CN106146525A - Three and ring class anaplastic lymphoma kinase inhibitor - Google Patents
Three and ring class anaplastic lymphoma kinase inhibitor Download PDFInfo
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- CN106146525A CN106146525A CN201510168569.3A CN201510168569A CN106146525A CN 106146525 A CN106146525 A CN 106146525A CN 201510168569 A CN201510168569 A CN 201510168569A CN 106146525 A CN106146525 A CN 106146525A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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Abstract
The invention belongs to pharmaceutical technology field, be specifically related to three shown in formula (I) ring class anaplastic lymphoma kinase inhibitor, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, wherein R1、R2、R3、R4, A ring and B ring be defined as in the description.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 treatment and/or prevention are mediated by anaplastic lymphoma kinase.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a tricyclic 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). 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 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. 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 tricyclic 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，-SO2R5、-S(O2)OR5or-SO2NRR5；
R2、R3、R、R5Independently selected from hydrogen atom, C1-6Alkyl or 3-to 8-membered carbocyclic ring;
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, hydroxyC1-6Alkoxy, halo C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-6Alkylamino radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, (C)1-6Alkyl radical)2Amino, amino C1-6Alkyl or sulfonyl C1-6An alkyl group;
ring A is optionally substituted by 1 to 3Q1A substituted 3-to 8-membered cycloalkyl group or a 3-to 8-membered heterocyclic group, said substituent Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms, 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;
ring B is optionally substituted by 1 to 3Q2A substituted 3-to 8-membered heterocyclic group, or optionally substituted with 1 to 3Q2Substituted 5-to 14-membered heteroaryl, said substituent Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms, 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, C1-6Alkoxy radical C1-6Alkoxy 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-CONRR5，-SO2R5or-SO2NRR5，
R、R5Independently selected from C1-6An alkyl group;
R2、R3independently selectFrom hydrogen atoms or C1-6An alkyl group;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, carboxyl group, C1-6Alkoxy or C1-6An alkyl group;
a ring is optionally substituted by 1 to 2Q1A substituted 4-to 7-membered cycloalkyl group or a 4-to 7-membered heterocyclic group, said substituent Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-6An alkyl group;
ring B is optionally substituted by 1 to 2Q2A substituted 5-to 6-membered heterocyclic group, or optionally substituted with 1-2Q2Substituted 5-to 6-membered heteroaryl, said substituent Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms 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，
R、R5Independently selected from C1-6An alkyl group;
R2、R3independently selected from a hydrogen atom or C1-6An alkyl group;
R4selected from halogen atoms;
a ring is optionally substituted by 1 to 2Q1A substituted 5-to 6-membered heterocyclic group, said substituent Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-4An alkyl group;
ring B is optionally substituted by 1 to 2Q2A substituted 5-to 6-membered heterocyclic group, said substituent Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-4An alkyl group.
4. The compound, pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof according to claim 3, wherein,
R1is selected from-SO2R5，
R5Independently selected from C1-4An alkyl group;
R2、R3independently selected from a hydrogen atom or C1-4An alkyl group;
R4selected from halogen atoms;
a ring is optionally substituted by 1 to 2Q1A substituted 5-to 6-membered heterocyclic group containing 1 to 2O and/or S atoms, said substituent Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-4An alkyl group;
ring B is optionally substituted by 1 to 2Q2A substituted 5-to 6-membered heterocyclic group containing 1 to 2N atoms, said substituent Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-4An alkyl group.
5. The compound, pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof according to claim 3, wherein,
R1is selected from-SO2R5,
R5Independently selected from methyl, ethyl or isopropyl;
R2、R3independently selected from a hydrogen atom or a methyl group;
R4selected from chlorine atoms;
a ring is optionally substituted by 1 to 2Q1A substituted 5-to 6-membered heterocyclic group containing 1 to 2O and/or S atoms, said substituent Q1Selected from hydroxy, amino, halogen atoms or C1-4An alkyl group;
ring B is optionally substituted by 1 to 2Q2Substituted piperidinyl, piperazinesOxazinyl, morpholinyl, pyrrolidinyl, dihydropyrrolyl, tetrahydrofuryl, tetrahydropyranyl or 1, 4-dioxanyl, said substituent Q2Selected from methyl, ethyl, n-propyl, isopropyl or n-butyl.
