[go: up one dir, main page]

WO2018121400A1 - Dérivés d'amide et de thioamide, leur procédé de préparation et leur utilisation - Google Patents

Dérivés d'amide et de thioamide, leur procédé de préparation et leur utilisation Download PDF

Info

Publication number
WO2018121400A1
WO2018121400A1 PCT/CN2017/117710 CN2017117710W WO2018121400A1 WO 2018121400 A1 WO2018121400 A1 WO 2018121400A1 CN 2017117710 W CN2017117710 W CN 2017117710W WO 2018121400 A1 WO2018121400 A1 WO 2018121400A1
Authority
WO
WIPO (PCT)
Prior art keywords
aminoquinazoline
formyl
methyl
pyrazolyl
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2017/117710
Other languages
English (en)
Chinese (zh)
Inventor
赵冬梅
程卯生
郝晨洲
郭靖
张巧玲
王凯
王健
黄万旭
李丰
李晓东
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenyang Pharmaceutical University
Original Assignee
Shenyang Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenyang Pharmaceutical University filed Critical Shenyang Pharmaceutical University
Publication of WO2018121400A1 publication Critical patent/WO2018121400A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention belongs to the field of pharmaceutical synthesis, and relates to a novel class of amide/thioamide derivatives, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, and processes for their preparation and their use as therapeutic agents. It is used as a PAK inhibitor.
  • Protein kinase is the largest family of proteins encoded by human genes and is closely related to tumorigenesis, invasion, metastasis, angiogenesis and chemoresistance. Since some kinases are highly expressed only in tumor cells, their inhibition does not affect the biological functions of normal cells, making the anti-tumor drugs targeting protein kinases have the advantages of high selectivity and low toxicity. Therefore, protein kinase has become an important target for the development of anti-tumor drugs.
  • PAKs (p21 activated kinase) are a class of serine/threonine protein kinases belonging to the STE20 family.
  • PAK4 is a representative of class II PAKs, which can affect a variety of downstream proteins related to cell cycle, migration, invasion and apoptosis, resulting in abnormal cell differentiation, angiogenesis and proliferation. Therefore, PAK4 has become a potential target for tumor therapy.
  • PAKs include six family members (PAK1-PAK6), which are classified into two types according to their structure and activation mode: class I PAKs (PAK1, PAK2, PAK3), class II PAKs (PAK4, PAK5, PAK6). Among them, PAK4 is the most in-depth study of class II PAKs.
  • PAK4 p21 activated kinase 4
  • PBD p21-binding domain
  • AID Auto-inhibition domain
  • kinase A domain (Kinase Domain, KD) or a catalytic domain (Catalytic Domain) in which the p21 binding domain and the self-inhibiting domain are located at the N-terminus of the kinase, and the kinase domain is located at the conserved C-terminus of the kinase.
  • class II PAK does not contain a region rich in acidic amino acid residues and a PIX/Cool binding domain; the homology of the two subfamily kinase domains is only about 50%. The structural differences are large, and the homology in the same subfamily is as high as 92-96% and 79-86%, respectively, and the structure is similar.
  • PAK is a major target protein downstream of the Rho family of guanosine triphosphatase (Rho-GTPases) Cdc42 and Rac1. It regulates and controls various biological functions, such as cytoskeletal reorganization and cell migration, by participating in multiple signaling pathways in cells. Apoptosis, mitosis, cell differentiation, and the like. In addition to being involved in regulating the normal physiological activities of cells, PAK is closely related to the development of various diseases, especially tumors.
  • Rho-GTPases guanosine triphosphatase
  • Cdc42/Rac1 controls the formation of filopodia and lamellipodia, respectively, and PAK acts as a major effector downstream, in malignant transformation of cells and invasion of tumor cells. It plays an important role in the transfer process.
  • PAK kinases especially PAK1 and PAK4, have gene amplification, overexpression, and abnormal activation in a variety of tumor cells, leading to canceration and uncontrolled proliferation, invasion and metastasis of cells.
  • PAK1 is highly expressed in cell lines such as breast cancer, kidney cancer, and colon cancer; in a squamous skin cancer-bearing mouse model, PAK1 deletion significantly attenuates tumorigenesis by down-regulating MAPK and PI3K pathways; PAK1 can also phosphorylate BAD protein inhibits apoptosis of tumor cells; phosphorylation of DLC1 (Dynein light chain 1) promotes cell survival and malignant phenotype; mediates the expression of cyclinD1 in mammary epithelial cells and promotes the development of breast cancer.
  • DLC1 DLC1
  • PAK4 PAK4 protein kinase inhibitor 4
  • breast cancer pancreatic cancer
  • colon cancer lung cancer and ovarian cancer.
  • Activation of PAK4 can lead to anchorage-independent growth of tumor cells, PAK4 loss.
  • the live mutant is able to inhibit the malignant transformation caused by Ras.
  • the mechanism of PAK4 up-regulation is mainly gene amplification, especially in pancreatic cancer, ovarian cancer, oral squamous cell carcinoma and breast cancer.
  • PAK4 is expressed in a variety of solid tumors, the most prominent feature being its increased mRNA or protein expression through increased transcription or gene amplification.
  • studies have also reported that the PAK4 gene mutation (E329K) is associated with colon cancer.
  • Ras mutations are overexpressed in approximately 30% of tumors, including malignant tumors such as pancreatic cancer, colon cancer, and lung cancer.
  • Ras activates the Rho family small G protein Rac1/Cdc42 via PI-3k, thereby activating PAKs.
  • Activated PAKs further affect downstream cell signaling pathway transduction and promote tumor survival, angiogenesis, migration and invasion.
  • PAK4 can activate the survival signal pathway of tumor cells through NF- ⁇ B, and promote the survival of tumor cells; PAK4 can promote the migration of gastric cancer cells through LIMK1-Cofilin signaling pathway; PAK4 can also pass CREB and Wnt/ ⁇ -catenin signals Pathway, promote melanin production, cause diseases such as pigmentation disorder; PAK4/Raf/MEK/ERK signaling pathway exists in liver cancer cells, and PAK4 can inhibit the proliferation of liver cancer cells.
