WO2021259049A1 - Indole derivative, preparation method therefor and use thereof - Google Patents

Indole derivative, preparation method therefor and use thereof Download PDF

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Publication number
WO2021259049A1
WO2021259049A1 PCT/CN2021/098556 CN2021098556W WO2021259049A1 WO 2021259049 A1 WO2021259049 A1 WO 2021259049A1 CN 2021098556 W CN2021098556 W CN 2021098556W WO 2021259049 A1 WO2021259049 A1 WO 2021259049A1
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Prior art keywords
ethynyl
aminopyrimidin
hydroxycyclohexyl
alkyl
group
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PCT/CN2021/098556
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French (fr)
Chinese (zh)
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王健
程卯生
宋培鲁
粟媛
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沈阳药科大学
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Publication of WO2021259049A1 publication Critical patent/WO2021259049A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of drug synthesis, and relates to a class of indole derivatives and their preparation methods and applications, as well as pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds, their preparation methods and their use as therapeutic agents Especially as a PAK inhibitor.
  • Protein kinases are the largest known superprotein family. Since the discovery of protein kinases in 1954, about 538 protein kinases have been discovered, and their coding genes account for about 2% of the human genome. Protein kinases are a type of phosphotransferase, whose role is to transfer the ⁇ phosphate group at the end of ATP to the amino acid residue of a specific substrate to phosphorylate it, and then mediate the entire cell process.
  • phosphorylated amino acid residues of the substrate protein can be divided into five categories: serine/threonine (Ser/Thr) protein kinase, tyrosine (Tyr) protein kinase, histidine protein kinase, chromophore Protein kinase, aspartate/glutamine protein kinase.
  • Ser/Thr serine/threonine
  • Tyr tyrosine
  • histidine protein kinase histidine protein kinase
  • chromophore Protein kinase aspartate/glutamine protein kinase.
  • the main role of protein kinases in signal transduction has two aspects: one is to regulate the activity of proteins through phosphorylation, phosphorylation and phosphorylation are common mechanisms for reversible activation in many signal pathways; the other is through protein The gradual phosphorylation of the signal will amplify the signal step by step and cause the cell response.
  • protein kinases play a key role in regulating many important physiological processes in the body. Abnormal phosphorylation activity of protein kinases can lead to disturbances in cell regulation, which in turn leads to the occurrence of many diseases, such as tumors, immune diseases, and central nervous system. Nervous system diseases, diabetes, etc. Therefore, protein kinases are increasingly becoming an important target for the treatment of many diseases. Since 2001, Imatinib (Imatinib, STI571) was approved by the FDA for the treatment of chronic myelogenous leukemia (CML) and became the first kinase inhibitor anti-tumor drug to be marketed. In just 20 years since then, 52 protein kinase inhibitors have been marketed.
  • CML chronic myelogenous leukemia
  • kinases More than 170 kinase inhibitors currently undergoing clinical research mainly involve about 15-20 kinase targets, and about 50% of the inhibitors in research use the kinases of existing marketed drugs as their targets. Research on kinases with less research or kinases that have no marketed drugs is more likely to produce breakthrough progress. There is still huge room for development in the research of protein kinase inhibitor drugs.
  • PAKs p21 activated kinases
  • Cdc42 cell division cycle 42
  • Rac Rho family GTPases member Cdc42 (cell division cycle 42) and Rac.
  • PAKs are also the first discovered to be regulated by Rho family GTPase A member of the kinase family.
  • PAKs bind to and are regulated by Cdc42 and Rac through the N-terminal GTPase binding domain (GBD, GTPase binding domain), also called Cdc42/Rac binding domain (CRIB).
  • GCD GTPase binding domain
  • Cdc42/Rac binding domain Cdc42/Rac binding domain
  • PAKs of higher eukaryotes are divided into two categories: type I PAKs (PAK1-PAK3), and type II PAKs (PAK4-PAK6).
  • PAK can interact with a variety of proteins in the cell, indicating that PAKs are a type of multifunctional kinase. By participating in multiple signaling pathways in the cell, they can regulate and control many biological functions, such as cytoskeleton reorganization, cell migration, and movement. In addition to regulating the normal physiological activities of cells, apoptosis, mitosis, etc., PAK4 has also been found to be related to the occurrence and development of a variety of diseases, especially with the occurrence and development of malignant tumors. Therefore, PAK4 has been Become a new target for anti-tumor drug research.
  • PAK4 inhibitors have been published, such as Staurosporine, PF3758309, KPT-9274, GNE-2861, CZH226, etc. Although a series of PAK4 inhibitors have been published, no PAK inhibitor drugs are currently on the market. It is still necessary to develop compounds with novel structures and better pharmacological effects. After continuous efforts, the design of the present invention has the general formula (I) It has been found that compounds with such structures exhibit better PAK4 inhibitory activity and have better selectivity relative to class I PAKs.
  • the purpose of the present invention is to provide a new type of indole derivatives with the general formula (I), and geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:
  • W, X, Y, Z can be selected from C or N respectively;
  • R 1 is selected from: hydrogen, C 1-2 alkyl or -CH 2 -OH;
  • R 2 is selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and the aryl or heteroaryl may be further ⁇ 3 same or different R 2a substitutions, R 2a is selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl or C 1- 4 alkoxy;
  • R 1 and R 2 together with the carbon atoms to which they are connected form a C 3-7 cycloalkyl group or 5-10 membered heterocycloalkyl group, and the formed cycloalkyl group may be further substituted by a C 1-2 alkyl group or halogen Replaced by
  • R 3 is unsubstituted, or R 3 is selected from: hydrogen, halogen, cyano, C 1-6 alkyl;
  • the aliphatic and/or aromatic part of R 6 can be optionally substituted with one to more substituents selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, amino, cyano, free, salt-forming, Esterified, amidated carboxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl acyl, C 1-6 Alkylsulfinyl, sulfonyl, carbamoyl, optionally substituted by hydroxy, amino, halogenated C 1-6 alkyl or C 1-6 alkoxy, hydrogen, hydroxy, amino or free, salt , Esterified, amidated carboxyl substituted C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, mono or di (C 1-6 alkyl) substituted amino or C 1-6 alkane Amido group, a carbamoyl group substituted by a mono- or di-(C
  • R 7 is selected from: hydrogen, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkylamino.
  • the present invention preferably relates to the novel indole derivatives represented by the general formula (I), and their geometric isomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
  • W, X, Y, Z can be selected from C or N respectively;
  • R 1 is selected from: hydrogen, C 1-2 alkyl or -CH 2 -OH;
  • R 2 is selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; the aryl or heteroaryl is further divided by 1 to 3
  • R 2a is selected from halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl substituted by one or more fluorine, and substituted by one or C 1-4 alkyloxy substituted with multiple fluorine substituents;
  • R 1 and R 2 together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl group; the formed cycloalkyl group may be further substituted by a C 1-2 alkyl group or halogen;
  • R 3 is unsubstituted, or R 3 is selected from: hydrogen, halogen, cyano, C 1-4 alkyl;
  • R 5a and R 5b are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5- to 10-membered heterocyclic group; 6-membered aryl heterocyclic group; or R 5a and R 5b together with the carbon atoms to which they are attached form a C 3-10 cycloalkyl group or 5-10 membered heterocycloalkyl group; the formed cycloalkyl group
  • the aryl and heteroaryl groups involved in R 5 mainly include: phenyl, naphthyl, thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, Pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl, Quinolinyl, isoquinolinyl; and aryl or heterocyclyl may be optionally substituted with 1 to 3 substituents selected from the group consisting of hydrogen, hydroxyl, amino, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, substituted with one or more fluorine substituents, and C 1-4 alkyl substituted by one or more flu
  • the aliphatic and/or aromatic part of R 6 can be optionally substituted with 1 to 5 substituents selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, amine, cyano, free, and salt. , Esterified, amidated carboxy, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl acyl, C 1 -6 alkylsulfinyl, sulfonyl, carbamoyl, optionally substituted by hydroxy, amino, halogenated C 1-6 alkyl or C 1-6 alkoxy, hydrogen, hydroxy, amino or free, Salt-forming, esterified, amidated C 3-6 cycloalkyl or C 3-6 heterocycloalkyl substituted with carboxyl, mono or di (C 1-6 alkyl) substituted amino or C 1- 6 alkyl amide group, carbamoyl group substituted by mono or di (C 1-6 alky
  • R 7 is selected from: hydrogen, cyano, amino, methyl, methoxy, methylamino.
  • the present invention preferably relates to the novel indole derivatives represented by the general formula (I), and their geometric isomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
  • W, Y, Z can be selected from C or N respectively;
  • X is selected from C
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group; the formed cycloalkyl group may be further substituted by a C 1-2 alkyl group or fluorine;
  • R 3 is selected from: hydrogen, halogen, cyano, methyl
  • the aryl or heterocyclic group is selected from: phenyl, naphthyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, homopiperazinyl, azetidinyl, imidazolyl, pyridine Azolyl, tetrahydrofuranyl, thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl; and
  • the aryl group and the heterocyclic group can each be optionally substituted by 1 to 3 hydrogens, C 1-4 alkyl, amino, hydroxy, C 1-4 alkyl substituted by one hydroxy or amino substituent, or by one or more C 1-4 alkyl substituted with fluorine substituents;
  • the aryl or heteroaromatic group mainly includes: phenyl, naphthyl, thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, Pyridazinyl, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl; and the aryl group and the heterocyclic group can be optionally substituted by 1 to 3 is selected from the following substituents: hydrogen, hydroxy, amino, halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, fluoro substituted with one or more C 1-4 alkyl And C 1-4 alkyloxy substituted by one or more fluorine substituents;
  • the aliphatic and/or aromatic part of R 6 can be optionally substituted with 1 to 5 substituents selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, amine, cyano, free, and salt. , Esterified, amidated carboxy, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl acyl, C 1 -6 alkylsulfinyl, sulfonyl, carbamoyl, optionally substituted by hydroxy, amino, halogenated C 1-6 alkyl or C 1-6 alkoxy, hydrogen, hydroxy, amino or free, Salt-forming, esterified, amidated C 3-6 cycloalkyl or C 3-6 heterocycloalkyl substituted with carboxyl, mono or di (C 1-6 alkyl) substituted amino or C 1- 6 alkyl amide group, carbamoyl group substituted by mono or di (C 1-6 alky
  • R 7 is selected from: hydrogen, amino, methyl, and methoxy.
  • the present invention preferably relates to the novel indole derivatives represented by the general formula (I), and their geometric isomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
  • W, X, Y, and Z are respectively selected from C;
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group; the formed cycloalkyl group may be further substituted by a C 1-2 alkyl group and fluorine;
  • R 3 is selected from: hydrogen, fluorine, and chlorine
  • the heterocyclic group is selected from: piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, homopiperazinyl, imidazolyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, pyridyl; And the phenyl group and heterocyclic group can be optionally substituted by 1 to 3 C 1-4 alkyl groups, amino groups, hydroxy groups, C 1-4 alkyl groups substituted by one hydroxy group or amino group, or by one or more fluorine groups. ⁇ C 1-4 alkyl;
  • R 5a and R 5b are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl;
  • the aryl and heteroaryl groups involved in R 5 mainly include: phenyl, thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, pyridyl, indolyl; and aryl and aryl groups.
  • the hetero group may be optionally substituted with 1 to 3 substituents selected from the group consisting of hydrogen, hydroxy, amino, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, one or more fluorine substituents, and C 1-4 alkyl substituted by one or more fluorine substituents C 1-4 alkyl group;
  • the aliphatic and/or aromatic part of R 6 can be optionally substituted with 1 to 5 substituents selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, amine, cyano, free, and salt. , Esterified, amidated carboxy, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl acyl, C 1 -6 alkylsulfinyl, sulfonyl, carbamoyl, optionally substituted by hydroxy, amino, halogenated C 1-6 alkyl or C 1-6 alkoxy, hydrogen, hydroxy, amino or free, Salt-forming, esterified, amidated C 3-6 cycloalkyl or C 3-6 heterocycloalkyl substituted with carboxyl, mono or di (C 1-6 alkyl) substituted amino or C 1- 6 alkyl amide group, carbamoyl group substituted by mono or di (C 1-6 alky
  • R 7 is selected from the group consisting of hydrogen, amino, methyl, and methoxy.
  • the present invention preferably relates to the novel indole derivatives represented by the general formula (I), and their geometric isomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
  • W, X, Y, and Z are respectively selected from C;
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group
  • R 3 is selected from: hydrogen, fluorine, and chlorine
  • the heterocyclic group is selected from: phenyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, homopiperazinyl, pyrazolyl, thiazolyl; and the phenyl and heterocyclic groups Can be arbitrarily substituted by methyl, amino, hydroxyl, hydroxyethyl, morpholino;
  • R 5a and R 5b are each independently selected from: hydrogen, C 1-3 alkyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl group;
  • the aryl or heteroaromatic group includes: phenyl, thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, pyridyl, indolyl; and aryl and aromatic heterocycles can be any The selected ones are substituted by 1 to 3 of the following substituents: hydrogen, hydroxyl, amino, fluorine, chlorine, cyano, nitro, methyl, methoxy, trifluoromethyl, trifluoromethoxy;
  • R 6 is selected from: hydrogen, C 1-3 alkyl, methoxyethyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C 1 alkylene)-(6 Member aryl), -(C 1 alkylene)-(5-6 membered heteroaryl); wherein aryl and heteroaryl include: thienyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidine And aryl and heterocyclic groups can be optionally substituted with 1 to 3 substituents selected from the following: hydrogen, hydroxyl, amino, fluorine, chlorine, cyano, nitro, methyl, methoxy, Trifluoromethyl, trifluoromethoxy, sulfonamido, methylsulfonamido;
  • R 7 is selected from: hydrogen, amino, methyl, and methoxy.
  • the present invention preferably relates to the novel indole derivatives represented by the general formula (I), and their geometric isomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs, preferably the following compounds, but these compounds are not Means any restriction on the present invention:
  • the derivatives of the general formula (I) in the present invention can form pharmaceutically acceptable salts with acids.
  • Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, and the following acid addition salts are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid , Benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.
  • the present invention also includes prodrugs of the derivatives of the present invention.
  • the prodrugs of the derivatives of the present invention are derivatives of the general formula (I), and they may have weak or even no activity by themselves, but after administration, under physiological conditions (for example, by metabolism, solvolysis or other means) ) Is converted into the corresponding biologically active form.
  • halogen refers to fluorine, chlorine, bromine or iodine
  • alkyl refers to straight or branched chain alkyl
  • alkylene refers to straight or branched alkylene
  • Aryl refers to an organic group obtained by removing one or two hydrogen atoms at different positions in aromatic hydrocarbons, such as phenyl and naphthyl
  • heteroaryl refers to containing one or more selected from N, O, A monocyclic or polycyclic ring system of S heteroatoms.
  • the ring system refers to an organic group obtained by removing one or two hydrogen atoms at different positions in the ring system, such as thiazole.
  • heterocycloalkyl means containing one or more selected from N, O , S heteroatom monocyclic ring system, such as tetrahydropyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyrazolidinyl, tetrahydroimidazolidinyl and tetrahydrothiazolinyl Wait.
  • the present invention may contain derivatives of general formula (I), and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as active ingredients, and mixed with pharmaceutically acceptable carriers or excipients to prepare a composition , And prepared into a clinically acceptable dosage form.
  • pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical field.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
  • the pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some commonly used excipients in the pharmaceutical field.
  • the several dosage forms mentioned above can adopt injections, tablets, capsules, aerosols, suppositories, films, dripping pills, topical liniments, ointments and other dosage forms of drugs.
  • the carrier used in the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, including: binders, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents, non-coloring, and flavoring agents , Preservatives, solubilizers and substrates, etc.
  • Pharmaceutical preparations can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.
  • the compounds of the present invention and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs or their pharmaceutical compositions can be used as protein kinase inhibitors and used to prepare anti-tumor drugs.
  • the protein kinase is the second type of PAK protein kinase.
  • the present invention also includes the compound, and the pharmaceutically acceptable salt, hydrate, solvate or prodrug or the pharmaceutical composition thereof to treat a mammalian disease condition mediated by protein kinase activity, which comprises a method for lactating Animals are administered an acceptable amount of a compound, salt, hydrate, solvate, or prodrug of the invention.
  • Suitable amino groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenylmethoxycarbonyl (Fmoc).
  • the compound of formula (I) of the present invention can be synthesized according to the following proposed scheme, where "R” each time it appears independently represents a non-interfering substituent.
  • Route 1 shows the method of preparing the compound of formula (I), wherein W, X, Y, Z and R 1 -R 7 are as defined in the claims.
  • tetrakis (triphenylphosphine) palladium (Pd(PPh) 3 ) 4 , CuI and a base (such as Et 3 N) can be used to make the indole of formula 1 and alkynyl alcohol undergo a coupling reaction (Sonogashira coupling reaction) to obtain the compound of formula (I).
  • Alkynyl alcohols of formula are commercially available or prepared by synthetic methods.
  • Route 2 The N-heteroindole A-1 and 2-amino-4-chloropyrimidine undergo a nucleophilic reaction under the condition of cesium carbonate to obtain intermediate A-2, and then the Sonogashira reaction of A-2 is carried out by the method of Route 1. Cost of the compound of the invention.
  • Route 3 The 6-bromoindole is treated with trifluoroacetic anhydride and sodium hydroxide to obtain the 6-bromoindole-3-carboxylic acid of intermediate A-4, and the intermediate A- is treated with oxalyl chloride and methanol 5.
  • the esterification intermediate A-6 is obtained; then the intermediate A-6 and heteroaromatics are mixed under appropriate nucleophilic substitution conditions (such as cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium hydride) to form N -Heteroarylated indole; mixing compound A-7 with alkynyl alcohol under appropriate Sonogashira-type palladium-mediated coupling conditions to obtain compound A-8 (as in Route 1), and finally in sodium hydroxide Under conditions, it is hydrolyzed and condensed with different primary or secondary amines to form the compound of the present invention, such as compound A-10.
  • nucleophilic substitution conditions such as cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium hydride
  • Route 4 The raw material 6-bromoindole is treated with phosphorus oxychloride to obtain 3-aldehyde substituted indole, and then the intermediate A-11 is mixed with hydroxylamine hydrochloride, sodium acetate, acetic anhydride, and acetic acid to obtain a cyano group.
  • Substituting intermediate A-12, mixing A-11 and A-12 with aromatic heterohydrocarbons under alkaline cesium carbonate conditions to obtain N-heteroarylated indole to obtain A-13 and A-14, and then A -14 oxidized intermediate A-15, and finally A-13, A-14, and A-15 can undergo Sonogashira reaction by the method of Route 1 to produce the compound of the present invention.
  • Route 5 Treat indole B-1 and dichloroheteroarene with potassium tert-butoxide to obtain N-heteroarene B-2, and then nucleophilic reaction with different substituted amines under acid catalysis to obtain amino intermediate B- 3. Finally, the Sonogashira reaction of B-3 can be carried out by the method of Route 1 to produce the compound of the present invention.
  • Route 6 This route can be divided into two methods for the synthesis of C-5 according to the different starting materials of the heteroaromatic ring.
  • Method 1 Mixing 5-bromo-2-iodoaniline with the heteroaromatic ring under acid catalysis to obtain an intermediate C-2, then buckle with different alkynyl groups to obtain intermediate C-3, and then use mCPBA to perform nucleophilic substitution to obtain intermediate C-5.
  • Method 2 Mixing and heating 5-bromo-2-iodoaniline and heteroaromatic ring under acidic conditions to obtain intermediate C-10, C-10 and different alkynyl rings are combined to obtain intermediate C-5. Then, they are treated separately according to the different alkynyl substitutions. Finally, the Sonogashira reaction of C-8 and C-9 can be carried out by the method of Route 1 to produce the compound of the present invention.
  • Chloro-heteroaryl groups generate bromo-heteroaryl groups under the action of TMS bromine, which is then coupled with C-13 under cuprous iodide catalyzed coupling conditions to obtain N-heteroaromatics, and then use mCPBA to oxidize and use different amino groups for nucleophilicity Substitution to obtain intermediate C-17, intermediate C-17 is hydrolyzed under alkaline conditions, and then undergoes condensation reaction to obtain intermediate C-19. Finally, the Sonogashira reaction of C-19 can be carried out by the method of Route 1 to produce the compound of the present invention.
  • Step 1 Dissolve compound A-1 (1.9g, 9.8mmol) in 20mL DMF, then add cesium carbonate (6.4g, 19.6mmol), stir at room temperature for 10min, then add 2-amino-4-chloropyrimidine (1.34g , 10.3mmol), after the reaction was heated to 100°C for 5h, the reaction solution was cooled to room temperature and poured into 100mL of water. A large amount of solids were precipitated out, washed and dried to obtain 2.45g of product, with a yield of 86.7%.
  • ESI-MS (m/z): 289 [M+H] + .
  • Step 2 Add compound A-2 (1.25g, 4.32mmol) to 20mL of anhydrous DMF, then add anhydrous TEA (3mL, 21.6mmol) and cyclohexylalkynol (0.81g, 6.48mmol) to the solution, Ultrasound in a nitrogen environment to exhaust the oxygen in the solution, then add CuI (0.16g, 0.86mmol), and tetrakistriphenylphosphonium palladium (0.25g, 0.22mmol), under the protection of nitrogen, increase the temperature to 80°C for reaction 6h.
  • anhydrous TEA 3mL, 21.6mmol
  • cyclohexylalkynol 0.81g, 6.48mmol
  • reaction solution was cooled to room temperature, then poured into 80 mL of water, and then extracted with EA (60*3 mL), then the EA layer was washed with saturated brine, anhydrous sodium sulfate was added to remove water, and the EA layer was suspended and dried to obtain a crude compound.
  • Column chromatography PE:EA 1:1, 0.95g of light yellow product was obtained, and the yield was 66%.
  • Example 1 According to the method of Example 1, the preparation of Examples 2-6 can be carried out by reacting with different N-heteroindoles.
  • Step 1 Dissolve 6-bromoindole (5g, 25.5mmol) in 30mL DMF, slowly (about 10min) add trifluoroacetic anhydride (4.3mL, 30.6mmol) dropwise under ice bath, and react at room temperature for 1.5 h. Then, the reaction solution was poured into 100 ml of ice water to precipitate an off-white solid, which was filtered with suction to obtain a crude product.
  • Step 2 Add Intermediate A-4 (3.7g, 15.4mmol) to 25mL DCM.
  • Compound 3 is not completely dissolved.
  • 3 drops of DMF can be added with stirring, and then oxalyl chloride (6.6mL, 77.1mmol) Dissolved in 10mL of DCM, slowly added dropwise to the compound, reacted at room temperature for 2h, the reaction solution was distilled under reduced pressure to remove the solvent and excess oxalyl chloride, then the above solid was re-dissolved in 20mL of DCM, and then 30mL of anhydrous methanol was added dropwise In a mixed solution of triethylamine (6 mL, 46.2 mmol), react for 1 h.
  • Step 3 Dissolve Intermediate A-6 (2.5g, 9.8mmol) in 30mL DMF, then add cesium carbonate (6.4g, 19.6mmol), stir at room temperature for 10min, then add 2-amino-4-chloropyrimidine (1.34 g, 10.3 mmol), the reaction was heated to 100°C for 5 hours, the reaction solution was cooled to room temperature, and poured into 100 mL of water. A large amount of solids were precipitated, washed, and dried to obtain 2.95 g of the product, with a yield of 86.7%.
  • ESI-MS (m/z): 347 [M+H] + .
  • Step 4 Add Intermediate A-7 (1.5g, 4.32mmol) to 20mL of anhydrous DMF, then add anhydrous TEA (3mL, 21.6mmol) and cyclohexylalkynol (0.81g, 6.48mmol) to the solution , Ultrasound in a nitrogen environment to exhaust the oxygen in the solution, then add CuI (0.16g, 0.86mmol), and tetrakistriphenylphosphonium palladium (0.25g, 0.22mmol), under the protection of nitrogen, increase the temperature to 80°C Reaction 6h.
  • anhydrous TEA 3mL, 21.6mmol
  • cyclohexylalkynol 0.81g, 6.48mmol
  • reaction solution was cooled to room temperature, then poured into 80 mL of water, and then extracted with EA (60*3 mL), then the EA layer was washed with saturated brine, anhydrous sodium sulfate was added to remove water, and the organic layer was dried to obtain a crude compound.
  • Column chromatography PE:EA 1:1, 1.12g of light yellow product was obtained, and the yield was 66%. 86.7%.
  • ESI-MS (m/z): 375 [MH] - .
  • Step 1 Drop 25ml DMF into a 50ml three-necked flask, evacuate, and protect with nitrogen. In a zero-degree ice bath, slowly drop 2.85ml of phosphorus oxychloride into a 50ml three-necked flask, and let it stir for about 30 minutes, the solution becomes clear and transparent. Dissolve 6-bromoindole (5.0g, 25.5mmol) with 15ml DMF, drop it into the dropping funnel, seal it, add slowly, place it to room temperature and stir for about 1 hour. After detecting the completion of the reaction, the reaction solution was added dropwise to a 5% NaOH (200 ml) solution for quenching.
  • a 5% NaOH 200 ml
  • Step 2 Dissolve Intermediate A-11 (5.7g, 25.45mM) in 65mL of glacial acetic acid, then add sodium acetate (3.13g, 38.17mM) and hydroxylamine hydrochloride (7.1g, 101.78mM) in sequence, and react at 90°C for 1h , Then add acetic anhydride (5.2g, 50.9mM), heat to reflux and react for 4h. After the reaction, the reaction solution was poured into 150 mL of water, and then washed with water, saturated sodium bicarbonate, 1N dilute hydrochloric acid and saturated brine, and dried with anhydrous sodium sulfate. 2.8 g of dark red crude product was obtained by pressure drying (50% yield). ESI-MS (m/z): 221 [M+H] + .
  • Examples 9-39 can be carried out by reacting with appropriate primary or secondary amines.
  • Example 22 (1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(4-(2-hydroxyethyl) )Piperazin-1-yl)methanone
  • Example 28 (3-Amino-1H-pyrazol-1-yl)(1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole -3-yl) ketone
  • Example 30 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2,2,2-trifluoroethyl)-1H-indole -3-carboxamide
  • Step 2 Add 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole (0.2g, 0.648mM) and aniline (63.4mg, 0.68mM) into the pressure bottle, and then add 4mL Isopropanol and 1d concentrated hydrochloric acid, pyridine seal, heated to 120 °C for 3h, the reaction solution is fully cooled, crystals precipitate, suction filtration, cold ethanol washing, water washing, and drying. The obtained product is white 0.22 g (yield 92.6%).
  • ESI-MS (m/z): 379 [M+H] + .
  • Step 3 The title compound uses the 4-(6-bromo-1H-indol-1-yl)pyrimidin-2-amine in step 2 to use 4-(6-bromo-1H- Indol-1-yl)-N-phenylpyrimidin-2-amine was substituted, and the reaction was carried out at 80°C for 5 hours.
  • Example 41 the preparation of Examples 41-59 can be carried out by reacting with an appropriate primary or secondary amine.
  • Example 54 1-((1-(2-((4-(Trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl -1-ol
  • Step 1 Dissolve 5-bromo-2-iodoaniline (1g, 3.357mmol) and 2-methylthiopyrimidine (0.4ml, 0.3439mmol) in 10ml isopropanol, add concentrated hydrochloric acid for 2d, and heat the reaction to 60 After reacting at °C for 20h, Tlc detects the end of the reaction.
  • the reaction solution was poured into 50 ml of ice water, the pH was adjusted to about 8 with 20% sodium hydroxide solution, filtered with suction, washed, and dried to obtain 1.18 g of off-white solid. The yield was 83.2%.
  • ESI-MS (m/z): 422 [M+H] + .
  • Step 2 Combine N-(5-bromo-2-iodophenyl)-2-(methylthio)pyrimidin-4-amine (1g, 2.37mmol), N-Boc aminopropyne (0.4g, 2.61mmol) , TEA (1ml, 7.11mmol), add 10ml DMF, ultrasonic to remove bubbles, and vacuum nitrogen protection, then add CuI (0.09g, 0.474mmol), bistriphenylphosphine palladium dichloride (83mg, 0.12mmol) Reaction at room temperature, after about 2h, add 0.8eq CuI, heat to 70°C and react for 8h, TLC detects the end of the reaction.
  • Step 3 Dissolve N-Boc(6-bromo-1-(2-(methylthio)pyrimidin-4-yl)1H-indol-2-yl)methylamine (6.4g, 14.24mmol) in DCM Then, the temperature is lowered to minus 4°C in a cold trap, and mCPBA is added in batches, and the reaction is tested at this temperature for 5 hours, and the reaction is complete. The reaction solution was quenched with saturated sodium thiosulfate, and then washed with saturated sodium bicarbonate, and then dried with saturated brine, the solvent was evaporated under reduced pressure, and directly cast to the next step. ESI-MS (m/z): 481 [M+H] + .
  • ESI-MS (m/z): 418 [M+H] + .
  • Step 5 Dissolve N-Boc(1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indol-2-yl)methylamine (2g, 4.78mmol) in dioxane hydrochloric acid The solution (1N) was reacted at room temperature for 3 hours, and 1.6 g of dark yellow powder was obtained by direct suction filtration, with a yield of 91%.
  • Step 6 Dissolve 4-(2-aminomethyl)-6-bromo-1H-indol-1-yl)pyrimidin-2-amine hydrochloride (0.2g, 0.564mmol) in 3ml DMF, then Add 0.12ml of triethylamine, stir at room temperature, the solution turns from turbid to clear and then becomes turbid. Then HATU (0.257g, 0.67mmol) and benzoic acid (0.083mg, 0.67mmol) were dissolved in 3ml DMF, and 0.12ml of triethylamine was added. After stirring for 10min, dripped into the above reaction solution. React at room temperature for 1h and the reaction is over.
  • Step 7 The title compound was adjusted to the method described in Example 1, and the 4-(6-bromo-1H-indol-1-yl)pyrimidin-2-amine in step 2 was N-((1-(2- Aminopyrimidin-4-yl)6-bromo-1H-indol-2-yl)methyl)benzamide was substituted, and the reaction was carried out at 80°C for 5 hours.
  • Example 60 the preparation of Examples 61-69 can be carried out by reacting with an appropriate primary or secondary amine or alcohol.
  • Example 70 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-phenyl-1H-indole-2-carboxamide
  • Step 1 Under the protection of Ar atmosphere, add potassium tert-butoxide (22.44 g, 0.2 mol) to ethanol (25 mL) in batches under stirring at room temperature. When the resulting viscous solution was sufficiently cooled, ether (300 Ml) was added, followed by diethyl oxalate (27.2 mL, 0.2 mol). After stirring for 10 minutes, add 4-bromo-2-nitrotoluene (21.5g, 0.1mol), the phenomenon at this time is that the yellow solution turns into a deep red solution, then the reaction mixture is transferred to an Erlenmeyer flask, and the stopper is stoppered.
  • the isolated product is 25.8g
  • the yield is 73.0%, and it can be used directly without further purification.
  • the mixture was extracted with ether (3 ⁇ 400mL), the ether layers were collected and combined, and the extract was washed repeatedly with saturated aqueous sodium bicarbonate solution until bubbling ceased, and then water (400mL) and 1N HC1 (2 ⁇ 300mL) ) Was washed, the organic extract was dried (magnesium sulfate) and the solvent was removed in a vacuum environment to obtain 10.1 g of off-white solid crude product with a yield of 76%.
  • the crude product obtained was recrystallized using toluene to obtain 7.1 g product , The yield is 70%.
  • Step 3 Dissolve 6-bromo-1-(2-(methylsulfide)pyrimidin-4-yl)-1H-indole-2-carboxylic acid ethyl ester (5.58g, 14.24mmol) in DCM, Then, the temperature was lowered to minus 4°C in a cold trap, and mCPBA was added in batches, and the reaction was carried out at this temperature for 5 hours, and the reaction was completed. The reaction solution was quenched with saturated sodium thiosulfate, and then washed with saturated sodium bicarbonate, and then dried with saturated brine, the solvent was evaporated under reduced pressure, and directly cast to the next step.
  • ESI-MS (m/z): 423 [MH] - .
  • ESI-MS (m/z): 362 [M+H] + .
  • Step 5 This title compound uses 1-(2-aminopyrimidine-4) as 4-(6-bromo-1H-indol-1-yl)pyrimidin-2-amine in step 2 by adjusting the method described in Example 1. -Yl)-6-bromo-1H-indole-2-carboxylic acid ethyl ester to obtain the title compound.
  • ESI-MS (m/z): 405 [M+H] + .
  • Step 6 The title compound was adjusted to the method described in Example 7, and the 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole Replace -3-carboxylic acid methyl ester with 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxylic acid ethyl ester to get the title Compound.
  • ESI-MS (m/z): 375 [MH] - .
  • Step 7 The title compound was adjusted by the method described in Example 7, using 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole in step 6. -2-carboxylic acid instead of 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carboxylic acid to react with different substituted amines , The reaction is carried out at room temperature to obtain the title compound.
  • Example 70 the preparation of Examples 71-80 can be carried out by reacting with an appropriate primary or secondary amine or alcohol.
  • Example 77 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-hydroxyethyl)-1H-indole-2-carboxamide
  • Example 78 1-(2-Aminopyrimidin-4-yl)-N-cyclopropyl-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxamide
  • Example 80 1-(2-Aminopyrimidin-4-yl)-N-ethyl-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxamide
  • Example 81 1-((1-(2-Aminopyrimidin-4-yl)-2-(2-hydroxypropyl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol preparation
  • Step 1 Dissolve 5-bromo-2-iodoaniline (1g, 3.357mmol) and 2-methylthiopyrimidine (0.4ml, 0.3439mmol) in 10ml of isopropanol, add concentrated hydrochloric acid for 2d, and heat the reaction to 60 After reacting at °C for 20h, Tlc detects the end of the reaction. The reaction solution was poured into 50 ml of ice water, the pH was adjusted to about 8 with 20% sodium hydroxide solution, filtered with suction, washed, and dried to obtain 1.18 g of off-white solid. The yield was 83.2%. ESI-MS (m/z): 422 [MH] - .
  • Step 2 Add N-(5-bromo-2-iodophenyl)-2-(methylthio)pyrimidin-4-amine (1g, 2.37mmol), 4-pentyn-2-ol (0.22g, 2.61 mmol), TEA (1ml, 7.11mmol), add 10ml DMF, ultrasonic to remove bubbles, and vacuum nitrogen protection, then add CuI (0.09g, 0.474mmol), bistriphenylphosphine palladium dichloride (83mg, 0.12 mmol) react at room temperature. After about 2 hours, add 0.8 eq CuI and heat to 70° C. to react for 8 hours. TLC detects the end of the reaction.
  • Step 3 1-(6-Bromo-1-(2-(methylthio)pyrimidin-4-yl)1H-indol-2-yl)propyl-2 alcohol (0.8g, 1.9mmol), dissolved in In DCM, the temperature was lowered to minus 4°C in a cold trap, and mCPBA (1.01 g, 5.85 mmol) was added in batches, and the reaction was carried out at this temperature for 5 hours, and the reaction was completed. The reaction solution was quenched with saturated sodium thiosulfate, and then washed with saturated sodium bicarbonate, and then dried with saturated brine, the solvent was evaporated under reduced pressure, and directly cast to the next step.
  • ESI-MS m/z
  • ESI-MS (m/z): 348 [M+H] + .
  • Step 5 The title compound was adjusted to the method described in Example 1, and 4-(6-bromo-1H-indol-1-yl)pyrimidin-2-amine in step 2 was used as 1-(1-(2- Aminopyrimidin-4-yl)-6-bromo-1H-indol-2-yl)propyl-2-ol was replaced, and the reaction was carried out at 80°C for 5 hours to obtain the title compound 1-((1-(2 -Aminopyrimidin-4-yl)-2-(2-hydroxypropyl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol.
  • Example 81 the preparation of Examples 82 and 83 can be carried out by reacting with an appropriate terminal alkyne.
  • Example 82 1-((1-(2-Aminopyrimidin-4-yl)-2-(2-hydroxy-2-(thiophen-2-yl)ethyl)-1H-indol-6-yl) (Ethynyl) cyclohexyl-1-ol
  • Example 83 1-((1-(2-Aminopyrimidin-4-yl)-2-(2-hydroxy-2-phenylethyl)-1H-indol-6-yl)ethynyl)cyclohexyl- 1-alcohol
  • Example 84 Study on in vitro enzyme inhibitory activity of some products of the present invention
  • Multifunctional microplate reader (Tecan, Infinite F500), HTRF KinEASE-STK S2 Kit (CisBio), Kit includes: STK Substrate 2-biotin, Streptavidin-XL-665, STK Antibody-Cryptate, 5x Enzymatic buffer, HTRF Detection buffer.
  • PAK4 protein (Full-length, Carna ), DL-Dithiothreitol (DTT), ATP, etc.
  • This experiment uses Kinase test method.
  • the operation steps include enzymatic reaction and detection reaction.
  • the specific operation is as follows: follow the kit instructions to prepare Kinase buffer; first prepare the compound to be tested into a 8000 ⁇ M stock solution with DMSO, then dilute it to 25.0 ⁇ M with Kinase buffer, and then dilute it 3 times to 0.4nM, a total of 11 concentrations.
  • the compound to be tested (4 ⁇ L), the mixed solution (4 ⁇ L) of STK Substrate 2 and ATP (Km concentration), and PAK4 protein (Full-length) (2 ⁇ L) were mixed, centrifuged at high speed, and incubated at 25° C. for 1.0 h.
  • Detection reagents Dilute Streptavidin-XL-665 and STK Antibody-Cryptate with Detection buffer to prepare Detection reagents, add 10 ⁇ L Detection reagents to the above 1.0h incubation reaction solution, centrifuge at high speed, incubate at 25°C for 1.0h, and use the multifunctional microplate reader ( Tecan, Infinite F500) measured the scattered light intensity of Cryptate (620nm) and XL-665 (665nm) under 340nm wavelength excitation light, and calculated the 665/620 ratio.
  • Tecan, Infinite F500 measured the scattered light intensity of Cryptate (620nm) and XL-665 (665nm) under 340nm wavelength excitation light, and calculated the 665/620 ratio.
  • the four-parameter logistic regression method of GraphPad Prism 6 software was used to make the inhibition curve to obtain the IC50 of the test compound for PAK4.
  • Example 85 In vitro A549 cell migration activity study of some products of the present invention
  • Human-derived A549 tumor cells were inoculated in RPMI-1640 medium containing 10% fetal bovine serum, 100U/mL penicillin, and 100 ⁇ g/mL streptomycin.
