CN105524045B - Tetracyclic anaplastic lymphoma kinase inhibitors - Google Patents

Tetracyclic anaplastic lymphoma kinase inhibitors Download PDF

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CN105524045B
CN105524045B CN201410567216.6A CN201410567216A CN105524045B CN 105524045 B CN105524045 B CN 105524045B CN 201410567216 A CN201410567216 A CN 201410567216A CN 105524045 B CN105524045 B CN 105524045B
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CN105524045A (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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Xuanzhu Pharma Co Ltd
Xuanzhu Hainan Biopharmaceutical Co Ltd
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a tetracyclic anaplastic lymphoma kinase inhibitor shown as a general formula (I), and pharmaceutically acceptable salt or a stereoisomer thereof, wherein R is1、R2、R3、R4、R5And ring A is as defined in the specification. The invention also relates to 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 thereof or the stereoisomers thereof in preparing medicines for treating and/or preventing cancer-related diseases mediated by anaplastic lymphoma kinase.

Description

Tetracyclic anaplastic lymphoma kinase inhibitors
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a tetracyclic anaplastic lymphoma kinase inhibitor, pharmaceutically acceptable salts 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 or the 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).
Aberrant expression of ALK in certain ALCL/NSCLC stem from different chromosomal translocations. These chromosomal translocations can each produce a corresponding fusion protein. Analysis of these fusion genes shows that they all contain the gene sequence of the intracellular kinase region coded by the 3' end of the ALK gene, and the gene segments fused with the ALK all contain promoter elements and sequences for mediating dimerization, so that the fusion protein with the ALK kinase activity in the cell is highly expressed and over-activated, and the malignant transformation of the cell is caused. Therefore, the activity of the intracellular kinase domain of ALK and the corresponding signaling pathways are important molecular mechanisms leading to ALCL formation.
Therefore, the research and development of the micromolecule inhibitor aiming at the ALK can effectively reduce the influence of the mutated ALK gene on downstream proteins, further influence the effects of invasion, proliferation and the like of tumor cells, finally influence the growth of the tumor cells and play a role in resisting tumors. Currently, Crizotinib (Crizotinib) from pfeiri is successfully marketed, and ALK inhibitors exhibit good inhibitory activity for specific patients. However, a large number of clinical trials prove that the first generation ALK inhibitor, namely Crizotinib, is easy to generate drug resistance, so that the second generation ALK inhibitor which has good curative effect on patients who generate drug resistance to Crizotinib is designed and screened, and the clinical significance is remarkable.
The ALK inhibitors which are already on the market comprise Crizotinib developed by Perey and Alectonib developed by Roche, and the structural formula is shown in the specification
Figure BDA0000591508460000011
Ceritinib (Ceritinib) developed by Novartis and having a structural formula
Figure BDA0000591508460000021
AZD-3463 developed by AstraZeneca and having a structural formula
Figure BDA0000591508460000022
Are currently in preclinical studies.
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 tetracyclic anaplastic lymphoma kinase inhibitor with good effect on treating and/or preventing ALK-mediated cancer-related diseases. The specific technical scheme is as follows:
scheme 1. compounds of general formula (i), pharmaceutically acceptable salts thereof, or stereoisomers thereof:
Figure BDA0000591508460000023
wherein the content of the first and second substances,
R1is selected from-COR6，-CO2R6，-CONRR6，-SOR6，-SO2R6or-SO2NRR6，
R、R6Independently selected from hydrogen atom, C1-6Alkyl or 3-to 8-membered carbocyclic ring;
R2、R3independently selected from hydrogen atom, C1-6Alkyl or 3-to 8-membered carbocyclic ring;
R4selected from hydrogen atom, halogen atom, nitro group, cyano group, amino group, hydroxyl group, carboxyl group, C1-6Alkyl, hydroxy C1-6Alkyl, carboxyl C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, halo C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl radical, C1-6Alkoxy, hydroxy C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkylamino radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-6Alkylthio radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino group, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylsulfonylamino group, C1-6Alkylaminosulfonyl, (C)1-6Alkyl radical)2Aminosulfonyl or C1-6An alkylsulfonyl group;
R5selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, carboxyl group, hydroxyl group, C1-6Alkoxy, -OR7、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 group, C1-6Alkylcarbonyloxy, (C)1-6Alkyl radical)2Amino or sulfonyl C1-6An alkyl group, a carboxyl group,
R7selected from 3-8 membered carbocycle or 3-8 membered heterocyclic group;
the A ring is selected from 5-6-membered heterocyclic group containing 1-3O, S and/or N atoms and optionally substituted by 1-3Q, or 5-14-membered heteroaryl containing 1-3O, S and/or N atoms and optionally substituted by 1-3Q, wherein 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.
Scheme 2. the compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein the content of the first and second substances,
R1is selected from-CONRR6，-SO2R6or-SO2NRR6，
R、R6Independently selected from C1-6An alkyl group;
R2、R3independently selected from a hydrogen atom or C1-4An alkyl group;
R4is selected from C1-6An alkoxy group;
R5selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, carboxyl group, C1-6Alkoxy or C1-6An alkyl group;
the A ring is selected from 5-6-membered heterocyclic group containing 1-2O and/or N atoms and optionally substituted by 1-2Q, or 5-6-membered heteroaryl containing 1-2O and/or N atoms and optionally substituted by 1-2Q, wherein the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6An alkyl group.
Scheme 3. the compound according to claim 2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
wherein the content of the first and second substances,
R1is selected from-SO2R6or-SO2NRR6，
R、R6Independently selected from C1-4An alkyl group;
R2、R3independently selected from hydrogen atoms;
R4is selected from C1-4An alkoxy group;
R5selected from halogen atoms;
the A ring is selected from 5-6 membered heterocyclic group containing 1-2O 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 C1-4An alkyl group.
Scheme 4. the compound of claim 3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein the content of the first and second substances,
the A ring is selected from a 5-6 membered heterocyclic group containing 1N atom and optionally substituted by 1-2Q, and the substituent Q is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-4An alkyl group.