  • PAK4 is closely related to the occurrence and development of various tumors, inhibiting the abnormal function of PAK4, and can effectively inhibit the invasion and metastasis, excessive proliferation of tumor cells, and promote the apoptosis of tumor cells. Therefore, the research of PAK4 inhibitors has important value.
  • PAK inhibitors Because of the close correlation between PAK and tumors, the current research on small molecule PAK inhibitors is in a rapid development stage. Most of the PAK inhibitors have been found to be ATP-competitive PAK inhibitors acting on the kinase domain. The ATP-competitive inhibitors have high affinity and clear site of action, and are the most studied types of kinase inhibitors. However, the kinase domain of the kinase catalyzes the same biochemical reaction, which is structurally and sequence-conserved. The selective selectivity of the inhibitor between the kinases is a common problem encountered in the current ATP competitive inhibitor research.
  • PAK subtype selective inhibitors are highly challenging studies with a large spatial and flexible personality.
  • more and more highly selective ATP competitive kinase inhibitors have been discovered, which is the mainstream trend in the field of current kinase inhibitor research.
  • PAK4IC 50 19nM
  • PAK1IC 50 14nM.
  • Phase I clinical studies of PF-3758309 were forced to terminate due to factors such as poor oral bioavailability (about 1%) and gastrointestinal side effects.
  • PAK4 protein kinase inhibitors
  • PAK4 inhibitors have become a new target for cancer therapy due to its important role in tumor development, migration and invasion.
  • the present invention is designed to synthesize a compound having the structure represented by the general formula (I), and it has been found that a compound having such a structure exhibits a good PAK4 inhibitory activity and has a good selectivity of PAK4/1.
  • the object of the present invention is to provide a novel amide/thioamide derivative represented by the formula (I), and a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof;
  • a ring portion is selected from
  • R 1 is selected hydrogen, C 1 -C 6 alkyl, halo-substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen substituted cycloalkyl C 3 -C 6 -alkyl, C 1 a -C 4 alkoxy group, a six-membered aryl group, a benzyl group, wherein the aryl group and the benzyl group may be further substituted with from 1 to 6 R x .
  • the B ring is selected from the group consisting of a 5-6 membered aromatic ring, a 5-6 membered aromatic heterocyclic ring, a 5-7 membered saturated aliphatic ring, and a 5-7 membered unsaturated fatty ring.
  • the B ring can be further substituted with from 1 to 4 R 2 .
  • R 2 is selected from the group consisting of hydrogen, halogen (fluoro, chloro, bromo, iodo), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, halo C 1 -C 6 alkyl.
  • Part of Z is selected from O or S.
  • the C ring is a 4-7 membered heterocyclic group, a 5-7 membered unsaturated heterocyclic group, and a 4-7 membered bicyclic heterocyclic group, and the above ring contains at least one nitrogen (N) atom, and the nitrogen atom and the acyl group or sulfur Acyl moiety An amide bond is formed.
  • the ring also includes an additional 0-2 heteroatoms of N, O or S. This ring can be further substituted with 1-4 Rx.
  • the chiral carbon atom formed after the substitution of R x may be in the R configuration, the S configuration or the racemic form.
  • R x is -H, hydroxy, halogen, nitro, amino, cyano, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, optionally substituted by hydroxy, amino or halo(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy, singly or di(C 1 -C 6 alkane Substituted amino, (C 1 -C 6 )alkylamido, free, salt-forming, esterified and amidated carboxyl, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl acyl, carbamoy
  • the present invention is preferably a novel amide/thioamide derivative of the formula (I), and a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein
  • a ring portion is selected from
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl substituted by halogen, C 3 -C 6 cycloalkyl substituted by halogen, C 2 -C 4 alkoxy, six A aryl group, a benzyl group, wherein the aryl group and the benzyl group may be further substituted with 1 to 6 R x groups.
  • the B ring is selected from the group consisting of a 5-6 membered aromatic ring and a 5-6 membered aromatic heterocyclic ring.
  • the B ring can be further substituted with from 1 to 4 R 2 .
  • R 2 is selected from the group consisting of hydrogen, halogen (fluoro, chloro, bromo, iodo), C 1 -C 4 alkyl, C 1 -C 4 alkoxy, methoxy, hydroxy, halogen-substituted C 1 -C 4 alkyl .
  • Part of Z is selected from O, S.
  • the C ring is a 4-7 membered heterocyclic group having at least one nitrogen (N) atom and the nitrogen atom and the acyl or thioacyl moiety An amide bond is formed.
  • the ring also includes an additional 0-2 heteroatoms of N, O, S. This ring can be further substituted with 1-4 Rx.
  • the chiral carbon atom formed after the substitution of R x may be in the R configuration, the S configuration or the racemic form.
  • R x is -H, hydroxy, halogen, nitro, amino, cyano, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, optionally substituted by hydroxy, amino or halo(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy, singly or di(C 1 -C 6 alkane Substituted amino, (C 1 -C 6 )alkylamido, free, salt-forming, esterified and amidated carboxyl, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl acyl, carbamoy
  • Preferred in the invention are novel amide/thioamide derivatives of the formula (I), and geometric isomers thereof, or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
  • a ring portion is selected from
  • R 1 is selected hydrogen, C 1 -C 6 alkyl, halo-substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen substituted C 3 -C 6 cycloalkyl, C 2 a -C 4 alkoxy group, a six-membered aryl group, a benzyl group, wherein the aryl group and the benzyl group may be further substituted with from 1 to 6 R x .
  • the B ring is selected from the group consisting of a 5-6 membered aromatic ring and a 5-6 membered aromatic heterocyclic ring.