6. The compound, pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof according to claim 1, wherein,
R1is selected from-SO2R5or-SO2NRR5，
R、R5Independently selected from C1-6An alkyl group;
R2、R3independently selected from a hydrogen atom or C1-6An alkyl group;
R4selected from hydrogen atom, halogen atom, amino group, C1-6Alkoxy or C1-6An alkyl group;
a ring is optionally substituted by 1 to 2Q1A substituted 5-to 6-membered saturated heterocyclic group, said substituent Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-6An alkyl group;
ring B is optionally substituted by 1 to 2Q2A substituted 5-to 6-membered saturated heterocyclic group, said substituent Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-6An alkyl group.
7. The compound, pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof according to claim 6, wherein,
a ring is optionally substituted by 1 to 2Q1A substituted 5-6 membered saturated heterocyclic group containing 1-2O, S and/or N atoms, the substituent Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-6An alkyl group;
ring B is optionally substituted by 1 to 2Q2Substituted 5 containing 1-2O, S and/or N atoms6-membered saturated heterocyclic group, said substituent Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-6An alkyl group.
8. The compound, pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof according to claim 7, wherein,
a ring is optionally substituted by 1 to 2Q1A substituted 5-to 6-membered saturated heterocyclic group containing 1 to 2O and/or S atoms, the substituent Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-6An alkyl group;
ring B is optionally substituted by 1 to 2Q2A substituted 5-to 6-membered saturated heterocyclic group containing 1 to 2N atoms, the substituent Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-6An alkyl group.
9. The compound, pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof according to claim 8, wherein,
a ring is optionally substituted by 1 to 2Q1A substituted 5-membered saturated heterocyclic group containing 1 to 2O and/or S atoms, the substituent Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-6An alkyl group;
ring B is optionally substituted by 1 to 2Q2A substituted 5-membered saturated heterocyclic group containing 1 to 2N atoms, the substituent Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-6An alkyl group.
10. The compound, pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof according to claim 8, wherein,
a ring is optionally substituted by 1 to 2Q1A substituted 5-to 6-membered saturated heterocyclic group containing 1O atom, the substituent Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-6Alkyl radical；
Ring B is optionally substituted by 1 to 2Q2A substituted 5-to 6-membered saturated heterocyclic group containing 1N atom, the substituent Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or 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 alkyl having 1 to 6 carbon atoms, 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-propenyl group, 2-pentenyl group, 3-pentenyl group, 2-,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, 1, 3-dimethyl-2-butenyl, 2-dimethyl-3-butenyl, 2-methyl-3-butenyl, 1, 3-dimethyl-2-butenyl, 2-dimethyl-3-butenyl, 2-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-penten, 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, cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl 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, C1-6Alkyl radicalCarbonyl group, 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-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, C1-4Alkylcarbonyloxy 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-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 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 having 3-8 carbon atoms by removing one hydrogen atom, and includes, for example, "3-6 membered cycloalkyl group", "4-7 membered cycloalkyl group", "4-8 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 heteroatom (e.g., 1,2, 3,4 or 5 heteroatoms), and 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 nitrogen-containing heterocyclic group", "5-to 6-membered heterocyclic group containing 1 to 2N atoms", "5-to 2-membered heterocyclic group containing 1 to 2O and/or S atoms", "5-to 6-membered saturated heterocyclic group containing 1 to 2O, S and/or N atoms" "a 5-to 6-membered saturated heterocyclic group containing 1 to 2O and/or S atoms", "a 5-to 6-membered saturated heterocyclic group containing 1 to 2N atoms", "a 5-membered saturated heterocyclic group containing 1 to 2O and/or S atoms", "a 5-membered saturated heterocyclic group containing 1 to 2N atoms", "a 5-to 6-membered saturated heterocyclic group containing 1O atom", "a 5-to 6-membered saturated heterocyclic group containing 1N atom", 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, 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 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
Dissolving the intermediate 1 in a solvent (such as methanol), adding palladium carbon, reacting at 25 ℃ under the protection of hydrogen (such as 15-25 hours), filtering, and concentrating to obtain an intermediate 2.
Step 3 preparation of intermediate 3
Intermediate 2 is dissolved in a suitable solvent (e.g. acetonitrile), cooled to 0 ℃, N-bromosuccinimide is added, stirred at room temperature (e.g. 0.5-1.5 hours), 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 3.
