WO2018121400A1 - 酰胺及硫代酰胺类衍生物及其制备方法和应用 - Google Patents

酰胺及硫代酰胺类衍生物及其制备方法和应用 Download PDF

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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
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aminoquinazoline
formyl
methyl
pyrazolyl
chloro
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PCT/CN2017/117710
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English (en)
French (fr)
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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
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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
    • C07D403/12—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

Abstract

本发明属于医药技术领域，涉及酰胺及硫代酰胺类衍生物及其制备方法和应用，具体涉及如通式(I)的衍生物及其几何异构体或其药学上可接受的盐、水合物、溶剂化物、前药和它们的制备方法。所述的衍生物具有作为蛋白激酶抑制剂，特别是PAK激酶抑制剂的活性。

Description

酰胺及硫代酰胺类衍生物及其制备方法和应用 技术领域
本发明属药物合成领域，涉及一类新型酰胺/硫代酰胺类衍生物，以及所述化合物的药学可接受的盐、水合物、溶剂化物或前药，它们的制备方法及其作为治疗剂特别是作为PAK抑制剂的用途。
背景技术
肿瘤的治疗已经成为一个世界性的难题，高效低毒的抗肿瘤药物研发迫在眉睫。靶向抗肿瘤药物凭借其特异性好、有效性强、毒副作用低等特点，在肿瘤治疗中取得巨大成功。
蛋白激酶是人类基因编码的蛋白中最大的家族，与肿瘤的发生、侵袭、转移、血管生成及化疗耐药性密切相关。由于部分激酶仅在肿瘤细胞中高度表达，其抑制并不影响正常细胞的生物学功能，使得以蛋白激酶为靶点的抗肿瘤药物具有高选择性、低毒性的优点。所以，蛋白激酶已经成为抗肿瘤药物研发的重要靶点。
2001年Bcr-Abl激酶抑制剂伊马替尼
Figure PCTCN2017117710-appb-000001
被FDA批准用于治疗慢性粒细胞白血病，成为第一个上市的蛋白激酶抑制剂类抗肿瘤药物。之后短短的十五年中，已有42个蛋白激酶抑制剂上市，仅2013年以来，FDA批准上市的用于肿瘤治疗的小分子激酶抑制剂已有8个。具有抗肿瘤活性的蛋白激酶抑制剂的研究得到了生物制药行业的高度重视。
PAKs(p21活化激酶)是一类丝氨酸/苏氨酸蛋白激酶，属于STE20家族。PAK4是II类PAKs的代表，可以影响下游多种与细胞周期、迁移、侵袭和凋亡相关的蛋白，从而引起肿瘤细胞分化异常、血管生成、增殖等。因此，PAK4成为潜在的肿瘤治疗靶点。
PAKs包括六个家族成员(PAK1-PAK6)，根据其结构和活化方式的不同分为两类：I类PAKs(PAK1,PAK2,PAK3)，II类PAKs(PAK4,PAK5,PAK6)。其中PAK4是II类PAKs中研究最为深入的。
PAK4(p21活化激酶4)激酶全长包括591个氨基酸残基，主要分为三个结构域：p21结合域(P21-binding Domain,PBD)、自抑制域(Auto-inhibition Domain,AID)和激酶域(Kinase Domain,KD)或催化域(Catalytic Domain)，其中p21结合域和自抑制域位于激酶的N-端，激酶域位于激酶保守的C-端。I类PAKs和II类PAKs存在明显的结构差异性，例如，II类PAK不含富含酸性氨基酸残基的区域及PIX/Cool结合域；两个亚家族激酶域同源性仅约50％，结构差异较大，而相同亚家族内同源性分别高达92-96％和79-86％，结构较为相似。
PAK为Rho家族鸟苷三磷酸酶(Rho-GTPases)Cdc42和Rac1下游的主要靶蛋白，通过参与细胞内的多条信号通路，调节控制多种生物学功能，如细胞骨架重组、细胞迁移运动、细胞凋亡、有丝***、细胞分化等。除了参与调节细胞正常的生理活动外，PAK与多种疾病特别是肿瘤的发生发展密切相关。在细胞内RAS-Cdc42/Rac1-PAK信号通路中，Cdc42/Rac1分别控制细胞丝状伪足和片状伪足的生成，PAK作为其下游的主要效应器，在细胞的恶性转化和肿瘤细胞侵袭转移过程中具有重要作用。
研究表明PAK激酶特别是PAK1和PAK4，在多种肿瘤细胞中存在基因扩增、过度表达、异常活化的现象，从而导致细胞的癌变和不可控制的增殖、侵袭和转移。例如，PAK1在乳腺癌、肾癌、结肠癌等细胞系中高度表达；在鳞状皮肤癌荷瘤鼠模型中，PAK1缺失将通过下调MAPK和PI3K通路显著减弱肿瘤发生发展；PAK1还可以磷酸化BAD蛋白，抑制肿瘤细胞的凋亡；磷酸化DLC1(Dynein light chain 1)，促进细胞存活和恶性表型；介导乳腺上皮细胞cyclinD1表达，促进乳腺癌发生发展。另一方面，超过70％的多种人癌细胞系高表达PAK4，包括乳腺癌、胰腺癌、结肠癌、肺癌和卵巢癌等，PAK4的活化可导致肿瘤细胞锚定非依赖性生长，PAK4失活型突变体能够抑制Ras引起的恶性转化。PAK4上调的机制主要是基因扩增，特别是在胰腺癌、卵巢癌、口腔鳞状细胞癌和乳腺癌中。PAK4在多种实体瘤中表达，最突出的特点是其通过转录增加或者基因扩增而增加mRNA或蛋白质的表达。但研究也报道了PAK4 的基因突变(E329K)与结肠癌有关。
研究表明，在大约30％的肿瘤中蛋白Ras突变过表达，这些肿瘤中包括胰腺癌、结肠癌和肺癌等恶性肿瘤。Ras通过PI-3k激活Rho家族小G蛋白Rac1/Cdc42，从而激活PAKs。活化的PAKs进一步影响下游的细胞信号通路转导，促进肿瘤的存活、血管生成、迁移侵袭等。研究表明，PAK4可以通过NF-κB，活化肿瘤细胞的生存信号通路，促进肿瘤细胞的生存；PAK4可以通过LIMK1-Cofilin信号通路促进胃癌细胞的迁移；PAK4还可以通过CREB及Wnt/β-catenin信号通路，促进黑色素生成，导致色素沉着紊乱等疾病；肝癌细胞中存在PAK4/Raf/MEK/ERK信号通路，可以通过PAK4抑制肝癌细胞的增殖。
PAK4与多种肿瘤的发生发展密切相关，抑制PAK4的异常功能，能够有效抑制肿瘤细胞的侵袭转移、过度增殖，促进肿瘤细胞凋亡。因此，PAK4抑制剂的研究具有重要的价值。
因为PAK与肿瘤的密切相关性，所以当前小分子PAK抑制剂的研究正处于一个快速发展阶段。已发现的PAK抑制剂大多为作用于激酶域的ATP竞争性PAK抑制剂，ATP竞争性抑制剂具有亲和性高、作用位点明确的特点，也是目前研究最多的激酶抑制剂类型。但激酶的激酶域催化相同的生物化学反应，具有结构和序列的保守性，抑制剂在激酶间选择性的实现是当前ATP竞争性抑制剂研究遇到的共性问题；同时，PAK的ATP结合腔具有空间较大、柔性较高的个性特点，因此PAK亚型选择性抑制剂的发现是一项具有显著挑战性的研究。但随着相关学科的快速发展，越来越多的高选择性ATP竞争性激酶抑制剂已被发现，是当前激酶抑制剂研究领域的主流趋势。
目前PAKs抑制的研究尚处于起步阶段，仅有辉瑞公司研发的PF-3758309进入了Ⅰ期临床研究。PF-3758309是辉瑞公司2009年报道的具有吡咯并吡唑结构PAKs抑制剂，是唯一进入临床研究的PAKs抑制剂，其PAK4IC 50＝19nM，PAK1IC 50＝14nM。在体外抑瘤实验和荷瘤鼠在体模型研究中，PF-3758309显著地抑制肿瘤细胞增殖和促进肿瘤细胞凋亡。但是，由于其口服生物利用度差(约1％)、胃肠道不良反应等因素，PF-3758309的I期临床研究被迫终止。随后基因泰克公司2014年报道的具有苯并咪唑类结构的选择性作用于II类PAKs的化合物，可以对PAK4产生选择性抑制作用(PAK1IC 50＝5.4μM，PAK4IC 50＝7.5nM)。虽然这类化合物仍存在细胞活性弱、成药性差的缺陷，但该研究已初步证明了亚型选择性PAK抑制剂发现的可能性。
综上，以蛋白激酶抑制剂为代表的靶向抗肿瘤药物已经成为国内外抗肿瘤药物研发的主流。PAK4由于其在肿瘤发生发展、迁移和侵袭中的重要作用，成为肿瘤治疗的新靶点。目前，PAK4抑制剂的研究尚处于起步阶段，高活性、高选择性抑制剂的研发具有重要意义。但是目前尚无PAK抑制剂药物上市，仍需要开发结构新颖的具有更好药效的化合物。本发明设计合成了具有通式(I)所示结构的化合物，并发现具有此类结构的化合物表现出较好的PAK4抑制活性，且具有良好的PAK4/1的选择性。
发明内容：
本发明的目的在于提供一种通式(I)所示的新型酰胺/硫代酰胺类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药；
Figure PCTCN2017117710-appb-000002
其中，A环部分选自
Figure PCTCN2017117710-appb-000003
R 1选自氢、C 1-C 6烷基、被卤素取代的C 1-C 6烷基、C 3-C 6环烷基、被卤素取代的C 3-C 6环烷基、C 1-C 4烷氧基、六元芳基、苄基，其中所述芳基、苄基可进一步被1-6个R x取代。
B环选自5-6元芳香环、5-6元芳香杂环、5-7元饱和脂肪环、5-7元不饱和脂肪环。B环可进一步被1-4个R 2所取代。
R 2选自氢、卤素(氟，氯，溴，碘)，C 1-C 6烷基，C 1-C 6烷氧基，羟基，卤代的C 1-C 6烷基。
通式(I)中
Figure PCTCN2017117710-appb-000004
部分的Z选自O或S。
C环为4-7元杂环基、5-7元不饱和杂环基、4-7元双环杂环基，上述环至少含1个氮(N)原子，且该氮原子与酰基或硫代酰基部分
Figure PCTCN2017117710-appb-000005
形成酰胺键。该环还包括另外0-2个N,O或S的杂原子。该环可进一步被1-4个Rx取代。R x取代后形成的手性碳原子可以为R构型、S构型或者消旋形式。