  • the culture flask was placed in an incubator at 37°C and 5% CO2 saturated humidity. Change the culture medium every 1-2 days. When the cells grow enough to cover most of the surface of the bottom wall of the flask, the adherent cells are digested with 0.25% trypsin and passaged.
  • Cells in the logarithmic growth phase are cultured in a 6-well culture plate.
  • Use marker pens to draw lines on the back of the 6-well plate at intervals of about 1 cm. The lines should be as even as possible and run across the holes. Draw about 5 to 7 lines for each hole.
  • To count the cells add 70,000-120,000 A549 cells to each well of the 6-well plate, and then place the 6-well plate into the incubator and incubate until a uniform monolayer of cells is formed. The next day, take out the 6-well plate, wash each well with PBS 3 times, compare the ruler with the pipette tip, and make a mark perpendicular to the horizontal line at the bottom of the 6-well plate. Then each well was washed three times with PBS to remove the marked cells.
  • the control group was added with the same volume of solvent as the administration group and incubated in a 37°C, 5% CO2 incubator. . Put it into an incubator for cultivation. Sampling according to 72h, taking pictures and measuring.
  • the compound of general formula (I) in the present invention can be administered alone, but is usually administered as a mixture with a pharmaceutical carrier.
  • a pharmaceutical carrier depends on the desired route of administration and standard pharmaceutical practice. Each of these compounds is used below.
  • Preparation methods of various pharmaceutical dosage forms such as tablets, capsules, injections, aerosols, suppositories, films, dripping pills, external liniments and ointments, illustrate their new applications in the pharmaceutical field.
  • the activated carbon adsorption was carried out, filtered by a 0.65 ⁇ m microporous membrane, and filled into a nitrogen tank to make a water injection preparation. Each pack is 2mL, a total of 100 bottles are filled.

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Abstract

Disclosed are an indole derivative, a preparation method therefor and the use thereof; and a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug of the compound, preparation methods therefor and the use thereof as a therapeutic agent, in particular, as a PAK inhibitor. The indole derivative and a geometric isomer or a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof is represented by general formula (I), wherein each variable is as described in the claims and description.

Description

吲哚类衍生物及其制备方法和应用Indole derivatives and preparation method and application thereof 技术领域Technical field
本发明属药物合成领域，涉及一类吲哚衍生物及其制备方法和应用，以及所述化合物的药学可接受的盐、水合物、溶剂化物或前药，它们的制备方法及其作为治疗剂特别是作为PAK抑制剂的用途。The present invention belongs to the field of drug synthesis, and relates to a class of indole derivatives and their preparation methods and applications, as well as pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds, their preparation methods and their use as therapeutic agents Especially as a PAK inhibitor.
背景技术Background technique
蛋白激酶是目前已知最大的超蛋白家族，自1954年发现蛋白激酶以来，目前已发现的蛋白激酶约有538种，其编码基因约占人类基因组的2％左右。蛋白激酶是一类磷酸转移酶，其作用是将ATP末端的γ磷酸基团转移到特定底物的氨基酸残基上，使其磷酸化，进而介导整个细胞进程。根据底物蛋白被磷酸化氨基酸残基的种类，可以将他们分为5类：丝氨酸/苏氨酸(Ser/Thr)蛋白激酶、酪氨酸(Tyr)蛋白激酶、组氨酸蛋白激酶、色氨酸蛋白激酶、天冬氨酸/谷氨酰胺蛋白激酶。蛋白激酶在信号转导中的主要作用有两个方面：其一是通过磷酸化作用调节蛋白的活性，在许多信号通路中磷酸化和被磷酸化是可逆激活的共同机制；其二是通过蛋白的逐级磷酸化，使信号逐级放大，引起细胞反应。研究表明，蛋白激酶对体内许多重要的生理过程起着关键性的调节作用，蛋白激酶磷酸化活性的异常会导致细胞调节发生紊乱，进而导致多种疾病的发生，如肿瘤、免疫性疾病、中枢神经系统疾病、糖尿病等。因此，蛋白激酶越来越成为治疗多种疾病的重要靶点。自2001年伊马替尼(Imatinib，
Figure PCTCN2021098556-appb-000001
STI571)获得FDA批准用于治疗慢性粒细胞白血病(CML)，成为第一个上市的激酶抑制剂类抗肿瘤药以来，之后短短20年，已有52个蛋白激酶抑制剂上市。目前正在进行临床研究的170余个激酶抑制剂主要涉及约15-20种激酶靶标，约有50％的在研抑制剂是以已有上市药物的激酶作为靶标，从这个角度来说，对目前研究较少的激酶或尚无上市药物的激酶进行研究更容易产生突破性的进展，蛋白激酶抑制剂类药物的研究仍有巨大的发展空间。 Protein kinases are the largest known superprotein family. Since the discovery of protein kinases in 1954, about 538 protein kinases have been discovered, and their coding genes account for about 2% of the human genome. Protein kinases are a type of phosphotransferase, whose role is to transfer the γ phosphate group at the end of ATP to the amino acid residue of a specific substrate to phosphorylate it, and then mediate the entire cell process. According to the types of phosphorylated amino acid residues of the substrate protein, they can be divided into five categories: serine/threonine (Ser/Thr) protein kinase, tyrosine (Tyr) protein kinase, histidine protein kinase, chromophore Protein kinase, aspartate/glutamine protein kinase. The main role of protein kinases in signal transduction has two aspects: one is to regulate the activity of proteins through phosphorylation, phosphorylation and phosphorylation are common mechanisms for reversible activation in many signal pathways; the other is through protein The gradual phosphorylation of the signal will amplify the signal step by step and cause the cell response. Studies have shown that protein kinases play a key role in regulating many important physiological processes in the body. Abnormal phosphorylation activity of protein kinases can lead to disturbances in cell regulation, which in turn leads to the occurrence of many diseases, such as tumors, immune diseases, and central nervous system. Nervous system diseases, diabetes, etc. Therefore, protein kinases are increasingly becoming an important target for the treatment of many diseases. Since 2001, Imatinib (Imatinib,
Figure PCTCN2021098556-appb-000001
STI571) was approved by the FDA for the treatment of chronic myelogenous leukemia (CML) and became the first kinase inhibitor anti-tumor drug to be marketed. In just 20 years since then, 52 protein kinase inhibitors have been marketed. More than 170 kinase inhibitors currently undergoing clinical research mainly involve about 15-20 kinase targets, and about 50% of the inhibitors in research use the kinases of existing marketed drugs as their targets. Research on kinases with less research or kinases that have no marketed drugs is more likely to produce breakthrough progress. There is still huge room for development in the research of protein kinase inhibitor drugs.
p21活化激酶(PAKs,p21 activated kinases)属于丝氨酸/苏氨酸家族，是Rho家族GTPases成员Cdc42(cell division cycle 42)和Rac的下游效应器，PAKs也是首个被发现的由Rho家族GTPase调节的激酶家族成员。PAKs通过N端的GTP酶结合域(GBD,GTPase binding domain)，也称作Cdc42/Rac结合域(CRIB)，结合在Cdc42和Rac上并受其调控。根据其生化和结构特征，高等真核生物的PAKs被分为两类：I类PAKs(PAK1-PAK3)，和II类PAKs(PAK4-PAK6)。p21 activated kinases (PAKs, p21 activated kinases) belong to the serine/threonine family and are downstream effectors of Rho family GTPases member Cdc42 (cell division cycle 42) and Rac. PAKs are also the first discovered to be regulated by Rho family GTPase A member of the kinase family. PAKs bind to and are regulated by Cdc42 and Rac through the N-terminal GTPase binding domain (GBD, GTPase binding domain), also called Cdc42/Rac binding domain (CRIB). According to their biochemical and structural characteristics, PAKs of higher eukaryotes are divided into two categories: type I PAKs (PAK1-PAK3), and type II PAKs (PAK4-PAK6).
研究发现PAK能够与细胞内的多种蛋白产生相互作用，说明PAKs是一类多功能激酶，通过参与细胞内的多条信号通路，调节控制许多生物学功能，如细胞骨架重组、细胞迁移运动、细胞凋亡、有丝分裂等，除了参与调节细胞正常的生理活动外，PAK4还被发现与多种疾病的发生发展嘧切相关，特别是与恶性肿瘤的发生发展有嘧切的关系，因此，PAK4已经成为抗肿瘤药物研究的新的靶点。目前已经公开了一系列PAK4抑制剂，例如Staurosporine、PF3758309，KPT-9274、GNE-2861、CZH226等。尽管目前已经公开了一系列PAK4抑制剂，但是目前尚无PAK抑制剂药物上市，仍需要开发结构新颖的具有更好药效的化合物，经过不断努力，本发明设计具有通式(I)所示结构的化合物，并发现具有此类结构的化合物表现出较好的PAK4抑制活性并相对I类PAKs具有较好的选择性。Studies have found that PAK can interact with a variety of proteins in the cell, indicating that PAKs are a type of multifunctional kinase. By participating in multiple signaling pathways in the cell, they can regulate and control many biological functions, such as cytoskeleton reorganization, cell migration, and movement. In addition to regulating the normal physiological activities of cells, apoptosis, mitosis, etc., PAK4 has also been found to be related to the occurrence and development of a variety of diseases, especially with the occurrence and development of malignant tumors. Therefore, PAK4 has been Become a new target for anti-tumor drug research. A series of PAK4 inhibitors have been published, such as Staurosporine, PF3758309, KPT-9274, GNE-2861, CZH226, etc. Although a series of PAK4 inhibitors have been published, no PAK inhibitor drugs are currently on the market. It is still necessary to develop compounds with novel structures and better pharmacological effects. After continuous efforts, the design of the present invention has the general formula (I) It has been found that compounds with such structures exhibit better PAK4 inhibitory activity and have better selectivity relative to class I PAKs.
发明内容Summary of the invention
本发明的目的在于提供一种通式为(I)的新型吲哚类衍生物，及其几何异构体或药学上可接受的盐、水合物、溶剂化物或前药：The purpose of the present invention is to provide a new type of indole derivatives with the general formula (I), and geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:
Figure PCTCN2021098556-appb-000002
Figure PCTCN2021098556-appb-000002
其中：in:
W,X,Y,Z可以分别选自C或N；W, X, Y, Z can be selected from C or N respectively;
R 1选自：氢、C 1-2烷基或-CH 2-OH； R 1 is selected from: hydrogen, C 1-2 alkyl or -CH 2 -OH;
R 2选自：氢、C 1-6烷基、C 3-6环烷基、6～10元芳基，5～10元杂芳基，且所述芳基或杂芳基可进一步被1～3个相同或不同的R 2a取代，R 2a选自氢、卤素、氰基、C 1-4烷基、C 1-4烷氧基、卤素取代的C 1-4烷基或C 1-4烷氧基； R 2 is selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and the aryl or heteroaryl may be further ~3 same or different R 2a substitutions, R 2a is selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl or C 1- 4 alkoxy;
或R 1和R 2连同他们所连接的碳原子一起形成一个C 3-7环烷基或5-10元杂环烷基，所形成的环烷基可进一步被C 1-2烷基或卤素所取代； Or R 1 and R 2 together with the carbon atoms to which they are connected form a C 3-7 cycloalkyl group or 5-10 membered heterocycloalkyl group, and the formed cycloalkyl group may be further substituted by a C 1-2 alkyl group or halogen Replaced by
R 3无取代，或R 3选自：氢、卤素、氰基、C 1-6烷基； R 3 is unsubstituted, or R 3 is selected from: hydrogen, halogen, cyano, C 1-6 alkyl;
R 4选自：氢、醛基、氰基、C 1-6烷基、羰基、被-OH或氨基取代的C 1-6烷基、-C 1-6烷基氧基C 1-4烷基、-C 1-6烷基-C(＝O)-NR 4aR 4b、-OC 1-6烷基、被卤素取代的-OC 1-6烷基、-C(＝O)NR 4aR 4b、-NR 4aR 4b，其中R 4a和R 4b各自独立的选自氢、C 1-4烷基、C 2-4烷基氧基C 1-4烷基、6～10元芳基，5～10元杂芳基；或R 4a和R 4b连同它们所连接的氮原子一起形成一个3-10元杂环基；且所述的芳基、杂芳基、杂环基可以任意地被1至3个氢、C 1-4烷基、氨基、羟基、被一个羟基或氨基取代的C 1-4烷基、或被一个或多个卤素取代的C 1-4烷基、5～10元杂环基、6～10元芳基、5～10元芳杂基； R 4 is selected from: hydrogen, aldehyde group, cyano group, C 1-6 alkyl group, carbonyl group, C 1-6 alkyl group substituted by -OH or amino group, -C 1-6 alkyloxy C 1-4 alkane group, -C 1-6 alkyl -C (= O) -NR 4a R 4b, -OC 1-6 alkyl, -OC 1-6 alkyl substituted by halogen, -C (= O) NR 4a R 4b , -NR 4a R 4b , wherein R 4a and R 4b are each independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkyloxy C 1-4 alkyl, 6-10 membered aryl, 5-10 membered heteroaryl; or R 4a and R 4b together with the nitrogen atom to which they are connected form a 3-10 membered heterocyclic group; and the aryl, heteroaryl, and heterocyclic groups can be optionally 1-3 hydrogen, C 1-4 alkyl, amino, hydroxy, a substituted hydroxy or amino C 1-4 alkyl, halo-substituted by one or more C 1-4 alkyl, 5 to 10 Membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group;
R 5无取代，或R 5选自：氢、氰基、C 1-4醛基、C 1-4酯基、C 1-6烷基、C 3-6环烷基、-C(＝O)-NR 5aR 5b、-CNR 5aR 5b、NR 5aR 5b、6～10元芳环、5～10元杂环、被1～3个选自下组取代基取代的C 1-6烷基：卤素、硝基、-OH、-OC 1-4烷基、6～10元芳环以及5～10元杂环，R 5a和R 5b各自独立的选自下组：氢、C 1-6烷基、C 3-6环烷基、6～10元芳基、5～10元芳杂基，或R 5a和R 5b连同他们所连接的碳原子一起形成一个C 3-7环烷基或5-10元杂环烷基；所形成的环烷基可进一步被C 1-2烷基或卤素所取代；其中芳基和杂环可以任选的被1至3个选自以下各项的取代基取代：氢、羟基、氨基、卤素、氰基、C 1-4烷基、C 1-4烷氧基、被一个或多个卤素或羟基取代的C 1-4烷基以及被一个或多个卤素或羟基取代的C 1-4烷基氧基、5～10元杂环基、6～10元芳基、5～10元芳杂基； R 5 is unsubstituted, or R 5 is selected from: hydrogen, cyano, C 1-4 aldehyde, C 1-4 ester, C 1-6 alkyl, C 3-6 cycloalkyl, -C(=O ) -NR 5a R 5b , -CNR 5a R 5b , NR 5a R 5b , 6-10 membered aromatic ring, 5-10 membered heterocyclic ring, C 1-6 alkane substituted by 1 to 3 substituents selected from the following group Group: halogen, nitro, -OH, -OC 1-4 alkyl, 6-10 membered aromatic ring and 5-10 membered heterocyclic ring, R 5a and R 5b are each independently selected from the following group: hydrogen, C 1- 6 alkyl group, C 3-6 cycloalkyl group, 6-10 membered aryl group, 5-10 membered heteroaryl group, or R 5a and R 5b together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group Or a 5-10 membered heterocycloalkyl group; the formed cycloalkyl group may be further substituted by a C 1-2 alkyl group or a halogen; wherein the aryl group and the heterocyclic ring may be optionally substituted by 1 to 3 selected from the following substituents: hydrogen, hydroxy, amino, halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, substituted with one or more halogen or hydroxy and C 1-4 alkyl substituted by one Or multiple halogen or hydroxy substituted C 1-4 alkyloxy groups, 5 to 10 membered heterocyclic groups, 6 to 10 membered aryl groups, 5 to 10 membered aryl hetero groups;
R 6选自：氢、C 1-6烷基、C 3-6的环烷基、C 1-6亚烷基-C 3-6环烷基、苯基、5-6元杂芳基、5-6元芳基或5-6元杂芳基取代的C 1-6烷基、-C(＝O)R 6a，其中R 6a选自氢、C 1-6烷基、C 2-6链烯基、C 2-6炔基、C 1-6杂烷基、3-6元环烷基、3-6元杂烷基、-(C 1-6亚烷基)-(3-8元环烷基)、-(C 1-6亚烷基)-(3-8元杂环烷基)、-(C 1-6亚烷基)-(6元芳基)、(C 1-6亚烷基)-(5-6元杂芳基)、苯基和5-6元杂芳基，所述的杂烷基、杂芳基含有1-3个N、O或S的杂原子； R 6 is selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylene-C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, C 1-6 alkyl substituted with 5-6 membered aryl or 5-6 membered heteroaryl, -C(=O)R 6a , wherein R 6a is selected from hydrogen, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, 3-6 membered cycloalkyl, 3-6 membered heteroalkyl, -(C 1-6 alkylene)-(3-8 Membered cycloalkyl), -(C 1-6 alkylene)-(3-8 membered heterocycloalkyl), -(C 1-6 alkylene)-(6-membered aryl), (C 1- 6 alkylene)-(5-6 membered heteroaryl), phenyl and 5-6 membered heteroaryl, said heteroalkyl and heteroaryl contain 1-3 N, O or S heteroatoms ；
其中R 6的脂肪基和/或芳香基部分，可以任选的被1至多个选自下列的取代基取代：氢，羟基，卤素，硝基，氨基，氰基，游离的、成盐的、酯化的、酰胺化的羧基，C 1-6烷基，C 2-6烯基，C 2-6炔基，C 1-6烷氧基，C 1-6烷基酰基，C 1-6烷基亚磺酰基、磺酰基，氨基甲酰基，任选被羟基、氨基、卤代的C 1-6烷基或C 1-6烷氧基，被氢、羟基、氨基或游离的、成盐的、酯化的、酰胺化的羧基取代的C 3-6环烷基或C 3-6杂环烷基，被单或二(C 1-6烷基)取代的胺基或C 1-6烷基酰胺基，被单或二(C 1-6烷基)取代的胺基甲酰基，被氢、羟基、氨基、烷基取代的5～10元杂芳基，其中所述杂环烷基与杂芳基分别含有1至3个选自O、N和S的杂原子； The aliphatic and/or aromatic part of R 6 can be optionally substituted with one to more substituents selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, amino, cyano, free, salt-forming, Esterified, amidated carboxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl acyl, C 1-6 Alkylsulfinyl, sulfonyl, carbamoyl, optionally substituted by hydroxy, amino, halogenated C 1-6 alkyl or C 1-6 alkoxy, hydrogen, hydroxy, amino or free, salt , Esterified, amidated carboxyl substituted C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, mono or di (C 1-6 alkyl) substituted amino or C 1-6 alkane Amido group, a carbamoyl group substituted by a mono- or di-(C 1-6 alkyl) group, a 5- to 10-membered heteroaryl group substituted by hydrogen, a hydroxyl group, an amino group, or an alkyl group, wherein the heterocycloalkyl group and the hetero Aryl groups each contain 1 to 3 heteroatoms selected from O, N and S;
R 7选自：氢、氰基、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基。 R 7 is selected from: hydrogen, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkylamino.
本发明优选涉及通式(I)所示新型吲哚类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，The present invention preferably relates to the novel indole derivatives represented by the general formula (I), and their geometric isomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
其中：in:
W,X,Y,Z可以分别选自C或N；W, X, Y, Z can be selected from C or N respectively;
R 1选自：氢、C 1-2烷基或-CH 2-OH； R 1 is selected from: hydrogen, C 1-2 alkyl or -CH 2 -OH;
R 2选自：氢、C 1-6烷基、C 3-6环烷基、6～10元芳基，5～10元杂芳基；所述芳基或杂芳基进一步被1～3个相同或不同的R 2a取代，R 2a选自卤素、氰基、C 1-4烷基、C 1-4烷氧基、被 一个或多个氟取代的C1-4烷基以及被一个或多个氟取代基取代的C 1-4烷基氧基； R 2 is selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; the aryl or heteroaryl is further divided by 1 to 3 The same or different R 2a is substituted, R 2a is selected from halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl substituted by one or more fluorine, and substituted by one or C 1-4 alkyloxy substituted with multiple fluorine substituents;
或R 1和R 2连同他们所连接的碳原子一起形成一个C 3-7环烷基；所形成的环烷基可进一步被C 1-2烷基或卤素所取代； Or R 1 and R 2 together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl group; the formed cycloalkyl group may be further substituted by a C 1-2 alkyl group or halogen;
R 3无取代，或R 3选自：氢、卤素、氰基、C 1-4烷基； R 3 is unsubstituted, or R 3 is selected from: hydrogen, halogen, cyano, C 1-4 alkyl;
R 4选自：氢、C 1-4醛基、C 1-4酯基、羰基、氰基、C 1-6烷基、被一个-OH或氨基取代的C 1-6烷基、-C 1-6烷基氧基C 1-4烷基、-C 1-6烷基-C(＝O)-NR 4aR 4b、-OC 1-6烷基、被一个氟或多个氟取代基取代的C 1-6烷氧基、-C(＝O)NR 4aR 4b、-NR 4aR 4b；其中R 4a和R 4b各自独立的选自氢和C 1-4烷基、C 2-4烷基氧基C 1-4烷基、6～10元芳基，5～10元杂芳基；或R 4a和R 4b连同它们所连接的氮原子一起形成一个3-10元杂环基；且芳基、杂芳基、杂环基这些基团各自可以任意地被1至3个C 1-4烷基、氨基、羟基、被一个羟基或氨基取代基取代的C 1-4烷基取代或被一个或多个氟取代基取代的C 1-4烷基取代； R 4 is selected from: hydrogen, C 1-4 aldehyde, C 1-4 ester group, carbonyl, cyano, C 1-6 alkyl group, a substituted amino group substituted with one -OH or C 1-6 alkyl, -C 1-6 alkyloxy C 1-4 alkyl, -C 1-6 alkyl-C(=O)-NR 4a R 4b , -OC 1-6 alkyl, substituted by one or more fluorine Substituted C 1-6 alkoxy, -C(=O)NR 4a R 4b , -NR 4a R 4b ; wherein R 4a and R 4b are each independently selected from hydrogen and C 1-4 alkyl, C 2- 4 alkyloxy C 1-4 alkyl, 6-10 membered aryl, 5-10 membered heteroaryl; or R 4a and R 4b together with the nitrogen atom to which they are attached form a 3-10 membered heterocyclic group ; And aryl, heteroaryl, heterocyclyl and these groups can be arbitrarily substituted by 1 to 3 C 1-4 alkyl, amino, hydroxy, C 1-4 alkyl substituted by a hydroxy or amino substituent C 1-4 alkyl substituted or substituted with one or more fluorine substituents;
R 5无取代，或R 5选自：氢、氰基、C 1-4醛基、C 1-6烷基、C 3-6环烷基、-C(＝O)-NR 5aR 5b、-CNR 5aR 5b、NR 5aR 5b、苯基、5～6元杂环基、被1～3个如下取代基取代的C 1-6烷基：卤素、-OH、C 1-4烷氧基、6～10元芳基以及5～10元杂环基；R 5a和R 5b各自独立的选自：氢、C 1-6烷基、C 3-6环烷基、苯基、5～6元芳杂基；或R 5a和R 5b连同他们所连接的碳原子一起形成一个C 3-10环烷基或5-10元杂环烷基；所形成的环烷基可进一步被C 1-2烷基或氟所取代； R 5 is unsubstituted, or R 5 is selected from: hydrogen, cyano, C 1-4 aldehyde, C 1-6 alkyl, C 3-6 cycloalkyl, -C(=O)-NR 5a R 5b , -CNR 5a R 5b , NR 5a R 5b , phenyl, 5-6 membered heterocyclic group, C 1-6 alkyl substituted by 1 to 3 of the following substituents: halogen, -OH, C 1-4 alkoxy R 5a and R 5b are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5- to 10-membered heterocyclic group; 6-membered aryl heterocyclic group; or R 5a and R 5b together with the carbon atoms to which they are attached form a C 3-10 cycloalkyl group or 5-10 membered heterocycloalkyl group; the formed cycloalkyl group may be further substituted by C 1 -2 substituted by alkyl or fluorine;
R 5中所涉及的芳基和芳杂基主要包括：苯基、萘基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并噻吩基、苯并呋喃基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基；且芳基或杂环基可以任选的被1至3个选自以下各项的取代基取代：氢、羟基、氨基、卤素、氰基、C 1-4烷基、C 1-4烷氧基、被一个或多个氟取代的C 1-4烷基以及被一个或多个氟取代基取代的C 1-4烷基氧基； The aryl and heteroaryl groups involved in R 5 mainly include: phenyl, naphthyl, thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, Pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl, Quinolinyl, isoquinolinyl; and aryl or heterocyclyl may be optionally substituted with 1 to 3 substituents selected from the group consisting of hydrogen, hydroxyl, amino, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, substituted with one or more fluorine substituents, and C 1-4 alkyl substituted by one or more fluorine substituents C 1-4 alkyl group;
R 6选自：氢、C 1-6烷基、C 3-6的环烷基、C 1-6亚烷基-C 3-6环烷基、苯基、5-6元杂芳基、苯基取代的C 1-6烷基、5-6元杂芳基取代的C 1-6烷基、-C(＝O)R 6a，其中R 6a选自氢、C 1-6烷基、C 2-6链烯基、C 2-6炔基、C 1-6杂烷基、3-6元环烷基、3-6元杂烷基、-(C 1-6亚烷基)-(3-8元环烷基)、-(C 1-6亚烷基)-(3-8元杂环烷基)、-(C 1-6亚烷基)-(6元芳基)、(C 1-6亚烷基)-(5-6元杂芳基)、6元芳基和5-6元杂芳基；其中芳基和芳杂基包括：噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并噻吩基、苯并呋喃基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基； R 6 is selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylene-C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, Phenyl substituted C 1-6 alkyl, 5-6 membered heteroaryl substituted C 1-6 alkyl, -C(=O)R 6a , wherein R 6a is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, 3-6 membered cycloalkyl, 3-6 membered heteroalkyl, -(C 1-6 alkylene)- (3-8 membered cycloalkyl), -(C 1-6 alkylene)-(3-8 membered heterocycloalkyl), -(C 1-6 alkylene)-(6-membered aryl), (C 1-6 alkylene)-(5-6 membered heteroaryl), 6-membered aryl and 5-6 membered heteroaryl; wherein aryl and heteroaryl include: thienyl, thiazolyl, pyrrolyl , Oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzene Bisimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl;
其中R 6的脂肪基和/或芳香基部分，可以任选的被1至5个选自下列的取代基取代：氢，羟基，卤素，硝基，胺基，氰基，游离的、成盐的、酯化的、酰胺化的羧基，C 1-6烷基，C 1-6烯基，C 1-6炔基，C 1-6烷氧基，C 1-6烷基酰基，C 1-6烷基亚磺酰基、磺酰基，氨基甲酰基，任选被羟基、氨基、卤代的C 1-6烷基或C 1-6烷氧基，被氢、羟基、氨基或游离的、成盐的、酯化的、酰胺化的羧基取代的C 3-6环烷基或C 3-6杂环烷基，被单或二(C 1-6烷基)取代的胺基或C 1-6烷基酰胺基，被单或二(C 1-6烷基)取代的胺基甲酰基，被氢、羟基、氨基、烷基取代的5～10元杂芳基，其中所述杂环烷基与杂芳基分别含有1至3个选自O、N和S的杂原子； The aliphatic and/or aromatic part of R 6 can be optionally substituted with 1 to 5 substituents selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, amine, cyano, free, and salt. , Esterified, amidated carboxy, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl acyl, C 1 -6 alkylsulfinyl, sulfonyl, carbamoyl, optionally substituted by hydroxy, amino, halogenated C 1-6 alkyl or C 1-6 alkoxy, hydrogen, hydroxy, amino or free, Salt-forming, esterified, amidated C 3-6 cycloalkyl or C 3-6 heterocycloalkyl substituted with carboxyl, mono or di (C 1-6 alkyl) substituted amino or C 1- 6 alkyl amide group, carbamoyl group substituted by mono or di (C 1-6 alkyl), 5-10 membered heteroaryl group substituted by hydrogen, hydroxy, amino, alkyl, wherein the heterocycloalkyl And the heteroaryl group respectively contain 1 to 3 heteroatoms selected from O, N and S;
R 7选自：氢、氰基、氨基、甲基、甲氧基、甲氨基。 R 7 is selected from: hydrogen, cyano, amino, methyl, methoxy, methylamino.
本发明优选涉及通式(I)所示新型吲哚类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，The present invention preferably relates to the novel indole derivatives represented by the general formula (I), and their geometric isomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
其中：in:
W,Y,Z可以分别选自C或N；W, Y, Z can be selected from C or N respectively;
X选自C；X is selected from C;
R 1和R 2连同他们所连接的碳原子一起形成一个C 3-7环烷基；所形成的环烷基可进一步被C 1-2烷基或氟所取代； R 1 and R 2 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group; the formed cycloalkyl group may be further substituted by a C 1-2 alkyl group or fluorine;
R 3选自：氢、卤素、氰基、甲基； R 3 is selected from: hydrogen, halogen, cyano, methyl;
当Y为N时，R 3无取代； When Y is N, R 3 is not substituted;
R 4选自：氢、C 1-4醛基、C 1-4酯基、羰基、氰基、C 1-4烷基、被一个-OH或氨基取代的C 1-6烷基、-C(＝O)NR 4aR 4b；其中R 4a和R 4b各自独立的选自氢、C 1-4烷基、C 2-4烷基氧基C 1-4烷基、6-10元芳基，5～6元杂环基；或R 4a和R 4b连同它们所连接的氮原子一起形成一个3-10元杂环基； R 4 is selected from: hydrogen, C 1-4 aldehyde group, C 1-4 ester group, carbonyl group, cyano group, C 1-4 alkyl group, C 1-6 alkyl group substituted by one -OH or amino group, -C (=O)NR 4a R 4b ; wherein R 4a and R 4b are each independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkyloxy C 1-4 alkyl, 6-10 membered aryl , 5-6 membered heterocyclic group; or R 4a and R 4b together with the nitrogen atom to which they are attached form a 3-10 membered heterocyclic group;
所述的芳基或杂环基选自：苯基、萘基、哌啶基、哌嗪基、吗啉基、吡咯烷基、高哌嗪基、氮杂环丁烷基、咪唑基、吡唑基、四氢呋喃基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基以及吡嗪基；且芳基、杂环基各自可以任意地被1至3个氢、C 1-4烷基、氨基、羟基、被一个羟基或氨基取代基取代的C 1-4烷基取代或被一个或多个氟取代基取代的C 1-4烷基取代； The aryl or heterocyclic group is selected from: phenyl, naphthyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, homopiperazinyl, azetidinyl, imidazolyl, pyridine Azolyl, tetrahydrofuranyl, thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl; and The aryl group and the heterocyclic group can each be optionally substituted by 1 to 3 hydrogens, C 1-4 alkyl, amino, hydroxy, C 1-4 alkyl substituted by one hydroxy or amino substituent, or by one or more C 1-4 alkyl substituted with fluorine substituents;
R 5选自：氢、氰基、醛基、C 1-6烷基、C 3-6环烷基、-C(＝O)-NR 5aR 5b、-CNR 5aR 5b、NR 5aR 5b、6-10元芳基、5～6元杂环、被1～3个选自下组取代基取代的C 1-6烷基：卤素、-OH、-OC 1-4烷基、苯基以及5～6元杂环基；R 5a和R 5b各自独立的选自：氢、C 1-6烷基、C 3-6环烷基、6元芳基、5～6元芳杂基；或R 5a和R 5b连同他们所连接的碳原子一起形成一个C 3-10环烷基或杂环烷基；所形成的环烷基可进一步被C 1-2烷基和氟所取代； R 5 is selected from: hydrogen, cyano, aldehyde, C 1-6 alkyl, C 3-6 cycloalkyl, -C(=O)-NR 5a R 5b , -CNR 5a R 5b , NR 5a R 5b , 6-10 membered aryl, 5-6 membered heterocycle, C 1-6 alkyl substituted by 1 to 3 substituents selected from the group: halogen, -OH, -OC 1-4 alkyl, phenyl And a 5- to 6-membered heterocyclic group; R 5a and R 5b are each independently selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 6-membered aryl, 5 to 6-membered heteroaryl; Or R 5a and R 5b together with the carbon atom to which they are attached form a C 3-10 cycloalkyl or heterocycloalkyl group; the formed cycloalkyl group may be further substituted by a C 1-2 alkyl group and fluorine;
所述的芳基或芳杂基主要包括：苯基、萘基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、哒嗪基、苯并噻吩基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基；且芳基和杂环可以任选的被1至3个选自以下各项的取代基取代：氢、羟基、氨基、卤素、氰基、C 1-4烷基、C 1-4烷氧基、被一个或多个氟取代的C 1-4烷基以及被一个或多个氟取代基取代的C 1-4烷基氧基； The aryl or heteroaromatic group mainly includes: phenyl, naphthyl, thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, Pyridazinyl, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl; and the aryl group and the heterocyclic group can be optionally substituted by 1 to 3 is selected from the following substituents: hydrogen, hydroxy, amino, halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, fluoro substituted with one or more C 1-4 alkyl And C 1-4 alkyloxy substituted by one or more fluorine substituents;
当W为N时，R 5无取代； When W is N, R 5 is not substituted;
R 6选自：氢、C 1-6烷基、C 3-6的环烷基、C 1-6亚烷基-C 3-6环烷基、苯基、5-6元杂芳基、苯基取代的C 1-6烷基、5-6元杂芳基取代的C 1-6烷基-、-C(＝O)R 6a；其中R 6a选自氢、C 1-6烷基、C 2-6链烯基、C 1-6杂烷基、3-6元环烷基、3-6元杂烷基、-(C 1-6亚烷基)-(3-8元环烷基)、-(C 1-6亚烷基)-(3-8元杂环烷基)、-(C 1-6亚烷基)-(6元芳基)、(C 1-6亚烷基)-(5-6元杂芳基)、苯基和5-6元杂芳基；其中芳基和芳杂基包括：噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并噻吩基、苯并呋喃基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基； R 6 is selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylene-C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, Phenyl substituted C 1-6 alkyl, 5-6 membered heteroaryl substituted C 1-6 alkyl-, -C(=O)R 6a ; wherein R 6a is selected from hydrogen, C 1-6 alkyl , C 2-6 alkenyl, C 1-6 heteroalkyl, 3-6 membered cycloalkyl, 3-6 membered heteroalkyl, -(C 1-6 alkylene)-(3-8 membered ring Alkyl), -(C 1-6 alkylene)-(3-8 membered heterocycloalkyl), -(C 1-6 alkylene)-(6-membered aryl), (C 1-6 alkylene) Alkyl)-(5-6 membered heteroaryl), phenyl and 5-6 membered heteroaryl; wherein aryl and heteroaryl include: thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl , Imidazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, benzopyrazole Group, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl;
其中R 6的脂肪基和/或芳香基部分，可以任选的被1至5个选自下列的取代基取代：氢，羟基，卤素，硝基，胺基，氰基，游离的、成盐的、酯化的、酰胺化的羧基，C 1-6烷基，C 1-6烯基，C 1-6炔基，C 1-6烷氧基，C 1-6烷基酰基，C 1-6烷基亚磺酰基、磺酰基，氨基甲酰基，任选被羟基、氨基、卤代的C 1-6烷基或C 1-6烷氧基，被氢、羟基、氨基或游离的、成盐的、酯化的、酰胺化的羧基取代的C 3-6环烷基或C 3-6杂环烷基，被单或二(C 1-6烷基)取代的胺基或C 1-6烷基酰胺基，被单或二(C 1-6烷基)取代的胺基甲酰基，被氢、羟基、氨基、烷基取代的5～10元杂芳基，其中所述杂环烷基与杂芳基分别含有1至3个选自O、N和S的杂原子； The aliphatic and/or aromatic part of R 6 can be optionally substituted with 1 to 5 substituents selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, amine, cyano, free, and salt. , Esterified, amidated carboxy, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl acyl, C 1 -6 alkylsulfinyl, sulfonyl, carbamoyl, optionally substituted by hydroxy, amino, halogenated C 1-6 alkyl or C 1-6 alkoxy, hydrogen, hydroxy, amino or free, Salt-forming, esterified, amidated C 3-6 cycloalkyl or C 3-6 heterocycloalkyl substituted with carboxyl, mono or di (C 1-6 alkyl) substituted amino or C 1- 6 alkyl amide group, carbamoyl group substituted by mono or di (C 1-6 alkyl), 5-10 membered heteroaryl group substituted by hydrogen, hydroxy, amino, alkyl, wherein the heterocycloalkyl And the heteroaryl group respectively contain 1 to 3 heteroatoms selected from O, N and S;
R 7选自：氢、氨基、甲基、甲氧基。 R 7 is selected from: hydrogen, amino, methyl, and methoxy.