Step 4 preparation of intermediate 4
Intermediate 3 is dissolved in a suitable solvent (e.g., N-dimethylformamide), cuprous cyanide is added, the reaction is carried out at 150 ℃ (e.g., 1-3 hours), cooled, poured into aqueous ammonia, extracted with an organic solvent (e.g., ethyl acetate), concentrated, and purified (e.g., by silica gel column chromatography) to give intermediate 4.
Step 5 preparation of intermediate 5
Intermediate 4 is dissolved in a suitable solvent (e.g., methanol), ammonia (10mL) and Raney nickel are added, reacted at 25 deg.C (15-25 hours), filtered, concentrated, and the intermediate 5 is obtained by a suitable method.
Step 6 preparation of the Compound of the general formula (I) of the present invention
Intermediate 5 is dissolved in a suitable solvent (e.g. sec-amyl alcohol), intermediate 6 and p-toluenesulfonic acid are added, and stirring is carried out at 120 ℃ (e.g. 10-30 hours). Adding saturated sodium bicarbonate solution, extracting with organic solvent (such as ethyl acetate), drying, concentrating, and subjecting to appropriate method (such as silica gel column chromatography) to obtain the compound of formula (I) of the present invention.
In the reaction equation, R1、R2、R3、R4Ring A and ring B are 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 tumor, lung cancer, non-small cell lung cancer, squamous epithelial 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, brain tumor, central nervous system tumor, namely glioma, glioblastoma multiforme, glioma, prostate cancer, thyroid cancer, female genital tract cancer, 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; 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 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.
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 compound 1 of the invention are shown in the preparation example of the compound 1.
Control drug ceritinib, prepared by the method for preparing compound 66 in patent WO2008/073687a 2.
The abbreviations used in the following experiments have the following meanings:
DMSO, DMSO: dimethyl sulfoxide
DTT: dithiothreitol
ALK: anaplastic lymphoma kinase
HEPES (high efficiency particulate air): 4-hydroxyethyl piperazine ethanesulfonic acid
Brij-35: dodecyl polyglycol ether
EDTA: ethylenediaminetetraacetic acid
The experimental method comprises the following steps: measurement of ALK kinase inhibitory Activity Using Caliper Mobility Shift method
1.1 times of kinase buffer 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%.
Preparing 3.5 times of test solution:
preparing a DMSO stock solution of a test sample: respectively weighing appropriate amount of the compound (see the following table), adding appropriate amount of DMSO, dissolving, and mixing.
The stock solution of DMSO from the test sample was diluted with DMSO to prepare a 50. mu.M solution as a stock solution. 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 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 mul of the prepared 5-fold test solution and 10 mul of the prepared 2.5-fold kinase solution are respectively added into corresponding wells of a 384-well plate, and the mixture is incubated for 10 minutes at room temperature.
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. And (3) enzymatic detection:
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 (%) (max-sample value)/(max-min) × 100 was curve-fitted 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 1 in vitro enzymatic inhibitory Activity of the Compounds of the invention
As can be seen from table 1, 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.
Examples of the experiments
2
In vitro cell Activity assay of Compounds of the invention
And (3) testing the sample: the chemical name and preparation method of the compound 1 of the invention are shown in the preparation example of the compound 1.
Control drug Ceritinib, prepared by itself (see WO2008/073687A2 for compound 66 preparation).
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) preparing a culture medium:
RPMI1640 medium containing 2.5% fetal bovine serum was prepared and used.
(2) Cell culture:
at 5% CO2In an incubator at 37 ℃ NCI-H3122 cells were placed in a T25 flask and the cells were cultured in the medium prepared in "(1)" until 80% confluence.
(3) Inoculating cells:
digesting the cells with pancreatin, centrifuging at 1000rpm for 4min, removing the supernatant, resuspending with medium, adjusting the cell density, taking 90 μ L of the cell suspension, inoculating into a 96-well plate to obtain the final cell density: 3000 cells/well; then at 5% CO2And culturing in an incubator at 37 ℃ for 24 hours.