R x为-H、羟基、卤素、硝基、氨基、氰基、(C 1-C 6)烷基、(C 2-C 6)烯基、(C 2-C 6)炔基、(C 1-C 6)烷氧基、任选被羟基、氨基或卤代的(C 1-C 6)烷基或(C 1-C 6)烷氧基、被单或二(C 1-C 6烷基)取代的氨基、(C 1-C 6)烷基酰氨基、游离的、成盐的、酯化的和酰胺化的羧基、(C 1-C 6)烷基亚磺酰基、(C 1-C 6)烷基磺酰基、(C 1-C 6)烷氧基、(C 1-C 6)烷基、(C 1-C 6)烷基酰基、氨基甲酰基、被单或二(C 1-C 6烷基)取代的氨基甲酰基、(C 1-C 3)亚烷基二氧基。
本发明优选通式(I)所示的新型酰胺/硫代酰胺类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其中
其中，A环部分选自
Figure PCTCN2017117710-appb-000006
R 1选自氢、C 1-C 6烷基、被卤素取代的C 3-C 6环烷基、被卤素取代的C 3-C 6环烷基、C 2-C 4烷氧基、六元芳基、苄基，其中所述芳基、苄基可进一步被1-6个R x取代。
B环选自5-6元芳香环、5-6元芳香杂环。B环可进一步被1-4个R 2所取代。
R 2选自氢、卤素(氟，氯，溴，碘)，C 1-C 4烷基，C 1-C 4烷氧基，甲氧基，羟基，卤素取代的C 1-C 4烷基。
通式(I)中
Figure PCTCN2017117710-appb-000007
部分的Z选自O，S。
C环为4-7元杂环基，该环至少含1个氮(N)原子，且该氮原子与酰基或硫代酰基部分
Figure PCTCN2017117710-appb-000008
形成酰胺键。该环还包括另外0-2个N,O,S的杂原子。该环可进一步被1-4个Rx取代。R x取代后形成的手性碳原子可以为R构型、S构型或者消旋形式。
R x为-H、羟基、卤素、硝基、氨基、氰基、(C 1-C 6)烷基、(C 2-C 6)烯基、(C 2-C 6)炔基、(C 1-C 6)烷氧基、任选被羟基、氨基或卤代的(C 1-C 6)烷基或(C 1-C 6)烷氧基、被单或二(C 1-C 6烷基)取代的氨基、(C 1-C 6)烷基酰氨基、游离的、成盐的、酯化的和酰胺化的羧基、(C 1-C 6)烷基亚磺酰基、(C 1-C 6)烷基磺酰基、(C 1-C 6)烷氧基、(C 1-C 6)烷基、(C 1-C 6)烷基酰基、氨基甲酰基、被单或二(C 1-C 6烷基)取代的氨基甲酰基、(C 1-C 3)亚烷基二氧基。
本发明优选通式(I)所示的新型酰胺/硫代酰胺类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
其中，A环部分选自
Figure PCTCN2017117710-appb-000009
R 1选自氢、C 1-C 6烷基、被卤素取代的C 1-C 6烷基、C 3-C 6环烷基、被卤素取代的C 3-C 6环烷基、C 2-C 4烷氧基、六元芳基、苄基，其中所述芳基、苄基可进一步被1-6个R x取代。
B环选自5-6元芳香环、5-6元芳香杂环。B环可进一步被1-4个R 2所取代。
R 2选自氢、卤素(氟，氯，溴，碘)，甲基，甲氧基，羟基，三氟甲基。
通式(I)中
Figure PCTCN2017117710-appb-000010
部分的Z选自O，S。
C环为6元杂环基，该环至少含1个氮(N)原子，且该氮原子与酰基或硫代酰基部分
Figure PCTCN2017117710-appb-000011
形成酰胺键。该环还包括0-1个N,O,S的杂原子。该环可进一步被1-4个R x取代。R x取代后形成的手性碳原子可以为R构型、S构型或者消旋形式。
R x为-H、羟基、卤素、硝基、氨基、氰基、(C 1-C 6)烷基、(C 2-C 6)烯基、(C 2-C 6)炔基、(C 1-C 6)烷氧基、任选被羟基、氨基或卤代的(C 1-C 6)烷基或(C 1-C 6)烷氧基、被单或二(C 1-C 6烷基)取代的氨基、(C 1-C 6)烷基酰氨基、游离的、成盐的、酯化的和酰胺化的羧基、(C 1-C 6)烷基亚磺酰基、(C 1-C 6)烷基磺酰基、(C 1-C 6)烷氧基、(C 1-C 6)烷基、(C 1-C 6)烷基酰基、氨基甲酰基、被单或二(C 1-C 6烷基)取代的氨基甲酰基、(C 1-C 3)亚烷基二氧基。
本发明优选通式(I)所示的新型酰胺/硫代酰胺类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其中
其中，A环部分选自
Figure PCTCN2017117710-appb-000012
R 1选自氢、C 1-C 3烷基、被卤素取代的C 1-C 3烷基、C 3-C 5环烷基、被卤素取代的C 3-C 5环烷基、苯基、苄基，其中所述苯基、苄基可进一步被1-6个R x取代。
B环为苯环，该苯环与其相邻的嘧啶环组成的苯并嘧啶环进一步被1-4个R 2所取代。R 2选自氢、卤素(氟，氯，溴，碘)，甲基，甲氧基，羟基，三氟甲基。
通式(I)中
Figure PCTCN2017117710-appb-000013
部分的Z选自O，S。
C环优选为哌嗪环
Figure PCTCN2017117710-appb-000014
且环与酰基或硫代酰基部分
Figure PCTCN2017117710-appb-000015
形成酰胺键。该环可进一步被1-2个Rx取代，Rx选自氢，(C1-C6)烷基，卤代的(C1-C6)烷基，(C 3-C 6)环烷基，卤代的(C 3-C 6)环烷基。Rx取代后形成的手性碳原子可以为R构型、S构型或者消旋形式。
本发明优选通式(I)所所示的新型酰胺/硫代酰胺类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药。
其中，A环部分选自
Figure PCTCN2017117710-appb-000016
R 1选自氢、C 1-C 3烷基、被卤素取代的C 1-C 3烷基、C 3-C 5环烷基、被卤素取代的C 3-C 5环烷基、苯基，其中所述苯基可进一步被1-2个Rx取代。
B环选自苯环，该苯环与其相邻的嘧啶环组成的苯并嘧啶环6位或7位可进一步被R 2所取代。R 2选自氢、卤素(氟，氯，溴，碘)，甲基，甲氧基，羟基，三氟甲基等。进一步优选氯原子取代。
Figure PCTCN2017117710-appb-000017
通式(I)中
Figure PCTCN2017117710-appb-000018
部分的Z选自O，S。
C环为哌嗪环
Figure PCTCN2017117710-appb-000019
且环与酰基或硫代酰基部分
Figure PCTCN2017117710-appb-000020
形成酰胺键。C环最优选的范围如下：
Figure PCTCN2017117710-appb-000021
而且，按照本发明所属领域的一些通常方法，本发明中通式(I)的部分化合物具有碱性基团，可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐，与下列酸加成的盐是特别优选的：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。最优选为盐酸。
此外，本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式(I)的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
通式(I)所示的化合物可以以非溶剂化形式和含有药学上可接受的溶剂(如水、乙醇等)的溶剂化形式。通式(I)所示的化合物可以含有不对称或手性中心，因此可以以不同立体异构形式存在。本发明的所有立体异构形式，包括但不限于非对映异构体、对映异构体和阻转异构体以及它们的混合物(如外消旋混合物)，均包括在本发明的范围内。
通式(I)所示的化合物可以以不同的互变异构体形式存在，所有这些形式均包括在本发明的范围内。术语“互变异构体”或“互变异构形式”是指经由低能垒互相转化的不同能量的结构异构体。
本发明中“卤素”是指氟、氯、溴或碘代；“烷基”是指直链或支链的烷基；“芳基”是指除去芳烃中的一个或不同位置的两个氢原子而得到的有机基团，如苯基、萘基；“杂芳基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系，该环状体系是指具有芳香性的，并且除去环状体系中的一个或不同位置的两个氢原子而得到的有机基团，如噻唑基，咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-***基、呋喃基、噻吩基、吡咯基，吲哚基，苯并噻唑基，噁唑基，异噁唑基，萘基，喹啉基，异喹啉基，苯并咪唑基，苯并噁唑基等；杂环基是指含有一个或多个选自N、O、S的杂原子的单环的环状体系，如哌嗪基、四氢吡咯烷基、吗啉基、哌啶基、四氢吡唑烷基、四氢咪唑烷基和四氢噻唑啉基等。
本发明可以含有通式(I)的衍生物，及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成份，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型，上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用，只要它们不产生其他不利的作用，例如过敏反应。
本发明的药用组合物可配制成若干种剂型，其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下不稳定的，可将其配制成肠衣片剂。
本发明可以含有通式(I)的衍生物可以通过包括化学领域众所周知的方法来合成，尤其根据本发明的说明来合成。
原料一般可以从商业来源例如阿拉丁、达瑞等试剂公司获得或者使用本领域技术人员所熟知的方法来制备。
本发明中室温指环境温度，为10摄氏度至30摄氏度。
本发明的积极进步效果在于：本发明提供了一种与现有技术完全不同的酰胺/硫代酰胺类衍 生物，其制备方法、药物组合物和应用。本发明的酰胺/硫代酰胺类化合物对与PAK4激酶具有良好的选择性抑制效果，可以用于预防、治疗或辅助治疗与PAK4激酶的表达或活性有关的多种疾病。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实例和制备例的范围并不以任何方式限制本发明的范围。按照本发明的式I的化合物，可按照合成路线1-3的方法制备得来，这些路线中应用的全部可变因数如权利要求中的定义。
合成路线1
Figure PCTCN2017117710-appb-000022
如路线1所示，部分化合物的合成主要有几个步骤：
步骤a：原料I-1经酰化反应得到中间体I-2。
步骤b：中间体I-2经草酰氯单乙酯酰化反应得到中间体I-3。
步骤c：中间体I-3经与乙醇钠反应环合得到中间体I-4。
步骤d：中间体I-4经碱水解反应得到中间体I-5。
步骤e：中间体I-5经氯代反应得到中间体I-6。