本发明优选涉及通式(I)所示新型吲哚类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，The present invention preferably relates to the novel indole derivatives represented by the general formula (I), and their geometric isomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
其中：in:
W,X,Y,Z分别选自C；W, X, Y, and Z are respectively selected from C;
R 1和R 2连同他们所连接的碳原子一起形成一个C 3-7环烷基；所形成的环烷基可进一步被C 1-2烷基和氟所取代； R 1 and R 2 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group; the formed cycloalkyl group may be further substituted by a C 1-2 alkyl group and fluorine;
R 3选自：氢、氟、氯； R 3 is selected from: hydrogen, fluorine, and chlorine;
R 4选自：氢、C 1-4醛基、氰基、-C(＝O)NR 4aR 4b；其中R 4a和R 4b各自独立的选自氢和C 1-3烷基、C 2-4烷基氧基C 1-4烷基、苯基，5～6元杂环基；或R 4a和R 4b连同它们所连接的氮 原子一起形成一个3-10元杂环基； R 4 is selected from: hydrogen, C 1-4 aldehyde, cyano, -C(=O)NR 4a R 4b ; wherein R 4a and R 4b are each independently selected from hydrogen and C 1-3 alkyl, C 2 -4 Alkyloxy C 1-4 alkyl, phenyl, 5-6 membered heterocyclic group; or R 4a and R 4b together with the nitrogen atom to which they are attached form a 3-10 membered heterocyclic group;
所述的杂环基选自：哌啶基、哌嗪基、吗啉基、吡咯烷基、高哌嗪基、咪唑基、吡唑基、噻吩基、噻唑基、噁唑基、吡啶基；且所述的苯基、杂环基可以任意地被1至3个C 1-4烷基、氨基、羟基、被一个羟基或氨基取代的C 1-4烷基或被一个或多个氟取代的C 1-4烷基； The heterocyclic group is selected from: piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, homopiperazinyl, imidazolyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, pyridyl; And the phenyl group and heterocyclic group can be optionally substituted by 1 to 3 C 1-4 alkyl groups, amino groups, hydroxy groups, C 1-4 alkyl groups substituted by one hydroxy group or amino group, or by one or more fluorine groups.的 C 1-4 alkyl;
R 5选自：氢、氰基、C 1-4醛基、C 1-6烷基、C 3-6环烷基、-C(＝O)-NR 5aR 5b、-CNR 5aR 5b、NR 5aR 5b、苯基、5～6元杂环基、被1～3个如下取代基取代的C 1-6烷基：-OH、-OC 1-4烷基、苯基以及5～6元杂环；R 5a和R 5b各自独立的选自下组：氢、C 1-4烷基、C 3-6环烷基、苯基、5～6元芳杂基； R 5 is selected from: hydrogen, cyano, C 1-4 aldehyde, C 1-6 alkyl, C 3-6 cycloalkyl, -C(=O)-NR 5a R 5b , -CNR 5a R 5b , NR 5a R 5b , phenyl, 5- to 6-membered heterocyclic group, C 1-6 alkyl substituted with 1 to 3 of the following substituents: -OH, -OC 1-4 alkyl, phenyl and 5-6 Membered heterocyclic ring; R 5a and R 5b are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl;
R 5中所涉及的芳基和芳杂基主要包括：苯基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、吡啶基、吲哚基；且芳基和芳杂基可以任选的被1至3个选自以下各项的取代基取代：氢、羟基、氨基、卤素、氰基、C 1-4烷基、C 1-4烷氧基、被一个或多个氟取代的C 1-4烷基以及被一个或多个氟取代基取代的C 1-4烷基氧基； The aryl and heteroaryl groups involved in R 5 mainly include: phenyl, thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, pyridyl, indolyl; and aryl and aryl groups. The hetero group may be optionally substituted with 1 to 3 substituents selected from the group consisting of hydrogen, hydroxy, amino, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, one or more fluorine substituents, and C 1-4 alkyl substituted by one or more fluorine substituents C 1-4 alkyl group;
R 6选自：氢、C 1-4烷基、C 3-6的环烷基、C 1-6亚烷基-C 3-6环烷基、苯基、5-6元杂芳基、-C 1-6亚烷基-6元芳基、C 1-6亚烷基-5-6元杂芳基、-C(＝O)R 6a；其中R 6a选自氢、C 1-6烷基、C 1-6杂烷基、3-6元环烷基、3-6元杂烷基、-(C 1-6亚烷基)-(3-8元环烷基)、-(C 1-6亚烷基)-(3-6元杂环烷基)、-(C 1-6亚烷基)-(6元芳基)、(C 1-6亚烷基)-(5-6元杂芳基)、苯基和5-6元杂芳基；其中芳基和芳杂基包括：噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、吡啶基、嘧啶基； R 6 is selected from: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-6 alkylene-C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, -C 1-6 alkylene-6-membered aryl, C 1-6 alkylene-5-6-membered heteroaryl, -C(=O)R 6a ; wherein R 6a is selected from hydrogen, C 1-6 Alkyl, C 1-6 heteroalkyl, 3-6 membered cycloalkyl, 3-6 membered heteroalkyl, -(C 1-6 alkylene)-(3-8 membered cycloalkyl), -( C 1-6 alkylene)-(3-6 membered heterocycloalkyl), -(C 1-6 alkylene)-(6 membered aryl), (C 1-6 alkylene)-(5 -6-membered heteroaryl), phenyl and 5-6-membered heteroaryl; wherein aryl and heteroaryl include: thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, pyridyl , Pyrimidinyl;
其中R 6的脂肪基和/或芳香基部分，可以任选的被1至5个选自下列的取代基取代：氢，羟基，卤素，硝基，胺基，氰基，游离的、成盐的、酯化的、酰胺化的羧基，C 1-6烷基，C 1-6烯基，C 1-6炔基，C 1-6烷氧基，C 1-6烷基酰基，C 1-6烷基亚磺酰基、磺酰基，氨基甲酰基，任选被羟基、氨基、卤代的C 1-6烷基或C 1-6烷氧基，被氢、羟基、氨基或游离的、成盐的、酯化的、酰胺化的羧基取代的C 3-6环烷基或C 3-6杂环烷基，被单或二(C 1-6烷基)取代的胺基或C 1-6烷基酰胺基，被单或二(C 1-6烷基)取代的胺基甲酰基，被氢、羟基、氨基、烷基取代的5～10元杂芳基，其中所述杂环烷基与杂芳基分别含有1至3个选自O、N和S的杂原子； The aliphatic and/or aromatic part of R 6 can be optionally substituted with 1 to 5 substituents selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, amine, cyano, free, and salt. , Esterified, amidated carboxy, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl acyl, C 1 -6 alkylsulfinyl, sulfonyl, carbamoyl, optionally substituted by hydroxy, amino, halogenated C 1-6 alkyl or C 1-6 alkoxy, hydrogen, hydroxy, amino or free, Salt-forming, esterified, amidated C 3-6 cycloalkyl or C 3-6 heterocycloalkyl substituted with carboxyl, mono or di (C 1-6 alkyl) substituted amino or C 1- 6 alkyl amide group, carbamoyl group substituted by mono or di (C 1-6 alkyl), 5-10 membered heteroaryl group substituted by hydrogen, hydroxy, amino, alkyl, wherein the heterocycloalkyl And the heteroaryl group respectively contain 1 to 3 heteroatoms selected from O, N and S;
R 7选自下组：氢、氨基、甲基、甲氧基。 R 7 is selected from the group consisting of hydrogen, amino, methyl, and methoxy.
本发明优选涉及通式(I)所示新型吲哚类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，The present invention preferably relates to the novel indole derivatives represented by the general formula (I), and their geometric isomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs,
其中：in:
W,X,Y,Z分别选自C；W, X, Y, and Z are respectively selected from C;
R 1和R 2连同他们所连接的碳原子一起形成C 3-7环烷基； R 1 and R 2 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group;
R 3选自：氢、氟、氯； R 3 is selected from: hydrogen, fluorine, and chlorine;
R 4选自：氢、C 1-4醛基、氰基、-C(＝O)NR 4aR 4b；其中R 4a和R 4b各自独立的选自氢和C 1-3烷基、C 2-4烷基氧基C 1-4烷基、苯基、5～6元杂环基；或R 4a和R 4b连同它们所连接的氮原子一起形成一个3-10元杂环基； R 4 is selected from: hydrogen, C 1-4 aldehyde, cyano, -C(=O)NR 4a R 4b ; wherein R 4a and R 4b are each independently selected from hydrogen and C 1-3 alkyl, C 2 -4 alkyloxy C 1-4 alkyl, phenyl, 5-6 membered heterocyclic group; or R 4a and R 4b together with the nitrogen atom to which they are attached form a 3-10 membered heterocyclic group;
所述的杂环基选自：苯基、哌啶基、哌嗪基、吗啉基、吡咯烷基、高哌嗪基、吡唑基、噻唑基；且所述的苯基、杂环基可以任意地被甲基、氨基、羟基、羟乙基、吗啉基取代；The heterocyclic group is selected from: phenyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, homopiperazinyl, pyrazolyl, thiazolyl; and the phenyl and heterocyclic groups Can be arbitrarily substituted by methyl, amino, hydroxyl, hydroxyethyl, morpholino;
R 5选自：氢、氰基、C 1-4醛基、-C(＝O)-NR 5aR 5b、-CNR 5aR 5b、被1～3个如下取代基取代的C 1-6烷基：-OH、C 1-4烷氧基、6元芳环以及5～6元芳杂环；R 5a和R 5b各自独立的选自：氢、C 1-3烷基、C 3-6环烷基、苯基、5～6元芳杂基；； R 5 is selected from: hydrogen, cyano, C 1-4 aldehyde group, -C(=O)-NR 5a R 5b , -CNR 5a R 5b , C 1-6 alkane substituted by 1 to 3 of the following substituents Group: -OH, C 1-4 alkoxy, 6-membered aromatic ring and 5-6 membered aromatic heterocyclic ring; R 5a and R 5b are each independently selected from: hydrogen, C 1-3 alkyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl group;
所述的芳基或芳杂基包括：苯基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、吡啶基、吲哚基；且芳基和芳杂环可以任选的被1至3个如下取代基取代：氢、羟基、氨基、氟、氯、氰基、硝基、甲基、甲氧基、三氟甲基、三氟甲氧基；The aryl or heteroaromatic group includes: phenyl, thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, pyridyl, indolyl; and aryl and aromatic heterocycles can be any The selected ones are substituted by 1 to 3 of the following substituents: hydrogen, hydroxyl, amino, fluorine, chlorine, cyano, nitro, methyl, methoxy, trifluoromethyl, trifluoromethoxy;
R 6选自：氢、C 1-3烷基、甲氧基乙基、C 3-6的环烷基、苯基、5-6元杂芳基、(C 1亚烷基)-(6元芳基)、-(C 1亚烷基)-(5-6元杂芳基)；其中芳基和芳杂基包括：噻吩基、噻唑基、吡唑基、咪唑基、吡啶基、嘧啶基；且芳基和杂环可以任选的被1至3个选自以下各项的取 代基取代：氢、羟基、氨基、氟、氯、氰基、硝基、甲基、甲氧基、三氟甲基、三氟甲氧基、磺酰氨基、甲基磺酰氨基； R 6 is selected from: hydrogen, C 1-3 alkyl, methoxyethyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, (C 1 alkylene)-(6 Member aryl), -(C 1 alkylene)-(5-6 membered heteroaryl); wherein aryl and heteroaryl include: thienyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidine And aryl and heterocyclic groups can be optionally substituted with 1 to 3 substituents selected from the following: hydrogen, hydroxyl, amino, fluorine, chlorine, cyano, nitro, methyl, methoxy, Trifluoromethyl, trifluoromethoxy, sulfonamido, methylsulfonamido;
R 7选自：氢、氨基、甲基、甲氧基。 R 7 is selected from: hydrogen, amino, methyl, and methoxy.
本发明优选涉及通式(I)所示新型吲哚类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药优选以下化合物，但这些化合物并不意味着对本发明的任何限制：The present invention preferably relates to the novel indole derivatives represented by the general formula (I), and their geometric isomers or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs, preferably the following compounds, but these compounds are not Means any restriction on the present invention:
1-((1-(2-氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-Aminopyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1-((1-(2-氨基嘧啶-4-基)-5-氟-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-Aminopyrimidin-4-yl)-5-fluoro-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1-((1-(2-氨基嘧啶-4-基)1H-吡咯[3,2-b]并吡啶-6-基)乙炔基)环己基-1-醇1-((1-(2-Aminopyrimidin-4-yl)1H-pyrrole[3,2-b]pyridin-6-yl)ethynyl)cyclohexyl-1-ol
1-((1-(2-氨基嘧啶-4-基)-1H-吲唑-6-基)乙炔基)环己基-1-醇1-((1-(2-Aminopyrimidin-4-yl)-1H-indazol-6-yl)ethynyl)cyclohexyl-1-ol
1-((2-氨基嘧啶-4-基)-1H-吡咯[2,3-b]并吡啶-6-基)乙炔基)环己基-1-醇1-((2-Aminopyrimidin-4-yl)-1H-pyrrole[2,3-b]pyridin-6-yl)ethynyl)cyclohexyl-1-ol
1-((2-氨基嘧啶-4-基)-1H-吡咯[3,2-c]并吡啶-6-基)乙炔基)环己基-1-醇1-((2-Aminopyrimidin-4-yl)-1H-pyrrole[3,2-c]pyridin-6-yl)ethynyl)cyclohexyl-1-ol
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌嗪-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(piperazin-1-yl)methanone
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carboxamide
1-((1-(2,6-二氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2,6-Diaminopyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1-(2-氨基嘧啶-4-基)-6-(1-羟基环己基)乙炔基)-1H-吲哚-3-甲醛1-(2-Aminopyrimidin-4-yl)-6-(1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carbaldehyde
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(吡咯-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(pyrrol-1-yl)methanone
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌啶-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(piperidin-1-yl)methanone
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N,N-二甲基-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N,N-dimethyl-1H-indole-3-carboxamide
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(吗啉基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(morpholinyl)methanone
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-甲基哌嗪-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(4-methylpiperazin-1-yl)methan ketone
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-甲基-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-methyl-1H-indole-3-carboxamide
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(噻唑-2-基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(thiazol-2-yl)-1H-indole-3-carboxamide
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-phenyl-1H-indole-3-carboxamide
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲腈1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carbonitrile
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-甲氧乙基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-methoxyethyl)-1H-indole-3-carboxamide
1-(2-氨基嘧啶-4-基)-N-苄基-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-N-benzyl-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carboxamide
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-(2-羟乙基)哌嗪-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(4-(2-hydroxyethyl)piperazine- 1-yl) ketone
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(2-(羟乙基)吡咯-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(2-(hydroxyethyl)pyrrol-1-yl )Methone
1-(2-氨基嘧啶-4-基)-N-(5-羟基-1H-吡唑-3-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-N-(5-hydroxy-1H-pyrazol-3-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3 -Formamide
(R)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-甲基哌嗪-1-基)甲酮(R)-(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3-methylpiperazine-1 -Base) ketone
(S)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-甲基哌嗪-1-基)甲酮(S)-(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3-methylpiperazine-1 -Base) ketone
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3,5-二甲基哌嗪-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3,5-dimethylpiperazine-1- Ketone
(3-氨基-1H-吡唑-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮(3-Amino-1H-pyrazol-1-yl)(1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl )Methone
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(1H-吡唑-3-基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(1H-pyrazol-3-yl)-1H-indole-3-carboxamide
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2,2,2-三氟乙基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2,2,2-trifluoroethyl)-1H-indole-3-methyl Amide
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-吗啉基哌啶-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(4-morpholinylpiperidin-1-yl) Ketone
(R)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-羟基哌啶-1-基)甲酮(R)-(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3-hydroxypiperidine-1- Ketone
(S)-(3-氨基哌啶-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮(S)-(3-Aminopiperidin-1-yl)(1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3- Ketone
(S)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(哌啶-3-基)1H-吲哚-3-甲酰胺(S)-1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(piperidin-3-yl)1H-indole-3-carboxamide
(R)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(哌啶-3-基)1H-吲哚-3-甲酰胺(R)-1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(piperidin-3-yl)1H-indole-3-carboxamide
(R)-(3-氨基哌啶-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮(R)-(3-Aminopiperidin-1-yl)(1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3- Ketone
(S)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-氨基吡咯-1-基)甲酮(S)-(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3-aminopyrrol-1-yl )Methone
(S)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡咯-3-基)1H-吲哚-3-甲酰胺(S)-1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(pyrrol-3-yl)1H-indole-3-carboxamide
(R)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡咯-3-基)1H-吲哚-3-甲酰胺(R)-1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(pyrrol-3-yl)1H-indole-3-carboxamide
4-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羰基)哌嗪-2-酮4-(1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carbonyl)piperazin-2-one
1-((1-(2-苄胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-Benzylamine)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1-((1-(2-((噻吩-2-甲基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇1-((1-(2-((thiophen-2-methyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
1-((1-(2-((2-氟苯基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇1-((1-(2-((2-Fluorophenyl)amino)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
1-((1-(2-((2-甲氧乙基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇1-((1-(2-((2-Methoxyethyl)amino)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
1-((1-(2-((2-氯苄基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇1-((1-(2-((2-Chlorobenzyl)amino)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
1-((1-(2-((4-氟苯基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇1-((1-(2-((4-Fluorophenyl)amino)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
1-((1-(2-(苯胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔)环己基-1-醇1-((1-(2-(aniline)pyrimidin-4-yl)-1H-indol-6-yl)acetylene)cyclohexyl-1-ol
1-((1-(2-((3-氯苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔)环己基-1-醇1-((1-(2-((3-chlorophenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)acetylene)cyclohexyl-1-ol
1-((1-(2-((3-氯-4-氟苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-((3-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
3-((4-(6-((1-羟基环己基)乙炔基)-1H-吲哚-1-基)嘧啶-2-基)氨基)苯甲腈3-((4-(6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-1-yl)pyrimidin-2-yl)amino)benzonitrile
1-((1-(2-((4-甲氧基苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-((4-methoxyphenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1-((1-(2-((3-硝基苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-((3-nitrophenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1-((1-(2-(间甲基苯氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-(m-methylphenylamino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1-((1-(2-((4-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-((4-(Trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1-((1-(2-((2-(三氟甲基)苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-((2-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1-((1-(2-(邻甲基苯氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-(O-methylphenylamino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1-((1-(2-((2-氟苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-((2-Fluorophenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1-((1-(2-((2-甲氧基乙基)氨基)嘧啶-4-基)-1H-吲哚-6基)乙炔基)环己基-1-醇1-((1-(2-((2-Methoxyethyl)amino)pyrimidin-4-yl)-1H-indol-6yl)ethynyl)cyclohexyl-1-ol
3-((4-(6-((1-羟基环己基)乙炔基)1H-吲哚-1-基)嘧啶-2-基)氨基)苯磺酰胺3-((4-(6-((1-hydroxycyclohexyl)ethynyl)1H-indol-1-yl)pyrimidin-2-yl)amino)benzenesulfonamide
1-((1-(2-(环己氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-(Cyclohexylamino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)benzamide
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-3-甲基苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-3-methylbenzyl Amide
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-硝基苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-4-nitrobenzyl Amide
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-2-硝基苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-2-nitrobenzyl Amide
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-甲氧基苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-4-methoxybenzene Formamide
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-氟苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-4-fluorobenzamide
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-2-氟苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-2-fluorobenzamide
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-异戊酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-isovaleramide
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-1H-吲哚-6-甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-1H-indole-6 -Formamide
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-1H-吲哚-2-甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-1H-indole-2 -Formamide
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-phenyl-1H-indole-2-carboxamide
乙基1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-羧酸酯Ethyl 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxylate
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡啶-4-基)-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(pyridin-4-yl)-1H-indole-2-carboxamide
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(间甲苯基)-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(m-tolyl)-1H-indole-2-carboxamide
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N,N-二甲基-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N,N-dimethyl-1H-indole-2-carboxamide
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-甲氧基乙基)-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-methoxyethyl)-1H-indole-2-carboxamide
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-羟基乙基)-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-hydroxyethyl)-1H-indole-2-carboxamide
1-(2-氨基嘧啶-4-基)-N-环丙基-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-N-cyclopropyl-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxamide
N-烯丙基-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺N-allyl-1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxamide
1-(2-氨基嘧啶-4-基)-N-乙基-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-N-ethyl-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxamide
1-((1-(2-氨基嘧啶-4-基)-2-(2-羟丙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇的制备Preparation of 1-((1-(2-aminopyrimidin-4-yl)-2-(2-hydroxypropyl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1-((1-(2-氨基嘧啶-4-基)-2-(2-羟基-2-(噻吩-2-基)乙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-Aminopyrimidin-4-yl)-2-(2-hydroxy-2-(thiophen-2-yl)ethyl)-1H-indol-6-yl)ethynyl) ring Hexyl-1-ol
1-((1-(2-氨基嘧啶-4-基)-2-(2-羟基-2-苯乙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-Aminopyrimidin-4-yl)-2-(2-hydroxy-2-phenylethyl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
而且，按照本发明所属领域的一些通常方法，本发明中通式(I)的衍生物可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐，与下列酸加成的盐是特别优 选的：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。Moreover, according to some common methods in the field of the present invention, the derivatives of the general formula (I) in the present invention can form pharmaceutically acceptable salts with acids. Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, and the following acid addition salts are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid , Benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.
此外，本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式(I)的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。In addition, the present invention also includes prodrugs of the derivatives of the present invention. The prodrugs of the derivatives of the present invention are derivatives of the general formula (I), and they may have weak or even no activity by themselves, but after administration, under physiological conditions (for example, by metabolism, solvolysis or other means) ) Is converted into the corresponding biologically active form.
本发明中“卤素”是指氟、氯、溴或碘代；“烷基”是指直链或支链的烷基；“亚烷基”是指直链或支链的亚烷基；“芳基”是指除去芳烃中的一个或不同位置的两个氢原子而得到的有机基团，如苯基、萘基；“杂芳基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系，该环状体系是指具有芳香性的，并且除去环状体系中的一个或不同位置的两个氢原子而得到的有机基团，如噻唑基，咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、呋喃基、噻吩基、吡咯基，吲哚基，苯并噻唑基，噁唑基，异噁唑基，萘基，喹啉基，异喹啉基，苯并咪唑基，苯并噁唑基等；杂环烷基是指含有一个或多个选自N、O、S的杂原子的单环的环状体系，如四氢吡咯烷基、吗啉基、哌嗪基、哌啶基、四氢吡唑烷基、四氢咪唑烷基和四氢噻唑啉基等。In the present invention, "halogen" refers to fluorine, chlorine, bromine or iodine; "alkyl" refers to straight or branched chain alkyl; "alkylene" refers to straight or branched alkylene; "Aryl" refers to an organic group obtained by removing one or two hydrogen atoms at different positions in aromatic hydrocarbons, such as phenyl and naphthyl; "heteroaryl" refers to containing one or more selected from N, O, A monocyclic or polycyclic ring system of S heteroatoms. The ring system refers to an organic group obtained by removing one or two hydrogen atoms at different positions in the ring system, such as thiazole. Group, imidazolyl, pyridyl, pyrazolyl, (1,2,3)-and (1,2,4)-triazolyl, furyl, thienyl, pyrrolyl, indolyl, benzothiazolyl , Oxazolyl, isoxazolyl, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, etc.; heterocycloalkyl means containing one or more selected from N, O , S heteroatom monocyclic ring system, such as tetrahydropyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyrazolidinyl, tetrahydroimidazolidinyl and tetrahydrothiazolinyl Wait.
本发明可以含有通式(I)的衍生物，及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成份，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型，上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用，只要它们不产生其他不利的作用，例如过敏反应。The present invention may contain derivatives of general formula (I), and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as active ingredients, and mixed with pharmaceutically acceptable carriers or excipients to prepare a composition , And prepared into a clinically acceptable dosage form. The above-mentioned pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical field. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
本发明的药用组合物可配制成若干种剂型，其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。The pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some commonly used excipients in the pharmaceutical field. The several dosage forms mentioned above can adopt injections, tablets, capsules, aerosols, suppositories, films, dripping pills, topical liniments, ointments and other dosage forms of drugs.
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下不稳定的，可将其配制成肠衣片剂。The carrier used in the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, including: binders, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents, non-coloring, and flavoring agents , Preservatives, solubilizers and substrates, etc. Pharmaceutical preparations can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.
本发明所述的化合物，及其药学上可接受的盐、水合物、溶剂化物或前药或其药物组合物可以作为蛋白激酶抑制剂，并用于制备抗肿瘤药物。The compounds of the present invention, and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs or their pharmaceutical compositions can be used as protein kinase inhibitors and used to prepare anti-tumor drugs.
所述的蛋白激酶为二类PAK蛋白激酶。The protein kinase is the second type of PAK protein kinase.
本发明还包括所述的化合物，及其药学上可接受的盐、水合物、溶剂化物或前药或其药物组合物治疗由蛋白激酶活性介导的哺乳动物疾病状况的方法，它包含对哺乳动物施以可接受量的本发明的化合物、盐、水合物、溶剂合物或前药。The present invention also includes the compound, and the pharmaceutically acceptable salt, hydrate, solvate or prodrug or the pharmaceutical composition thereof to treat a mammalian disease condition mediated by protein kinase activity, which comprises a method for lactating Animals are administered an acceptable amount of a compound, salt, hydrate, solvate, or prodrug of the invention.
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实例和制备例的范围并不以任何方式限制本发明的范围。按照本发明的式(I)的化合物，可按照以下路线1-7所示的方法制备得来，这些合成路线中应用的全部可变因数如权利要求中的定义。The examples and preparation examples provided below further illustrate and exemplify the compounds of the present invention and the preparation methods thereof. It should be understood that the scope of the following examples and preparation examples does not limit the scope of the present invention in any way. The compound of formula (I) according to the present invention can be prepared according to the methods shown in the following routes 1-7, and all the variable factors used in these synthetic routes are as defined in the claims.
制备式(I)化合物时，可能需要对中间体的远程官能团(例如伯胺或仲胺)进行保护。进行该保护的必要性取决于远程官能团的性质和制备方法的条件。适当的氨基保护包括乙酰基、三氟乙酰基、叔丁氧基羰基(Boc)、苄氧基羰基(CBz)和9-芴基甲氧基羰基(Fmoc)。When preparing the compound of formula (I), it may be necessary to protect the remote functional group (for example, primary or secondary amine) of the intermediate. The necessity of this protection depends on the nature of the remote functional group and the conditions of the preparation method. Suitable amino groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenylmethoxycarbonyl (Fmoc).
本发明的式(I)化合物可按照以下所提出来的流程来合成，其中“R”在每次出现时独立的代表非干扰取代基。The compound of formula (I) of the present invention can be synthesized according to the following proposed scheme, where "R" each time it appears independently represents a non-interfering substituent.
在此，‘Cs 2CO 3’意指碳酸铯，‘DCM’意指二氯甲烷，‘DMF’意指N,N-二甲基甲酰胺，‘DMSO’意指二甲亚砜，‘Et 3N’意指三乙胺，‘EA’意指乙酸乙酯，‘HATU’意指六氟磷酸(二甲基氨基)-N,N-二甲基(3H-[1,2,3]三唑[4,5-b]吡啶-3-基氧基)甲亚基，‘MeOH’意指甲醇，‘THF’意指四氢呋喃，‘TFAA’意指三氟乙酸酐，‘HCl’意指盐酸，‘Boc’意指叔丁氧羰基。 Here,'Cs 2 CO 3 'means cesium carbonate,'DCM' means dichloromethane,'DMF' means N,N-dimethylformamide,'DMSO' means dimethyl sulfoxide,'Et 3 N'means triethylamine,'EA' means ethyl acetate,'HATU' means hexafluorophosphoric acid (dimethylamino)-N,N-dimethyl (3H-[1,2,3] Triazole[4,5-b]pyridin-3-yloxy)methylidene,'MeOH' means methanol,'THF' means tetrahydrofuran,'TFAA' means trifluoroacetic anhydride, and'HCl' means Hydrochloric acid,'Boc' means tert-butoxycarbonyl.
路线1Route 1
Figure PCTCN2021098556-appb-000003
Figure PCTCN2021098556-appb-000003
路线1：示出了制备式(I)化合物的方法，其中W,X,Y,Z和R 1-R 7如权利要求书中所定义。可以在加热条件下DMF中，使用四(三苯基膦)钯(Pd(PPh) 3) 4、CuI以及碱(如Et 3N)使式1的吲哚与炔基醇发生薗头偶合反应(Sonogashira coupling reaction)，得到式(I)化合物。式炔基醇是可商业购买或通过合成方法制备。 Route 1: shows the method of preparing the compound of formula (I), wherein W, X, Y, Z and R 1 -R 7 are as defined in the claims. In DMF under heating conditions, tetrakis (triphenylphosphine) palladium (Pd(PPh) 3 ) 4 , CuI and a base (such as Et 3 N) can be used to make the indole of formula 1 and alkynyl alcohol undergo a coupling reaction (Sonogashira coupling reaction) to obtain the compound of formula (I). Alkynyl alcohols of formula are commercially available or prepared by synthetic methods.
路线2Route 2
Figure PCTCN2021098556-appb-000004
Figure PCTCN2021098556-appb-000004
路线2：将N杂吲哚A-1和2-氨基-4-氯嘧啶在碳酸铯条件下发生亲核反应得中间体A-2，然后通过路线1的方法将A-2发生Sonogashira反应，生成本发明的化合物。Route 2: The N-heteroindole A-1 and 2-amino-4-chloropyrimidine undergo a nucleophilic reaction under the condition of cesium carbonate to obtain intermediate A-2, and then the Sonogashira reaction of A-2 is carried out by the method of Route 1. Cost of the compound of the invention.
路线3Route 3
Figure PCTCN2021098556-appb-000005
Figure PCTCN2021098556-appb-000005
路线3：将6-溴吲哚在三氟乙酸酐和氢氧化钠的处理下，得到中间体A-4的6-溴吲哚-3-羧酸，使用草酰氯和甲醇处理中间体A-5，得酯化中间体A-6；然后将中间体A-6和杂芳烃在适当亲核取代条件下(例如碳酸铯、碳酸钾、叔丁醇钾、氢化钠)相混合，已形成N-杂芳基化的吲哚；将化合物A-7与炔基醇在适当的Sonogashira型钯介导的偶联条件下相混合以得到化合物A-8(如路线1)，最后在氢氧化钠条件下水解并与不同的伯胺或仲胺进行缩合以形成本发明化合物，例如化合物A-10。Route 3: The 6-bromoindole is treated with trifluoroacetic anhydride and sodium hydroxide to obtain the 6-bromoindole-3-carboxylic acid of intermediate A-4, and the intermediate A- is treated with oxalyl chloride and methanol 5. The esterification intermediate A-6 is obtained; then the intermediate A-6 and heteroaromatics are mixed under appropriate nucleophilic substitution conditions (such as cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium hydride) to form N -Heteroarylated indole; mixing compound A-7 with alkynyl alcohol under appropriate Sonogashira-type palladium-mediated coupling conditions to obtain compound A-8 (as in Route 1), and finally in sodium hydroxide Under conditions, it is hydrolyzed and condensed with different primary or secondary amines to form the compound of the present invention, such as compound A-10.
路线4Route 4
Figure PCTCN2021098556-appb-000006
Figure PCTCN2021098556-appb-000006
路线4：将原料6-溴吲哚使用三氯氧磷处理以得到3-醛基取代吲哚，然后将中间体A-11和盐酸羟胺、醋酸钠、乙酸酐、乙酸混合加热处理得氰基取代中间体A-12，将A-11和A-12分别和芳杂烃在碱碳酸铯条件下相混合，得N-杂芳基化吲哚得A-13、A-14，再将A-14氧化的中间体A-15，最后可通过路线1的方法将A-13、A-14、A-15发生Sonogashira反应，生成本发明的化合物。Route 4: The raw material 6-bromoindole is treated with phosphorus oxychloride to obtain 3-aldehyde substituted indole, and then the intermediate A-11 is mixed with hydroxylamine hydrochloride, sodium acetate, acetic anhydride, and acetic acid to obtain a cyano group. Substituting intermediate A-12, mixing A-11 and A-12 with aromatic heterohydrocarbons under alkaline cesium carbonate conditions to obtain N-heteroarylated indole to obtain A-13 and A-14, and then A -14 oxidized intermediate A-15, and finally A-13, A-14, and A-15 can undergo Sonogashira reaction by the method of Route 1 to produce the compound of the present invention.
路线5Route 5
Figure PCTCN2021098556-appb-000007
Figure PCTCN2021098556-appb-000007
路线5：将吲哚B-1和双氯代杂芳烃在叔丁醇钾处理下得到N-杂芳烃B-2，然后在酸催化下和不同取代胺发生亲核反应得胺代中间体B-3，最后可通过路线1的方法将B-3发生Sonogashira反应，生成本发明的化合物。Route 5: Treat indole B-1 and dichloroheteroarene with potassium tert-butoxide to obtain N-heteroarene B-2, and then nucleophilic reaction with different substituted amines under acid catalysis to obtain amino intermediate B- 3. Finally, the Sonogashira reaction of B-3 can be carried out by the method of Route 1 to produce the compound of the present invention.
路线6Route 6
Figure PCTCN2021098556-appb-000008
Figure PCTCN2021098556-appb-000008
路线6：本路线根据杂芳环起始原料的不同合成C-5的方法可分为两种，方法1：将5-溴-2-碘苯胺在酸催化下和杂芳环混合得中间体C-2，然后和不同炔基扣环得到中间体C-3，然后使用mCPBA氧化后进行亲核取代得中间体C-5。方法2：将5-溴-2-碘苯胺和杂芳环酸性条件下混合加热得中间体C-10，C-10和不同炔基环合得中间体C-5。然后根据炔基取代的不同分别处理，最后可通过路线1的方法将C-8和C-9发生Sonogashira反应，生成本发明的化合物。Route 6: This route can be divided into two methods for the synthesis of C-5 according to the different starting materials of the heteroaromatic ring. Method 1: Mixing 5-bromo-2-iodoaniline with the heteroaromatic ring under acid catalysis to obtain an intermediate C-2, then buckle with different alkynyl groups to obtain intermediate C-3, and then use mCPBA to perform nucleophilic substitution to obtain intermediate C-5. Method 2: Mixing and heating 5-bromo-2-iodoaniline and heteroaromatic ring under acidic conditions to obtain intermediate C-10, C-10 and different alkynyl rings are combined to obtain intermediate C-5. Then, they are treated separately according to the different alkynyl substitutions. Finally, the Sonogashira reaction of C-8 and C-9 can be carried out by the method of Route 1 to produce the compound of the present invention.
路线7：Route 7:
Figure PCTCN2021098556-appb-000009
Figure PCTCN2021098556-appb-000009
路线7：以4-溴-2-硝基甲苯为起始原料和草酸二乙酯在叔丁醇钾的作用下生成中间体C-12，然后在铁酸还原条件下进行还原环化得关键中间体吲哚C-13。氯代杂芳基在TMS溴的作用下生成溴代杂芳基，然后与C-13在碘化亚铜催化偶联条件下得N-杂芳烃，然后使用mCPBA氧化并使用不同氨基进行亲核取代得中间体C-17，中间体C-17在碱性条件下水解，然后做缩合反应得中间体C-19。最后可通过路线1的方法将C-19发生Sonogashira反应，生成本发明的化合物。Route 7: Using 4-bromo-2-nitrotoluene as the starting material and diethyl oxalate under the action of potassium tert-butoxide to generate intermediate C-12, then reductive cyclization under ferric acid reduction conditions is the key Intermediate indole C-13. Chloro-heteroaryl groups generate bromo-heteroaryl groups under the action of TMS bromine, which is then coupled with C-13 under cuprous iodide catalyzed coupling conditions to obtain N-heteroaromatics, and then use mCPBA to oxidize and use different amino groups for nucleophilicity Substitution to obtain intermediate C-17, intermediate C-17 is hydrolyzed under alkaline conditions, and then undergoes condensation reaction to obtain intermediate C-19. Finally, the Sonogashira reaction of C-19 can be carried out by the method of Route 1 to produce the compound of the present invention.
具体实施方式：detailed description:
通过参考一下实施例可更充分的理解本发明。然而，他们不应该被解释成为对本发明范围的限制。这些实施例的目的不是限制本发明的范围，而是为熟练技术人员提供指导以制备和使用本发明化合物、组合物的方法。虽然描述了本发明的特定实施方案，但熟练的技术人员会意识到可进行各种改变和修饰而不偏离本发明的精神实质和范围。The present invention can be more fully understood by referring to the following examples. However, they should not be construed as limiting the scope of the present invention. The purpose of these examples is not to limit the scope of the present invention, but to provide guidance for the skilled artisan to prepare and use the compounds and compositions of the present invention. Although specific embodiments of the present invention have been described, those skilled in the art will recognize that various changes and modifications can be made without departing from the spirit and scope of the present invention.
实施例1：Example 1:
1-((1-(2-氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-Aminopyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
Figure PCTCN2021098556-appb-000010
Figure PCTCN2021098556-appb-000010
4-(6-溴-1H-吲哚-1-基)嘧啶-2-胺的制备Preparation of 4-(6-bromo-1H-indol-1-yl)pyrimidin-2-amine
Figure PCTCN2021098556-appb-000011
Figure PCTCN2021098556-appb-000011
步骤1：将化合物A-1(1.9g,9.8mmol)溶于20mL DMF中，再加入碳酸铯(6.4g,19.6mmol),常温搅拌10min，再加入2-氨基-4-氯嘧啶(1.34g,10.3mmol)，升温至100℃反应5h后，将反应液冷却至室温后，倒入100mL的水中，有大量固体析出，洗涤，干燥得产品2.45g，产率86.7％。ESI-MS(m/z)：289[M+H] +。 Step 1: Dissolve compound A-1 (1.9g, 9.8mmol) in 20mL DMF, then add cesium carbonate (6.4g, 19.6mmol), stir at room temperature for 10min, then add 2-amino-4-chloropyrimidine (1.34g , 10.3mmol), after the reaction was heated to 100°C for 5h, the reaction solution was cooled to room temperature and poured into 100mL of water. A large amount of solids were precipitated out, washed and dried to obtain 2.45g of product, with a yield of 86.7%. ESI-MS (m/z): 289 [M+H] + .
1-((1-(2-氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇的制备Preparation of 1-((1-(2-aminopyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
步骤2：将化合物A-2(1.25g,4.32mmol)加入20mL的无水DMF中，再在溶液中加入无水TEA(3mL,21.6mmol)和环己基炔醇(0.81g,6.48mmol)，在氮气环境下超声，使溶液中的氧气排尽，再加入CuI(0.16g,0.86mmol)，和四三苯基磷钯(0.25g,0.22mmol)，在氮气保护下，升温至80℃反应6h。将反应液冷却至室温，然后倒入80mL的水中，再用EA(60*3mL)萃取，之后用饱和食盐水洗涤EA层，加入无水硫酸钠除水，再悬干EA层得化合物粗品。柱层析PE:EA＝1:1，得淡黄色产品0.95g，产率66％。 1H NMR(600MHz, DMSO-d 6)δ8.66(d,J＝1.2Hz,1H),8.30(d,J＝5.6Hz,1H),8.09(d,J＝3.6Hz,1H),7.60(d,J＝8.1Hz,1H),7.22(dd,J＝8.1,1.4Hz,1H),6.97–6.88(m,3H),6.79(d,J＝3.5Hz,1H),5.36(s,1H),1.93–1.46(m,10H).ESI-MS(m/z)：333.1740[M+H] +。 Step 2: Add compound A-2 (1.25g, 4.32mmol) to 20mL of anhydrous DMF, then add anhydrous TEA (3mL, 21.6mmol) and cyclohexylalkynol (0.81g, 6.48mmol) to the solution, Ultrasound in a nitrogen environment to exhaust the oxygen in the solution, then add CuI (0.16g, 0.86mmol), and tetrakistriphenylphosphonium palladium (0.25g, 0.22mmol), under the protection of nitrogen, increase the temperature to 80℃ for reaction 6h. The reaction solution was cooled to room temperature, then poured into 80 mL of water, and then extracted with EA (60*3 mL), then the EA layer was washed with saturated brine, anhydrous sodium sulfate was added to remove water, and the EA layer was suspended and dried to obtain a crude compound. Column chromatography PE:EA=1:1, 0.95g of light yellow product was obtained, and the yield was 66%. 1 H NMR(600MHz, DMSO-d 6 )δ8.66(d,J=1.2Hz,1H), 8.30(d,J=5.6Hz,1H), 8.09(d,J=3.6Hz,1H), 7.60 (d,J=8.1Hz,1H), 7.22(dd,J=8.1,1.4Hz,1H), 6.97–6.88(m,3H), 6.79(d,J=3.5Hz,1H), 5.36(s, 1H), 1.93–1.46 (m, 10H). ESI-MS (m/z): 333.1740 [M+H] + .
