CN106146478A - Triazine derivatives species anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase inhibitor - Google Patents

Triazine derivatives species anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase inhibitor Download PDF

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CN106146478A
CN106146478A CN201510169843.9A CN201510169843A CN106146478A CN 106146478 A CN106146478 A CN 106146478A CN 201510169843 A CN201510169843 A CN 201510169843A CN 106146478 A CN106146478 A CN 106146478A
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cancer
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CN106146478B (en
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吴永谦
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Xuanzhu Biopharmaceutical Co Ltd
Shandong Xuanzhu Pharma Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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Abstract

The invention belongs to pharmaceutical technology field, be specifically related to logical triazine derivatives species anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase inhibitor, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, wherein R shown in formula I1、R2、R3、R4、R6、R7It is defined as in the description with A ring.The invention still further relates to the preparation method of these compounds, pharmaceutical preparation containing these compounds and pharmaceutical composition, and the application that this compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer are in the medicine of the cancer-related diseases that preparation is treated and/or prevention is mediated by anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase.

Description

Triazine derivative anaplastic lymphoma kinase inhibitor
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a triazine derivative type anaplastic lymphoma kinase inhibitor, pharmaceutically acceptable salts, esters, solvates or stereoisomers thereof, a preparation method of the compounds, a pharmaceutical preparation and a pharmaceutical composition containing the compounds, and application of the compounds, the pharmaceutically acceptable salts, esters, solvates or stereoisomers thereof in preparation of medicines for treating and/or preventing cancer-related diseases mediated by anaplastic lymphoma kinase.
Background
Anaplastic Lymphoma Kinase (ALK) is a member of the receptor tyrosine kinase family, and can recruit downstream proteins through autophosphorylation, thereby expressing specific genes and regulating cellular metabolism and growth. Anaplastic lymphoma kinase was first found in Anaplastic Large Cell Lymphoma (ALCL) and was later found to be highly expressed in non-small cell lung cancer (NSCLC). Research finds that about half of patients generate oncogenic abnormal anaplastic lymphoma kinase fusion protein (such as NPM-ALK), and the variant protein has important guiding significance for clinical diagnosis, treatment and prognosis and becomes a hotspot of the current research.
The micromolecule inhibitor of ALK can effectively reduce the influence of the mutated ALK gene on downstream proteins, further influence the effects of tumor cell invasion, proliferation and the like, finally influence the growth of tumor cells and play a role in resisting tumors. At present, Crizotinib (Crizotinib) of the company pfeiri successfully comes on the market, but a large number of clinical trials prove that the Crizotinib of the first generation of ALK inhibitor is easy to generate drug resistance, so that the second generation of ALK inhibitor which has good curative effect on patients with drug resistance to Crizotinib is designed and screened, and the clinical significance is remarkable.
Therefore, a new compound structure is searched through compound structure modification, the physicochemical property of the compound is improved, the drug forming property is improved, for example, the bioavailability of the compound is improved, and a small molecule inhibitor active to ALK mutation is searched, so that the method has important significance for treating diseases caused by ALK mutation clinically.
Disclosure of Invention
The invention aims at developing a small molecule inhibitor aiming at ALK, and provides a triazine derivative anaplastic lymphoma kinase inhibitor with good effect on treating and/or preventing ALK-mediated cancer-related diseases. The specific technical scheme is as follows:
1. a compound of formula (I), a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof:
wherein,
R1is selected from-COR5，-CO2R5，-CONRR5，-SOR5，-SO2R5or-SO2NRR5；
R2Selected from hydrogen atom, halogen atom, nitro group, cyano group, amino group, hydroxyl group, carboxyl group, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl radical, C1-6Alkoxy, hydroxy C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino group, C1-6Alkylthio radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylsulfonylamino group, C1-6Alkylaminosulfonyl, (C)1-6Alkyl radical)2Aminosulfonyl or C1-6An alkylsulfonyl group;
R3selected from 5-14 membered heteroaryl optionally substituted with 1-3W or 3-8 membered heterocyclic group,
w is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino, halogeno C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylsulfonyl radical, C2-8Alkenyl or C2-8An alkynyl group;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, carboxyl group, C1-6Alkoxy radical, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkoxy, halo C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-6Alkylamino radical, C1-6Alkylcarbonyl or C1-6An alkylcarbonyloxy group;
R、R5independently selected from hydrogen atom, C1-6Alkyl or 3 to 8-membered carbonA ring;
R6、R7independently selected from hydrogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, amino C1-6Alkyl or sulfonyl C1-6An alkyl group;
a is selected from 3-8 membered cycloalkyl optionally substituted by 1-3Q or 3-8 membered heterocyclic group optionally substituted by 1-3Q, and the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino, halogeno C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl or 3-to 8-membered heterocyclic group.
2. The compound, pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof according to claim 1, wherein,
R1is selected from-CO2R5、-CONRR5、-SO2R5or-SO2NRR5；
R2Selected from hydrogen atom, halogen atom, nitro group, cyano group, amino group, hydroxyl group, carboxyl group, C1-6Alkyl, hydroxy C1-6Alkyl or halo C1-6An alkyl group;
R3selected from 5-6 membered heterocyclic group optionally substituted with 1-2W,
w is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl or C1-6An alkoxy group;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, carboxyl group, C1-6Alkoxy or C1-6An alkyl group;
R、R5independently selected from a hydrogen atom or C1-6An alkyl group;
R6、R7independently selected from a hydrogen atom or C1-6An alkyl group;
a is selected from 5-6 membered cycloalkyl optionally substituted by 1-2Q or 5-6 membered heterocyclic group optionally substituted by 1-2Q, and the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6An alkyl group.