步骤f：中间体I-6与相应的胺C片段经选择性酰化反应得到中间体I-7。相应的胺可以为带有适当保护基团的胺片段。
步骤g：中间体I-7经芳香亲核取代反应与A环片段反应，再脱除相应保护基得到终产物。
优选条件如下：
在步骤a中，反应物溶于无水四氢呋喃溶剂中，加入三光气，在加热回流条件下反应12小时。降温至室温，加入1N氨水，65摄氏度反应1小时，降温至室温，析出白色固体，抽滤得到中间体I-2。
在步骤b中，反应物溶于无水四氢呋喃溶剂中，0摄氏度下加入三乙胺，搅拌下滴加草酰氯单乙酯。滴加完毕升温至室温反应半小时，析出白色固体。加入少量水，蒸除四氢呋喃，加入乙酸乙酯萃取，有机层干燥得中间体I-3。
在步骤c中，反应物溶于乙醇中，摄氏度下加入乙醇钠，加毕升温至室温反应12小时，2N盐酸调PH为中性，白色固体抽滤得到中间体I-4。
在步骤d中，反应物溶于乙醇-水(1-1)混合溶剂中，加入氢氧化钠加热回流2小时2N盐酸调PH为酸性，白色固体抽滤得到中间体I-5。
在步骤e中，反应物溶于氯仿中，加入氯化亚砜加热回流3小时蒸除溶剂及氯化亚砜得到中间体I-6。
在步骤f中，反应物溶于无水二氯甲烷中，降温至-35摄氏度，加入相应的胺搅拌1小时，加水淬灭反应，二氯甲烷提取，有机层干燥，经硅胶柱层析纯化得中间体I-7。
在步骤g中，反应物溶于DMF中，加入相应A环片段和碘化钾，升温至65摄氏度，搅拌10小时，倾入水中，析出物经硅胶柱层析纯化得化合物终产品。如此时化合物含有保护基，则再在相应常规脱保护反应条件下脱除相应保护基得到终产品。其中，A环片段的定义如上述所述。
保护基团是指在有机合成中，含有2个或多个官能团的分子，为使其中某个官能团免遭反 应的破坏，常用某种试剂先将其保护，待反应完成后再脱去保护剂。保护基团包括叔丁氧羰基(Boc)、苄基(Bn)等。
合成路线2
如路线2所示，部分化合物可按以下步骤合成：
Figure PCTCN2017117710-appb-000023
优选条件如下：
在步骤e中，反应物溶于四氢呋喃或者甲苯中，加入劳森试剂加热回流3小时，蒸除溶剂，经硅胶柱层析纯化得到化合物终产品。
合成路线3
A环片段合成：
A环片段为取代咪唑时，合成可采用方法A，即步骤i，取代的4-硝基咪唑与卤代烷(R 1-X)反应在DMF或者乙腈中加热反应生成1-位取代4-硝基咪唑衍生物，经步骤j氢气还原得到咪唑片段。
也可采用方法B，即步骤k取代的4-硝基咪唑经硝酸醋酸酐在零摄氏度硝化反应1小时，萃取干燥得到1-位硝基取代4-硝基咪唑。将1-硝基-4-硝基咪唑经与胺片段(R 1-NH 2)反应溶于水-乙醇混合物中(1-1)，室温搅拌过夜，萃取干燥，经硅胶柱层析纯化得到1-位R 1取代4-硝基咪唑衍生物。经步骤m氢气还原得到1-位R 1取代4-氨基咪唑片段。其中，A环片段和R 1的定义如上述所述。
Figure PCTCN2017117710-appb-000024
A环片段为取代吡唑时，可采用如下方法：
Figure PCTCN2017117710-appb-000025
优选条件如下：
在步骤n中，将氢钠加入无水四氢呋喃中，升温至65摄氏度，滴加R 1取代的羧酸酯与乙腈的混合物，加入回流12小时，降温至室温，***萃取3次，水层用2N盐酸调PH为酸性，乙酸乙酯萃取，干燥，经硅胶柱层析纯化得到R 1取代的β-羰基腈。
在步骤o中，将R 1取代的β-羰基腈溶于乙醇，加入水合肼和甲磺酸，加热回流1小时，降温至室温，蒸除溶剂，经硅胶柱层析纯化得到R 1取代的3-氨基吡唑。
具体实施方式：
不需进一步详细说明，认为本领域熟练技术人员借助于前面的描述，可以最大程度地利用本发明。因此下面提供的实施例旨在阐述而不是限制本发明的范围。
原料一般可以从商业来源获得或者使用本领域技术人员所熟知的方法来制备，或根据本发明所述的方法制备。未经特殊说明，所用试剂均为分析纯或化学纯。
化合物结构确证所用质谱用Agilent 1100LC/MSD测定。柱层析纯化产物使用的是青岛海洋化工厂生产的100-200目或者200-300目硅胶。
Figure PCTCN2017117710-appb-000026
表1实施例1-55的结构式
Figure PCTCN2017117710-appb-000027
Figure PCTCN2017117710-appb-000028
Figure PCTCN2017117710-appb-000029
Figure PCTCN2017117710-appb-000030
实施例1：6-氯-2-[1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000031
合成路线为：
Figure PCTCN2017117710-appb-000032
试剂与条件：a)四氢呋喃，乙腈，氢钠，66摄氏度；b)乙醇，甲磺酸，水合肼，回流；c)1.三光气，四氢呋喃，65摄氏度；2.1N氨水，65摄氏度；d)四氢呋喃，草酰氯单乙酯，0摄氏度至室温；e)乙醇钠，乙醇，0摄氏度至室温；f)氢氧化钠，乙醇，水，室温；g)氯仿，氯化亚砜，回流；h)二氯甲烷，三乙胺，N-Boc-哌嗪，零下35摄氏度；i)5-甲基3-氨基吡唑，DMF，65摄氏度；j)2N氯化氢-乙酸乙酯溶液室温。
a)将8.80g(100mmol)乙酸乙酯(I-1)和12.3g(300mmol)乙腈溶于180mL无水四氢呋喃中，0摄氏度搅拌下分批加入12.5g(300mmol)氢化钠，升温至回流反应1.5h。降至室温，将反应液缓慢倾入200mL冰水中，用2N盐酸调节pH至2-3，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤有机相，无水硫酸钠干燥，减压蒸除溶剂，得浅黄色油状物(I-2)3.68g，收率45.4％。GC-MSm/z:83.1[M]+。
b)将0.83g(10.0mmol)3-氧代丁腈(I-2)和0.70mL(10.0mmol)水合肼溶于50mL无水乙醇中，向混合溶液中加入96.0mg(1.0mmol)甲磺酸，升温至回流反应45min，TLC检测反应完全(碘熏)。减压蒸出溶剂，得黄色油状物，经硅胶色谱柱纯化(石油醚：乙酸乙酯＝3:1)，得浅黄色油状物(I-3)0.82g，收率84.5％。GC-MS m/z:97.1[M]+。
c)将2.00g(11.6mmol)2-氨基-5-氯苯甲酸(I-4)溶于20mL干燥四氢呋喃中，搅拌下加入1.20g(3.90mmol)三光气，升温至60摄氏度反应12h，TLC监测反应完全。降至室温，减压蒸除溶剂，加入1N氨水，升温至60摄氏度反应1h，析出白色固体，TLC监测反应完全。降至室温，抽滤，水(10mL×3)洗，滤饼干燥至恒重，得白色粉末状固体1.68g，收率84.9％。1H-NMR(400MHz,DMSO-d6)δ:7.85(s,1H),7.60(d,J＝2.44Hz,1H),7.18-7.16(m,2H),6.72(d,J＝8.80Hz,1H),6.40(br,2H)。
d)将1.68g(9.85mmol)2-氨基-5-氯苯甲酰胺(I-5)和1.63Ml(11.8mmol)三乙胺溶于34mL干燥四氢呋喃中，0摄氏度搅拌下向反应液中滴加1.15mL(10.8mmol)草酰氯单乙酯，滴加完毕，升至室温反应1h，TLC监测反应完全。减压蒸除溶剂，加入40mL乙酸乙酯溶解，水(10mL×3)洗，饱和食盐水(10mL×3)洗，无水硫酸钠干燥，减压蒸除溶剂，经硅胶色谱柱纯化(二氯甲烷：丙酮＝50:1)，得类白色粉末状固体2.50g，收率93.9％。 1H-NMR(400MHz,DMSO-d6)δ:13.02(s,1H),8.56(d,J＝8.96Hz,1H),8.47(s,1H),7.99(s,1H),7.97(d,J＝2.44Hz,1H),7.66(dd,J＝2.44,8.92Hz,1H),4.30(q,J＝7.12Hz,2H),1.31(t,J＝7.12Hz,3H)。
e)将2.50g(9.24mmol)2-(2-甲酰胺基-4-氯-苯基)氨基乙二酸乙酯(I-6)溶于28mL乙醇中，0摄氏度搅拌下向溶液中缓慢滴加7.60mL(11.1mmol)10％乙醇钠乙醇溶液，继续反应3h，TLC监测反应完全。用1N盐酸调节pH＝3-4，析出白色固体，抽滤，水(10mL×3)洗，滤饼干燥至恒重，经硅胶色谱柱纯化(二氯甲烷：丙酮＝100:1)，得白色粉末状固体2.00g，收率85.8％。 1H-NMR(400MHz,DMSO-d6)δ:12.83(s,1H),8.10(d,J＝2.36Hz,1H),7.92(dd,J＝2.46,8.68Hz,1H),7.85(d,J＝8.68Hz,1H),4.39(q,J＝7.12Hz,2H),1.35(t,J＝7.12Hz,3H)。
f)将2.00g(7.92mmol)6-氯-4-氧代-3H,4H-喹唑啉-2-羧酸乙酯(I-7)溶于25mL乙醇中，室温搅拌下向溶液中加入25.5mL(63.4mmol)10％氢氧化钠水溶液，继续反应0.5h，TLC监测反应完全。用2N盐酸调节pH＝3，析出白色固体，抽滤，水(10mL×3)洗，滤饼干燥至恒重，得类白色粉末状固体1.70g，收率95.5％。
g)将0.23g(1.00mmol)6-氯-4-氧代-3H,4H-喹唑啉-2-羧酸(I-8)溶于5mL三氯甲烷中，向溶液中加入0.87mL(12.0mmol)氯化亚砜和一滴N,N-二甲基甲酰胺，升温至回流反应0.5h，TLC监测反应完全。降至室温，减压蒸除溶剂，得中间体(I-6),立即进行下一步反应。
h)将中间体(I-9)溶于5mL干燥的二氯甲烷中，-35摄氏度搅拌下，向溶液中依次缓慢滴加0.42mL(3.00mmol)三乙胺和185mg(1.00mmol)N-Boc-哌嗪，继续反应0.5h，TLC监测反应完全。加水淬灭，加入30mL二氯甲烷，水(10mL×3)洗，饱和食盐水(10mL×3)洗，无水硫酸钠干燥，蒸除溶剂，经硅胶色谱柱纯化(二氯甲烷：甲醇＝50:1)，得黄色粉末状固体0.40g，收率48.7％。 1H-NMR(400MHz,CDCl3)δ:8.30(d,J＝2.12Hz,1H),8.07(d,J＝8.96Hz,1H),7.96(dd,J＝2.24,8.96Hz,1H),3.85-3.82(m,2H),3.61-3.58(m,2H),3.52-3.49(m,2H),3.43-3.41(m,2H),1.48(s,9H)。
i)将0.20g(0.49mmol)4,6-二氯-2-[1-(4-N-叔丁氧羰基)哌嗪基]甲酰基喹唑啉(I-10)、47.5mg(0.49mmol)5-甲基-3-氨基-1H-吡唑(I-3)和0.096mL(0.59mmol)N,N-二异丙基乙胺溶于4mL1,4-二氧六环中，升温至回流反应3h，析出浅黄色固体，TLC监测反应完全。降至室温，抽滤，滤饼经硅胶色谱柱纯化(二氯甲烷：甲醇＝20:1，0.5％三乙胺)、10倍甲醇热打浆，得白 色粉末状固体0.07g，收率30.3％。 1H-NMR(400MHz,DMSO-d6)δ:12.28(s,1H),10.71(s,1H),8.89(s,1H),7.89(dd,J＝2.00,8.92Hz,1H),7.79(d,J＝8.92Hz,1H),6.56(s,1H),3.64-3.62(m,2H),3.44(s,2H),3.29-3.27(m,4H),2.27(s,3H),1.40(s,9H)。