Scheme 5. the compound of claim 3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein the content of the first and second substances,
R1is selected from-SO2R6or-SO2NRR6，
R、R6Independently selected from methyl, ethyl or isopropyl;
R2、R3independently selected from hydrogen atoms;
R4selected from methoxy, ethoxy or isopropoxy;
R5selected from fluorine atom, bromine atom or chlorine atom;
ring A is selected from piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, dihydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl or 1, 4-dioxanyl optionally substituted with 1Q selected from methyl, ethyl, n-propyl, isopropyl or n-butyl.
Scheme 6. the compound of claim 5, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein the content of the first and second substances,
ring a together with the benzene ring to which it is attached forms the following group:
Figure BDA0000591508460000041
part of the Compounds of the invention
Figure BDA0000591508460000042
Figure BDA0000591508460000051
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 alkyl having 1 to 6 carbon atoms, including for example" C1-4Alkyl group "," C1-3Alkyl group "," C1-2Alkyl "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 groupA base, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-3-butenyl, 3-methyl-3-butenyl, 2-methyl-3-pentenyl, 3-methyl-1-pentenyl, 3-methyl-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, 2, 4-pentadienyl, 1, 4-hexadienyl, 2, 4-hexadienyl, 1, 5-heptadienyl, 2, 6-octadienyl and the like.
"C" according to the invention2-8Alkynyl 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, C1-6Alkylsulfonylamino group, C1-6Alkylaminosulfonyl, (C)1-6Alkyl radical)2Aminosulfonyl radical, C1-6Alkylsulfonyl radical, C1-6Alkylcarbonyloxy "means substituted with C1-6alkyl-O-, C1-6alkyl-NH-, (C)1-6Alkyl radical)2-N-、C1-6alkyl-S-, C1-6alkyl-C (O) -, C1-6alkyl-SO2NH-、C1-6alkyl-NHSO2-、(C1-6Alkyl radical)2-NHSO2-、C1-6alkyl-SO2-、C1-6alkyl-C (O) -O-form radicals in which "C" is1-6Alkyl "is as defined above.
"C" according to the invention1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino group, C1-4Alkylthio radical, C1-4Alkylcarbonyl group, C1-4Alkylsulfonylamino group, C1-4Alkylaminosulfonyl, (C)1-4Alkyl radical)2Aminosulfonyl radical, C1-4Alkylsulfonyl radical, C1-4Alkylcarbonyloxy "means substituted with C1-4alkyl-O-, C1-4alkyl-NH-, (C)1-4Alkyl radical)2-N-、C1-4alkyl-S-, C1-4alkyl-C (O) -, C1-4alkyl-SO2NH-、C1-4alkyl-NHSO2-、(C1-4Alkyl radical)2-NHSO2-、C1-4alkyl-SO2-、C1-4alkyl-C (O) -O-form radicals in which "C" is1-4Alkyl "is as defined above.
The "halo C" of the present invention1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl, carboxyl C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkoxy, hydroxy C1-6The "alkylamino group" means one or more, for example, 1 to 4, 1 to 3, 1 to 2 halogen atoms, hydroxyl group, amino group, sulfonyl group, carboxyl group, C1-6Alkoxy radicals each being substituted for C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Radicals formed by hydrogen atoms in alkylamino radicals。
The "halo C" of the present invention1-4Alkyl, hydroxy C1-4Alkyl, amino C1-4Alkyl, sulfonyl C1-4Alkyl, carboxyl C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl, halo C1-4Alkoxy, hydroxy C1-4Alkoxy, hydroxy C1-4The "alkylamino group" means one or more, for example, 1 to 4, 1 to 3, 1 to 2 halogen atoms, hydroxyl group, amino group, sulfonyl group, carboxyl group, C1-4Alkoxy radicals each being substituted for C1-4Alkyl radical, C1-4Alkoxy radical, C1-4A group formed by a hydrogen atom in an alkylamino group.
The "3-8-membered cycloalkyl group" refers to a monocyclic cycloalkyl group derived from an alkane having 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, etc.
The term "5-to 14-membered heteroaryl" refers to a heteroaryl group having 5-to 14-membered ring atoms and containing at least one heteroatom, including "5-to 8-membered heteroaryl" and "6-to 14-membered fused heteroaryl", wherein the heteroatom includes nitrogen, oxygen, sulfur and the like, and includes a case where carbon atom, nitrogen atom and sulfur atom are oxo. Specifically, the heteroaryl group may be a "5-14-membered heteroaryl group containing 1-3O, S and/or N", a "5-8-membered heteroaryl group containing 1-2O, S and/or N", or a "5-8-membered heteroaryl group containing 2-3O, S and/or N".
The "5-to 8-membered heteroaryl group" includes, for example, "5-to 7-membered heteroaryl group", "5-to 6-membered heteroaryl group" and the like. Specifically, the heteroaryl group may be a "5-to 6-membered heteroaryl group containing 1 to 2O and/or N atoms" or a "5-to 6-membered heteroaryl group containing 1O and/or N atom". Specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidinyl, 1, 4-dioxadienyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, Pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepinyl, 1, 3-diazacycloheptenyl, and azepinyl, etc., preferably "5-to 6-membered heteroaryl".
The "6-to 14-membered thick heteroaryl group" includes, for example, "6-to 10-membered thick heteroaryl group", "7-to 10-membered thick heteroaryl group", "9-to 10-membered thick heteroaryl group", and the like. Specific examples include, but are not limited to: benzofuranyl, benzoisoturanyl, benzothienyl, indolyl, isoindole, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, phenazine, phenothiazine, and the like.
The 3-8 membered heterocyclic group refers to a cyclic group containing 3-8 ring atoms and at least one heteroatom, and includes 3-8 membered saturated heterocyclic groups and 3-8 membered partially saturated heterocyclic groups, and specifically may be a 3-7 membered heterocyclic group, a 3-6 membered heterocyclic group, a 3-5 membered heterocyclic group, a 4-7 membered heterocyclic group, a 4-6 membered heterocyclic group, a 5-6 membered heterocyclic group, a 6-7 membered heterocyclic group, a 6-8 membered heterocyclic group, and the like. The method can specifically comprise the following steps: "5 to 6-membered heterocyclic group containing 1 to 3O, S and/or N 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 N atoms", "5 to 6-membered heterocyclic group containing 1O or N atom", "5-to 6-membered heterocyclic group containing 1N atom", "5 to 6-membered heterocyclic group containing 1O or N atom", "5 to 6-membered heterocyclic group containing 1O atom". Specific examples include, but are not limited to: aziridinyl, 2H-aziridinyl, diazacyclopropenyl, 3H-diazacyclopropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuranyl, tetrahydropyranyl, 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, 2, 5-dihydrothienyl, 3, 4-dihydro-2H-pyranyl, 5, 6-dihydro-4H-1, 3-oxazinyl, 1,2,3, 6-tetrahydropyridinyl, 1,2,3, 4-tetrahydropyridinyl, 2,3,4, 5-tetrahydropyridinyl and the like, preferably a "5-to 6-membered heterocyclic group".