3. The compound, pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof according to claim 2, wherein,
R1is selected from-SO2R5or-SO2NRR5；
R2Selected from hydrogen atom, halogen atom, nitro group, cyano group, amino group, hydroxyl group, carboxyl group or C1-6An alkyl group;
R3selected from 5-6 membered nitrogen-containing heterocyclic group optionally substituted with 1-2W,
w is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6An alkyl group;
R4selected from hydrogen atoms or C1-6An alkyl group;
R、R5independently selected from C1-6An alkyl group;
R6、R7independently selected from a hydrogen atom or C1-6An alkyl group;
a is selected from 5-6 membered heterocyclic group containing 1-2O, S and/or N atoms and optionally substituted by 1-2Q, and the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6An alkyl group.
4. The compound, pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof according to claim 3, wherein,
R1is selected from-SO2R5；
R2Selected from hydrogen atom, halogen atom, nitro group, cyano group, amino group, hydroxyl group, carboxyl group or C1-4An alkyl group;
R3selected from 5-6 membered heterocyclic group containing 1-2N atoms optionally substituted with 1-2W,
w is selected from hydroxy, amino, carboxyl or C1-6An alkyl group;
R4selected from hydrogen atoms or C1-4An alkyl group;
R5independently selected from C1-4An alkyl group;
R6、R7independently selected from a hydrogen atom or C1-4An alkyl group;
a is selected from 5-6 membered heterocyclic group containing 1-2O and/or S atoms optionally substituted by 1-2Q, and the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4An alkyl group.
5. The compound, pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof according to claim 4, wherein,
R3selected from pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
a is selected from 6-membered heterocyclic group containing 2O and/or S atoms and optionally substituted by 1-2Q, and the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom and C1-4An alkyl group.
6. The compound, pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof according to claim 1, wherein,
R1is selected from-SO2R5or-SO2NRR5；
R2Selected from hydrogen atom, halogen atom, nitro group, cyano group, amino group, hydroxyl group, carboxyl group orC1-6An alkyl group;
R3selected from 5-6 membered heterocyclic group optionally substituted with 1-2W,
w is selected from hydroxyl, amino, carboxyl, halogen atom, C1-6Alkyl or C1-6An alkoxy group;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, carboxyl group, C1-6Alkoxy or C1-6An alkyl group;
R、R5independently selected from a hydrogen atom or C1-6An alkyl group;
R6、R7independently selected from a hydrogen atom or C1-6An alkyl group;
a is selected from 5-6 membered heterocyclic group optionally substituted by 1-2Q, and the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6An alkyl group.
7. The compound, pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof according to claim 6, wherein,
R3selected from 5-6 membered nitrogen-containing heterocyclic group optionally substituted with 1-2W,
w is selected from hydroxyl, amino, carboxyl, halogen atom, C1-6Alkyl or C1-6An alkoxy group;
a is selected from 5-6 membered heterocyclic group containing 1-2O and/or S atoms optionally substituted by 1-2Q, and the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6An alkyl group.
8. The compound, pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof according to claim 7, wherein,
R1is selected from-SO2R5；
R2Is selected fromHydrogen atom or C1-6An alkyl group;
R3selected from 6-membered saturated nitrogen-containing heterocyclic groups optionally substituted with 1 to 2W,
w is selected from C1-6An alkyl group;
R4selected from hydrogen atoms or C1-6An alkyl group;
R、R5independently selected from a hydrogen atom or C1-6An alkyl group;
R6、R7independently selected from a hydrogen atom or C1-6An alkyl group;
a is selected from 6-membered saturated heterocyclic group containing 1-2O and/or S atoms optionally substituted by 1-2Q, and the substituent Q is selected from C1-6An alkyl group.
9. The compound, pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof according to claim 7, wherein,
R3selected from pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl optionally substituted with 1-2W,
w is selected from C1-6An alkyl group;
a is selected from 6-membered saturated heterocyclic group containing 1-2O and/or S atoms optionally substituted by 1-2Q, and the substituent Q is selected from C1-6An alkyl group.
Part of the Compounds of the invention
Detailed Description
The "halogen atom" in the present invention includes fluorine atom, chlorine atom, bromine atom, iodine atom and the like.
"C" according to the invention1-6Alkyl "denotes straight or branched chainAlkyl radicals containing 1 to 6 carbon atoms in the chain, including, for example, "C1-4Alkyl group "," C1-3Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-dimethylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.
"C" according to the invention2-8Alkenyl "means a straight or branched chain or cyclic alkenyl group of 2 to 8 carbon atoms containing at least one double bond, including, for example," C2-6Alkenyl group "," C2-4Alkenyl group "," C2-3Alkenyl group "," C3-6Cycloalkenyl "and the like, specific examples include, but are not limited to: vinyl group, 1-propenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 1-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 2-methyl-1-butenyl group, 3-methyl-1-butenyl group, 2-methyl-3-butenyl group, 1-dimethyl-2-propenyl group, 1-ethyl-2-propenyl group, 2-hexenyl group, 3-hexenyl group, 2-methyl-1-pentenyl group, 3-methyl-1-pentenyl group, 1-methyl-2-pentenyl group, 3-methyl-1-pentenyl group, 3-methyl-2-pentenyl group, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-2-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-1-butenyl, 2-ethyl-3-butenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 4-octenyl, 1, 3-butadienyl, 1-pentenyl, 3-pentenyl, 2-dimethyl-3-butenyl, 2, 3-heptenyl, 4-heptenyl, 2, 4-pentadienyl, 1, 4-hexadienyl, 2, 4-hexadienyl, 1, 5-heptadienyl, 2, 6-octadienyl, cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl and the like.