j)将上述固体(I-11)溶于2mL盐酸/乙酸乙酯中，室温搅拌下反应6h，析出白色固体，抽滤，滤饼干燥至恒重，得白色粉末状固体0.06g，收率96.7％。mp 341.8～342.6摄氏度。ESI-MS m/z:372.1[M+H]+。1H-NMR(400MHz,DMSO-d6)δ:11.47(s,1H),9.59(s,2H),9.01(s,1H),8.01(dd,J＝8.92Hz,1H),7.91(d,J＝2.42,8.84Hz,1H),6.56(s,1H),3.92-3.91(m,2H),3.71(s,2H),3.23(s,2H),3.09(s,2H),2.32(s,2H)。
实施例2：2-[1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000033
按照实施例1的方法，将步骤c)中原料2-氨基-5-氯苯甲酸替换为2-氨基苯甲酸，
经步骤a-j得到实施例2。ESI-MS m/z:338.4[M+H]+。
实施例3：2-[1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000034
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤c)中原料2-氨基-5-氯苯甲酸替换为2-氨基苯甲酸，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例3。ESI-MS m/z:364.2[M+H]+。
实施例4：2-[1-哌嗪基]甲酰基-4-[1H-3-(5-异丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000035
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为异丁酸乙酯，将步骤c)中原料2-氨基-5-氯苯甲酸替换为2-氨基苯甲酸，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-异丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例4。ESI-MS m/z:366.1[M+H]+。
实施例5：2-[1-哌嗪基]甲酰基-4-[1H-3-(5-环丁基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000036
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丁酸乙酯，将步骤c)中原料2-氨基-5-氯苯甲酸替换为2-氨基苯甲酸，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丁基-3-氨基-1H-吡唑，经步骤a-j得到实施例5。ESI-MS m/z:377.1[M+H]+。
实施例6：2-[1-哌嗪基]甲酰基-4-[1H-3-(5-苯基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000037
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为苯甲酸甲酯，将步骤c)中原料2-氨基 -5-氯苯甲酸替换为2-氨基苯甲酸，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-苯基-3-氨基-1H-吡唑，经步骤a-j得到实施例6。ESI-MS m/z:400.3[M+H]+。
实施例7：2-[1-哌嗪基]甲酰基-4-[1H-3-(5-苄基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000038
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为苯乙酸甲酯，将步骤c)中原料2-氨基-5-氯苯甲酸替换为2-氨基苯甲酸，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-苄基-3-氨基-1H-吡唑，经步骤a-j得到实施例7。ESI-MS m/z:414.4[M+H]+。
实施例8：6-氯-2-[1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000039
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例8。ESI-MS m/z:398.5[M+H]+。
实施例9：6-氯-2-[1-哌嗪基]甲酰基-4-[1H-3-(5-异丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000040
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为异丁酸乙酯，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-异丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例9。ESI-MS m/z:400.6[M+H]+。
实施例10：6-氯-2-[1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000041
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为苯甲酸乙酯，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-苯基-3-氨基-1H-吡唑，经步骤a-j得到实施例10。ESI-MS m/z:434.5[M+H]+。
实施例11：6-氯-2-[4-吗啉基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
Figure PCTCN2017117710-appb-000042
合成路线如下：
Figure PCTCN2017117710-appb-000043
试剂与条件：a)1.三光气，四氢呋喃，65摄氏度；2.1N氨水，65摄氏度；b)四氢呋喃，草酰氯单乙酯，0摄氏度至室温；c)乙醇钠，乙醇，0摄氏度至室温；d)氢氧化钠，乙醇，水，室温；e)氯仿，氯化亚砜，回流；f)二氯甲烷，三乙胺，吗啉，零下35摄氏度；g)5-甲基3-氨基吡唑，DMF，65摄氏度；h)2N氯化氢-乙酸乙酯溶液室温。
a)将2.00g(11.6mmol)2-氨基-5-氯苯甲酸(I-1)溶于20mL干燥四氢呋喃中，搅拌下加入1.20g(3.90mmol)三光气，升温至60摄氏度反应12h，TLC监测反应完全。降至室温，减压蒸除溶剂，加入1N氨水，升温至60C反应1h，析出白色固体，TLC监测反应完全。降至室温，抽滤，水(10mL×3)洗，滤饼干燥至恒重，得白色粉末状固体1.68g，收率84.9％。 1H-NMR(400MHz,DMSO-d6)δ:7.85(s,1H),7.60(d,J＝2.44Hz,1H),7.18-7.16(m,2H),6.72(d,J＝8.80Hz,1H),6.40(br,2H)。
b)将1.68g(9.85mmol)2-氨基-5-氯苯甲酰胺(I-2)和1.63Ml(11.8mmol)三乙胺溶于34mL干燥四氢呋喃中，0摄氏度搅拌下向反应液中滴加1.15mL(10.8mmol)草酰氯单乙酯，滴加完毕，升至室温反应1h，TLC监测反应完全。减压蒸除溶剂，加入40mL乙酸乙酯溶解，水(10mL×3)洗，饱和食盐水(10mL×3)洗，无水硫酸钠干燥，减压蒸除溶剂，经硅胶色谱柱纯化(二氯甲烷：丙酮＝50:1)，得类白色粉末状固体2.50g，收率93.9％。 1H-NMR(400MHz,DMSO-d6)δ:13.02(s,1H),8.56(d,J＝8.96Hz,1H),8.47(s,1H),7.99(s,1H),7.97(d,J＝2.44Hz,1H),7.66(dd,J＝2.44,8.92Hz,1H),4.30(q,J＝7.12Hz,2H),1.31(t,J＝7.12Hz,3H)。
c)将2.50g(9.24mmol)2-(2-甲酰胺基-4-氯-苯基)氨基乙二酸乙酯(I-3)溶于28mL乙醇中，0摄氏度搅拌下向溶液中缓慢滴加7.60mL(11.1mmol)10％乙醇钠乙醇溶液，继续反应3h，TLC监测反应完全。用1N盐酸调节pH＝3-4，析出白色固体，抽滤，水(10mL×3)洗，滤饼干燥至恒重，经硅胶色谱柱纯化(二氯甲烷：丙酮＝100:1)，得白色粉末状固体2.00g，收率85.8％。 1H-NMR(400MHz,DMSO-d6)δ:12.83(s,1H),8.10(d,J＝2.36Hz,1H),7.92(dd,J＝2.46,8.68Hz,1H),7.85(d,J＝8.68Hz,1H),4.39(q,J＝7.12Hz,2H),1.35(t,J＝7.12Hz,3H)。
d)将2.00g(7.92mmol)6-氯-4-氧代-3H,4H-喹唑啉-2-羧酸乙酯(I-4)溶于25mL乙醇中，室温搅拌下向溶液中加入25.5mL(63.4mmol)10％氢氧化钠水溶液，继续反应0.5h，TLC监测反应完全。用2N盐酸调节pH＝3，析出白色固体，抽滤，水(10mL×3)洗，滤饼干燥至恒重，得类白色粉末状固体1.70g，收率95.5％。
e)将0.23g(1.00mmol)6-氯-4-氧代-3H,4H-喹唑啉-2-羧酸(I-5)溶于5mL三氯甲烷中，向溶液中加入0.87mL(12.0mmol)氯化亚砜和一滴N,N-二甲基甲酰胺，升温至回流反应0.5h，TLC监测反应完全。降至室温，减压蒸除溶剂，得中间体(I-6),立即进行下一步反应。
f)将中间体(I-6)溶于5mL干燥的二氯甲烷中，-35摄氏度搅拌下，向溶液中依次缓慢滴加0.42mL(3.00mmol)三乙胺和0.087mL(1.00mmol)吗啉，继续反应0.5h，TLC监测反应完全。加水淬灭，加入30mL二氯甲烷，水(10mL×3)洗，饱和食盐水(10mL×3)洗，无水硫酸钠干燥，蒸除溶剂，经硅胶色谱柱纯化(二氯甲烷：甲醇＝50:1)，得黄色粉末状固体0.27g，收率86.5％。
