert-butyl 4-(4-((6-((3-(methoxymethoxy)-6-(trifluoromethyl)naphthalen-1-yl)thio)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylate

[0178] 4-(4-((6-((3-(methoxymethoxy)-6-(trifluoromethyl)naphth-1-yl)thio)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester

[0179] 6-((3-(methoxymethoxy)-6-(trifluoromethyl)naphthio-1-yl)thio)hexanal 1k (85 mg, 219.96 μmol), 4-(4-amino-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 1l (64.09 mg, 219.96 μmol, commercially available), and sodium cyanoborohydride (20.73 mg, 329.95 μmol) were added to methanol (2 mL). The reaction was carried out at 25 °C for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 4-(4-((6-((3-(methoxymethoxy)-6-(trifluoromethyl)naphthio-1-yl)thio)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 1m (60 mg), yield 41.22%.

[0180] MS m / z(ESI): 662.4 [M+1]

[0181] Step 10

[0182] 4-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)-7-(trifluoromethyl)naphthalen-2-ol

[0183] 4-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)-7-(trifluoromethyl)naphthalene-2-ol)

[0184] 4-(4-((6-((3-(methoxymethoxy)-6-(trifluoromethyl)naphth-1-yl)thio)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 1m (30mg, 45.33μmol), trimethylbromosilane (27.76mg, 181.32μmol), molecular sieve Type 1 (79.86 mg) was added to dichloromethane (1 mL). The reaction was carried out at 0 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give 4-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)-7-(trifluoromethyl)naphthol-2-phenol 1 (5.8 mg), yield 24.72%.

[0185] MS m / z(ESI): 518.2 [M+1]

[0186] 1H NMR(400MHz,MeOD)δ8.30(dd,J=27.8,8.4Hz,1H),8.00(d,J=12.6Hz,1H),7.58- 7.44(m,1H),7.35–7.27(m,1H),7.12-6.88(m,1H),6.88-6.85(m,1H),6.52(s,1 H),6.49-6.42(m,1H),3.15-3.08(m,4H),3.08-2.98(m,4H),2.92-2.84(m,4H), 2.22(d,J=2.0Hz,3H),1.76-1.66(m,2H),1.62–1.50(m,4H),1.47–1.41(m,2H).

[0187] Example 2

[0188] 1,3-dimethyl-5-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0189] 1,3-Dimethyl-5-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)-1,3-dihydro-2H-benzo[d]imidazol-2-

[0190] ketone

[0191]

[0192] first step

[0193] tert-butyl 4-(4-((6-chlorohexyl)amino)-2-methylphenyl)piperazine-1-carboxylate

[0194] tert-butyl 4-(4-((6-chlorohexyl)amino)-2-methylphenyl)piperazine-1-carboxylate

[0195] tert-butyl 4-(4-((6-chlorohexyl)amino)-2-methylphenyl)piperazine-1-carboxylate

[0196] MS m / z (ESI): 410.2 [M+1]

[0197] Second step

[0198] 5-(tert-butylthio)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0199] 5-(tert-butylthio)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0200] Dissolve 5-bromo-1,3-dimethyl-benzimidazol-2-one 2c (500 mg, 2.0 mmol, prepared according to published patent WO2007084451) in 1,4-dioxane (15 mL), add tert-butyl mercaptan 2d (280.58 mg, 3.11 mmol), tris(dibenzylideneacetone)dipalladium (189.92 mg, 207.40 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (240.01 mg, 414.79 μmol), N,N-diisopropylethylamine (670.10 mg, 5.18 mmol) into the reaction solution, replace with nitrogen for 3-5 times, heat to 130 °C under microwave reaction stirring for 1 hour. After the reaction is completed, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL x 3), combine the organic phase, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, separate and purify the residue by silica gel column chromatography (eluent: A system) to obtain 5-(tert-butylthio)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 2e (433 mg), yield 83.39%.

[0201] MS m / z (ESI): 251.2 [M+1]

[0202] Third step

[0203] 5-mercapto-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0204] 5-mercapto-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0205] Dissolve 5-(tert-butylthio)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 2e (200 mg, 798.85 μmol) in dichloromethane (5 mL), slowly add boron tribromide (2 M, 1.20 mL) to the reaction solution, then stir the reaction mixture at room temperature for 2 hours. After the reaction is completed, quench the boron tribromide with methanol under ice bath, concentrate the reaction solution under reduced pressure, separate and purify the residue by silica gel column chromatography (eluent: B system) to obtain 5-mercapto-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 2f (130 mg), yield 63.67%.

[0206] MS m / z (ESI): 195.0 [M+1]

[0207] Fourth step

[0208] tert-butyl 4-(4-((6-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-

[0209] yl)thio)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylate

[0210] 4-(4-((6-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)thio)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester

[0211] 5-Mercapto-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 2f (130 mg, 669.23 μmol) and 4-(4-((6-chlorohexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 2b (219.50 mg, 535.38 μmol) were dissolved in a solution of N,N-dimethylformamide (2 mL). Potassium carbonate (184.98 mg, 1.34 mmol) and sodium iodide (5.02 mg, 33.46 μmol) were added to the reaction mixture, and the reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 2 g (100 mg) of 4-(4-((6-((1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)thio)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester, with a yield of 26.32%.

[0212] MS m / z(ESI): 568.4 [M+1]

[0213] Step 5

[0214] 1,3-dimethyl-5-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)-1,3-dihydro-2H-

[0215] benzo[d]imidazol-2-one

[0216] 1,3-dimethyl-5-((6-((3-methyl-4-(piperazin-1 -yl)phenyl)amino)hexyl)thio)-1,3- dihydro-2H-benzo[d]imidazol-2-one

[0217] ketone

[0218] tert-Butyl 4-(4-((6-((1,3-dimethyl-2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-5- yl)thio)hexyl)amino)-2-methylphenyl)piperazine-1 -carboxylate 2g (100 mg, 176.12 pmol) was dissolved in a mixture solution of dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL), the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 10 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give 1,3-dimethyl-5-((6-((3-methyl-4-(piperazin-1 -yl)phenyl)amino)hexyl)thio)-1,3- dihydro-2H-benzo[d]imidazol-2-one 2 (57.48 mg), yield 69.78%.

[0219] MS m / z (ESI): 468.2 [M+1 ]

[0220] 1H NMR (400 MHz, DMSO) d 7.20 (s, 1 H), 7.09 (s, 2H), 6.78 (d, J = 8.8 Hz, 1 H), 6.36 (s, 1 H), 6.32 (d, J = 8.0 Hz, 1 H), 5.10 (s, 1 H), 3.30 (s, 6H), 2.94-2.84 (m, 8H), 2.69-2.63 (m, 4H), 2.13 (s, 3H), 1.56-1.45 (m, 4H), 1.42-1.30 (m, 4H).

[0221] Example 3

[0222] 1 -methyl-5-((6-((3-methyl-4-(piperazin-1 -yl)phenyl)amino)hexyl)thio)indolin-2-one

[0223] 1 -methyl-5-((6-((3-methyl-4-(piperazin-1 -yl)phenyl)amino)hexyl)thio)indolin-2-one

[0224] First step

[0225] 5-bromo-1-methylindolin-2-one

[0226] 5-bromo-1-methylindolin-2-one

[0227] 5-bromo-1-methylindolin-2-one

[0228] MS m / z (ESI): 226.0 [M+2]

[0229] Second step

[0230] 5-bromo-1-methylindolin-2-one

[0231] 5-bromo-1-methylindolin-2-one

[0232] 5-bromo-1-methylindolin-2-one

[0233] MS m / z (ESI): 236.2 [M+1]

[0234] Third step

[0235] 5-mercapto-1-methylindolin-2-one

[0236] 5-mercapto-1-methylindolin-2-one

[0237] 5-mercapto-1-methylindolin-2-one

[0238] MS m / z (ESI): 180.0 [M+1]

[0239] Fourth step

[0240] tert-butyl 4-(2-methyl-4-((6-((1-methyl-2-oxoindolin-5-yl)thio)hexyl)amino)phenyl)piperazine-

[0241] 1-carboxylate

[0242] 4-(2-methyl-4-((6-((1-methyl-2-oxoindolin-5-yl)thio)hexyl)amino)phenyl)piperazine-1- carboxylate

[0243] A mixture of 5-mercapto-1-methylindolin-2-one 3d (85 mg, 474.23 pmol), 4-(4-((6- chlorohexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 2b (233.32 mg, 569.07 pmol) and potassium carbonate (131.09 mg, 948.46 pmol) and sodium iodide (3.55 mg, 23.71 pmol) was dissolved in N,N-dimethylformamide (2 mL), the reaction mixture was stirred at 60 °C for 1 h. After the reaction was completed, water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain 4-(2-methyl-4-((6-((1-methyl-2-oxoindolin-5-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 3e (85 mg) in a yield of 32.43%.

[0244] MS m / z (ESI): 553.4 [M+1]

[0245] Fifth step

[0246] 1-methyl-5-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)indolin-2-one

[0247] 1-methyl-5-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)indolin-2-one

[0248] A mixture of 5-mercapto-1-methylindolin-2-one 3d (85 mg, 474.23 pmol), 4-(4-((6- chlorohexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 2b (233.32 mg, 569.07 pmol) and potassium carbonate (131.09 mg, 948.46 pmol) and sodium iodide (3.55 mg, 23.71 pmol) was dissolved in N,N-dimethylformamide (2 mL), the reaction mixture was stirred at 60 °C for 1 h. After the reaction was completed, water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain 4-(2-methyl-4-((6-((1-methyl-2-oxoindolin-5-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 3e (85 mg) in a yield of 32.43%.