The invention isThe above-mentioned "C2-8Alkynyl refers to a straight or branched chain alkynyl group of 2-8 carbon atoms containing a triple bond, including, for example, "C2-6Alkynyl group "," C2-4Alkynyl group "," C2-3Alkynyl "and the like, specific examples include, but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, 2-heptynyl, 3-heptynyl, 4-methyl-2-hexynyl, 2-ethyl-2-propynyl, 3-pentynyl, 1-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 5-methyl-2-hexynyl, 2-methyl-3-hexynyl, 5-methyl-3-hexynyl, 2-methyl-4-hexynyl, 4-methyl-5-hexynyl, 2-octynyl, 3-octynyl, 4-methyl-2-heptynyl, 5-methyl-3-heptynyl, 6-methyl-3-heptynyl, 2-methyl-4-heptynyl, 2-methyl-5-heptynyl, 3-methyl-6-heptynyl and the like.
"C" according to the invention1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino group, C1-6Alkylthio radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylsulfonylamino group, C1-6Alkylaminosulfonyl, (C)1-6Alkyl radical)2Aminosulfonyl radical, C1-6Alkylsulfonyl "means with C1-6alkyl-O-, C1-6alkyl-NH-, (C)1-6Alkyl radical)2-N-、C1-6alkyl-S-, C1-6alkyl-C (O) -, C1-6alkyl-C (O) -O-, C1-6alkyl-SO2NH-、C1-6alkyl-NHSO2-、(C1-6Alkyl radical)2-NHSO2-、C1-6alkyl-SO2A group formed in the formula (I) wherein "C1-6Alkyl "is as defined above.
"C" according to the invention1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino group, C1-4Alkylthio radical, C1-4Alkyl radicalCarbonyl group, C1-4Alkylcarbonyloxy, C1-4Alkylsulfonylamino group, C1-4Alkylaminosulfonyl, (C)1-4Alkyl radical)2Aminosulfonyl radical, C1-4Alkylsulfonyl "means with C1-4alkyl-O-, C1-4alkyl-NH-, (C)1-4Alkyl radical)2-N-、C1-4alkyl-S-, C1-4alkyl-C (O) -, C1-4alkyl-C (O) -O-, C1-4alkyl-SO2NH-、C1-4alkyl-NHSO2-、(C1-4Alkyl radical)2-NHSO2-、C1-4alkyl-SO2A group formed in the formula (I) wherein "C1-4Alkyl "is as defined above.
The "halo C" of the present invention1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkoxy radical, C1-6Alkoxy radical C1-6The "alkoxy group" means one or more, for example, 1 to 4, 1 to 3, 1 to 2 halogen atoms, hydroxyl group, amino group, sulfonyl group, C1-6Alkoxy radicals each being substituted for C1-6Alkyl radical, C1-6A group formed by a hydrogen atom in an alkoxy group.
The "halo C" of the present invention1-4Alkyl, hydroxy C1-4Alkyl, amino C1-4Alkyl, sulfonyl C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl, halo C1-4Alkoxy, hydroxy C1-4Alkoxy radical, C1-4Alkoxy radical C1-4The "alkoxy group" means one or more, for example, 1 to 4, 1 to 3, 1 to 2 halogen atoms, hydroxyl group, amino group, sulfonyl group, C1-4Alkoxy radicals each being substituted for C1-4Alkyl radical, C1-4A group formed by a hydrogen atom in an alkoxy group.
The "3-8 membered cycloalkyl group" refers to a monocyclic cycloalkyl group derived from an alkane moiety of 3-8 carbon atoms by removing one hydrogen atom, and includes, for example, "3-6 membered cycloalkyl group", "4-7 membered cycloalkyl group", "4-6 membered cycloalkyl group", "5-6 membered cycloalkyl group" and the like. Examples include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane, methylcyclohexane, dimethylcyclohexane, etc.
The term "heteroatom" as used herein means N, O, C (O), S, SO and/or SO2Etc., preferably N, O, S, more preferably N, O.
The "3-to 8-membered heterocyclic group" as used herein refers to a group obtained by removing one hydrogen atom from a saturated or partially saturated monocyclic heterocyclic compound containing 3 to 8 ring atoms and at least one (e.g., 1,2, 3,4 or 5) hetero atom. The 3-to 8-membered partially saturated heteromonocyclic group is a cyclic group containing a double bond and a hetero atom. The 3-to 8-membered saturated monocyclic heterocyclic group is a cyclic group containing a hetero atom and all of which are saturated bonds. The "3-to 8-membered heterocyclic group" includes, for example, "3-to 7-membered heterocyclic group", "3-to 6-membered heterocyclic group", "4-to 7-membered heterocyclic group", "4-to 6-membered heterocyclic group", "5-to 6-membered heterocyclic group", "6-membered saturated heterocyclic group", "5-to 6-membered nitrogen-containing heterocyclic group", "5-to 6-membered saturated nitrogen-containing heterocyclic group", "6-membered saturated nitrogen-containing heterocyclic group", and the like, and specifically may include "5-to 6-membered heterocyclic group containing 1 to 2N atoms", "5-to 6-membered heterocyclic group containing 1 to 2O, S and/or N atoms", "5-to 6-membered heterocyclic group containing 1 to 2O and/or S atoms", "6-membered heterocyclic group containing 2O and/or S atoms", "5-to 6-membered saturated heterocyclic group containing 1 to 2O and/or S atoms" "a 6-membered saturated heterocyclic group containing 1 to 2O and/or S atoms", and the like. Specific examples include, but are not limited to: aziridinyl, 2H-aziridinyl, diazacyclopropenyl, 3H-diazacyclopropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuryl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, 2H-1, 2-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl and the like.