按照实施例1的方法，可与不同的N杂吲哚进行反应来进行实施例2-6的制备。According to the method of Example 1, the preparation of Examples 2-6 can be carried out by reacting with different N-heteroindoles.
实施例2：1-((1-(2-氨基嘧啶-4-基)-5-氟-1H-吲哚-6-基)乙炔基)环己基-1-醇Example 2: 1-((1-(2-Aminopyrimidin-4-yl)-5-fluoro-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1H NMR(600MHz,DMSO-d 6)δ8.76(d,J＝6.3Hz,1H),8.41(s,1H),8.19(d,J＝3.6Hz,1H),7.50(d,J＝9.6Hz,1H),7.10–6.90(m,3H),6.79(d,J＝3.5Hz,1H),5.45(s,1H),1.98–1.43(m,10H).ESI-MS(m/z)：351.1620[M+H] +。 1 H NMR(600MHz,DMSO-d 6 )δ8.76(d,J=6.3Hz,1H), 8.41(s,1H), 8.19(d,J=3.6Hz,1H), 7.50(d,J= 9.6Hz,1H),7.10–6.90(m,3H),6.79(d,J=3.5Hz,1H),5.45(s,1H),1.98–1.43(m,10H).ESI-MS(m/z ): 351.1620[M+H] + .
实施例3：1-((1-(2-氨基嘧啶-4-基)1H-吡咯[3,2-b]并吡啶-6-基)乙炔基)环己基-1-醇Example 3: 1-((1-(2-Aminopyrimidin-4-yl)1H-pyrrole[3,2-b]pyridin-6-yl)ethynyl)cyclohexyl-1-ol
1H NMR(600MHz,DMSO-d 6)δ9.02(d,J＝1.6Hz,1H),8.50(s,1H),8.46(d,J＝3.7Hz,1H),8.34(d,J＝5.6Hz,1H),7.08(s,2H),7.02(d,J＝5.6Hz,1H),6.93(d,J＝3.6Hz,1H),5.47(s,1H),1.96–1.46(m,10H).ESI-MS(m/z)：333.1667[M+H] +。 1 H NMR(600MHz,DMSO-d 6 )δ9.02(d,J=1.6Hz,1H), 8.50(s,1H), 8.46(d,J=3.7Hz,1H), 8.34(d,J= 5.6Hz, 1H), 7.08 (s, 2H), 7.02 (d, J = 5.6 Hz, 1H), 6.93 (d, J = 3.6 Hz, 1H), 5.47 (s, 1H), 1.96–1.46 (m, 10H). ESI-MS (m/z): 333.1667 [M+H] + .
实施例4：1-((1-(2-氨基嘧啶-4-基)-1H-吲唑-6-基)乙炔基)环己基-1-醇Example 4: 1-((1-(2-Aminopyrimidin-4-yl)-1H-indazol-6-yl)ethynyl)cyclohexyl-1-ol
1H NMR(600MHz,DMSO-d 6)δ8.89(s,1H),8.50(s,1H),8.32(d,J＝5.5Hz,1H),7.89(d,J＝8.2Hz,1H),7.36(dd,J＝8.1,1.3Hz,1H),7.12(d,J＝5.5Hz,1H),7.06(s,2H),5.48(s,1H),2.00–1.43(m,10H).ESI-MS(m/z)：333.1667[M+H] +。 1 H NMR(600MHz,DMSO-d 6 )δ8.89(s,1H),8.50(s,1H),8.32(d,J=5.5Hz,1H),7.89(d,J=8.2Hz,1H) , 7.36 (dd, J = 8.1, 1.3 Hz, 1H), 7.12 (d, J = 5.5 Hz, 1H), 7.06 (s, 2H), 5.48 (s, 1H), 2.00-1.43 (m, 10H). ESI-MS (m/z): 333.1667 [M+H] + .
实施例5：1-((2-氨基嘧啶-4-基)-1H-吡咯[2,3-b]并吡啶-6-基)乙炔基)环己基-1-醇Example 5: 1-((2-Aminopyrimidin-4-yl)-1H-pyrrole[2,3-b]pyridin-6-yl)ethynyl)cyclohexyl-1-ol
1H NMR(600MHz,DMSO-d 6)δ8.42(d,J＝5.2Hz,1H),8.40(d,J＝4.0Hz,1H),8.10(d,J＝5.0Hz,1H),8.08(d,J＝2.4Hz,1H),7.39(d,J＝8.0Hz,1H),6.82(s,2H),6.81(s,1H),5.60(s,1H),1.99–1.43(m,10H).ESI-MS(m/z)：333.1667[M+H] +。 1 H NMR(600MHz,DMSO-d 6 )δ8.42(d,J=5.2Hz,1H), 8.40(d,J=4.0Hz,1H), 8.10(d,J=5.0Hz,1H), 8.08 (d,J=2.4Hz,1H),7.39(d,J=8.0Hz,1H),6.82(s,2H),6.81(s,1H),5.60(s,1H),1.99–1.43(m, 10H). ESI-MS (m/z): 333.1667 [M+H] + .
实施例6：1-((2-氨基嘧啶-4-基)-1H-吡咯[3,2-c]并吡啶-6-基)乙炔基)环己基-1-醇Example 6: 1-((2-Aminopyrimidin-4-yl)-1H-pyrrole[3,2-c]pyridin-6-yl)ethynyl)cyclohexyl-1-ol
1H NMR(600MHz,DMSO-d 6)δ8.86(d,J＝1.1Hz,1H),8.62(t,J＝0.9Hz,1H),8.34(d,J＝5.5Hz,1H),8.20(d,J＝3.6Hz,1H),7.07(s,2H),7.00(d,J＝5.6Hz,1H),6.94(dd,J＝3.6,0.8Hz,1H),5.46(s,1H),1.92–1.47(m,10H).ESI-MS(m/z)：333.1667[M+H] +。 1 H NMR (600MHz, DMSO-d 6 ) δ 8.86 (d, J = 1.1 Hz, 1H), 8.62 (t, J = 0.9 Hz, 1H), 8.34 (d, J = 5.5 Hz, 1H), 8.20 (d,J=3.6Hz,1H), 7.07(s,2H), 7.00(d,J=5.6Hz,1H), 6.94(dd,J=3.6,0.8Hz,1H), 5.46(s,1H) ,1.92–1.47(m,10H). ESI-MS(m/z): 333.1667[M+H] + .
实施例7：Example 7:
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌嗪-1-基)甲酮的制备Preparation of (1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(piperazin-1-yl)methanone
Figure PCTCN2021098556-appb-000012
Figure PCTCN2021098556-appb-000012
6-溴吲哚-3-羧酸的制备Preparation of 6-bromoindole-3-carboxylic acid
Figure PCTCN2021098556-appb-000013
Figure PCTCN2021098556-appb-000013
步骤1：将6-溴吲哚(5g,25.5mmol)，溶于30mL DMF中，在冰浴下，缓慢(10min左右)滴加三氟乙酸酐(4.3mL,30.6mmol),常温下反应1.5h。然后将反应液倒入100ml冰水中，析出类白色固体，抽滤得粗产品。Step 1: Dissolve 6-bromoindole (5g, 25.5mmol) in 30mL DMF, slowly (about 10min) add trifluoroacetic anhydride (4.3mL, 30.6mmol) dropwise under ice bath, and react at room temperature for 1.5 h. Then, the reaction solution was poured into 100 ml of ice water to precipitate an off-white solid, which was filtered with suction to obtain a crude product.
然后将上一步的粗品加入100mL的20％NaOH溶液中，加热至回流反应3h，将反应液冷却后，使用EA(50*3mL)萃取水层，然后弃去有机层。使用6M的盐酸调节pH到3-4，有大量固体析出，抽滤，然后使用水洗涤至pH为中性，干燥得产品5.2g，产率84.9％。ESI-MS(m/z)：239[M-H] -。 Then the crude product from the previous step was added to 100 mL of 20% NaOH solution, heated to reflux and reacted for 3 hours, after cooling the reaction solution, the aqueous layer was extracted with EA (50*3 mL), and then the organic layer was discarded. Using 6M hydrochloric acid to adjust the pH to 3-4, a large amount of solids were precipitated, filtered with suction, then washed with water until the pH was neutral, and dried to obtain 5.2 g of the product, with a yield of 84.9%. ESI-MS (m/z): 239 [MH] - .
6-溴-1H-吲哚-3-羧酸甲酯的制备Preparation of 6-bromo-1H-indole-3-carboxylic acid methyl ester
Figure PCTCN2021098556-appb-000014
Figure PCTCN2021098556-appb-000014
步骤2：将中间体A-4(3.7g,15.4mmol)加入25mL DCM中，化合物3并不全溶，此时可以在搅拌下加入3滴的DMF，然后将草酰氯(6.6mL,77.1mmol)溶于10mL的DCM中，缓慢滴加入化合物中，室温反应2h，将反应液减压蒸馏去除溶剂和多余草酰氯，然后将上述固体重新溶于20mL的DCM中，然后逐滴加入30mL无水甲醇和三乙胺(6mL，46.2mmol)的混合溶液中，反应1h。将反应液加圧蒸留除去溶剂，然后用水洗涤固体3次，干燥后得化合物A-6 3.85g，收率98.4％。ESI-MS(m/z)：254[M+H] +。 Step 2: Add Intermediate A-4 (3.7g, 15.4mmol) to 25mL DCM. Compound 3 is not completely dissolved. At this time, 3 drops of DMF can be added with stirring, and then oxalyl chloride (6.6mL, 77.1mmol) Dissolved in 10mL of DCM, slowly added dropwise to the compound, reacted at room temperature for 2h, the reaction solution was distilled under reduced pressure to remove the solvent and excess oxalyl chloride, then the above solid was re-dissolved in 20mL of DCM, and then 30mL of anhydrous methanol was added dropwise In a mixed solution of triethylamine (6 mL, 46.2 mmol), react for 1 h. The reaction solution was pressurized and evaporated to remove the solvent, and then the solid was washed with water three times, and after drying, 3.85 g of compound A-6 was obtained, with a yield of 98.4%. ESI-MS (m/z): 254 [M+H] + .
1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-3-羧酸甲酯的制备Preparation of 1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indole-3-carboxylic acid methyl ester
Figure PCTCN2021098556-appb-000015
Figure PCTCN2021098556-appb-000015
步骤3：将中间体A-6(2.5g,9.8mmol)溶于30mL DMF中，再加入碳酸铯(6.4g,19.6mmol),常温搅拌10min，再加入2-氨基-4-氯嘧啶(1.34g,10.3mmol)，升温至100℃反应5h后，将反应液冷却至室温后，倒入100mL的水中，有大量固体析出，洗涤，干燥得产品2.95g，产率86.7％。ESI-MS(m/z)：347[M+H] +。 Step 3: Dissolve Intermediate A-6 (2.5g, 9.8mmol) in 30mL DMF, then add cesium carbonate (6.4g, 19.6mmol), stir at room temperature for 10min, then add 2-amino-4-chloropyrimidine (1.34 g, 10.3 mmol), the reaction was heated to 100°C for 5 hours, the reaction solution was cooled to room temperature, and poured into 100 mL of water. A large amount of solids were precipitated, washed, and dried to obtain 2.95 g of the product, with a yield of 86.7%. ESI-MS (m/z): 347 [M+H] + .
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羧酸甲酯的制备Preparation of 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carboxylic acid methyl ester
Figure PCTCN2021098556-appb-000016
Figure PCTCN2021098556-appb-000016
步骤4：将中间体A-7(1.5g,4.32mmol)加入20mL的无水DMF中，再在溶液中加入无水TEA(3mL,21.6mmol)和环己基炔醇(0.81g,6.48mmol)，在氮气环境下超声，使溶液中的氧气排尽，再加入CuI(0.16g,0.86mmol)，和四三苯基磷钯(0.25g,0.22mmol)，在氮气保护下，升温至80℃反应6h。将反应液冷却至室温，然后倒入80mL的水中，再用EA(60*3mL)萃取，之后用饱和食盐水洗涤EA层，加入无水硫酸钠除水，再将有机层干燥得化合物粗品。柱层析PE:EA＝1:1，得淡黄色产品1.12g，产率66％。86.7％。ESI-MS(m/z)：390[M+H] +。 Step 4: Add Intermediate A-7 (1.5g, 4.32mmol) to 20mL of anhydrous DMF, then add anhydrous TEA (3mL, 21.6mmol) and cyclohexylalkynol (0.81g, 6.48mmol) to the solution , Ultrasound in a nitrogen environment to exhaust the oxygen in the solution, then add CuI (0.16g, 0.86mmol), and tetrakistriphenylphosphonium palladium (0.25g, 0.22mmol), under the protection of nitrogen, increase the temperature to 80℃ Reaction 6h. The reaction solution was cooled to room temperature, then poured into 80 mL of water, and then extracted with EA (60*3 mL), then the EA layer was washed with saturated brine, anhydrous sodium sulfate was added to remove water, and the organic layer was dried to obtain a crude compound. Column chromatography PE:EA=1:1, 1.12g of light yellow product was obtained, and the yield was 66%. 86.7%. ESI-MS (m/z): 390 [M+H] + .
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羧酸的制备Preparation of 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carboxylic acid
Figure PCTCN2021098556-appb-000017
Figure PCTCN2021098556-appb-000017
步骤5：将中间体A-8(1g,2.56mmol)溶于30mL混合溶液(THF：H 2O＝1:1)中，再加入NaOH(0.41g,10.24mmol),升温至60℃反应。反应结束后加入20mL水，用EA多次萃取反应液，直至没有荧光为止，弃去有机层，用1M HCl调节水层PH至6-7，大量固体析出，抽滤，洗涤滤饼至中性，干燥得产品0.72g，产率75％。ESI-MS(m/z)：375[M-H] -。 Step 5: Intermediate A-8 (1 g, 2.56 mmol) was dissolved in 30 mL of mixed solution (THF: H 2 O=1:1), and NaOH (0.41 g, 10.24 mmol) was added, and the temperature was raised to 60° C. for reaction. After the reaction, add 20 mL of water, extract the reaction solution with EA several times until there is no fluorescence, discard the organic layer, adjust the pH of the water layer to 6-7 with 1M HCl, a large amount of solids precipitate out, filter with suction, and wash the filter cake until it is neutral , And dried to obtain 0.72 g of the product, with a yield of 75%. ESI-MS (m/z): 375 [MH] - .
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌嗪-1-基)甲酮的制备Preparation of (1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(piperazin-1-yl)methanone
步骤6：将化合物A-9(0.2g,0.53mmol)溶于10mL DMF中，冰浴下加入HATU(0.22g,0.58mmol)和三乙胺(0.22mL,1.59mmol),搅拌10min，再加入哌嗪(94.8mg，1.1mmol)，室温反应1h。反应结束后将反应液倒入40mL的水中，再用EA萃取至有机层无荧光，之后用饱和食盐水洗涤EA层，加入无水硫酸钠除水后，柱层析DCM：MeOH＝5:1。 1H NMR(400MHz,DMSO-d 6)δ8.66(d,J＝1.3Hz,1H),8.35–8.31(m,2H),7.65(d,J＝8.2Hz,1H),7.29(dd,J＝8.2,1.5Hz,1H),7.03(d,J＝6.0Hz,3H),5.41(s,1H),3.58(t,J＝4.9Hz,4H),2.77(t,J＝5.0Hz,4H),1.92–1.48(m,11H).HRMS(ESI+)[M+H] +:445.2351. Step 6: Dissolve compound A-9 (0.2g, 0.53mmol) in 10mL DMF, add HATU (0.22g, 0.58mmol) and triethylamine (0.22mL, 1.59mmol) under ice bath, stir for 10min, then add Piperazine (94.8 mg, 1.1 mmol) was reacted at room temperature for 1 h. After the reaction, the reaction solution was poured into 40 mL of water, and then extracted with EA until the organic layer had no fluorescence. Then, the EA layer was washed with saturated brine, anhydrous sodium sulfate was added to remove water, column chromatography DCM: MeOH = 5:1 . 1 H NMR(400MHz,DMSO-d 6 )δ8.66(d,J=1.3Hz,1H), 8.35–8.31(m,2H), 7.65(d,J=8.2Hz,1H), 7.29(dd, J = 8.2, 1.5 Hz, 1H), 7.03 (d, J = 6.0 Hz, 3H), 5.41 (s, 1H), 3.58 (t, J = 4.9 Hz, 4H), 2.77 (t, J = 5.0 Hz, 4H),1.92–1.48(m,11H).HRMS(ESI+)[M+H] + :445.2351.
实施例8：Example 8:
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺的制备Preparation of 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carboxamide
Figure PCTCN2021098556-appb-000018
Figure PCTCN2021098556-appb-000018
6-溴-1H-吲哚-3-甲醛的制备Preparation of 6-bromo-1H-indole-3-carbaldehyde
Figure PCTCN2021098556-appb-000019
Figure PCTCN2021098556-appb-000019
步骤1：将25ml DMF滴于50ml三颈瓶中，抽真空，用氮气加以保护。在零度冰浴下，向50ml三颈瓶缓慢滴加2.85ml的三氯氧磷，使其搅拌30分钟左右，溶液变为澄清透明。将6-溴吲哚(5.0g,25.5mmol)用15ml DMF溶解，滴入滴液漏斗中，嘧封，缓慢滴加，放置至室温搅拌1小时左右。检测反应完全后，将反应液逐滴加入5％NaOH(200ml)溶液中，加以淬灭。有大量白色固体析出，过滤，滤液可用乙酸乙酯萃取提高产率，得终产物5.2g，产率为91.2％。ESI-MS(m/z)：224[M+H] +。 Step 1: Drop 25ml DMF into a 50ml three-necked flask, evacuate, and protect with nitrogen. In a zero-degree ice bath, slowly drop 2.85ml of phosphorus oxychloride into a 50ml three-necked flask, and let it stir for about 30 minutes, the solution becomes clear and transparent. Dissolve 6-bromoindole (5.0g, 25.5mmol) with 15ml DMF, drop it into the dropping funnel, seal it, add slowly, place it to room temperature and stir for about 1 hour. After detecting the completion of the reaction, the reaction solution was added dropwise to a 5% NaOH (200 ml) solution for quenching. A large amount of white solid precipitated, filtered, and the filtrate can be extracted with ethyl acetate to increase the yield, to obtain 5.2 g of the final product, with a yield of 91.2%. ESI-MS (m/z): 224 [M+H] + .
6-溴-1H-吲哚-3-甲腈的制备Preparation of 6-bromo-1H-indole-3-carbonitrile
Figure PCTCN2021098556-appb-000020
Figure PCTCN2021098556-appb-000020
步骤2：将中间体A-11(5.7g,25.45mM)溶于65mL冰醋酸中，然后依次加入醋酸钠(3.13g,38.17mM)、盐酸羟胺(7.1g,101.78mM)，90℃反应1h，然后加入醋酐(5.2g,50.9mM)，加热至回流反应4h。反应结束后，将反应液倒入150mL水中，然后分别用水，饱和碳酸氢钠，1N稀盐酸和饱和食盐水洗涤，并用无水硫酸钠干燥。加压干燥得暗红色粗产品2.8g(产率为50％)。ESI-MS(m/z)：221[M+H] +。 Step 2: Dissolve Intermediate A-11 (5.7g, 25.45mM) in 65mL of glacial acetic acid, then add sodium acetate (3.13g, 38.17mM) and hydroxylamine hydrochloride (7.1g, 101.78mM) in sequence, and react at 90℃ for 1h , Then add acetic anhydride (5.2g, 50.9mM), heat to reflux and react for 4h. After the reaction, the reaction solution was poured into 150 mL of water, and then washed with water, saturated sodium bicarbonate, 1N dilute hydrochloric acid and saturated brine, and dried with anhydrous sodium sulfate. 2.8 g of dark red crude product was obtained by pressure drying (50% yield). ESI-MS (m/z): 221 [M+H] + .
1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-3-甲腈1-(2-Aminopyrimidin-4-yl)-6-bromo-1H-indole-3-carbonitrile
Figure PCTCN2021098556-appb-000021
Figure PCTCN2021098556-appb-000021
将中间体A-12(2.73g,12.35mM)溶于50mL DMF中，加入碳酸铯(12g,37.5mM),室温搅拌30min后，加入2-氨基-4-氯嘧啶(1.68g,12.96mM)，加热至80℃反应7h。将反应液倒入150mL水中，搅拌30min后抽滤，并用水洗涤、干燥，得产品3.41g(产率87.8％)。ESI-MS(m/z)：314[M+H] + Intermediate A-12 (2.73g, 12.35mM) was dissolved in 50mL DMF, cesium carbonate (12g, 37.5mM) was added, after stirring for 30min at room temperature, 2-amino-4-chloropyrimidine (1.68g, 12.96mM) was added , Heat to 80°C for 7h. The reaction solution was poured into 150 mL of water, stirred for 30 min, filtered with suction, washed with water, and dried to obtain 3.41 g of the product (yield 87.8%). ESI-MS(m/z): 314[M+H] +
1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-bromo-1H-indole-3-carboxamide
Figure PCTCN2021098556-appb-000022
Figure PCTCN2021098556-appb-000022
将中间体A-14(2.19g,6.99mM)溶于15mL DMSO中，冰浴下加入碳酸钾(2g)和30％过氧化氢，将反应液加热至室温(反应中会有剧烈放热)，10min后，稀释至150mL水中，冷却，将产物过滤收集，并使用30mL乙酸乙酯打浆处理，得淡黄色纯品2.0g(产率87.6％)。Dissolve Intermediate A-14 (2.19g, 6.99mM) in 15mL DMSO, add potassium carbonate (2g) and 30% hydrogen peroxide under ice bath, and warm the reaction solution to room temperature (there will be a violent exotherm during the reaction) After 10 minutes, it was diluted into 150 mL of water, cooled, and the product was collected by filtration, and treated with 30 mL of ethyl acetate to obtain 2.0 g of pure light yellow product (yield 87.6%).
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)acetylene)-1H-indole-3-carboxamide
将中间体A-15(3.6g，10.85mM)，乙炔基环己醇(2.7g，21.71mM)，TEA(7.75mL， 54.25mM)溶于40mL DMF中，超声除气泡，并使用氩气保护下，加入CuI(0.42g，2.17mM)，四三苯基膦钯(0.63g，0.54mM)，抽真空氮气保护，80℃温度下反应五小时，将反应液倒入水中，萃取，洗涤，干燥，然后柱层析(MeOH:DCM＝1:50),得淡黄色粉末状产品2.5g(产率64.4％)。 1H NMR(600MHz,DMSO-d 6)δ8.78(s,1H),8.60(s,1H),8.46–8.35(m,1H),8.23(d,J＝8.2Hz,1H),7.74(s,1H),7.35–7.29(m,1H),7.21(s,1H),7.10(s,2H),6.87(d,J＝5.5Hz,1H),5.42(s,1H),1.99–1.41(m,10H).HRMS(ESI+)[M+H] +:375.4322. Intermediate A-15 (3.6g, 10.85mM), ethynylcyclohexanol (2.7g, 21.71mM), TEA (7.75mL, 54.25mM) were dissolved in 40mL DMF, ultrasonicated to remove air bubbles, and protected with argon Add CuI (0.42g, 2.17mM), tetrakistriphenylphosphine palladium (0.63g, 0.54mM), vacuum nitrogen protection, react at 80℃ for five hours, pour the reaction solution into water, extract, wash, After drying, and then column chromatography (MeOH:DCM=1:50), 2.5 g (yield 64.4%) of a pale yellow powder was obtained. 1 H NMR(600MHz,DMSO-d 6 )δ8.78(s,1H),8.60(s,1H),8.46-8.35(m,1H),8.23(d,J=8.2Hz,1H),7.74( s,1H),7.35–7.29(m,1H),7.21(s,1H),7.10(s,2H),6.87(d,J=5.5Hz,1H),5.42(s,1H),1.99–1.41 (m,10H).HRMS(ESI+)[M+H] + :375.4322.
按照实施例7和8的方法，可与适当的伯胺或仲胺进行反应来进行实施例9-39的制备。According to the methods of Examples 7 and 8, the preparation of Examples 9-39 can be carried out by reacting with appropriate primary or secondary amines.
实施例9：1-((1-(2,6-二氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇Example 9: 1-((1-(2,6-Diaminopyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1H-NMR(600MHz,DMSO-d 6,ppm)δ:1.48-1.60(m,6H),1.65-1.66(m,2H),1.86-1.89(m,2H),5.36(s,1H),5.93(s,1H),6.22(s,2H),6.50(s,2H),6.69(d,J＝3.4Hz,1H),7.16(dd,J＝1.02Hz,J＝8.1Hz,1H),7.58(d,J＝8.1Hz,1H),7.85(d,J＝3.42Hz,1H),8.31(s,1H).HRMS(ESI+)[M+H] +:348.1829 1 H-NMR (600MHz, DMSO-d 6 , ppm) δ: 1.48-1.60 (m, 6H), 1.65-1.66 (m, 2H), 1.86-1.89 (m, 2H), 5.36 (s, 1H), 5.93(s,1H), 6.22(s,2H), 6.50(s,2H), 6.69(d,J=3.4Hz,1H), 7.16(dd,J=1.02Hz,J=8.1Hz,1H), 7.58(d,J=8.1Hz,1H),7.85(d,J=3.42Hz,1H),8.31(s,1H).HRMS(ESI+)[M+H] + :348.1829
实施例10：1-(2-氨基嘧啶-4-基)-6-(1-羟基环己基)乙炔基)-1H-吲哚-3-甲醛Example 10: 1-(2-Aminopyrimidin-4-yl)-6-(1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carbaldehyde
1H NMR(600MHz,DMSO-d 6)δ10.07(s,1H),9.03(s,1H),8.58(s,1H),8.47(s,1H),8.16(d,J＝8.2Hz,1H),7.41(d,J＝9.5Hz,1H),7.17(s,2H),7.06(d,J＝5.2Hz,1H),5.42(s,1H),1.95–1.46(m,10H).HRMS(ESI+)[M+Na] +:383.1477. 1 H NMR(600MHz,DMSO-d 6 )δ10.07(s,1H), 9.03(s,1H), 8.58(s,1H), 8.47(s,1H), 8.16(d,J=8.2Hz, 1H), 7.41 (d, J = 9.5 Hz, 1H), 7.17 (s, 2H), 7.06 (d, J = 5.2 Hz, 1H), 5.42 (s, 1H), 1.95-1.46 (m, 10H). HRMS(ESI+)[M+Na] + :383.1477.
实施例11：(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(吡咯-1-基)甲酮Example 11: (1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(pyrrol-1-yl)methanone
1H NMR(600MHz,DMSO-d 6)δ8.66(s,1H),8.40(s,1H),8.30(s,1H),7.62(d,J＝8.2Hz,1H),7.32–7.27(m,1H),7.11–6.94(m,3H),5.39(s,1H),3.57(s,4H),1.90–1.51(m,14H).HRMS(ESI+)[M+Na] +:452.2075. 1 H NMR(600MHz,DMSO-d 6 )δ8.66(s,1H), 8.40(s,1H), 8.30(s,1H), 7.62(d,J=8.2Hz,1H), 7.32–7.27( m,1H),7.11–6.94(m,3H),5.39(s,1H),3.57(s,4H),1.90–1.51(m,14H).HRMS(ESI+)[M+Na] + :452.2075.
实施例12：(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌啶-1-基)甲酮Example 12: (1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(piperidin-1-yl)methan ketone
1H NMR(600MHz,DMSO-d 6)δ8.62(s,1H),8.40(s,1H),8.36(s,1H),7.99(d,J＝8.2Hz,1H),7.29(dd,J＝8.3,1.2Hz,1H),7.05(s,1H),7.04(s,2H),5.39(s,1H),3.75(s,2H),3.54(s,2H),1.89(s,6H),1.74–1.43(m,8H).HRMS(ESI+)[M+Na] +:466.2223. 1 H NMR(600MHz,DMSO-d 6 )δ8.62(s,1H), 8.40(s,1H), 8.36(s,1H), 7.99(d,J=8.2Hz,1H), 7.29(dd, J = 8.3, 1.2Hz, 1H), 7.05 (s, 1H), 7.04 (s, 2H), 5.39 (s, 1H), 3.75 (s, 2H), 3.54 (s, 2H), 1.89 (s, 6H) ),1.74–1.43(m,8H).HRMS(ESI+)[M+Na] + :466.2223.
实施例13：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N,N-二甲基-1H-吲哚-3-甲酰胺Example 13: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N,N-dimethyl-1H-indole-3-carboxamide
1H NMR(600MHz,DMSO-d 6)δ8.65(d,J＝1.4Hz,1H),8.35(s,2H),7.73(d,J＝8.3Hz,1H),7.29(dd,J＝8.2,1.5Hz,1H),7.02(d,J＝5.1Hz,3H),5.38(s,1H),3.09(d,J＝12.8Hz,6H),1.92–1.52(m,10H).HRMS(ESI+)[M+Na] +:426.1921. 1 H NMR(600MHz,DMSO-d 6 )δ8.65(d,J=1.4Hz,1H), 8.35(s,2H), 7.73(d,J=8.3Hz,1H), 7.29(dd,J= 8.2,1.5Hz,1H),7.02(d,J=5.1Hz,3H),5.38(s,1H),3.09(d,J=12.8Hz,6H),1.92-1.52(m,10H).HRMS( ESI+)[M+Na] + :426.1921.
实施例14：(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(吗啉基)甲酮Example 14: (1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(morpholinyl)methanone
1H NMR(600MHz,DMSO-d 6)δ8.66(s,2H),8.35(s,1H),7.69(d,J＝8.2Hz,1H),7.30(d,J＝8.2Hz,1H),7.05(s,3H),5.38(s,1H),3.64(s,8H),1.94–1.43(m,10H).HRMS(ESI+)[M+Na] +:468.2018. 1 H NMR(600MHz,DMSO-d 6 )δ8.66(s,2H),8.35(s,1H),7.69(d,J=8.2Hz,1H),7.30(d,J=8.2Hz,1H) ,7.05(s,3H),5.38(s,1H),3.64(s,8H),1.94-1.43(m,10H).HRMS(ESI+)[M+Na] + :468.2018.
实施例15：(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-甲基哌嗪-1-基)甲酮Example 15: (1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(4-methylpiperazine-1 -Base) ketone
1H NMR(600MHz,DMSO-d 6)δ8.66(s,1H),8.34(d,J＝5.9Hz,1H),8.33(s,1H),7.65(d,J＝8.2Hz,1H),7.30(dd,J＝8.2,1.3Hz,1H),7.03(s,2H),7.02(s,1H),5.39(s,1H),3.63(s,4H),2.36(s,4H),2.22(s,3H),1.94–1.43(m,10H).HRMS(ESI+)[M+H] +:458.1877. 1 H NMR(600MHz,DMSO-d 6 )δ8.66(s,1H), 8.34(d,J=5.9Hz,1H), 8.33(s,1H), 7.65(d,J=8.2Hz,1H) ,7.30(dd,J=8.2,1.3Hz,1H),7.03(s,2H),7.02(s,1H),5.39(s,1H),3.63(s,4H),2.36(s,4H), 2.22(s,3H),1.94-1.43(m,10H).HRMS(ESI+)[M+H] + :458.1877.
实施例16：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-甲基-1H-吲哚-3-甲酰胺Example 16: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-methyl-1H-indole-3-carboxamide
1H NMR(600MHz,DMSO-d 6)δ8.66(s,1H),8.58(d,J＝1.3Hz,1H),8.39(d,J＝5.5Hz,1H),8.20(dd,J＝6.5,4.8Hz,2H),7.31(dd,J＝8.2,1.4Hz,1H),7.08(s,2H),6.85(d,J＝5.5Hz,1H),5.40(s,1H),2.81(d,J＝4.5Hz,3H),1.95–1.42(m,10H).HRMS(ESI+)[M+Na] +:412.1744. 1 H NMR(600MHz,DMSO-d 6 )δ8.66(s,1H), 8.58(d,J=1.3Hz,1H), 8.39(d,J=5.5Hz,1H), 8.20(dd,J= 6.5, 4.8 Hz, 2H), 7.31 (dd, J = 8.2, 1.4 Hz, 1H), 7.08 (s, 2H), 6.85 (d, J = 5.5 Hz, 1H), 5.40 (s, 1H), 2.81 ( d,J=4.5Hz,3H),1.95-1.42(m,10H).HRMS(ESI+)[M+Na] + :412.1744.
实施例17：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(噻唑-2-基)-1H-吲哚-3- 甲酰胺Example 17: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(thiazol-2-yl)-1H-indole-3-carboxamide
1H NMR(600MHz,DMSO-d 6)δ12.42(s,1H),9.28(s,1H),8.65(s,1H),8.45(d,J＝5.2Hz,1H),8.30(d,J＝8.1Hz,1H),7.56(d,J＝2.8Hz,1H),7.39(d,J＝8.0Hz,1H),7.33–7.24(m,1H),7.17(s,2H),6.90(d,J＝5.2Hz,1H),5.44(s,1H),1.95–1.45(m,10H).HRMS(ESI+)[M+Na] +:481.1420. 1 H NMR (600MHz, DMSO-d 6 ) δ 12.42 (s, 1H), 9.28 (s, 1H), 8.65 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.33-7.24 (m, 1H), 7.17 (s, 2H), 6.90 ( d,J=5.2Hz,1H),5.44(s,1H),1.95-1.45(m,10H).HRMS(ESI+)[M+Na] + :481.1420.
实施例18：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-3-甲酰胺Example 18: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-phenyl-1H-indole-3-carboxamide
1H NMR(600MHz,DMSO-d 6)δ10.04(s,1H),8.96(s,1H),8.60(s,1H),8.47(s,1H),8.24(d,J＝8.2Hz,1H),7.77(d,J＝8.0Hz,2H),7.37(q,J＝8.9,8.3Hz,3H),7.12(d,J＝12.5Hz,2H),7.09(d,J＝7.3Hz,1H),6.96(d,J＝5.1Hz,1H),5.42(s,1H),2.02–1.37(m,10H).HRMS(ESI+)[M+Na] +:474.1904. 1 H NMR (600MHz, DMSO-d 6 ) δ 10.04 (s, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.37 (q, J = 8.9, 8.3 Hz, 3H), 7.12 (d, J = 12.5 Hz, 2H), 7.09 (d, J = 7.3 Hz, 1H),6.96(d,J=5.1Hz,1H),5.42(s,1H),2.02–1.37(m,10H).HRMS(ESI+)[M+Na] + :474.1904.
实施例19：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲腈Example 19: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carbonitrile
1H NMR(600MHz,DMSO-d 6)δ9.02(s,1H),8.68(s,1H),8.42(s,1H),7.74–7.68(m,1H),7.42(dd,J＝8.2,1.4Hz,1H),7.19(s,2H),7.01(d,J＝5.5Hz,1H),5.44(s,1H),1.95–1.42(m,10H).HRMS(ESI+)[M+Na] +:380.1479. 1 H NMR(600MHz,DMSO-d 6 )δ9.02(s,1H),8.68(s,1H),8.42(s,1H),7.74-7.68(m,1H),7.42(dd,J=8.2 ,1.4Hz,1H),7.19(s,2H),7.01(d,J=5.5Hz,1H),5.44(s,1H),1.95-1.42(m,10H).HRMS(ESI+)[M+Na ] + :380.1479.
实施例20：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-甲氧乙基)-1H-吲哚-3-甲酰胺Example 20: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-methoxyethyl)-1H-indole-3-methyl Amide
1H NMR(600MHz,DMSO-d 6)δ8.77(s,1H),8.59(s,1H),8.47(d,J＝31.0Hz,1H),8.30(t,J＝5.2Hz,1H),8.22(d,J＝8.2Hz,1H),7.31(dd,J＝8.2,1.2Hz,1H),7.10(s,2H),6.88(d,J＝3.2Hz,1H),5.41(s,1H),3.48(dq,J＝9.7,5.2Hz,4H),3.30(s,3H),1.95–1.41(m,10H).HRMS(ESI+)[M+Na] +:456.2103. 1 H NMR(600MHz,DMSO-d 6 )δ8.77(s,1H),8.59(s,1H),8.47(d,J=31.0Hz,1H), 8.30(t,J=5.2Hz,1H) ,8.22(d,J=8.2Hz,1H),7.31(dd,J=8.2,1.2Hz,1H),7.10(s,2H),6.88(d,J=3.2Hz,1H),5.41(s, 1H), 3.48(dq,J=9.7,5.2Hz,4H), 3.30(s,3H),1.95-1.41(m,10H).HRMS(ESI+)[M+Na] + :456.2103.
实施例21：1-(2-氨基嘧啶-4-基)-N-苄基-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺Example 21: 1-(2-Aminopyrimidin-4-yl)-N-benzyl-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carboxamide
1H NMR(600MHz,DMSO-d 6)δ8.81(s,1H),8.77(t,J＝5.9Hz,1H),8.59(s,1H),8.41(s,1H),8.24(d,J＝8.2Hz,1H),7.36(dt,J＝15.2,7.5Hz,4H),7.33(dd,J＝8.3,1.3Hz,1H),7.26(t,J＝7.1Hz,1H),7.10(s,2H),6.86(d,J＝5.5Hz,1H),5.41(s,1H),4.53(d,J＝5.8Hz,2H),1.98–1.40(m,10H).HRMS(ESI+)[M+Na] +:488.2071. 1 H NMR(600MHz,DMSO-d 6 )δ8.81(s,1H), 8.77(t,J=5.9Hz,1H), 8.59(s,1H), 8.41(s,1H), 8.24(d, J = 8.2 Hz, 1H), 7.36 (dt, J = 15.2, 7.5 Hz, 4H), 7.33 (dd, J = 8.3, 1.3 Hz, 1H), 7.26 (t, J = 7.1 Hz, 1H), 7.10 ( s,2H),6.86(d,J=5.5Hz,1H),5.41(s,1H),4.53(d,J=5.8Hz,2H),1.98–1.40(m,10H).HRMS(ESI+)[ M+Na] + :488.2071.