  • the B ring can be further substituted with from 1 to 4 R 2 .
  • R 2 is selected from the group consisting of hydrogen, halogen (fluorine, chlorine, bromine, iodine), methyl, methoxy, hydroxy, trifluoromethyl.
  • Part of Z is selected from O, S.
  • the C ring is a 6-membered heterocyclic group having at least one nitrogen (N) atom, and the nitrogen atom and the acyl or thioacyl moiety An amide bond is formed.
  • the ring also includes 0-1 heteroatoms of N, O, S.
  • the ring can be further substituted with from 1 to 4 R x .
  • the chiral carbon atom formed after the substitution of R x may be in the R configuration, the S configuration or the racemic form.
  • R x is -H, hydroxy, halogen, nitro, amino, cyano, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, optionally substituted by hydroxy, amino or halo(C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy, singly or di(C 1 -C 6 alkane Substituted amino, (C 1 -C 6 )alkylamido, free, salt-forming, esterified and amidated carboxyl, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl acyl, carbamoy
  • the present invention is preferably a novel amide/thioamide derivative of the formula (I), and a geometric isomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein
  • a ring portion is selected from
  • R 1 is selected hydrogen, C 1 -C 3 alkyl, halo substituted C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, halogen substituted C 3 -C 5 cycloalkyl, phenyl And a benzyl group, wherein the phenyl group and the benzyl group are further substituted by 1 to 6 R x .
  • the B ring is a benzene ring, and the benzopyrimidine ring composed of the benzene ring and its adjacent pyrimidine ring is further substituted with 1-4 R 2 .
  • R 2 is selected from the group consisting of hydrogen, halogen (fluorine, chlorine, bromine, iodine), methyl, methoxy, hydroxy, trifluoromethyl.
  • Part of Z is selected from O, S.
  • the C ring is preferably a piperazine ring Ring and acyl or thioacyl moiety An amide bond is formed.
  • the ring may be further substituted with 1-2 Rx, Rx is selected from hydrogen, (C1-C6) alkyl, halogenated (C1-C6) alkyl, (C 3 -C 6) cycloalkyl, halogenated (C 3 -C 6 )cycloalkyl.
  • the chiral carbon atom formed after the Rx substitution may be in the R configuration, the S configuration, or the racemic form.
  • the present invention is preferably a novel amide/thioamide derivative represented by the formula (I), and a geometric isomer thereof or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
  • a ring portion is selected from
  • R 1 is selected hydrogen, C 1 -C 3 alkyl, halo substituted C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, halogen substituted C 3 -C 5 cycloalkyl, phenyl Wherein the phenyl group may be further substituted with 1-2 Rx.
  • the B ring is selected from a benzene ring, and the 6 or 7 position of the benzopyrimidine ring composed of the benzene ring and its adjacent pyrimidine ring may be further substituted by R 2 .
  • R 2 is selected from the group consisting of hydrogen, halogen (fluorine, chlorine, bromine, iodine), methyl, methoxy, hydroxy, trifluoromethyl and the like. Further preferred is a chlorine atom substitution.
  • Part of Z is selected from O, S.
  • C ring is piperazine ring Ring and acyl or thioacyl moiety An amide bond is formed.
  • the most preferred range of the C ring is as follows:
  • a part of the compound of the formula (I) in the present invention has a basic group and can form a pharmaceutically acceptable salt with an acid.
  • the pharmaceutically acceptable addition salts include inorganic acids and organic acid addition salts, and salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid , benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like. Most preferred is hydrochloric acid.
  • the invention also includes prodrugs of the derivatives of the invention.
  • Prodrugs of the derivatives of the invention are derivatives of formula (I) which may themselves have weak or even no activity, but after administration, under physiological conditions (for example by metabolism, solvolysis or otherwise) ) is converted to the corresponding biologically active form.
  • the compound of the formula (I) may be in an unsolvated form and in a solvated form containing a pharmaceutically acceptable solvent such as water, ethanol or the like.
  • a pharmaceutically acceptable solvent such as water, ethanol or the like.
  • the compounds of the formula (I) may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. All stereoisomeric forms of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof (such as racemic mixtures), are included within the scope of the invention. Inside.
  • halogen means fluorine, chlorine, bromine or iodo
  • alkyl means a straight or branched alkyl group
  • aryl means two hydrogens at one or different positions in the aromatic hydrocarbon.
  • heteroaryl means a monocyclic or polycyclic ring system containing one or more hetero atoms selected from N, O, S, which is a ring
  • the system refers to an organic group which is aromatic and which removes two hydrogen atoms at one or different positions in the cyclic system, such as thiazolyl, imidazolyl, pyridyl, pyrazolyl, (1, 2, 3)- and (1,2,4)-triazolyl, furyl, thienyl, pyrrolyl, fluorenyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl,
  • the present invention may contain a derivative of the formula (I), and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient, and mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition.
  • a pharmaceutically acceptable carrier or excipient means any diluent, adjuvant and/or carrier which 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 cause other adverse effects such as allergic reactions.
  • compositions of the present invention can be formulated in a number of dosage forms containing some of the commonly used excipients in the pharmaceutical arts.
  • a plurality of dosage forms as described above may be administered as a medicament such as an injection, a tablet, a capsule, an aerosol, a suppository, a film, a pill, a topical tincture, or an ointment.
  • the carrier used in the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, including: a binder, a lubricant, a disintegrant, a solubilizer, a diluent, a stabilizer, a suspending agent, a non-pigment, a flavoring agent. , preservatives, solubilizers and matrices.