g)将0.15g(0.49mmol)4,6-二氯-2-(4-吗啉基)甲酰基喹唑啉(I-7)、47.5mg(0.49mmol)5-甲基-3-氨基-1H-吡唑(如前述制得)、0.096mL(0.59mmol)N,N-二异丙基乙胺和4mL 1,4-二氧六环投入封管中，升温至130摄氏度反应24h，析出浅黄色固体，TLC监测反应完全。抽滤，滤 饼干燥至恒重，30倍甲醇热打浆，得类白色粉末状固体0.09g，收率49.4％。mp 326.9～327.4摄氏度。ESI-MS m/z:373.1[M+H]+。 1H-NMR(400MHz,DMSO-d6)δ:12.29(s,1H),10.71(s,1H),8.89(d,J＝1.88Hz,1H),7.88(dd,J＝2.04,8.92Hz,1H),7.80(d,J＝8.92Hz,1H),6.58(s,1H),3.68-3.66(m,4H),3.54-3.52(m,2H),3.31-3.28(m,2H),2.28(s,3H)。
实施例12：6-氯-2-[4-甲基哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
Figure PCTCN2017117710-appb-000044
按照实施例11的方法，将步骤f)中吗啉替换为4-甲基哌嗪，经步骤a-g得到实施例12。ESI-MSm/z:434.5[M+H]+。
实施例13：6-氯-2-[哌啶基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
Figure PCTCN2017117710-appb-000045
按照实施例11的方法，将步骤f)中吗啉替换为哌啶，经步骤a-g得到实施例13。ESI-MS m/z:371.6[M+H]+。
实施例14：6-氯-2-[1,1-二氧代硫代吗啉基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
Figure PCTCN2017117710-appb-000046
按照实施例11的方法，将步骤f)中吗啉替换为1,1-二氧代硫代吗啉，经步骤a-g得到实施例14。ESI-MS m/z:412.7[M+H]+。
实施例15：6-氯-2-[3-氧代哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
Figure PCTCN2017117710-appb-000047
按照实施例11的方法，将步骤f)中吗啉替换为哌嗪2-酮，经步骤a-g得到实施例15。ESI-MSm/z:386.5[M+H]+。
实施例16：6-氯-2-[4-羟基哌啶基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
Figure PCTCN2017117710-appb-000048
按照实施例11的方法，将步骤f)中吗啉替换为4-羟基哌啶，经步骤a-g得到实施例16。ESI-MSm/z:387.5[M+H]+。
实施例17：6-氯-2-[4-羟基-4-甲基哌啶基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
Figure PCTCN2017117710-appb-000049
按照实施例11的方法，将步骤f)中吗啉替换为4-羟基-4-甲基哌啶，经步骤a-g得到实施例17。ESI-MS m/z:401.5[M+H]+。
实施例18：6-氯-2-[4-氨基哌啶基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000050
按照实施例1的方法，将步骤h)中N-Boc-哌嗪替换为4-N-Boc-氨基哌啶，经步骤a-g得到实施例18。ESI-MS m/z:386.5[M+H]+。
实施例19：6-氯-2-[4-羟基-4-甲基哌啶基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000051
按照实施例1的方法，将步骤h)中N-Boc-哌嗪替换为4-N-Boc-氨基4-甲基哌啶，经步骤a-j得到实施例19。ESI-MS m/z:400.5[M+H]+。
实施例20：6-氯-2-[2,6-二氮杂螺[3.3]庚烷-2-基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000052
按照实施例1的方法，将步骤i)中N-Boc-哌嗪替换为3-N-Boc-氨基单杂环丁烷，经步骤a-j得到实施例20。ESI-MS m/z:358.5[M+H]+。
实施例21：6-氯-2-[3-氨基单杂环丁基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000053
按照实施例1的方法，将步骤i)中N-Boc-哌嗪替换为2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯，经步骤a-j得到实施例21。ESI-MS m/z:384.5[M+H]+。
施例22：6-氯-2-[(1R,4R)2,5-二氮双环(2.2.1)庚烷-2-基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000054
按照实施例1的方法，将步骤h)中N-Boc-哌嗪替换为(1R,4R)-2-叔丁氧羰基-2,5-二氮双环(2.2.1)庚烷，经步骤a-j得到实施例22。ESI-MS m/z:384.5[M+H]+。
实施例23：6-氯-2-[(六氢吡咯并[3,4-c]吡咯-2-基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000055
按照实施例1的方法，将步骤h)中N-Boc-哌嗪替换为六氢吡咯并[3,4-c]吡咯-2-羧酸叔丁酯，经步骤a-j得到实施例24。ESI-MS m/z:400.5[M+H]+。
实施例24：6-氯-2-[4-氨基哌啶基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000056
按照实施例1的方法，将步骤h)中N-Boc-哌嗪替换为4-N-Boc-氨基4-甲基哌啶，经步骤a-j得到实施例24。ESI-MS m/z:400.5[M+H]+。
实施例25(S)-6-氯-2-[2-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000057
按照实施例1的方法，将步骤h)中N-Boc-哌嗪替换为(S)-2-甲基-N-Boc-哌嗪，经步骤a-j得到
实施例25。ESI-MS m/z:386.6[M+H]+。
实施例26：(R)-6-氯-2-[2-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000058
按照实施例1的方法，将步骤h)中N-Boc-哌嗪替换为(R)-2-甲基-N-Boc-哌嗪，经步骤a-j得到
实施例26。ESI-MS m/z:386.5[M+H]+。
实施例27：(R)-6-氯-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000059
按照实施例1的方法，将步骤h)中N-Boc-哌嗪替换为(R)-3-甲基-N-Boc-哌嗪，经步骤a-j得到
实施例27。ESI-MS m/z:386.6[M+H]+。
实施例28：(S)-6-氯-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000060
按照实施例1的方法，将步骤h)中N-Boc-哌嗪替换为(S)-3-甲基-N-Boc-哌嗪，经步骤a-j得到
实施例28。ESI-MS m/z:386.4[M+H]+。
实施例29：6-氯-2-[3,5-二甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000061
按照实施例1的方法，将步骤h)中N-Boc-哌嗪替换为3,5-二甲基-N-Boc-哌嗪，经步骤a-j得到
实施例29。ESI-MS m/z:400.5[M+H]+。
实施例30：6-氯-2-[3,3’-二甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000062
按照实施例1的方法，将步骤h)中N-Boc-哌嗪替换为3,3’-二甲基-N-Boc-哌嗪，经步骤a-j得到实施例30。ESI-MS m/z:400.5[M+H]+。
实施例31：6-氯-2-[3,3’-二甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000063
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤h)中N-Boc-哌嗪替换为3,3’-二甲基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例31。ESI-MS m/z:426.5[M+H]+。
实施例32：(S)-6-氯-2-[2-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000064
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤h)中N-Boc-哌嗪替换为(S)-2-甲基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例32。ESI-MS m/z:412.6[M+H]+。
实施例33：(R)-6-氯-2-[2-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000065
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤h)中N-Boc-哌嗪替换为(R)-2-甲基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例33。ESI-MS m/z:412.5[M+H]+。
实施例34：(R)-6-氯-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000066
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤h)中N-Boc-哌嗪替换为(R)-3-甲基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例34。ESI-MS m/z:412.6[M+H]+。
实施例35：(S)-6-氯-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000067