实施例22：(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-(2-羟乙基)哌嗪-1-基)甲酮Example 22: (1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(4-(2-hydroxyethyl) )Piperazin-1-yl)methanone
1H NMR(400MHz,DMSO-d 6)δ8.65(d,J＝1.3Hz,1H),8.33(d,J＝5.6Hz,1H),8.32(s,1H),7.65(d,J＝8.3Hz,1H),7.30(dd,J＝8.2,1.4Hz,1H),7.03(s,1H),7.02(s,2H),5.38(s,1H),4.43(t,J＝5.3Hz,1H),3.62(t,J＝4.8Hz,4H),3.52(q,J＝5.8Hz,2H),2.45(dd,J＝13.0,6.6Hz,6H),1.95–1.43(m,10H).HRMS(ESI+)[M+H] +:489.2625. 1 H NMR(400MHz,DMSO-d 6 )δ8.65(d,J=1.3Hz,1H), 8.33(d,J=5.6Hz,1H), 8.32(s,1H), 7.65(d,J= 8.3Hz, 1H), 7.30 (dd, J = 8.2, 1.4 Hz, 1H), 7.03 (s, 1H), 7.02 (s, 2H), 5.38 (s, 1H), 4.43 (t, J = 5.3 Hz, 1H), 3.62 (t, J = 4.8 Hz, 4H), 3.52 (q, J = 5.8 Hz, 2H), 2.45 (dd, J = 13.0, 6.6 Hz, 6H), 1.95-1.43 (m, 10H). HRMS(ESI+)[M+H] + :489.2625.
实施例23：(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(2-(羟乙基)吡咯-1-基)甲酮Example 23: (1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(2-(hydroxyethyl)pyrrole -1-yl) ketone
1H NMR(400MHz,DMSO-d 6)δ8.61(s,1H),8.40(s,1H),8.35(d,J＝5.6Hz,1H),7.93(s,1H),7.34–7.22(m,1H),7.02(s,3H),5.38(s,1H),4.83(t,J＝5.6Hz,1H),4.26(t,J＝5.6Hz,1H),3.83–3.57(m,3H),3.57–3.39(m,1H),2.05–1.18(m,16H).HRMS(ESI+)[M+Na] +:496.2334. 1 H NMR(400MHz,DMSO-d 6 )δ8.61(s,1H), 8.40(s,1H), 8.35(d,J=5.6Hz,1H), 7.93(s,1H), 7.34-7.22( m, 1H), 7.02 (s, 3H), 5.38 (s, 1H), 4.83 (t, J = 5.6 Hz, 1H), 4.26 (t, J = 5.6 Hz, 1H), 3.83-3.57 (m, 3H ),3.57–3.39(m,1H),2.05–1.18(m,16H).HRMS(ESI+)[M+Na] + :496.2334.
实施例24：1-(2-氨基嘧啶-4-基)-N-(5-羟基-1H-吡唑-3-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺Example 24: 1-(2-Aminopyrimidin-4-yl)-N-(5-hydroxy-1H-pyrazol-3-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H- Indole-3-carboxamide
1H NMR(600MHz,DMSO-d 6)δ10.44(s,1H),9.39(s,1H),8.47–8.44(m,2H),8.34(d,J＝8.3Hz,1H),7.39(dd,J＝8.3,1.4Hz,1H),7.16(s,2H),6.94(d,J＝5.4Hz,1H),6.88(s,2H),5.41(s,1H),4.88(s,1H),1.91–1.49(m,15H).HRMS(ESI+)[M+Na] +:496.2334. 1 H NMR (600MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 9.39 (s, 1H), 8.47-8.44 (m, 2H), 8.34 (d, J = 8.3 Hz, 1H), 7.39 ( dd,J=8.3,1.4Hz,1H),7.16(s,2H),6.94(d,J=5.4Hz,1H),6.88(s,2H),5.41(s,1H),4.88(s,1H) ),1.91–1.49(m,15H).HRMS(ESI+)[M+Na] + :496.2334.
实施例25：(R)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-甲基哌嗪-1-基)甲酮Example 25: (R)-(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3-methyl Piperazin-1-yl)methanone
1H NMR(400MHz,DMSO-d 6)δ8.66(d,J＝1.3Hz,1H),8.41–8.32(m,2H),7.66(d,J＝8.2Hz,1H),7.30(dd,J＝8.2,1.5Hz,1H),7.03(d,J＝5.5Hz,3H),5.76(s,1H),5.40(s,1H),4.16(s,2H),3.08–2.75(m,4H),1.93–1.45(m,10H),1.25(d,J＝11.0Hz,1H),1.09(d,J＝5.4Hz,3H).HRMS(ESI+)[M+H] +:459.2521. 1 H NMR (400MHz, DMSO-d 6 ) δ8.66 (d, J = 1.3Hz, 1H), 8.41-8.32 (m, 2H), 7.66 (d, J = 8.2Hz, 1H), 7.30 (dd, J = 8.2, 1.5 Hz, 1H), 7.03 (d, J = 5.5 Hz, 3H), 5.76 (s, 1H), 5.40 (s, 1H), 4.16 (s, 2H), 3.08-2.75 (m, 4H) ),1.93-1.45(m,10H),1.25(d,J=11.0Hz,1H),1.09(d,J=5.4Hz,3H).HRMS(ESI+)[M+H] + :459.2521.
实施例26：(S)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-甲基哌嗪-1-基)甲酮Example 26: (S)-(1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3-methyl Piperazin-1-yl)methanone
1H NMR(400MHz,DMSO-d 6)δ8.66(d,J＝1.3Hz,1H),8.41–8.32(m,2H),7.66(d,J＝8.2Hz,1H),7.30(dd,J＝8.2,1.5Hz,1H),7.03(d,J＝5.5Hz,3H),5.76(s,1H),5.40(s,1H),4.16(s,2H),3.08–2.75(m,4H),1.93–1.45(m,10H),1.25(d,J＝11.0Hz,1H),1.09(d,J＝5.4Hz,3H).HRMS(ESI+)[M+H] +:459.2521. 1 H NMR (400MHz, DMSO-d 6 ) δ8.66 (d, J = 1.3Hz, 1H), 8.41-8.32 (m, 2H), 7.66 (d, J = 8.2Hz, 1H), 7.30 (dd, J = 8.2, 1.5 Hz, 1H), 7.03 (d, J = 5.5 Hz, 3H), 5.76 (s, 1H), 5.40 (s, 1H), 4.16 (s, 2H), 3.08-2.75 (m, 4H) ),1.93-1.45(m,10H),1.25(d,J=11.0Hz,1H),1.09(d,J=5.4Hz,3H).HRMS(ESI+)[M+H] + :459.2521.
实施例27：(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3,5-二甲基哌嗪-1-基)甲酮Example 27: (1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3,5-dimethylpiperidine (Azin-1-yl) ketone
1H NMR(400MHz,DMSO-d 6)δ8.66(d,J＝1.3Hz,1H),8.34(d,J＝5.3Hz,2H),7.65(d,J＝8.2Hz,1H),7.30(dd,J＝8.2,1.4Hz,1H),7.07–6.97(m,3H),5.39(s,1H),4.18(s,2H),3.01–2.62(m,4H),1.95–1.43(m,10H),1.25(d,J＝16.2Hz,1H),1.17–0.92(m,6H).HRMS(ESI+)[M+H] +:473.2670. 1 H NMR(400MHz,DMSO-d 6 )δ8.66(d,J=1.3Hz,1H), 8.34(d,J=5.3Hz,2H), 7.65(d,J=8.2Hz,1H), 7.30 (dd,J=8.2,1.4Hz,1H),7.07–6.97(m,3H),5.39(s,1H),4.18(s,2H),3.01–2.62(m,4H),1.95–1.43(m ,10H),1.25(d,J=16.2Hz,1H),1.17–0.92(m,6H).HRMS(ESI+)[M+H] + :473.2670.
实施例28：(3-氨基-1H-吡唑-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮Example 28: (3-Amino-1H-pyrazol-1-yl)(1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole -3-yl) ketone
1H NMR(400MHz,DMSO-d 6)δ9.47(s,1H),8.47(d,J＝1.3Hz,1H),8.45(d,J＝5.4Hz,1H),8.34(d,J＝8.2Hz,1H),8.25(d,J＝2.9Hz,1H),7.40(dd,J＝8.3,1.4Hz,1H),7.16(s,2H),7.00(d,J＝5.5Hz,1H),6.01(d,J＝2.9Hz,1H),5.72(s,2H),5.41(s,1H),1.94–1.44(m,10H).HRMS(ESI+)[M+Na] +:456.1809. 1 H NMR(400MHz,DMSO-d 6 )δ9.47(s,1H), 8.47(d,J=1.3Hz,1H), 8.45(d,J=5.4Hz,1H), 8.34(d,J= 8.2Hz, 1H), 8.25 (d, J = 2.9 Hz, 1H), 7.40 (dd, J = 8.3, 1.4 Hz, 1H), 7.16 (s, 2H), 7.00 (d, J = 5.5 Hz, 1H) ,6.01(d,J=2.9Hz,1H),5.72(s,2H),5.41(s,1H),1.94-1.44(m,10H).HRMS(ESI+)[M+Na] + :456.1809.
实施例29：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(1H-吡唑-3-基)-1H-吲哚-3-甲酰胺Example 29: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(1H-pyrazol-3-yl)-1H-indole-3 -Formamide
1H NMR(400MHz,DMSO-d 6)δ9.36(s,1H),8.44(d,J＝5.4Hz,1H),8.39(s,1H),8.36(d,J＝8.4Hz,1H),7.54(d,J＝1.7Hz,1H),7.42(d,J＝8.4Hz,1H),7.17(s,2H),6.97(d,J＝5.4Hz,1H),6.82(s,2H),5.44(d,J＝1.8Hz,1H),5.41(s,1H),1.94–1.45(m,10H).HRMS(ESI+)[M+Na] +:456.1809. 1 H NMR(400MHz,DMSO-d 6 )δ9.36(s,1H),8.44(d,J=5.4Hz,1H),8.39(s,1H),8.36(d,J=8.4Hz,1H) ,7.54(d,J=1.7Hz,1H),7.42(d,J=8.4Hz,1H),7.17(s,2H),6.97(d,J=5.4Hz,1H),6.82(s,2H) ,5.44(d,J=1.8Hz,1H),5.41(s,1H),1.94-1.45(m,10H).HRMS(ESI+)[M+Na] + :456.1809.
实施例30：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2,2,2-三氟乙基)-1H-吲哚-3-甲酰胺Example 30: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2,2,2-trifluoroethyl)-1H-indole -3-carboxamide
1H NMR(400MHz,DMSO-d 6)δ8.94(s,1H),8.92(d,J＝6.4Hz,1H),8.57(d,J＝1.3Hz,1H),8.41(d,J＝5.5Hz,1H),8.20(d,J＝8.2Hz,1H),7.33(dd,J＝8.3,1.4Hz,1H),7.09(s,2H),6.90(d,J＝5.6Hz,1H),5.39(s,1H),4.13(dh,J＝14.3,5.6,4.9Hz,2H),1.94–1.40(m,10H).HRMS(ESI+)[M+Na] +:480.1614. 1 H NMR(400MHz,DMSO-d 6 )δ8.94(s,1H), 8.92(d,J=6.4Hz,1H), 8.57(d,J=1.3Hz,1H), 8.41(d,J= 5.5Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.33 (dd, J = 8.3, 1.4 Hz, 1H), 7.09 (s, 2H), 6.90 (d, J = 5.6 Hz, 1H) ,5.39(s,1H),4.13(dh,J=14.3,5.6,4.9Hz,2H),1.94-1.40(m,10H).HRMS(ESI+)[M+Na] + :480.1614.
实施例31：(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-吗啉基哌啶-1-基)甲酮Example 31: (1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(4-morpholinylpiperidine- 1-yl) ketone
1H NMR(400MHz,DMSO-d 6)δ8.66(d,J＝1.3Hz,1H),8.33(d,J＝6.1Hz,2H),7.63(d,J＝8.2Hz,1H),7.29(dd,J＝8.3,1.4Hz,1H),7.07–6.97(m,3H),5.40(s,1H),4.23(s,2H),3.57(s,4H),3.00(s,2H),2.47(s,4H),1.94–1.34(m,14H).HRMS(ESI+)[M+Na] +:551.2754. 1 H NMR(400MHz,DMSO-d 6 )δ8.66(d,J=1.3Hz,1H), 8.33(d,J=6.1Hz,2H), 7.63(d,J=8.2Hz,1H), 7.29 (dd,J=8.3,1.4Hz,1H),7.07–6.97(m,3H), 5.40(s,1H), 4.23(s,2H),3.57(s,4H), 3.00(s,2H), 2.47(s,4H),1.94-1.34(m,14H).HRMS(ESI+)[M+Na] + :551.2754.
实施例32：(R)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-羟基哌啶-1-基)甲酮Example 32: (R)-(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3-hydroxypiper (Pyridin-1-yl) ketone
1H NMR(400MHz,DMSO-d 6)δ8.64(d,J＝1.3Hz,1H),8.34(d,J＝5.5Hz,1H),8.31(s,1H),7.63(d,J＝8.2Hz,1H),7.29(dd,J＝8.2,1.4Hz,1H),7.02(s,2H),6.99(d,J＝5.6Hz,1H),5.38(s,1H),4.90(s,1H),4.00–3.46(m,3H),3.26(s,1H),3.07(s,1H),1.95–1.41(m,14H).HRMS(ESI+)[M+Na] +:482.2178. 1 H NMR(400MHz,DMSO-d 6 )δ8.64(d,J=1.3Hz,1H), 8.34(d,J=5.5Hz,1H), 8.31(s,1H), 7.63(d,J= 8.2Hz, 1H), 7.29 (dd, J = 8.2, 1.4 Hz, 1H), 7.02 (s, 2H), 6.99 (d, J = 5.6 Hz, 1H), 5.38 (s, 1H), 4.90 (s, 1H), 4.00–3.46(m,3H), 3.26(s,1H),3.07(s,1H), 1.95–1.41(m,14H).HRMS(ESI+)[M+Na] + :482.2178.
实施例33：(S)-(3-氨基哌啶-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲 哚-3-基)甲酮Example 33: (S)-(3-Aminopiperidin-1-yl)(1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indyl Dol-3-yl)methanone
1H NMR(400MHz,DMSO-d 6)δ8.65(d,J＝1.3Hz,1H),8.33(d,J＝5.6Hz,1H),8.31(s,1H),7.62(d,J＝8.2Hz,1H),7.29(dd,J＝8.2,1.5Hz,1H),7.01(s,2H),7.00(s,1H),5.38(s,1H),4.02(s,2H),3.00(t,J＝11.9Hz,1H),2.68(td,J＝21.0,16.2,9.9Hz,2H),2.03–1.37(m,16H).HRMS(ESI+)[M+H] +:459.2518. 1 H NMR (400MHz, DMSO-d 6 ) δ8.65 (d, J = 1.3 Hz, 1H), 8.33 (d, J = 5.6 Hz, 1H), 8.31 (s, 1H), 7.62 (d, J = 8.2Hz, 1H), 7.29 (dd, J = 8.2, 1.5 Hz, 1H), 7.01 (s, 2H), 7.00 (s, 1H), 5.38 (s, 1H), 4.02 (s, 2H), 3.00 ( t,J＝11.9Hz,1H),2.68(td,J＝21.0,16.2,9.9Hz,2H),2.03-1.37(m,16H).HRMS(ESI+)[M+H] + :459.2518.
实施例34：(S)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(哌啶-3-基)1H-吲哚-3-甲酰胺Example 34: (S)-1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(piperidin-3-yl)1H-indole- 3-formamide
1H NMR(400MHz,DMSO-d 6)δ8.76(s,1H),8.56(s,1H),8.39(d,J＝5.6Hz,1H),8.20(d,J＝8.2Hz,1H),7.92(d,J＝7.9Hz,1H),7.30(d,J＝8.2Hz,1H),7.06(s,2H),6.90(d,J＝5.6Hz,1H),5.39(s,1H),3.84(d,J＝10.4Hz,1H),3.09–2.95(m,1H),2.81(d,J＝12.1Hz,1H),2.45–2.28(m,2H),1.95–1.35(m,15H).HRMS(ESI+)[M+H] +:459.2507. 1 H NMR(400MHz,DMSO-d 6 )δ8.76(s,1H),8.56(s,1H),8.39(d,J=5.6Hz,1H), 8.20(d,J=8.2Hz,1H) ,7.92(d,J=7.9Hz,1H),7.30(d,J=8.2Hz,1H),7.06(s,2H),6.90(d,J=5.6Hz,1H),5.39(s,1H) ,3.84(d,J=10.4Hz,1H),3.09–2.95(m,1H), 2.81(d,J=12.1Hz,1H), 2.45–2.28(m,2H),1.95–1.35(m,15H ).HRMS(ESI+)[M+H] + :459.2507.
实施例35：(R)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(哌啶-3-基)1H-吲哚-3-甲酰胺Example 35: (R)-1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(piperidin-3-yl)1H-indole- 3-formamide
1H NMR(400MHz,DMSO-d 6)δ8.76(s,1H),8.56(s,1H),8.39(d,J＝5.6Hz,1H),8.20(d,J＝8.2Hz,1H),7.92(d,J＝7.9Hz,1H),7.30(d,J＝8.2Hz,1H),7.06(s,2H),6.90(d,J＝5.6Hz,1H),5.39(s,1H),3.84(d,J＝10.4Hz,1H),3.09–2.95(m,1H),2.81(d,J＝12.1Hz,1H),2.45–2.28(m,2H),1.95–1.35(m,15H).HRMS(ESI+)[M+H] +:459.2507. 1 H NMR(400MHz,DMSO-d 6 )δ8.76(s,1H),8.56(s,1H),8.39(d,J=5.6Hz,1H), 8.20(d,J=8.2Hz,1H) ,7.92(d,J=7.9Hz,1H),7.30(d,J=8.2Hz,1H),7.06(s,2H),6.90(d,J=5.6Hz,1H),5.39(s,1H) ,3.84(d,J=10.4Hz,1H),3.09–2.95(m,1H), 2.81(d,J=12.1Hz,1H), 2.45–2.28(m,2H),1.95–1.35(m,15H ).HRMS(ESI+)[M+H] + :459.2507.
实施例36：(R)-(3-氨基哌啶-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮Example 36: (R)-(3-Aminopiperidin-1-yl)(1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indyl Dol-3-yl)methanone
1H NMR(400MHz,DMSO-d 6)δ8.65(d,J＝1.3Hz,1H),8.33(d,J＝5.6Hz,1H),8.31(s,1H),7.62(d,J＝8.2Hz,1H),7.29(dd,J＝8.2,1.5Hz,1H),7.01(s,2H),7.00(s,1H),5.38(s,1H),4.02(s,2H),3.00(t,J＝11.9Hz,1H),2.68(td,J＝21.0,16.2,9.9Hz,2H),2.03–1.37(m,16H).HRMS(ESI+)[M+H] +:459.2507. 1 H NMR (400MHz, DMSO-d 6 ) δ8.65 (d, J = 1.3 Hz, 1H), 8.33 (d, J = 5.6 Hz, 1H), 8.31 (s, 1H), 7.62 (d, J = 8.2Hz, 1H), 7.29 (dd, J = 8.2, 1.5 Hz, 1H), 7.01 (s, 2H), 7.00 (s, 1H), 5.38 (s, 1H), 4.02 (s, 2H), 3.00 ( t,J＝11.9Hz,1H),2.68(td,J＝21.0,16.2,9.9Hz,2H),2.03-1.37(m,16H).HRMS(ESI+)[M+H] + :459.2507.
实施例37：(S)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-氨基吡咯-1-基)甲酮Example 37: (S)-(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3-aminopyrrole -1-yl) ketone
1H NMR(400MHz,DMSO-d 6)δ8.61(d,J＝1.4Hz,1H),8.39(s,1H),8.36(d,J＝5.6Hz,1H),7.99(d,J＝8.3Hz,1H),7.29(dd,J＝8.3,1.5Hz,1H),7.04(d,J＝5.7Hz,3H),5.38(s,1H),4.20(s,1H),3.91(s,1H),3.62(s,2H),3.42(s,2H),2.06(d,J＝11.1Hz,1H),1.96–1.41(m,12H).HRMS(ESI+)[M+Na] +:469.2173. 1 H NMR (400MHz, DMSO-d 6 ) δ8.61 (d, J = 1.4 Hz, 1H), 8.39 (s, 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 8.3Hz, 1H), 7.29 (dd, J = 8.3, 1.5 Hz, 1H), 7.04 (d, J = 5.7 Hz, 3H), 5.38 (s, 1H), 4.20 (s, 1H), 3.91 (s, 1H),3.62(s,2H),3.42(s,2H),2.06(d,J=11.1Hz,1H),1.96-1.41(m,12H).HRMS(ESI+)[M+Na] + :469.2173 .
实施例38：(S)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡咯-3-基)1H-吲哚-3-甲酰胺Example 38: (S)-1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(pyrrol-3-yl)1H-indole-3 -Formamide
1H NMR(400MHz,DMSO-d 6)δ8.61(s,1H),8.42(s,1H),8.37(d,J＝5.6Hz,1H),8.18(s,1H),8.00(d,J＝8.3Hz,1H),7.30(dd,J＝8.3,1.5Hz,1H),7.09–7.00(m,3H),5.38(s,1H),3.80(d,J＝45.6Hz,5H),2.31–2.19(m,1H),2.06(s,1H),1.94–1.44(m,11H).HRMS(ESI+)[M+Na] +:469.2173. 1 H NMR(400MHz,DMSO-d 6 )δ8.61(s,1H), 8.42(s,1H), 8.37(d,J=5.6Hz,1H), 8.18(s,1H), 8.00(d, J = 8.3Hz, 1H), 7.30 (dd, J = 8.3, 1.5 Hz, 1H), 7.09-7.00 (m, 3H), 5.38 (s, 1H), 3.80 (d, J = 45.6 Hz, 5H), 2.31–2.19(m,1H),2.06(s,1H),1.94-1.44(m,11H).HRMS(ESI+)[M+Na] + :469.2173.
实施例39：(R)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡咯-3-基)1H-吲哚-3-甲酰胺Example 39: (R)-1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(pyrrol-3-yl)1H-indole-3 -Formamide
1H NMR(400MHz,DMSO-d 6)δ8.61(s,1H),8.42(s,1H),8.37(d,J＝5.6Hz,1H),8.18(s,1H),8.00(d,J＝8.3Hz,1H),7.30(dd,J＝8.3,1.5Hz,1H),7.09–7.00(m,3H),5.38(s,1H),3.80(d,J＝45.6Hz,5H),2.31–2.19(m,1H),2.06(s,1H),1.94–1.44(m,11H).HRMS(ESI+)[M+Na] +:469.2173. 1 H NMR(400MHz,DMSO-d 6 )δ8.61(s,1H), 8.42(s,1H), 8.37(d,J=5.6Hz,1H), 8.18(s,1H), 8.00(d, J = 8.3Hz, 1H), 7.30 (dd, J = 8.3, 1.5 Hz, 1H), 7.09-7.00 (m, 3H), 5.38 (s, 1H), 3.80 (d, J = 45.6 Hz, 5H), 2.31–2.19(m,1H),2.06(s,1H),1.94-1.44(m,11H).HRMS(ESI+)[M+Na] + :469.2173.
实施例40：4-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羰基)哌嗪-2-酮Example 40: 4-(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carbonyl)piperazin-2-one
1H NMR(600MHz,DMSO-d 6)δ8.66(d,J＝1.3Hz,1H),8.41(s,1H),8.35(d,J＝5.5Hz,1H),8.16(d,J＝2.7Hz,1H),7.73(d,J＝8.2Hz,1H),7.30(dd,J＝8.3,1.4Hz,1H),7.05(s,2H),7.03(d,J＝5.6Hz,1H),5.40(s,1H),4.19(s,2H),3.81(t,J＝5.4Hz,2H),3.31–3.27(m,2H), 1.93–1.45(m,10H).HRMS(ESI+)[M+H] +:458.2068. 1 H NMR(600MHz,DMSO-d 6 )δ8.66(d,J=1.3Hz,1H), 8.41(s,1H), 8.35(d,J=5.5Hz,1H), 8.16(d,J= 2.7Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.30 (dd, J = 8.3, 1.4 Hz, 1H), 7.05 (s, 2H), 7.03 (d, J = 5.6 Hz, 1H) ,5.40(s,1H),4.19(s,2H),3.81(t,J=5.4Hz,2H),3.31–3.27(m,2H), 1.93–1.45(m,10H).HRMS(ESI+)[ M+H] + :458.2068.
实施例41：Example 41:
1-((1-(2-苄胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-Benzylamine)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
Figure PCTCN2021098556-appb-000023
Figure PCTCN2021098556-appb-000023
6-溴-1-(2-氯嘧啶-4-基)-1H-吲哚的制备Preparation of 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole
Figure PCTCN2021098556-appb-000024
Figure PCTCN2021098556-appb-000024
步骤1：将6-溴吲哚(5g,25.5mM)溶于50mL THF中，冰浴至0℃，然后分批加入叔丁醇钾(3.15g,28.05mM)，冰浴下搅拌30min，然后加入2,4-二氯嘧啶(4.18g,28.05mM)，室温反应5h，将反应液倒入100mL水中，使用EA萃取(70*3mL)，饱和食盐水洗涤，无水硫酸钠干燥，柱层析(PE：EA＝10:1)，得淡黄色产品3.2g(产率40.1％)。Step 1: Dissolve 6-bromoindole (5g, 25.5mM) in 50mL THF, ice bath to 0℃, then add potassium tert-butoxide (3.15g, 28.05mM) in batches, stir for 30min under ice bath, then Add 2,4-dichloropyrimidine (4.18g, 28.05mM), react at room temperature for 5h, pour the reaction solution into 100mL water, extract with EA (70*3mL), wash with saturated saline, dry with anhydrous sodium sulfate, column layer After analysis (PE:EA=10:1), 3.2 g of light yellow product (yield 40.1%) was obtained.
4-(6-溴-1H-吲哚-1-基)-N-苯基嘧啶-2-胺的制备Preparation of 4-(6-bromo-1H-indol-1-yl)-N-phenylpyrimidin-2-amine
Figure PCTCN2021098556-appb-000025
Figure PCTCN2021098556-appb-000025
步骤2：将6-溴-1-(2-氯嘧啶-4-基)-1H-吲哚(0.2g,0.648mM)和苯胺(63.4mg,0.68mM)加入耐压瓶中，然后加入4mL异丙醇和1d浓盐酸，嘧封，加热至120℃反应3h，将反应液充分冷却，结晶析出，抽滤，冷乙醇洗，水洗，干燥。得产品白色0.22g(产率92.6％)。ESI-MS(m/z)：379[M+H] +。 Step 2: Add 6-bromo-1-(2-chloropyrimidin-4-yl)-1H-indole (0.2g, 0.648mM) and aniline (63.4mg, 0.68mM) into the pressure bottle, and then add 4mL Isopropanol and 1d concentrated hydrochloric acid, pyridine seal, heated to 120 ℃ for 3h, the reaction solution is fully cooled, crystals precipitate, suction filtration, cold ethanol washing, water washing, and drying. The obtained product is white 0.22 g (yield 92.6%). ESI-MS (m/z): 379 [M+H] + .
1-((1-(2-苄胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇的制备Preparation of 1-((1-(2-benzylamine)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
步骤3：该标题化合物通过调整实例1所述方法，将步骤2中的4-(6-溴-1H-吲哚-1-基)嘧啶-2-胺使用4-(6-溴-1H-吲哚-1-基)-N-苯基嘧啶-2-胺代替，反应在80℃下进行5个小时。得标题化合物1-((1-(2-苄胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇。 1H NMR(600MHz,DMSO-d 6)δ8.84(s,1H),8.35(s,1H),8.20–8.04(m,2H),7.60(d,J＝8.0Hz,1H),7.45(s,2H),7.31(t,J＝7.3Hz,2H),7.26–7.17(m,2H),7.00(s,1H),6.80(d,J＝3.2Hz,1H),5.41(s,1H),4.63(s,2H),1.76–1.49(m,10H).HRMS(ESI+)[M+H] +:423.2182。 Step 3: The title compound uses the 4-(6-bromo-1H-indol-1-yl)pyrimidin-2-amine in step 2 to use 4-(6-bromo-1H- Indol-1-yl)-N-phenylpyrimidin-2-amine was substituted, and the reaction was carried out at 80°C for 5 hours. The title compound 1-((1-(2-benzylamine)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol was obtained. 1 H NMR (600MHz, DMSO-d 6 ) δ 8.84 (s, 1H), 8.35 (s, 1H), 8.20-8.04 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.45 ( s, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.26-7.17 (m, 2H), 7.00 (s, 1H), 6.80 (d, J = 3.2 Hz, 1H), 5.41 (s, 1H) ), 4.63(s, 2H), 1.76–1.49(m, 10H). HRMS(ESI+)[M+H] + : 423.2182.
按照实施例41的方法，可与适当的伯胺或仲胺进行反应来进行实施例41-59的制备。According to the method of Example 41, the preparation of Examples 41-59 can be carried out by reacting with an appropriate primary or secondary amine.
实施例42：1-((1-(2-((噻吩-2-甲基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇Example 42: 1-((1-(2-((thiophen-2-methyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
1H NMR(600MHz,DMSO-d 6)δ8.86(s,1H),8.40(s,1H),8.16(s,1H),8.13(s,1H),7.61(d,J＝8.1Hz,1H),7.33(d,J＝3.9Hz,1H),7.23(dd,J＝8.1,1.2Hz,1H),7.13(s,1H),7.03(d,J＝5.0Hz,1H),6.98–6.90(m,1H),6.82(d,J＝3.5Hz,1H),5.39(s,1H),4.78(s,2H),2.04–1.30(m,10H).HRMS(ESI+)[M+H] +:429.1748。 1 H NMR(600MHz,DMSO-d 6 )δ8.86(s,1H), 8.40(s,1H), 8.16(s,1H), 8.13(s,1H), 7.61(d,J=8.1Hz, 1H), 7.33 (d, J = 3.9 Hz, 1H), 7.23 (dd, J = 8.1, 1.2 Hz, 1H), 7.13 (s, 1H), 7.03 (d, J = 5.0 Hz, 1H), 6.98- 6.90(m,1H),6.82(d,J=3.5Hz,1H),5.39(s,1H),4.78(s,2H),2.04--1.30(m,10H).HRMS(ESI+)[M+H ] + :429.1748.
实施例43：1-((1-(2-((2-氟苄基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇Example 43: 1-((1-(2-((2-Fluorobenzyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
1H NMR(600MHz,DMSO-d 6)δ8.74(s,1H),8.36(s,1H),8.13(d,J＝3.6Hz,1H),7.97(s,1H),7.61(d,J＝8.1Hz,1H),7.45(s,1H),7.33–7.27(m,1H),7.22(d,J＝7.6Hz,1H),7.21–7.16(m,1H),7.14(t,J＝7.5Hz,1H),7.01(d,J＝5.5Hz,1H),6.81(d,J＝3.3Hz,1H),5.37(s,1H),4.69(s,2H),1.97–1.42(m,10H).HRMS(ESI+)[M+H] +:441.2089。 1 H NMR(600MHz,DMSO-d 6 )δ8.74(s,1H),8.36(s,1H),8.13(d,J=3.6Hz,1H),7.97(s,1H),7.61(d, J = 8.1Hz, 1H), 7.45 (s, 1H), 7.33-7.27 (m, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.21-7.16 (m, 1H), 7.14 (t, J =7.5Hz,1H),7.01(d,J=5.5Hz,1H),6.81(d,J=3.3Hz,1H),5.37(s,1H),4.69(s,2H),1.97–1.42(m ,10H).HRMS(ESI+)[M+H] + :441.2089.
实施例44：1-((1-(2-((2-甲氧乙基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇Example 44: 1-((1-(2-((2-methoxyethyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
1H NMR(600MHz,DMSO-d 6)δ8.77(s,1H),8.34(s,1H),8.14(s,1H),7.61(d,J＝8.1Hz, 1H),7.49(s,1H),7.23(d,J＝8.0Hz,1H),6.97(d,J＝5.5Hz,1H),6.81(d,J＝3.2Hz,1H),5.41(s,1H),3.58(s,4H),3.29(s,3H),1.96–1.41(m,10H).HRMS(ESI+)[M+H] +:391.2136。 1 H NMR(600MHz,DMSO-d 6 )δ8.77(s,1H), 8.34(s,1H), 8.14(s,1H), 7.61(d,J=8.1Hz, 1H), 7.49(s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 5.5 Hz, 1H), 6.81 (d, J = 3.2 Hz, 1H), 5.41 (s, 1H), 3.58 (s, 4H), 3.29(s, 3H), 1.96–1.41(m,10H). HRMS(ESI+)[M+H] + :391.2136.
实施例45：1-((1-(2-((2-氯苄基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇Example 45: 1-((1-(2-((2-Chlorobenzyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
1H NMR(400MHz,DMSO-d 6)δ8.77(s,1H),8.33(d,J＝5.4Hz,1H),8.13(d,J＝3.3Hz,1H),8.07(t,J＝6.0Hz,1H),7.60(d,J＝8.1Hz,1H),7.46(s,2H),7.22(d,J＝8.1Hz,1H),7.13(t,J＝8.8Hz,2H),6.99(d,J＝5.6Hz,1H),6.80(d,J＝3.5Hz,1H),5.39(s,1H),4.61(d,J＝5.2Hz,2H),1.85–1.41(m,10H).HRMS(ESI+)[M+H] +:457.1792。 1 H NMR(400MHz,DMSO-d 6 )δ8.77(s,1H), 8.33(d,J=5.4Hz,1H), 8.13(d,J=3.3Hz,1H), 8.07(t,J= 6.0Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.46 (s, 2H), 7.22 (d, J = 8.1 Hz, 1H), 7.13 (t, J = 8.8 Hz, 2H), 6.99 (d,J=5.6Hz,1H), 6.80(d,J=3.5Hz,1H), 5.39(s,1H), 4.61(d,J=5.2Hz,2H),1.85-1.41(m,10H) .HRMS(ESI+)[M+H] + :457.1792.
实施例46：1-((1-(2-((4-氟苄基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇Example 46: 1-((1-(2-((4-Fluorobenzyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
1H NMR(400MHz,DMSO-d 6)δ8.70(s,1H),8.35(s,1H),8.22–8.09(m,1H),8.00(s,1H),7.61(d,J＝8.1Hz,1H),7.53–7.44(m,1H),7.44(d,J＝2.4Hz,1H),7.31(dd,J＝7.8,2.3Hz,1H),7.29–7.26(m,1H),7.24(dd,J＝12.2,5.1Hz,1H),7.00(d,J＝5.6Hz,1H),6.81(d,J＝3.5Hz,1H),5.33(s,1H),4.71(s,2H),2.10–1.23(m,10H).HRMS(ESI+)[M+H] +:441.2089。 1 H NMR(400MHz,DMSO-d 6 )δ8.70(s,1H),8.35(s,1H),8.22-8.09(m,1H),8.00(s,1H),7.61(d,J=8.1 Hz,1H),7.53-7.44(m,1H),7.44(d,J=2.4Hz,1H),7.31(dd,J=7.8,2.3Hz,1H),7.29-7.26(m,1H),7.24 (dd,J=12.2,5.1Hz,1H), 7.00(d,J=5.6Hz,1H), 6.81(d,J=3.5Hz,1H),5.33(s,1H), 4.71(s,2H) ,2.10–1.23(m,10H).HRMS(ESI+)[M+H] + :441.2089.
实施例47：1-((1-(2-(苯胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔)环己基-1-醇Example 47: 1-((1-(2-(Aniline)pyrimidin-4-yl)-1H-indol-6-yl)acetylene)cyclohexyl-1-ol
1H NMR(600MHz,DMSO-d 6)δ9.87(s,1H),8.67(s,1H),8.53(d,J＝5.6Hz,1H),8.18(d,J＝3.6Hz,1H),7.78(s,1H),7.77(s,1H),7.63(d,J＝8.1Hz,1H),7.37(t,J＝7.9Hz,2H),7.25(dd,J＝8.1,1.2Hz,1H),7.21(d,J＝5.6Hz,1H),7.01(t,J＝7.3Hz,1H),6.85(d,J＝3.5Hz,1H),5.36(s,1H),1.92–1.42(m,10H).HRMS(ESI+)[M+H] +:409.2109。 1 H NMR(600MHz,DMSO-d 6 )δ9.87(s,1H),8.67(s,1H),8.53(d,J=5.6Hz,1H), 8.18(d,J=3.6Hz,1H) ,7.78(s,1H),7.77(s,1H),7.63(d,J=8.1Hz,1H),7.37(t,J=7.9Hz,2H),7.25(dd,J=8.1,1.2Hz, 1H), 7.21 (d, J = 5.6 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 6.85 (d, J = 3.5 Hz, 1H), 5.36 (s, 1H), 1.92–1.42 ( m,10H).HRMS(ESI+)[M+H] + : 409.2109.
实施例48：1-((1-(2-((3-氯苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔)环己基-1-醇Example 48: 1-((1-(2-((3-chlorophenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)acetylene)cyclohexyl-1-ol
1H NMR(400MHz,DMSO-d 6)δ10.06(s,1H),8.63(s,1H),8.58(d,J＝5.6Hz,1H),8.17(d,J＝3.3Hz,1H),7.95(s,1H),7.74(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.37(t,J＝8.1Hz,1H),7.26(t,J＝6.4Hz,2H),7.03(d,J＝7.6Hz,1H),6.86(d,J＝3.1Hz,1H),5.32(s,1H),1.91–1.42(m,10H).HRMS(ESI+)[M+H] +:443.1628。 1 H NMR(400MHz,DMSO-d 6 )δ10.06(s,1H),8.63(s,1H),8.58(d,J=5.6Hz,1H), 8.17(d,J=3.3Hz,1H) ,7.95(s,1H),7.74(d,J=8.0Hz,1H), 7.64(d,J=8.0Hz,1H), 7.37(t,J=8.1Hz,1H), 7.26(t,J= 6.4Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 3.1 Hz, 1H), 5.32 (s, 1H), 1.91-1.42 (m, 10H).HRMS (ESI+) [M+H] + :443.1628.