  • the pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they can be formulated into enteric coated tablets.
  • the derivatives of the present invention which may contain the general formula (I) can be synthesized by a method well known in the chemical art, especially in accordance with the description of the present invention.
  • the starting materials can generally be obtained from commercial sources such as Aladdin, Darry, and the like, or can be prepared using methods well known to those skilled in the art.
  • room temperature refers to an ambient temperature of from 10 degrees Celsius to 30 degrees Celsius.
  • a positive progressive effect of the present invention is that the present invention provides an amide/thioamide derivative which is completely different from the prior art, a preparation method, a pharmaceutical composition and use thereof.
  • the amide/thioamide compound of the present invention has a good selective inhibitory effect on PAK4 kinase and can be used for the prevention, treatment or adjuvant treatment of various diseases associated with the expression or activity of PAK4 kinase.
  • Step a The starting material I-1 is subjected to acylation to give Intermediate I-2.
  • Step b Intermediate I-2 is acylated with oxalyl chloride monoethyl ester to give intermediate I-3.
  • Step c Intermediate I-3 is cyclized by reaction with sodium ethoxide to give Intermediate I-4.
  • Step d Intermediate I-4 is subjected to basic hydrolysis to give Intermediate I-5.
  • Step e Intermediate I-5 is chlorinated to give intermediate I-6.
  • Step f Intermediate 1-6 is subjected to selective acylation with the corresponding amine C fragment to give intermediate I-7.
  • the corresponding amine can be an amine fragment bearing a suitable protecting group.
  • Step g Intermediate I-7 is reacted with an A ring fragment by an aromatic nucleophilic substitution reaction, and the corresponding protecting group is removed to obtain the final product.
  • the preferred conditions are as follows:
  • the reactant was dissolved in an anhydrous tetrahydrofuran solvent, and triphosgene was added thereto, followed by heating under reflux for 12 hours.
  • the mixture was cooled to room temperature, and 1N aqueous ammonia was added thereto, and the mixture was reacted at 65 ° C for 1 hour, and the mixture was cooled to room temperature to precipitate a white solid.
  • step b the reactant was dissolved in an anhydrous tetrahydrofuran solvent, triethylamine was added at 0 ° C, and oxalyl chloride monoethyl ester was added dropwise with stirring. After the dropwise addition, the mixture was heated to room temperature for half an hour to precipitate a white solid. A small amount of water was added, the tetrahydrofuran was evaporated, ethyl acetate was added and the organic layer was dried to give Intermediate-1.
  • the reactant is dissolved in ethanol, sodium ethoxide is added at a temperature of Celsius, and the mixture is heated to room temperature for 12 hours, 2N hydrochloric acid is adjusted to pH, and the white solid is suction filtered to give the intermediate I-4.
  • the reactant was dissolved in a mixed solvent of ethanol-water (1-1), and the mixture was heated under reflux for 2 hours with 2N hydrochloric acid to adjust the pH to acid.
  • step e the reactant was dissolved in chloroform, and refluxed with thionyl chloride for 3 hours to evaporate the solvent and the thionyl chloride to afford Intermediate I-6.
  • step f the reactant is dissolved in anhydrous dichloromethane, the temperature is lowered to -35 ° C, the corresponding amine is added and stirred for 1 hour, the reaction is quenched with water, extracted with dichloromethane, and dried over silica gel. Intermediate I-7 was obtained.
  • step g the reactant is dissolved in DMF, the corresponding A ring fragment and potassium iodide are added, the temperature is raised to 65 ° C, stirred for 10 hours, poured into water, and the precipitate is purified by silica gel column chromatography to obtain the final product of the compound.
  • the compound contains a protecting group
  • the corresponding protecting group is removed under the corresponding conventional deprotection reaction conditions to obtain the final product.
  • the definition of the A loop fragment is as described above.
  • a protecting group refers to a molecule containing two or more functional groups in organic synthesis. In order to protect one of the functional groups from the reaction, a certain reagent is used to protect it first, and then the protective agent is removed after the reaction is completed.
  • Protecting groups include tert-butoxycarbonyl (Boc), benzyl (Bn) and the like.
  • the preferred conditions are as follows:
  • the reactant is dissolved in tetrahydrofuran or toluene, heated to reflux with a Lawson reagent for 3 hours, the solvent is distilled off, and purified by silica gel column chromatography to give a compound product.
  • the synthesis can be carried out by the method A, that is, the step i, the substituted 4-nitroimidazole is reacted with an alkyl halide (R 1 -X) in DMF or acetonitrile to form a 1-position substituted 4-nitro group.
  • the imidazole derivative is subjected to hydrogen reduction in step j to obtain an imidazole fragment.
  • Method B can also be employed.
  • the 4-nitroimidazole substituted in step k is nitrated by nitric acid anhydride at zero degrees Celsius for 1 hour, and extracted to obtain a 1-nitro substituted 4-nitroimidazole.
  • 1-Nitro-4-nitroimidazole is dissolved in a water-ethanol mixture (1-1) by reaction with an amine fragment (R 1 -NH 2 ), stirred at room temperature overnight, extracted and dried, and purified by silica gel column chromatography.
  • the 1-position R 1 is substituted for the 4-nitroimidazole derivative.
  • Hydrogen reduction by the step m gives a 1-position R 1 substituted 4-aminoimidazole fragment.
  • the definition of the A loop fragment and R 1 is as described above.
  • a loop fragment is a substituted pyrazole
  • the following method can be employed:
  • the preferred conditions are as follows:
  • step n sodium hydride was added to anhydrous tetrahydrofuran, the temperature was raised to 65 ° C, and a mixture of the R 1 -substituted carboxylic acid ester and acetonitrile was added dropwise, and the mixture was refluxed for 12 hours, cooled to room temperature, and extracted with diethyl ether three times.