[0249] MS m / z (ESI): 453.4 [M+1]

[0250] 1H NMR (400 MHz, DMSO) δ 7.29 (d, J = 6.4 Hz, 2H), 6.92 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.38 (s, 1H), 6.34 (d, J = 8.8 Hz, 1H), 3.53 (s, 2H), 3.14 - 3.01 (m, 4H), 2.92 - 2.84 (m, 4H), 2.96 - 2.71 (m, 4H), 2.14 (s, 3H), 1.53 - 1.46 (m, 4H), 1.42 - 1.29 (m, 4H).

[0251] Example 4

[0252] 1 -methyl-6-((6-((3-methyl-4-(piperazin-1 -yl)phenyl)amino)hexyl)thio)quinolin- 2(1 H)-one

[0253] 1 -methyl-6-((6-((3-methyl-4-(piperazin-1 -yl)phenyl)amino)hexyl)thio)quinolin- 2(1 H)-one

[0254] First Step

[0255] tert-butyl 4-(2-methyl-4-((6-((1-methyl-2-oxo-1,2-dihydroquinolin-6-

[0256] yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

[0257] 4-(2-methyl-4-((6-((1-methyl-2-oxo-1,2-dihydroquinolin-6- yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

[0258] tert-butyl 4-(2-methyl-4-((6-((1-methyl-2-oxo-1,2-dihydroquinolin-6-

[0259] tert-Butyl 4-(4-((6-chlorohexyl)amino)-2-methylphenyl)piperazine-1 -carboxylate 2b (180.08 mg, 439.22 pmol), 6-mercapto-1 -methylquinolin-2(1 H)-one 4a (70 mg, 366.01 pmol) and potassium carbonate (101.17 mg, 732.03 pmol), sodium iodide (2.75 mg, 18.30 pmol) were dissolved in N,N-dimethylformamide (5 mL), warmed to 80 °C and stirred for 2 hours. After the reaction was completed, water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl 4-(2-methyl-4-((6-((1 -methyl-2-oxo-1,2-dihydroquinolin-6- yl)thio)hexyl)amino)phenyl)piperazine-1 -carboxylate 4b (100 mg) in a yield of 48.38%.

[0260] MS m / z (ESI): 565.3 [M+1]

[0261] Second step

[0262] 1 -methyl-6-((6-((3-methyl-4-(piperazin-1 -yl)phenyl)amino)hexyl)thio)quinolin-2(1 H)-one

[0263] 1 -methyl-6-((6-((3-methyl-4-(piperazin-1 -yl)phenyl)amino)hexyl)thio)quinolin-2(1 H)-one

[0264] tert-Butyl 4-(2-methyl-4-((6-((1 -methyl-2-oxo-1,2-dihydroquinolin-6- yl)thio)hexyl)amino)phenyl)piperazine-1 -carboxylate 4b (100 mg, 177.06 pmol) was dissolved in a mixed solution of dichloromethane (4 mL) and trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to adjust the pH to 8-9, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, concentrated under reduced pressure, and the residue was separated and purified by preparative liquid chromatography (separation column C18 waters SunFire preparative column; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.1 % FA + H20, mobile phase B: CH3CN) to obtain 1 -methyl-6-((6-((3-methyl-4-(piperazin-1 -yl)phenyl)amino)hexyl)thio)quinolin-2(1 H)-one 4 (13 mg) in a yield of 15.80%.

[0265] MS m / z (ESI): 465.3 [M+1]

[0266] 1H NMR (400 MHz, DMSO) δ 7.86 (d, J = 9.6 Hz, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 8.8, 2.2 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 9.4 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 6.32 (dd, J = 8.6, 2.6 Hz, 1H), 3.59 (s, 3H), 3.04 - 2.93 (m, 6H), 2.90 (t, J = 6.8 Hz, 2H), 2.81 - 2.63 (m, 4H), 2.13 (s, 3H), 1.61 - 1.29 (m, 8H).

[0267] Example 5

[0268] 1-methyl-7-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)quinolin-2(1H)-one

[0269] 1-methyl-7-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)quinolin-2(1H)-one

[0270] First step

[0271] 7-bromo-1-methylquinolin-2(1H)-one

[0272] 7-bromo-1-methylquinolin-2(1H)-one

[0273] 7-bromo-1-methylquinolin-2(1H)-one

[0274] MS m / z (ESI): 238.0 [M+1]

[0275] Second step

[0276] 7-(tert-butylthio)-1-methylquinolin-2(1H)-one

[0277] 7-(tert-butylthio)-1-methylquinolin-2(1H)-one

[0278] 7-(tert-butylthio)-1-methylquinolin-2(1H)-one

[0279] Third step

[0280] 7-(tert-butylthio)-1-methylquinolin-2(1H)-one

[0281] 7-(tert-butylthio)-1-methylquinolin-2(1H)-one

[0282] 7-(tert-butylthio)-1-methylquinolin-2(1H)-one

[0283] MS m / z (ESI): 192.0 [M+1]

[0284] Step 4

[0285] tert-butyl 4-(2-methyl-4-((6-((1-methyl-2-oxo-1,2-dihydroquinolin-7-

[0286] yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

[0287] 4-(2-Methyl-4-((6-((1-Methyl-2-oxo-1,2-dihydroquinoline-7-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl

[0288] ester

[0289] 7-Mercapto-1-methylquinoline-2(1H)-one 5d (40 mg, 209.15 μmol), 4-(4-(6-chlorohexylamino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 2b (85.75 mg, 209.15 μmol), potassium carbonate (57.81 mg, 418.30 μmol), and sodium iodide (1.57 mg, 10.46 μmol) were added to N,N-dimethylformamide (1 mL) and reacted at 80 °C for 2 hours. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 5e (25 mg) of 4-(2-methyl-4-((6-((1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester, with a yield of 21.16%.

[0290] MS m / z (ESI): 565.4 [M+1]

[0291] Step 5

[0292] 1-methyl-7-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)quinolin-2(1H)-one

[0293] 1-Methyl-7-((6-((3-methyl-4-(piperazin-1-yl)phenyl)amino)hexyl)thio)quinoline-2(1H)-one

[0294] tert-Butyl 4-(2-methyl-4-((6-((1-methyl-2-oxo-1,2-dihydroquinolin-7- yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate 5e (25 mg, 44.27 pmol) was added to trifluoroacetic acid (0.5 mL), dichloromethane (2 mL) and reacted at 25 °C for 2 h. The reaction mixture was stirred at room temperature for 2 h, saturated sodium bicarbonate was added to adjust the pH to 8-9, extracted with ethyl acetate (20 mL x 3), the organic phase was combined and concentrated under reduced pressure, the residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H20, mobile phase B: CH3CN) to give 1-methyl-7-((6-((3-methyl-4-(piperazin-1- yl)phenyl)amino)hexyl)thio)quinolin-2(1H)-one 5 (8.6 mg) in 41.81% yield.

[0295] MS m / z (ESI): 465.2 [M+1]

[0296] 1H NMR (400 MHz, DMSO) d 7.84 (d, J = 9.2 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.31-7.29 (m, 1H), 7.18 (dd, J = 1.6, 1.6 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 9.2 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 6.32 (dd, J = 2.8, 2.8 Hz, 1H), 3.60 (s, 3H), 3.32-3.26 (m, 2H), 3.15-3.09 (m, 2H), 2.94-2.88 (m, 2H), 2.82-2.79 (m, 3H), 2.64-2.60 (m, 3H), 2.13 (s, 3H), 1.69-1.62 (m, 2H), 1.53-1.44 (m, 4H), 1.42-1.36 (m, 2H).

[0297] Example 6

[0298] 3-methyl-N-(6-((3-phenylquinolin-5-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

[0299] 3-methyl-N-(6-((3-phenylquinolin-5-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

[0300]

[0301] First step

[0302] 3-phenylquinolin-5-ol

[0303] 3-phenylquinolin-5-ol

[0304] Dissolve 3-bromoquinolin-5-ol 6a (640 mg, 2.86 mmol, commercially available) and phenylboronic acid 6b (417.95 mg, 3.43 mmol, commercially available) and sodium carbonate (605.57 mg, 5.71 mmol) in a mixed solution of toluene:ethanol:water (6 mL:1.2 mL:1.2 mL), finally add tetrakis(triphenylphosphine)palladium (330.08 mg, 285.65 μmol), replace nitrogen, and stir at 60 °C for 16 h. After the reaction is completed, add water (100 mL) to the reaction mixture, extract with ethyl acetate (100 mL x 3), combine the organic phases, wash with saturated sodium chloride solution (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (eluent: A system) to obtain 3-phenylquinolin-5-ol 6c (287 mg) with a yield of 45.41%. MS m / z (ESI): 222.1 [M+1]

[0305] Second step

[0306] 3-phenylquinolin-5-yl trifluoromethanesulfonate

[0307] 3-phenylquinolin-5-yl trifluoromethanesulfonate

[0308] Dissolve 3-phenylquinolin-5-ol 6c (150 mg, 677.96 μmol) in dichloromethane (4 mL), add N,N-diisopropylethylamine (175.24 mg, 1.36 mmol) and trifluoromethanesulfonic anhydride (286.92 mg, 1.02 mmol) at 0 °C, and stir for 2 h. After the reaction is completed, concentrate the reaction mixture under reduced pressure, and separate and purify the residue by column chromatography (eluent: A system) to obtain 3-phenylquinolin-5-yl trifluoromethanesulfonate 6d (200 mg) with a yield of 83.50%.

[0309] MS m / z (ESI): 354.0 [M+H]

[0310] Third step

[0311] 6-((3-phenylquinolin-5-yl)thio)hexan-1-ol

[0312] 6-((3-phenylquinolin-5-yl)thio)hexan-1-ol

[0313] Dissolve 3-phenylquinoline-5-carbothioic acid 6a (200 mg, 566.07 μmol), 6- thiohexan-1-ol 1i (113.98 mg, 849.10 μmol), potassium acetate (166.42 mg, 1.70 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (65.51 mg, 113.21 μmol) and tris(dibenzylideneacetone)dipalladium (51.84 mg, 56.61 μmol) in 1,4-dioxane (4 mL), warm to 90 °C and stir for 4 h. After the reaction is completed, add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL x 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (eluent: A system) to obtain 6-((3-phenylquinolin-5-yl)thio)hexan-1-ol 6e (100 mg) in a yield of 52.35%.