实施例49：1-((1-(2-((3-氯-4-氟苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇Example 49: 1-((1-(2-((3-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1 -alcohol
1H NMR(400MHz,DMSO-d 6)δ10.06(s,1H),8.61(s,1H),8.57(d,J＝5.7Hz,1H),8.16(d,J＝3.6Hz,1H),8.09(dd,J＝6.8,2.5Hz,1H),7.72(ddd,J＝9.0,4.1,2.8Hz,1H),7.64(d,J＝8.1Hz,1H),7.38(t,J＝9.1Hz,1H),7.26(s,1H),7.26–7.23(m,1H),6.86(d,J＝3.5Hz,1H),5.25(s,1H),1.91–1.41(m,10H).HRMS(ESI+)[M+Na] +:483.1362。 1 H NMR(400MHz,DMSO-d 6 )δ10.06(s,1H),8.61(s,1H),8.57(d,J=5.7Hz,1H), 8.16(d,J=3.6Hz,1H) ,8.09(dd,J=6.8,2.5Hz,1H),7.72(ddd,J=9.0,4.1,2.8Hz,1H),7.64(d,J=8.1Hz,1H),7.38(t,J=9.1 Hz, 1H), 7.26 (s, 1H), 7.26-7.23 (m, 1H), 6.86 (d, J = 3.5 Hz, 1H), 5.25 (s, 1H), 1.91-1.41 (m, 10H).HRMS (ESI+)[M+Na] + :483.1362.
实施例50：3-((4-(6-((1-羟基环己基)乙炔基)-1H-吲哚-1-基)嘧啶-2-基)氨基)苯甲腈Example 50: 3-((4-(6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-1-yl)pyrimidin-2-yl)amino)benzonitrile
1H NMR(400MHz,DMSO-d 6)δ10.22(s,1H),8.65–8.57(m,2H),8.26(t,J＝1.9Hz,1H),8.19(d,J＝3.7Hz,1H),8.07(ddd,J＝8.5,2.3,1.1Hz,1H),7.64(d,J＝8.1Hz,1H),7.56(t,J＝8.0Hz,1H),7.43(dt,J＝7.6,1.3Hz,1H),7.31(d,J＝5.7Hz,1H),7.26(dd,J＝8.1,1.4Hz,1H),6.87(d,J＝3.6Hz,1H),5.33(s,1H),1.90–1.41(m,10H).HRMS(ESI+)[M+Na] +:456.1793。 1 H NMR(400MHz,DMSO-d 6 )δ10.22(s,1H),8.65-8.57(m,2H), 8.26(t,J=1.9Hz,1H), 8.19(d,J=3.7Hz, 1H), 8.07 (ddd, J = 8.5, 2.3, 1.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.43 (dt, J = 7.6 ,1.3Hz,1H),7.31(d,J=5.7Hz,1H),7.26(dd,J=8.1,1.4Hz,1H),6.87(d,J=3.6Hz,1H),5.33(s,1H ),1.90–1.41(m,10H).HRMS(ESI+)[M+Na] + :456.1793.
实施例51：1-((1-(2-((4-甲氧基苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇Example 51: 1-((1-(2-((4-methoxyphenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1H NMR(400MHz,DMSO-d 6)δ9.66(s,1H),8.60(s,1H),8.48(d,J＝5.6Hz,1H),8.13(d,J＝3.6Hz,1H),7.66(d,J＝9.0Hz,2H),7.63(d,J＝8.2Hz,1H),7.24(dd,J＝8.1,1.2Hz,1H),7.13(d,J＝5.6Hz,1H),6.93(d,J＝9.0Hz,2H),6.84(d,J＝3.5Hz,1H),5.30(s,1H),3.74(s,3H),1.92–1.38(m,10H).HRMS(ESI+)[M+Na] +:461.1852。 1 H NMR(400MHz,DMSO-d 6 )δ9.66(s,1H),8.60(s,1H),8.48(d,J=5.6Hz,1H),8.13(d,J=3.6Hz,1H) ,7.66(d,J=9.0Hz,2H), 7.63(d,J=8.2Hz,1H), 7.24(dd,J=8.1,1.2Hz,1H), 7.13(d,J=5.6Hz,1H) ,6.93(d,J=9.0Hz,2H),6.84(d,J=3.5Hz,1H),5.30(s,1H),3.74(s,3H),1.92-1.38(m,10H).HRMS( ESI+)[M+Na] + :461.1852.
实施例52：1-((1-(2-((3-硝基苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇Example 52: 1-((1-(2-((3-nitrophenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1H NMR(400MHz,DMSO-d 6)δ10.38(s,1H),8.83(t,J＝2.1Hz,1H),8.62(d,J＝5.7Hz,2H),8.21(d,J＝3.6Hz,1H),8.18–8.13(m,1H),7.85(dd,J＝8.1,2.1Hz,1H),7.68–7.61(m,2H),7.33(d,J＝5.7Hz,1H),7.25(dd,J＝8.1,1.2Hz,1H),6.88(d,J＝3.6Hz,1H),5.30(s,1H),1.88–1.37(m,10H).HRMS(ESI+)[M+Na] +:476.1658。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 8.83 (t, J = 2.1 Hz, 1H), 8.62 (d, J = 5.7 Hz, 2H), 8.21 (d, J = 3.6Hz,1H), 8.18–8.13(m,1H), 7.85(dd,J=8.1,2.1Hz,1H), 7.68–7.61(m,2H), 7.33(d,J=5.7Hz,1H), 7.25(dd,J=8.1,1.2Hz,1H),6.88(d,J=3.6Hz,1H),5.30(s,1H),1.88–1.37(m,10H).HRMS(ESI+)[M+Na ] + :476.1658.
实施例53：1-((1-(2-(间甲基苯氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇Example 53: 1-((1-(2-(m-methylphenylamino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1H NMR(400MHz,DMSO-d 6)δ9.78(s,1H),8.64(s,1H),8.52(d,J＝5.6Hz,1H),8.16(d,J＝3.6Hz,1H),7.70–7.60(m,2H),7.54(d,J＝8.1Hz,1H),7.30–7.21(m,2H),7.19(d,J＝5.6Hz,1H),6.85(d,J＝3.5Hz,1H),6.82(d,J＝7.5Hz,1H),5.31(s,1H),2.30(s,3H),1.91–1.39 (m,10H).HRMS(ESI+)[M+Na] +:445.2007。 1 H NMR(400MHz,DMSO-d 6 )δ9.78(s,1H),8.64(s,1H),8.52(d,J=5.6Hz,1H), 8.16(d,J=3.6Hz,1H) ,7.70–7.60(m,2H),7.54(d,J=8.1Hz,1H),7.30–7.21(m,2H),7.19(d,J=5.6Hz,1H),6.85(d,J=3.5 Hz,1H),6.82(d,J=7.5Hz,1H),5.31(s,1H),2.30(s,3H),1.91-1.39 (m,10H).HRMS(ESI+)[M+Na] + :445.2007.
实施例54：1-((1-(2-((4-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇Example 54: 1-((1-(2-((4-(Trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl -1-ol
1H NMR(400MHz,DMSO-d 6)δ10.07(s,1H),8.62(s,1H),8.56(d,J＝5.6Hz,1H),8.17(d,J＝3.6Hz,1H),7.92(d,J＝2.0Hz,1H),7.90(d,J＝2.0Hz,1H),7.64(d,J＝8.1Hz,1H),7.33(d,J＝8.8Hz,2H),7.28–7.23(m,2H),6.86(d,J＝3.6Hz,1H),5.33(s,1H),1.92–1.40(m,10H).HRMS(ESI+)[M+Na] +:493.1848。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.07 (s, 1H), 8.62 (s, 1H), 8.56 (d, J = 5.6 Hz, 1H), 8.17 (d, J = 3.6 Hz, 1H) ,7.92(d,J=2.0Hz,1H),7.90(d,J=2.0Hz,1H), 7.64(d,J=8.1Hz,1H), 7.33(d,J=8.8Hz,2H), 7.28 –7.23(m,2H), 6.86(d,J=3.6Hz,1H),5.33(s,1H),1.92–1.40(m,10H).HRMS(ESI+)[M+Na] + :493.1848.
实施例55：1-((1-(2-((2-(三氟甲基)苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇Example 55: 1-((1-(2-((2-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl- 1-alcohol
1H NMR(400MHz,DMSO-d 6)δ10.42(s,1H),8.64(d,J＝1.3Hz,1H),8.62(d,J＝5.7Hz,1H),8.19(d,J＝3.7Hz,1H),8.03(d,J＝1.9Hz,1H),8.01(d,J＝2.1Hz,1H),7.79–7.73(m,2H),7.65(d,J＝8.1Hz,1H),7.35(d,J＝5.7Hz,1H),7.27(dd,J＝8.1,1.4Hz,1H),6.88(dd,J＝3.6,0.8Hz,1H),5.32(s,1H),1.92–1.40(m,10H).HRMS(ESI+)[M+Na] +:499.1718。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 8.64 (d, J = 1.3 Hz, 1H), 8.62 (d, J = 5.7 Hz, 1H), 8.19 (d, J = 3.7Hz, 1H), 8.03 (d, J = 1.9 Hz, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.79–7.73 (m, 2H), 7.65 (d, J = 8.1 Hz, 1H) ,7.35(d,J=5.7Hz,1H),7.27(dd,J=8.1,1.4Hz,1H),6.88(dd,J=3.6,0.8Hz,1H),5.32(s,1H),1.92– 1.40(m,10H).HRMS(ESI+)[M+Na] + :499.1718.
实施例56：1-((1-(2-(邻甲基苯氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇Example 56: 1-((1-(2-(O-methylphenylamino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1H NMR(400MHz,DMSO-d 6)δ9.08(s,1H),8.45(s,1H),8.37(s,1H),8.11(d,J＝3.7Hz,1H),7.57(d,J＝8.1Hz,1H),7.55–7.45(m,1H),7.32(t,J＝7.7Hz,2H),7.25–7.06(m,3H),6.80(d,J＝3.5Hz,1H),5.36(s,1H),2.29(s,3H),1.99–1.43(m,10H).HRMS(ESI+)[M+H] +:423.2190。 1 H NMR(400MHz,DMSO-d 6 )δ9.08(s,1H),8.45(s,1H),8.37(s,1H),8.11(d,J=3.7Hz,1H),7.57(d, J=8.1Hz,1H), 7.55–7.45(m,1H), 7.32(t,J=7.7Hz,2H), 7.25–7.06(m,3H), 6.80(d,J=3.5Hz,1H), 5.36(s,1H),2.29(s,3H),1.99–1.43(m,10H).HRMS(ESI+)[M+H] + : 423.2190.
实施例57：1-((1-(2-((2-氟苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇Example 57: 1-((1-(2-((2-Fluorophenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1H NMR(400MHz,DMSO-d 6)δ9.40(s,1H),8.46(d,J＝20.5Hz,2H),8.24–8.05(m,1H),7.79–7.54(m,2H),7.51–7.10(m,5H),6.81(s,1H),5.38(s,1H),2.06–1.32(m,10H).HRMS(ESI+)[M+Na] +:449.1744。 1 H NMR(400MHz,DMSO-d 6 )δ9.40(s,1H), 8.46(d,J=20.5Hz,2H), 8.24–8.05(m,1H), 7.79–7.54(m,2H), 7.51–7.10(m,5H), 6.81(s,1H), 5.38(s,1H), 2.06–1.32(m,10H). HRMS(ESI+)[M+Na] + : 449.1744.
实施例58：3-((4-(6-((1-羟基环己基)乙炔基)1H-吲哚-1-基)嘧啶-2-基)氨基)苯磺酰胺Example 58: 3-((4-(6-((1-hydroxycyclohexyl)ethynyl)1H-indol-1-yl)pyrimidin-2-yl)amino)benzenesulfonamide
1H NMR(600MHz,DMSO-d 6)δ10.22(s,1H),8.64(s,1H),8.58(d,J＝5.6Hz,1H),8.28(t,J＝2.0Hz,1H),8.21(d,J＝3.7Hz,1H),8.09(dd,J＝8.2,2.1Hz,1H),7.64(d,J＝8.1Hz,1H),7.57(t,J＝8.0Hz,1H),7.47(dt,J＝7.7,1.2Hz,1H),7.35(s,2H),7.30(d,J＝5.7Hz,1H),7.27(dd,J＝8.1,1.4Hz,1H),6.86(d,J＝3.5Hz,1H),5.37(s,1H),1.95–1.42(m,10H).HRMS(ESI+)[M+Na] +:510.1572。 1 H NMR (600MHz, DMSO-d 6 ) δ 10.22 (s, 1H), 8.64 (s, 1H), 8.58 (d, J = 5.6 Hz, 1H), 8.28 (t, J = 2.0 Hz, 1H) ,8.21(d,J=3.7Hz,1H), 8.09(dd,J=8.2,2.1Hz,1H), 7.64(d,J=8.1Hz,1H), 7.57(t,J=8.0Hz,1H) ,7.47(dt,J=7.7,1.2Hz,1H),7.35(s,2H),7.30(d,J=5.7Hz,1H),7.27(dd,J=8.1,1.4Hz,1H),6.86( d, J = 3.5 Hz, 1H), 5.37 (s, 1H), 1.95-1.42 (m, 10H). HRMS (ESI+) [M+Na] + : 510.1572.
实施例59：1-((1-(2-(环己氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇Example 59: 1-((1-(2-(Cyclohexylamino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
1H NMR(600MHz,DMSO-d 6)δ8.79(s,1H),8.38–8.25(m,1H),8.15(s,1H),7.61(d,J＝8.0Hz,1H),7.36(d,J＝7.7Hz,1H),7.24(d,J＝8.2Hz,1H),6.93(d,J＝5.4Hz,1H),6.81(d,J＝3.5Hz,1H),5.35(s,1H),3.80(tdt,J＝11.0,7.5,3.8Hz,1H),2.02(d,J＝14.3Hz,2H),1.90–1.44(m,15H),1.32(dtd,J＝23.0,11.4,10.4,4.8Hz,3H).HRMS(ESI+)[M+H] +:415.2502。 1 H NMR(600MHz,DMSO-d 6 )δ8.79(s,1H), 8.38–8.25(m,1H), 8.15(s,1H), 7.61(d,J=8.0Hz,1H), 7.36( d, J = 7.7 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 5.4 Hz, 1H), 6.81 (d, J = 3.5 Hz, 1H), 5.35 (s, 1H), 3.80 (tdt, J = 11.0, 7.5, 3.8 Hz, 1H), 2.02 (d, J = 14.3 Hz, 2H), 1.90-1.44 (m, 15H), 1.32 (dtd, J = 23.0, 11.4, 10.4,4.8Hz,3H).HRMS(ESI+)[M+H] + :415.2502.
实施例60：N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)苯甲酰胺Example 60: N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)benzamide
Figure PCTCN2021098556-appb-000026
Figure PCTCN2021098556-appb-000026
N-(5-溴-2-碘苯基)-2-(甲硫基)嘧啶-4-胺的制备Preparation of N-(5-bromo-2-iodophenyl)-2-(methylthio)pyrimidin-4-amine
Figure PCTCN2021098556-appb-000027
Figure PCTCN2021098556-appb-000027
步骤1：将5-溴-2-碘苯胺(1g，3.357mmol)和2-甲硫基嘧啶(0.4ml，0.3439mmol) 溶于10ml异丙醇中，加入浓盐酸2d，将反应加热至60℃反应20h，Tlc检测反应结束。将反应液倾入50ml冰水中，用20％的氢氧化钠溶液调PH至8左右，抽滤，洗涤，干燥得类白色固体1.18g。产率83.2％。ESI-MS(m/z)：422[M+H] +。 Step 1: Dissolve 5-bromo-2-iodoaniline (1g, 3.357mmol) and 2-methylthiopyrimidine (0.4ml, 0.3439mmol) in 10ml isopropanol, add concentrated hydrochloric acid for 2d, and heat the reaction to 60 After reacting at ℃ for 20h, Tlc detects the end of the reaction. The reaction solution was poured into 50 ml of ice water, the pH was adjusted to about 8 with 20% sodium hydroxide solution, filtered with suction, washed, and dried to obtain 1.18 g of off-white solid. The yield was 83.2%. ESI-MS (m/z): 422 [M+H] + .
N-Boc(6-溴-1-(2-(甲硫基)嘧啶-4-基)1H-吲哚-2-基)甲胺的制备Preparation of N-Boc(6-bromo-1-(2-(methylthio)pyrimidin-4-yl)1H-indol-2-yl)methylamine
Figure PCTCN2021098556-appb-000028
Figure PCTCN2021098556-appb-000028
步骤2：将N-(5-溴-2-碘苯基)-2-(甲硫基)嘧啶-4-胺(1g，2.37mmol)，N-Boc氨基丙炔(0.4g，2.61mmol)，TEA(1ml，7.11mmol)，加入10ml DMF中，超声除气泡，并抽真空氮气保护，然后加入CuI(0.09g，0.474mmol)，双三苯基膦二氯化钯(83mg，0.12mmol)室温反应，大约2h后，补加0.8eq CuI，加热至70℃反应8h，TLC检测反应结束。将反应液倒入50ml水中使用EA 30ml*3萃取，饱和食盐水洗涤，干燥，然后进行柱层析分离(EA:PE＝1:10)，最后得白色絮状固体0.81g，产率75％。ESI-MS(m/z)：448[M+H] -。 Step 2: Combine N-(5-bromo-2-iodophenyl)-2-(methylthio)pyrimidin-4-amine (1g, 2.37mmol), N-Boc aminopropyne (0.4g, 2.61mmol) , TEA (1ml, 7.11mmol), add 10ml DMF, ultrasonic to remove bubbles, and vacuum nitrogen protection, then add CuI (0.09g, 0.474mmol), bistriphenylphosphine palladium dichloride (83mg, 0.12mmol) Reaction at room temperature, after about 2h, add 0.8eq CuI, heat to 70℃ and react for 8h, TLC detects the end of the reaction. The reaction solution was poured into 50ml water and extracted with EA 30ml*3, washed with saturated brine, dried, and then separated by column chromatography (EA:PE=1:10). Finally, 0.81g of white flocculent solid was obtained, and the yield was 75%. . ESI-MS (m/z): 448 [M+H] - .
N-Boc(6-溴-1-(2-(甲磺酰基)嘧啶-4-基)1H-吲哚-2-基)甲胺的制备Preparation of N-Boc(6-bromo-1-(2-(methylsulfonyl)pyrimidin-4-yl)1H-indol-2-yl)methylamine
Figure PCTCN2021098556-appb-000029
Figure PCTCN2021098556-appb-000029
步骤3：将N-Boc(6-溴-1-(2-(甲硫基)嘧啶-4-基)1H-吲哚-2-基)甲胺(6.4g，14.24mmol)，溶于DCM中，然后于冷阱中降温至零下4℃，再分批加入mCPBA，并于此温度下反应5h后检测，反应完毕。将反应液使用饱和硫代硫酸钠淬灭，然后用饱和碳酸氢钠洗涤，再用饱和食盐水干燥，减压蒸出溶剂，直接投下一步。ESI-MS(m/z)：481[M+H] +。 Step 3: Dissolve N-Boc(6-bromo-1-(2-(methylthio)pyrimidin-4-yl)1H-indol-2-yl)methylamine (6.4g, 14.24mmol) in DCM Then, the temperature is lowered to minus 4°C in a cold trap, and mCPBA is added in batches, and the reaction is tested at this temperature for 5 hours, and the reaction is complete. The reaction solution was quenched with saturated sodium thiosulfate, and then washed with saturated sodium bicarbonate, and then dried with saturated brine, the solvent was evaporated under reduced pressure, and directly cast to the next step. ESI-MS (m/z): 481 [M+H] + .
N-Boc(1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-2-基)甲胺的制备Preparation of N-Boc(1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indol-2-yl)methylamine
Figure PCTCN2021098556-appb-000030
Figure PCTCN2021098556-appb-000030
步骤4：将N-Boc(6-溴-1-(2-(甲磺酰基)嘧啶-4-基)1H-吲哚-2-基)甲胺(10g)，分别加入氨水(15ml)，氯化铵(2g)(氨水和氯化铵都为大过量),异丙醇(50ml)，封管60度反应，1.5h后反应结束，柱层析(PE:EA＝1.5:1)得淡黄色固体，产率41％。ESI-MS(m/z)：418[M+H] +。 Step 4: Add N-Boc(6-bromo-1-(2-(methylsulfonyl)pyrimidin-4-yl)1H-indol-2-yl)methylamine (10g) to ammonia (15ml), Ammonium chloride (2g) (ammonia and ammonium chloride are both in large excess), isopropanol (50ml), the tube is sealed for 60°C reaction, the reaction is over after 1.5h, column chromatography (PE:EA=1.5:1) is obtained Pale yellow solid, the yield is 41%. ESI-MS (m/z): 418 [M+H] + .
4-(2-(氨甲基)-6-溴-1H-吲哚-1-基)嘧啶-2-胺盐酸盐的制备Preparation of 4-(2-(aminomethyl)-6-bromo-1H-indol-1-yl)pyrimidine-2-amine hydrochloride
Figure PCTCN2021098556-appb-000031
Figure PCTCN2021098556-appb-000031
步骤5：将N-Boc(1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-2-基)甲胺(2g，4.78mmol)溶于二氧六环的盐酸溶液(1N)，室温反应3h，直接抽滤得暗黄色粉末1.6g，产率91％。Step 5: Dissolve N-Boc(1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indol-2-yl)methylamine (2g, 4.78mmol) in dioxane hydrochloric acid The solution (1N) was reacted at room temperature for 3 hours, and 1.6 g of dark yellow powder was obtained by direct suction filtration, with a yield of 91%.
N-((1-(2-氨基嘧啶-4-基)6-溴-1H-吲哚-2-基)甲基)苯甲酰胺的制备Preparation of N-((1-(2-aminopyrimidin-4-yl)6-bromo-1H-indol-2-yl)methyl)benzamide
Figure PCTCN2021098556-appb-000032
Figure PCTCN2021098556-appb-000032
步骤6：将4-(2-氨甲基)-6-溴-1H-吲哚-1-基)嘧啶-2-胺盐酸盐(0.2g，0.564mmol)，溶于3ml DMF中，然后加入0.12ml三乙胺，室温搅拌，溶液由浑浊变为澄清后复现浑浊。 再将HATU(0.257g，0.67mmol)和苯甲酸(0.083mg，0.67mmol)溶于3ml DMF中，加入0.12ml三乙胺，搅拌10min后滴入上述反应液，室温反应1h反应结束，将反应液倾入30ml水中，使用EA 20ml*3进行萃取，然后使用饱和碳酸氢钠和饱和食盐水洗涤，干燥，蒸出溶剂，直接用于下一部反应。ESI-MS(m/z)：422[M+H] +。 Step 6: Dissolve 4-(2-aminomethyl)-6-bromo-1H-indol-1-yl)pyrimidin-2-amine hydrochloride (0.2g, 0.564mmol) in 3ml DMF, then Add 0.12ml of triethylamine, stir at room temperature, the solution turns from turbid to clear and then becomes turbid. Then HATU (0.257g, 0.67mmol) and benzoic acid (0.083mg, 0.67mmol) were dissolved in 3ml DMF, and 0.12ml of triethylamine was added. After stirring for 10min, dripped into the above reaction solution. React at room temperature for 1h and the reaction is over. Pour the liquid into 30ml water, use EA 20ml*3 for extraction, then wash with saturated sodium bicarbonate and saturated brine, dry, distill the solvent, and use it directly in the next reaction. ESI-MS (m/z): 422 [M+H] + .
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)苯甲酰胺的制备Preparation of N-((1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)benzamide
步骤7：该标题化合物通过调整实例1所述方法，将步骤2中的4-(6-溴-1H-吲哚-1-基)嘧啶-2-胺使用N-((1-(2-氨基嘧啶-4-基)6-溴-1H-吲哚-2-基)甲基)苯甲酰胺代替，反应在80℃下进行5个小时。得标题化合物N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)苯甲酰胺。 1H NMR(600MHz,DMSO-d 6)δ9.04(t,J＝5.7Hz,1H),8.45(d,J＝5.2Hz,1H),7.87(s,1H),7.86(s,1H),7.61(s,1H),7.54(d,J＝7.8Hz,2H),7.48(t,J＝7.6Hz,2H),7.15(d,J＝8.0Hz,1H),7.02(s,2H),6.85(d,J＝5.2Hz,1H),6.60(s,1H),5.38(s,1H),4.80(d,J＝5.5Hz,2H),1.89–1.42(m,10H).HRMS(ESI+)[M+Na] +:488.2060。 Step 7: The title compound was adjusted to the method described in Example 1, and the 4-(6-bromo-1H-indol-1-yl)pyrimidin-2-amine in step 2 was N-((1-(2- Aminopyrimidin-4-yl)6-bromo-1H-indol-2-yl)methyl)benzamide was substituted, and the reaction was carried out at 80°C for 5 hours. The title compound N-((1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)benzamide was obtained. 1 H NMR(600MHz,DMSO-d 6 )δ9.04(t,J=5.7Hz,1H), 8.45(d,J=5.2Hz,1H), 7.87(s,1H), 7.86(s,1H) ,7.61(s,1H),7.54(d,J=7.8Hz,2H),7.48(t,J=7.6Hz,2H),7.15(d,J=8.0Hz,1H),7.02(s,2H) ,6.85(d,J=5.2Hz,1H),6.60(s,1H),5.38(s,1H),4.80(d,J=5.5Hz,2H),1.89–1.42(m,10H).HRMS( ESI+)[M+Na] + :488.2060.
按照实施例60的方法，可与适当的伯胺或仲胺或者醇进行反应来进行实施例61-69的制备。According to the method of Example 60, the preparation of Examples 61-69 can be carried out by reacting with an appropriate primary or secondary amine or alcohol.
实施例61：N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-3-甲基苯甲酰胺Example 61: N-((1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-3- Methylbenzamide
1H NMR(600MHz,DMSO-d 6)δ9.10–9.00(m,1H),8.45(d,J＝5.2Hz,1H),7.69(s,1H),7.67(s,1H),7.61(s,1H),7.54(d,J＝8.1Hz,1H),7.36(d,J＝5.1Hz,2H),7.15(d,J＝8.1Hz,1H),7.03(s,2H),6.85(d,J＝5.2Hz,1H),6.60(s,1H),5.39(s,1H),4.79(d,J＝5.5Hz,2H),2.37(s,3H),1.88–1.44(m,10H).HRMS(ESI+)[M+Na] +:502.2232。 1 H NMR(600MHz,DMSO-d 6 )δ9.10–9.00(m,1H), 8.45(d,J=5.2Hz,1H), 7.69(s,1H), 7.67(s,1H), 7.61( s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 5.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 1H), 7.03 (s, 2H), 6.85 ( d,J=5.2Hz,1H),6.60(s,1H),5.39(s,1H),4.79(d,J=5.5Hz,2H),2.37(s,3H),1.88–1.44(m,10H ).HRMS(ESI+)[M+Na] + :502.2232.
实施例62：N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-硝基苯甲酰胺Example 62: N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-4- Nitrobenzamide
1H NMR(600MHz,DMSO-d 6)δ9.50(d,J＝5.0Hz,1H),8.45(d,J＝5.2Hz,1H),8.33(s,1H),8.32(s,1H),8.13(s,1H),8.11(s,1H),7.60(s,1H),7.55(d,J＝8.1Hz,1H),7.15(d,J＝8.0Hz,1H),7.03(s,2H),6.85(d,J＝5.2Hz,1H),6.65(s,1H),5.40(s,1H),4.84(d,J＝5.4Hz,2H),1.91–1.42(m,10H).HRMS(ESI+)[M+Na] +:533.1914。 1 H NMR(600MHz,DMSO-d 6 )δ9.50(d,J=5.0Hz,1H), 8.45(d,J=5.2Hz,1H), 8.33(s,1H), 8.32(s,1H) ,8.13(s,1H),8.11(s,1H),7.60(s,1H),7.55(d,J=8.1Hz,1H),7.15(d,J=8.0Hz,1H),7.03(s, 2H), 6.85(d,J=5.2Hz,1H), 6.65(s,1H), 5.40(s,1H), 4.84(d,J=5.4Hz,2H), 1.91-1.42(m,10H). HRMS(ESI+)[M+Na] + : 533.1914.
实施例63：N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-2-硝基苯甲酰胺Example 63: N-((1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-2- Nitrobenzamide
1H NMR(600MHz,DMSO-d 6)δ9.33(s,1H),8.46(s,1H),8.05(d,J＝6.6Hz,1H),7.81(s,1H),7.71(s,1H),7.61(s,2H),7.58(d,J＝7.0Hz,1H),7.17(d,J＝6.4Hz,1H),7.05(s,2H),6.85(s,1H),6.75(s,1H),5.41(s,1H),4.78(s,2H),1.92–1.41(m,10H).HRMS(ESI+)[M+Na] +:533.1918。 1 H NMR(600MHz,DMSO-d 6 )δ9.33(s,1H),8.46(s,1H),8.05(d,J=6.6Hz,1H),7.81(s,1H),7.71(s, 1H), 7.61 (s, 2H), 7.58 (d, J = 7.0 Hz, 1H), 7.17 (d, J = 6.4 Hz, 1H), 7.05 (s, 2H), 6.85 (s, 1H), 6.75 ( s, 1H), 5.41 (s, 1H), 4.78 (s, 2H), 1.92–1.41 (m, 10H). HRMS (ESI+) [M+Na] + : 533.1918.
实施例64：N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-甲氧基苯甲酰胺Example 64: N-((1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-4- Methoxybenzamide
1H NMR(600MHz,DMSO-d 6)δ8.94(t,J＝5.7Hz,1H),8.45(d,J＝5.2Hz,1H),7.88(s,1H),7.86(s,1H),7.60(s,1H),7.54(d,J＝8.1Hz,1H),7.14(d,J＝8.1Hz,1H),7.02(s,2H),7.02(s,1H),7.00(s,1H),6.85(d,J＝5.2Hz,1H),6.58(s,1H),5.39(s,1H),4.77(d,J＝5.5Hz,2H),3.82(s,3H),1.89–1.40(m,10H).HRMS(ESI+)[M+Na] +:518.2179。 1 H NMR(600MHz,DMSO-d 6 )δ8.94(t,J=5.7Hz,1H), 8.45(d,J=5.2Hz,1H),7.88(s,1H),7.86(s,1H) ,7.60(s,1H),7.54(d,J=8.1Hz,1H),7.14(d,J=8.1Hz,1H),7.02(s,2H),7.02(s,1H),7.00(s, 1H), 6.85 (d, J = 5.2 Hz, 1H), 6.58 (s, 1H), 5.39 (s, 1H), 4.77 (d, J = 5.5 Hz, 2H), 3.82 (s, 3H), 1.89- 1.40(m,10H).HRMS(ESI+)[M+Na] + :518.2179.
实施例65：N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-氟苯甲酰胺Example 65: N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-4- Fluorobenzamide
1H NMR(600MHz,DMSO-d 6)δ9.11(t,J＝5.7Hz,1H),8.44(d,J＝5.2Hz,1H),7.93–7.85(m,2H),7.60(s,1H),7.56(d,J＝1.9Hz,1H),7.55(d,J＝8.3Hz,2H),7.15(dd,J＝8.1,1.3Hz,1H),7.02(s,2H),6.84(d,J＝5.2Hz,1H),6.61(s,1H),5.38(s,1H),4.80(d,J＝5.5Hz,2H),1.94–1.39(m,10H).HRMS(ESI+)[M+K] +:522.1668。 1 H NMR(600MHz,DMSO-d 6 )δ9.11(t,J=5.7Hz,1H), 8.44(d,J=5.2Hz,1H),7.93-7.85(m,2H), 7.60(s, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.15 (dd, J = 8.1, 1.3 Hz, 1H), 7.02 (s, 2H), 6.84 ( d,J=5.2Hz,1H),6.61(s,1H),5.38(s,1H),4.80(d,J=5.5Hz,2H),1.94-1.39(m,10H).HRMS(ESI+)[ M+K] + :522.1668.
实施例66：N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-2-氟苯甲酰胺Example 66: N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-2- Fluorobenzamide
1H NMR(600MHz,DMSO-d 6)δ8.89(dt,J＝5.6,2.8Hz,1H),8.45(d,J＝5.2Hz,1H),7.64–7.59(m,2H),7.57(d,J＝8.1Hz,1H),7.56–7.52(m,1H),7.34–7.30(m,1H),7.30–7.27(m,1H),7.16(dd,J＝8.1,1.3Hz,1H),7.02(s,2H),6.85(d,J＝5.3Hz,1H),6.67–6.63(m,1H),5.38(s,1H),4.80(d,J＝5.7Hz,2H),1.89–1.44(m,10H).HRMS(ESI+)[M+Na] +:506.1974。 1 H NMR (600MHz, DMSO-d 6 ) δ 8.89 (dt, J = 5.6, 2.8 Hz, 1H), 8.45 (d, J = 5.2 Hz, 1H), 7.64-7.59 (m, 2H), 7.57 ( d,J=8.1Hz,1H),7.56–7.52(m,1H),7.34–7.30(m,1H),7.30–7.27(m,1H),7.16(dd,J=8.1,1.3Hz,1H) ,7.02(s,2H),6.85(d,J=5.3Hz,1H),6.67–6.63(m,1H),5.38(s,1H),4.80(d,J=5.7Hz,2H),1.89– 1.44(m,10H).HRMS(ESI+)[M+Na] + :506.1974.
实施例67：N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-异戊酰胺Example 67: N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-isopentyl Amide
1H NMR(600MHz,DMSO-d 6)δ8.45(d,J＝5.4Hz,1H),8.34(t,J＝5.4Hz,1H),7.61(s,1H),7.56(d,J＝8.1Hz,1H),7.27(s,2H),7.16(d,J＝8.0Hz,1H),6.86(d,J＝5.4Hz,1H),6.59(s,1H),5.38(s,1H),4.59(d,J＝5.5Hz,2H),2.03(d,J＝7.0Hz,2H),1.97(tt,J＝13.8,6.5Hz,1H),1.87–1.45(m,10H),0.86(d,J＝6.5Hz,6H).HRMS(ESI+)[M+Na] +:468.2383。 1 H NMR(600MHz,DMSO-d 6 )δ8.45(d,J=5.4Hz,1H), 8.34(t,J=5.4Hz,1H), 7.61(s,1H), 7.56(d,J= 8.1Hz, 1H), 7.27 (s, 2H), 7.16 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 5.4 Hz, 1H), 6.59 (s, 1H), 5.38 (s, 1H) ,4.59(d,J=5.5Hz,2H),2.03(d,J=7.0Hz,2H),1.97(tt,J=13.8,6.5Hz,1H),1.87–1.45(m,10H),0.86( d, J=6.5 Hz, 6H). HRMS(ESI+)[M+Na] + : 468.2383.
实施例68：N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-1H-吲哚-6-甲酰胺Example 68: N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-1H- Indole-6-carboxamide
1H NMR(600MHz,DMSO-d 6)δ11.41(s,1H),8.95(t,J＝5.7Hz,1H),8.47(d,J＝4.8Hz,1H),8.00(s,1H),7.63(s,1H),7.60(d,J＝8.3Hz,1H),7.58–7.56(m,1H),7.54(d,J＝8.1Hz,1H),7.52(t,J＝2.7Hz,1H),7.18–7.13(m,1H),7.04(s,2H),6.87(d,J＝5.2Hz,1H),6.60(s,1H),6.50(s,1H),5.39(s,1H),4.82(d,J＝5.5Hz,2H),1.89–1.42(m,10H).HRMS(ESI+)[M+Na] +:527.2182。 1 H NMR(600MHz,DMSO-d 6 )δ11.41(s,1H), 8.95(t,J=5.7Hz,1H), 8.47(d,J=4.8Hz,1H),8.00(s,1H) ,7.63(s,1H),7.60(d,J=8.3Hz,1H),7.58–7.56(m,1H),7.54(d,J=8.1Hz,1H),7.52(t,J=2.7Hz, 1H), 7.18–7.13 (m, 1H), 7.04 (s, 2H), 6.87 (d, J = 5.2 Hz, 1H), 6.60 (s, 1H), 6.50 (s, 1H), 5.39 (s, 1H) ), 4.82 (d, J = 5.5 Hz, 2H), 1.89-1.42 (m, 10H). HRMS (ESI+) [M+Na] + : 527.2182.
实施例69：N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-1H-吲哚-2-甲酰胺Example 69: N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-1H- Indole-2-carboxamide
1H NMR(600MHz,DMSO-d 6)δ11.66(s,1H),9.08(t,J＝5.8Hz,1H),8.47(d,J＝5.1Hz,1H),7.63(t,J＝3.9Hz,2H),7.55(d,J＝8.1Hz,1H),7.45(d,J＝8.3Hz,1H),7.25–7.21(m,1H),7.19(t,J＝7.6Hz,1H),7.16(d,J＝8.1Hz,1H),7.09–7.02(m,3H),6.88(d,J＝5.2Hz,1H),6.64(s,1H),5.40(s,1H),4.86(d,J＝5.7Hz,2H),1.90–1.43(m,10H).HRMS(ESI+)[M+Na] +:527.2164。 1 H NMR(600MHz,DMSO-d 6 )δ11.66(s,1H), 9.08(t,J=5.8Hz,1H), 8.47(d,J=5.1Hz,1H), 7.63(t,J= 3.9Hz, 2H), 7.55 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.25-7.21 (m, 1H), 7.19 (t, J = 7.6 Hz, 1H) ,7.16(d,J=8.1Hz,1H),7.09–7.02(m,3H), 6.88(d,J=5.2Hz,1H), 6.64(s,1H), 5.40(s,1H), 4.86( d, J = 5.7 Hz, 2H), 1.90-1.43 (m, 10H). HRMS (ESI+) [M+Na] + : 527.2164.
