CN117143107A - 1, 2-dihydropyridine derivative, preparation method and application thereof - Google Patents

1, 2-dihydropyridine derivative, preparation method and application thereof Download PDF

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CN117143107A
CN117143107A CN202311003253.XA CN202311003253A CN117143107A CN 117143107 A CN117143107 A CN 117143107A CN 202311003253 A CN202311003253 A CN 202311003253A CN 117143107 A CN117143107 A CN 117143107A
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optionally substituted
deuterium
substituted
halogen
compound
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许志勇
梁永宏
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Zhejiang Weitai Biotechnology Co ltd
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Zhejiang Weitai Biotechnology Co ltd
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention provides a compound with a brand new structure as an SHP2 inhibitor, a preparation method of the compound and application of the compound in treating SHP2 mediated diseases. Experiments prove that the compounds have strong inhibition effect on SHP2 enzyme and can be used as a prospect compound for treating SHP2 mediated diseases.

Description

1, 2-dihydropyridine derivative, preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a compound serving as an SHP2 inhibitor, and particularly relates to a 1, 2-dihydropyridine derivative, a preparation method and application thereof.
Background
Intracellular protein tyrosine phosphatase SHP2 (SH 2 domain-containing protein-tyrosine phosphatase-2), also known as PTPN11, is a non-receptor protein tyrosine phosphatase belonging to the Protein Tyrosine Phosphatase (PTP) family and plays an important role downstream of cellular signal transduction. As sink nodes for a variety of signaling pathways including the Ras-Raf-MEK-ERK, JAK-STAT, PI3K-AKT-mTOR and PD-1/PD-L1 pathways, SHP2 can enhance or antagonize the immunomodulatory pathways associated with classical cell survival and with substrate specificity. The N-terminus of SHP2 consists of two SH2 domains (N-SH 2 and C-SH 2) and one catalytically active PTP domain, the C-terminus comprising two p-Tyr sites (Y542 and Y580) and a proline-rich motif.
In the inactive state, the SHP2 protein is automatically inhibited by residues on the catalytic surfaces of the PTP domain and the N-SH2 domain, thereby inhibiting the activity of the SHP2 protein and limiting the entry of the substrate into the catalytic site. Under the stimulation of growth factors or cytokines, SHP2 is recruited through the combination of SH2 domains and phosphotyrosine sites, so that the SHP2 is subjected to conformational change to expose the catalytic sites, thereby realizing accurate catalytic activation of the SHP2 and activating downstream signal channels. It was found that SHP2 has a bifacial role in cancer, and it can serve both as a phosphatase for significant oncogenic functions and as a tumor suppressor in an environmentally dependent manner.
Development based on SHP2 inhibitors has made significant progress in the last few years. Early developed SHP2 inhibitors targeting the catalytic site have failed to be formulated due to poor selectivity, low bioavailability, and the like. A number of inhibitors targeting the allosteric site of SHP2 have been successfully developed and a number of SHP2 inhibitors have been approved for clinical use. Wherein TNO-155 of North China, ERAS-601 of Erasca, JBA-3312 and JBA-3068 of additionally provided sciences, RMC-4630 of Sainofil and the like have entered phase 2 clinic. North TNO-155 is used for oral treatment of advanced solid tumors, either as monotherapy or in combination with other therapeutic agents. ERAS-601 from Erasca is useful in the treatment of advanced or metastatic solid tumors, including advanced non-squamous non-small cell lung cancer (NSNSCLC). Gaboxa JAB-3312 for use in combination with other therapeutic agents to treat patients with advanced solid tumors; JAB-3068 is used to treat advanced solid tumors, either as monotherapy or in combination with torepazumab. RMC-4630 of celecoxib in combination with sotoracoside is used for secondary or post-treatment of KRASG12C mutated non-small cell lung cancer (NSCLC) patients.
Furthermore, the use of SHP2 inhibitors in combination with other target inhibitors for the treatment of drug resistant cancers is a promising strategy.
Although some small molecules of SHP2 inhibitors have been disclosed, no SHP2 inhibitors are developed and marketed at present, so that the development of new compounds with market potential, better drug effect and drug generation result is still urgent.
Disclosure of Invention
The invention aims to provide a novel SHP2 inhibitor compound, a preparation method of the compound and application of the compound in treating SHP2 mediated diseases. The novel compounds are biochemically effective and physiologically active and have good pharmacokinetic and low toxicological properties.
In a first aspect of the present invention there is provided a compound of formula (I) as follows, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically-labelled analogues thereof:
wherein X is N or CR X ；R X Is H, deuterium, halogen, -CN, -NO 2 、-NH 2 -OH or optionally substituted: c (C) 1-3 An alkyl group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
Q is optionally substituted: a 6-10 membered aryl, a 6-10 membered heteroaryl ring group, wherein optional substitution means by one or more groups selected from deuterium, halogen, -CN, -NO 2 、-OH、-SH、-NH 2 、C 1-4 Alkoxy, C 1-4 A substituent of alkylthio;
or Q is C optionally substituted with one or more R 2-4 Alkynyl; r' is optionally substituted: c (C) 1-4 Alkyl, C 3-6 Cycloalkyl, C 4-6 Heterocyclyl, phenyl, 5-6 membered heteroaryl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkyl, halogenated C 1-3 Substituted with alkoxy;
R 1 is optionally substituted: c (C) 1-3 An alkyl group; wherein optionally substituted means substituted with one or more substituents selected from deuterium, halogen;
R 2 selected from H,Deuterium, halogen, -CN, -NO 2 、-NH 2 -OH or optionally substituted: c (C) 1-3 Alkyl, C 1-3 An alkoxy group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
ring W is a 4-16 membered heterocyclyl;
R w is deuterium, halogen, -CN, -NO 2 、-NH 2 -OH, acetamido or optionally substituted: c (C) 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
m is 1, 2, 3 or 4;
the hetero atoms in the heterocyclic group and the heteroaryl group are independently selected from O, N or S, and the number of the hetero atoms is preferably 1, 2 or 3;
in a preferred embodiment of the invention, X is N;
in a preferred embodiment of the invention, X is CR X ；R X Is H, deuterium, -F, -Cl, -Br, -CN, -NO 2 、-NH 2 -OH or optionally substituted: methyl, ethyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
in a preferred embodiment of the invention, R X Is H, deuterium or optionally substituted: methyl, ethyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
in a preferred embodiment of the invention, R X Is H, -CH 2 OH；
In a preferred embodiment of the invention, X is CH, C-CH 2 OH；
In a preferred embodiment of the invention, Q is optionally substituted: a 6 membered aryl group, a 6 membered heterocyclic group; wherein optionally substituted means substituted with one or more substituents selected fromDeuterium, halogen, -CN, -NO 2 、-OH、-SH、-NH 2 、C 1-4 Alkoxy, C 1-4 A substituent of alkylthio;
or Q is C optionally substituted with one or more R 2-4 Alkynyl; r' is optionally substituted C 3-6 Cycloalkyl, C 4-6 Heterocyclyl, phenyl, 5-6 membered heteroaryl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
in a preferred embodiment of the invention, Q is optionally substituted: a 6 membered aryl group, a 6 membered heterocyclic group; wherein optionally substituted means substituted with one or more substituents selected from deuterium, -F, -Cl, -OH, methoxy, ethoxy, methylthio, ethylthio;
or Q is ethynyl optionally substituted with one or more R'; r' is optionally substituted cyclopropyl, cyclopenta, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, phenyl, pyridinyl, pyrrolyl, imidazolyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, -F, -Cl, -CN, -NO 2 、-NH 2 -OH, methyl, ethyl;
in a preferred embodiment of the invention, Q is optionally substituted: phenyl, pyridyl; wherein optionally substituted means substituted with one or more substituents selected from deuterium, -F, -Cl, -OH, methoxy, ethoxy, methylthio, ethylthio;
or Q is ethynyl optionally substituted with one or more R'; r' is optionally substituted cyclopropyl, phenyl, pyridinyl; wherein optionally substituted means substituted with one or more substituents selected from-F, -OH, methoxy;
In a preferred embodiment of the invention, Q is
In a preferred embodiment of the invention, Q is
In a preferred embodiment of the invention, R 1 Is optionally substituted: methyl, ethyl, isopropyl; wherein optionally substituted means substituted with one or more substituents selected from deuterium, halogen;
in a preferred embodiment of the invention, R 1 Is optionally substituted: a methyl group; wherein optionally substituted means substituted with one or more substituents selected from deuterium, -F, -Cl, -Br;
in a preferred embodiment of the invention, R 1 is-CH 3 、CD 3 ；
In a preferred embodiment of the invention, R 2 Selected from H, deuterium, halogen, -CN, -NO 2 、-NH 2 -OH or optionally substituted: c (C) 1-3 An alkyl group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
in a preferred embodiment of the invention, R 2 Selected from H, deuterium, -F, -Cl, -Br, -CN, -NO 2 、-NH 2 -OH or optionally substituted: methyl, ethyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, -F, -Cl, -Br, -CN, -NO 2 、-NH 2 -OH;
in a preferred embodiment of the invention, R 2 Selected from H and NH 2 、-CH 3 ；
In a preferred embodiment of the invention, ring W is a 6 membered heterocyclyl, 7-12 membered bicyclic heterocyclyl, 8-16 membered tricyclic heterocyclyl;
in a preferred embodiment of the invention, ring W is
In a preferred embodiment of the invention, R w Is deuterium, halogen, -CN, -NO 2 、-NH 2 -OH, acetamido or optionally substituted: c (C) 1-3 An alkyl group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
in a preferred embodiment of the invention, R w Deuterium, -F, -Cl, -Br, -CN, -NH 2 -OH, acetamido or optionally substituted: methyl, ethyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
in a preferred embodiment of the invention, R w is-NH 2 、-CH 3 、
In a preferred embodiment of the invention, m is 1, 2 or 3;
in a preferred embodiment of the invention, m is 1;
in a preferred embodiment of the invention, m is 2;
the present invention also provides a compound of the following formula (ii-a), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically-labeled analogs thereof:
Wherein R is 1 、R 2 、X、R w Ring and ringW, m is as described for the compounds of formula (I);
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 respectively and independently N or CR Y ；
R Y Is hydrogen, deuterium, halogen, -CN, -NO 2 、-NH 2 -OH or optionally substituted: c (C) 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
in a preferred embodiment of the invention, Y 1 、Y 2 、Y 3 、Y 4 、Y 5 Are all CR Y ；
In a preferred embodiment of the invention, Y 1 、Y 2 、Y 4 、Y 5 Are all CR Y ，Y 3 Is N;
in a preferred embodiment of the invention, R Y Is hydrogen, deuterium, -F, -Cl, -Br, -CN, -NO 2 、-NH 2 -OH or optionally substituted: c (C) 1-3 Alkyl, C 1-3 An alkoxy group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
in a preferred embodiment of the invention, R Y Is hydrogen, deuterium, -F, -Cl, -Br, -CN, -NO 2 、-NH 2 -OH or optionally substituted: methyl, methoxy; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
in a preferred embodiment of the invention, R Y Is hydrogen, -Cl, -OH, methoxy;
in a preferred embodiment of the invention, Y 1 、Y 2 、Y 4 、Y 5 Are all CH, Y 3 Is N;
the present invention also provides a compound of the following formula (ii-b), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically-labeled analogs thereof:
wherein R', R 1 、R 2 、X、R w Ring W, m is as described for compounds of formula (I);
the invention also provides a compound shown in the following formulas (III-1) - (III-4), wherein the stereoisomer, tautomer or mixture thereof of the compound, or pharmaceutically acceptable salt of the compound:
wherein R is 1 、R 2 、X、R w Ring W, m is as described for compounds of formula (I) or (II-a);
the present invention also provides a compound of formula (iii-5), as shown below, and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled analogs thereof:
wherein R', R 1 、R 2 、R w Ring W, m is as described for compounds of formula (I) or (II-b);
the invention also provides a compound shown in the following formulas (IV-1) - (IV-5), and stereoisomers, geometric isomers, tautomers, medicinal salts, prodrugs, hydrates, solvates or isotopically labeled analogues thereof:
wherein R', R 1 、R 2 X is as described for the compound of formula (I);
R w1 And R is w2 Are independently selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH or optionally substituted: c (C) 1-3 Alkyl, C 1-3 An alkoxy group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
or R is w1 、R w2 Together with the attached C form an optionally substituted 5-6 membered heterocyclyl, 7-12 membered bicyclic heterocyclyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
in a preferred embodiment of the invention, R w1 And R is w2 Are respectively and independently selected from deuterium and NH 2 -OH or optionally substituted: c (C) 1-3 An alkyl group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
or R is w1 、R w2 Together with the attached C form an optionally substituted 6 membered heterocyclyl, 7-10 membered bicyclic heterocyclyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
in a preferred embodiment of the invention, R w1 And R is w2 Independently selected from-NH 2 、-CH 3 、
In a preferred embodiment of the invention, R w1 And R is w2 Independently selected from-NH 2 、-CH 3 ；
Or R is w1 、R w2 Together with C attached to form * Is a point of connection with C;
The invention also provides a compound represented by the following formulas (a) - (d), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled analogues thereof:
wherein R is 2 、R w1 、R w2 As described by the compounds of formula (I) or (IV-1) to (IV-5);
the invention also provides a compound represented by the following formulas (a 1) to (d 1), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled analogues thereof:
wherein R is w1 、R w2 As described for the compounds of formula (I) or formulae (IV-1) to (IV-5).