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤h)中N-Boc- 哌嗪替换为(S)-3-甲基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例35。ESI-MS m/z:412.4[M+H]+。
实施例36：6-氯-2-[3,5-二甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000068
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤h)中N-Boc-哌嗪替换为3,5-二甲基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例36。ESI-MS m/z:426.5[M+H]+。
实施例37：(R)-6-氯-2-[3-乙基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000069
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤h)中N-Boc-哌嗪替换为(R)-3-乙基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例37。ESI-MS m/z:426.6[M+H]+。
实施例38：(R)-6-氯-2-[3-异丙基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000070
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤h)中N-Boc-哌嗪替换为(R)-3-异丙基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例38。ESI-MS m/z:440.6[M+H]+。
实施例39：(R)-6-氯-2-[3-异丙基-1-哌嗪基]甲酰基-4-[1H-3-(5-苯基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000071
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤h)中N-Boc-哌嗪替换为(R)-3-苯基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例39。ESI-MS m/z:474.5[M+H]+。
实施例40：6-氯-2-[1-哌嗪基]硫代甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
Figure PCTCN2017117710-appb-000072
合成路线为：
Figure PCTCN2017117710-appb-000073
试剂与条件：a)劳森试剂，甲苯，回流。
a)将124mg(0.33mmol)6-氯-2-[1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉加 入溶于5mL干燥甲苯中，搅拌下加入404mg(1.00mmol)劳森试剂，升温至回流反应12h，TLC监测反应。降至室温，减压蒸除溶剂，硅胶柱层析得白色粉末状固体32mg，收率24.9％。ESI-MS m/z:388.5[M+H]+。
实施例41：6-氯-2-[1-哌嗪基]硫代甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉
Figure PCTCN2017117710-appb-000074
按照实施例43的方法，将步骤g)中6-氯-2-[1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉替换为6-氯-2-[1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉，经步骤a得到实施例41。ESI-MS m/z:414.5[M+H]+。
实施例42：(R)-6-氯-2-[3-甲基-1-哌嗪基]硫代甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
Figure PCTCN2017117710-appb-000075
按照实施例43的方法，将步骤g)中6-氯-2-[1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉替换为(R)-6-氯-2-[3-甲基基-1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉，经步骤a得到实施例42。ESI-MS m/z:402.5[M+H]+。
实施例43：(R)-6-氯-2-[3-甲基-1-哌嗪基]硫代甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉
Figure PCTCN2017117710-appb-000076
按照实施例43的方法，将步骤g)中6-氯-2-[1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉替换为(R)-6-氯-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉，经步骤a得到实施例43。ESI-MS m/z:428.5[M+H]+。
实施例44：(R)-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000077
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤c)中原料2-氨基5-氯苯甲酸替换为2-氨基苯甲酸，将步骤h)中N-Boc-哌嗪替换为(R)-3-甲基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例44。ESI-MS m/z:378.2[M+H]+。
实施例45：(R)-6-氟-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000078
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤c)中原料2-氨基5-氯苯甲酸替换为2-氨基5-氟苯甲酸，将步骤h)中N-Boc-哌嗪替换为(R)-3-甲基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例45。ESI-MS m/z:396.2[M+H]+。
实施例46：(R)-6-溴-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000079
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤c)中原料2-氨基5-氯苯甲酸替换为2-氨基5-溴苯甲酸，将步骤h)中N-Boc-哌嗪替换为(R)-3-甲基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例46。ESI-MS m/z:456.2[M+H]+。
实施例47：(R)-6-甲基-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000080
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤c)中原料2-氨基5-氯苯甲酸替换为2-氨基5-甲基苯甲酸，将步骤h)中N-Boc-哌嗪替换为(R)-3-甲基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例47。ESI-MS m/z:392.2[M+H]+。
实施例48：(R)-6-甲氧基-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000081
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤c)中原料2-氨基5-氯苯甲酸替换为2-氨基5-甲氧基苯甲酸，将步骤h)中N-Boc-哌嗪替换为(R)-3-甲基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例48。ESI-MS m/z:408.3[M+H]+。
实施例49：(R)-7-氯-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000082
按照实施例1的方法，将步骤a)中原料乙酸乙酯替换为环丙甲酸乙酯，将步骤c)中原料2-氨基5-氯苯甲酸替换为2-氨基6-氯苯甲酸，将步骤h)中N-Boc-哌嗪替换为(R)-3-甲基-N-Boc-哌嗪，将步骤i)中5-甲基-3-氨基-1H-吡唑替换为5-环丙基-3-氨基-1H-吡唑，经步骤a-j得到实施例49。ESI-MS m/z:412.5[M+H]+。
实施例50：6-氯-2-[1-哌嗪基]甲酰基-4-[1-甲基-1H-咪唑4-基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000083
合成路线如下：
Figure PCTCN2017117710-appb-000084
试剂与条件：a)碘甲烷，乙腈，碳酸钾，65摄氏度；b)1).氢气，钯碳，室温搅拌2).氯化氢-乙醇溶液，乙醇，0摄氏度；c)1).三光气，四氢呋喃，65摄氏度；2).1N氨水，65摄氏度；d)四氢呋喃，草酰氯单乙酯，0摄氏度至室温；e)乙醇钠，乙醇，0摄氏度至室温；f)氢氧化钠，乙醇，水，室温；g)氯仿，氯化亚砜，回流；h)二氯甲烷，三乙胺，N-Boc-哌嗪，零下35摄氏度；i)5-甲基3-氨基吡唑，DMF，65摄氏度；j)2N氯化氢-乙酸乙酯溶液室温。
a)将4-硝基咪唑(I-1)11.3g(0.10mol)与25ml DMF混合均匀，加入碳酸钾20.7(0.15mol)，室温搅拌下向溶液中缓慢滴加7.5mL碘甲烷(0.12mol)，维持反应温度65℃反应24小时后，加入二乙胺5ml，室温搅拌半小时，蒸除溶剂，加入100ml水，50ml乙酸乙酯提取5次，合并有机相，干燥，减压浓缩后，柱层析分离得到类白色固体9.2g，收率72.4％。ESI-MS(m/z)：128[M+H] +.
b)将1-甲基-1H-4-4-硝基咪唑(I-2)6.4g(0.05mol)溶于50ml无水乙醇中，加入10％钯碳1.0g，氢气氛室温搅拌下反应6小时，滤除钯碳，蒸除溶剂，加入50ml氯化氢-乙醇溶液，冰浴搅拌，析出固体，过滤得类白色固体5.2g，收率63.5％。ESI-MS(m/z)：98[M+H] +.