The "3-to 8-membered carbocyclic ring" refers to a saturated, partially saturated or unsaturated monocyclic compound having 3 to 8 carbon atoms. Including, for example, "3-to 7-membered carbocyclic ring", "3-to 6-membered carbocyclic ring", "4-to 7-membered carbocyclic ring", "4-to 6-membered carbocyclic ring", "5-to 6-membered carbocyclic ring", etc. Specific examples include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl, phenyl and the like. Preferably a 5-to 6-membered saturated or partially saturated carbocyclic ring.
The invention also provides a preparation method of the compound, but not limited to the following method, and the reaction equation is as follows:
the reaction steps are as follows:
step 1 preparation of intermediate 1
Intermediate 1 was purchased or prepared by an appropriate method.
Step 2 preparation of intermediate 2
Intermediate 1 is dissolved in a solvent (e.g., N-dimethylformamide), N-bromosuccinimide is added, and heated (e.g., 50-70 ℃) overnight, the reaction is completed, quenched with water, extracted with an organic solvent (e.g., ethyl acetate), concentrated, and purified (e.g., silica gel column chromatography) to give intermediate 2.
Step 3 preparation of intermediate 3
Intermediate 2 is dissolved in a suitable solvent (e.g., ethanol), an organic solvent (e.g., acetic acid) is added, heating (e.g., 70 ℃) is performed, iron powder is added, temperature is raised (e.g., 80 ℃) to react (e.g., 2 to 4 hours), the reaction is completed, cooling (e.g., room temperature), filtering, extraction with an organic solvent (e.g., ethyl acetate), concentration, and purification (e.g., silica gel column chromatography) is performed to obtain intermediate 3.
Step 4 preparation of intermediate 4
Intermediate 3 is dissolved in a suitable solvent (e.g., toluene), appropriate amounts of acetic acid and N-iodosuccinimide are added, the reaction is carried out at room temperature (e.g., 2-4 hours), the reaction is completed, water is added for quenching, extraction is carried out with an organic solvent (e.g., ethyl acetate), concentration is carried out, and purification (e.g., silica gel column chromatography) is carried out to obtain intermediate 4.
Step 5 preparation of intermediate 5
The intermediate 4 and the starting material 1 are dissolved in a suitable solvent (e.g., 1, 4-dioxane), water, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium and potassium carbonate are added, heated (e.g., 70 to 90 ℃) and reacted (e.g., 2 to 4 hours), the reaction is completed, quenched with water, extracted with an organic solvent (e.g., dichloromethane), washed with a saturated saline solution, concentrated, and purified (e.g., silica gel column chromatography) to obtain an intermediate 5.
Step 6 preparation of intermediate 6
Dissolving the intermediate 5 in a proper solvent (such as methanol), adding palladium carbon, reacting overnight under the protection of hydrogen, completing the reaction, filtering, and concentrating to obtain an intermediate 6.
Step 7 preparation of intermediate 7
Starting materials 2 and 3 are dissolved in a suitable solvent (e.g., N-dimethylformamide), diisopropylethylamine is added, heating (e.g., 60-80 ℃) is carried out overnight, the reaction is completed, quenching is performed with water, extraction is carried out with an organic solvent (e.g., ethyl acetate), washing with a saturated saline solution, concentration, and purification (e.g., silica gel column chromatography) is carried out to obtain intermediate 7.
Step 8 preparation of the Compound of the general formula (I) according to the invention
The intermediate 6 and the intermediate 7 are dissolved in a suitable solvent (e.g., 1, 4-dioxane), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium and cesium carbonate are added, heated (e.g., 70-90 ℃) overnight, the reaction is completed, filtered, concentrated, and subjected to a suitable method (e.g., silica gel column chromatography) to obtain the compound of the general formula (I) of the present invention.
In the reaction equation, R1、R2、R3、R4、R6、R7And ring A is as defined above, and X represents a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
"stereoisomers" of the compounds of formula (I) according to the present invention means that enantiomers are produced when asymmetric carbon atoms are present in the compounds of formula (I), cis-trans isomers are produced when carbon-carbon double bonds or cyclic structures are present in the compounds, tautomers are produced when ketones or oximes are present in the compounds, and all enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of the compounds of formula (I) are included in the scope of the present invention.
When any compound shown in the general formula (I) of the invention is synthesized to obtain a racemate, the required enantiomer-pure compound can be obtained by a chiral resolution method: can be prepared by chromatography with chiral stationary phase (such as high pressure preparative liquid chromatography, supercritical fluid chromatography). Chiral fillers include, but are not limited to: chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, and Chiralpak AS-H.
The pharmaceutically acceptable salt of any compound shown in the general formula (I) refers to a salt prepared from pharmaceutically acceptable and nontoxic alkali or acid, and comprises organic acid salt, inorganic acid salt, organic alkali salt and inorganic alkali salt.
The organic acid salts include salts of formic acid, acetic acid, trifluoroacetate, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, and the like.
The inorganic acid salt includes salts of hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
Organic base salts include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins selected from the group consisting of betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Natural amino acid salts such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, and the like.
Inorganic base salts include ammonium and salts of lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminum, iron, ketone, ferrous, manganese, manganous, and the like.
The "ester" of the compound of formula (I) of the present invention means an ester which can be formed by esterification with an alcohol when a carboxyl group is present in the compound of formula (I), and which can be formed by esterification with an organic acid, an inorganic acid, an organic acid salt or the like when a hydroxyl group is present in the compound of formula (I). The ester can be hydrolyzed in the presence of acid or alkali to generate corresponding acid or alcohol.