In a preferred embodiment of the invention, the compounds of the invention are selected from:
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the object of the present invention is also to provide a process for preparing the compounds of formulae (a 1), (c 1), (d 1), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically labeled analogues thereof.
The compounds of the general formula may be prepared by a variety of methods including, but not limited to, the following:
scheme one:
scheme II:
scheme III:
the invention also provides a pharmaceutical composition comprising a compound of the invention, or a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate or an isotopically labeled analogue thereof, and pharmaceutically acceptable auxiliary materials.
The object of the present invention also consists in providing the use of a compound according to the invention, or a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate or an isotopically labelled analogue thereof, for the preparation of a medicament for the prophylaxis and/or treatment of diseases mediated by SHP2 inhibitors.
In some embodiments, the disorder mediated by an SHP2 inhibitor is cancer or a tumor-associated disorder.
In some embodiments, the disorder mediated by an SHP2 inhibitor is an immunoinflammatory-related disorder.
In some embodiments, the disorder mediated by an SHP2 inhibitor is an infectious related disorder.
In some embodiments, the disorder mediated by an SHP2 inhibitor is a metabolic-related disorder.
The object of the present invention is also to provide a method for preventing and/or treating a disorder mediated by an SHP2 inhibitor, comprising administering to a patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopically-labeled analog or a pharmaceutical composition of the present invention.
In some embodiments, the disorder mediated by an SHP2 inhibitor is cancer or a tumor-associated disorder.
In some embodiments, the disorder mediated by an SHP2 inhibitor is an immunoinflammatory-related disorder.
In some embodiments, the disorder mediated by an SHP2 inhibitor is an infectious related disorder.
In some embodiments, the disorder mediated by an SHP2 inhibitor is a metabolic-related disorder.
The compounds of the present invention or pharmaceutically acceptable salts thereof may provide enhanced anticancer effects when administered in combination with additional anticancer agents or immune checkpoint inhibitors for the treatment of cancer or tumors.
The invention has the beneficial effects that:
the invention designs a compound with novel structure, and provides a new direction for the development of SHP2 inhibitor medicines. In vitro enzyme activity inhibition activity researches show that the compounds have strong inhibition effect on SHP2 enzyme, so that the compounds can be used as the prospect compounds for treating SHP2 inhibitor-mediated diseases. In addition, the invention researches a specific synthesis method, and the synthesis method has simple process and convenient operation, and is beneficial to large-scale industrial production and application.
Definition of the definition
Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C1-10 alkyl), further preferably containing 1 to 8 carbon atoms (C1-8 alkyl), more preferably containing 1 to 6 carbon atoms (i.e., C1-6 alkyl), e.g., "C1-6 alkyl" refers to the group being alkyl, and the number of carbon atoms in the carbon chain being between 1 and 6 (specifically 1,2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.
Unless otherwise specified, the term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon atoms and hydrogen atoms. Alkenyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkenyl groups), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkenyl groups), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkenyl), 2 to 5 carbon atoms (i.e. C 2-5 Alkenyl), 2 to 4 carbon atoms (i.e. C 2-4 Alkenyl), 2 to 3 carbon atoms (i.e. C 2-3 Alkenyl), 2 carbon atoms (i.e. C 2 Alkenyl), e.g. "C 2-6 Alkenyl "means that the group is alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.
Except for other gaugesThe term "alkynyl" refers, aside from, to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, having at least one triple bond. Alkynyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl groups), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkynyl groups), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkynyl), 2 to 5 carbon atoms (i.e. C 2-5 Alkynyl), 2 to 4 carbon atoms (i.e. C 2-4 Alkynyl), 2 to 3 carbon atoms (i.e. C 2-3 Alkynyl), 2 carbon atoms (i.e. C 2 Alkynyl groups), e.g. "C 2-6 Alkynyl "means that the group is alkynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.
"alkoxy" means an-O-alkyl group as defined above, i.e., containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1,2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-dimethylpropoxy, 1-ethylpropoxy, and the like.
Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic radical having a specific number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C3-12 cycloalkyl), more preferably containing 3 to 10 carbon atoms (C3-10 cycloalkyl), still more preferably 3 to 6 carbon atoms (C3-6 cycloalkyl), 4 to 6 carbon atoms (C4-6 cycloalkyl), 5 to 6 carbon atoms (C5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like. The term "alkoxy", unless otherwise specified, refers to an-O-alkyl group, which is as defined above, i.e. comprising 1 to 20 carbon atoms, preferably comprising 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (in particular 1,2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-dimethylpropoxy, 1-ethylpropoxy, and the like.
The term "halogen" or "halo" refers to F, cl, br, I unless otherwise specified. The term "haloalkyl" means that one, two or more hydrogen atoms or all hydrogen atoms in an alkyl group as defined above are replaced by halogen. Representative examples of haloalkyl groups include CCl3, CF3, CHCl2, CH2 Cl, CH2 Br, CH 2I, CH2 CF3, CF2 CF3, and the like.
Unless otherwise specified, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure, containing 3 to 20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S and the remaining ring atoms are C. Preferably 3 to 12 ring atoms, more preferably 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 5 to 6 ring atoms. The heteroatoms are preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.
Unless otherwise specified, the term "aryl" means a monocyclic, bicyclic and tricyclic aromatic carbocyclic ring system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms, and the term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, and the like.
Unless otherwise specified, the term "heteroaryl" means an aromatic monocyclic or polycyclic ring system containing a 5-12 membered structure, or preferably a 5-10 membered structure, a 5-8 membered structure, more preferably a 5-6 membered structure, wherein 1,2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, the number of heteroatoms preferably being 1,2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo [2,3-b ] pyridyl, imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,5-a ] triazolo [1,5-a ] pyridyl, and the like.
Unless otherwise specified, the term "pharmaceutically acceptable salt", "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, especially humans, without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, such as are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the free base or free acid with a suitable reagent alone, as outlined below. For example, the free base function may be reacted with a suitable acid.
The term "solvate" means, unless otherwise specified, the physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In some cases, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may be present in a regular arrangement and/or in a disordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric solvent molecule. "solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolamides. Solvation methods are well known in the art.
The term "stereoisomer" refers to compounds having the same chemical structure, but spatially different arrangements of atoms or groups, unless otherwise specified. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers and the like. The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
Unless otherwise specified, the term "tautomer" refers to structural isomers having different energies that can be converted to each other by a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers include interconversions by recombination of some of the bond-forming electrons.
The term "optionally substituted" means, unless otherwise specified, that the hydrogen of the substitutable site of the group is unsubstituted or substituted with one or more substituents, preferably selected from the group consisting of: halogen, hydroxy, mercapto, cyano, nitro, amino, azido, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl sulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-10 membered heteroaryl ring group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl sulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-to 10-membered heteroarylThe cyclic groups may optionally be selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 Substituted by one or more substituents in an alkoxy group, the oxo group means that two H's at the same substitution position are replaced by the same O to form a double bond.
The term "prodrug" refers to a drug that is converted in vivo to the parent drug, unless otherwise specified. Prodrugs are often useful because, in some instances, they may be easier to administer than the parent drug. For example, they may be bioavailable orally, whereas the parent is not. The solubility of the prodrug in the pharmaceutical composition is also improved compared to the parent drug. An example of a prodrug, but not limited thereto, may be any compound of formula (I) that is administered as an ester ("prodrug") to facilitate transport across the cell membrane, where water solubility is detrimental to mobility, but is beneficial once inside the cell, which is then metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, wherein the peptide is metabolized to reveal an active moiety.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials are presented herein for illustrative purposes only.