(4) Adding a test article:
(4.1) preparation of test solution
Control drug solution: weighing 2.17mg of the control drug, adding a proper amount of DMSO (dimethyl sulfoxide) to dissolve, diluting with DMSO gradient respectively to prepare mother liquor (1000 × control drug solution) with a series of concentrations, then diluting the mother liquor by 100 times with culture medium respectively to obtain 10 × control drug solution, taking 10 μ L of the solution respectively, adding into corresponding wells of a 96-well plate to obtain the final concentration of the control drug solution: 10 μ M, 2.5 μ M, 625nM, 156nM, 39nM, 9.8nM, 2.5nM, 0.625 nM.
Compound 1 solution: weighing 8mg of the compound, adding a proper amount of DMSO (dimethyl sulfoxide), dissolving, performing gradient dilution by using DMSO respectively to prepare mother liquor (1000 multiplied by the compound 1 solution) with a series of concentrations, then diluting the mother liquor by 100 times by using culture media respectively to obtain 10 multiplied by the compound 1 solution, taking 10 mu L of the solution respectively, adding the solution into corresponding holes of a 96-well plate, and obtaining the final concentration of the compound 1 solution: 10 μ M, 2.5 μ M, 625nM, 156nM, 39nM, 9.8nM, 2.5nM, 0.625 nM.
(4.2) control well settings:
vehicle control: 0.1% DMSO.
Blank control: medium, instrument zero.
(4.3) placing the 96-well plate at 37 ℃ with 5% CO2Culturing for 72h in an incubator.
(5) And (3) detection:
to each test well of a 96-well plate, 10. mu.L of CCK-8 reagent was added and 5% CO was put back2And then cultured in an incubator at 37 ℃ for 1 hour. Setting enzyme labelsThe wavelength of the detector is 450nm, and the result is read.
(6)IC50Calculating the cell survival rate (%) (sample value-blank value)/(maximum value-blank value) × 100, and curve fitting with Graph prism software to obtain IC50The value is obtained.
Maximum value: cell control without compound plus vehicle alone, i.e. vehicle control, blank value: media blank.
Experimental results and conclusions:
TABLE 2 cytostatic Activity of Compounds of the invention
As can be seen from table 2, compared with the control drug, the compound of the present invention has better inhibitory activity on cell NCI-H3122, can be used for treating ALK kinase-mediated disorders 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.
Examples
1
5-
Chlorine
-N
4
- (2-isopropylsulfonyl)
)
Phenyl radical
)-N
2
- (2,3,7, 8-tetrahydro-2
-1H-
Furo
[3,2-e]
Isoindoles
-5-
Base of
)
Pyrimidines
-2,4-
Preparation of diamines
(1) Preparation of methyl 2, 3-dihydrobenzofuran-5-carboxylate
2, 3-Dihydrobenzofuran-5-carboxylic acid (15g,0.091mol) was dissolved in methanol (800mL), concentrated sulfuric acid (2mL) was added, the reaction was allowed to proceed at 65 ℃ for 20 hours, cooled, sodium bicarbonate was added, the mixture was concentrated, diluted with water (200mL), extracted with ethyl acetate (150 mL. times.3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the product (15.8g, 97.5% yield).
(2) Preparation of methyl 7-nitro-2, 3-dihydrobenzofuran-5-carboxylate
Dissolving methyl 2, 3-dihydrobenzofuran-5-carboxylate (14g,78.6mmol) in acetic anhydride (200mL), cooling to 0 ℃, dropwise adding concentrated nitric acid (mass fraction 65%, 7mL,102.2mmol), heating to room temperature after dropwise addition, stirring for 1 hour, pouring into water (200mL) after reaction, extracting with ethyl acetate (150mL × 3), drying with anhydrous sodium sulfate, filtering, concentrating, and purifying the crude product by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to obtain the product (13g, yield 74.3%).
(3) Preparation of methyl 7-amino-2, 3-dihydrobenzofuran-5-carboxylate
Methyl 7-nitro-2, 3-dihydrobenzofuran-5-carboxylate (10g,44.8mmol) was dissolved in methanol (300mL), palladium on carbon (1g) was added, the reaction was carried out at 25 ℃ for 20 hours under a hydrogen atmosphere, the reaction solution was filtered, and the filtrate was concentrated to obtain a product (6g, yield 69.4%).