[0314] MS m / z (ESI): 338.0 [M+1]

[0315] Fourth step

[0316] 6-((3-phenylquinolin-5-yl)thio)hexanal

[0317] 6-((3-phenylquinolin-5-yl)thio)hexanal

[0318] Dissolve 6-((3-phenylquinolin-5-yl)thio)hexan-1-ol 6e (90 mg, 266.68 μmol) in dichloromethane (4 mL), add Dess-Martin reagent (169.61 mg, 400.03 μmol) at 0 °C, and stir for 4 h under a nitrogen atmosphere. After the reaction is completed, concentrate the reaction mixture under reduced pressure, separate and purify the residue by silica gel column chromatography (eluent: A system) to obtain 6-((3-phenylquinolin-5-yl)thio)hexanal 6f (80 mg) in a yield of 89.6%.

[0319] MS m / z (ESI): 336.1 [M+1]

[0320] Fifth step

[0321] tert-butyl 4-(2-methyl-4-((6-((3-phenylquinolin-5-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

[0322] 4-(2-methyl-4-((6-((3-phenylquinolin-5-yl)thio)hexyl)amino)phenyl)piperazine-1- carboxylic acid tert-butyl ester

[0323] Dissolve 6-((3-phenylquinolin-5-yl)thio)hexanal 6f (110 mg, 327.91 μmol), 4-(4-amino-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 11 (114.66 mg, 393.49 μmol), sodium borohydride (139.03 mg, 655.81 μmol) in methanol (4 mL), stir at room temperature for 12 hours. After the reaction is completed, the reaction mixture is concentrated under reduced pressure, the residue is separated and purified by silica gel column chromatography (eluent: A system), to obtain 4-(2-methyl-4-((6-((3-phenylquinolin-5-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 6g (70 mg), in a yield of 34.95%.

[0324] MS m / z (ESI): 611.3 [M+1]

[0325] Sixth step

[0326] 3-methyl-N-(6-((3-phenylquinolin-5-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

[0327] 3-methyl-N-(6-((3-phenylquinolin-5-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

[0328] Dissolve 4-(2-methyl-4-((6-((3-phenylquinolin-5-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 6g (60 mg, 98.22 μmol) in a solution of dichloromethane (4 ml) and trifluoroacetic acid (0.5 ml), stir at room temperature for 2 hours. After the reaction is completed, the reaction mixture is concentrated under reduced pressure, the residue is separated and purified by preparative liquid chromatography (separation column SunFire C18; 19*250 mm; 10 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), to obtain 3-methyl-N-(6-((3-phenylquinolin-5-yl)thio)hexyl)-4-(piperazin-1-yl)aniline 6 (15 mg), in a yield of 29.90%.

[0329] MS m / z (ESI): 511.3 [M+1]

[0330] 1H NMR (400 MHz, MeOD) δ 9.28 (d, J = 2.0 Hz, 1H), 9.09 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 6.6, 2.8 Hz, 1H), 7.89 - 7.74 (m, 4H), 7.59 (t, J = 7.4 Hz, 2H), 7.51 (t, J = 7.2 Hz, 1H), 7.37 - 7.10 (m, 3H), 3.46 - 3.36 (m, 4H), 3.27 - 3.26 (s, 2H), 3.20 - 3.01 (m, 6H), 2.37 (s, 3H), 1.76 - 1.68 (m, 4H), 1.63 - 1.51 (m, 2H), 1.48 - 1.39 (m, 2H).

[0331] Example 7

[0332] 1 -(4-((naphthalen-1 - ylthio)methyl)piperidin-1 -yl)-3-((4-(piperazin-1 -yl)-3- (trifluoromethyl)phenyl)amino)propan-1 -one

[0333] 1 -(4-((naphthalen-1 - ylthio)methyl)piperidin-1 -yl)-3-((4-(piperazin-1 -yl)-3- (trifluoromethyl)phenyl)amino)propan-1 -one

[0334] First Step

[0335] tert-butyl 4-(4-((3-methoxy-3-oxopropyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0336] tert-butyl 4-(4-((3-methoxy-3-oxopropyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0337] Methyl 3-bromopropanoate 7b (362.67 mg, 2.17 mmol, commercial) and tert-butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 7a (300 mg, 868.66 μmol, commercial) were dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (40 mg, 2.61 mmol) was added to the reaction mixture, the reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed, water (80 mL) was added to the reaction mixture, extracted with ethyl acetate (80 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl 4-(4-((3-methoxy-3-oxopropyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 7c (300 mg), yield 64.04%.

[0338] MS m / z (ESI): 432.2 [M+1]

[0339] Second step

[0340] 3-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)propanoic acid

[0341] 3-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)propanoic acid

[0342] Tert-butyl 4-(4-((3-methoxy-3-oxopropyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 7c (300 mg, 556.27 μmol) and lithium hydroxide monohydrate (26.65 mg, 1.11 mmol) were dissolved in a mixed solution of tetrahydrofuran (2 mL) and water (2 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, the pH was adjusted to 6, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)propanoic acid 7d (150 mg), yield 64.60%.

[0343] MS m / z (ESI): 418.2 [M+1]

[0344] Third step

[0345] tert-butyl 4-(4-((3-(4-((naphthalen-1-ylthio)methyl)piperidin-1-yl)-3-oxopropyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0346] tert-butyl 4-(4-((3-(4-((naphthalen-1-ylthio)methyl)piperidin-1-yl)-3-oxopropyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0347] tert-butyl 4-(4-((3-(4-((naphthalen-1-ylthio)methyl)piperidin-1-yl)-3-oxopropyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0348] MS m / z (ESI): 577.2 [M+1]

[0349] Fourth step

[0350] tert-butyl 4-(4-((3-(4-((naphthalen-1-ylthio)methyl)piperidin-1-yl)-3-oxopropyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0351] tert-butyl 4-(4-((3-(4-((naphthalen-1-ylthio)methyl)piperidin-1-yl)-3-oxopropyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0352] tert-Butyl 4-(4-((3-(4-(bromomethyl)piperidin-1-yl)-3-oxopropyl)amino)-2- (trifluoromethyl)phenyl)piperazine-1-carboxylate 7f (43.25 mg, 74.89 µmol), naphthalen-1- thiol 7g (10 mg, 62.41 µmol, commercially available) and potassium carbonate (17.1 mg, 124.82 µmol) were dissolved in N,N-dimethylformamide (0.5 mL), the reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed, water (30 mL) was added to the reaction mixture, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain tert-butyl 4-(4-((3-(4-((naphthalen-1-ylthio)methyl)piperidin-1-yl)-3-oxopropyl)amino)-2- (trifluoromethyl)phenyl)piperazine-1-carboxylate 7h (40 mg), yield 97.59 %.

[0353] MS m / z (ESI): 557.4 [M-99]

[0354] Fifth step

[0355] 1-(4-((naphthalen-1-ylthio)methyl)piperidin-1-yl)-3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)propan-1-one

[0356] 1-(4-((naphthalen-1-ylthio)methyl)piperidin-1-yl)-3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)propan-1-one

[0357] tert-Butyl 4-(4-((3-(4-((naphthalen-1-ylsulfanyl)methyl)piperidin-1-yl)-3- oxopropyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 7h (30 mg, 45.68 pmol) was dissolved in a mixed solution of dichloromethane (0.5 mL) and trifluoroacetic acid (0.1 mL), the reaction mixture was stirred at room temperature for 2 hours, saturated sodium bicarbonate was added to adjust the pH to 8-9, extracted with ethyl acetate (50 mL x 3), the organic phase was combined and concentrated under reduced pressure, the residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give 1-(4-((naphthalen-1-ylsulfanyl)methyl)piperidin-1-yl)-3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)propan-1-one 7 (11 mg), yield 43.26%.

[0358] MS m / z (ESI): 557.2 [M+1]

[0359] 1H NMR (400 MHz, MeOD) d 8.35 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.61-49 (m, 3H), 7.43 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 2.8 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H), 3.94 (d, J = 15.6 Hz, 1H), 3.45-3.38 (m, 2H), 3.26-3.17 (m, 5H), 3.08-3.00 (m, 5H), 2.93-2.87 (m, 2H), 2.77-2.65 (m, 1H), 2.62-2.50 (m, 2H), 2.06-1.86 (m, 3H), 1.82-1.69 (m, 1H).

[0360] Example 8

[0361] 1-(4-(((6-phenylnaphthalen-1-yl)thio)methyl)piperidin-1-yl)-3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)propan-1-one

[0362] 1-(4-(((6-phenylnaphthalen-1-yl)thio)methyl)piperidin-1-yl)-3-((4-(piperazin-1-yl)-3- (trifluoromethyl)phenyl)amino)propan-1-one

[0363]

[0364] First step

[0365] 6-phenylnaphthalen-1-ol

[0366] 6-phenylnaphthalen-1-ol

[0367] Dissolve 6-bromonaphthalen-1-ol 8a (300 mg, 1.34 mmol, commercially available) and phenylboronic acid 6b (327.97 mg, 2.69 mmol) in 1,4-dioxane: water (5 mL: 0.5 mL), add potassium phosphate (570.96 mg, 2.69 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (98.41 mg, 134.49 μmol) to the reaction mixture, replace the reaction mixture with nitrogen for 3-5 times, stir the reaction mixture at 90 °C overnight. After the reaction is complete, filter, remove the solvent under reduced pressure, separate and purify the residue by silica gel column chromatography (eluent: A system) to obtain 6-phenylnaphthalen-1-ol 8b (290 mg) with a yield of 97.90%. MS m / z (ESI): 221.1 [M+1]

[0368] Second step

[0369] 6-phenylnaphthalen-1-yl trifluoromethanesulfonate

[0370] 6-phenylnaphthalen-1-yl trifluoromethanesulfonate

[0371] Dissolve 6-phenylnaphthalen-1-ol 8b (290 mg, 1.32 mmol) in dichloromethane (5 mL), lower the reaction mixture to 0 °C, add triethylamine (532.90 mg, 5.27 mmol) to the reaction solution, then dissolve trifluoromethanesulfonic anhydride (742.93 mg, 2.63 mmol) in dichloromethane (1 mL), slowly add, and stir at 0 °C for 1 hour. After monitoring the reaction to completion, remove the solvent under reduced pressure to obtain 6-phenylnaphthalen-1-yl trifluoromethanesulfonate 8c (450 mg) as a crude product with a yield of 97.01%.