Column chromatography purification uses 300-400 mesh silica gel from the Qingdao marine chemical plant, unless otherwise indicated; preparation of thin layer chromatography A thin layer chromatography silica gel prefabricated plate (HSGF 254) manufactured by Kagaku chemical industry research institute of tobacco, inc.;
the structures of the compounds of the invention are obtained by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS) or. MS was determined using a Therno LCD Fleet type (ESI) liquid chromatograph-mass spectrometer.
As nuclear magnetic data (1H NMR), bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic instruments were used, and the solvents used for the nuclear magnetic data were CDCl3, CD3OD, D2O, DMSO-D6, etc., based on tetramethylsilane (0.000 ppm) or residual solvents (CDCl 3:7.26ppm; CD3OD:3.31ppm; D2O:4.79ppm; DMSO-D6:2.50 ppm). When peak shape diversity is indicated, the following abbreviations represent the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet). If the coupling constant is given, it is in Hertz (Hz).
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
The invention provides a preparation method of the compound. The compounds can be prepared by the following steps.
Preparation example 1
Synthesis of 5-bromo-N- (2-chloro-3-mercaptophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the first step: to a solution of methyl 3- (methylamino) propionate (11.7 g,0.1 mol) in methylene chloride (100 mL) were added triethylamine (30 mL,0.3 mol) and 4-dimethylaminopyridine (1.22 g,0.01 mol), cooled to 0℃and ethyl chloroformylacetate (13.6 g,0.1 mol) was slowly added, and the reaction temperature was maintained below 5 ℃. The mixture was stirred for an additional 30 minutes, naturally warmed to room temperature and stirred overnight. The mixture was poured into dilute hydrochloric acid (2 m,90 ml) and the organic phase was separated. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The target compound methyl 3- ((3-methoxy-3-oxopropyl) (methyl) amino) -3-oxopropanoate (17.2 g, 79% yield) was collected by silica gel column chromatography (gradient n-hexane/ethyl acetate 9:1 to 3:7). LCMS (ESI) m/z=218.1 [ m+h ] ] + 。
And a second step of: methanol (100 mL) was added to a single-port flask, and methyl 3- ((3-methoxy-3-oxopropyl) (methyl) amino) -3-oxopropionate (15 g,0.07 mol) as an intermediate was added to form a clear solution, followed by addition of sodium methoxide (10 g,0.18 mol) as a solid in portions. The resulting mixture was heated under reflux for 2 hours. The mixture was cooled and acidified to pH 3 with dilute hydrochloric acid. The aqueous solution was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give the title compound, methyl 4-hydroxy-1-methyl-2-carbonyl-1, 2,5, 6-tetrahydropyridine-3-carboxylate (13 g, crude). Without further purification, it was used directly in the next reaction. LCMS (ESI) m/z=186.0 [ m+h ]] + 。
And a third step of: crude 4-hydroxy-1-methyl-2-carbonyl-1, 2,5, 6-tetrahydropyridine-3-carboxylic acid methyl ester (13 g) was dissolved in toluene (150 mL), and 10% palladium on carbon catalyst (10%, 5.75 g) was added. The reaction mixture was stirred at reflux overnight. After cooling to room temperature, the reaction mixture was diluted with methanol (300 mL), filtered off with a short silica gel sand funnel under reduced pressure, followed by washing with methanol (300 mL). The solvent was removed from the filtrate under reduced pressure, and the crude product was purified by silica gel column chromatography (gradient n-hexane/ethyl acetate 5:1 to 1:1) to give the target compound methyl 4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxylate (8.2 g, yield 74.6%). LCMS (ESI) m/z=184.1 [ m+h ] ] + 。
Fourth step: the compound methyl 4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxylate (7.4 g,0.04 mol) was dissolved in tetrahydrofuran (100 mL), 1, 3-dibromo-5, 5-dimethylhydantoin (12.7 g,0.044 mol) was added under ice-bath cooling, the reaction was allowed to proceed at room temperature for 2 hours, the reaction was completed by thin layer detection, water (100 mL) was added to the reaction solution, ethyl acetate (100 mL), and the mixture was allowed to stand for separation, and the organic phase was separated, washed with saturated sodium thiosulfate, saturated saline solution and dried over anhydrous sodium sulfate. Filtration, concentration to dryness, silica gel column chromatography (gradient n-hexane/ethyl acetate 10:1 to 3:1) afforded the target compound 5-bromo-4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxylic acid methyl ester (6.6 g, yield 63%). LCMS (ESI) m/z=262.1 [ m+h ]] + 。
Fifth step: the compound 3- (tert-butylsulfanyl) -2-chloroaniline (5.4 g,0.025 mol) and 5-bromo-4-hydroxy-1-methylMethyl-2-oxo-1, 2-dihydropyridine-3-carboxylate (6 g,0.023 mol) was dissolved in dimethylformamide (50 mL), heated to reflux and stirred for 3 hours. Cooled to room temperature, ethyl acetate (50 mL) was added, stirred for 30 minutes, filtered, washed with N-hexane and dried to give the target compound 5-bromo-N- (3- (tert-butylsulfanyl) -2-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide (7.3 g, yield 71%). LCMS (ESI) m/z=447.0 [ m+h ] ] + 。
Sixth step: the compound 5-bromo-N- (3- (tert-butylsulfanyl) -2-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide (7 g,0.015 mol) was suspended in dilute hydrochloric acid (2N, 100 ml), heated under stirring at reflux for 20 hours, cooled to room temperature, filtered, and the resulting solid was washed with ice water and dried to give the target compound 5-bromo-N- (2-chloro-3-mercaptophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide (4.2 g, yield 72%). LCMS (ESI) m/z=390.9 [ m+h ]] + 。
Preparation example 2
Synthesis of tert-butyl ((1S, 2S) -8- (5-bromopyrazin-2-yl) -2-methyl-8-azaspiro [4.5] dec-1-yl) carbamate:
the first step: a solution of (3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (5.00 g,20.6mmol,2 HCl) in methylene chloride (50 mL) was cooled to 0deg.C with ice, triethylamine (12.4 g,122.7 mmol) and 2, 5-dibromopyrazine (4.90 g,20.6 mmol) were added and the mixture stirred at 25deg.C for 4 hours and TLC showed the reaction to end. Spin-drying to obtain the target compound (3S, 4S) -8- (5-bromopyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (11 g, crude product). Without further purification, it was used directly in the next reaction.
And a second step of: the crude product of the previous step (3S, 4S) -8- (5-bromopyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] ]Decane-4-amine (11 g) was dissolved in methylene chloride (50 mL), triethylamine (12.4 g,122.7 mmol) and di-tert-butyl dicarbonate (5.0 g,22.9 mmol) were added, and the reaction mixture was stirred overnight at room temperature and diluted with water (100 mL)Extracted with dichloromethane (3X 200 mL). The combined organic layers were washed with saturated brine (3×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was chromatographed on silica gel (n-hexane/ethyl acetate 10:1 to 3:1) to give the title compound ((1 s,2 s) -8- (5-bromopyrazin-2-yl) -2-methyl-8-azaspiro [ 4.5)]Tert-butyl decan-1-yl) carbamate (4.9 g, yield 55.8%). LCMS (ESI) m/z=427.1 [ m+h ]] + 。
Preparation example 3
Synthesis of tert-butyl (S) - (1 '- (5-bromopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) carbamate:
in a similar manner to preparation 2 (starting material was changed to (S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-amine dihydrochloride) to give the target compound (S) - (1 '- (5-bromopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) carbamic acid tert-butyl ester. LCMS (ESI) m/z=459.1 [ m+h ]] + 。
Preparation example 4
Synthesis of tert-butyl (R) - (1 '- (5-bromopyrazin-2-yl) -3H-spiro [ benzofuran-2, 4' -piperidin ] -3-yl) carbamate:
in a similar manner to preparation 2 (starting material was changed to (R) -3H-spiro [ benzofuran-2, 4' -piperidine) ]-3-amine dihydrochloride) to give the target compound (R) - (1 '- (5-bromopyrazin-2-yl) -3H-spiro [ benzofuran-2, 4' -piperidine)]-3-yl) carbamic acid tert-butyl ester. LCMS (ESI) m/z=461.1 [ m+h ]] + 。
Preparation example 5
Synthesis of tert-butyl (S) - (1 '- (5-bromopyrazin-2-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4' -piperidin ] -5-yl) carbamate:
in a similar manner to preparation 2 (starting material was changed to (S) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine tri-hydrochloride) to give the target compound (S) - (1' - (5-bromopyrazin-2-yl) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-yl) carbamic acid tert-butyl ester. LCMS (ESI) m/z=460.1 [ m+h ]] + 。
Preparation example 6
Synthesis of tert-butyl (S) - (1 '- (5-bromopyrazin-2-yl) -4, 6-dihydrospiro [ cyclopenta [ d ] thiazol-5, 4' -piperidin ] -6-yl) carbamate:
in a similar manner to preparation 2 (starting material was changed to (S) -4, 6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines]-6-amine dihydrochloride) to give the target compound (S) - (1' - (5-bromopyrazin-2-yl) -4, 6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines]-6-yl) carbamic acid tert-butyl ester. LCMS (ESI) m/z=468.0 [ m+h ]] + 。
Preparation example 7
Synthesis of (1- (5-bromopyrazin-2-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester:
2, 5-Dibromopyrazine (10 g,42.3 mmol) tert-butyl (4-methylpiperidin-4-yl) carbamate (9.0 g,42 mmol) was dissolved in dichloromethane (100 mL) and triethylamine (25 g,0.19 mol) was added and the resulting solution was stirred at room temperature for 16 hours, and thin layer chromatography showed the starting material had been consumed. The reaction mixture was diluted with water and extracted with dichloromethane (3X 100 mL). The combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (0 to 30% gradient of n-hexane/ethyl acetate) to give the title compound tert-butyl (1- (5-bromopyrazin-2-yl) -4-methylpiperidin-4-yl) carbamate (8.3 g)Yield 53%). LCMS (ESI) m/z=371.1 [ m+h ]] + 。
Preparation example 8
Synthesis of tert-butyl ((1- (5-bromopyrazin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamate:
in a manner similar to that of preparation 7 (starting material was changed to N- [ (4-methylpiperidin-4-yl) methyl)]Tert-butyl carbamate) to give the target compound tert-butyl ((1- (5-bromopyrazin-2-yl) -4-methylpiperidin-4-yl) methyl) carbamate. LCMS (ESI) m/z=385.1 [ m+h ]] + 。
Preparation example 9
Synthesis of tert-butyl (1- (5-bromo-6- ((tert-butoxycarbonyl) amino) pyrazin-2-yl) -4-methylpiperidin-4-yl) carbamate:
The first step: tert-butyl 3-bromo-6-chloropyrazin-2-amine (10.0 g,48.0 mmol) and (4-methylpiperidin-4-yl) carbamate (10.3 g,48.0 mmol) were dissolved in dimethylformamide (50 mL), N-diisopropylethylamine (25 g,0.19 mol) was added, the resulting solution was heated at 80℃for 5 hours with stirring, thin layer chromatography showed the starting material to have been consumed, cooled to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3X 200 mL). The combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the target compound tert-butyl 1- (6-amino-5-bromopyrazin-2-yl) -4-methylpiperidin-4-yl) carbamate (23 g, crude).