(4) Preparation of methyl 7-amino-4-bromo-2, 3-dihydrobenzofuran-5-carboxylate
Methyl 7-amino-2, 3-dihydrobenzofuran-5-carboxylate (5.4g,28mmol) was dissolved in acetonitrile (100mL), cooled to 0 ℃, added N-bromosuccinimide (5.98g,33.6mmol) in portions, stirred at room temperature for 1 hour to complete the reaction, poured into water (100mL), extracted with ethyl acetate (150mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the product (5g, 65.6% yield).
(5) Preparation of methyl 7-amino-4-cyano-2, 3-dihydrobenzofuran-5-carboxylate
Methyl 7-amino-4-bromo-2, 3-dihydrobenzofuran-5-carboxylate (4g,14.7mmol) was dissolved in N, N-dimethylformamide (50mL), cuprous cyanide (1.57g,17.6mmol) was added, reaction was performed at 150 ℃ for 2 hours, cooled, poured into aqueous ammonia (80mL), extracted with ethyl acetate (150mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 30:1) to give the product (1.4g, yield 43.7%).
(6) Preparation of 5-amino-1, 2,7, 8-tetrahydro-3H-furo [3,2-e ] isoindol-3-one
Methyl 7-amino-4-cyano-2, 3-dihydrobenzofuran-5-carboxylate (0.4g,1.83mmol) was dissolved in methanol (100mL), and ammonia (10mL) and Raney nickel (0.1g) were added to react at 25 ℃ for 20 hours. Filtration and concentration of the filtrate afforded the product (0.28g, 80% yield).
(7) Preparation of tert-butyl 5-amino-1, 3,7, 8-tetrahydro-2H-furo [3,2-e ] isoindole-2-carboxylic acid ester
5-amino-1, 2,7, 8-tetrahydro-3H-furo [3,2-e ] isoindol-3-one (0.28g,1.47mmol) was dissolved in tetrahydrofuran (20mL), and borane-dimethyl sulfide solution (2mol/L,2.57mL,5.14mmol) was added dropwise at 0 ℃ and reacted at 65 ℃ for 24 hours. The reaction mixture was cooled to 0 ℃ and quenched by the addition of methanol (5mL), followed by addition of 4mol/L hydrochloric acid (5mL) and stirring at 65 ℃ for 4 hours. After cooling, the solvent was removed by rotary evaporation, diluted with water, adjusted to pH 10 by the addition of sodium hydroxide solution, di-tert-butyl dicarbonate (416mg,1.91mmol) was added, stirred at room temperature for 1 hour, extracted with ethyl acetate (10mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the product (75mg, 18.5% yield).
(8) Preparation of 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine
2- (isopropylsulfonyl) aniline (1g,5mmol) and 2,4, 5-trichloropyrimidine (1.1g,6mmol) were dissolved in N, N-dimethylformamide (30mL), and sodium hydride (60% in content, 0.4g,10mmol) was added to react at 25 ℃ for 12 hours. Water was added, extraction was performed with ethyl acetate (30mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo, and the crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 25:1) to give the product (0.8g, yield 46%).
(9) 5-chloro-N4- (2-isopropylsulfonyl) phenyl) -N2- (2,3,7, 8-tetrahydro-1H-furo [3, 2-e)]Preparation of isoindol-5-yl) pyrimidine-2, 4-diamines
Tert-butyl 5-amino-1, 3,7, 8-tetrahydro-2H-furo [3,2-e ] isoindole-2-carboxylate (70mg,0.25mmol) was dissolved in sec-amyl alcohol (8mL), 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine (104mg,0.3mmol) and p-toluenesulfonic acid (86mg,0.5mmol) were added, and stirring was carried out at 120 ℃ for 20 hours. The solvent was removed by rotary evaporation, saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (10mL × 3), dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was subjected to silica gel column chromatography (dichloromethane: methanol: aqueous ammonia: 10:1:0.1) to give the final product (10mg, yield 8.2%).