c)将2.00g(11.6mmol)2-氨基-5-氯苯甲酸(I-4)溶于20mL干燥四氢呋喃中，搅拌下加入1.20g(3.90mmol)三光气，升温至60摄氏度反应12h，TLC监测反应完全。降至室温，减压蒸除溶剂，加入1N氨水，升温至60C反应1h，析出白色固体，TLC监测反应完全。降至室温，抽滤，水(10mL×3)洗，滤饼干燥至恒重，得白色粉末状固体1.68g，收率84.9％。 1H-NMR(400MHz,DMSO-d6)δ:7.85(s,1H),7.60(d,J＝2.44Hz,1H),7.18-7.16(m,2H),6.72(d,J＝8.80Hz,1H),6.40(br,2H)。
d)将1.68g(9.85mmol)2-氨基-5-氯苯甲酰胺(I-5)和1.63Ml(11.8mmol)三乙胺溶于34mL干燥四氢呋喃中，0摄氏度搅拌下向反应液中滴加1.15mL(10.8mmol)草酰氯单乙酯，滴加完毕，升至室温反应1h，TLC监测反应完全。减压蒸除溶剂，加入40mL乙酸乙酯溶解，水(10mL×3)洗，饱和食盐水(10mL×3)洗，无水硫酸钠干燥，减压蒸除溶剂，经硅胶色谱柱纯化(二氯甲烷：丙酮＝50:1)，得类白色粉末状固体2.50g，收率93.9％。 1H-NMR(400MHz,DMSO-d6)δ:13.02(s,1H),8.56(d,J＝8.96Hz,1H),8.47(s,1H),7.99(s,1H),7.97(d,J＝2.44Hz,1H),7.66(dd,J＝2.44,8.92Hz,1H),4.30(q,J＝7.12Hz,2H),1.31(t,J＝7.12Hz,3H)。
e)将2.50g(9.24mmol)2-(2-甲酰胺基-4-氯-苯基)氨基乙二酸乙酯(I-6)溶于28mL乙醇中，0摄氏度搅拌下向溶液中缓慢滴加7.60mL(11.1mmol)10％乙醇钠乙醇溶液，继续反应3h，TLC监测反应完全。用1N盐酸调节pH＝3-4，析出白色固体，抽滤，水(10mL×3)洗，滤饼干燥至恒重，经硅胶色谱柱纯化(二氯甲烷：丙酮＝100:1)，得白色粉末状固体2.00g，收率85.8％。 1H-NMR(400MHz,DMSO-d 6)δ:12.83(s,1H),8.10(d,J＝2.36Hz,1H),7.92(dd,J＝2.46,8.68Hz, 1H),7.85(d,J＝8.68Hz,1H),4.39(q,J＝7.12Hz,2H),1.35(t,J＝7.12Hz,3H)。
f)将2.00g(7.92mmol)6-氯-4-氧代-3H,4H-喹唑啉-2-羧酸乙酯(I-7)溶于25mL乙醇中，室温搅拌下向溶液中加入25.5mL(63.4mmol)10％氢氧化钠水溶液，继续反应0.5h，TLC监测反应完全。用2N盐酸调节pH＝3，析出白色固体，抽滤，水(10mL×3)洗，滤饼干燥至恒重，得类白色粉末状固体1.70g，收率95.5％。
g)将0.23g(1.00mmol)6-氯-4-氧代-3H,4H-喹唑啉-2-羧酸(I-8)溶于5mL三氯甲烷中，向溶液中加入0.87mL(12.0mmol)氯化亚砜和一滴N,N-二甲基甲酰胺，升温至回流反应0.5h，TLC监测反应完全。降至室温，减压蒸除溶剂，得中间体(I-6),立即进行下一步反应。
h)将中间体(I-9)溶于5mL干燥的二氯甲烷中，-35摄氏度搅拌下，向溶液中依次缓慢滴加0.42mL(3.00mmol)三乙胺和185mg(1.00mmol)N-Boc-哌嗪，继续反应0.5h，TLC监测反应完全。加水淬灭，加入30mL二氯甲烷，水(10mL×3)洗，饱和食盐水(10mL×3)洗，无水硫酸钠干燥，蒸除溶剂，经硅胶色谱柱纯化(二氯甲烷：甲醇＝50:1)，得黄色粉末状固体0.40g，收率48.7％。 1H-NMR(400MHz,CDCl 3)δ:8.30(d,J＝2.12Hz,1H),8.07(d,J＝8.96Hz,1H),7.96(dd,J＝2.24,8.96Hz,1H),3.85-3.82(m,2H),3.61-3.58(m,2H),3.52-3.49(m,2H),3.43-3.41(m,2H),1.48(s,9H)。
i)将0.20g(0.49mmol)4,6-二氯-2-[1-(4-N-叔丁氧羰基)哌嗪基]甲酰基喹唑啉(I-10)、65.0mg(0.49mmol)1-甲基-1H-咪唑-4-胺盐酸盐(I-3)和0.18mL(1.08mmol)N,N-二异丙基乙胺溶于4mLDMF中，升温至65摄氏度反应12h。降至室温，倾入水中，抽滤，滤饼经硅胶色谱柱纯化(二氯甲烷：甲醇＝20:1，0.5％三乙胺)、得白色粉末状固体0.023g，收率10.3％。
j)将上述固体(I-11)溶于2mL盐酸/乙酸乙酯中，室温搅拌下反应6h，析出黄色固体，抽滤，滤饼干燥至恒重，得黄色粉末状固体0.017g，收率95.0％。ESI-MS m/z:372.1[M+H]+。
实施例51：6-氯-2-[1-哌嗪基]甲酰基-4-[1-环丙基-1H-咪唑4-基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000085
合成路线如下：
Figure PCTCN2017117710-appb-000086
试剂与条件：a)硝酸，醋酸酐，醋酸，0摄氏度至室温；b)水，甲醇，环丙胺，室温；c)1).氢气，钯碳，室温搅拌2).氯化氢-乙醇溶液，乙醇，0摄氏度；d)1.三光气，四氢呋喃，65摄氏度；2.1N氨水，65摄氏度；e)四氢呋喃，草酰氯单乙酯，0摄氏度至室温；f)乙醇钠，乙醇，0摄氏度至室温；j)氢氧化钠，乙醇，水，室温；h)氯仿，氯化亚砜，回流；i)二氯甲烷，三乙胺，吗啉，零下35摄氏度；j)1-环丙基-1H-咪唑4-胺盐酸盐，DMF，65摄氏度；k)2N氯化氢-乙酸乙酯溶液，室温。
a)将4-硝基咪唑(I-1)11.3g(0.10mol)分散于醋酸200ml，冰浴搅拌下向溶液中依次缓慢滴加50mL硝酸和139ml醋酸酐，滴毕维持反应温度25℃反应1小时后，倾入1.5L冰水中，100ml乙酸乙酯提取5次，合并有机相，碳酸氢钠溶液洗涤，干燥，减压浓缩后，得到类白色固体。 1H NMR(400MHz,CDCl 3)8.54(d,J＝1.60Hz,1H),8.40(d,J＝1.56Hz,1H).
b)将1，4-二硝基咪唑(I-2)溶于200ml甲醇中，加入200ml水，滴加环丙胺8.6g(0.15mol)，滴毕维持反应温度25℃反应24小时后，蒸除溶剂，加入100ml水，50ml乙酸乙酯提取5次，合并有机相，干燥，减压浓缩后，柱层析分离得到类白色固体7.3g，收率47.4％。ESI-MS(m/z)：154[M+H] +. 1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.47(s,1H),3.45-3.40(m,1H),1.12-0.99(m,4H).
c)将1-环丙基4-硝基咪唑(I-3)4.6g(0.03mol)溶于50ml无水乙醇中，加入10％钯碳0.6g，氢气氛室温搅拌下反应6小时，滤除钯碳，蒸除溶剂，加入30ml氯化氢-乙醇溶液，冰浴搅拌，析出固体，过滤得类白色固体2.0g，收率53.8％。ESI-MS(m/z)：124[M+H] +.
d)将2.00g(11.6mmol)2-氨基-5-氯苯甲酸(I-5)溶于20mL干燥四氢呋喃中，搅拌下加入1.20g(3.90mmol)三光气，升温至60摄氏度反应12h，TLC监测反应完全。降至室温，减压蒸除溶剂，加入1N氨水，升温至60C反应1h，析出白色固体，TLC监测反应完全。降至室温，抽滤，水(10mL×3)洗，滤饼干燥至恒重，得白色粉末状固体1.68g，收率84.9％。 1H-NMR(400MHz,DMSO-d 6)δ:7.85(s,1H),7.60(d,J＝2.44Hz,1H),7.18-7.16(m,2H),6.72(d,J＝8.80Hz,1H),6.40(br,2H)。
e)将1.68g(9.85mmol)2-氨基-5-氯苯甲酰胺(I-6)和1.63Ml(11.8mmol)三乙胺溶于34mL干燥四氢呋喃中，0摄氏度搅拌下向反应液中滴加1.15mL(10.8mmol)草酰氯单乙酯，滴加完毕，升至室温反应1h，TLC监测反应完全。减压蒸除溶剂，加入40mL乙酸乙酯溶解，水(10mL×3)洗，饱和食盐水(10mL×3)洗，无水硫酸钠干燥，减压蒸除溶剂，经硅胶色谱柱纯化(二氯甲烷：丙酮＝50:1)，得类白色粉末状固体2.50g，收率93.9％。 1H-NMR(400MHz,DMSO-d 6)δ:13.02(s,1H),8.56(d,J＝8.96Hz,1H),8.47(s,1H),7.99(s,1H),7.97(d,J＝2.44Hz,1H),7.66(dd,J＝2.44,8.92Hz,1H),4.30(q,J＝7.12Hz,2H),1.31(t,J＝7.12Hz,3H)。
f)将2.50g(9.24mmol)2-(2-甲酰胺基-4-氯-苯基)氨基乙二酸乙酯(I-7)溶于28mL乙醇中，0摄氏度搅拌下向溶液中缓慢滴加7.60mL(11.1mmol)10％乙醇钠乙醇溶液，继续反应3h，TLC监测反应完全。用1N盐酸调节pH＝3-4，析出白色固体，抽滤，水(10mL×3)洗，滤饼干燥至恒重，经硅胶色谱柱纯化(二氯甲烷：丙酮＝100:1)，得白色粉末状固体2.00g，收率85.8％。 1H-NMR(400MHz,DMSO-d 6)δ:12.83(s,1H),8.10(d,J＝2.36Hz,1H),7.92(dd,J＝2.46,8.68Hz,1H),7.85(d,J＝8.68Hz,1H),4.39(q,J＝7.12Hz,2H),1.35(t,J＝7.12Hz,3H)。
g)将2.00g(7.92mmol)6-氯-4-氧代-3H,4H-喹唑啉-2-羧酸乙酯(I-8)溶于25mL乙醇中，室温搅拌下向溶液中加入25.5mL(63.4mmol)10％氢氧化钠水溶液，继续反应0.5h，TLC监测反应完全。用2N盐酸调节pH＝3，析出白色固体，抽滤，水(10mL×3)洗，滤饼干燥至恒重，得类白色粉末状固体1.70g，收率95.5％。