And a second step of: the crude t-butyl 1- (6-amino-5-bromopyrazin-2-yl) -4-methylpiperidin-4-yl) carbamate (23 g) obtained in the above step was dissolved in methylene chloride (100 mL), and 4-dimethylaminopyridine (0.6 g,4.9 mmol) and di-t-butyl dicarbonate (11.6 g,53 mmol) were added thereto and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3X 200 mL). The combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel chromatography (0 to 30% gradient of n-hexane/ethyl acetate) to give tert-butyl (1- (5-bromo-6- ((tert-butoxycarbonyl) amino) pyrazin-2-yl) -4-methylpiperidin-4-yl) carbamate (8.3 g, yield 35.4%) of the title compound. LCMS (ESI) m/z=486.1 [ m+h ] ] + 。
Preparation example 10
Synthesis of tert-butyl (3-bromo-6- (4- (((tert-butoxycarbonyl) amino) methyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) carbamate:
in a similar manner to preparation 9 (starting material was changed to N- [ (4-methylpiperidin-4-yl) methyl)]Tert-butyl carbamate) to give the target compound (3-bromo-6- (4- (((tert-butoxycarbonyl) amino) methyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) carbamic acid tert-butyl ester. LCMS (ESI) m/z=500.1 [ m+h ]] + 。
PREPARATION EXAMPLE 11
Synthesis of tert-butyl ((3S, 4S) -8- (5-bromo-6- ((tert-butoxycarbonyl) amino) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamate:
the first step: 3-bromo-6-chloropyrazin-2-amine (5.0 g,24.0 mmol), (3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine dihydrochloride (5.8 g,24.0 mmol) was dissolved in dimethylformamide (50 mL), N-diisopropylethylamine (25 g,0.19 mol) was added, the resulting solution was heated at 80℃for 5 hours, thin layer chromatography showed the starting material to have been consumed, cooled to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3X 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (3 s,4 s) -8- (6-amino-5-bromopyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (11 g, crude).
And a second step of: the crude (3S, 4S) -8- (6-amino-5-bromopyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5 ] compound obtained in the above step]Decane-4-amine (11 g) was dissolved in methylene chloride (100 mL), 4-dimethylaminopyridine (0.6 g,4.9 mmol) and di-tert-butyl dicarbonate (11.6 g,53 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3X 200 mL). The combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (0 to 40% gradient of n-hexane/ethyl acetate) to give the title compound ((3 s,4 s) -8- (5-bromo-6- ((tert-butoxycarbonyl) amino) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [ 4.5)]Tert-butyl decan-4-yl) carbamate (4.5 g, 34.6% yield). LCMS (ESI) m/z=542.1 [ m+h ]] + 。
Preparation example 12
Synthesis of tert-butyl (S) - (1 '- (5-bromopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) carbamate:
using a method similar to preparation 11 (starting material was changed to (S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-amine dihydrochloride) to give the target compound (S) - (1 '- (5-bromo-6- ((tert-butoxycarbonyl) amino) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) ]-1-yl) carbamic acid tert-butyl ester. LCMS (ESI) m/z=574.2 [ m+h] + 。
Preparation example 13
Synthesis of tert-butyl (R) - (1 '- (5-bromo-6- ((tert-butoxycarbonyl) amino) pyrazin-2-yl) -3H-spiro [ benzofuran-2, 4' -piperidin ] -3-yl) carbamate:
using a method similar to preparation 11 (starting material was changed to (R) -3H-spiro [ benzofuran-2, 4' -piperidine)]-3-amine dihydrochloride) to give the target compound (R) - (1 '- (5-bromo-6- ((tert-butoxycarbonyl) amino) pyrazin-2-yl) -3H-spiro [ benzofuran-2, 4' -piperidine)]-3-yl) carbamic acid tert-butyl ester. LCMS (ESI) m/z=576.1 [ m+h ]] + 。
PREPARATION EXAMPLE 14
Synthesis of tert-butyl (S) - (1 '- (5-bromo-6- ((tert-butoxycarbonyl) amino) pyrazin-2-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4' -piperidin ] -5-yl) carbamate:
using a method similar to preparation 11 (starting material was changed to (S) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-amine tri-hydrochloride) to give the target compound (S) - (1' - (5-bromo-6- ((tert-butoxycarbonyl) amino) pyrazin-2-yl) -5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-5-yl) carbamic acid tert-butyl ester. LCMS (ESI) m/z=575.1 [ m+h ]] + 。
Preparation example 15
Synthesis of tert-butyl ((3S, 4S) -8- (5-bromo-3- (hydroxymethyl) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamate:
The first step: to a solution of methyl 3, 6-dibromopyrazine-2-carboxylate (3.5 g,11.8 mmol) in dichloromethane (100 mL) was added N, N-diisopropylethylamine (7.74 g, 60 mmol) and (3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine dihydrochloride (2.0 g,11.76 mmol), and the mixture was stirred at room temperature for 16 h. The disappearance of starting material was checked as a thin layer, the reaction mixture was diluted with water and extracted with dichloromethane (3X 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound methyl 3- (4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6-bromopyrazine-2-carboxylate (7.5 g, crude).
And a second step of: the 3- (4-)Amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decane-8-yl) -6-bromopyrazine-2-carboxylic acid methyl ester (7.5 g) was dissolved in methylene chloride (100 mL), N-diisopropylethylamine (7.74 g, 60 mmol) and di-tert-butyl dicarbonate (2.83 g,13 mmol) were added, stirring was continued at room temperature for 4 hours, and thin layer detection showed new spot formation and disappearance of intermediate. The reaction mixture was diluted with 100mL of water, the mixture was extracted with dichloromethane (3X 100 mL), the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a brown oil which was chromatographed on silica gel (0 to 40% gradient of n-hexane/ethyl acetate) to give the title compound 6-bromo-3- ((3S, 4S) -4- ((t-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5] ]Decane-8-yl) pyrazine-2-carboxylic acid methyl ester (3.5 g, yield 61%). LCMS (ESI) m/z=485.1 [ m+h ]] + 。
And a third step of: the compound 6-bromo-3- ((3S, 4S) -4- ((tert-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-8-yl) pyrazine-2-carboxylic acid methyl ester (3 g,6.2 mmol) was dissolved in dichloromethane (50 mL), DIBAL-H (1M n-hexane solution, 12.4 mL) was slowly added at-60℃and stirred at-60℃for 30 minutes, naturally warmed to room temperature, cooled again to-60℃after completion of the reaction, dichloromethane (50 mL) and saturated potassium tartrate aqueous solution (10 mL) were added to the reaction solution, stirred overnight and naturally warmed to room temperature. The product was extracted with dichloromethane and the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to give the crude product which was chromatographed on silica gel (0 to 50% gradient of n-hexane/ethyl acetate) to give the title compound ((3 s,4 s) -8- (5-bromo-3- (hydroxymethyl) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-4-yl) carbamic acid tert-butyl ester (1.27 g, yield 45%). LCMS (ESI) m/z=459.1 [ m+h ]] + 。
PREPARATION EXAMPLE 16
Synthesis of tert-butyl ((3S, 4S) -8- (5-bromo-3- (hydroxymethyl) -6-methylpyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamate:
Use and preparation example 15 (starting material was changed to ethyl 3, 6-dibromo-5-methylpyrazine-2-carboxylate) to give the title compound ((3S, 4S) -8- (5-bromo-3- (hydroxymethyl) -6-methylpyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-4-yl) carbamic acid tert-butyl ester. LCMS (ESI) m/z=471.1 [ m+h ]] + 。
Preparation example 17
Synthesis of tert-butyl ((3S, 4S) -8- (6-bromo-1, 2, 4-triazin-3-yl) -3-methyl-2-oxo-8-azaspiro [4.5] dec-4-yl) carbamate:
the title compound ((3S, 4S) -8- (6-bromo-1, 2, 4-triazin-3-yl) -3-methyl-2-oxo-8-azaspiro [4.5] was obtained by a preparation method similar to that of preparation 2 (starting material was changed to 3, 6-dibromo-1, 2, 4-triazine)]Dec-4-yl) carbamic acid tert-butyl ester. LCMS (ESI) m/z=428.1 [ m+h ]] + 。
Example 1
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the first step: 5-bromo-N- (2-chloro-3-mercaptophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide (3.9 g,0.01 mol) and ((1S, 2S) -8- (5-bromopyrazin-2-yl) -2-methyl-8-azaspiro [ 4.5)]Decyl-1-yl) carbamic acid tert-butyl ester (4.26 g,0.01 mol) is suspended in 1, 4-dioxane (50 mL), N-diisopropylethylamine (2.6 g,0.02 mol) is added, the resulting mixture is refluxed at 100℃for 12 hours, thin layer chromatography detection shows the disappearance of one starting material, spin-drying, and the resulting crude product is chromatographed on silica gel column (0 to 50% gradient of N-hexane/ethyl acetate) to give the title compound ((3S, 4S) -8- (5- ((3- (5-bromo-4-hydroxy-1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide) -2-chlorophenyl) thio) pyrazine-2- Phenyl) -3-methyl-2-oxa-8-azaspiro [4.5]Decane-4-yl) carbamic acid tert-butyl ester (4.6 g, yield 63%). LCMS (ESI) m/z=737.1 [ m+h ]] + 。
And a second step of: the compound ((3S, 4S) -8- (5- ((3- (5-bromo-4-hydroxy-1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamido) -2-chlorophenyl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamic acid tert-butyl ester (0.5 g,0.68 mmol) was suspended in a mixed solvent of ethanol and water (20 mL,5:1 volume ratio), 4-hydroxy-3-methoxyphenylboronic acid (140 mg,0.83 mmol), potassium carbonate (0.5 g,3.6 mmol) and 1,1' -bis (diphenylphosphino) ferrocene) palladium dichloride (50 mg,0.068 mmol) were added, stirred, the reaction system was purged three times with nitrogen, heated to 80℃and reacted for 3 hours, cooled to room temperature. Spin-drying to give the target compound ((3 s,4 s) -8- (5- ((2-chloro-3- (4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide) phenyl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamic acid tert-butyl ester (1.3 g, crude).