Molecular formula C23H24ClN5O3S molecular weight 485.99LC-MS (M/z):486[ M]+
1H-NMR(400MHz,MeOD-d4):8.49(d,J＝8.0Hz,1H),8.14(s,1H),7.90(d,J＝8.0Hz,1H),7.72(s,1H),7.70-7.67(m,1H),7.39-7.35(m,1H),4.65(t,J＝8.6Hz,2H),4.53(s,2H),4.45(s,2H),3.26(t,J＝8.8Hz,2H),1.19(d,J＝6.8Hz,6H)。
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，-SO2R5、-S(O2)OR5or-SO2NRR5；
R2、R3、R、R5Independently selected from hydrogen atom, C1-6Alkyl or 3-to 8-membered carbocyclic ring;
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 group, C1-6Alkylcarbonyloxy, (C)1-6Alkyl radical)2Amino or sulfonyl C1-6An alkyl group;
ring A is optionally substituted by 1 to 3Q1A substituted 3-to 8-membered cycloalkyl group or a 3-to 8-membered heterocyclic group, said substituent Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms, 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;
ring B is optionally substituted by 1 to 3Q2A substituted 3-to 8-membered heterocyclic group, or optionally substituted with 1 to 3Q2Substituted 5-to 14-membered heteroaryl, said substituent Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms, 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-CONRR5，-SO2R5or-SO2NRR5，
R、R5Independently selected from C1-6An alkyl group;
R2、R3independently selected from a hydrogen atom or C1-6An alkyl group;
R4selected from hydrogen atom, halogen atom, cyano group, nitro group, amino group, carboxyl group, C1-6Alkoxy or C1-6An alkyl group;
a ring is optionally substituted by 1 to 2Q1A substituted 4-to 7-membered cycloalkyl group or a 4-to 7-membered heterocyclic group, said substituent Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-6An alkyl group;
ring B is optionally substituted by 1 to 2Q2A substituted 5-to 6-membered heterocyclic group, or optionally substituted with 1-2Q2Substituted 5-to 6-membered heteroaryl, said substituent Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms 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，
R、R5Independently selected from C1-6An alkyl group;
R2、R3independently selected from a hydrogen atom or C1-6An alkyl group;
R4selected from halogen atoms;
a ring is optionally substituted by 1 to 2Q1A substituted 5-to 6-membered heterocyclic group, said substituent Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-4An alkyl group;
ring B is optionally substituted by 1 to 2Q2A substituted 5-to 6-membered heterocyclic group, said substituent Q2Selected from hydroxy, amino, carboxyl, cyanoRadical, nitro radical, halogen atom or C1-4An alkyl group.
4. The compound of claim 3, a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof:
wherein,
R1is selected from-SO2R5，
R5Independently selected from C1-4An alkyl group;
R2、R3independently selected from a hydrogen atom or C1-4An alkyl group;
R4selected from halogen atoms;
a ring is optionally substituted by 1 to 2Q1A substituted 5-to 6-membered heterocyclic group containing 1 to 2O and/or S atoms, said substituent Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-4An alkyl group;
ring B is optionally substituted by 1 to 2Q2A substituted 5-to 6-membered heterocyclic group containing 1 to 2N atoms, said substituent Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atoms or C1-4An alkyl group.
5. The compound of claim 3, a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof:
wherein,
R1is selected from-SO2R5,
R5Independently selected from methyl, ethyl or isopropyl;
R2、R3independently selected from a hydrogen atom or a methyl group;
R4selected from chlorine atoms;
a ring is optionally substituted by 1 to 2Q1A substituted 5-to 6-membered heterocyclic group containing 1 to 2O and/or S atoms, said substituent Q1Selected from hydroxy, amino, halogen atoms or C1-4An alkyl group;
ring B is optionally substituted by 1 to 2Q2Substituted piperidinyl, piperazinesOxazinyl, morpholinyl, pyrrolidinyl, dihydropyrrolyl, tetrahydrofuryl, tetrahydropyranyl or 1, 4-dioxanyl, said substituent Q2Selected from methyl, ethyl, n-propyl, isopropyl or n-butyl.
6. The compound, pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof of claim 1, wherein the compound is selected from:
7. a pharmaceutical preparation of a compound, a pharmaceutically acceptable salt, an ester, a solvate or a stereoisomer thereof according to any one of claims 1 to 6, in any pharmaceutically acceptable form, together with one or more pharmaceutically acceptable carriers.
8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, and one or more pharmaceutically active ingredients.