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 carbocyclic ring" refers to a saturated, partially saturated or unsaturated monocyclic compound having 3 to 8 carbon atoms, and may be, for example, a 3-to 8-membered cycloalkyl group, a 3-to 8-membered cycloalkenyl group, a 6-to 8-membered aryl group, or the like. 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.
"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 invention further claims a pharmaceutical preparation which comprises any compound shown in the formula (I) and pharmaceutically acceptable salts or stereoisomers thereof and one or more pharmaceutically acceptable carriers and/or diluents, and 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-mentioned formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof together with one or more other anti-neoplastic agents and/or immunosuppressive agents. The antineoplastic agent and/or immunosuppressant is antimetabolite and is selected from capecitabine, gemcitabine and 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 vorinostat, cytarabine, methotrexate, hydroxyurea, hydroxycamptothecin, camptothecin, topotecan, irinotecan.
The invention also provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, for the manufacture of a medicament for the treatment and/or prevention of an ALK-mediated proliferative disease or a cancer-related disease selected from lung cancer, brain tumor, squamous cell, 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, central nervous system tumors, prostate cancer, thyroid cancer, cancer of the female reproductive tract, carcinoma in situ, lymphoma, histiocytic lymphoma, neurofibromatosis, bone cancer, skin cancer, colon cancer, small cell lung cancer, non-small cell lung cancer, testicular cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, astrocytoma, neuroblastoma, sarcoma; a proliferative disease selected from benign hyperplasia of the skin or prostate.
The invention also provides a preparation method of the compound, but not limited to the following method, and the reaction equation is as follows:
Figure BDA0000591508460000101
in the reaction equation, R1、R2、R3、R4、R5And ring A is as defined above, and X represents a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Reaction step
The method comprises the following steps: dissolving the intermediate 1 and the intermediate 2 in a solvent (such as dioxane), adding a metal palladium catalyst, adding a proper amount (such as 1-5 equivalents) of inorganic base (such as cesium carbonate), heating (such as 70-90 ℃) under the protection of nitrogen for reaction (such as 12-24 hours), filtering, concentrating the filtrate, and purifying by a proper method (such as preparation of high performance liquid phase) to obtain the compound of the general formula (I).
The second method comprises the following steps: dissolving the intermediate 1 and the intermediate 2 in an organic solvent (such as secondary amyl alcohol and p-toluenesulfonic acid), and heating (such as 100-150 ℃) to react (such as 10-30 h). The solvent is removed, water is added, extraction with an organic solvent (e.g., ethyl acetate), concentration and purification by a suitable method (e.g., silica gel column chromatography) affords the compounds of formula (I) of the present invention.
In the reaction equation, the groups not participating in the reaction may be present in the form of protecting groups, which are then removed by a suitable method.
The compound of the invention has the following advantages:
(1) the compound of formula (I), the pharmaceutically acceptable salt thereof or the stereoisomer thereof has excellent ALK inhibitory activity;
(2) the compound of formula (I), the pharmaceutically acceptable salt thereof or the 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 and cytological inhibitory activity assays, but this should not be understood as meaning that the compounds of the present invention have only the following beneficial effects.
The abbreviations used in the following experiments have the following meanings:
DMSO, DMSO: dimethyl sulfoxide (Dimethyl sulfoxide)
DTT: dithiothreitol (DL-Dithiothreitol)
SEB: enzyme catalyst buffer solution (Supplement enzyme buffer)
ATP: adenosine Triphosphate (Adenosine Triphosphate)
ALK: anaplastic Lymphoma Kinase (Anaplastic Lymphoma Kinase)
SA-XL 665: streptavidin-labeled donor (Streptavidin-XL665)
HEPES (high efficiency particulate air): 4-hydroxyethyl piperazine ethanesulfonic acid
Brij-35: dodecyl polyglycol ether
EDTA: ethylenediaminetetraacetic acid
2.5X, 5X, 10X wherein "X": multiple times
Experimental example 1 in vitro enzymatic Activity test of the Compound of the present invention
Test article: the chemical name and preparation method of the compound 3 are shown in the preparation examples of the compound.
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 (2500 nM), DTT (100 mM), 5 Xenzyme buffer were added to ultrapure water so that the final concentrations were: 5mM, 25nM, 1mM, 1 Xenzyme buffer, mixing, standby.
2.5 × test substance solution preparation:
1mM stock solution preparation of compound: weighing 1.1mg of the compound, adding a proper amount of DMSO for dissolving, and uniformly mixing for later use.
1mM stock solutions were each diluted with DMSO to prepare a 200. mu.M solution 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 each 2.5 times of test substance 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 Xtest 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.
IC50: calculating the inhibition rate (%) (maximum value-sample value)/(maximum value-minimum value) × 100, and curve-fitting with Graphprisim 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
Figure BDA0000591508460000121
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.
Experimental example 2 in vitro enzymatic Activity test of the Compound of the present invention
Test article: for the chemical names and preparation methods of the compounds 1 and 2 of the present invention, see the preparation examples of the respective compounds.
Control drug Ceritinib, self-made (refer to the preparation method of WO 2008/073687A 2).
The experimental method comprises the following steps: measurement of ALK kinase inhibitory Activity Using Caliper Mobility Shift method
1.1 times of kinase buffer solution preparation
Respectively taking HEPES with pH of 7.5, Brij-35 with concentration of 30% and MgCl with mother liquor concentration of 1M2Mixing the solution and DTT with mother liquor concentration of 1M with ultrapure water to obtain HEPES solution with final concentration of 50mM, Brij-35 with final concentration of 0.0015%, and MgCl2Was 10mM and DTT was 2 mM.