And a third step of: crude ((3S, 4S) -8- (5- ((2-chloro-3- (4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide) phenyl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [ 4.5) ]Deck-4-yl) carbamic acid tert-butyl ester (1.3 g) was dissolved in methylene chloride (50 mL), trifluoroacetic acid (20 mL) was added under ice-bath cooling, stirring was continued at room temperature overnight, and the crude product was obtained by spin-drying. 50mL of water, 50mL of aqueous ammonia, dichloromethane extraction, separation of the dichloromethane layer, drying, and concentration to dryness were added, and the resulting oil was separated using a preparative plate to give the title compound 1 (220 mg, yield 47.8%). 1 H NMR(400MHz,DMSO-d 6 ):δ10.8(s,1H),8.63(s,1H),8.44(s,1H),8.26(s,1H),7.93-7.90(m,2H),6.91-6.85(m,3H),6.79(m,1H),5.45(s,1H),4.24(m,2H),4.09-4.05(m,1H),4.03(s,3H),3.92-3.80(m,2H),3.68-3.66(m,1H),3.49-3.42(m,3H),3.12(s,3H),2.02-1.97(m,1H),1.78-1.45(m,4H),1.23(d,3H)；LCMS(ESI):m/z＝679.2[M+H] + 。
Example 2
Preparation of (R) -N- (3- ((5- (3-amino-3H-spiro [ benzofuran-2, 4 '-piperidine ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide:
the title compound 2 (238 mg, yield 49.2%) was obtained in a similar manner to example 1. LCMS (ESI) m/z=713.1 [ m+h ]] + 。
Example 3
Preparation of (S) -N- (3- ((5- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide:
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the title compound 3 (149 mg, yield 31%) was obtained by a similar method to example 1. LCMS (ESI) m/z=711.2 [ m+h ]] + 。
Example 4
Preparation of (S) -N- (3- ((5- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1- (methyl-d 3) -2-oxo-1, 2-dihydropyridine-3-carboxamide:
The title compound 4 (315 mg, yield 65%) was obtained by a method similar to example 1. LCMS (ESI) m/z=714.2 [ m+h ]] + 。
Example 5
Preparation of (S) -N- (3- ((5- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide:
the title compound 5 (227 mg, yield 47%) was obtained in a similar manner to example 1. LCMS (ESI) m/z=712.2 [ m+h ]] + 。
Example 6
Preparation of (S) -N- (3- ((5- (6-amino-4, 6-dihydrospiro [ cyclopenta [ d ] thiazol-5, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide:
the title compound 6 (253 mg, yield 52%) was obtained by a method similar to example 1. LCMS (ESI) m/z=718.1 [ m+h ]] + 。
Example 7
Preparation of N- (3- ((5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide:
the title compound 7 (242 mg, yield 56%) was obtained by a method similar to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ10.8(s,1H),8.63(s,1H),8.44(s,1H),8.26(s,1H),7.93-7.90(m,2H),6.91-6.85(m,3H),6.79(dd,1H),5.45(s,1H),4.25(br,2H),4.03(s,3H),3.71-3.51(m,4H),3.12(s,3H),2.06-2.02(m,4H),1.20(s,3H)；LCMS(ESI):m/z＝639.2[M+H] + 。
Example 8
Preparation of N- (3- ((5- (4- (aminomethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide:
The title compound 8 (211 mg, yield 49%) was obtained by a method similar to example 1. LCMS (ESI) m/z=637.1 [ m+h ]] + 。
Example 9
Preparation of (S) -N- (3- ((5- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-1-methyl-6-carbonyl-1, 6-dihydro- [3,4' -bipyridine ] -5-carboxamide:
the title compound 9 (167 mg, yield 37%) was obtained in a similar manner to example 1. LCMS (ESI) m/z=666.2 [ m+h ]] + 。
Example 10
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-1-methyl-6-carbonyl-1, 6-dihydro- [3,4' -bipyridine ] -5-carboxamide:
the title compound 10 (236 mg, yield 55%) was obtained by a method similar to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ10.8(s,1H),8.77(m,2H),8.53(s,1H),8.44(s,1H),8.26(s,1H),8.10(m,2H),7.93-7.90(m,2H),6.79(d,1H),4.24(m,2H),4.09-4.05(m,1H),3.92-3.80(m,2H),3.68-3.66(m,1H),3.49-3.42(m,3H),3.12(s,3H),2.02-1.97(m,1H),1.78-1.45(m,4H),1.23(d,3H)；LCMS(ESI):m/z＝634.1[M+H] + 。
Example 11
Preparation of (S) -N- (3- ((5- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4' -piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-1-methyl-6-carbonyl-1, 6-dihydro- [3,4' -bipyridine ] -5-carboxamide:
the title compound 11 (171 mg, yield 37.8%) was obtained by a method similar to example 1. LCMS (ESI) m/z=667.1 [ m+h ]] + 。
Example 12
Preparation of N- (3- ((5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-1-methyl-6-carbonyl-1, 6-dihydro- [3,4' -bipyridine ] -5-carboxamide:
The title compound 12 (164 mg, yield 42%) was obtained by a method similar to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ10.8(s,1H),8.77(m,2H),8.53(s,1H),8.44(s,1H),8.26(s,1H),8.10(m,2H),7.93-7.90(m,2H),6.79(d,1H),4.25(br,2H),3.71-3.51(m,4H),3.12(s,3H),2.06-2.02(m,4H),1.20(s,3H)；LCMS(ESI):m/z＝578.1[M+H] + 。
Example 13
Preparation of (R) -N- (3- ((5- (3-amino-3H-spiro [ benzofuran-2, 4' -piperidine ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-1-methyl-6-carbonyl-1, 6-dihydro- [3,4' -bipyridine ] -5-carboxamide:
the title compound 13 (208 mg, yield 46%) was obtained by a method similar to example 1. LCMS (ESI) m/z=668.1 [ m+h ]] + 。
Example 14
Preparation of N- (3- ((5- (4- (aminomethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-1-methyl-6-carbonyl-1, 6-dihydro- [3,4' -bipyridine ] -5-carboxamide:
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the title compound 14 (217 mg, yield 54%) was obtained in a similar manner to example 1. LCMS (ESI) m/z=592.1 [ m+h ]] + 。
Example 15
Preparation of N- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 15 (212 mg, yield 49%) was obtained in a similar manner to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ10.8(s,1H),8.63(s,1H),8.26(s,1H),7.93-7.90(m,2H),6.92-6.85(m,3H),6.79(dd,1H),5.45(s,1H),4.25(br,4H),4.03(s,3H),3.72-3.53(m,4H),3.12(s,3H),2.08-2.02(m,4H),1.20(s,3H)；LCMS(ESI):m/z＝638.1[M+H] + 。
Example 16
Preparation of N- (3- ((3-amino-5- (4- (aminomethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
The title compound 16 (203 mg, yield 46%) was obtained by a method similar to example 1. LCMS (ESI) m/z=652.2 [ m+h] + 。
Example 17
Preparation of N- (3- ((3-amino-5- (4- (1-aminoethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 17 (239 mg, yield 53%) was obtained by a method similar to example 1. LCMS (ESI) m/z=666.2 [ m+h ]] + 。
Example 18
Preparation of N- (3- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 18 (225 mg, yield 47.8%) was obtained by a method similar to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ10.8(s,1H),8.63(s,1H),8.26(s,1H),7.93-7.90(m,2H),6.91-6.85(m,3H),6.79(dd,1H),5.45(s,1H),4.24(m,2H),4.10-4.05(m,1H),4.03(s,3H),3.89-3.80(m,2H),3.69-3.66(m,1H),3.53-3.42(m,3H),3.12(s,3H),2.02-1.97(m,1H),1.81-1.45(m,4H),1.23(d,3H)；LCMS(ESI):m/z＝694.2[M+H] + 。
Example 19
Preparation of (S) -N- (3- ((3-amino-5- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 19 (202 mg, yield 41%) was obtained by a method similar to example 1. LCMS (ESI) m/z=726.2 [ m+h ] ] + 。
Example 20
Preparation of N- (3- ((3-amino-5- (4- (aminomethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1- (methyl-d 3) -2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 20 (151 mg, yield 34%) was obtained by a method similar to example 1. LCMS (ESI) m/z=655.2 [ m+h ]] + 。
Example 21
Preparation of (S) -N- (3- ((3-amino-5- (6-amino-4, 6-dihydrospiro [ cyclopenta [ d ] thiazol-5, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 21 (283 mg, yield 57%) was obtained by a similar method to example 1. LCMS (ESI) m/z=733.1 [ m+h ]] + 。
Example 22
Preparation of (S) -N- (3- ((3-amino-5- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 22 (238 mg, yield 48.3%) was obtained in a similar manner to example 1. LCMS (ESI) m/z=727.2 [ m+h ]] + 。
Example 23
Preparation of (S) -N- (3- ((5- (6-amino-4, 6-dihydrospiro [ cyclopenta [ d ] thiazol-5, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (3-hydroxy-5-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
The title compound 23 (224 mg, yield 46%) was obtained by a method similar to example 1. LCMS (ESI) m/z=718.1 [ m+h ]] + 。
Example 24
Preparation of (S) -N- (3- ((5- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (3-hydroxy-5-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 24 (207 mg, yield 43%) was obtained by a method similar to example 1. LCMS (ESI) m/z=711.2 [ m+h ]] + 。
Example 25
Preparation of (S) -N- (3- ((5- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (3-hydroxy-5-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 25 (203 mg, yield 42%) was obtained by a method similar to example 1. LCMS (ESI) m/z=712.2 [ m+h ]] + 。
Example 26
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (3-hydroxy-5-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
use and examples1 to give the objective compound 26 (175 mg, yield 38%). 1 H NMR(400MHz,DMSO-d 6 ):δ11.8(s,1H),9.8(s,1H),8.63(s,1H),8.44(s,1H),8.26(s,1H),7.93-7.90(m,2H),6.79(m,1H),6.69-6.61(m,2H),6.41(d,1H),4.45(m,2H),4.09-4.05(m,1H),3.92-3.80(m,2H),3.79(s,3H),3.68-3.66(m,1H),3.49-3.42(m,3H),3.12(s,3H),2.02-1.97(m,1H),1.78-1.45(m,4H),1.23(d,3H)；LCMS(ESI):m/z＝679.2[M+H] + 。
Example 27