[0372] MS m / z (ESI): 353.2 [M+1]

[0373] Third step

[0374] tert-butyl(6-phenylnaphthalen-1-yl)sulfane

[0375] tert-butyl(6-phenylnaphthalen-1-yl)sulfane

[0376] tert-butyl(6-phenylnaphthalen-1-yl)sulfane

[0377] 1H NMR (400 MHz, DMSO) δ 8.65 (d, J = 8.8 Hz, 1H), 8.24 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.75 (d, J = 7.2 Hz, 1H), 7.50 (dt, J = 18.4, 7.6 Hz, 3H), 7.37 (t, J = 7.2 Hz, 1H), 1.23 (s, 9H).

[0378] Fourth step

[0379] 6-phenylnaphthalene-1-thiol

[0380] 6-phenylnaphthalene-1-thiol

[0381] tert-butyl(6-phenylnaphthalen-1-yl)sulfane

[0382] 1H NMR (400MHz, CDCl3) δ8.24(d,J=8.8Hz,1H),8.06–8.01(m,1H),7.84(dd,J=8.8,1.6Hz,1H),7.75(d d,J=16.0,8.0Hz,3H),7.56(d,J=7.2Hz,1H),7.50(t,J=7.6Hz,2H),7.43–7.33(m,2H),3.63(s,1H).

[0383] Step 5

[0384] tert-butyl 4-(((6-phenylnaphthalen-1-yl)thio)methyl)piperidine-1-carboxylate

[0385] 4-(((6-phenylnaphthyl-1-yl)thio)methyl)piperidine-1-carboxylic acid tert-butyl ester

[0386] 6-Phenynaphthyl-1-thiol 8e (43 mg, 181.95 μmol) and 4-(bromomethyl)piperidine-1-carboxylic acid tert-butyl ester 8f (50.62 mg, 181.95 μmol) were dissolved in N,N-dimethylformamide (1 mL). Potassium carbonate (50.29 mg, 363.90 μmol) was added to the reaction mixture, and the mixture was stirred at 80 °C for 2 hours. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 8 g (40 mg) of 4-(((6-phenylnaphthyl-1-yl)thio)methyl)piperidine-1-carboxylic acid tert-butyl ester, with a yield of 50.70%.

[0387] 1H NMR (400MHz, CDCl3) δ8.50–8.42(m,1H),8.07–8.02(m,1H),7.84–7.77(m,2H),7.73(d,J=7.0Hz,2H),7.56–7.47(m,3H),7.42(dd,J=15.6,8 .0Hz,2H),4.17–4.02(m,2H),2.93(d,J=6.8Hz,2H),2.67(s,2H),2.06–1.96(m,1H),1.90(d,J=12.0Hz,2H),1.76–1.66(m,2H),1.45(s,9H).

[0388] Step 6

[0389] 4-(((6-phenylnaphthalen-1-yl)thio)methyl)piperidine

[0390] 4-(((6-phenylnaphthalen-1-yl)thio)methyl)piperidine

[0391] tert-butyl 4-(4-((3-oxo-3-(4-(((6-phenylnaphthalen-1-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0392] Seventh step

[0393] tert-butyl 4-(4-((3-oxo-3-(4-(((6-phenylnaphthalen-1-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0394] tert-butyl 4-(4-((3-oxo-3-(4-(((6-phenylnaphthalen-1-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0395] To a solution of 4-((6-phenylnaphthalen-1-yl)thiomethyl)piperidine 8h (20 mg, 59.97 μmol) and 3-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3- (trifluoromethyl)phenyl)amino)propanoic acid 7d (25.03 mg, 59.97 μmol) in N,N- dimethylformamide (1 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27.36 mg, 71.97 μmol) and N,N-diisopropylethylamine (23.25 mg, 179.92 μmol) were added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, water (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: A system) to give tert-butyl 4-(4-((3-oxo-3-(4-(((6-phenylnaphthalen-1-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2- (trifluoromethyl)phenyl)piperazine-1-carboxylate 8i (40 mg) in 91.01% yield.

[0396] MS m / z (ESI): 733.4 [M+1]

[0397] Eighth step

[0398] 1-(4-(((6-phenylnaphthalen-1-yl)thio)methyl)piperidin-1-yl)-3-((4-(piperazin-1-yl)-3- (trifluoromethyl)phenyl)amino)propan-1-one

[0399] 1-(4-(((6-phenylnaphthalen-1-yl)thio)methyl)piperidin-1-yl)-3-((4-(piperazin-1-yl)-3- (trifluoromethyl)phenyl)amino)propan-1-one

[0400] tert-Butyl 4-(4-((3-oxo-3-(4-(((6-phenylnaphthalen-1-yl)thio)methyl)piperidin-1- yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 8i (37 mg, 50.48 pmol) was dissolved in a mixture solution of dichloromethane (1 mL) and trifluoroacetic acid (0.2 mL), the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 10 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give 1-(4-(((6-phenylnaphthalen-1-yl)thio)methyl)piperidin-1-yl)-3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)propan-1-one 8 (7.81 mg), yield 20.72%.

[0401] MS m / z (ESI): 633.3 [M+1]

[0402] 1H NMR (400 MHz, MeOD) d 8.42 (d, J = 8.8 Hz, 1H), 8.10 (s, 1H), 7.86-7.79 (m, 2H), 7.75 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 7.2 Hz, 1H), 7.51-7.41 (m, 3H), 7.37 (t, J = 7.2 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 6.91 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.50 (d, J = 12.8 Hz, 1H), 3.91 (d, J = 13.2 Hz, 1H), 3.45-3.38 (m, 2H), 3.28-3.21 (m, 4H), 3.07-3.01 (m, 4H), 2.97-2.84 (m, 3H), 2.74-2.65 (m, 1H), 2.62-2.49 (m, 2H), 1.96-1.85 (m, 2H), 1.82-1.70 (m, 1H), 1.20-1.04 (m, 2H).

[0403] Example 9

[0404] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((3-(trifluoromethyl)quinolin-8-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0405] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((3-(trifluoromethyl)quinolin-8-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0406]

[0407]

[0408] First step

[0409] 3-iodo-8-nitroquinoline

[0410] 3-iodo-8-nitroquinoline

[0411] 3-iodo-8-nitroquinoline

[0412] MS m / z (ESI): 300.9 [M+1]

[0413] Second step

[0414] 8-nitro-3-(trifluoromethyl)quinoline

[0415] 8-nitro-3-(trifluoromethyl)quinoline

[0416] 8-nitro-3-(trifluoromethyl)quinoline

[0417] MS m / z (ESI): 243.1 [M+1]

[0418] Third step

[0419] 3-(trifluoromethyl)quinolin-8-amine

[0420] 3-(trifluoromethyl)quinolin-8-amine

[0421] 3-(trifluoromethyl)quinolin-8-amine

[0422] MS m / z (ESI): 213.1 [M+1]

[0423] Fourth step

[0424] 8-bromo-3-(trifluoromethyl)quinolone

[0425] 8-bromo-3-(trifluoromethyl)quinolone

[0426] 8-bromo-3-(trifluoromethyl)quinolone

[0427] MS m / z (ESI): 275.9 [M+1]

[0428] Fifth step

[0429] 8-bromo-3-(trifluoromethyl)quinolone

[0430] 8-bromo-3-(trifluoromethyl)quinolone

[0431] To a solution of 8-bromo-3-trifluoromethylquinoline 9h (487 mg, 1.76 mmol), tert-butyl mercaptan 2d (206.87 mg, 2.65 mmol) in toluene (2 mL) was added lithium bis(trimethylsilyl)amide (590.38 mg, 3.53 mmol, 360.00 μL) followed by 2-bis(cyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (336.40 mg, 705.66 μmol) and tris(dibenzylideneacetone)dipalladium (323.09 mg, 352.83 μmol). The mixture was purged with nitrogen for 5 min and then sealed and heated at 120 °C overnight. After the reaction was completed, the toluene was removed by rotary evaporation, the residue was diluted with dichloromethane (20 mL), filtered through celite, and the celite was washed with dichloromethane (20 mL). The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: system A) to give 8-tert-butylsulfanyl-3-trifluoromethylquinoline 9j (315 mg, 65.33% yield).

[0432] MS m / z (ESI): 286.1 [M+1]

[0433] Step 6

[0434] 3-(trifluoromethyl)quinoline-8-thiol

[0435] 3-(trifluoromethyl)quinoline-8-thiol

[0436] To a solution of 8-tert-butylsulfanyl-3-trifluoromethylquinoline 9j (291 mg, 1.06 mmol) in dichloromethane (20 mL) was added tri-bromo-borane 9k (800.20 mg, 3.19 mmol, 3 mL) dropwise at 0 °C. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was quenched with ice and extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: system A) to give 3-(trifluoromethyl)quinoline-8-thiol 9l (140 mg, 57.36% yield).