实施例70：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-2-甲酰胺Example 70: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-phenyl-1H-indole-2-carboxamide
Figure PCTCN2021098556-appb-000033
Figure PCTCN2021098556-appb-000033
6-溴吲哚-2-甲酸乙酯的制备：Preparation of ethyl 6-bromoindole-2-carboxylate:
Figure PCTCN2021098556-appb-000034
Figure PCTCN2021098556-appb-000034
步骤1：在Ar气氛保护下，在室温、搅拌下，分批的向乙醇(25mL)中加入叔丁醇钾(22.44g,0.2mol)。当所得的粘稠溶液进行充分冷却后加入乙醚(300Ml)，随后加入草酸二乙酯(27.2mL,0.2mol)。搅拌10分钟后加入4-溴-2-硝基甲苯(21.5g,0.1mol)，此时的现象为黄色溶液变成深红色溶液，再将反应混合物转移到锥形瓶中，塞好瓶塞并在室温下放置4h，然后在冰箱中放置1小时,之后进行过滤收集反应生成的固体，将所得到的固体用乙醚洗至滤液流无色并抽干15分钟，分离出的产物为25.8g，产率为73.0％，可以不经进一步纯化直接使用。Step 1: Under the protection of Ar atmosphere, add potassium tert-butoxide (22.44 g, 0.2 mol) to ethanol (25 mL) in batches under stirring at room temperature. When the resulting viscous solution was sufficiently cooled, ether (300 Ml) was added, followed by diethyl oxalate (27.2 mL, 0.2 mol). After stirring for 10 minutes, add 4-bromo-2-nitrotoluene (21.5g, 0.1mol), the phenomenon at this time is that the yellow solution turns into a deep red solution, then the reaction mixture is transferred to an Erlenmeyer flask, and the stopper is stoppered. And place it at room temperature for 4 hours, then place it in the refrigerator for 1 hour, then filter to collect the solid produced by the reaction, wash the obtained solid with ether until the filtrate stream is colorless and drain for 15 minutes. The isolated product is 25.8g The yield is 73.0%, and it can be used directly without further purification.
将上述产物(17.7g,0.05mol)中加入乙酸(250mL)溶液，再加入加入铁粉(8.4g,0.15mol)并进行加热使混合物到90℃。此时混合物变成浅粽色悬浮液。在90℃下反应过3小时后将反应混合物冷却至45℃,然后倒入冰水(5 00mL)中。将该混合物用乙醚(3×400mL)进行萃取，收集乙醚层进行合并，将萃取液用饱和的碳酸氢钠水溶液进行反复洗涤，直到停止冒泡、 再用水(400mL)和1N HC1(2×300mL)进行洗涤，有机萃取液经过(硫酸镁)干燥并且在真空环境下除去溶剂得到类白色固体粗产品10.1g，产率为76％，将所得的粗产品使用甲苯进行重结晶，得7.1g产品，产率为70％。 1H NMR(600MHz,DMSO-d 6)δ12.03(s,1H),δ7.63(d,J＝8.52Hz,1H),δ7.61(m,J＝0.72Hz,1H),δ7.22(dd,J＝1.8Hz,1H),δ7.17(m,J＝0.9Hz,1H),δ4.35(dd,J＝7.08Hz,2H)，δ1.34(t,J＝7.14Hz,3H)。 Add acetic acid (250 mL) solution to the above product (17.7 g, 0.05 mol), then add iron powder (8.4 g, 0.15 mol) and heat the mixture to 90°C. At this time the mixture became a light rice-colored suspension. After reacting at 90°C for 3 hours, the reaction mixture was cooled to 45°C, and then poured into ice water (500 mL). The mixture was extracted with ether (3×400mL), the ether layers were collected and combined, and the extract was washed repeatedly with saturated aqueous sodium bicarbonate solution until bubbling ceased, and then water (400mL) and 1N HC1 (2×300mL) ) Was washed, the organic extract was dried (magnesium sulfate) and the solvent was removed in a vacuum environment to obtain 10.1 g of off-white solid crude product with a yield of 76%. The crude product obtained was recrystallized using toluene to obtain 7.1 g product , The yield is 70%. 1 H NMR (600MHz, DMSO-d 6 ) δ 12.03 (s, 1H), δ 7.63 (d, J = 8.52 Hz, 1H), δ 7.61 (m, J = 0.72 Hz, 1H), δ 7. 22(dd,J=1.8Hz,1H),δ7.17(m,J=0.9Hz,1H),δ4.35(dd,J=7.08Hz,2H),δ1.34(t,J=7.14Hz ,3H).
6-溴-1-(2-(甲基硫醚)嘧啶-4-基)-1H-吲哚-2-羧酸乙酯的制备Preparation of 6-bromo-1-(2-(methylsulfide)pyrimidin-4-yl)-1H-indole-2-carboxylic acid ethyl ester
Figure PCTCN2021098556-appb-000035
Figure PCTCN2021098556-appb-000035
步骤2：将6-溴吲哚-2-甲酸乙酯(0.5g,1.86mmol)和2-甲硫基-4-溴嘧啶(0.46g,2.24mmol)溶于10mL干燥甲苯中，然后分别加入无水磷酸钾(1.18g,5.58mmol)、碘化亚铜(0.36g,1.86mmol)以及配体1,2-二氨基环己烷(0.43g,3.72mmol)，加热至回流反映，反应10h完毕后，将反应液使用30mL乙酸乙酯进行稀释，通过硅藻土滤除不溶物后进行柱层析(PE：EA＝5：1)得白色纯品0.57g，产率为78％。Step 2: Ethyl 6-bromoindole-2-carboxylate (0.5g, 1.86mmol) and 2-methylthio-4-bromopyrimidine (0.46g, 2.24mmol) were dissolved in 10mL of dry toluene, and then added separately Anhydrous potassium phosphate (1.18g, 5.58mmol), cuprous iodide (0.36g, 1.86mmol) and the ligand 1,2-diaminocyclohexane (0.43g, 3.72mmol), heated to reflux, and reacted for 10h After completion, the reaction solution was diluted with 30 mL of ethyl acetate, the insoluble matter was filtered through diatomaceous earth, and then column chromatography (PE:EA=5:1) was performed to obtain 0.57 g of a white pure product with a yield of 78%.
6-溴-1-(2-(甲磺酰基)嘧啶-4-基)-1H-吲哚-2-羧酸乙酯的制备Preparation of 6-bromo-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-indole-2-carboxylic acid ethyl ester
Figure PCTCN2021098556-appb-000036
Figure PCTCN2021098556-appb-000036
步骤3：将6-溴-1-(2-(甲基硫醚)嘧啶-4-基)-1H-吲哚-2-羧酸乙酯(5.58g，14.24mmol)，溶于DCM中，然后于冷阱中降温至零下4℃，再分批加入mCPBA，并于此温度下反应5h后检测，反应完毕。将反应液使用饱和硫代硫酸钠淬灭，然后用饱和碳酸氢钠洗涤，再用饱和食盐水干燥，减压蒸出溶剂，直接投下一步。ESI-MS(m/z)：423[M-H] -。 Step 3: Dissolve 6-bromo-1-(2-(methylsulfide)pyrimidin-4-yl)-1H-indole-2-carboxylic acid ethyl ester (5.58g, 14.24mmol) in DCM, Then, the temperature was lowered to minus 4°C in a cold trap, and mCPBA was added in batches, and the reaction was carried out at this temperature for 5 hours, and the reaction was completed. The reaction solution was quenched with saturated sodium thiosulfate, and then washed with saturated sodium bicarbonate, and then dried with saturated brine, the solvent was evaporated under reduced pressure, and directly cast to the next step. ESI-MS (m/z): 423 [MH] - .
1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-2-羧酸乙酯的制备Preparation of 1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indole-2-carboxylic acid ethyl ester
Figure PCTCN2021098556-appb-000037
Figure PCTCN2021098556-appb-000037
步骤4：将上述中间体6-溴-1-(2-(甲磺酰基)嘧啶-4-基)-1H-吲哚-2-羧酸乙酯，分别加入氨水(10mL)，氯化铵(2g)(氨水和氯化铵都为大过量),异丙醇(50mL)，封管60℃反应，1.5h后反应结束，柱层析(PE:EA＝1.5:1)得淡黄色固体，产率41％。ESI-MS(m/z)：362[M+H] +。 Step 4: Add the above-mentioned intermediate 6-bromo-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-indole-2-carboxylic acid ethyl ester, respectively, add ammonia water (10mL), ammonium chloride (2g) (ammonia and ammonium chloride are both in large excess), isopropanol (50mL), the tube is sealed and reacted at 60℃, the reaction is over after 1.5h, and the column chromatography (PE:EA=1.5:1) gives a pale yellow solid , The yield is 41%. ESI-MS (m/z): 362 [M+H] + .
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-羧酸乙酯的制备Preparation of 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxylic acid ethyl ester
Figure PCTCN2021098556-appb-000038
Figure PCTCN2021098556-appb-000038
步骤5：该标题化合物通过调整实例1所述方法，将步骤2中的4-(6-溴-1H-吲哚-1-基)嘧啶-2-胺使用1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-2-羧酸乙酯替换，得标题化合物。ESI-MS(m/z)：405[M+H] +。 Step 5: This title compound uses 1-(2-aminopyrimidine-4) as 4-(6-bromo-1H-indol-1-yl)pyrimidin-2-amine in step 2 by adjusting the method described in Example 1. -Yl)-6-bromo-1H-indole-2-carboxylic acid ethyl ester to obtain the title compound. ESI-MS (m/z): 405 [M+H] + .
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-羧酸的制备Preparation of 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxylic acid
Figure PCTCN2021098556-appb-000039
Figure PCTCN2021098556-appb-000039
步骤6：该标题化合物通过调整实例7所述方法，将步骤5中的1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羧酸甲酯用1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔 基)-1H-吲哚-2-羧酸乙酯代替，得标题化合物。ESI-MS(m/z)：375[M-H] -。 Step 6: The title compound was adjusted to the method described in Example 7, and the 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole Replace -3-carboxylic acid methyl ester with 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxylic acid ethyl ester to get the title Compound. ESI-MS (m/z): 375 [MH] - .
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-2-甲酰胺的制备Preparation of 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-phenyl-1H-indole-2-carboxamide
步骤7：该标题化合物通过调整实例7所述方法，在步骤6中用1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-羧酸代替1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羧酸来与不同的取代胺进行反应，反应在常温下进行，得标题化合物。 1H NMR(600MHz,DMSO-d 6)δ10.66(s,1H),8.35(d,J＝5.2Hz,1H),7.80–7.74(m,2H),7.71(d,J＝8.0Hz,2H),7.40(s,1H),7.34(t,J＝7.8Hz,2H),7.26(dd,J＝8.1,1.4Hz,1H),7.10(t,J＝7.4Hz,1H),6.96(s,2H),6.58(d,J＝5.2Hz,1H),5.43(s,1H),1.89–1.45(m,10H).HRMS(ESI+)[M+Na] +:474.1911。 Step 7: The title compound was adjusted by the method described in Example 7, using 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole in step 6. -2-carboxylic acid instead of 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carboxylic acid to react with different substituted amines , The reaction is carried out at room temperature to obtain the title compound. 1 H NMR(600MHz,DMSO-d 6 )δ10.66(s,1H), 8.35(d,J=5.2Hz,1H), 7.80–7.74(m,2H), 7.71(d,J=8.0Hz, 2H), 7.40 (s, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.26 (dd, J = 8.1, 1.4 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.96 ( s, 2H), 6.58 (d, J=5.2 Hz, 1H), 5.43 (s, 1H), 1.89-1.45 (m, 10H). HRMS (ESI+) [M+Na] + : 474.1911.
按照实施例70的方法，可与适当的伯胺或仲胺或者醇进行反应来进行实施例71-80的制备。According to the method of Example 70, the preparation of Examples 71-80 can be carried out by reacting with an appropriate primary or secondary amine or alcohol.
实施例71：乙基1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-羧酸酯Example 71: Ethyl 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxylate
1H NMR(600MHz,DMSO-d 6)δ8.42(d,J＝5.2Hz,1H),7.76(d,J＝8.2Hz,1H),7.57(s,1H),7.45(s,1H),7.25(dd,J＝8.2,1.3Hz,1H),7.00(s,2H),6.74(d,J＝5.2Hz,1H),5.43(s,1H),4.22(q,J＝7.1Hz,2H),1.86–1.45(m,10H),1.19(t,J＝7.1Hz,3H).HRMS(ESI+)[M+Na] +:405.1923。 1 H NMR(600MHz,DMSO-d 6 )δ8.42(d,J=5.2Hz,1H),7.76(d,J=8.2Hz,1H),7.57(s,1H),7.45(s,1H) ,7.25(dd,J=8.2,1.3Hz,1H),7.00(s,2H),6.74(d,J=5.2Hz,1H),5.43(s,1H),4.22(q,J=7.1Hz, 2H), 1.86–1.45 (m, 10H), 1.19 (t, J=7.1 Hz, 3H). HRMS(ESI+)[M+Na] + : 405.1923.
实施例72：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡啶-4-基)-1H-吲哚-2-甲酰胺Example 72: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(pyridin-4-yl)-1H-indole-2-carboxamide
1H NMR(600MHz,DMSO-d 6)δ11.65(s,1H),8.48(s,2H),8.30(d,J＝5.2Hz,1H),8.01–7.89(m,2H),7.70(d,J＝8.2Hz,1H),7.66(s,1H),7.59(s,1H),7.22–7.16(m,1H),6.89(s,2H),6.60(d,J＝5.2Hz,1H),5.38(s,1H),1.82–1.31(m,10H).HRMS(ESI+)[M+H] +:453.2036。 1 H NMR (600MHz, DMSO-d 6 ) δ 11.65 (s, 1H), 8.48 (s, 2H), 8.30 (d, J = 5.2 Hz, 1H), 8.01-7.89 (m, 2H), 7.70 ( d,J=8.2Hz,1H),7.66(s,1H),7.59(s,1H),7.22-7.16(m,1H),6.89(s,2H),6.60(d,J=5.2Hz,1H ),5.38(s,1H),1.82–1.31(m,10H).HRMS(ESI+)[M+H] + :453.2036.
实施例73：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(间甲苯基)-1H-吲哚-2-甲酰胺Example 73: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(m-tolyl)-1H-indole-2-carboxamide
1H NMR(600MHz,DMSO-d 6)δ10.59(s,1H),8.36(d,J＝5.2Hz,1H),7.76(d,J＝8.7Hz,1H),7.75(s,1H),7.59(s,1H),7.49(d,J＝8.1Hz,1H),7.40(s,1H),7.26(dd,J＝8.2,1.1Hz,1H),7.22(t,J＝7.8Hz,1H),6.97(s,2H),6.92(d,J＝7.5Hz,1H),6.58(d,J＝5.2Hz,1H),5.43(s,1H),2.30(s,3H),1.92–1.41(m,10H).HRMS(ESI+)[M+Na] +:488.2071。 1 H NMR(600MHz,DMSO-d 6 )δ10.59(s,1H), 8.36(d,J=5.2Hz,1H), 7.76(d,J=8.7Hz,1H), 7.75(s,1H) ,7.59(s,1H),7.49(d,J=8.1Hz,1H),7.40(s,1H),7.26(dd,J=8.2,1.1Hz,1H),7.22(t,J=7.8Hz, 1H), 6.97 (s, 2H), 6.92 (d, J = 7.5 Hz, 1H), 6.58 (d, J = 5.2 Hz, 1H), 5.43 (s, 1H), 2.30 (s, 3H), 1.92- 1.41(m,10H).HRMS(ESI+)[M+Na] + :488.2071.
实施例74：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-异丙基-1H-吲哚-2-甲酰胺Example 74: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-isopropyl-1H-indole-2-carboxamide
1H NMR(600MHz,DMSO-d 6)δ8.55(d,J＝7.8Hz,1H),8.33(d,J＝5.2Hz,1H),7.77(s,1H),7.68(d,J＝8.2Hz,1H),7.26–7.19(m,1H),7.13(s,1H),6.93(s,2H),6.44(d,J＝5.2Hz,1H),5.41(s,1H),4.04–3.92(m,J＝6.7Hz,1H),1.90–1.41(m,10H),1.16(d,J＝6.6Hz,6H).HRMS(ESI+)[M+Na] +:440.2073。 1 H NMR(600MHz,DMSO-d 6 )δ8.55(d,J=7.8Hz,1H), 8.33(d,J=5.2Hz,1H), 7.77(s,1H), 7.68(d,J= 8.2Hz,1H), 7.26–7.19(m,1H), 7.13(s,1H), 6.93(s,2H), 6.44(d,J=5.2Hz,1H), 5.41(s,1H),4.04– 3.92 (m, J = 6.7 Hz, 1H), 1.90-1.41 (m, 10H), 1.16 (d, J = 6.6 Hz, 6H). HRMS (ESI+) [M+Na] + : 440.2073.
实施例75：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N,N-二甲基-1H-吲哚-2-甲酰胺Example 75: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N,N-dimethyl-1H-indole-2-carboxamide
1H NMR(600MHz,DMSO-d 6)δ8.35(d,J＝5.3Hz,1H),7.90(s,1H),7.65(d,J＝8.1Hz,1H),7.24(dd,J＝8.1,1.2Hz,1H),6.92(d,J＝4.5Hz,3H),6.58(d,J＝5.3Hz,1H),5.42(s,1H),3.09(s,3H),2.98(s,3H),1.95–1.43(m,10H).HRMS(ESI+)[M+Na] +:426.1913。 1 H NMR(600MHz,DMSO-d 6 )δ8.35(d,J=5.3Hz,1H), 7.90(s,1H), 7.65(d,J=8.1Hz,1H), 7.24(dd,J= 8.1, 1.2Hz, 1H), 6.92 (d, J = 4.5 Hz, 3H), 6.58 (d, J = 5.3 Hz, 1H), 5.42 (s, 1H), 3.09 (s, 3H), 2.98 (s, 3H),1.95–1.43(m,10H).HRMS(ESI+)[M+Na] + : 426.1913.
实施例76：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-甲氧基乙基)-1H-吲哚-2-甲酰胺Example 76: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-methoxyethyl)-1H-indole-2- Formamide
1H NMR(600MHz,DMSO-d 6)δ8.78(t,J＝5.7Hz,1H),8.34(d,J＝5.2Hz,1H),7.78(s,1H),7.70(d,J＝8.1Hz,1H),7.23(dd,J＝8.2,1.2Hz,1H),7.15(s,1H),6.96(s,2H),6.48(d,J＝5.2Hz,1H),5.42(s,1H),3.47(t,J＝5.8Hz,2H),3.43–3.38(m,2H),3.29(s,3H),1.95–1.41(m,10H).HRMS(ESI+)[M+Na] +:456.2026。 1 H NMR (600MHz, DMSO-d 6 ) δ8.78 (t, J = 5.7 Hz, 1H), 8.34 (d, J = 5.2 Hz, 1H), 7.78 (s, 1H), 7.70 (d, J = 8.1Hz, 1H), 7.23 (dd, J = 8.2, 1.2 Hz, 1H), 7.15 (s, 1H), 6.96 (s, 2H), 6.48 (d, J = 5.2 Hz, 1H), 5.42 (s, 1H), 3.47(t,J=5.8Hz,2H),3.43–3.38(m,2H),3.29(s,3H),1.95–1.41(m,10H).HRMS(ESI+)[M+Na] + :456.2026.
实施例77：1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-羟基乙基)-1H-吲哚-2-甲酰胺Example 77: 1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-hydroxyethyl)-1H-indole-2-carboxamide
1H NMR(600MHz,DMSO-d 6)δ8.71(t,J＝5.7Hz,1H),8.32(d,J＝5.3Hz,1H),7.75(s, 1H),7.69(d,J＝8.1Hz,1H),7.22(d,J＝8.1Hz,1H),7.16(s,1H),6.94(s,2H),6.49(d,J＝5.3Hz,1H),5.41(s,1H),4.82–4.77(m,1H),3.51(q,J＝6.1Hz,2H),3.28(q,J＝6.1Hz,2H),1.89–1.42(m,10H).HRMS(ESI+)[M+Na] +:442.1869。 1 H NMR(600MHz,DMSO-d 6 )δ8.71(t,J=5.7Hz,1H), 8.32(d,J=5.3Hz,1H), 7.75(s, 1H), 7.69(d,J= 8.1Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 6.94 (s, 2H), 6.49 (d, J = 5.3 Hz, 1H), 5.41 (s, 1H) ,4.82–4.77(m,1H),3.51(q,J=6.1Hz,2H), 3.28(q,J=6.1Hz,2H),1.89–1.42(m,10H).HRMS(ESI+)[M+ Na] + :442.1869.
实施例78：1-(2-氨基嘧啶-4-基)-N-环丙基-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺Example 78: 1-(2-Aminopyrimidin-4-yl)-N-cyclopropyl-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxamide
1H NMR(600MHz,DMSO-d 6)δ8.72(d,J＝4.1Hz,1H),8.34(d,J＝5.2Hz,1H),7.73(s,1H),7.68(d,J＝8.1Hz,1H),7.21(dd,J＝8.2,1.2Hz,1H),7.11(s,1H),6.95(s,2H),6.46(d,J＝5.2Hz,1H),5.40(s,1H),2.77(tq,J＝7.8,4.0Hz,1H),1.89–1.43(m,10H),0.69(td,J＝7.0,4.9Hz,2H),0.61–0.55(m,2H).HRMS(ESI+)[M+Na] +:438.1914。 1 H NMR (600MHz, DMSO-d 6 ) δ8.72 (d, J = 4.1 Hz, 1H), 8.34 (d, J = 5.2 Hz, 1H), 7.73 (s, 1H), 7.68 (d, J = 8.1Hz, 1H), 7.21 (dd, J = 8.2, 1.2 Hz, 1H), 7.11 (s, 1H), 6.95 (s, 2H), 6.46 (d, J = 5.2 Hz, 1H), 5.40 (s, 1H),2.77(tq,J=7.8,4.0Hz,1H),1.89–1.43(m,10H),0.69(td,J=7.0,4.9Hz,2H),0.61–0.55(m,2H).HRMS (ESI+)[M+Na] + :438.1914.
实施例79：N-烯丙基-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺Example 79: N-allyl-1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxamide
1H NMR(600MHz,DMSO-d 6)δ8.90(t,J＝5.7Hz,1H),8.33(d,J＝5.2Hz,1H),7.72(s,1H),7.70(d,J＝8.2Hz,1H),7.22(d,J＝9.2Hz,1H),7.20(s,1H),6.94(s,2H),6.47(d,J＝5.2Hz,1H),5.88(ddt,J＝15.5,10.3,5.1Hz,1H),5.41(s,1H),5.28–5.19(m,1H),5.16–5.06(m,1H),3.85(t,J＝5.3Hz,2H),1.89–1.43(m,10H).HRMS(ESI+)[M+Na] +:438.1903。 1 H NMR(600MHz,DMSO-d 6 )δ8.90(t,J=5.7Hz,1H), 8.33(d,J=5.2Hz,1H),7.72(s,1H),7.70(d,J= 8.2Hz, 1H), 7.22 (d, J = 9.2 Hz, 1H), 7.20 (s, 1H), 6.94 (s, 2H), 6.47 (d, J = 5.2 Hz, 1H), 5.88 (ddt, J = 15.5, 10.3, 5.1 Hz, 1H), 5.41 (s, 1H), 5.28–5.19 (m, 1H), 5.16–5.06 (m, 1H), 3.85 (t, J = 5.3 Hz, 2H), 1.89–1.43 (m,10H).HRMS(ESI+)[M+Na] + :438.1903.
实施例80：1-(2-氨基嘧啶-4-基)-N-乙基-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺Example 80: 1-(2-Aminopyrimidin-4-yl)-N-ethyl-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxamide
1H NMR(600MHz,DMSO-d 6)δ8.70(t,J＝5.6Hz,1H),8.32(d,J＝5.2Hz,1H),7.74(s,1H),7.68(d,J＝8.2Hz,1H),7.22(dd,J＝8.2,1.1Hz,1H),7.13(s,1H),6.94(s,2H),6.45(d,J＝5.2Hz,1H),5.40(s,1H),3.28–3.18(m,2H),1.92–1.41(m,10H),1.12(t,J＝7.2Hz,3H).HRMS(ESI+)[M+H] +:404.2083。 1 H NMR (600MHz, DMSO-d 6 ) δ8.70 (t, J = 5.6 Hz, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J = 8.2Hz, 1H), 7.22 (dd, J = 8.2, 1.1 Hz, 1H), 7.13 (s, 1H), 6.94 (s, 2H), 6.45 (d, J = 5.2 Hz, 1H), 5.40 (s, 1H), 3.28–3.18(m, 2H), 1.92–1.41(m, 10H), 1.12(t, J=7.2Hz, 3H). HRMS(ESI+)[M+H] + : 404.2083.
实施例81：1-((1-(2-氨基嘧啶-4-基)-2-(2-羟丙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇的制备Example 81: 1-((1-(2-Aminopyrimidin-4-yl)-2-(2-hydroxypropyl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol preparation
Figure PCTCN2021098556-appb-000040
Figure PCTCN2021098556-appb-000040
N-(5-溴-2-碘苯基)-2-(甲硫基)嘧啶-4-胺的合成的制备Synthesis of N-(5-bromo-2-iodophenyl)-2-(methylthio)pyrimidin-4-amine
Figure PCTCN2021098556-appb-000041
Figure PCTCN2021098556-appb-000041
步骤1：将5-溴-2-碘苯胺(1g，3.357mmol)和2-甲硫基嘧啶(0.4ml，0.3439mmol)溶于10ml异丙醇中，加入浓盐酸2d，将反应加热至60℃反应20h，Tlc检测反应结束。将反应液倾入50ml冰水中，用20％的氢氧化钠溶液调PH至8左右，抽滤，洗涤，干燥得类白色固体1.18g。产率83.2％。ESI-MS(m/z)：422[M-H] -。 Step 1: Dissolve 5-bromo-2-iodoaniline (1g, 3.357mmol) and 2-methylthiopyrimidine (0.4ml, 0.3439mmol) in 10ml of isopropanol, add concentrated hydrochloric acid for 2d, and heat the reaction to 60 After reacting at ℃ for 20h, Tlc detects the end of the reaction. The reaction solution was poured into 50 ml of ice water, the pH was adjusted to about 8 with 20% sodium hydroxide solution, filtered with suction, washed, and dried to obtain 1.18 g of off-white solid. The yield was 83.2%. ESI-MS (m/z): 422 [MH] - .
1-(6-溴-1-(2-(甲硫基)嘧啶-4-基)1H-吲哚-2-基)丙基-2醇的制备Preparation of 1-(6-bromo-1-(2-(methylthio)pyrimidin-4-yl)1H-indol-2-yl)propyl-2 alcohol
Figure PCTCN2021098556-appb-000042
Figure PCTCN2021098556-appb-000042
步骤2：将N-(5-溴-2-碘苯基)-2-(甲硫基)嘧啶-4-胺(1g，2.37mmol)，4-戊炔-2-醇(0.22g，2.61mmol)，TEA(1ml，7.11mmol)，加入10ml DMF中，超声除气泡，并抽真空氮气保护，然后加入CuI(0.09g，0.474mmol)，双三苯基膦二氯化钯(83mg，0.12mmol)室温反应，大约2h后，补加0.8eq CuI，加热至70℃反应8h，TLC检测反应结束。将反应液倒入50ml水中使用EA 30ml*3萃取，饱和食盐水洗涤，干燥，然后进行柱层析分离(EA:PE＝2:1)，最后得白色絮状固体0.81g，产率75％。ESI-MS(m/z)：378[M-H] -。 Step 2: Add N-(5-bromo-2-iodophenyl)-2-(methylthio)pyrimidin-4-amine (1g, 2.37mmol), 4-pentyn-2-ol (0.22g, 2.61 mmol), TEA (1ml, 7.11mmol), add 10ml DMF, ultrasonic to remove bubbles, and vacuum nitrogen protection, then add CuI (0.09g, 0.474mmol), bistriphenylphosphine palladium dichloride (83mg, 0.12 mmol) react at room temperature. After about 2 hours, add 0.8 eq CuI and heat to 70° C. to react for 8 hours. TLC detects the end of the reaction. The reaction solution was poured into 50ml water and extracted with EA 30ml*3, washed with saturated brine, dried, and then separated by column chromatography (EA:PE=2:1). Finally, 0.81g of white flocculent solid was obtained, and the yield was 75%. . ESI-MS (m/z): 378 [MH] - .
1-(6-溴-1-(2-(甲磺酰基)嘧啶-4-基)1H-吲哚-2-基)丙基-2-醇的制备Preparation of 1-(6-bromo-1-(2-(methylsulfonyl)pyrimidin-4-yl)1H-indol-2-yl)propyl-2-ol
Figure PCTCN2021098556-appb-000043
Figure PCTCN2021098556-appb-000043
步骤3：1-(6-溴-1-(2-(甲硫基)嘧啶-4-基)1H-吲哚-2-基)丙基-2醇(0.8g，1.9mmol)，溶于DCM中，然后于冷阱中降温至零下4℃，再分批加入mCPBA(1.01g,5.85mmol)，并于此温度下反应5h后检测，反应完毕。将反应液使用饱和硫代硫酸钠淬灭，然后用饱和碳酸氢钠洗涤，再用饱和食盐水干燥，减压蒸出溶剂，直接投下一步。ESI-MS(m/z)：410[M-H] -。 Step 3: 1-(6-Bromo-1-(2-(methylthio)pyrimidin-4-yl)1H-indol-2-yl)propyl-2 alcohol (0.8g, 1.9mmol), dissolved in In DCM, the temperature was lowered to minus 4°C in a cold trap, and mCPBA (1.01 g, 5.85 mmol) was added in batches, and the reaction was carried out at this temperature for 5 hours, and the reaction was completed. The reaction solution was quenched with saturated sodium thiosulfate, and then washed with saturated sodium bicarbonate, and then dried with saturated brine, the solvent was evaporated under reduced pressure, and directly cast to the next step. ESI-MS (m/z): 410 [MH] - .
1-(1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-2-基)丙基-2-醇的制备Preparation of 1-(1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indol-2-yl)propyl-2-ol
Figure PCTCN2021098556-appb-000044
Figure PCTCN2021098556-appb-000044
步骤4：将1-(6-溴-1-(2-(甲磺酰基)嘧啶-4-基)1H-吲哚-2-基)丙基-2-醇溶于20mL异丙醇中，加入氨水(2ml)，氯化铵(0.5g)(氨水和氯化铵都为大过量)，封管80度反应，1.5h后反应结束，柱层析(DCM：MeOH＝50:1)得淡黄色固体，产率41％。ESI-MS(m/z)：348[M+H] +。 Step 4: Dissolve 1-(6-bromo-1-(2-(methylsulfonyl)pyrimidin-4-yl)1H-indol-2-yl)propyl-2-ol in 20 mL of isopropanol, Add ammonia (2ml), ammonium chloride (0.5g) (both ammonia and ammonium chloride are in large excess), seal the tube to react at 80 degrees, and the reaction is over after 1.5h, column chromatography (DCM:MeOH=50:1) Pale yellow solid, the yield is 41%. ESI-MS (m/z): 348 [M+H] + .
1-((1-(2-氨基嘧啶-4-基)-2-(2-羟丙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇的制备Preparation of 1-((1-(2-aminopyrimidin-4-yl)-2-(2-hydroxypropyl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
步骤5：该标题化合物通过调整实施例1所述方法，将步骤2中的4-(6-溴-1H-吲哚-1-基)嘧啶-2-胺使用1-(1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-2-基)丙基-2-醇代替，反应在80℃下进行5个小时，得标题化合物1-((1-(2-氨基嘧啶-4-基)-2-(2-羟丙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇。 1H NMR(400MHz,DMSO-d 6)δ8.69(s,1H),7.97(d,J＝1.6Hz,1H),7.87(d,J＝5.9Hz,1H),7.36(d,J＝8.0Hz,1H),7.06(dd,J＝7.9,1.7Hz,1H),6.52(s,2H),6.16(d,J＝5.9Hz,1H),5.43(s,1H),5.02(d,J＝4.9Hz,1H),3.84(hept,J＝6.0Hz,1H),2.54(d,J＝5.1Hz,2H),1.90–1.43(m,10H),1.15(d,J＝6.2Hz,3H).HRMS(ESI+)[M+H] +:391.2135。 Step 5: The title compound was adjusted to the method described in Example 1, and 4-(6-bromo-1H-indol-1-yl)pyrimidin-2-amine in step 2 was used as 1-(1-(2- Aminopyrimidin-4-yl)-6-bromo-1H-indol-2-yl)propyl-2-ol was replaced, and the reaction was carried out at 80°C for 5 hours to obtain the title compound 1-((1-(2 -Aminopyrimidin-4-yl)-2-(2-hydroxypropyl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol. 1 H NMR(400MHz,DMSO-d 6 )δ8.69(s,1H), 7.97(d,J=1.6Hz,1H), 7.87(d,J=5.9Hz,1H), 7.36(d,J= 8.0Hz, 1H), 7.06 (dd, J = 7.9, 1.7 Hz, 1H), 6.52 (s, 2H), 6.16 (d, J = 5.9 Hz, 1H), 5.43 (s, 1H), 5.02 (d, J = 4.9 Hz, 1H), 3.84 (hept, J = 6.0 Hz, 1H), 2.54 (d, J = 5.1 Hz, 2H), 1.90-1.43 (m, 10H), 1.15 (d, J = 6.2 Hz, 3H).HRMS(ESI+)[M+H] + :391.2135.
按照实施例81的方法，可与适当的端炔进行反应来进行实施例82和83的制备。According to the method of Example 81, the preparation of Examples 82 and 83 can be carried out by reacting with an appropriate terminal alkyne.
实施例82：1-((1-(2-氨基嘧啶-4-基)-2-(2-羟基-2-(噻吩-2-基)乙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇Example 82: 1-((1-(2-Aminopyrimidin-4-yl)-2-(2-hydroxy-2-(thiophen-2-yl)ethyl)-1H-indol-6-yl) (Ethynyl) cyclohexyl-1-ol
1H NMR(600MHz,DMSO-d 6)δ8.29(s,1H),8.13(s,1H),7.88(d,J＝5.7Hz,1H),7.39(d,J＝5.0Hz,1H),7.31(d,J＝8.0Hz,1H),7.05(d,J＝3.4Hz,1H),7.01(d,J＝7.9Hz,1H),6.95(t,J＝4.3Hz,1H),6.34(s,2H),6.16(d,J＝4.9Hz,1H),6.14(d,J＝5.8Hz,1H),5.41(s,1H),5.10(q,J＝5.6Hz,1H),2.98–2.88(m,2H),1.89–1.45(m,10H).HRMS(ESI+)[M+H] +:459.1868。 1 H NMR(600MHz,DMSO-d 6 )δ8.29(s,1H),8.13(s,1H),7.88(d,J=5.7Hz,1H),7.39(d,J=5.0Hz,1H) ,7.31(d,J=8.0Hz,1H),7.05(d,J=3.4Hz,1H), 7.01(d,J=7.9Hz,1H), 6.95(t,J=4.3Hz,1H), 6.34 (s, 2H), 6.16 (d, J = 4.9 Hz, 1H), 6.14 (d, J = 5.8 Hz, 1H), 5.41 (s, 1H), 5.10 (q, J = 5.6 Hz, 1H), 2.98 –2.88(m,2H),1.89–1.45(m,10H).HRMS(ESI+)[M+H] + :459.1868.
实施例83：1-((1-(2-氨基嘧啶-4-基)-2-(2-羟基-2-苯乙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇Example 83: 1-((1-(2-Aminopyrimidin-4-yl)-2-(2-hydroxy-2-phenylethyl)-1H-indol-6-yl)ethynyl)cyclohexyl- 1-alcohol
1H NMR(400MHz,DMSO-d 6)δ8.29(s,1H),8.11(d,J＝1.6Hz,1H),7.89(d,J＝5.7Hz,1H),7.52–7.39(m,2H),7.36–7.20(m,4H),7.00(dd,J＝7.9,1.7Hz,1H),6.33(s,2H),6.14(d,J＝5.8Hz,1H),5.79(d,J＝4.6Hz,1H),5.41(s,1H),4.84(q,J＝5.7Hz,1H),2.85(d,J＝6.1Hz,2H),1.89–1.45(m,10H).HRMS(ESI+)[M+H] +:453.2294。 1 H NMR(400MHz,DMSO-d 6 )δ8.29(s,1H),8.11(d,J=1.6Hz,1H),7.89(d,J=5.7Hz,1H),7.52-7.39(m, 2H), 7.36–7.20 (m, 4H), 7.00 (dd, J = 7.9, 1.7 Hz, 1H), 6.33 (s, 2H), 6.14 (d, J = 5.8 Hz, 1H), 5.79 (d, J =4.6Hz, 1H), 5.41 (s, 1H), 4.84 (q, J = 5.7 Hz, 1H), 2.85 (d, J = 6.1 Hz, 2H), 1.89-1.45 (m, 10H). HRMS (ESI+ )[M+H] + :453.2294.
实施例84：本发明部分产物的体外酶抑制活性研究Example 84: Study on in vitro enzyme inhibitory activity of some products of the present invention
实验材料:多功能酶标仪(Tecan,Infinite F500)，HTRF KinEASE-STK S2 Kit(CisBio)，Kit中包括：STK Substrate 2-biotin，Streptavidin-XL-665，STK Antibody-Cryptate，5x Enzymatic buffer，HTRF Detection buffer。PAK4蛋白(Full-length，Carna
Figure PCTCN2021098556-appb-000045
)，二硫苏糖醇(DL-Dithiothreitol，DTT)，ATP等。 Experimental materials: Multifunctional microplate reader (Tecan, Infinite F500), HTRF KinEASE-STK S2 Kit (CisBio), Kit includes: STK Substrate 2-biotin, Streptavidin-XL-665, STK Antibody-Cryptate, 5x Enzymatic buffer, HTRF Detection buffer. PAK4 protein (Full-length, Carna
Figure PCTCN2021098556-appb-000045
), DL-Dithiothreitol (DTT), ATP, etc.
实验方法：本实验采用
Figure PCTCN2021098556-appb-000046
激酶测试方法。操作步骤包括酶促反应和检测反应。具体操作如下：按照试剂盒说明，配制Kinase buffer；先将待测试化合物用DMSO配制成8000μM的储备液，后用Kinase buffer稀释至25.0μM，接着依次3倍稀释至 0.4nM，共11个浓度。将待测试化合物(4μL)、STK Substrate 2和ATP(Km浓度)的混合液(4μL)、PAK4蛋白(Full-length)(2μL)混合，高速离心后，25℃孵育1.0h。用Detection buffer稀释Streptavidin-XL-665和STK Antibody-Cryptate配制Detection reagents，将10μL Detection reagents加到上述1.0h孵育后的反应液中，高速离心，25℃孵育1.0h后利用多功能酶标仪(Tecan,Infinite F500)测定Cryptate(620nm)和XL-665(665nm)在340nm波长激发光照射下的散射光强度，计算665/620比值。使用GraphPad Prism 6软件的四参数逻辑回归法做抑制曲线，得到待测化合物对于PAK4的IC50。 Experimental method: This experiment uses
Figure PCTCN2021098556-appb-000046
Kinase test method. The operation steps include enzymatic reaction and detection reaction. The specific operation is as follows: follow the kit instructions to prepare Kinase buffer; first prepare the compound to be tested into a 8000μM stock solution with DMSO, then dilute it to 25.0μM with Kinase buffer, and then dilute it 3 times to 0.4nM, a total of 11 concentrations. The compound to be tested (4 μL), the mixed solution (4 μL) of STK Substrate 2 and ATP (Km concentration), and PAK4 protein (Full-length) (2 μL) were mixed, centrifuged at high speed, and incubated at 25° C. for 1.0 h. Dilute Streptavidin-XL-665 and STK Antibody-Cryptate with Detection buffer to prepare Detection reagents, add 10μL Detection reagents to the above 1.0h incubation reaction solution, centrifuge at high speed, incubate at 25℃ for 1.0h, and use the multifunctional microplate reader ( Tecan, Infinite F500) measured the scattered light intensity of Cryptate (620nm) and XL-665 (665nm) under 340nm wavelength excitation light, and calculated the 665/620 ratio. The four-parameter logistic regression method of GraphPad Prism 6 software was used to make the inhibition curve to obtain the IC50 of the test compound for PAK4.