9. The pharmaceutical composition of claim 8, wherein said one or more pharmaceutically active ingredients are an antineoplastic agent and/or an immunosuppressive agent, said antineoplastic agent and/or immunosuppressive agent being 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 SAHA, cytarabine, methotrexate, hydroxyurea, hydroxycamptothecin, topotecan, irinotecan.
10. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of an ALK-mediated cancer-related disease or proliferative disease selected from brain tumor, 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, solid tumors, non-Hodgkin's lymphoma, central nervous system tumors, i.e., glioma, glioblastoma multiforme, gliosarcoma, prostate cancer, thyroid cancer, cancer of the female genital tract, carcinoma in situ, lymphoma, histiocytic lymphoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, brain 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; a proliferative disease selected from benign hyperplasia of the skin or prostate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112384508A (en) * | 2018-09-30 | 2021-02-19 | 山东轩竹医药科技有限公司 | Tricyclic ASK1 inhibitor and application thereof |
| EP4079726A4 (en) * | 2019-12-16 | 2024-01-24 | Korea Research Institute of Chemical Technology | NOVEL PYRIMIDINE DERIVATIVE AND USE THEREOF |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005026158A1 (en) * | 2003-09-16 | 2005-03-24 | Novartis Ag | 2,4 di (hetero) -arylamino-pyrimidine derivatives as zap-70 and/or syk inhibitors |
| WO2005026130A1 (en) * | 2003-09-18 | 2005-03-24 | Novartis Ag | 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders |
| WO2006021454A2 (en) * | 2004-08-27 | 2006-03-02 | Novartis Ag | Pyrimidine derivatives |
| CN1832929A (en) * | 2003-08-15 | 2006-09-13 | 诺瓦提斯公司 | 2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders |
| WO2012106540A1 (en) * | 2011-02-02 | 2012-08-09 | Irm Llc | Methods of using alk inhibitors |
| WO2014071832A1 (en) * | 2012-11-06 | 2014-05-15 | Shanghai Fochon Pharmaceutical Co Ltd | Alk kinase inhibitors |
| WO2015003658A1 (en) * | 2013-07-11 | 2015-01-15 | Betta Pharmaceuticals Co., Ltd | Protein tyrosine kinase modulators and methods of use |
| WO2015038868A1 (en) * | 2013-09-13 | 2015-03-19 | Cephalon, Inc. | Fused bicyclic 2,4-diaminopyrimidine derivatives |
-
2015
- 2015-04-10 CN CN201510168569.3A patent/CN106146525B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1832929A (en) * | 2003-08-15 | 2006-09-13 | 诺瓦提斯公司 | 2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders |
| WO2005026158A1 (en) * | 2003-09-16 | 2005-03-24 | Novartis Ag | 2,4 di (hetero) -arylamino-pyrimidine derivatives as zap-70 and/or syk inhibitors |
| WO2005026130A1 (en) * | 2003-09-18 | 2005-03-24 | Novartis Ag | 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders |
| WO2006021454A2 (en) * | 2004-08-27 | 2006-03-02 | Novartis Ag | Pyrimidine derivatives |
| WO2012106540A1 (en) * | 2011-02-02 | 2012-08-09 | Irm Llc | Methods of using alk inhibitors |
| WO2014071832A1 (en) * | 2012-11-06 | 2014-05-15 | Shanghai Fochon Pharmaceutical Co Ltd | Alk kinase inhibitors |
| WO2015003658A1 (en) * | 2013-07-11 | 2015-01-15 | Betta Pharmaceuticals Co., Ltd | Protein tyrosine kinase modulators and methods of use |
| WO2015038868A1 (en) * | 2013-09-13 | 2015-03-19 | Cephalon, Inc. | Fused bicyclic 2,4-diaminopyrimidine derivatives |
Non-Patent Citations (1)
| Title |
|---|
| ZHIQING LIU ET AL.: "Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent c-Met/ALK Multikinase Inhibitory Activities", 《ACS MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112384508A (en) * | 2018-09-30 | 2021-02-19 | 山东轩竹医药科技有限公司 | Tricyclic ASK1 inhibitor and application thereof |
| EP4079726A4 (en) * | 2019-12-16 | 2024-01-24 | Korea Research Institute of Chemical Technology | NOVEL PYRIMIDINE DERIVATIVE AND USE THEREOF |
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| CN106146525B (en) | 2018-11-02 |
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