The compound represented by the general formula (I), a pharmaceutically acceptable salt, an ester or a stereoisomer thereof may be in the form of a solvate. Where the solvate is a hydrate, the hydration may be accomplished during the manufacturing process or may be gradual, taking advantage of the hygroscopic properties of the original anhydrous product.
The invention further claims a pharmaceutical composition comprising any compound shown in the formula (I), pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof and one or more pharmaceutically acceptable carriers and/or diluents, and the pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. Administered to a patient in need of such treatment by oral, parenteral, rectal, or pulmonary administration. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, it can be made into suppository, etc. For pulmonary administration, it can be made into inhalant or spray.
The present invention further claims pharmaceutical compositions comprising a compound of any of the above-described formula (I), pharmaceutically acceptable salts, esters, solvates, or stereoisomers thereof, in combination with one or more other antineoplastic agents and immunosuppressive agents. The antineoplastic agent and the immunosuppressant are antimetabolites, including but not limited to capecitabine, gemcitabine and pemetrexed disodium; are growth factor inhibitors including, but not limited to, pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib; antibodies including but not limited to herceptin, bevacizumab; is mitotic inhibitor selected from paclitaxel, vinorelbine, docetaxel, and doxorubicin; is an antitumor hormone selected from letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; are alkylating agents including, but not limited to, cyclophosphamide, mechlorethamine, melphalan, cinchonine, carmustine; is a metal platinum group, including but not limited to carboplatin, cisplatin, oxaliplatin; are immunosuppressive, including but not limited to everolimus, sirolimus, and temazepride; are purine analogs including, but not limited to, 6-mercaptopurine, 6-thioguanine, azathioprine; is an antibiotic including, but not limited to, rhzomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, plicamycin; is a platinum complex including, but not limited to, cisplatin, carboplatin; are adrenocortical suppressants including, but not limited to, aminoglutethimide; are enzyme inhibitors including, but not limited to, SAHA, cytarabine, methotrexate, hydroxyurea, hydroxycamptothecin, topotecan, irinotecan.
The invention also provides application of the compound shown in the formula (I), pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof in preparing a medicament for treating and/or preventing ALK-mediated cancer-related diseases or proliferative diseases, wherein the cancer-related diseases comprise but are not limited to brain tumors, lung cancers, non-small cell lung cancers, squamous epithelial cells, bladder cancers, gastric cancers, ovarian cancers, peritoneal cancers, pancreatic cancers, breast cancers, head and neck cancers, cervical cancers, endometrial cancers, colorectal cancers, liver cancers, kidney cancers, esophageal adenocarcinomas, esophageal squamous cell cancers, non-Hodgkin lymphomas, brain tumors, central nervous system tumors, namely gliomas, glioblastoma multiforme, gliosarcomas, prostate cancers, thyroid cancers, female genital tract cancers, in situ cancers, lymphomas, histiocytic lymphomas and neurofibromatosis, bone cancer, skin cancer, colon cancer, testicular cancer, small cell lung cancer, gastrointestinal stromal tumors, prostate tumors, mast cell tumors, multiple myeloma, melanoma, glioma, glioblastoma, astrocytoma, neuroblastoma, sarcoma; proliferative diseases, including but not limited to benign hyperplasia of the skin or prostate.
The compound of the invention has the following advantages:
(1) the compound of formula (I), pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof has excellent ALK inhibitory activity;
(2) the compound of formula (I), pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof shows good biological stability, longer action and high bioavailability;
(3) the compound of the invention has simple preparation process, high medicine purity, stable quality and easy large-scale industrial production.
The beneficial effects of the compounds of the present invention are further illustrated below by in vitro enzymatic inhibitory activity assays, but this should not be understood as meaning that the compounds of the present invention have only the following beneficial effects.
Examples of the experiments 1 In vitro enzymatic Activity assays for Compounds of the invention
And (3) testing the sample: the chemical name and preparation method of the trifluoroacetate salt of compound 1 of the present invention are shown in the preparation examples of trifluoroacetate salt of compound 1.
The abbreviations used in the following experiments have the following meanings:
DMSO, DMSO: dimethyl sulfoxide
DTT: dithiothreitol
SEB: enzyme catalyst buffer solution
ATP: adenosine triphosphate
ALK: anaplastic lymphoma kinase
SA-XL 665: streptavidin-labeled donors
2.5X, 5X, 10X wherein "X": multiple times
The experimental method comprises the following steps:
preparation of an ALK kinase buffer:
respectively taking a proper amount of MgCl with the mother liquor concentration of 1000mM2SEB of 2500nM, DTT of 100mM and enzyme buffer 5 × were added to ultrapure water to give final concentrations of 5mM, 25nM, 1mM and 1 × enzyme buffer, respectively, and mixed well for use.
2.5 times of preparation of test solution:
1mM stock solution preparation of compound: weighing 1.62mg of compound, adding a proper amount of DMSO for dissolving, and uniformly mixing for later use.
A stock solution of 1mM was diluted with DMSO to prepare a solution having a concentration of 200. mu.M, which was used as a stock solution. The mother liquor is diluted three times step by DMSO to prepare a series of solutions with concentration, and then each concentration is diluted 80 times by ALK kinase buffer solution to prepare 2.5 times of test solution, the concentration is respectively: 2500nM, 833.33nM, 277.78nM, 92.59nM, 30.86nM, 10.29nM, 3.43nM, 1.14nM, 0.38nM, 0.13nM, 0.04 nM.
Various other reagent formulations:
the required 5 XALK kinase solution, 5 Xsubstrate solution and 5 XATP solution are prepared by ALK kinase buffer solution for standby.
ALK enzymatic reaction:
1) mu.L of the prepared 2.5 Xsample solution and 2. mu.L of the prepared 5 XALK kinase solution were added to corresponding wells of a 384-well plate, and incubated at 25 ℃ for 10 minutes.