  • step o the R 1 -substituted ⁇ -carbonyl nitrile is dissolved in ethanol, hydrazine hydrate and methanesulfonic acid are added, and the mixture is heated under reflux for 1 hour, cooled to room temperature, and the solvent is evaporated, and purified by silica gel column chromatography to give R 1 substituted. 3-aminopyrazole.
  • the starting materials can generally be obtained from commercial sources or prepared using methods well known to those skilled in the art or prepared according to the methods described herein.
  • the reagents used were of analytical or chemical purity, unless otherwise stated.
  • the structure of the compound was confirmed to be determined by Agilent 1100 LC/MSD.
  • the column chromatography purification product used was 100-200 mesh or 200-300 mesh silica gel produced by Qingdao Ocean Chemical Plant.
  • the synthetic route is:
  • Reagents and conditions a) tetrahydrofuran, acetonitrile, sodium hydrogen, 66 degrees Celsius; b) ethanol, methanesulfonic acid, hydrazine hydrate, reflux; c) 1. triphosgene, tetrahydrofuran, 65 degrees Celsius; 2.1N ammonia, 65 degrees Celsius; d) Tetrahydrofuran, oxalyl chloride monoethyl ester, 0 ° C to room temperature; e) sodium ethoxide, ethanol, 0 ° C to room temperature; f) sodium hydroxide, ethanol, water, room temperature; g) chloroform, thionyl chloride, reflux; h) Dichloromethane, triethylamine, N-Boc-piperazine, minus 35 degrees Celsius; i) 5-methyl 3-aminopyrazole, DMF, 65 degrees C; j) 2N hydrogen chloride-ethyl acetate solution at room temperature.
  • step c) The starting material 2-amino-5-chlorobenzoic acid in step c) was replaced with 2-aminobenzoic acid according to the method of Example 1.
  • Example 2 was obtained via steps a-j. ESI-MS m/z: 338.4 [M+H]+.
  • Example 3 Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoformate, and the starting material 2-amino-5-chlorobenzoic acid was replaced with 2-aminobenzoic acid in step c).
  • the 5-methyl-3-amino-1H-pyrazole was replaced with 5-cyclopropyl-3-amino-1H-pyrazole, and Example 3 was obtained via step aj.
  • the ethyl acetate of the starting material in step a) was replaced with ethyl isobutyrate, and the starting material 2-amino-5-chlorobenzoic acid in step c) was replaced with 2-aminobenzoic acid.
  • the 5-methyl-3-amino-1H-pyrazole was replaced with 5-isopropyl-3-amino-1H-pyrazole, and Example 4 was obtained via step aj.
  • Example 1 According to the method of Example 1, the ethyl acetate in the step a) was replaced with ethyl cyclobutyrate, and the starting material 2-amino-5-chlorobenzoic acid in the step c) was replaced with 2-aminobenzoic acid.
  • the 5-methyl-3-amino-1H-pyrazole was replaced with 5-cyclobutyl-3-amino-1H-pyrazole, and Example 5 was obtained via step aj.
  • the ethyl acetate of the starting material in step a) was replaced with methyl benzoate, and the starting material 2-amino-5-chlorobenzoic acid in step c) was replaced with 2-aminobenzoic acid.
  • Step i) The 5-methyl-3-amino-1H-pyrazole was replaced with 5-phenyl-3-amino-1H-pyrazole, and Example 6 was obtained via step aj.
  • Example 8 was obtained via step aj.
  • Example 9 was obtained via step aj.
  • Example 10 was obtained via step aj.
  • the synthetic route is as follows:
  • Reagents and conditions a) 1. triphosgene, tetrahydrofuran, 65 degrees Celsius; 2.1N ammonia, 65 degrees Celsius; b) tetrahydrofuran, oxalyl chloride monoethyl ester, 0 degrees Celsius to room temperature; c) sodium ethoxide, ethanol, 0 degrees Celsius to room temperature; d) sodium hydroxide, ethanol, water, room temperature; e) chloroform, thionyl chloride, reflux; f) dichloromethane, triethylamine, morpholine, minus 35 degrees Celsius; g) 5-methyl 3-aminopyridinium Azole, DMF, 65 ° C; h) 2N hydrogen chloride-ethyl acetate solution at room temperature.
  • Example 12 Following the procedure of Example 11, the morpholine in step f) was replaced with 4-methylpiperazine, and Example 12 was obtained via steps a-g. ESI-MS m/z: 434.5 [M+H]+.
  • Example 13 Following the procedure of Example 11, morpholine was replaced with piperidine in step f) and Example 13 was obtained via steps a-g. ESI-MS m/z: 371.6 [M+H]+.
  • Example 14 was obtained via steps a-g. ESI-MS m/z: 412.7 [M+H]+.
  • Example 16 Following the procedure of Example 11, the morpholine in step f) was replaced with 4-hydroxypiperidine, and Example 16 was obtained via steps a-g. ESI-MS m/z: 387.5 [M+H]+.
  • Example 17 Following the procedure of Example 11, morpholine was replaced with 4-hydroxy-4-methylpiperidine in step f), and Example 17 was obtained via steps a-g. ESI-MS m/z: 401.5 [M+H]+.
  • Example 18 was obtained from step a-g. ESI-MS m/z: 386.5 [M+H]+.
  • Example 19 was obtained from step a-j.
  • Example 20 was obtained via steps a-j.
  • Example 22 Following the procedure of Example 1, replacing N-Boc-piperazine in step h) with (1R,4R)-2-tert-butoxycarbonyl-2,5-diazabicyclo(2.2.1) heptane, stepwise Example 22 was obtained from aj. ESI-MS m/z: 384.5 [M+H]+.
  • Example 24 was obtained via steps a-j.
  • Example 30 was obtained via steps a-j.
  • Example 32 Following the procedure of Example 1, the ethyl acetate of the starting material in step a) was replaced with ethyl cyanoformate, and the N-Boc-piperazine in step h) was replaced with (S)-2-methyl-N-Boc- Piperazine, replacing 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl-3-amino-1H-pyrazole, gave Example 32 via step aj.
  • the synthetic route is:
  • Reagents and conditions a) Lawson's reagent, toluene, reflux.
  • Step h) Substituting N-Boc-piperazine for (R)-3-methyl-N-Boc-piperazine, replacing 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl -3-Amino-1H-pyrazole, Example 44 was obtained via step aj. ESI-MS m/z: 378.2 [M+H]+.
  • step h) replace N-Boc-piperazine with (R)-3-methyl-N-Boc-piperazine, and replace 5-methyl-3-amino-1H-pyrazole in step i) with 5- Cyclopropyl-3-amino-1H-pyrazole,
  • Example 45 was obtained via step aj. ESI-MS m/z: 396.2 [M+H]+.
  • step h) replace N-Boc-piperazine with (R)-3-methyl-N-Boc-piperazine, and replace 5-methyl-3-amino-1H-pyrazole in step i) with 5- Cyclopropyl-3-amino-1H-pyrazole,