[0437] MS m / z (ESI): 230.1 [M+1]

[0438] Step 7

[0439] tert-butyl 4-(4-((3-oxo-3-(4-(((3-(trifluoromethyl)quinolin-8-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0440] tert-butyl 4-(4-((3-oxo-3-(4-(((3-(trifluoromethyl)quinolin-8-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0441] tert-butyl 4-(4-((3-oxo-3-(4-(((3-(trifluoromethyl)quinolin-8-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0442] MS m / z (ESI): 726.3 [M+1]

[0443] Eighth step

[0444] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((3-(trifluoromethyl)quinolin-8-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0445] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((3-(trifluoromethyl)quinolin-8-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0446] Propan-1-one

[0447] tert-Butyl 4-(4-((3-oxo-3-(4-((3-(trifluoromethyl)quinolin-8-yl)thio)methyl)piperidin-1- yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 9m (282 mg, 388.54 pmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3.46 g, 30.31 mmol, 1 mL) was added dropwise, the mixture was reacted at room temperature for 2 hours, after the reaction was completed, it was purified by preparative liquid phase separation (separation column Water 3767 Column: SunFire Sunfire C18; 19 x 250 mm I.D.; 10 pm, 20 mL / min; mobile phase A: 0.1% FA + H20, mobile phase B: CH3CN) to give 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((3-(trifluoromethyl)quinolin-8-yl)thio)methyl)piperidin-1-yl)propan-1-one 9 (22.88 mg), yield 12.71%.

[0448] MS m / z (ESI): 626.4 [M+1]

[0449] 1H NMR (400 MHz, DMSO) d 9.19 (d, J = 2.0 Hz, 1H), 8.95 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.28 - 7.24 (m, 1H), 6.82 - 6.78 (m, 2H), 5.98 - 5.90 (m, 1H), 4.42 (d, J = 12.8 Hz, 1H), 3.87 (d, J = 13.2 Hz, 1H), 3.30 - 3.25 (m, 2H), 3.09 - 2.89 (m, 3H), 3.02 - 2.91 (m, 4H), 2.81 - 2.76 (m, 4H), 2.63 - 2.53 (m, 3H), 1.98 - 1.87 (m, 3H), 1.25 - 1.08 (m, 2H).

[0450] Example 10

[0451] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((2-(trifluoromethyl)quinolin-5-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0452] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((2-(trifluoromethyl)quinolin-5-yl)thio)methyl)piperidin-1-yl)prop-1-one

[0453]

[0454]

[0455] first step

[0456] 5-bromoquinoline 1-oxide

[0457] 5-Bromoquinoline 1-oxide

[0458] 5-Bromoquinoline 10a (2 g, 9.61 mmol, commercially available) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid 10b (2.16 g, 12.50 mmol, commercially available) was slowly added in portions. The mixture was reacted at room temperature for 3 hours under nitrogen protection. After the reaction was complete, 1 mol / L NaOH (30 mL) was added, and the mixture was extracted three times with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 5-bromoquinoline-1-oxide 10c (1.73 g), with a yield of 80.51%.

[0459] MS m / z(ESI): 224.0 [M+1]

[0460] Step 2

[0461] 5-bromo-2-(trifluoromethyl)quinolone

[0462] 5-Bromo-2-(trifluoromethyl)quinoline

[0463] 5-Bromoquinoline-1-oxide 10c (1 g, 4.46 mmol) and trimethyl(trifluoromethyl)silane 10d (951.97 mg, 6.69 mmol, commercially available) were dissolved in tetrahydrofuran / dichloromethane (10 mL), and potassium tert-butoxide (1.50 g, 13.39 mmol) was slowly added dropwise at -20 °C. The mixture was reacted at -20 °C for 2 hours, and then at room temperature under nitrogen protection for 4 hours. After the reaction was complete, the mixture was directly evaporated to dryness, and the residue was purified by silica gel column chromatography (eluent: system A) to give 5-bromo-2-trifluoromethylquinoline 10e (230 mg), in 18.67% yield.

[0464] MS m / z(ESI): 276.0 [M+1]

[0465] Third step

[0466] 5-(tert-butylthio)-2-(trifluoromethyl)quinoline

[0467] 5-(tert-butylthio)-2-(trifluoromethyl)quinoline

[0468] 5-(tert-butylthio)-2-(trifluoromethyl)quinoline 10f (181 mg) was obtained in the yield of 76.14% by dissolving 5-bromo-2-trifluoromethylquinoline 10e (230 mg, 833.18 umol), tert-butyl mercaptan 2d (112.71 mg, 1.25 mmol) in toluene (2 mL), successively adding lithium bis(trimethylsilyl)amide (278.82 mg, 1.67 mmol, 0.2 mL), 2-bis(cyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (158.87 mg, 333.27 umol), tris(dibenzylideneacetone)dipalladium (152.59 mg, 166.64 umol), and replacing the nitrogen for 5 minutes, and then sealing the tube for reaction at 120 °C for 16 hours. After the reaction was completed, toluene was removed under reduced pressure, diluted with dichloromethane (20 mL), filtered with celite, concentrated under reduced pressure, added water (15 mL), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: A system) from the residue to obtain 5-(tert-butylthio)-2-(trifluoromethyl)quinoline 10f (181 mg) in the yield of 76.14%.

[0469] MS m / z (ESI): 286.1 [M+1]

[0470] Fourth step

[0471] 2-(trifluoromethyl)quinoline-5-thiol

[0472] 2-(trifluoromethyl)quinoline-5-thiol

[0473] 2-(trifluoromethyl)quinoline-5-thiol 10g (185 mg) was obtained in the yield of 82.24% by dissolving 5-(tert-butylthio)-2-(trifluoromethyl)quinoline 10f (280 mg, 981.33 umol) in dichloromethane (2 mL), adding tribromoborane 9k (491.69 mg, 1.96 mmol, 0.15 mL) dropwise under ice bath conditions, and stirring the mixture at room temperature for 2 hours. After the reaction was completed, ice was added for quenching, dichloromethane (50 mL x 3) was extracted three times, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: A system) from the residue to obtain 2-(trifluoromethyl)quinoline-5-thiol 10g (185 mg) in the yield of 82.24%.

[0474] MS m / z (ESI): 230.0 [M+1]

[0475] Fifth step

[0476] tert-butyl 4-(4-((3-oxo-3-(4-(((2-(trifluoromethyl)quinolin-5-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0477] 4-(4-((3-oxo-3-(4-((2-(trifluoromethyl)quinolin-5-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl) piperazine-1-carboxylate

[0478] Under nitrogen protection condition, 2-(trifluoromethyl)quinoline-5-thiol 10g (165 mg, 719.83 μmol) and tert-butyl 4-(4-((3-(4-(bromomethyl)piperidin-1-yl)-3-oxopropyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 7f (456.19 mg, 792.0 μmol) were dissolved in N,N-dimethylformamide (2 mL), potassium carbonate (198.97 mg, 1.44 mmol) was added at room temperature, and the mixture was reacted at 80 °C for 2 hours. After the reaction was completed, water was added for dilution, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed twice with saturated brine (30 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl 4-(4-((3-oxo-3-(4-((2-(trifluoromethyl)quinolin-5-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 10h (363 mg), yield 69.48%.

[0479] MS m / z (ESI): 726.3 [M+1]

[0480] Sixth step

[0481] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((2-(trifluoromethyl)quinolin-5-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0482] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((2- (trifluoromethyl)quinolin-5-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0483] tert-Butyl 4-((3-oxo-3-(4-((2-(trifluoromethyl)quinolin-5-yl)thio)methyl)piperidin-1- yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 10h (80 mg, 110.23 pmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (879.78 mg, 7.72 mmol, 1.6 mL) was added dropwise, the mixture was stirred at room temperature for 2 hours, after the reaction was completed, it was separated and purified by preparative liquid phase (separation column Water 3767 / Qda Column: SunFire Sunfire C18; 19 x 250 mm I.D.; 10 pm, 20 mL / min; mobile phase A: 0.1% FA + H2O, mobile phase B: CH3CN), to give 3-(4-((piperazin-1-yl)-3-trifluoromethylphenyl)amino)-1-(4-((2- (trifluoromethyl)quinolin-5-yl)thio)methyl)piperidin-1-yl)propanone 10 (49.71 mg), yield 72.08%.

[0484] MS m / z (ESI): 626.4 [M+1]

[0485] 1H NMR (400 MHz, DMSO) d 8.93 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.91-7.84 (m, 2H), 7.26 (d, J = 9.2 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 6.82-6.79 (m, 2H), 6.00 (t, J = 5.6 Hz, 1H), 4.39 (d, J = 13.2 Hz, 1H), 3.83 (d, J = 12.8 Hz, 1H), 3.30-3.23 (m, 3H), 3.14 (s, 3H), 3.12-3.06 (m, 2H), 2.97-2.89 (m, 5H), 2.60-2.53 (m, 3H), 1.89-1.77 (m, 3H), 1.21-1.05 (m, 2H).

[0486] Example 11

[0487] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((2-(trifluoromethyl)quinazolin-5-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0488] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((2-(trifluoromethyl)quinazolin-5-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0489]

[0490] First step

[0491] (2-amino-6-methoxyphenyl)methanol

[0492] (2-amino-6-methoxyphenyl)methanol

[0493] Dissolve 2-amino-6-methoxybenzoic acid 11a (2 g, 11.96 mmol, commercially available) in tetrahydrofuran (20 mL), add lithium aluminum hydride (908.20 mg, 23.93 mmol) into the reaction solution, then stir at room temperature for 3 hours. After the reaction is completed, remove the solvent under reduced pressure to obtain 2-amino-6-methoxyphenylmethanol 11b (1.8 g), which is directly used in the next step. MS m / z (ESI): 154.2 [M+1]

[0494] Second step

[0495] 2-amino-6-methoxybenzaldehyde

[0496] 2-amino-6-methoxybenzaldehyde

[0497] Dissolve 2-amino-6-methoxyphenylmethanol 11b (1.8 g, 11.75 mmol) in dichloromethane (20 mL), add manganese dioxide (4.90 g, 56.40 mmol) into the reaction solution, then stir at room temperature for 2 hours. After the reaction is completed, filter, remove the solvent under reduced pressure to obtain 2-amino-6-methoxybenzaldehyde 11c (1.75 g), which is directly used in the next step.