2) mu.L of the prepared 5 Xsubstrate solution and 2. mu.L of the prepared 5 XATP solution were added to the corresponding wells, respectively, to initiate the enzymatic reaction, and incubated at 25 ℃ for 30 minutes.
And (3) enzymatic detection:
and (3) preparing SA-XL665 with a required concentration by using a detection buffer solution (detection buffer), then uniformly mixing the SA-XL665 with the tyrosine kinase antibody with the same volume, and respectively adding 10 mu L of the prepared antibody solution into corresponding holes to terminate the reaction. Incubate at 25 ℃ for 1 h.
The plate reader is 665nm/615 nm.
IC50The inhibition ratio (%) was calculated as (max-sample value)/(max-min) × 100, and curve-fitting was performed using Graph prism software to obtain IC50The value is obtained.
Maximum value: positive control without compound, minimum: negative control without enzyme.
Experimental results and conclusions:
TABLE 1 in vitro enzymatic inhibitory Activity of the Compounds of the invention
As can be seen from table 1, the compound of the present invention has good inhibitory activity on ALK kinase, and can be used for treating diseases related to kinase, particularly ALK kinase-mediated disorders or conditions, with significant clinical significance.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The following abbreviations represent the following definitions:
DMF: n, N-dimethylformamide
Pd(dppf)Cl2: [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
DIPEA: diisopropylethylamine
TFA: trifluoroacetic acid
Example 1N2- (2- (isopropylsulfonyl) phenyl) -N4- (7-methyl-8- (piperidin-4-yl) -2, 3-dihydrobenzo [ b)][1,4]Preparation of Dioxin-5-yl) -1,3, 5-triazine-2, 4-diamine (Compound 1)
(1) Preparation of 2-methoxy-4-methyl-6-nitrophenol
2-methoxy-4-methylphenol (50.0g,0.362mol) was dissolved in 1L chloroform, fuming nitric acid (22.8g,0.362mol) was dissolved in 120mL acetic acid by cooling to 0 ℃ and slowly dropped into the solution, the internal temperature was controlled to 0 ℃ or lower, and the reaction was continued by raising the temperature to room temperature for 0.5 hour. The reaction was complete, the solvent was removed by rotary evaporation, and the residue was taken up in 200mL of methanol, filtered and dried in vacuo to give the product (30g, 45.3% yield).
(2) Preparation of 5-methyl-3-nitrobenzene-1, 2-diol
2-methoxy-4-methyl-6-nitrophenol (30.0g,0.164mol) was added to 200mL of hydrobromic acid (80%), 20g of tetrabutylammonium fluoride was added, and the mixture was heated to 110 ℃ and reacted overnight. After completion of the reaction, 1000mL of water was added, extracted with ethyl acetate (5X 500mL), the organic phases were combined, washed with 250mL of saturated brine, and dried over anhydrous sodium sulfate. Filtration and rotary evaporation removed the solvent and the residue was used directly in the next step (20g, 72.2% yield).
(3) Preparation of 7-methyl-5-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxine
5-methyl-3-nitrobenzene-1, 2-diol (20g,0.118mol) was dissolved in 100mL of N, N-dimethylformamide and 1, 2-dibromoethane (44.4g,0.236mol) and potassium carbonate (49.2g,0.354mol) were added. The reaction was heated to 60 ℃ and allowed to react overnight. After completion of the reaction, 300mL of water was added, extracted with ethyl acetate (3 × 200mL), the organic phases were combined, the solvent was removed by rotary evaporation, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the product (19g, yield 82.6%).
(4) Preparation of 6-bromo-7-methyl-5-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxine
7-methyl-5-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxine (19g,0.097mol) was dissolved in 200mL of N, N-dimethylformamide, and N-bromosuccinimide (34.5g,0.194mol) was added in portions. The reaction was heated to 60 ℃ and allowed to react overnight. After completion of the reaction, 300mL of water was added, extracted with ethyl acetate (3 × 200mL), the organic phases were combined, the solvent was removed by rotary evaporation, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the product (18g, yield 67.7%).
(5) Preparation of 6-bromo-7-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-amine
6-bromo-7-methyl-5-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxine (18g,65.7mmol) was dissolved in 200mL of ethanol, 20mL of acetic acid was added, heated to 70 ℃, and iron powder (36.8g,657.1mmol) was added in portions. The temperature was raised to 80 ℃ and reaction was carried out for 3 hours, after completion of the reaction, cooling to room temperature, filtration was carried out, 300mL of water was added to the filtrate, extraction was carried out with ethyl acetate (3 × 300mL), the organic phases were combined, the solvent was removed by rotary evaporation, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the product (12g, yield 75%).
(6) Preparation of 6-bromo-8-iodo-7-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-amine
6-bromo-7-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-amine (12g,49.2mmol) was dissolved in 100mL of toluene, and 5mL of acetic acid and N-iodosuccinimide (16.6g,73.8mmol) were added and reacted at room temperature for 3 hours. After the reaction was completed, 100mL of water was added, and extraction was performed with ethyl acetate (3 × 200mL), the organic phases were combined, washed with 200mL of a sodium hydrogen sulfite solution, the organic phase was removed by rotary evaporation, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to obtain a product (7g, yield 38.5%).
(7) Preparation of tert-butyl 4- (8-amino-7-bromo-6-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate
6-bromo-8-iodo-7-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-amine (7.0g,18.9mmol) and tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (5.8g,18.8mmol) were dissolved in 100mL of 1, 4-dioxane, 15mL of water and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (1.4g,1.91 mmol), potassium carbonate (7.83g,56.7mmol) were added, heated to 80 ℃ and reacted for 3 hours. The reaction was completed, 100mL of water was added, 3 × 200mL of dichloromethane (3 × 200mL) was extracted, the organic phases were combined, washed with 100mL of saturated brine, the organic phase was removed by rotary evaporation, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the product (5g, yield 62.1%).