2. Preparation of stop solution
Coating solution Coating Reagent #3 (Coating solution carried in 12-coater chip used by Caliper instrument) with mother solution concentration of 4%, HEPES with mother solution concentration of 1000mM and pH7.5, EDTA with mother solution concentration of 0.5M and Brij-35 with mother solution concentration of 30% were respectively taken, and ultrapure water was added to mix them, so that the final concentration of Coating Reagent #3 was 0.2%, the final concentration of HEPES was 100mM, the final concentration of EDTA was 50mM and the final concentration of Brij-35 was 0.015%.
Preparation of 3.5 times of test substance solution
DMSO stock preparation of the test substances: respectively weighing appropriate amount of the compound (see the following table), adding appropriate amount of DMSO, dissolving, and mixing.
Figure BDA0000591508460000131
Test samples were taken as stock solutions in DMSO and diluted with DMSO to give solutions of 50. mu.M concentration as stock solutions. The stock solution was diluted four-fold stepwise with DMSO, and then diluted 10-fold with 1-fold kinase buffer solution for each concentration to prepare 5-fold test substance solutions.
4. Preparation of various other Agents
1 time of kinase buffer solution is used for preparing 2.5 times of ALK kinase solution and 2.5 times of polypeptide solution for later use.
5. Enzymatic reaction
1)5 μ L of the prepared 5-fold test solution and 10 μ L of the prepared 2.5-fold kinase solution were added to corresponding wells of a 384-well plate, and incubated at room temperature for 10 minutes.
2) mu.L of the prepared 2.5-fold polypeptide solution was added to the corresponding wells to give final concentrations of 1000nM, 250nM, 63nM, 16nM, 4nM, 1nM, 0.2nM, 0.1nM, 0.02nM, and 0.004 nM. The enzyme reaction was started and incubated at 28 ℃ for 1 hour.
6. Enzymatic assay
And adding 25 mu L of stop solution into each corresponding hole to stop the reaction. The Caliper instrument reads data, calculates the inhibition rate through the data,
inhibition (%) (maximum-sample value)/(maximum-minimum) × 100, and curve fitting was performed using XLFIT software to obtain IC50The value is obtained.
Maximum value: positive control without test, minimum: negative control without enzyme.
Experimental results and conclusions:
TABLE 2 in vitro enzymatic inhibitory Activity of the Compounds of the invention
Figure BDA0000591508460000132
As can be seen from table 2, the compounds of the present invention have good inhibitory activity against ALK kinase, and can be used for treating diseases associated with kinase, in particular, ALK kinase-mediated disorders or conditions, with significant clinical significance.
Experimental example 3 in vitro cell Activity test of the Compound of the present invention
Test article: the chemical names and the preparation methods of the compounds 1 and 2 of the present invention are shown in the preparation examples of the respective compounds.
Control drug Ceritinib, self-made (refer to the preparation method of WO 2008/073687A 2).
The abbreviations used in the following experiments have the following meanings:
rpm: rotate per minute
DMSO, DMSO: dimethyl sulfoxide
MTS: blue tetrazolium thiazole bromide
RPMI 1640: 1640 medium (RPMI: Roswell Park molar Institute)
500X, 1000X, 10X wherein "X": multiple times
The experimental method comprises the following steps:
NCI-H3122 cells:
(1) cell preparation:
with RPMI containing 10% fetal bovine serum, 100U/ml penicillin, 100mg/ml streptomycin1640 medium, 5% CO2And culturing the cells in an incubator at 37 ℃ until the cells are 80% fused for later use.
(2) Inoculating cells:
digesting cells with pancreatin, centrifuging at 1000rpm for 4min, removing supernatant, resuspending with RPMI-1640 medium containing 2.5% fetal calf serum, adjusting cell density, taking 90 μ L of the cell suspension, and inoculating to 96-well plate to obtain final cell density of 3000 cells/well; then at 5% CO2And culturing in an incubator at 37 ℃ for 24 hours.
(3) Adding a test substance:
(3.1) preparation of test substance solution
Preparing a test substance solution: weighing appropriate amount of test substance (specific sample amount is shown in the following table), adding appropriate amount of DMSO to dissolve, diluting with DMSO gradient to obtain a series of concentration mother liquor (1000 × test substance solution), diluting the mother liquor 100 times with culture medium to obtain 10 × test substance solution, adding 10 μ L of the solution into corresponding wells of 96-well plate to obtain final concentration of each test substance solution: 10 μ M, 2.5 μ M, 625nM, 156nM, 39nM, 9.8nM, 2.5 nM.
Figure BDA0000591508460000141
(3.2) control well settings:
vehicle control: 0.1% DMSO.
Cell control: cells were seeded only, without compound addition.
Blank control: medium, instrument zero.
(3.3) placing the 96-well plate at 37 ℃ with 5% CO2Culturing for 72h in an incubator.
(4) And (3) detection:
the MTS detection method comprises the following steps:
① CellTiter
Figure BDA0000591508460000142
The reagents in the single-solution 96-well cell proliferation detection kit are placed at room temperature for 90 min.
② into each test well of a 96-well plateAdding CellTiter
Figure BDA0000591508460000151
AQueous single solution reagent 20. mu.L.
③ Place 96-well plates with 5% CO2And cultured in an incubator at 37 ℃ for 40 min.
④ setting the detection wavelength of enzyme labeling instrument at 490nm, and reading the result.
(5) And (4) processing a result:
IC50and (3) calculating: cell survival (%) ═ (OD)Sample value－ODBlank value)/(ODMaximum value－ODBlank value) X 100, curve fitting with Graphprism software to obtain IC50The value is obtained.
ODMaximum value: cell control without Compound plus vehicle alone, ODBlank value: blank control values.
(II) NCI-H2228 cells:
(1) cell preparation:
using RPMI-1640 medium containing 10% fetal bovine serum in 5% CO2And culturing the cells in an incubator at 37 ℃ until the cells are 80% fused for later use.