实施例85：本发明部分产物的体外A549细胞迁移活性研究Example 85: In vitro A549 cell migration activity study of some products of the present invention
人源A549肿瘤细胞接种于含10％胎牛血清，100U/mL青霉素，100μg/mL链霉素的RPMI-1640培养基中，将培养瓶置于37℃，5％CO2饱和湿度培养箱培养，每1-2天换培养液一次。当细胞生长到足以覆盖瓶底壁的大部分表面时，贴壁细胞用0.25％胰蛋白酶消化，传代。Human-derived A549 tumor cells were inoculated in RPMI-1640 medium containing 10% fetal bovine serum, 100U/mL penicillin, and 100μg/mL streptomycin. The culture flask was placed in an incubator at 37°C and 5% CO2 saturated humidity. Change the culture medium every 1-2 days. When the cells grow enough to cover most of the surface of the bottom wall of the flask, the adherent cells are digested with 0.25% trypsin and passaged.
对数生长期细胞培养于6孔培养板内，在6孔板背面使用marker笔画线，间隔1厘米左右，线尽量均匀，横穿过孔，每个孔约画5至7条线。细胞计数，在6孔板中每孔加入70000-120000左右个A549细胞，然后将6孔板放入培养箱孵育至形成均匀单层细胞。次日，取出6孔板，每个孔用PBS洗3次，用枪头比着直尺，垂直于6孔板底部的横线划痕。之后每孔再用PBS洗三次，去除划下的细胞。对照组加入与给药组等体积的溶剂，置37℃，5％CO2温箱中培养。。放入培养箱培养。按照72h取样，拍照测量。Cells in the logarithmic growth phase are cultured in a 6-well culture plate. Use marker pens to draw lines on the back of the 6-well plate at intervals of about 1 cm. The lines should be as even as possible and run across the holes. Draw about 5 to 7 lines for each hole. To count the cells, add 70,000-120,000 A549 cells to each well of the 6-well plate, and then place the 6-well plate into the incubator and incubate until a uniform monolayer of cells is formed. The next day, take out the 6-well plate, wash each well with PBS 3 times, compare the ruler with the pipette tip, and make a mark perpendicular to the horizontal line at the bottom of the 6-well plate. Then each well was washed three times with PBS to remove the marked cells. The control group was added with the same volume of solvent as the administration group and incubated in a 37°C, 5% CO2 incubator. . Put it into an incubator for cultivation. Sampling according to 72h, taking pictures and measuring.
表1部分实施例化合物在1μM、10μM浓度下体外PAK4抑制活性百分比Table 1 Part of the example compounds in vitro PAK4 inhibitory activity percentage at the concentration of 1μM, 10μM
Figure PCTCN2021098556-appb-000047
Figure PCTCN2021098556-appb-000047
本发明中通式(I)的化合物可单独施用，但通常是和药用载体混合物给予，所述药用载体的选择要根据所需用药途径和标准药物实践，下面分别用该类化合物的各种药物剂型，例如片剂、胶囊剂、注射剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂和软膏剂的制备方法，说明其在制药领域中的新应用。The compound of general formula (I) in the present invention can be administered alone, but is usually administered as a mixture with a pharmaceutical carrier. The choice of the pharmaceutical carrier depends on the desired route of administration and standard pharmaceutical practice. Each of these compounds is used below. Preparation methods of various pharmaceutical dosage forms, such as tablets, capsules, injections, aerosols, suppositories, films, dripping pills, external liniments and ointments, illustrate their new applications in the pharmaceutical field.
实施例86：片剂Example 86: Tablet
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g，按照药剂学一般压片法加辅料20g混匀后，压制成100片，每片重300mg。Using 10g of the compound containing the compound of claim 1 (taking the compound of Example 8 as an example), according to the general tableting method of pharmacy, adding 20g of auxiliary materials and mixing them, compressed into 100 tablets, each weighing 300mg.
实施例87：胶囊剂Example 87: Capsules
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g，按照药剂学胶囊剂的要求将辅料20g混匀后，装入空心胶囊，每个胶囊重300mg。Using 10 g of the compound containing the compound of claim 1 (taking the compound of Example 8 as an example), 20 g of the excipients were mixed according to the requirements of pharmaceutical capsules, and then filled into hollow capsules, each capsule weighing 300 mg.
实施例88：注射剂Example 88: Injection
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g，按照药剂学常规方法，进行活性炭吸附，经0.65μm微孔滤膜过滤后，填入氮气罐制成水针制剂，每只装2mL，共灌装100瓶。Using 10g of the compound containing the compound of claim 1 (taking the compound of Example 8 as an example), according to the conventional method of pharmaceutics, the activated carbon adsorption was carried out, filtered by a 0.65μm microporous membrane, and filled into a nitrogen tank to make a water injection preparation. Each pack is 2mL, a total of 100 bottles are filled.
实施例89：气雾剂Example 89: Aerosol
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g，用适量丙二醇溶解后，加入蒸馏水及其他辐料后，制成500mL的澄清溶液即得。Use 10 g of the compound containing the compound of claim 1 (take the compound of Example 8 as an example), dissolve it with an appropriate amount of propylene glycol, add distilled water and other radiation materials, and make 500 mL of a clear solution.
实施例90：栓剂Example 90: Suppositories
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g，将之研细加入甘油适量，研匀后加入已熔化的甘油明胶，研磨均匀，倾入已涂润滑剂的模型中，制得栓剂50颗Use 10g of the compound containing the compound of claim 1 (take the compound of Example 8 as an example), grind it into an appropriate amount of glycerin, grind it evenly, add melted glycerin gelatin, grind it evenly, and pour it into a mold coated with lubricant , Made 50 suppositories
实施例91：膜剂Example 91: Film
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g，将聚乙烯醇、药用甘油、水等搅拌膨胀后加热溶解，80目筛网过滤，再将实施例18化合物加入到滤液中搅拌溶解，涂膜机制膜100片。Using 10g of the compound containing the compound of claim 1 (take the compound of Example 8 as an example), stir and expand the polyvinyl alcohol, medicinal glycerin, water, etc., and then heat to dissolve, filter with an 80 mesh screen, and then add the compound of Example 18 Stir and dissolve in the filtrate, and coat 100 pieces of film.
实施例92：滴丸剂Example 92: Dropping pills
用含有权利要求1中化合物的化合物(以实施例35化合物为例)10g，与明胶等基质50g加热熔化混匀后，滴入低温液体石蜡中，共制得滴丸1000丸。10g of the compound containing the compound of claim 1 (taking the compound of Example 35 as an example), heated and melted and mixed with 50g of a base such as gelatin, and then dropped into low-temperature liquid paraffin to prepare 1000 dropping pills in total.
实施例93：外用搽剂Example 93: Liniment for external use
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g，按照常规药剂学方法与乳化剂等辅料2.5g混合研磨，再加蒸馏水至200mL制得。It is prepared by using 10 g of the compound containing the compound of claim 1 (taking the compound of Example 8 as an example), mixing and grinding with 2.5 g of emulsifier and other auxiliary materials according to conventional pharmacy methods, and adding distilled water to 200 mL.
实施例94：软膏剂Example 94: Ointment
用含有权利要求1中化合物的化合物(以实施例35化合物为例)10g，研细后与凡士林等油性基质500g研匀制得。Use 10g of the compound containing the compound of claim 1 (taking the compound of Example 35 as an example), grind it and make it evenly with 500g of oily base such as petroleum jelly.
尽管已经通过特定实施方案描述了本发明，但修改和等价变化对于精通此领域的技术人员而言是显见的，且它们都包含在本发明范围。Although the present invention has been described through specific embodiments, modifications and equivalent changes are obvious to those skilled in the art, and they are all included in the scope of the present invention.

Claims (10)

  1. 一种通式(I)的吲哚类衍生物，及其几何异构体或药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：所述通式如下，An indole derivative of general formula (I), and geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, characterized in that: the general formula is as follows,
    Figure PCTCN2021098556-appb-100001
    Figure PCTCN2021098556-appb-100001
    其中：in:
    R 1选自：氢、C 1-2烷基或-CH 2-OH； R 1 is selected from: hydrogen, C 1-2 alkyl or -CH 2 -OH;
    R 2选自：氢、C 1-6烷基、C 3-6环烷基、6～10元芳基，5～10元杂芳基，且所述芳基或杂芳基可进一步被1～3个相同或不同的R 2a取代，其中R 2a选自氢、卤素、氰基、C 1-4烷基、C 1-4烷氧基、卤素取代的C 1-4烷基或C 1-4烷氧基； R 2 is selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and the aryl or heteroaryl may be further ~3 same or different R 2a substitutions, wherein R 2a is selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl or C 1 -4 alkoxy;
    或R 1和R 2连同他们所连接的碳原子一起形成一个C 3-7环烷基或5-10元杂环烷基，所形成的环烷基可进一步被C 1-2烷基或卤素所取代； Or R 1 and R 2 together with the carbon atoms to which they are connected form a C 3-7 cycloalkyl group or 5-10 membered heterocycloalkyl group, and the formed cycloalkyl group may be further substituted by a C 1-2 alkyl group or halogen Replaced by
    R 3无取代，或R 3选自：氢、卤素、氰基、C 1-6烷基； R 3 is unsubstituted, or R 3 is selected from: hydrogen, halogen, cyano, C 1-6 alkyl;
    R 4选自：氢、醛基、氰基、C 1-6烷基、羰基、被-OH或氨基取代的C 1-6烷基、-C 1-6烷基氧基C 1-4烷基、-C 1-6烷基-C(＝O)-N R 4aR 4b、-OC 1-6烷基、被卤素取代的-OC 1-6烷基、-C(＝O)NR 4aR 4b、-NR 4aR 4b，其中R 4a和R 4b各自独立的选自氢、C 1-4烷基、C 2-4烷基氧基C 1-4烷基、6～10元芳基，5～10元杂芳基；或R 4a和R 4b连同他们所连接的氮原子一起形成一个3-10元杂环基；且所述的芳基、杂芳基、杂环基可以任意地被1至3个氢、C 1-4烷基、氨基、羟基、被一个羟基或氨基取代的C 1-4烷基、或被一个或多个卤素取代的C 1-4烷基、5～10元杂环基、6～10元芳基、5～10元芳杂基； R 4 is selected from: hydrogen, aldehyde group, cyano group, C 1-6 alkyl group, carbonyl group, C 1-6 alkyl group substituted by -OH or amino group, -C 1-6 alkyloxy C 1-4 alkane group, -C 1-6 alkyl -C (= O) -N R 4a R 4b, -OC 1-6 alkyl, -OC 1-6 alkyl substituted by halogen, -C (= O) NR 4a R 4b , -NR 4a R 4b , wherein R 4a and R 4b are each independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkyloxy C 1-4 alkyl, 6-10 membered aryl, 5-10 membered heteroaryl; or R 4a and R 4b together with the nitrogen atom to which they are connected form a 3-10 membered heterocyclic group; and the aryl, heteroaryl, and heterocyclic groups can be optionally 1-3 hydrogen, C 1-4 alkyl, amino, hydroxy, a substituted hydroxy or amino C 1-4 alkyl, halo-substituted by one or more C 1-4 alkyl, 5 to 10 Membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group;
    R 5无取代，或R 5选自：氢、氰基、C 1-4醛基、C 1-4酯基、C 1-6烷基、C 3-6环烷基、-C(＝O)-NR 5aR 5b、-CNR 5aR 5b、NR 5aR 5b、6～10元芳环、5～10元杂环、被1～3个选自下组取代基取代的C 1-6烷基：卤素、硝基、-OH、-OC 1-4烷基、6～10元芳环以及5～10元杂环，R 5a和R 5b各自独立的选自下组：氢、C 1-6烷基、C 3-6环烷基、6～10元芳基、5～10元芳杂基，或R 5a和R 5b连同他们所连接的碳原子一起形成一个C 3-7环烷基或5-10元杂环烷基；所形成的环烷基可进一步被C 1-2烷基或卤素所取代，其中芳基和杂环可以任选的被1至3个选自以下各项的取代基取代：氢、羟基、氨基、卤素、氰基、C 1-4烷基、C 1-4烷氧基、被一个或多个卤素或羟基取代的C 1-4烷基以及被一个或多个卤素或羟基取代的C 1-4烷基氧基、5～10元杂环基、6～10元芳基、5～10元芳 杂基； R 5 is unsubstituted, or R 5 is selected from: hydrogen, cyano, C 1-4 aldehyde, C 1-4 ester, C 1-6 alkyl, C 3-6 cycloalkyl, -C(=O ) -NR 5a R 5b , -CNR 5a R 5b , NR 5a R 5b , 6-10 membered aromatic ring, 5-10 membered heterocyclic ring, C 1-6 alkane substituted by 1 to 3 substituents selected from the following group Group: halogen, nitro, -OH, -OC 1-4 alkyl, 6-10 membered aromatic ring and 5-10 membered heterocyclic ring, R 5a and R 5b are each independently selected from the following group: hydrogen, C 1- 6 alkyl group, C 3-6 cycloalkyl group, 6-10 membered aryl group, 5-10 membered heteroaryl group, or R 5a and R 5b together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group Or a 5-10 membered heterocycloalkyl group; the formed cycloalkyl group may be further substituted by a C1-2 alkyl group or halogen, wherein the aryl group and the heterocyclic ring may be optionally substituted by 1 to 3 selected from the following substituents: hydrogen, hydroxy, amino, halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, substituted with one or more halogen or hydroxy and C 1-4 alkyl substituted by one Or multiple halogen or hydroxy substituted C 1-4 alkyloxy groups, 5 to 10 membered heterocyclic groups, 6 to 10 membered aryl groups, 5 to 10 membered aryl hetero groups;
    R 6选自：氢、C 1-6烷基、C 3-6的环烷基、C 1-6亚烷基-C 3-6环烷基、苯基、5-6元杂芳基、5-6元芳基或5-6元杂芳基取代的C 1-6烷基、-C(＝O)R 6a，其中R 6a选自氢、C 1-6烷基、C 2-6链烯基、C 2-6炔基、C 1-6杂烷基、3-6元环烷基、3-6元杂烷基、-(C 1-6亚烷基)-(3-8元环烷基)、-(C 1-6亚烷基)-(3-8元杂环烷基)、-(C 1-6亚烷基)-(6元芳基)、(C 1-6亚烷基)-(5-6元杂芳基)、苯基和5-6元杂芳基，所述的杂烷基、杂芳基含有1-3个N、O或S的杂原子； R 6 is selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylene-C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, C 1-6 alkyl substituted with 5-6 membered aryl or 5-6 membered heteroaryl, -C(=O)R 6a , wherein R 6a is selected from hydrogen, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, 3-6 membered cycloalkyl, 3-6 membered heteroalkyl, -(C 1-6 alkylene)-(3-8 Membered cycloalkyl), -(C 1-6 alkylene)-(3-8 membered heterocycloalkyl), -(C 1-6 alkylene)-(6-membered aryl), (C 1- 6 alkylene)-(5-6 membered heteroaryl), phenyl and 5-6 membered heteroaryl, said heteroalkyl and heteroaryl contain 1-3 N, O or S heteroatoms ；
    其中R 6的脂肪基和/或芳香基部分，可以任选的被1至多个选自下列的取代基取代：氢，羟基，卤素，硝基，氨基，氰基，游离的、成盐的、酯化的、酰胺化的羧基，C 1-6烷基，C 2-6烯基，C 2-6炔基，C 1-6烷氧基，C 1-6烷基酰基，C 1-6烷基亚磺酰基、磺酰基，氨基甲酰基，任选被羟基、氨基、卤代的C 1-6烷基或C 1-6烷氧基，被氢、羟基、氨基或游离的、成盐的、酯化的、酰胺化的羧基取代的C 3-6环烷基或C 3-6杂环烷基，被单或二(C 1-6烷基)取代的胺基或C 1-6烷基酰胺基，被单或二(C 1-6烷基)取代的胺基甲酰基，被氢、羟基、氨基、烷基取代的5～10元杂芳基，其中所述杂环烷基与杂芳基分别含有1至3个选自O、N和S的杂原子； The aliphatic and/or aromatic part of R 6 can be optionally substituted with one to more substituents selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, amino, cyano, free, salt-forming, Esterified, amidated carboxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl acyl, C 1-6 Alkylsulfinyl, sulfonyl, carbamoyl, optionally substituted by hydroxy, amino, halogenated C 1-6 alkyl or C 1-6 alkoxy, hydrogen, hydroxy, amino or free, salt , Esterified, amidated carboxyl substituted C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, mono or di (C 1-6 alkyl) substituted amino or C 1-6 alkane Amido group, a carbamoyl group substituted by a mono- or di-(C 1-6 alkyl) group, a 5- to 10-membered heteroaryl group substituted by hydrogen, a hydroxyl group, an amino group, or an alkyl group, wherein the heterocycloalkyl group and the hetero Aryl groups each contain 1 to 3 heteroatoms selected from O, N and S;
    R 7选自：氢、氰基、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基。 R 7 is selected from: hydrogen, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkylamino.
  2. 如权利要求1所述的通式(I)的化合物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：The compound of general formula (I), and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof according to claim 1, characterized in that:
    所述的R 1和R 2连同他们所连接的碳原子一起形成环戊基、环己基，所形成的环戊基、环己基可进一步被C 1-2烷基或氟所取代。 Said R 1 and R 2 together with the carbon atom to which they are connected form a cyclopentyl group and a cyclohexyl group, and the formed cyclopentyl group and cyclohexyl group may be further substituted by a C 1-2 alkyl group or fluorine.
  3. 如权利要求1或2任何一项所述的通式(I)的化合物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：The compound of general formula (I) according to any one of claims 1 or 2, and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, characterized in that:
    所述的R 4选自：氢、C 1-4醛基、C 1-4酯基、羰基、氰基、C 1-4烷基、被一个-OH或氨基取代的C 1-6烷基、-C(＝O)NR 4aR 4b，其中R 4a和R 4b各自独立的选自氢、C 1-4烷基、C 2-4烷基氧基C 1-4烷基、6-10元芳基，5～6元杂环基；或R 4a和R 4b连同它们所连接的氮原子一起形成一个3-10元杂环基； Said R 4 is selected from: hydrogen, C 1-4 aldehyde group, C 1-4 ester group, carbonyl group, cyano group, C 1-4 alkyl group, C 1-6 alkyl group substituted by one -OH or amino group , -C(=O)NR 4a R 4b , wherein R 4a and R 4b are each independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkyloxy C 1-4 alkyl, 6-10 Membered aryl group, 5-6 membered heterocyclic group; or R 4a and R 4b together with the nitrogen atom to which they are attached form a 3-10 membered heterocyclic group;
    所述的芳基或杂环基选自：苯基、萘基、哌啶基、哌嗪基、吗啉基、吡咯烷基、高哌嗪基、氮杂环丁烷基、咪唑基、吡唑基、四氢呋喃基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基以及吡嗪基，且芳基、杂环基各自可以任意地被1至3个氢、C 1-4烷基、氨基、羟基、被一个羟基或氨基取代基取代的C 1-4烷基取代或被一个或多个氟取代基取代的C 1-4烷基取代。 The aryl or heterocyclic group is selected from: phenyl, naphthyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, homopiperazinyl, azetidinyl, imidazolyl, pyridine Azolyl, tetrahydrofuranyl, thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, and The aryl group and the heterocyclic group may each be optionally substituted by 1 to 3 hydrogens, C 1-4 alkyl, amino, hydroxy, C 1-4 alkyl substituted by one hydroxy or amino substituent, or by one or more C 1-4 alkyl substituted with fluorine substituents.
  4. 如权利要求1-3任何一项所述的通式(I)的化合物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：The compound of general formula (I) according to any one of claims 1 to 3, and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, characterized in that:
    所述的R 5选自：氢、氰基、醛基、C 1-6烷基、C 3-6环烷基、-C(＝O)-NR 5aR 5b、-CNR 5aR 5b、NR 5aR 5b、6元芳环、5～6元杂环、被1～3个选自如下取代基取代的C 1-6烷基：卤素、-OH、-OC 1-4烷基、6～10元芳基以及5～10元杂基，R 5a和R 5b各自独立的选自：氢、C 1-6烷基、C 3-6环烷基、苯基、5～6元芳杂基，或R 5a和R 5b连同他们所连接的碳原子一起形成一个C 3-10环烷基或杂环烷基，所形成的环烷基可进一步被C 1-2烷基和氟所取代。 The R 5 is selected from: hydrogen, cyano, aldehyde, C 1-6 alkyl, C 3-6 cycloalkyl, -C(=O)-NR 5a R 5b , -CNR 5a R 5b , NR 5a R 5b , 6-membered aromatic ring, 5-6 membered heterocyclic ring, C 1-6 alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, -OH, -OC 1-4 alkyl, 6~ 10-membered aryl group and 5- to 10-membered hetero group, R 5a and R 5b are each independently selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5 to 6-membered heteroaryl , Or R 5a and R 5b together with the carbon atoms to which they are attached form a C 3-10 cycloalkyl or heterocycloalkyl group, and the formed cycloalkyl group may be further substituted with a C 1-2 alkyl group and fluorine.
    所述的R 5中所涉及的芳基和芳杂基主要包括：苯基、萘基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并噻吩基、苯并呋喃基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基，且芳基和杂环基可以任选的被1至3个选自以下各项的取代基取代：氢、羟基、氨基、卤素、氰基、C 1-4烷基、C 1-4烷氧基、被一个或多个氟取代的C 1-4烷基以及被一个或多个氟取代基取代的C 1-4烷基氧基。 The aryl and heteroaryl groups involved in R 5 mainly include: phenyl, naphthyl, thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, iso Thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxanyl Azolyl, quinolinyl, isoquinolinyl, and aryl and heterocyclic groups can be optionally substituted with 1 to 3 substituents selected from the group consisting of hydrogen, hydroxyl, amino, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, substituted with one or more fluorine substituents, and C 1-4 alkyl substituted by one or more fluorine substituents C 1-4 alkyl group.
  5. 如权利要求1-4任何一项所述的通式(I)的化合物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：The compound of general formula (I) according to any one of claims 1 to 4, and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, characterized in that:
    所述的R 6选自：氢、C 1-6烷基、C 3-6的环烷基、C 1-6亚烷基-C 3-6环烷基、苯基、5-6元杂芳基、-C 1-6亚烷基-6元芳基、C 1-6亚烷基-5-6元杂芳基、-C(＝O)R 6a，其中R 6a选自氢、C 1-6烷基、C 2-6链烯基、C 2-6炔基、C 1-6杂烷基、3-6元环烷基、3-6元杂烷基、-(C 1-6亚烷基)-(3-8元环烷基)、-(C 1-6亚烷基)-(3-8元杂环烷基)、-(C 1-6亚烷基)-(6元芳基)、(C 1-6亚烷基)-(5-6元杂芳基)、苯基和5-6元杂芳基，其中芳基和芳杂基包括：噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并噻吩基、苯并呋喃基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基； The R 6 is selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylene-C 3-6 cycloalkyl, phenyl, 5-6 membered hetero Aryl, -C 1-6 alkylene-6-membered aryl, C 1-6 alkylene-5-6-membered heteroaryl, -C(=O)R 6a , wherein R 6a is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, 3-6 membered cycloalkyl, 3-6 membered heteroalkyl, -(C 1- 6 alkylene)-(3-8 membered cycloalkyl), -(C 1-6 alkylene)-(3-8 membered heterocycloalkyl), -(C 1-6 alkylene)-( 6-membered aryl), (C 1-6 alkylene)-(5-6-membered heteroaryl), phenyl and 5-6-membered heteroaryl, where aryl and heteroaryl include: thienyl, thiazole Base, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuranyl, indino Dolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl;
    所述的R 6的脂肪族和/或芳香族部分，可以任选的被1至5个选自下列的取代基取代：氢，羟基，卤素，硝基，胺基，氰基，游离的、成盐的、酯化的、酰胺化的羧基，C 1-6烷基，C 1-6烯基，C 1-6炔基，C 1-6烷氧基，C 1-6烷基酰基，C 1-6烷基亚磺酰基、磺酰基，氨基甲酰基，任选被羟基、氨基、卤代的C 1-6烷基或C 1-6烷氧基，被氢、羟基、氨基或游离的、成盐的、酯化的、酰胺化的羧基取代的C 3-6环烷基或C 3-6杂环烷基，被单或二(C 1-6烷基)取代的胺基或C 1-6烷基酰胺基，被单或二(C 1-6烷基)取代的胺基甲酰基，被氢、羟基、氨基、烷基取代的5～10元杂芳基，其中所述杂环烷基与杂芳基分别含有1至3个选自O、N和S的杂原子。 The aliphatic and/or aromatic part of R 6 can be optionally substituted with 1 to 5 substituents selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, amine, cyano, free, Salt-forming, esterified, amidated carboxyl, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl acyl, C 1-6 alkylsulfinyl, sulfonyl, carbamoyl, optionally substituted by hydroxy, amino, halogenated C 1-6 alkyl or C 1-6 alkoxy, hydrogen, hydroxy, amino or free C 3-6 cycloalkyl or C 3-6 heterocycloalkyl substituted with carboxyl, salt-forming, esterified, amidated, amine substituted with mono- or di-(C 1-6 alkyl) or C 1-6 alkyl amide group, carbamoyl group substituted by mono or di (C 1-6 alkyl), 5-10 membered heteroaryl group substituted by hydrogen, hydroxy, amino, alkyl, wherein the heterocyclic ring Alkyl groups and heteroaryl groups each contain 1 to 3 heteroatoms selected from O, N and S.
  6. 如权利要求1-6任何一项所述的通式(I)的吲哚类衍生物，及其几何异构体或药学上可接受的盐、水合物、溶剂化物或前药，其特征在于，选自：The indole derivatives of general formula (I) according to any one of claims 1-6, and geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, characterized in , Selected from:
    1-((1-(2-氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-Aminopyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    1-((1-(2-氨基嘧啶-4-基)-5-氟-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-Aminopyrimidin-4-yl)-5-fluoro-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    1-((1-(2-氨基嘧啶-4-基)1H-吡咯[3,2-b]并吡啶-6-基)乙炔基)环己基-1-醇1-((1-(2-Aminopyrimidin-4-yl)1H-pyrrole[3,2-b]pyridin-6-yl)ethynyl)cyclohexyl-1-ol
    1-((1-(2-氨基嘧啶-4-基)-1H-吲唑-6-基)乙炔基)环己基-1-醇1-((1-(2-Aminopyrimidin-4-yl)-1H-indazol-6-yl)ethynyl)cyclohexyl-1-ol
    1-((2-氨基嘧啶-4-基)-1H-吡咯[2,3-b]并吡啶-6-基)乙炔基)环己基-1-醇1-((2-Aminopyrimidin-4-yl)-1H-pyrrole[2,3-b]pyridin-6-yl)ethynyl)cyclohexyl-1-ol
    1-((2-氨基嘧啶-4-基)-1H-吡咯[3,2-c]并吡啶-6-基)乙炔基)环己基-1-醇1-((2-Aminopyrimidin-4-yl)-1H-pyrrole[3,2-c]pyridin-6-yl)ethynyl)cyclohexyl-1-ol
    (1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌嗪-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(piperazin-1-yl)methanone
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carboxamide
    1-((1-(2,6-二氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2,6-Diaminopyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    1-(2-氨基嘧啶-4-基)-6-(1-羟基环己基)乙炔基)-1H-吲哚-3-甲醛1-(2-Aminopyrimidin-4-yl)-6-(1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carbaldehyde
    (1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(吡咯-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(pyrrol-1-yl)methanone
    (1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌啶-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(piperidin-1-yl)methanone
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N,N-二甲基-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N,N-dimethyl-1H-indole-3-carboxamide
    (1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(吗啉基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(morpholinyl)methanone
    (1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-甲基哌嗪-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(4-methylpiperazin-1-yl)methan ketone
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-甲基-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-methyl-1H-indole-3-carboxamide
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(噻唑-2-基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(thiazol-2-yl)-1H-indole-3-carboxamide
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-phenyl-1H-indole-3-carboxamide
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲腈1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carbonitrile
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-甲氧乙基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-methoxyethyl)-1H-indole-3-carboxamide
    1-(2-氨基嘧啶-4-基)-N-苄基-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-N-benzyl-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carboxamide
    (1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-(2-羟乙基)哌嗪-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(4-(2-hydroxyethyl)piperazine- 1-yl) ketone
    (1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(2-(羟乙基)吡咯-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(2-(hydroxyethyl)pyrrol-1-yl )Methone
    1-(2-氨基嘧啶-4-基)-N-(5-羟基-1H-吡唑-3-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-N-(5-hydroxy-1H-pyrazol-3-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3 -Formamide
    (R)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-甲基哌嗪-1-基)甲酮(R)-(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3-methylpiperazine-1 -Base) ketone
    (S)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-甲基哌嗪-1-基)甲酮(S)-(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3-methylpiperazine-1 -Base) ketone
    (1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3,5-二甲基哌嗪-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3,5-dimethylpiperazine-1- Ketone
    (3-氨基-1H-吡唑-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮(3-Amino-1H-pyrazol-1-yl)(1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl )Methone
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(1H-吡唑-3-基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(1H-pyrazol-3-yl)-1H-indole-3-carboxamide
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2,2,2-三氟乙基)-1H-吲哚-3-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2,2,2-trifluoroethyl)-1H-indole-3-methyl Amide
    (1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-吗啉基哌啶-1-基)甲酮(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(4-morpholinylpiperidin-1-yl) Ketone
    (R)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-羟基哌啶-1-基)甲酮(R)-(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3-hydroxypiperidine-1- Ketone
    (S)-(3-氨基哌啶-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮(S)-(3-Aminopiperidin-1-yl)(1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3- Ketone
    (S)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(哌啶-3-基)1H-吲哚-3-甲酰胺(S)-1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(piperidin-3-yl)1H-indole-3-carboxamide
    (R)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(哌啶-3-基)1H-吲哚-3-甲酰胺(R)-1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(piperidin-3-yl)1H-indole-3-carboxamide
    (R)-(3-氨基哌啶-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮(R)-(3-Aminopiperidin-1-yl)(1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3- Ketone
    (S)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-氨基吡咯-1-基)甲酮(S)-(1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-3-yl)(3-aminopyrrol-1-yl )Methone
    (S)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡咯-3-基)1H-吲哚-3-甲酰胺(S)-1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(pyrrol-3-yl)1H-indole-3-carboxamide
    (R)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡咯-3-基)1H-吲哚-3-甲酰胺(R)-1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(pyrrol-3-yl)1H-indole-3-carboxamide
    4-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羰基)哌嗪-2-酮4-(1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-3-carbonyl)piperazin-2-one
    1-((1-(2-苄胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-Benzylamine)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    1-((1-(2-((噻吩-2-甲基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇1-((1-(2-((thiophen-2-methyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
    1-((1-(2-((2-氟苯基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇1-((1-(2-((2-Fluorophenyl)amino)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
    1-((1-(2-((2-甲氧乙基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇1-((1-(2-((2-Methoxyethyl)amino)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
    1-((1-(2-((2-氯苄基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇1-((1-(2-((2-Chlorobenzyl)amino)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
    1-((1-(2-((4-氟苯基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇1-((1-(2-((4-Fluorophenyl)amino)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexane-1-ol
    1-((1-(2-(苯胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔)环己基-1-醇1-((1-(2-(aniline)pyrimidin-4-yl)-1H-indol-6-yl)acetylene)cyclohexyl-1-ol
    1-((1-(2-((3-氯苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔)环己基-1-醇1-((1-(2-((3-chlorophenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)acetylene)cyclohexyl-1-ol
    1-((1-(2-((3-氯-4-氟苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-((3-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    3-((4-(6-((1-羟基环己基)乙炔基)-1H-吲哚-1-基)嘧啶-2-基)氨基)苯甲腈3-((4-(6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-1-yl)pyrimidin-2-yl)amino)benzonitrile
    1-((1-(2-((4-甲氧基苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-((4-methoxyphenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    1-((1-(2-((3-硝基苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-((3-nitrophenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    1-((1-(2-(间甲基苯氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-(m-methylphenylamino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    1-((1-(2-((4-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-((4-(Trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    1-((1-(2-((2-(三氟甲基)苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-((2-(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    1-((1-(2-(邻甲基苯氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-(O-methylphenylamino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    1-((1-(2-((2-氟苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-((2-Fluorophenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    1-((1-(2-((2-甲氧基乙基)氨基)嘧啶-4-基)-1H-吲哚-6基)乙炔基)环己基-1-醇1-((1-(2-((2-Methoxyethyl)amino)pyrimidin-4-yl)-1H-indol-6yl)ethynyl)cyclohexyl-1-ol
    3-((4-(6-((1-羟基环己基)乙炔基)1H-吲哚-1-基)嘧啶-2-基)氨基)苯磺酰胺3-((4-(6-((1-hydroxycyclohexyl)ethynyl)1H-indol-1-yl)pyrimidin-2-yl)amino)benzenesulfonamide
    1-((1-(2-(环己氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-(Cyclohexylamino)pyrimidin-4-yl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)benzamide
    N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-3-甲基苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-3-methylbenzyl Amide
    N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-硝基苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-4-nitrobenzyl Amide
    N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-2-硝基苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-2-nitrobenzyl Amide
    N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-甲氧基苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-4-methoxybenzene Formamide
    N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-氟苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-4-fluorobenzamide
    N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-2-氟苯甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-2-fluorobenzamide
    N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-异戊酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-isovaleramide
    N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-1H-吲哚-6-甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-1H-indole-6 -Formamide
    N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-1H-吲哚-2-甲酰胺N-((1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indol-2-yl)methyl)-1H-indole-2 -Formamide
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-phenyl-1H-indole-2-carboxamide
    乙基1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-羧酸酯Ethyl 1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxylate
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡啶-4-基)-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(pyridin-4-yl)-1H-indole-2-carboxamide
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(间甲苯基)-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(m-tolyl)-1H-indole-2-carboxamide
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N,N-二甲基-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N,N-dimethyl-1H-indole-2-carboxamide
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-甲氧基乙基)-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-methoxyethyl)-1H-indole-2-carboxamide
    1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-羟基乙基)-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-N-(2-hydroxyethyl)-1H-indole-2-carboxamide
    1-(2-氨基嘧啶-4-基)-N-环丙基-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-N-cyclopropyl-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxamide
    N-烯丙基-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺N-allyl-1-(2-aminopyrimidin-4-yl)-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxamide
    1-(2-氨基嘧啶-4-基)-N-乙基-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺1-(2-Aminopyrimidin-4-yl)-N-ethyl-6-((1-hydroxycyclohexyl)ethynyl)-1H-indole-2-carboxamide
    1-((1-(2-氨基嘧啶-4-基)-2-(2-羟丙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇的制备Preparation of 1-((1-(2-aminopyrimidin-4-yl)-2-(2-hydroxypropyl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    1-((1-(2-氨基嘧啶-4-基)-2-(2-羟基-2-(噻吩-2-基)乙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-Aminopyrimidin-4-yl)-2-(2-hydroxy-2-(thiophen-2-yl)ethyl)-1H-indol-6-yl)ethynyl) ring Hexyl-1-ol
    1-((1-(2-氨基嘧啶-4-基)-2-(2-羟基-2-苯乙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇1-((1-(2-Aminopyrimidin-4-yl)-2-(2-hydroxy-2-phenylethyl)-1H-indol-6-yl)ethynyl)cyclohexyl-1-ol
    Figure PCTCN2021098556-appb-100002
    Figure PCTCN2021098556-appb-100002
    Figure PCTCN2021098556-appb-100003
    Figure PCTCN2021098556-appb-100003
    Figure PCTCN2021098556-appb-100004
    Figure PCTCN2021098556-appb-100004
  7. 一种药用组合物，包含权利要求1至6中任何一项的化合物及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。A pharmaceutical composition comprising the compound of any one of claims 1 to 6 and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient and a pharmaceutically acceptable excipient.
  8. 权利要求1-6任何一项的化合物及其药学上可接受的盐、水合物、溶剂化物或前药或权利要求7所述的药物组合物在制备PAK蛋白激酶抑制剂中的应用。The use of the compound of any one of claims 1 to 6 and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof or the pharmaceutical composition of claim 7 in the preparation of PAK protein kinase inhibitors.
  9. 权利要求1-6任何一项的化合物及其药学上可接受的盐、水合物、溶剂化物或前药或权利要求7所述的药物组合物在制备抗肿瘤的药物中的应用。The use of the compound of any one of claims 1 to 6 and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, or the pharmaceutical composition of claim 7 in the preparation of anti-tumor drugs.
  10. 权利要求9所述的应用，其特征在于，所述的肿瘤为肺癌、乳腺癌、胰腺癌、结肠癌、胃癌、卵巢癌、口腔鳞状细胞癌、前列腺癌、黑色素瘤、白血病、非霍奇金性淋巴瘤。The application of claim 9, wherein the tumor is lung cancer, breast cancer, pancreatic cancer, colon cancer, gastric cancer, ovarian cancer, oral squamous cell carcinoma, prostate cancer, melanoma, leukemia, non-Hodgé Gold lymphoma.
    Figure PCTCN2021098556-appb-100005
    Figure PCTCN2021098556-appb-100005
PCT/CN2021/098556 2020-06-23 2021-06-07 Indole derivative, preparation method therefor and use thereof WO2021259049A1 (en)

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Citations (3)

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WO2009158011A1 (en) * 2008-06-26 2009-12-30 Amgen Inc. Alkynyl alcohols as kinase inhibitors
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