[0498] MS m / z (ESI): 152.2 [M+1]

[0499] Third step

[0500] 5-methoxy-2-(trifluoromethyl)quinazoline

[0501] 5-methoxy-2-(trifluoromethyl)quinazoline

[0502] 5-methoxy-2-(trifluoromethyl)quinazoline 11d (1.74 g) was obtained in 65.68% yield. MS m / z (ESI): 229.1 [M+1]

[0503] Fourth step

[0504] 2-(trifluoromethyl)quinazolin-5-ol

[0505] 2-(trifluoromethyl)quinazolin-5-ol

[0506] 2-(trifluoromethyl)quinazolin-5-ol 11e (1.29 g) was obtained in 86.72% yield.

[0507] MS m / z (ESI): 215.1 [M+1]

[0508] Fifth step

[0509] 2-(trifluoromethyl)quinazolin-5-yl trifluoromethanesulfonate

[0510] 2-(trifluoromethyl)quinazoline-5-thiol

[0511] Dissolve 2-(trifluoromethyl)quinazoline-5-thiol 11e (1.24 g, 5.79 mmol) in dichloromethane (20 mL), reduce the reaction mixture to 0 °C, add triethylamine (2.34 g, 23.16 mmol) to the reaction solution, then dissolve trifluoromethanesulfonic anhydride (3.27 g, 11.58 mmol) in dichloromethane (5 mL), slowly add, and stir at 0 °C for 1 h. After the reaction is complete, remove the solvent under reduced pressure to obtain 2-(trifluoromethyl)quinazoline-5-yl trifluoromethanesulfonate 11f (1.8 g), which is directly used in the next step.

[0512] MS m / z (ESI): 347.0 [M+1]

[0513] Sixth step

[0514] 5-(tert-butylthio)-2-(trifluoromethyl)quinazoline

[0515] 5-(tert-butylthio)-2-(trifluoromethyl)quinazoline

[0516] Dissolve 2-(trifluoromethyl)quinazoline-5-yl trifluoromethanesulfonate 11f (1.8 g, 5.20 mmol) in 1,4-dioxane (15 mL), add tert-butyl mercaptan 2d (710.42 mg, 7.89 mmol), tris(dibenzylideneacetone)dipalladium (481.62 mg, 525.94 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (608.64 mg, 1.05 mmol), N,N-diisopropylethylamine (1.70 g, 13.15 mmol) to the reaction mixture, replace the reaction mixture with nitrogen for 3-5 times, and microwave the reaction mixture at 130 °C for 1 h. After the reaction is complete, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL x 3), wash the combined organic phase with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (eluent: A system) to obtain 5-(tert-butylthio)-2-(trifluoromethyl)quinazoline 11g (1.22 g), with a yield of 81.02%.

[0517] MS m / z (ESI): 287.2 [M+1]

[0518] Seventh step

[0519] 2-(trifluoromethyl)quinazoline-5-thiol

[0520] 2-(trifluoromethyl)quinazoline-5-thiol

[0521] 5-(tert-butylthio)-2-(trifluoromethyl)quinazoline 11g (100 mg, 349.27 μmol) was dissolved in dichloromethane solution (2 mL), the reaction solution was reduced to 0 °C, boron tribromide (3 mL) was slowly added, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the boron tribromide was quenched with methanol, the solvent was removed under reduced pressure to obtain 2-(trifluoromethyl)quinazoline-5-thiol 11h (70 mg), which was directly used in the next step.

[0522] MS m / z (ESI): 231.1 [M+1]

[0523] Eighth step

[0524] tert-butyl 4-(4-((3-oxo-3-(4-(((2-(trifluoromethyl)quinazolin-5-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0525] 4-(4-((3-oxo-3-(4-((2-(trifluoromethyl)quinazolin-5-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0526] 2-(trifluoromethyl)quinazoline-5-thiol 11h (70 mg, 304.07 μmol) and tert-butyl 4-(4-((3-(4-(bromomethyl)piperidin-1-yl)-3-oxopropyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 7f (193.15 mg, 334.48 μmol) were dissolved in N,N-dimethylformamide (1.5 mL), potassium carbonate (42.02 mg, 304.07 μmol) was added to the reaction mixture, and stirred at 80 °C for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl 4-(4-((3-oxo-3-(4-((2-(trifluoromethyl)quinazolin-5-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 11i (129 mg) with a yield of 58.37%.

[0527] MS m / z (ESI): 727.4 [M+1]

[0528] Ninth step

[0529] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((2-(trifluoromethyl)quinazolin-5-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0530] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((2-(trifluoromethyl)quinazolin-5-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0531] tert-Butyl 4-(4-((3-oxo-3-(4-((2-(trifluoromethyl)quinazolin-5-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 11i (110 mg, 151.35 pmol) was dissolved in a mixed solution of dichloromethane (2.0 mL) and trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 10 pm, 20 mL / min; mobile phase A: 0.1% FA + H2O, mobile phase B: CH3CN) to give 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((2-(trifluoromethyl)quinazolin-5-yl)thio)methyl)piperidin-1-yl)propan-1-one 11 (84.28 mg) with a yield of 82.78%.

[0532] MS m / z (ESI): 627.3 [M+1]

[0533] 1H NMR (400 MHz, MeOD) δ 10.01 (s, 1H), 8.06 (dd, J = 8.4, 7.2 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 2.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.55 (d, J = 13.2 Hz, 1H), 3.97 (d, J = 13.2 Hz, 1H), 3.45 - 3.39 (m, 4H), 3.15 - 3.01 (m, 8H), 2.82 - 2.43 (m, 4H), 1.99 - 1.87 (m, 3H), 1.29 - 1.15 (m, 2H).

[0534] Example 12

[0535] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0536] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0537]

[0538]

[0539] First Step

[0540] 5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate

[0541] 5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate

[0542] Dissolve 5,6,7,8-tetrahydronaphthalen-1-ol 12a (1 g, 6.75 mmol, commercially available) in dichloromethane (10 mL), cool the reaction mixture to 0 °C, add triethylamine (1.37 g, 13.50 mmol) to the reaction, then dissolve triflic anhydride (2.28 g, 8.10 mmol) in dichloromethane (4 mL), slowly add, stir at 0 °C to room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure to obtain 5,6,7,8-tetrahydronaphthalen-1-yl triflate 12b (1.85 g), which is directly used in the next step.

[0543] Second step

[0544] tert-butyl(5,6,7,8-tetrahydronaphthalen-1-yl)sulfane

[0545] tert-butyl(5,6,7,8-tetrahydronaphthalen-1-yl)sulfane

[0546] Dissolve 5,6,7,8-tetrahydronaphthalen-1-yl triflate 12b (1.85 g, 6.60 mmol) in 1,4-dioxane (15 mL), add tris(dibenzylideneacetone)dipalladium (604.46 mg, 660.09 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (763.89 mg, 1.32 mmol), N,N-diisopropylethylamine (2.13 g, 16.50 mmol) and tert-butyl mercaptan 2d (891.62 mg, 9.90 mmol) to the reaction mixture, replace the reaction mixture with nitrogen for 3-5 times, microwave the reaction mixture at 130 °C for 1 hour. After the reaction is complete, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL x 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, separate and purify the residue by silica gel column chromatography (eluent: A system) to obtain tert-butyl(5,6,7,8-tetrahydronaphthalen-1-yl)sulfane 12c (1.32 g) with a yield of 90.95%.

[0547] 1H NMR (400 MHz, DMSO) δ 7.33-7.27 (m, 1H), 7.10 (dd, J = 7.2, 5.6 Hz, 2H), 2.91-2.85 (m, 2H), 2.77-2.71 (m, 2H), 1.75-1.65 (m, 4H), 1.24 (s, 9H).

[0548] Third step

[0549] 5,6,7,8-tetrahydronaphthalene-1-thiol

[0550] 5,6,7,8-Tetrahydronaphthalen-1-thiol

[0551] tert-Butyl (5,6,7,8-tetrahydronaphthalen-1-yl)sulfanide 12c (550 mg, 2.50 mmol) was dissolved in dichloromethane solution (8 mL), the reaction was reduced to 0 °C, boron tribromide (1 M, 9.98 mL) was slowly added, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, boron tribromide was quenched with methanol, the solvent was removed under reduced pressure to obtain 5,6,7,8-tetrahydronaphthalen-1-thiol 12d (314 mg), the crude was directly used in the next step.

[0552] 1H NMR (400 MHz, DMSO) d 7.23 (dd, J = 47.6, 8.0 Hz, 1H), 7.04 (dd, J = 48.0, 10.8 Hz, 1H), 6.89 (dd, J = 39.6, 7.6 Hz, 1H), 5.02 (s, 1H), 2.76 - 2.65 (m, 4H), 1.81 - 1.73 (m, 2H), 1.73 - 1.66 (m, 2H).

[0553] Fourth Step

[0554] tert-Butyl 4-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0555] tert-Butyl 4-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0556] A mixture of 5,6,7,8-tetrahydronaphthalen-1-thiol 12d (50 mg, 304.38 μmol) and tert-butyl 4-(4-((3-(4-(bromomethyl)piperidin-1-yl)-3-oxopropyl)amino)-2- (trifluoromethyl)phenyl)piperazine-1-carboxylate 7f (193.35 mg, 334.82 μmol) was dissolved in N,N-dimethylformamide (1.5 mL), potassium carbonate (63.10 mg, 456.57 μmol) was added to the reaction mixture, and stirred at 80 °C for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl 4-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 12e (168 mg) in 83.52% yield.

