WO2021259049A1 - Dérivé d'indole, son procédé de préparation et son utilisation - Google Patents

Dérivé d'indole, son procédé de préparation et son utilisation Download PDF

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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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ethynyl
aminopyrimidin
hydroxycyclohexyl
alkyl
group
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PCT/CN2021/098556
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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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    • 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

L'invention concerne un dérivé d'indole, son procédé de préparation et son utilisation ; ainsi qu'un sel pharmaceutiquement acceptable, un hydrate, un solvate ou un promédicament dudit composé, des procédés de préparation associés et son utilisation en tant qu'agent thérapeutique, en particulier, en tant qu'inhibiteur de PAK. Le dérivé d'indole et un isomère géométrique ou un sel pharmaceutiquement acceptable, un hydrate, un solvate ou un promédicament de celui-ci sont représentés par la formule générale (I), dans laquelle chaque variable est telle que décrite dans les revendications et la description.
PCT/CN2021/098556 2020-06-23 2021-06-07 Dérivé d'indole, son procédé de préparation et son utilisation WO2021259049A1 (fr)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2009158011A1 (fr) * 2008-06-26 2009-12-30 Amgen Inc. Alcools d’alcynyle utilisés comme inhibiteurs de kinases
CN103476768A (zh) * 2011-03-16 2013-12-25 弗·哈夫曼-拉罗切有限公司 6,5-杂环炔丙醇化合物及其用途
WO2014170421A1 (fr) * 2013-04-19 2014-10-23 F. Hoffmann-La Roche Ag Inhibiteurs de sérine/thréonine kinases

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WO2009158011A1 (fr) * 2008-06-26 2009-12-30 Amgen Inc. Alcools d’alcynyle utilisés comme inhibiteurs de kinases
CN103476768A (zh) * 2011-03-16 2013-12-25 弗·哈夫曼-拉罗切有限公司 6,5-杂环炔丙醇化合物及其用途
WO2014170421A1 (fr) * 2013-04-19 2014-10-23 F. Hoffmann-La Roche Ag Inhibiteurs de sérine/thréonine kinases

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FENG JIANWEN A., LEE PATRICK, ALAOUI MOULAY HICHAM, BARRETT KATHY, CASTANEDO GEORGETTE, GODEMANN ROBERT, MCEWAN PAUL, WANG XIAOLU,: "Structure Based Design of Potent Selective Inhibitors of Protein Kinase D1 (PKD1)", ACS MEDICINAL CHEMISTRY LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 10, no. 9, 12 September 2019 (2019-09-12), US , pages 1260 - 1265, XP055882760, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.8b00658 *
STEVEN T. STABEN , JIANWEN A. FENG , KAREN LYLE , MARCIA BELVIN , JASON BOGGS , JASON D. BURCH , CHING-CHING CHUA, HAIFENG CUI , A: "Back pocket flexibility provides group II p21 activated kinase (PAK) selectivity for type I 1/2 kinase inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 57, no. 3, 13 February 2014 (2014-02-13), pages 1033 - 1045, XP002724447, DOI: 10.1021/jm401768t *

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