(2) Inoculating cells:
digesting the cells with pancreatin, centrifuging at 1000rpm for 4min, removing supernatant, resuspending with 2.5% fetal bovine serum-containing RPMI-1640 medium, adjusting cell density to 2 × 104And (4) taking 100 mu L of the cell suspension, inoculating the cell suspension into a 96-well plate, and obtaining the final cell density: 2000 cells/well.
(3) Adding a test substance:
(3.1) preparation of a test substance solution: weighing appropriate amount of test substance (see the following table), adding appropriate amount of DMSO, dissolving, mixing, and diluting with DMSO gradient to obtain solutions with various concentrations.
Figure BDA0000591508460000152
Add 99. mu.L of the medium to each well of a 96-well plate, and add 1. mu.L of the prepared solutions of different concentrations to the corresponding wells, so that the final concentrations of the compound and the control drug, Ceritinib, were: 10000nM, 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61 nM.
(3.2) control well settings:
vehicle control: 0.5% DMSO.
Cell control: cells were seeded only, without compound addition.
Blank control: medium, instrument zero.
(3.3) placing 5% CO in the 96-well plate2And culturing for 96 hours in an incubator at 37 ℃.
(4) And (3) detection:
the CTG detection method comprises the following steps:
① the medium was removed 80. mu.L per well of the 96-well plate and allowed to equilibrate at room temperature for 30 min.
② addition of CellTiter-
Figure BDA0000591508460000161
Reagent 60. mu.L.
③ 96 the well plate was uniformly mixed with a microplate oscillator in the dark for 2min to lyse the cells.
④ the 96-well plate was incubated in the dark for 10min at room temperature to stabilize the light signal value.
⑤ microplate reader read results in luminescence mode.
(5) And (4) processing a result:
IC50and (3) calculating: cell inhibition ratio (%) ═ ODMaximum value－ODCompound (I))/(ODMaximum value－ODBlank space) X 100, curve fitting with Graphprism software to obtain IC50The value is obtained.
ODMaximum value: cell control, OD, without Compound plus vehicle aloneBlank space: media blank control
The experimental results are as follows:
TABLE 3 cytostatic Activity of Compounds of the invention
Figure BDA0000591508460000162
As can be seen from Table 3, the compound of the invention has good inhibitory activity on cells NCI-H3122 and NCI-H2228, can be used for treating ALK kinase-mediated diseases or conditions, and has 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
Boc tert-butoxycarbonyl
TFA trifluoroacetic acid
DMSO dimethyl sulfoxide
EA ethyl acetate
TEA trifluoroacetic acid
THF tetrahydrofuran
DIEA N, N-diisopropylethylamine
2 4Example 15-chloro-N- (6-isopropoxyisoindolin-5-yl) -N- (2- (isopropylsulfonyl) phenyl) pyrimidine Preparation of pyridine-2, 4-diamines
Figure BDA0000591508460000171
(1) Preparation of dimethyl 4-hydroxyphthalite
Figure BDA0000591508460000172
4-Hydroxyphthalic acid (50g,274.5mmol) was dissolved in methanol (800mL), cooled to 10 deg.C, sulfuric acid (134g,1.37mol) was slowly added dropwise with stirring, and after the addition was complete, the temperature was raised to 70 deg.C for reaction overnight. Cooled to room temperature, concentrated in vacuo, ethyl acetate (700mL) was added, washed with water (500 mL. times.3), the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the product (32g, 55% yield).
(2) Preparation of dimethyl 4-hydroxy-5-nitrophthalate
Figure BDA0000591508460000173
Dimethyl 4-hydroxyphthalate (24g,114.2mmol) was dissolved in portions in concentrated sulfuric acid (240mL) at 0 ℃. Cooling to-10 ℃, dropwise adding concentrated nitric acid (65% by mass, 13.2mL,190.7mmol), reacting at 0 ℃ for 30 minutes, pouring into ice water (300mL) for quenching, extracting with ethyl acetate (300mL × 3), organically combining, washing with water (200mL × 3), drying with anhydrous sodium sulfate, filtering, concentrating, and purifying the crude product by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 20-1: 5) to obtain the product (16g, yield 55%).
(3) Preparation of dimethyl 4-isopropoxy-5-nitrophthalate
Figure BDA0000591508460000181
Dissolving dimethyl 4-hydroxy-5-nitrophthalate (16g,62.70mmol) in N, N-dimethylformamide (200mL), adding cesium carbonate (61g,187.2mmol) and 2-iodopropane (53g,311.8mmol), heating to 80 ℃ for reaction overnight, cooling to room temperature, filtering, washing a filter cake with ethyl acetate (200 mL. times.3), combining filtrates, adding water (300mL), separating, extracting an aqueous phase with ethyl acetate (300 mL. times.3), combining organic phases, washing with water (300 mL. times.3), drying over anhydrous sodium sulfate, concentrating, and purifying a crude product by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 20-1: 10) to obtain a product (10g, 54% yield).
(4) Preparation of (4-isopropoxy-5-nitro-1, 2-phenylene) dimethanol
Figure BDA0000591508460000182
Suspending lithium aluminum hydride (3.0g,79.1mmol) in tetrahydrofuran (100mL), slowly dropwise adding a tetrahydrofuran (30mL) solution of 4-isopropoxy-5-nitrophthalic acid dimethyl ester (10g,33.64mmol) at 0 ℃, reacting at 0 ℃ for 30 minutes after dropwise adding, sequentially dropwise adding water (3mL), sodium hydroxide solution (mass fraction 15%, 9mL) and water (3mL) to the reaction solution for quenching, filtering, washing a filter cake with tetrahydrofuran (100mL multiplied by 3), combining the filtrates, drying with anhydrous sodium sulfate, concentrating in vacuum, and purifying a crude product by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 10-1: 5) to obtain a product (4g, yield 49%).
(5) Preparation of 1, 2-bis (chloromethyl) -4-isopropoxy-5-nitrobenzene
Figure BDA0000591508460000183
(4-isopropoxy-5-nitro-1, 2-phenylene) dimethanol (4g,16.58mmol) was dissolved in toluene (50mL), sulfoxide chloride (9.8g,82.4mmol) and N, N-dimethylformamide (2.4g,32.8mmol) were added, the mixture was heated to 60 ℃ to react for 2 hours, cooled to room temperature, and ethyl acetate (50mL) was added to dilute the solution, and the resulting solution was washed with water (50mL × 3), dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:20 to 1:10) to give a product (3.2g, yield 69%).