(8) Preparation of tert-butyl 4- (8-amino-6-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) piperidine-1-carboxylate
Tert-butyl 4- (8-amino-7-bromo-6-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (5g,11.76mmol) was dissolved in 150mL of methanol, 4g of palladium on charcoal was added, hydrogen was introduced, and the reaction was allowed to proceed overnight at room temperature. The reaction was complete, filtered and the solvent removed by rotary evaporation to give the product (2.5g, 61.1% yield).
(9) Preparation of 4-chloro-N- (2- (isopropylsulfonyl) phenyl) -1,3, 5-triazin-2-amine
2- (isopropylsulfonyl) aniline (2.0g,10.0mmol), 2, 4-dichloro-1, 3, 5-triazine (2.26g,15.07mmol) were dissolved in 20mL of N, N-dimethylformamide, 2mL of diisopropylethylamine was added, and the reaction was allowed to proceed overnight at 70 ℃. After the reaction was completed, 100mL of water was added, and extraction was performed with ethyl acetate (3 × 50mL), the organic phases were combined, washed with 100mL of saturated brine, the organic phase was removed by rotary evaporation, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give a product (2.5g, yield 79.9%).
(10) Preparation of tert-butyl 4- (8- ((4- ((2- (isopropylsulfonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) -6-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) piperidine-1-carboxylate
4-chloro-N- (2- (isopropylsulfonyl) phenyl) -1,3, 5-triazin-2-amine (2.3g,7.35mmol) and tert-butyl 4- (8-amino-6-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) piperidine-1-carboxylate (1.28g,3.67mmol) were dissolved in 50mL of 1, 4-dioxane, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.404g,0.552mmol), cesium carbonate (3.59g,11.0mmol) were added, heated to 80 ℃ and reacted overnight. The reaction was complete, filtered, the solvent removed by rotary evaporation and the residue chromatographed on silica gel (dichloromethane: methanol ═ 20:1) to give the product (0.6g, 26.2% yield).
(11)N2- (2- (isopropylsulfonyl) phenyl) -N4- (7-methyl-8- (piperidin-4-yl) -2, 3-dihydrobenzo [ b)][1,4]Preparation of dioxin-5-yl) -1,3, 5-triazine-2, 4-diamine
Tert-butyl 4- (8- ((4- ((2- (isopropylsulfonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) -6-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) piperidine-1-carboxylate (0.6g,0.96mmol) was dissolved in 10mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2 hours. The reaction was completed, the solvent was removed by rotary evaporation, 50mL of ethyl acetate was added, the mixture was washed with saturated sodium bicarbonate, the organic phase was removed by rotary evaporation, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol ═ 15:1) to give the final product (0.3g, yield 59.6%).
The molecular formula is as follows: c26H32N6O4S molecular weight: 524.64 LC-MS (m/z): 525.3[ M + H]+
1H-NMR(400MHz,DMSO-d6):9.33(s,1H),9.01(s,1H),8.38(brs,1H),8.32(s,1H),7.80(d,J＝8.0Hz,1H),7.60(brs,1H),7.30(t,J＝7.6Hz,1H),6.93(s,1H),4.19(s,4H),3.40-3.44(m,3H),2.94-3.06(m,3H),2.37-2.43(m,2H),2.22(s,3H),1.63-1.66(m,2H),1.14(d,J＝7.2Hz,6H).
Example 2N2- (2- (isopropylsulfonyl) phenyl) -N4- (7-methyl-8- (piperidin-4-yl) -2, 3-dihydrobenzo [ b)][1,4]Preparation of Dioxin-5-yl) -1,3, 5-triazine-2, 4-diamine (Compound 1) trifluoroacetate salt
To a 100mL single-necked flask were added tert-butyl 4- (8- ((4- ((2- (isopropylsulfonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) -6-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) piperidine-1-carboxylate (prepared according to the method of example 1 step (1) -step (10), 20mg,0.03mmol), dichloromethane (10mL) and trifluoroacetic acid (2 mL). The mixture was then stirred at room temperature for 2 hours, concentrated under reduced pressure and the crude product was prepared by Prep-HPLC. Fractions were collected and concentrated under reduced pressure to give the product (8.9mg, 44% yield).
The molecular formula is as follows: c28H33N6F3O6S molecular weight: 638.66 LC-MS (M/z) 525[ M + H]+
1H-NMR(300MHz,CD3OD):1.324(m,6H),1.761-1.849(m,2H),2.566-2.698(m,2H),3.008-3.552(m,9H),4.300(s,3H),7.319-7.374(m,2H),7.609-7.699(m,1H),7.894-7.925(m,1H),8.319(s,1H),8.334-8.524(m,1H)。

Claims (10)

1. A compound of formula (I), a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof:
wherein,
R1is selected from-COR5，-CO2R5，-CONRR5，-SOR5，-SO2R5or-SO2NRR5；
R2Selected from hydrogen atom, halogen atom, nitro group, cyano group, amino group, hydroxyl group, carboxyl group, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl radical, C1-6Alkoxy, hydroxy C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino group, C1-6Alkylthio radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylsulfonylamino group, C1-6Alkylaminosulfonyl, (C)1-6Alkyl radical)2Aminosulfonyl or C1-6An alkylsulfonyl group;
R3selected from 5-14 membered heteroaryl optionally substituted with 1-3W or 3-8 membered heterocyclic group,
w is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino, halogeno C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylsulfonyl radical, C2-8Alkenyl or C2-8An alkynyl group;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, carboxyl group, C1-6Alkoxy radical, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkoxy, halo C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-6Alkylamino radical, C1-6Alkylcarbonyl or C1-6An alkylcarbonyloxy group;
R、R5independently selected from hydrogen atom, C1-6Alkyl or 3-to 8-membered carbocyclic ring;
R6、R7independently selected from hydrogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, amino C1-6Alkyl or sulfonyl C1-6An alkyl group;
a is selected from 3-8 membered cycloalkyl optionally substituted by 1-3Q or 3-8 membered heterocyclic group optionally substituted by 1-3Q, and the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino, halogeno C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl or 3-to 8-membered heterocyclic group.