Preparation of N- (3- ((5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (3-hydroxy-5-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 27 (245 mg, yield 58%) was obtained by a similar method to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ11.8(s,1H),9.8(s,1H),8.60(s,1H),8.44(s,1H),8.26(s,1H),7.93-7.90(m,2H),6.79-6.73(m,1H),6.69-6.61(m,2H),6.41(d,1H),4.25(br,2H),4.03(s,3H),3.71-3.51(m,4H),3.12(s,3H),2.06-2.02(m,4H),1.20(s,3H)；LCMS(ESI):m/z＝623.1[M+H] + 。
Example 28
Preparation of N- (3- ((5- (4- (aminomethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (3-hydroxy-5-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 28 (242 mg, yield 56%) was obtained by a method similar to example 1. LCMS (ESI) m/z=637.1 [ m+h ]] + 。
Example 29
Preparation of (S) -N- (3- ((3-amino-5- (6-amino-4, 6-dihydrospiro [ cyclopenta [ d ] thiazol-5, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (3-hydroxy-5-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 29 (229 mg, yield 46%) was obtained by a similar method to example 1. LCMS (ESI) m/z=733.1 [ m+h ]] + 。
Example 30
Preparation of (S) -N- (3- ((3-amino-5- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (3-hydroxy-5-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
The title compound 30 (172 mg, yield 35%) was obtained by a method similar to example 1. LCMS (ESI) m/z=726.2 [ m+h ]] + 。
Example 31
Preparation of N- (3- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (3-hydroxy-5-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 31 (216 mg, yield 46%) was obtained by a method similar to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ11.8(s,1H),9.8(s,1H),8.44(s,1H),8.26(s,1H),7.93-7.90(m,2H),6.79(m,1H),6.69-6.61(m,2H),6.41(d,1H),4.52(br,2H),4.45(m,2H),4.09-4.05(m,1H),3.92-3.80(m,2H),3.79(s,3H),3.68-3.66(m,1H),3.49-3.42(m,3H),3.12(s,3H),2.02-1.97(m,1H),1.78-1.45(m,4H),1.23(d,3H)；LCMS(ESI):m/z＝694.2[M+H] + 。
Example 32
Preparation of (S) -N- (3- ((3-amino-5- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (3-hydroxy-5-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 32 (242 mg, yield 49%) was obtained by a method similar to example 1. LCMS (ESI) m/z=727.2 [ m+h ]] + 。
Example 33
Preparation of N- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (3-hydroxy-5-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 33 (202 mg, yield 46.8%) was obtained by a method similar to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ11.8(s,1H),9.8(s,1H),8.60(s,1H),8.23(s,1H),7.93-7.90(m,2H),6.79-6.73(m,1H),6.69-6.61(m,2H),6.41(d,1H),4.30(br,2H),4.25(br,2H),4.03(s,3H),3.71-3.51(m,4H),3.12(s,3H),2.06-2.02(m,4H),1.20(s,3H)；LCMS(ESI):m/z＝637.1[M+H] + 。
Example 34
Preparation of N- (3- ((3-amino-5- (4- (aminomethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (3-hydroxy-5-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 34 (203 mg, yield 46%) was obtained by a method similar to example 1. LCMS (ESI): m/z=652.2[M+H] + 。
Example 35
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- (3-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 35 (212 mg, yield 47%) was obtained by a method similar to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ11.8(s,1H),8.53(s,1H),8.44(s,1H),8.26(s,1H),7.93-7.90(m,2H),7.61(m,1H),7.45(m,3H),6.79(m,1H),4.45(m,2H),4.09-4.05(m,1H),3.92-3.80(m,2H),3.68-3.66(m,1H),3.49-3.42(m,3H),3.12(s,3H),2.02-1.97(m,1H),1.78-1.45(m,4H),1.23(d,3H)；LCMS(ESI):m/z＝667.1[M+H] + 。
Example 36
Preparation of (S) -N- (3- ((5- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- (3-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 36 (246 mg, yield 52%) was obtained by a similar method to example 1. LCMS (ESI) m/z=699.1 [ m+h ]] + 。
Example 37
Preparation of (S) -N- (3- ((5- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- (3-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
By analogy with example 1The method gave the objective compound 37 (194 mg, yield 41%). LCMS (ESI) m/z=700.1 [ m+h ]] + 。
Example 38
Preparation of (R) -N- (3- ((5- (3-amino-3H-spiro [ benzofuran-2, 4 '-piperidine ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- (3-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 38 (214 mg, yield 45%) was obtained by a method similar to example 1. LCMS (ESI) m/z=701.1 [ m+h ]] + 。
Example 39
Preparation of N- (3- ((5- (4- (aminomethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- (3-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 39 (161 mg, yield 38%) was obtained by a method similar to example 1. LCMS (ESI) m/z=625.1 [ m+h ]] + 。
Example 40
Preparation of N- (3- ((5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- (3-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 40 (224 mg, yield 54%) was obtained by a method similar to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ11.2(s,1H),8.50(s,1H),8.43(s,1H),8.22(s,1H),7.93-7.90(m,2H),7.61(m,1H),7.45(m,3H),6.79(m,1H),4.25(br,2H),3.71-3.51(m,4H),3.12(s,3H),2.06-2.02(m,4H),1.20(s,3H)；LCMS(ESI):m/z＝611.1[M+H] + 。
Example 41
Preparation of N- (3- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- (3-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
The title compound 41 (194 mg, yield 42%) was obtained by a method similar to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ10.8(s,1H),8.53(s,1H),8.22(s,1H),7.93-7.90(m,2H),7.61(m,1H),7.45(m,3H),6.79(m,1H),4.45(m,2H),4.09-4.05(m,1H),3.92-3.80(m,2H),3.68-3.66(m,1H),3.49-3.42(m,3H),3.11(s,3H),2.02-1.97(m,1H),1.78-1.45(m,4H),1.25(d,3H)；LCMS(ESI):m/z＝682.1[M+H] + 。
Example 42
Preparation of (S) -N- (3- ((3-amino-5- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- (3-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 42 (276 mg, yield 57%) was obtained by a method similar to example 1. LCMS (ESI) m/z=714.1 [ m+h ]] + 。
Example 43
Preparation of (S) -N- (3- ((3-amino-5- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- (3-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 43 (238 mg, yield 49%) was obtained in a similar manner to example 1. LCMS (ESI) m/z=715.1 [ m+h ]] + 。
Example 44
Preparation of N- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- (3-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 44 (204 mg, yield 48%) was obtained in a similar manner to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ11.2(s,1H),8.50(s,1H),8.22(s,1H),7.93-7.90(m,2H),7.61(m,1H),7.45(m,3H),6.79(m,1H),4.45(br,2H),4.25(br,2H),3.71-3.51(m,4H),3.12(s,3H),2.06-2.02(m,4H),1.20(s,3H)；LCMS(ESI):m/z＝626.1[M+H] + 。
Example 45
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6- (hydroxymethyl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- (3-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
The title compound 45 (146 mg, yield 31%) was obtained by a similar method to example 1. LCMS (ESI) m/z=697.1 [ m+h ]] + 。
Example 46
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6- (hydroxymethyl) -3-methylpyrazin-2-yl) thio) -2-chlorophenyl) -5- (3-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 46 (159 mg, 33% yield) was obtained in a similar manner to example 1. LCMS (ESI) m/z=711.1 [ m+h ]] + 。
Example 47
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- ((3-chlorophenyl) ethynyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the first step: 5-bromo-N- (2-chloro-3-mercaptophenyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide (3.9 g,0.01 mol) and ((1S, 2S) -8- (5-bromopyrazin-2-yl) -2-methyl-8-azaspiro [ 4.5)]Decyl-1-yl) carbamic acid tert-butyl ester (4.26 g,0.01 mol) is suspended in 1, 4-dioxane (50 mL), N-diisopropylethylamine (2.6 g,0.02 mol) is added, the resulting mixture is refluxed at 100℃for 12 hours, thin layer chromatography detection shows the disappearance of one starting material, spin-drying, and the crude product obtained is separated by silica gel column chromatography (0 to 50% gradient of N-hexane/ethyl acetate) to give the target compound ((3S, 4S) -8- (5- ((3- (5-bromo-4-hydroxy-1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide) -2-chlorophenyl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5 ]Decane-4-yl) carbamic acid tert-butyl ester (4.6 g, yield 63%). LCMS (ESI) m/z=737.1 [ m+h ]] + 。
And a second step of: tert-butyl ((3 s,4 s) -8- (5- ((3- (5-bromo-4-hydroxy-1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamido) -2-chlorophenyl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamate (0.5 g,0.68 mmol) was dissolved in dimethylformamide (20 mL), 1-chloro-3-ethynylbenzene (277 mg,2.04 mmol), N-diisopropylethylamine (0.44 g,3.4 mmol), cuprous iodide (13 mg,0.068 mmol) and 1,1' -bis (diphenylphosphino) ferrocene) dichloropalladium (50 mg,0.068 mmol) were added, and after stirring, the reaction system was replaced with nitrogen three times and heated to 80 ℃ for 3 hours and cooled to room temperature. The title compound ((3S, 4S) -8- (5- ((2-chloro-3- (5- ((3-chlorophenyl) ethynyl) -4-hydroxy-1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide) phenyl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) carbamic acid tert-butyl ester crude (0.9 g, crude) was obtained by spin drying.