(6) Preparation of 2- (2, 4-dimethoxybenzyl) -5-isopropoxy-6-nitroisoindoline
Figure BDA0000591508460000191
1, 2-bis (chloromethyl) -4-isopropoxy-5-nitrobenzene (3g,10.79mmol) and 2, 4-dimethoxybenzylamine (5.4g,32.3mmol) were dissolved in tetrahydrofuran (30mL), N-diisopropylethylamine (6.9g,53.4mmol) was added dropwise at 0 ℃ and reacted at room temperature overnight. Ethyl acetate (50mL) was added for dilution, and the resulting reaction solution was washed with water (50mL × 3), dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:10 to 1:5) to give the product (3.1g, yield 77%).
(7) Preparation of 5-isopropoxy-6-nitroisoindoline
Figure BDA0000591508460000192
Dissolving 2- (2, 4-dimethoxybenzyl) -5-isopropoxy-6-nitroisoindoline (2.6g,6.98mmol) in dichloromethane (30mL), cooling to 0 ℃, dropwise adding 1-chloroethyl chloroformate (3g,20.98mmol), raising the temperature to 40 ℃ after dropwise addition to react for 1 hour, rotationally evaporating to remove the solvent, adding methanol (30mL), and reacting for 1 hour at 70 ℃. Cooled to room temperature, concentrated, added water (50mL), adjusted to pH 7-8 with sodium bicarbonate solution, extracted with ethyl acetate (50mL × 3), combined organic phases, washed with water (30mL × 3), dried over anhydrous sodium sulfate and concentrated to give the product (1.4g, 90% yield).
(8) Preparation of tert-butyl 5-isopropoxy-6-nitroisoindoline-2-carboxylate
Figure BDA0000591508460000193
5-Isopropoxy-6-nitroisoindoline (1.4g,6.3mmol) was dissolved in methanol (30mL), and triethylamine (3.18g,31.43mmol) and di-tert-butyl dicarbonate (4.12g,18.88mmol) were added. The reaction mixture was stirred at room temperature for 3 hours, concentrated, diluted with ethyl acetate (50mL), washed with water (30mL × 3), dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:10 to 1:3) to give the product (1.7g, 84% yield).
(9) Preparation of tert-butyl 5-amino-6-isopropoxyisoindoline-2-carboxylate
Figure BDA0000591508460000194
Tert-butyl 5-isopropoxy-6-nitroisoindoline-2-carboxylate (1.7g,5.27mmol) and palladium on carbon (0.3g) were charged in a reaction flask, ethyl acetate (20mL) was added, and the system was evacuated to replace hydrogen and reacted at room temperature for 2 hours. Filtration, cake washing with ethyl acetate (20 mL. times.3), filtrate combination, vacuum concentration to give the product (1.5g, 97% yield).
(10) Preparation of 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine
Figure BDA0000591508460000201
2- (isopropylsulfonyl) aniline (1g,5.02mmol) and 2,4, 5-trichloropyrimidine (1.1g,6mmol) were dissolved in N, N-dimethylformamide (30mL), and sodium hydride (60% by mass, 0.4g,10mmol) was added to the solution to react at 25 ℃ for 12 hours. Water (20mL) was added, extracted with ethyl acetate (30mL × 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 25:1) to give the product (0.8g, 46% yield).
(11) 5-chloro-N2- (6-Isopropoxylisoindolin-5-Yl) -N4Preparation of- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine
Figure BDA0000591508460000202
Tert-butyl 5-amino-6-isopropoxyisoindoline-2-carboxylate (100mg,0.34mmol) was dissolved in sec-amyl alcohol (8mL), and 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine (141mg,0.408mmol) and p-toluenesulfonic acid (117mg,0.68mmol) were added and reacted at 120 ℃ for 20 hours. The solvent was removed by rotary evaporation, water (10mL) was added, extraction was performed with ethyl acetate (10mL × 3), dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol: aqueous ammonia: 10:1:0.1) to give the final product (76mg, yield 44%).
The molecular formula is as follows: c24H28ClN5O3S molecular weight: 502.03LC-MS (M/z):502[ M]+
1H-NMR(400MHz,MeOD)δ:8.38(d,J＝8.0,1H),8.16(s,1H),7.99(s,1H),7.93(dd,J1＝8.0,J2＝1.2,1H),7.73-7.75(m,1H),7.39-7.43(m,1H),6.98(s,1H),4.61-4.67(m,1H),4.24(s,2H),4.11(s,2H),3.31-3.32(m,1H),2.68(s,2H),1.35(d,J＝6.0,6H),1.24(d,J＝6.8,6H).
Example 22- ((5-chloro-2- ((6-isopropoxyisoindolin-5-yl) amino) pyrimidin-4-yl) amino) -N, preparation of N-dimethylbenzenesulfonamide
Figure BDA0000591508460000211
(1) Preparation of N, N-dimethyl-2-nitrobenzenesulfonamide
Figure BDA0000591508460000212
2-Nitrobenzenesulfonyl chloride (4.43g,20mmol) was dissolved in dichloromethane (50mL), and triethylamine (8.08g,80mmol) and dimethylamine hydrochloride (1.63g,20mmol) were added to react at 25 ℃ for 12 hours. Water (35mL) was added, extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the product (2.3g, 50% yield).
(2) Preparation of 2-amino-N, N-dimethylbenzenesulfonamide
Figure BDA0000591508460000213
N, N-dimethyl-2-nitrobenzenesulfonamide (2g,8.7mmol) was dissolved in methanol (100mL), palladium on carbon (200mg) was added, the reaction was carried out at 25 ℃ for 12 hours, the solution was filtered, and the solvent was removed by rotary evaporation from the filtrate to give the product (1.5g, yield 86%).
(3) Preparation of 2- ((2, 5-dichloropyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide
Figure BDA0000591508460000214
2-amino-N, N-dimethylbenzenesulfonamide (1g,5mmol) was dissolved in N, N-dimethylformamide (20mL), and sodium hydride (60% by mass, 400mg,10mmol) and 2,4, 5-trichloropyrimidine (1.1g,6mmol) were added and reacted at 25 ℃ for 12 hours. Water (15mL) was added, extracted with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the product (270mg, yield 15.6%).