[0557] MS m / z (ESI): 661.4 [M+1]

[0558] Fifth step

[0559] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0560] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0561] tert-Butyl 4-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1- yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 12e (148 mg, 223.96 pmol) was dissolved in a mixture of dichloromethane (2.0 mL) and trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 10 pm, 20 mL / min; mobile phase A: 0.1% FA + H20, mobile phase B: CH3CN) to give 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8- tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propan-1-one 12 (77.16 mg) in 61.44% yield.

[0562] MS m / z (ESI): 561.4 [M+1]

[0563] 1H NMR (400 MHz, MeOD) d 7.28 (d, J = 8, 1H), 7.04 (dt, J = 15.2, 7.6 Hz, 2H), 6.87 (d, J = 3.2 Hz, 2H), 6.85-6.81 (m, 1H), 4.52 (d, J = 12.8 Hz, 1H), 3.96 (d, J = 13.2 Hz, 1H), 3.49-3.39 (m, 2H), 3.29-3.24 (m, 4H), 3.08-3.00 (m, 5H), 2.80-2.68 (m, 7H), 2.63-2.54 (m, 2H), 1.95-1.86 (m, 2H), 1.85-1.72 (m, 5H), 1.19-1.05 (m, 2H).

[0564] Example 13

[0565] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)methyl)piperidin-1-yl)propan-1-one

[0566] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)methyl)piperidin-1-yl)propan-1-one 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)methyl)piperidin-1-yl)propan-1-one

[0567] First step

[0568] tert-butyl 4-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0569] tert-butyl 4-(4-((3-oxo-3-(4-((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0570] tert-butyl 4-(4-((3-oxo-3-(4-((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0571] Second step

[0572] tert-butyl 4-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0573] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)methyl)piperidin-1-yl)propan-1-one

[0574] tert-Butyl 4-(4-((3-oxo-3-(4-((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 13a (55 mg, 45.68 μmol) was dissolved in a mixed solution of dichloromethane (0.5 mL) and trifluoroacetic acid (0.1 mL), the reaction mixture was stirred at room temperature for 2 hours, saturated sodium bicarbonate was added to adjust the pH to 8-9, extracted with ethyl acetate (50 mL x 3), the organic phase was combined and concentrated under reduced pressure, the residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)methyl)piperidin-1-yl)propan-1-one 13 (10 mg), yield 21.52%.

[0575] MS m / z (ESI): 545.4 [M+1]

[0576] 1H NMR (400 MHz, MeOD) δ 7.28 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.91-6.88 (m, 1H), 6.87-6.81 (m, 1H), 6.65-6.59 (m, 2H), 4.60 (d, J = 11.2 Hz, 1H), 4.02 (d, J = 13.2 Hz, 1H), 3.77-3.70 (m, 2H), 3.49-3.43 (m, 2H), 3.25-3.22 (m, 3H), 3.04-2.98 (m, 4H), 2.82-2.58 (m, 9H), 2.12-2.01 (m, 1H), 1.94-1.82 (m, 3H), 1.77-1.72 (m, 3H), 1.26-1.14 (m, 2H).

[0577] Example 14

[0578] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)amino)methyl)piperidin-1-yl)propan-1-one

[0579] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)amino)methyl)piperidin-1-yl)propan-1-one

[0580]

[0581] First step

[0582] tert-butyl 4-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)amino)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0583] tert-butyl 4-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)amino)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0584] After the reaction was completed by stirring tetrahydronaphthalen-5-amine 14a (15 mg, 101.89 μmol), tert-butyl 4-(4-((3-(4-(bromomethyl)piperidin-1-yl)-3-oxopropyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 7f (53.49 mg, 92.63 μmol), potassium carbonate (25.60 mg, 185.26 μmol) in N,N-dimethylformamide (2 mL) at 60 °C for 16 hours, water (10 mL) was added, the aqueous phase was extracted with ethyl acetate (10 mL x 3), the obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl 4-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)amino)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 14b (50.0 mg) with a yield of 83.85%.

[0585] MS m / z (ESI): 644.4 [M+1]

[0586] second step

[0587] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)amino)methyl)piperidin-1-yl)propan-1-one

[0588] 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)amino)methyl)piperidin-1-yl)propan-1-one

[0589] tert-Butyl 4-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)amino)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 14b (40 mg, 62.13 pmol), trifluoroacetic acid (7.08 mg, 62.13 pmol) in dichloromethane (1 mL) was stirred at 25 °C for 16 h, after the reaction was completed, concentrated under reduced pressure, the residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 5 pm, 20 mL / min; mobile phase A: 0.05% TFA + H20, mobile phase B: CH3CN) to give 3-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)amino)methyl)piperidin-1-yl)propan-1-one 14 (2.0 mg), yield 5.92%.

[0590] MS m / z (ESI): 544.4 [M+1]

[0591] 1H NMR (400 MHz, MeOD) d 7.29 (d, J = 8.6 Hz, 1H), 7.12-7.03 (m, 1H), 6.89 (d, J = 2.6 Hz, 1H), 6.87-6.83 (m, 1H), 6.81-6.73 (m, 2H), 4.58 (d, J = 13.2 Hz, 1H), 4.00 (d, J = 13.8 Hz, 1H), 3.46-3.36 (m, 2H), 3.29-3.24 (m, 4H), 3.15-3.01 (m, 7H), 2.81-2.53 (m, 7H), 1.92-1.82 (m, 4H), 1.81-1.72 (m, 2H), 1.36-1.28 (m, 1H), 1.24-1.06 (m, 2H).

[0592] Example 15

[0593] 3-((4-(2,6-diazaspiro[3.3]heptan-2-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0594] 3-((4-(2,6-diazaspiro[3.3]heptan-2-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0595]

[0596] First step

[0597] tert-butyl 6-(4-nitro-2-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0598] tert-butyl 6-(4-nitro-2-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0599] tert-butyl 6-(4-nitro-2-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0600] MS m / z (ESI): 388.2 [M+1]

[0601] Second step

[0602] tert-butyl 6-(4-amino-2-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0603] 6-(4-amino-2-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0604] 15c of 6-(4-nitro-2-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 15c (298 mg, 769.32 μmol) and 10% palladium on carbon (30 mg, 769.32 μmol) were dissolved in methanol (5 mL), and the mixture was purged with hydrogen 3–5 times. The reaction mixture was stirred at 40 °C for 2 hours. After the reaction was complete, the crude product was filtered and concentrated under vacuum to give 15d of 6-(4-amino-2-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 15d (270 mg), yield 98.21%. MS m / z (ESI): 358.2 [M+1]

[0605] Step 3

[0606] tert-butyl 4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidine-1-carboxylate

[0607] 4-(((5,6,7,8-tetrahydronaphthyl-1-yl)thio)methyl)piperidine-1-carboxylic acid tert-butyl ester

[0608] 5,6,7,8-Tetrahydronaphthyl-1-thiol 12d (170 mg, 1.03 mmol) and 4-(bromomethyl)piperidine-1-carboxylic acid tert-butyl ester 8f (316.68 mg, 1.14 mmol) were dissolved in N,N-dimethylformamide (2.5 mL). Potassium carbonate (214.55 mg, 1.55 mmol) was added to the reaction mixture, and the mixture was stirred at 80 °C for 2 hours. After the reaction was complete, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 4-(((5,6,7,8-tetrahydronaphthyl-1-yl)thio)methyl)piperidine-1-carboxylic acid tert-butyl ester 15e (336 mg), yield 89.80%.

[0609] MS m / z (ESI): 306.0 [M-55]

[0610] Fourth Step

[0611] 4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidine

[0612] 4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidine

[0613] tert-Butyl 4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidine-1- carboxylate 15e (80 mg, 221.28 pmol) was dissolved in a mixture solution of dichloromethane (1.5 mL) and trifluoroacetic acid (0.3 mL), the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure to give 4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidine 15f (55 mg), which was directly used in the next step.

[0614] MS m / z (ESI): 262.2 [M+1]

[0615] Fifth Step

[0616] 3,3-dimethoxy-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0617] 3,3-dimethoxy-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0618] To a solution of 4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidine 15f (55 mg, 210.39 μmol) and 3,3-dimethoxypropanoic acid 15g (66 mg, 492.06 μmol, commercially available) in N,N-dimethylformamide (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (95.99 mg, 252.46 μmol) and N,N-diisopropylethylamine (81.57 mg, 631.16 μmol) and stirred at room temperature for 2 h. After the reaction was completed, water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: A system) to give 3,3-dimethoxy-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propan-1-one 15h (45 mg) in a yield of 56.65%.

[0619] MS m / z (ESI): 378.2 [M+1]

[0620] Sixth step

[0621] 3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propanal

[0622] 3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propanal

[0623] To a solution of 3,3-dimethoxy-1-(4-((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propanone 15h (45 mg, 119.19 μmol) in a mixture of 1,4-dioxane (0.5 mL) and 1 N dilute hydrochloric acid (0.5 mL) was stirred at 65 °C for 2 h. After the reaction was completed, the crude product was adjusted to pH 8-9 with saturated sodium bicarbonate solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: A system) to give 3-oxo-3-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propanal 15i (40 mg) in a yield of 99.04%.