  • Example 46 was obtained via step aj. ESI-MS m/z: 456.2 [M+H]+.
  • step a) was replaced with ethyl cyanoacetate, and the starting material 2-amino 5-chlorobenzoic acid in step c) was replaced with 2-amino 5-methoxybenzoic acid.
  • step h) Substituting N-Boc-piperazine in step h) with (R)-3-methyl-N-Boc-piperazine, replacing 5-methyl-3-amino-1H-pyrazole in step i) with 5-cyclopropyl-3-amino-1H-pyrazole, Example 48 was obtained via step aj.
  • step h) replace N-Boc-piperazine with (R)-3-methyl-N-Boc-piperazine, and replace 5-methyl-3-amino-1H-pyrazole in step i) with 5- Cyclopropyl-3-amino-1H-pyrazole,
  • step i) replace N-Boc-piperazine with (R)-3-methyl-N-Boc-piperazine, and replace 5-methyl-3-amino-1H-pyrazole in step i) with 5- Cyclopropyl-3-amino-1H-pyrazole,
  • Example 49 was obtained via step aj.
  • the synthetic route is as follows:
  • Reagents and conditions a) methyl iodide, acetonitrile, potassium carbonate, 65 degrees Celsius; b) 1). hydrogen, palladium carbon, stirring at room temperature 2). hydrogen chloride-ethanol solution, ethanol, 0 degrees Celsius; c) 1).
  • the synthetic route is as follows:
  • Reagents and conditions a) nitric acid, acetic anhydride, acetic acid, 0 degrees Celsius to room temperature; b) water, methanol, cyclopropylamine, room temperature; c) 1). hydrogen, palladium carbon, stirring at room temperature 2). hydrogen chloride-ethanol solution, ethanol , 0 degrees Celsius; d) 1.
  • triphosgene tetrahydrofuran, 65 degrees Celsius; 2.1N ammonia, 65 degrees Celsius; e) tetrahydrofuran, oxalyl chloride monoethyl ester, 0 degrees Celsius to room temperature; f) sodium ethoxide, ethanol, 0 degrees Celsius to room temperature; j) sodium hydroxide, ethanol, water, room temperature; h) chloroform, thionyl chloride, reflux; i) dichloromethane, triethylamine, morpholine, minus 35 degrees Celsius; j) 1-cyclopropyl-1H- Imidazole 4-amine hydrochloride, DMF, 65 ° C; k) 2N hydrogen chloride-ethyl acetate solution, room temperature.
  • Example-1 was obtained via Step ak. ESI-MS m/z: 440.5 [M+H]+.
  • Example 53 was obtained via step aj.
  • Example 54 was obtained via step aj.
  • Example 57 was obtained via step ak. ESI-MS m/z: 468.5 [M+H]+.
  • KinEASE TM -STK kit (containing a biotinylated peptide substrate S2, Eu3 + labeled monoclonal antibody only against specific phosphorylation sites, Sa-XL665 labeled streptavidin, avidin, KinEASE enzyme reaction buffer), 384 shallow well plates, full length protein of PAK4.
  • PAK4 protein concentration 0.0256 ng/ ⁇ l, MgCl 2 , ethylenediaminetetraacetic acid (EDTA), dithiothreitol (DTT), DMSO.
  • the first step the kinase reaction.
  • the compound sample was first formulated into a 20 mM solution in DMSO, and then diluted to a concentration of 100 ⁇ M, 10 ⁇ M, 1 ⁇ M, etc., using a kinase reaction buffer solution according to the test. Then, PAK4 kinase (concentration: 0.0256 ng/ ⁇ l), ATP (4 ⁇ M), biotin-labeled polypeptide substrate S2 (1 ⁇ M) and compound sample (4 ⁇ l) were added to 10 ⁇ l of kinase reaction buffer solution (containing MgCl 2 ) In 5 mM and DTT 1 mM), the kinase incubated the substrate S2 for 40 minutes at room temperature. Then, 10 ⁇ l of a detection reagent containing EDTA was added to detect the phosphorylated product.
  • the second step detection of phosphorylated products.
  • the rare earth element cerium (Eu 3+ ) labeled antibody recognizes the phosphorylated substrate and the XL665 labeled streptavidin binds to biotin on the substrate.
  • Eu 3+ is a fluorescent donor and XL665 is a fluorescent acceptor. When Eu 3+ is close to XL665, Eu 3+ energy is transferred to XL665, producing an HTRF signal.
  • the fluorescence signal was generated from the 620 nm fluorescence absorption signal of Eu 3+ and 665665 of XL665. Therefore, the ratio of the HTRF signal (665/620) of each well plate reaction is calculated.
  • Example 1 Compound 1 ⁇ M 0.1 ⁇ M Compound 1 ⁇ M 0.1 ⁇ M Example 1 98% 89% Example 29 84% 52% Example 8 100% 99% Example 32 99% 79% Example 11 69% 26% Example 33 99% 92% Example 12 46% 25% Example 34 100% 95% Example 16 17% 0% Example 35 99% 75% Example 17 5% 0% Example 36 97% 62% Example 18 78% 36% Example 37 100% 97% Example 19 64% twenty two% Example 44 99% 92% Example 24 62% twenty four% Example 45 99% 95% Example 25 96% 72% Example 46 100% 96% Example 26 98% 86% Example 48 97% 92% Example 27 99% 93% Example 49 100% 95% Example 28 97% 59%
  • Example 57 In vitro selectivity test of PAK4/PAK1 for some products of the invention
  • Z'-LYTE TM kinase assay Z'-LYTE TM Kinase Assay
  • the test method is divided into a kinase reaction step, a transformation reaction step and a detection step.
  • Compound solution formulation The compound DMSO solution was diluted from 10 mM to 1 mM. The solution was serially diluted three times using a Agilent automated pipetting station (Bravo) for a total of 11 concentrations.
  • PAK1 kinase domain
  • PAK4 kinase domain
  • oxachacol ketone fluorescent donor
  • fluorescein fluorescent receptor labeled polypeptide substrate
  • test compounds were incubated in a kinase 22 ° C reaction.
  • the 10 ⁇ L reaction solution contained 50 mM HEPES (pH 7.5), 0.01% Brij-35, 10 mM MgCl 2 , 1 mM EGTA, 2 ⁇ M FRET polypeptide substrate, and PAK enzyme (20 pM PAK1 KD; 80 pM PAK 4 KD).
  • some of the compounds of the formula (I) of the present invention have significant inhibitory activity against PAK4 and PAK4/PAK1 selectivity, which is superior to the typical PAK4 inhibitor PF3758309 and staurosporine, and has significant technical progress and advantages.
  • the compound of the formula (I) in the present invention may be administered alone, but usually it is administered in a mixture with a pharmaceutically acceptable carrier which is selected according to the desired route of administration and standard pharmaceutical practice, each of which is separately used below.
  • a pharmaceutical dosage form such as a tablet, a capsule, an injection, an aerosol, a suppository, a film, a pill, a topical tincture and an ointment, illustrates its new application in the pharmaceutical field.
  • the activated carbon is adsorbed, filtered through a 0.65 ⁇ m microporous membrane, and filled into a nitrogen tank to prepare a water needle preparation. Only 2mL is installed, and a total of 100 bottles are filled.
  • Example 66 Topical tincture