(4) Preparation of 2- ((5-chloro-2- ((6-isopropoxyisoindolin-5-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide
Figure BDA0000591508460000221
Tert-butyl 5-amino-6-isopropoxyisoindoline-2-carboxylate (prepared as described in example 1, 100mg,0.34mmol) was dissolved in sec-amyl alcohol (8mL), and 2- ((2, 5-dichloropyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (142mg,0.409mmol) and p-toluenesulfonic acid (117mg,0.68mmol) were added and reacted at 120 ℃ for 20 hours. The solvent was removed by rotary evaporation, water (10mL) was added, extraction was performed with ethyl acetate (10mL × 3), dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol: aqueous ammonia 10:1:0.1) to give the final product (75mg, yield 44%).
Molecular formula C23H27ClN6O3Molecular weight of S503.02 LC-MS (M/z) 503[ M ]]+
1H-NMR(400MHz,DMSO)δ:8.34(d,J＝8.0,1H),8.24(s,1H),8.00(s,1H),7.81(d,J＝7.2,1H),7.69(s,1H),7.61-7.65(m,1H),7.35-7.39(m,1H),6.97(s,1H),4.51-4.57(m,1H),4.04(s,2H),3.93(s,2H),2.61(s,6H),1.23(d,J＝6.0,6H).
2 4Example 35-chloro-N- (7-isopropoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -N- (2- (isopropylsulfonyl) amine Phenyl) pyrimidine-2, 4-diamine 2,2, 2-trifluoroacetate preparation
Figure BDA0000591508460000222
(1) Preparation of tert-butyl 7-bromo-3, 4-dihydroisoquinoline-2 (1H) -carboxylate
Figure BDA0000591508460000223
In a 100mL three-necked flask, 7-bromo-1, 2,3, 4-tetrahydroisoquinoline (1g,4.72mmol), dichloromethane (30mL), triethylamine (712mg,7.04mmol) were added, and the mixture was stirred for 10 minutes, followed by addition of Boc2O (1.02g,4.67 mmol). The reaction mixture was stirred at room temperature for 24 hours, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 20:1) to give the product (1.1g, yield 75%).
(2) Preparation of tert-butyl 7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydroisoquinoline-2- (1H) -carboxylate
Figure BDA0000591508460000231
Into a 250mL three-necked flask were charged tert-butyl 7-bromo-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (1.1g,3.52mmol), pinacol diboron (1.07g,4.21mmol), 1, 4-dioxane (50mL), potassium acetate (1.03g,10.50mmol), tricyclohexylphosphine (196mg,0.70mmol), Pd2(dba)3.CHCl3(181mg,0.17 mmol). The reaction is carried out for 24 hours at 80 ℃ under the protection of nitrogen. The mixture was poured into water, followed by extraction with ethyl acetate (3 × 50mL), the organic phases were combined, washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 15:1) to give the product (500mg, yield 39%).
(3) Preparation of tert-butyl 7-hydroxy-3, 4-dihydroisoquinoline-2 (1H) -carboxylate
Figure BDA0000591508460000232
In a 100mL single-neck flask were added tert-butyl 7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydroisoquinoline-2- (1H) -carboxylate (500mg,1.39mmol), tetrahydrofuran (20mL), and 30% hydrogen peroxide (10 mL). After stirring at room temperature for 1 hour, the mixture was extracted with ethyl acetate (3 × 20mL), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the product (100mg, yield 29%).
(4) Preparation of 6-nitro-1, 2,3, 4-tetrahydroisoquinoline-7-ol
Figure BDA0000591508460000233
In a 100mL single-necked flask was added tert-butyl 7-hydroxy-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (600mg,2.41mmol), CF3COOH (15 mL). Adding NaNO for 5 times under stirring2(166mg,2.41 mmol). Stirring at room temperature for 1h, concentrating the mixture under reduced pressure, and separating the residue by preparative HPLC (column: Water Sunfire C)1819X 150mM,5 μm, Phase A water (20mM NH)4HCO3),B:CH3CN, 5-10% B,25mL/min) to give the product (90mg, 19% yield).
(5) Preparation of tert-butyl 7-hydroxy-6-nitro-3, 4-dihydroisoquinoline-2 (1H) -carboxylate
Figure BDA0000591508460000241
In a 100mL single-neck flask were added 6-nitro-1, 2,3, 4-tetrahydroisoquinolin-7-ol (90mg,0.46mmol), dichloromethane (15mL), triethylamine (70mg,0.69mmol), stirred at room temperature for 10 minutes, and dropwise added Boc2O (100mg,0.46mmol), stirring at room temperature for 24h, concentrating the mixture under reduced pressure, and separating the residue by preparative HPLC (column: Water Sunfire C)18,19×150mm,5μm,Phase A:H2O(20mM NH4HCO3),B:CH3CN, 5-10% B,25mL/min) to give the product (55mg, 40% yield).
(6) Preparation of tert-butyl 7-isopropoxy-6-nitro-3, 4-dihydroisoquinoline-2 (1H) -carboxylate
Figure BDA0000591508460000242
To a 40mL sealed tube was added tert-butyl 7-hydroxy-6-nitro-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (55mg,0.19mmol), N, N-dimethylformamide (5mL), cesium carbonate (187mg,0.57mmol), 2-iodopropane (323mg,1.90 mmol). The reaction mixture was stirred at 80 ℃ for 24 h. The reaction mixture was cooled, poured into water, and then extracted with ethyl acetate (3X 15mL), and the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give the product (50mg, yield 80%).
(7) Preparation of tert-butyl 6-amino-7-isopropoxy-3, 4-dihydroisoquinoline-2 (1H) -carboxylate
Figure BDA0000591508460000243
Ethyl acetate (20mL), 10% Pd-C (10mg), tert-butyl 7-isopropoxy-6-nitro-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (50mg,0.15mmol) were charged in a 100mL round-bottomed flask, and after purging nitrogen, hydrogenation was carried out under 4 atmospheres of hydrogen, and hydrogenation was carried out at room temperature for 24 hours. Filtration, filter cake washed with ethyl acetate and filtrate concentrated to give the product (33mg, 72% yield).