[0624] MS m / z (ESI): 332.0 [M+1]

[0625] Seventh step

[0626] tert-butyl 6-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0627] 6-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0628] tert-butyl 6-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0629] MS m / z (ESI): 673.3 [M+1]

[0630] Eighth step

[0631] 3-((4-(2,6-diazaspiro[3.3]heptan-2-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0632] 3-((4-(2,6-diazaspiro[3.3]oct-2-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propan-1-one

[0633] A mixture solution of 6-(4-((3-oxo-3-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]octane-2-carboxylic acid tert-butyl ester 15j (15 mg, 22.29 pmol) in dichloromethane (0.5 mL) and trifluoroacetic acid (0.1 mL) was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 x 21.2 mm I.D.; 10 pm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give 3-((4-(2,6-diazaspiro[3.3]oct-2-yl)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((5,6,7,8-tetrahydronaphthalen-1-yl)thio)methyl)piperidin-1-yl)propan-1-one 15 (8.4 mg) with a yield of 54.87%.

[0634] MS m / z (ESI): 573.4 [M+1]

[0635] 1H NMR (400 MHz, MeOD) d 7.51-7.26 (m, 2H), 7.09 (d, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 6.79-6.57 (m, 1H), 4.55 (d, J = 13.2 Hz, 1H), 4.29 (s, 4H), 4.26-2.18 (m, 2H), 3.87 (d, J = 13.6 Hz, 1H), 3.32-3.30 (m, 4H), 3.03 (t, J = 12.0 Hz, 1H), 2.89-2.81 (m, 2H), 2.77-2.69 (m, 6H), 2.66-2.18 (m, 1H), 1.99-1.90 (m, 2H), 1.84-1.73 (m, 5H), 1.24-1.11 (m, 2H).

[0636] Biological evaluation

[0637] Test Example 1, Cell proliferation activity of the compound of the present application on NCI-H2030 cell line

[0638] The following method was used to determine the effect of the compounds of the present application on the proliferation of NCI-H2030 cells. NCI-H2030 cells were purchased from Nanjing KeyGen Biotech Co., Ltd. and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U of penicillin and 100 μg / mL of streptomycin. Cell viability was determined by Luminescent Cell Viability Assay kit (Promega, Cat. No. G7573).

[0639] The experimental method was operated according to the steps of the kit instructions, and a brief description is as follows: the test compound was first dissolved in DMSO to prepare a 10 mM stock solution, then diluted with culture medium to prepare test samples, and the final concentration of the test compound ranged from 20000 nM to 3.05 nM. Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate at a density of 1000 cells per well, incubated in a 37°C, 5% CO2 incubator overnight, and then incubated for 72 hours after the addition of the test compound. After the end of the culture, 50 uL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes, and then incubated for 10 minutes. Then the luminescence value of each well was read on a microplate reader using the Luminescence mode. The percentage inhibition of the compound at each concentration point was calculated by comparing the values with the control group (0.3% DMSO), and then the compound concentration-log-inhibition was analyzed by non-linear regression analysis in GraphPad Prism 5 software to obtain the IC 50 value of the compound for inhibiting cell proliferation, as shown in Table 1.

[0640] Table 1 IC 50 data of the compounds of the present application for inhibiting the proliferation of NCI-H2030 cells.

[0641]

[0642]

[0643] Conclusion: As can be seen from Table 1, the compounds of the present application have a strong inhibitory effect on the proliferation of NCI-H2030 cells. Test Example 2, determination of the cell proliferation activity of the compounds of the present application on SW1573 cell line

[0644] The following method was used to determine the effect of the compounds of the present application on the proliferation of SW1573 cells. SW1573 cells were purchased from Nanjing KeyGen Biotech Co., Ltd. and cultured in DMEM medium containing 10% fetal bovine serum, 100 U of penicillin and 100 μg / mL of streptomycin. Cell viability was determined by The Luminescent Cell Viability Assay kit (Promega, Cat. No. G7573) was used to determine the cell viability.

[0645] The experimental procedure was performed according to the kit instruction, and the brief description was as follows: the test compound was first dissolved in DMSO to prepare a 10 mM stock solution, then diluted with culture medium to prepare test samples, and the final concentration of the compound was in the range of 20000 nM-3.05 nM. Cells in the logarithmic growth phase were inoculated into a 96-well cell culture plate at a density of 1000 cells per well, incubated in a 37°C, 5% CO2 incubator overnight, then incubated for 72 hours after adding the test compound. After the end of the culture, 50 uL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes, then placed for 10 minutes, then the luminescence value of each well of the sample was read on the enzyme-labeled instrument using the Luminescence mode. The percentage inhibition of the compound at each concentration point was calculated by comparing the value with the control group (0.3% DMSO), and then the compound concentration-log-inhibition was subjected to nonlinear regression analysis in the GraphPad Prism 5 software to obtain the IC 50 value of the compound for inhibiting cell proliferation, see Table 2.

[0646] Table 2 IC 50 data of the compound of the present application for inhibiting the proliferation of SW1573 cells.

[0647]

[0648]

[0649] Conclusion: As can be seen from Table 2, the compound of the present application has a strong inhibitory effect on the proliferation of SW1573 cells.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: ###0001### Formula (I) wherein: ###0002### ring A is selected from ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ###0110### ###0111### ###0112### ###0113### ###0114### ###0115### ###0116### ###0117### ###0118### ###0119### ###0120### ###0121### ###0122### ###0123### ###0124### ###0125### ###0126### ###0127### ###0128### ###0129### ###0130### ###0131### ###0132### ###0133### ###0134### ###0135### ###0136### ###0137### ###0138### ###0139### ###0140### ###0141### ###0142### ###0143### ###0144### ###0145### ###0146### ###0147### ###0148### ###0149### ###0150### ###0151### ###0152### ###0153### ###0154### ###0155### ###0156### ###0157### ###0158### ###0159### ###0160### ###0161### ###0162### ###0163### ###0164### ###0165### ###0166### ###0167### ###0168### ###0169### ###0170### ###0171### ###0172### ###0173### ###0174### ###0175### ###0176### ###0177### ###0178### ###0179### ###0180### ###0181### ###0182### ###0183### ###0184### ###0185### ###0186### ###0187### ###0188### ###0189### ###0190### ###0191### ###0192### ###0193### ###0194### ###0195### ###0196### ###0197### ###0198### ###0199### ###0200### ###0201### ###0202### ###0203### ###0204### ###0205### ###0206### ###0207### ###0208### ###0209### ###0210### ###0211### ###0212### ###0213### ###0214### ###0215### ###0216### ###0217### ###0218### ###0219### ###0220### ###0221### ###0222### ###0223### ###0224### ###0225### ###0226### ###0227### ###0228### ###0229### ###0230### ###0231### ###0232### ###0233### ###0234### ###0235### ###0236### ###0237### ###0238### ###0239### ###0240### ###0241### ###0242### ###0243### ###0244### ###0245### ###0246### ###0247### ###0248### ###0249### ###0250### ###0251### ###0252### ###0253### ###0254### ###0255### ###0256### ###0257### ###0258### ###0259### ###0260### ###0261### ###0262### ###0263### ###0264### ###0265### ###0266### ###0267### ###0268### ###0269### ###0270### ###0271### ###0272### ###0273### ###0274### ###0275### ###0276### ###0277### ###0278### ###0279### ###0280### ###0281### ###0282### ###0283### ###0284### ###0285### ###0286### ###0287### ###0288### ###0289### ###0290### ###0291### ###0292### ###0293### ###0294### ###0295### ###0296### ###0297### ###0298### ###0299### ###0300### ###0301### ###0302### ###0303### ###0304### ###0305### ###0306### ###0307### ###0308### ###0309### ###0310### ###0311### ###0312### ###0313### ###0314### ###0315### ###0316### ###0317### ###0318### ###0319### ###0320### ###0321### ###0322### ###0323### ###0324### ###0325### ###0326### ###0327### ###0328### ###0329### ###0330### ###0331### ###0332### ###0333### ###0334### ###0335### ###0336### ###0337### ###0338### ###0339### ###0340### ###0341### ###0342### ###0343### ###0344### ###0345### ###0346### ###0347### ###0348### ###0349### ###0350### ###0351### ###0352### ###0353### ###0354### ###0355### ###0356### ###0357### ###0358### ###0359### ###0360### ###0361### ###0362### ###0363### ###0364### ###0365### ###0366### ###0367### ###0368### ###0369### ###0370### ###0371### ###0372### ###0373### ###0374### ###0375### ###0376### ###0377### ###0378### ###0379### ###0380### ###0381### ###0382### ###0383### ###0384### ###0385### ###0386### ###0387### ###0388### ###0389### ###0390### ###0391### ###0392### ###0393### ###0394### ###0395### ###0396### ###0397### ###0398### ###0399### ###0400### ###0401### ###0402### ###0403### ###0404### ###0405### ###0406### ###0407### ###0408### ###0409### ###0410### ###0411### ###0412### ###0413### ​ R A selected from a hydrogen atom; R 2 , R 3 are each independently selected from a group G or a hydrogen atom, with the proviso that when R 2 is a group G, R 3 is a hydrogen atom; when R 2 is a hydrogen atom, R 3 is a group G; Group G is ; ​ , , or ; To ; Ring B is selected from ; X is selected from -0-, -S- or -NR a -; R a selected from a hydrogen atom; R 1 the same or different, each independently selected from the group consisting of C1-C6alkyl or C6-C10aryl; wherein the alkyl or aryl is optionally further substituted with one or more substituents selected from halogen; 10 aryl; wherein the alkyl or aryl is optionally further substituted with one or more substituents selected from halogen, R 4 the same or different, each independently selected from C1-C6alkyl or piperazinyl, wherein said alkyl or piperazinyl is optionally further substituted with one or more R F substituents; R F the same or different, each independently selected from halogen ​ ​ ​ wherein: Ring A, Ring B, X, W, R 1 , R A , R 4 , L 1 , L 2 , m and n are as defined in claim 1.

3. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein is selected from the group consisting of: or . ​ or . ​ ​ ​ 8. Use according to claim 7, characterized in that, ​ ​ 10. Use according to claim 9, characterized in that, ​

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