And a third step of: crude ((3S, 4S) -8- (5- ((2-chloro-3- (5- ((3-chlorophenyl) ethynyl) -4-hydroxy-1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide) phenyl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5 ]Deck-4-yl) carbamic acid tert-butyl ester (0.9 g) was dissolved in methylene chloride (50 mL), trifluoroacetic acid (20 mL) was added under ice-bath cooling, stirring was continued at room temperature overnight, and the crude product was obtained by spin-drying. 50mL of water, 50mL of aqueous ammonia, dichloromethane extraction, separation of the dichloromethane layer, drying, and concentration to dryness were added, and the resulting oil was separated using a preparative plate to give the title compound 47 (220 mg, yield 47%). 1 H NMR(400MHz,DMSO-d 6 ):δ9.8(s,1H),8.48(s,1H),8.44(s,1H),8.26(s,1H),7.93-7.90(m,2H),7.76(s,1H),7.64-7.56(m,2H),7.55-7.46(m,1H),6.79(m,1H),6.37-6.23(m,1H),4.45(m,2H),4.09-4.05(m,1H),3.92-3.80(m,2H),3.68-3.66(m,1H),3.49-3.42(m,3H),3.10(s,3H),2.02-1.97(m,1H),1.78-1.45(m,4H),1.23(d,3H)；LCMS(ESI):m/z＝691.1[M+H] + 。
Example 48
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- ((4-hydroxy-3-methoxyphenyl) ethynyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 48 (200 mg, yield 42%) was obtained by a method similar to example 47. 1 H NMR(400MHz,DMSO-d 6 ):δ10.8(s,1H),8.47(s,1H),8.44(s,1H),8.26(s,1H),7.93-7.90(m,2H),6.91-6.85(m,3H),6.79(m,1H),5.45(s,1H),4.24(m,2H),4.10-4.05(m,1H),4.03(s,3H),3.89-3.80(m,2H),3.69-3.66(m,1H),3.53-3.42(m,3H),3.12(s,3H),2.02-1.97(m,1H),1.81-1.45(m,4H),1.23(d,3H)；LCMS(ESI):m/z＝703.2[M+H] + 。
Example 49
Preparation of N- (3- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- ((3-chlorophenyl) ethynyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 49 (182 mg, yield 38%) was obtained by a method similar to example 47. LCMS (ESI) m/z=706.1 [ m+h ]] + 。
Example 50
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- ((3-hydroxy-5-methoxyphenyl) ethynyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
The title compound 50 (186 mg, 39% yield) was obtained in a similar manner to example 47. LCMS (ESI) m/z=703.2 [ m+h] + 。
Example 51
Preparation of N- (3- ((5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- ((3-chlorophenyl) ethynyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 51 (198 mg, yield 46%) was obtained by a similar method to example 47. 1H NMR (400 MHz,DMSO-d 6 ):δ9.8(s,1H),8.48(s,1H),8.44(s,1H),8.26(s,1H),7.93-7.90(m,2H),7.76(s,1H),7.64-7.56(m,2H),7.55-7.46(m,1H),6.79(m,1H),6.37-6.23(m,1H),4.25(br,2H),3.71-3.51(m,4H),3.12(s,3H),2.06-2.02(m,4H),1.20(s,3H)；LCMS(ESI):m/z＝635.1[M+H] + 。
example 52
Preparation of N- (3- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- ((4-hydroxy-3-methoxyphenyl) ethynyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 52 (209 mg, yield 43%) was obtained by a method similar to example 47. LCMS (ESI) m/z=718.2 [ m+h ]] + 。
Example 53
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-5- (pyridin-4-ylethynyl) -1, 2-dihydropyridine-3-carboxamide:
the title compound 53 (160 mg, yield 36%) was obtained by a method similar to example 47. 1 H NMR(400MHz,DMSO-d 6 ):δ10.5(s,1H),8.62-8.60(m,2H),8.47(s,1H),8.44(s,1H),8.26(s,1H),7.93-7.90(m,2H),7.42-7.40(m,2H),6.79(m,1H),4.45(m,2H),4.09-4.05(m,1H),3.92-3.80(m,2H),3.68-3.66(m,1H),3.49-3.42(m,3H),3.10(s,3H),2.02-1.97(m,1H),1.78-1.45(m,4H),1.23(d,3H)；LCMS(ESI):m/z＝658.1[M+H] + 。
Example 54
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- ((3-fluorophenyl) ethynyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
/>
the title compound 54 (201 mg, yield 44%) was obtained by a method similar to example 47. 1 H NMR(400MHz,DMSO-d 6 ):δ9.8(s,1H),8.48(s,1H),8.44(s,1H),8.26(s,1H),7.93-7.90(m,2H),7.38-7.21(m,3H),7.11-7.04(m,1H),6.79(m,1H),4.45(m,2H),4.09-4.05(m,1H),3.92-3.80(m,2H),3.68-3.66(m,1H),3.49-3.42(m,3H),3.10(s,3H),2.02-1.97(m,1H),1.78-1.45(m,4H),1.23(d,3H)；LCMS(ESI):m/z＝675.1[M+H] + 。
Example 55
Preparation of (S) -N- (3- ((5- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5- (cyclopropylethynyl) -4-hydroxy-1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 55 (142 mg, yield 32%) was obtained by a method similar to example 47. LCMS (ESI) m/z=654.2 [ m+h] + 。
Example 56
Preparation of N- (3- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-1-methyl-2-carbonyl-5- (pyridin-4-ylethynyl) -1, 2-dihydropyridine-3-carboxamide:
the title compound 56 (160 mg, yield 35%) was obtained by a method similar to example 47. 1 H NMR(400MHz,DMSO-d 6 ):δ10.5(s,1H),8.62-8.60(m,2H),8.47(s,1H),8.22(s,1H),7.93-7.90(m,2H),7.42-7.40(m,2H),6.79(m,1H),4.45(m,2H),4.09-4.05(m,1H),3.92-3.80(m,2H),3.68-3.66(m,1H),3.49-3.42(m,3H),3.10(s,3H),2.02-1.97(m,1H),1.78-1.45(m,4H),1.23(d,3H)；LCMS(ESI):m/z＝673.2[M+H] + 。
Example 57
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6- (hydroxymethyl) -3-methylpyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-1-methyl-6-carbonyl-1, 6-dihydro- [3,4' -bipyridine ] -5-carboxamide:
The title compound 57 (239 mg, yield 52%) was obtained by a similar method to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ10.5(s,1H),8.62-8.60(m,2H),8.48(s,1H),8.13-8.10(m,2H),7.93-7.90(m,2H),6.79(m,1H),4.65(s,2H),4.45(m,2H),4.38-4.26(m,1H),3.88(m,2H),3.30-3.15(m,4H),3.10(s,3H),2.68(s,1H),2.49(s,3H),2.02-1.65(m,4H),1.29(d,3H)；LCMS(ESI):m/z＝678.2[M+H] + 。
Example 58
Preparation of N- (3- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -1,2, 4-triazin-6-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 58 (160 mg, yield 34.7%) was obtained by a method similar to example 1. 1 H NMR(400MHz,DMSO-d 6 ):δ10.8(s,1H),8.63(s,1H),7.93-7.90(m,2H),6.91-6.85(m,3H),6.79(dd,1H),5.45(s,1H),4.24(m,2H),4.06(m,3H),4.03(s,3H),3.68(m,1H),3.60(m,2H),3.48(m,1H),3.12(s,3H),2.92(m,1H),1.76(m,1H),1.66(m,1H),1.58-1.45(m,2H),1.07(d,3H)；LCMS(ESI):m/z＝680.2[M+H] + 。
Example 59
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6- (hydroxymethyl) -3-methylpyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 59 (176 mg, yield 36%) was obtained by a method similar to example 1. LCMS (ESI) m/z=723.2 [ m+h] + 。
Example 60
Preparation of N- (3- ((5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6- (hydroxymethyl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-5- (4-hydroxy-3-methoxyphenyl) -1-methyl-2-carbonyl-1, 2-dihydropyridine-3-carboxamide:
the title compound 60 (202 mg, yield 42%) was obtained by a method similar to example 1. LCMS (ESI) m/z=709.2 [ m+h ] ] + 。
Biological test evaluation
Test example 1: determination of the inhibitory Effect of Compounds on SHP2 kinase Activity
The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
The purpose of this test is to measure the ability of a compound to inhibit the allosteric activity of the SHP2 full-length protein.
Experimental instrument:
centrifuge (5810R) was purchased from Eppendorf corporation, pipettor from Eppendor Rainin corporation, and microplate reader from BioTek corporation, U.S.A., model number SynergyHl full function microplate reader.
The experimental method comprises the following steps:
in vitro SHP2 activity assays were performed using the homogeneous full-length SHP-2 enzymology assay kit (BPS Bioscience, # 79330). First, 18. Mu.L of the reaction mixture was added to 96-well low adsorption microwell plates (NUNC, # 267342), namely, after centrifugation at 1000rpm for 1 min with a final concentration of 1X reaction buffer containing 0.5. Mu.L of SHP-2 activating polypeptide and 5mM of DTT.1000rpm, 5. Mu.L of DMSO (final DMSO content: 1%V/V) was added to each well, the test compound was dissolved in DMSO to lmM, three-fold serial dilutions were performed, 10 concentrations were performed, the final concentration of the reaction system was ranging from 1. Mu.M to 0.05 nM), SHP2 was diluted in 1X reaction buffer to a final concentration of 0.06nM, and then added to the reaction microwell plates, 2. Mu.L of each well was set up on the reaction plates, and after centrifugation, the reaction mixture was incubated at room temperature for 60 min.
After the incubation, 25. Mu.L of substrate working solution containing SHP2 substrate at a final concentration of 10. Mu.M and 5mM DTT was added to each well, and incubation was continued at room temperature for 30 minutes after centrifugation. After the reaction, the excitation wavelength of 340mm, the emission wavelength of 455nM and the gain value of 75 were set on a Synergy Hl full-function microplate reader (Biotek).
The experimental data processing method comprises the following steps:
calculating percent inhibition ratio data of wells treated with the compound (% inhibition ratio = 100-f (test compound-Min mean y (Max mean-Min mean)) (X100) from positive control wells (DMSO control wells) and negative control wells (no kinase added) on the reaction plate based on the values of total active control and total inhibitory control as Max and Min 50 Values.
Conclusion of experiment:
from the above schemes, it was found that the example compounds of the present invention showed the biological activities in the SHP2 kinase activity assay as shown in Table 1 below. Wherein "A" represents IC 50 Less than 10nM: "B" means 10 < IC 50 Less than or equal to 100nM; "C" means 100 < IC 50 Less than or equal to 1000nM; "D" means 1000nM < IC 50 。
IC of Table 1 Compounds inhibiting SHP2 50 Value:
examples IC 50 Examples IC 50 Examples IC 50
1 A 21 A 41 A
2 A 22 A 42 A
3 A 23 B 43 A
4 A 24 B 44 A
5 A 25 A 45 A
6 A 26 A 46 A
7 B 27 B 47 B
8 B 28 B 48 B
9 A 29 B 49 A
10 A 30 B 50 B
11 A 31 A 51 A
12 B 32 A 52 A
13 A 33 A 53 A
14 B 34 A 54 A
15 A 35 A 55 A
16 B 36 A 56 A
17 A 37 A 57 A
18 A 38 A 58 A
19 A 39 A 59 B
20 A 40 A 60 B
Although the invention has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes can be made thereto without departing from the spirit and scope of the invention. The scope of the invention is not limited by the detailed description set forth above, but rather is to be attributed to the claims.