2. The compound of claim 1, a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof:
wherein,
R1is selected from-CO2R5、-CONRR5、-SO2R5or-SO2NRR5；
R2Selected from hydrogen atom, halogen atom, nitro group, cyano group, amino group, hydroxyl group, carboxyl group, C1-6Alkyl, hydroxy C1-6Alkyl or halo C1-6An alkyl group;
R3selected from 5-6 membered heterocyclic group optionally substituted with 1-2W,
w is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl or C1-6An alkoxy group;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, carboxyl group, C1-6Alkoxy or C1-6An alkyl group;
R、R5independently selected from a hydrogen atom or C1-6An alkyl group;
R6、R7independently selected from a hydrogen atom or C1-6An alkyl group;
a is selected from a 5-6 membered cycloalkyl group optionally substituted with 1-2Q or a 5-6 membered heterocyclic group optionally substituted with 1-2Q,the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6An alkyl group.
3. The compound of claim 2, a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof:
wherein,
R1is selected from-SO2R5or-SO2NRR5；
R2Selected from hydrogen atom, halogen atom, nitro group, cyano group, amino group, hydroxyl group, carboxyl group or C1-6An alkyl group;
R3selected from 5-6 membered nitrogen-containing heterocyclic group optionally substituted with 1-2W,
w is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6An alkyl group;
R4selected from hydrogen atoms or C1-6An alkyl group;
R、R5independently selected from C1-6An alkyl group;
R6、R7independently selected from a hydrogen atom or C1-6An alkyl group;
a is selected from 5-6 membered heterocyclic group containing 1-2O, S and/or N atoms and optionally substituted by 1-2Q, and the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6An alkyl group.
4. The compound of claim 3, a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof:
wherein,
R1is selected from-SO2R5；
R2Selected from hydrogen atom, halogen atom, nitro group, cyano group, amino group, hydroxyl group, carboxyl group or C1-4An alkyl group;
R3selected from 5-6 membered heterocyclic group containing 1-2N atoms optionally substituted with 1-2W,
w is selected from hydroxy, amino, carboxyl or C1-6An alkyl group;
R4selected from hydrogen atoms or C1-4An alkyl group;
R5independently selected from C1-4An alkyl group;
R6、R7independently selected from a hydrogen atom or C1-4An alkyl group;
a is selected from 5-6 membered heterocyclic group containing 1-2O and/or S atoms optionally substituted by 1-2Q, and the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4An alkyl group.
5. The compound of claim 4, a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof:
wherein,
R3selected from pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
a is selected from 6-membered heterocyclic group containing 2O and/or S atoms and optionally substituted by 1-2Q, and the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom and C1-4An alkyl group.
6. The compound, pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof of claim 1, wherein the compound is selected from:
7. the compound, pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof according to any one of claims 1 to 6, and one or more pharmaceutically acceptable carriers, wherein the pharmaceutically acceptable form is any one of pharmaceutically acceptable forms.
8. A pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof according to any one of claims 1 to 6, and one or more antitumor agents and/or immunosuppressive agents.
9. The pharmaceutical composition of claim 8, further comprising one or more antineoplastic and/or immunosuppressive agents selected from the group consisting of capecitabine, gemcitabine, pemetrexed disodium; a growth factor inhibitor selected from the group consisting of pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib; is an antibody selected from herceptin and bevacizumab; is mitotic inhibitor selected from paclitaxel, vinorelbine, docetaxel, and doxorubicin; is an antitumor hormone selected from letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; is an alkylating agent selected from cyclophosphamide, mechlorethamine, melphalan, cremastin and carmustine; is a metal platinum group selected from carboplatin, cisplatin and oxaliplatin; is selected from everolimus, sirolimus and anticancer drugs; is purine analog selected from 6-mercaptopurine, 6-thioguanine, azathioprine; is an antibiotic selected from the group consisting of rhzomorph D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, and plicamycin; is a platinum complex selected from cisplatin and carboplatin; is an adrenocortical inhibitor selected from aminoglutethimide; is an enzyme inhibitor selected from SAHA, cytarabine, methotrexate, hydroxyurea, hydroxycamptothecin, topotecan, irinotecan.
10. Use of a compound, a pharmaceutically acceptable salt, an ester, a solvate or a stereoisomer thereof according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment and/or prevention of an ALK-mediated cancer-related disease selected from lung cancer, non-small cell lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, non-hodgkin's lymphoma, brain tumors, tumors of the central nervous system, i.e. glioma, glioblastoma multiforme, gliosarcoma, prostate cancer, thyroid cancer, cancer of the female genital tract, carcinoma in situ, lymphoma, histiocytic lymphoma, neurofibromatosis, bone cancer, skin cancer, colon cancer, testicular cancer, small cell lung cancer, gastrointestinal stromal tumors, prostate tumors, mast cell tumors, multiple myeloma, melanoma, glioma, glioblastoma, astrocytoma, neuroblastoma, sarcoma.
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