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se situe dans le domaine technique de la médecine et concerne des dérivés d'amide et de thioamide, leurs procédés de préparation et leur utilisation, et concerne en particulier des dérivés de formule générale (I) et des isomères géométriques de ceux-ci ou des sels, hydrates, solvates et promédicaments pharmaceutiquement acceptables de ceux-ci ainsi que leurs procédés de préparation. Les dérivés de la présente invention ont une activité en tant qu'inhibiteurs de protéine kinase, en particulier des inhibiteurs de kinase PAK.
PCT/CN2017/117710 2016-12-27 2017-12-21 Dérivés d'amide et de thioamide, leur procédé de préparation et leur utilisation Ceased WO2018121400A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201611223917.3 2016-12-27
CN201611223917.3A CN108239071B (zh) 2016-12-27 2016-12-27 酰胺及硫代酰胺类衍生物及其制备方法和应用

Publications (1)

Publication Number Publication Date
WO2018121400A1 true WO2018121400A1 (fr) 2018-07-05

Family

ID=62701570

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/117710 Ceased WO2018121400A1 (fr) 2016-12-27 2017-12-21 Dérivés d'amide et de thioamide, leur procédé de préparation et leur utilisation

Country Status (2)

Country Link
CN (1) CN108239071B (fr)
WO (1) WO2018121400A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2018283053B2 (en) * 2017-06-15 2022-09-08 Biocryst Pharmaceuticals, Inc. Imidazole-containing inhibitors of ALK2 kinase