Claims (20)

1. A compound of formula (I) as shown below, stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically-labeled analogues thereof:
wherein X is N, CR X ；R X Is H, deuterium, halogen, -CN, -NO 2 、-NH 2 -OH or optionally substituted: c (C) 1-3 An alkyl group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
q is optionally substituted: a 6-10 membered aryl, a 6-10 membered heteroaryl ring group, wherein optional substitution means by one or more groups selected from deuterium, halogen, -CN, -NO 2 、-OH、-SH、-NH 2 、C 1-4 Alkoxy, C 1-4 A substituent of alkylthio;
or Q is C optionally substituted with one or more R 2-4 Alkynyl; r' is optionally substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, C 4-6 Heterocyclyl, phenyl, 5-6 membered heteroaryl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkyl, halogenated C 1-3 Substituted with alkoxy;
R 1 is optionally substituted: c (C) 1-3 An alkyl group; wherein optionally substituted means substituted with one or more substituents selected from deuterium, halogen;
R 2 selected from H, deuterium, halogen, -CN, -NO 2 、-NH 2 -OH or optionally substituted: c (C) 1-3 Alkyl, C 1-3 An alkoxy group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
ring W is a 4-16 membered heterocyclyl;
R w is deuterium, halogen, -CN, -NO 2 、-NH 2 -OH, acetamido or optionally substituted: c (C) 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
m is 1, 2, 3 or 4;
the hetero atoms in the heterocyclic group and the heteroaryl group are independently selected from O, N or S, and the number of the hetero atoms is preferably 1, 2 or 3.
2. The compound of claim 1, which is a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotopically-labeled analog, wherein: x is N;
alternatively, X is CR X And R is X Is H, deuterium, -F, -Cl, -Br, -CN, -NO 2 、-NH 2 -OH or optionally substituted: methyl, ethyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH; preferably, X is CR X And R is X Is H, deuterium or optionally substituted: methyl, ethyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH; more preferably, X is CR X And R is X Is H, -CH 2 OH
Preferably, X is CH, C-CH 2 OH。
3. The compound of any one of claims 1-2, which is a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate, or an isotopically labeled analog, wherein: q is optionally substituted: a 6 membered aryl group, a 6 membered heterocyclic group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-OH、-SH、-NH 2 、C 1-4 Alkoxy, C 1-4 A substituent of alkylthio;
or Q is C optionally substituted with one or more R 2-4 Alkynyl; and R' is optionally substituted C 3-6 Cycloalkyl, C 4-6 Heterocyclyl, phenyl, 5-6 membered heteroaryl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
preferably, Q is optionally substituted: a 6 membered aryl group, a 6 membered heterocyclic group; wherein optionally substituted means substituted with one or more substituents selected from deuterium, -F, -Cl, -OH, methoxy, ethoxy, methylthio, ethylthio;
Or Q is ethynyl optionally substituted with one or more R'; and R' is optionally substituted cyclopropyl, cyclopentanyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, phenyl, pyridinyl, pyrrolyl, imidazolyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, -F, -Cl, -CN, -NO 2 、-NH 2 -OH, methyl, ethyl;
preferably, Q is optionally substituted: phenyl, pyridyl; wherein optionally substituted means substituted with one or more substituents selected from deuterium, -F, -Cl, -OH, methoxy, ethoxy, methylthio, ethylthio;
or Q is ethynyl optionally substituted with one or more R'; and R' is optionally substituted cyclopropyl, phenyl, pyridinyl; wherein optionally substituted means substituted with one or more substituents selected from-F, -OH, methoxy;
preferably, Q is
Preferably, Q is
4. A compound according to any one of claims 1-3, which is a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate or isotopically-labeled analog thereof, wherein: r is R 1 Is optionally substituted: methyl, ethyl, isopropyl; wherein optionally substituted means substituted with one or more substituents selected from deuterium, halogen;
preferably, R 1 Is optionally substituted: a methyl group; wherein optionally substituted means substituted with one or more substituents selected from deuterium, -F, -Cl, -Br;
preferably, R 1 is-CH 3 、CD 3 。
5. The compound of any one of claims 1-4, which is a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate, or an isotopically labeled analog, wherein: r is R 2 Selected from H, deuterium, halogen, -CN, -NO 2 、-NH 2 -OH or optionally substituted: c (C) 1-3 An alkyl group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
preferably, R 2 Selected from H, deuterium, -F, -Cl, -Br, -CN, -NO 2 、-NH 2 -OH or optionally substituted: methyl, ethyl; wherein optionally substituted means substituted with one or more substituentsFrom deuterium, -F, -Cl, -Br, -CN, -NO 2 、-NH 2 -OH;
preferably, R 2 Selected from H and NH 2 、-CH 3 。
6. The compound of any one of claims 1-5, which is a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate, or an isotopically labeled analog, wherein: ring W is a 6 membered heterocyclyl, 7-12 membered bicyclic heterocyclyl, 8-16 membered tricyclic heterocyclyl;
Preferably, ring W is
7. The compound of any one of claims 1-6, which is a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate, or an isotopically labeled analog, wherein: r is R w Is deuterium, halogen, -CN, -NO 2 、-NH 2 -OH, acetamido or optionally substituted: c (C) 1-3 An alkyl group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
preferably, R w Deuterium, -F, -Cl, -Br, -CN, -NH 2 -OH, acetamido or optionally substituted: methyl, ethyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
preferably, R w is-NH 2 、-CH 3 、
8. The compound of any one of claims 1-7, which is a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate, or an isotopically labeled analog, wherein: wherein: m is 1, 2 or 3; preferably, m is 1; preferably, m is 2.
9. A compound of formula (ii-a) wherein the compound is a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate or isotopically-labeled analog:
Wherein R is 1 、R 2 、X、R w Ring W, m is as described for compounds of formula (I) according to claims 1 to 8.
10. The compound of claim 9, which is a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotopically-labeled analog, wherein: y is Y 1 、Y 2 、Y 3 、Y 4 、Y 5 Respectively and independently N or CR Y The method comprises the steps of carrying out a first treatment on the surface of the And R is Y Is hydrogen, deuterium, halogen, -CN, -NO 2 、-NH 2 -OH or optionally substituted: c (C) 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
preferably, Y 1 、Y 2 、Y 3 、Y 4 、Y 5 Are all CR Y ；
Preferably, Y 1 、Y 2 、Y 4 、Y 5 Are all CR Y ，Y 3 Is N;
and R is Y Is hydrogen, deuterium, -F, -Cl, -Br, -CN, -NO 2 、-NH 2 -OH or optionally substituted: c (C) 1-3 Alkyl, C 1-3 An alkoxy group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
preferably, R Y Is hydrogen, deuterium, -F, -Cl, -Br, -CN, -NO 2 、-NH 2 -OH or optionally substituted: methyl, methoxy; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH;
preferably, R Y Is hydrogen, -Cl, -OH, methoxy.
11. A compound of the formula (ii-b) a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate, or an isotopically labeled analog of the compound:
Wherein R', R 1 、R 2 、X、R w Ring W, m is as described for compounds of formula (I) according to claims 1 to 8.
12. A compound represented by the following formulas (iii-1) to (iii-4), which is a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate, or an isotopically labeled analog:
wherein R is 1 、R 2 、X、R w Ring W, m is as described for compounds of formula (i) according to claims 1 to 8 or of formula (ii-a) according to claims 9 to 10.
13. A compound of formula (iii-5) as shown below, which is a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotopically-labeled analog thereof:
wherein R', R 1 、R 2 、R w Ring W, m is as described for compounds of formula (i) according to claims 1 to 8 or of formula (ii-b) according to claim 11.
14. A compound represented by the following formulas (iv-1) to (iv-5), which is a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate, or an isotopically labeled analog thereof:
wherein R', R 1 、R 2 X is as described for compounds of formula (I) in claims 1 to 8.
15. The compound of claim 14, which is a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotopically-labeled analog, wherein: r is R w1 And R is w2 Are independently selected from deuterium, halogen, -CN, -NO 2 、-NH 2 -OH or optionally substituted: c (C) 1-3 Alkyl, C 1-3 An alkoxy group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
or R is w1 、R w2 Together with the attached C form an optionally substituted 5-6 membered heterocyclyl, 7-12 membered bicyclic heterocyclyl; wherein the optional substitution isRefers to a material which is substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
preferably, R w1 And R is w2 Are respectively and independently selected from deuterium and NH 2 -OH or optionally substituted: c (C) 1-3 An alkyl group; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
or R is w1 、R w2 Together with the attached C form an optionally substituted 6 membered heterocyclyl, 7-10 membered bicyclic heterocyclyl; wherein optionally substituted means substituted with one or more groups selected from deuterium, halogen, -CN, -NO 2 、-NH 2 、-OH、C 1-3 Substituted by alkyl;
preferably, R w1 And R is w2 Independently selected from-NH 2 、-CH 3 、Preferably, R w1 And R is w2 Independently selected from-NH 2 、-CH 3 ；
Preferably, or R w1 、R w2 Together with C attached to form* Is the point of attachment to the C-link.
16. A compound represented by the following formulas (a) - (d), which is a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate, or an isotopically labeled analog thereof:
Wherein R is 2 、R w1 、R w2 The compounds of the formulae (I) according to claims 1 to 8 or (IV-1) to (IV-5) according to claims 14 to 15.
17. A compound represented by the following formulas (a 1) - (d 1), which is a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate, or an isotopically labeled analog thereof:
wherein R is w1 、R w2 The compounds of the formulae (I) according to claims 1 to 8 or (IV-1) to (IV-5) according to claims 14 to 15.
18. A compound selected from the group consisting of stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically-labeled analogs of said compound:
19. a pharmaceutical composition comprising a compound according to any one of claims 1 to 18, which is a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate or an isotopically labeled analog.
20. Use of a compound according to any one of claims 1 to 19, a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate, or an isotopically-labeled analog of said compound, or a pharmaceutical composition according to claim 18, for the manufacture of a medicament for the treatment or prophylaxis of a disorder mediated by SHP 2.
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