(8) Preparation of 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine
Figure BDA0000591508460000251
Sodium hydride (390mg,9.75mmol, 60%), DMSO/DMF (1mL/10mL) was added to a 250mL three-necked flask, the system was cooled to 0 deg.C, and a solution of 2- (isopropylsulfonyl) aniline (1.5g,7.53mmol) in DMSO/DMF (1mL/10mL) was added dropwise. The reaction mixture was reacted at 0 ℃ for 30 minutes. 2,4, 5-trichloropyrimidine (2.06g,11.23mmol) in DMSO/DMF (1mL/10mL) was added dropwise to the reaction system at 0 deg.C, after the addition, the reaction was allowed to warm to room temperature for further 24 hours. The reaction was quenched with water at 0 deg.C, adjusted to pH7 with 1M hydrochloric acid, the mixture was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentration and column chromatography of the residue (ethyl acetate: petroleum ether ═ 1:1) gave the product (700mg, 27% yield).
(9) Preparation of tert-butyl 6- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -7-isopropoxy-3, 4-dihydroisoquinoline-2 (1H) -carboxylate
Figure BDA0000591508460000252
To a 50mL round-bottomed flask was added 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine (37mg,0.11mmol), tert-butyl 6-amino-7-isopropylOxy-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (33mg,0.11mmol), 1, 4-dioxane (15mL), cesium carbonate (108mg,0.33mmol), Pd (dppf) Cl2.CH2Cl2(9mg,0.01mmol) and reacted at 80 ℃ for 24h under the protection of nitrogen. The reaction mass is cooled to room temperature, filtered, the filtrate is concentrated and the residue is purified by preparative high performance liquid chromatography (column Water Phenyl C)18,19×150mm,5μm,Phase A:H2O(0.05％TFA),B:CH3CN, 70-92% B,9min,20 mL/min). Fractions were collected and concentrated to give the product (10mg, 15% yield).
(10) 5-chloro-N2- (7-isopropoxy-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -N4Preparation of (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine 2,2, 2-trifluoroacetate salt
Figure BDA0000591508460000253
To a 50mL round-bottomed flask was added tert-butyl 6- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -7-isopropoxy-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (10mg,0.02mmol), dichloromethane (5 mL). Trifluoroacetic acid (0.3mL) was then added dropwise, the reaction stirred at room temperature for 24h, concentrated, and the residue was dehydrated to give the final product (3mg, 29% yield).
The molecular formula is as follows: c27H31ClF3N5O5S molecular weight: 630.08LC-MS (M/z) 516[ M + H]+
1H-NMR(300MHz,d6-DMSO)δ:9.47(1H,s),8.90(2H,brs),8.43-8.40(1H,d,J＝8.4Hz),8.29(1H,s),8.11(1H,s),7.89-7.86(1H,d,J＝7.8Hz),7.76-7.71(1H,t,J＝8.4Hz),7.64(1H,s),7.57-7.52(1H,br),7.43-7.38(1H,t,J＝7.5Hz),6.93(1H,s),4.58-4.54(1H,m),4.21(2H,m),3.37(1H,m),2.74-2.72(2H,m),1.27-1.25(6H,d,J＝6.0Hz),1.17-1.15(6H,d,J＝6.9Hz).

Claims (10)

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
Figure FDA0002312415480000011
wherein the content of the first and second substances,
R1is selected from-SO2NRR6；
R、R6Independently selected from a hydrogen atom or C1-6An alkyl group;
R2、R3independently selected from a hydrogen atom or C1-4An alkyl group;
R4is selected from C1-6An alkoxy group;
R5selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, carboxyl group, C1-6Alkoxy or C1-6An alkyl group;
the A ring is selected from a 5-6 membered heterocyclic group containing 1-2O and/or N atoms.
2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein the content of the first and second substances,
R1is selected from-SO2NRR6；
R、R6Independently selected from C1-4An alkyl group;
R2、R3independently selected from hydrogen atoms;
R4is selected from C1-4An alkoxy group;
R5selected from halogen atoms;
the A ring is selected from a 5-6 membered heterocyclic group containing 1-2O and/or N atoms.
3. The compound of claim 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein the content of the first and second substances,
the A ring is selected from a 5-6 membered heterocyclic group containing 1N atom.
4. The compound of claim 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein the content of the first and second substances,
R1selected from SO2NRR6；
R、R6Independently selected from methyl, ethyl or isopropyl;
R2、R3independently selected from hydrogen atoms;
R4selected from methoxy, ethoxy or isopropoxy;
R5selected from fluorine atom, bromine atom or chlorine atom;
ring A is selected from piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, dihydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl or 1, 4-dioxanyl.
5. The compound of claim 4, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
wherein the content of the first and second substances,
ring a together with the benzene ring to which it is attached forms the following group:
Figure FDA0002312415480000021
6. the compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound is selected from:
Figure FDA0002312415480000022
7. a pharmaceutical preparation of a compound as claimed in any one of claims 1 to 6, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in combination with one or more pharmaceutically acceptable carriers and/or diluents, in any pharmaceutically acceptable dosage form.
8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more antitumor agents and/or immunosuppressive agents.
9. The pharmaceutical composition of claim 8, wherein the antineoplastic agent and/or immunosuppressive agent is an antimetabolite 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 vorinostat, cytarabine, methotrexate, hydroxyurea, hydroxycamptothecin, camptothecin, topotecan, irinotecan.
10. Use of a compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof or a stereoisomer thereof for the manufacture of a medicament for the treatment and/or prevention of ALK-mediated proliferative diseases or cancer-related diseases selected from lung cancer, brain tumor, 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, central nervous system tumors, prostate cancer, thyroid cancer, female genital tract cancer, carcinoma in situ, lymphoma, histiocytic lymphoma, neurofibromatosis, bone cancer, skin cancer, colon cancer, small cell lung cancer, non-small cell lung cancer, testicular cancer, gastrointestinal stromal tumor, mast cell tumors, multiple myeloma, melanoma, glioma, astrocytoma, neuroblastoma, sarcoma; a proliferative disease selected from benign hyperplasia of the skin or prostate.
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