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111072640A (zh) * 2019-12-26 2020-04-28 沈阳药科大学 喹唑啉类衍生物及其制备方法和应用
WO2022033420A1 (fr) * 2020-08-14 2022-02-17 成都海博为药业有限公司 Composé utilisé en tant qu'inhibiteur de kinase pak4, son procédé de préparation et son application
CN114315957B (zh) * 2021-12-30 2023-07-07 深圳瑞德林生物技术有限公司 一种多肽的制备方法
CN115028547B (zh) * 2022-05-17 2023-09-12 浙江华伟医药科技有限公司 一种邻氨基苯甲酰胺的微通道化学合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004029045A2 (fr) * 2002-09-24 2004-04-08 Bayer Pharmaceuticals Corporation Procede de preparation d'inhibiteurs quinazoline de rho-kinase et leurs intermediaires
CN100340555C (zh) * 2000-12-21 2007-10-03 沃泰克斯药物股份有限公司 可用作蛋白激酶抑制剂的吡唑化合物
CN103301133A (zh) * 2012-12-11 2013-09-18 中国药科大学 一类氨基喹唑啉表皮生长因子受体拮抗剂的抗肿瘤治疗用途
CN105503837A (zh) * 2015-12-31 2016-04-20 中山大学 具有Aurora激酶抑制活性的取代喹唑啉类衍生物及其应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2004253967B2 (en) * 2003-07-03 2010-02-18 Cytovia, Inc. 4-arylamino-quinazolines as activators of caspases and inducers of apoptosis

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100340555C (zh) * 2000-12-21 2007-10-03 沃泰克斯药物股份有限公司 可用作蛋白激酶抑制剂的吡唑化合物
WO2004029045A2 (fr) * 2002-09-24 2004-04-08 Bayer Pharmaceuticals Corporation Procede de preparation d'inhibiteurs quinazoline de rho-kinase et leurs intermediaires
CN103301133A (zh) * 2012-12-11 2013-09-18 中国药科大学 一类氨基喹唑啉表皮生长因子受体拮抗剂的抗肿瘤治疗用途
CN105503837A (zh) * 2015-12-31 2016-04-20 中山大学 具有Aurora激酶抑制活性的取代喹唑啉类衍生物及其应用

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2018283053B2 (en) * 2017-06-15 2022-09-08 Biocryst Pharmaceuticals, Inc. Imidazole-containing inhibitors of ALK2 kinase
AU2018283053C1 (en) * 2017-06-15 2023-03-02 Biocryst Pharmaceuticals, Inc. Imidazole-containing inhibitors of ALK2 kinase
US11661426B2 (en) 2017-06-15 2023-05-30 Biocryst Pharmaceuticals, Inc. Imidazole-containing inhibitors of ALK2 kinase
US12054492B2 (en) 2017-06-15 2024-08-06 Biocryst Pharmaceuticals, Inc. Imidazole-containing inhibitors of ALK2 kinase

Also Published As

Publication number Publication date
CN108239071B (zh) 2020-12-04
CN108239071A (zh) 2018-07-03

Similar Documents

Publication Publication Date Title
RU2719428C2 (ru) Индазольные соединения в качестве ингибиторов киназы fgfr, их получение и применение
US10793543B2 (en) Selective C-KIT kinase inhibitor
CN106883213B (zh) 一种egfr和alk激酶的双重抑制剂
CN101379060B (zh) 作为Aurora激酶抑制剂的苯并唑系衍生物、组合物和使用方法
AU2012296411B2 (en) Amino quinazolines as kinase inhibitors
CN115322158B (zh) 作为krasg12c蛋白抑制剂的取代喹唑啉类化合物
WO2018045957A1 (fr) Inhibiteur de cdk4/6, son procédé de préparation et son application
KR20200100429A (ko) 단백질 키나아제 저해 활성을 갖는 신규한 피리도[3,4-d]피리미딘-8-온 유도체 및 이를 포함하는 암의 예방, 개선 또는 치료용 약학 조성물
WO2018121400A1 (fr) Dérivés d'amide et de thioamide, leur procédé de préparation et leur utilisation
CA2958671C (fr) Composes d'imidazopyridazine et leur utilisation
CN113454081A (zh) 咪唑并吡啶基化合物及其用于治疗增生性疾病的用途
JP7477846B2 (ja) Ｎを含むヘテロアリール誘導体およびこれを有効成分として含むがんの予防または治療用薬学的組成物
CN107074778A (zh) 苯并咪唑类似物和相关方法
EP3470415A1 (fr) Hétérocycle à 5 éléments fusionné avec [3,4-d]pyridazinone, son procédé de fabrication, composition pharmaceutique et son application
CN114656411A (zh) 一种用作egfr/her2双靶点抑制剂的多取代喹唑啉类化合物及其应用
WO2020156283A1 (fr) Composé alkynylpyrimidine ou alkynylpyridine, et composition et application de celui-ci
Jin et al. Pyrrolo [2, 3-b] pyridine-3-one derivatives as novel fibroblast growth factor receptor 4 inhibitors for the treatment of hepatocellular carcinoma
US12115152B2 (en) Pan-RAF kinase inhibitor and use thereof
WO2005103036A1 (fr) Pyrimidine-4-yl-1h-indazol-5yl-amines utiles comme inhibiteurs des chk1 kinases
WO2022194265A1 (fr) Composé à base de quinazoline, composition et utilisation d'un composé à base de quinazoline
JP7110335B2 (ja) プロテインキナーゼ阻害剤として有用なピリドキナゾリン誘導体
CN103373971A (zh) 作为蛋白激酶抑制剂的脲类化合物
CN111303024A (zh) 一种喹啉结构的pan-KIT激酶抑制剂及其用途
CN111138426A (zh) 吲唑类激酶抑制剂及其用途
CN107805240A (zh) 一种新型的pdgfr激酶抑制剂及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17885530

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17885530

Country of ref document: EP

Kind code of ref document: A1