h)将0.23g(1.00mmol)6-氯-4-氧代-3H,4H-喹唑啉-2-羧酸(I-9)溶于5mL三氯甲烷中，向溶液中加入0.87mL(12.0mmol)氯化亚砜和一滴N,N-二甲基甲酰胺，升温至回流反应0.5h，TLC监测反应完全。降至室温，减压蒸除溶剂，得中间体(I-6),立即进行下一步反应。
i)将中间体(I-10)溶于5mL干燥的二氯甲烷中，-35摄氏度搅拌下，向溶液中依次缓慢滴加0.42mL(3.00mmol)三乙胺和185mg(1.00mmol)N-Boc-哌嗪，继续反应0.5h，TLC监测反 应完全。加水淬灭，加入30mL二氯甲烷，水(10mL×3)洗，饱和食盐水(10mL×3)洗，无水硫酸钠干燥，蒸除溶剂，经硅胶色谱柱纯化(二氯甲烷：甲醇＝50:1)，得黄色粉末状固体0.40g，收率48.7％。 1H-NMR(400MHz,CDCl 3)δ:8.30(d,J＝2.12Hz,1H),8.07(d,J＝8.96Hz,1H),7.96(dd,J＝2.24,8.96Hz,1H),3.85-3.82(m,2H),3.61-3.58(m,2H),3.52-3.49(m,2H),3.43-3.41(m,2H),1.48(s,9H)。
j)将0.20g(0.49mmol)4,6-二氯-2-[1-(4-N-叔丁氧羰基)哌嗪基]甲酰基喹唑啉(I-11)、79mg(0.49mmol)1-环丙基-1H-咪唑-4-胺盐酸盐(I-4)和0.18mL(1.08mmol)N,N-二异丙基乙胺溶于4mL DMF中，升温至65摄氏度反应12h。降至室温，倾入水中，抽滤，滤饼经硅胶色谱柱纯化(二氯甲烷：甲醇＝20:1，0.5％三乙胺)、得白色粉末状固体0.018g，收率7.2％。
k)将上述固体(I-12)溶于2mL盐酸/乙酸乙酯中，室温搅拌下反应6h，析出黄色固体，抽滤，滤饼干燥至恒重，得黄色粉末状固体0.015g，收率98.0％。ESI-MS m/z:398.5[M+H]+。
实施例52：6-氯-2-[1-哌嗪基]甲酰基-4-[1-三氟乙基-1H-咪唑4-基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000087
按照实施例51的方法，将步骤b)中原料环丙胺替换为三氟乙胺，将步骤j)中1-环丙基-1H-咪唑-4-胺盐酸盐替换为1-三氟乙基-1H-咪唑-4-胺盐酸盐，经步骤a-k得到实施例52。ESI-MS m/z:440.5[M+H]+。
实施例53：6-氯-2-[1-哌嗪基]甲酰基-4-[1-环丙甲基-1H-咪唑4-基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000088
按照实施例50的方法，将步骤1)中原料碘甲烷替换为环丙甲基溴，溶剂换为DMF,将步骤i)中1-甲基-1H-咪唑-4-胺盐酸盐替换为1-环丙甲基-1H-咪唑-4-胺盐酸盐，经步骤a-j得到实施例53。ESI-MS m/z:440.5[M+H]+。
实施例54：6-氯-2-[1-哌嗪基]甲酰基-4-[1-异丙基-1H-咪唑4-基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000089
按照实施例50的方法，将步骤1)中原料碘甲烷替换为异丙基溴，溶剂换为DMF,将步骤i)中1-甲基-1H-咪唑-4-胺盐酸盐替换为1-异丙基-1H-咪唑-4-胺盐酸盐，经步骤a-j得到实施例54。ESI-MS m/z:400.5[M+H]+。
实施例55：6-氯-2-[1-哌嗪基]甲酰基-4-[1-异丙基-1H-咪唑4-基]胺基喹唑啉盐酸盐
Figure PCTCN2017117710-appb-000090
按照实施例51的方法，将步骤1)中原料环丙胺替换为3-氯苯胺,将步骤j)中1-甲基-1H-咪唑-4-胺盐酸盐替换为1-(3-氯苯基)-1H-咪唑-4-胺盐酸盐，经步骤a-k得到实施例57。ESI-MS m/z:468.5[M+H]+。
实施例56：本发明部分产物的体外酶抑制活性研究
实验材料：
Tecan
Figure PCTCN2017117710-appb-000091
F500酶标仪。
Figure PCTCN2017117710-appb-000092
KinEASE TM-STK试剂盒(包含生物素化的多肽底物S2，Eu3+标记的只针对特异性磷酸化位点的单抗，Sa-XL665标记的链霉亲和素，KinEASE酶反应缓冲液)，384浅孔板，PAK4全长蛋白。PAK4蛋白浓度0.0256ng/μl，MgCl 2，乙二胺四乙酸(EDTA)，二硫苏糖醇(DL-Dithiothreitol，DTT)，DMSO。
实验方法：
第一步：激酶反应。首先将化合物样品用DMSO配成20mM的溶液，之后根据测试需要，再用激酶反应缓冲溶液稀释成100μM、10μM、1μM等浓度。然后将PAK4激酶(浓度为0.0256ng/μl)、ATP(4μM)、生物素标记的多肽底物S2(1μM)和化合物样品(4μl)在)和)加入到10μl激酶反应缓冲溶液(含有MgCl 2 5mM和DTT 1mM)中，在室温下孵育40分钟，激酶将底物S2磷酸化。之后加入10μl的含有EDTA的检测试剂，来检测磷酸化产物。
第二步：检测磷酸化产物。稀土元素铕(Eu 3+)标记的抗体识别磷酸化底物，XL665标记的链霉亲和素与底物上的生物素结合。Eu 3+是荧光供体，XL665是荧光受体，当Eu 3+与XL665接近，Eu 3+能量转移给XL665，产生HTRF信号。
结果评定方法：荧光信号是由Eu 3+的620nm和XL665的665nm荧光吸收信号产生的。所以每一个孔板反应的HTRF信号(665/620)比值被计算。
Figure PCTCN2017117710-appb-000093
表2部分实施例化合物在1μM、0.1μM浓度下体外PAK4抑制活性百分比
化合物 1μM 0.1μM 化合物 1μM 0.1μM
实施例1 98％ 89％ 实施例29 84％ 52％
实施例8 100％ 99％ 实施例32 99％ 79％
实施例11 69％ 26％ 实施例33 99％ 92％
实施例12 46％ 25％ 实施例34 100％ 95％
实施例16 17％ 0％ 实施例35 99％ 75％
实施例17 5％ 0％ 实施例36 97％ 62％
实施例18 78％ 36％ 实施例37 100％ 97％
实施例19 64％ 22％ 实施例44 99％ 92％
实施例24 62％ 24％ 实施例45 99％ 95％
实施例25 96％ 72％ 实施例46 100％ 96％
实施例26 98％ 86％ 实施例48 97％ 92％
实施例27 99％ 93％ 实施例49 100％ 95％
实施例28 97％ 59％      
如上表所示，本发明中通式(I)的化合物中部分化合物对PAK4激酶活性具有明显的抑制作 用。
实施例57：本发明部分产物针对PAK4/PAK1体外选择性测试
实验材料：EnVision多标记微孔板检测仪，PAK4全长蛋白和PAK1全长蛋白，多肽底物，缓冲溶液Hepes，MgCl2溶液，EGTA，EDTA，Brij-35，DTT等缓冲液成分等。
实验方法：Z′-LYTE TM激酶实验(Z′-LYTE TMKinase Assay)，按照试剂盒标准测试条件。该测试方法分为激酶反应步骤，转化反应步骤和检测步骤。
反应步骤具体操作如下：
1.根据enzyme titration和ATP Km实验结果确定Ki测定实验反应条件。其中PAK1 Km＝180000nM，PAK4Km＝3000nM。
2.化合物溶液配制：将化合物DMSO溶液从10mM稀释至1mM。使用安捷伦自动移液工作站(Bravo)将溶液依次稀释三倍，共11个浓度。
3.酶反应：PAK1(激酶域)和PAK4(激酶域)蛋白、氧杂茶邻酮(荧光供体)和荧光素(荧光受体)标记的多肽底物(Ser/thr19,Ser/thr20)，ATP(Km)和测试化合物在激酶22℃反应液中孵育。该10μL反应液中含有50mM HEPES(pH7.5),0.01％Brij-35,10mM MgCl2,1mM EGTA,2μM FRET多肽底物,和PAK酶(20pM PAK1 KD；80pM PAK4KD).
4.60分钟后加入5μL of Z’-LYTE TM激酶反应转化试剂(Development Reagent)终止反应，进行非线性公式拟合曲线来计算Ki。实验结果如下：
表3部分实施例化合物对PAK4的Ki和对PAK1的Ki
Figure PCTCN2017117710-appb-000094
如上表所示，本发明中通式(I)的化合物中部分化合物对PAK4的抑制活性与PAK4/PAK1选择性明显优于典型PAK4抑制剂PF3758309及十字孢碱，具有显著的技术进步与优势。
实施例58：本发明部分产物的体外酶抑制活性研究
本发明中通式(I)的化合物可单独施用，但通常是和药用载体混合物给予，所述药用载体的选择要根据所需用药途径和标准药物实践，下面分别用该类化合物的各种药物剂型，例如片剂、胶囊剂、注射剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂和软膏剂的制备方法，说明其在制药领域中的新应用。
实施例59：片剂
用含有权利要求1中的化合物(以实施例34化合物为例)10g，按照药剂学一般压片法加辅料20g混匀后，压制成100片，每片重300mg。
实施例60：胶囊剂
用含有权利要求1中的化合物(以实施例34化合物为例)10g，按照药剂学胶囊剂的要求将辅料20g混匀后，装入空心胶囊，每个胶囊重300mg。
实施例61：注射剂
用含有权利要求1中的化合物(以实施例34化合物为例)10g，按照药剂学常规方法，进行活性炭吸附，经0.65μm微孔滤膜过滤后，填入氮气罐制成水针制剂，每只装2mL，共灌装100瓶。
实施例62：气雾剂
用含有权利要求1中的化合物(以实施例34化合物为例)10g，用适量丙二醇溶解后，加入蒸馏水及其他辐料后，制成500mL的澄清溶液即得。
实施例63：栓剂
用含有权利要求1中化合物的化合物(以实施例34化合物为例)10g，将之研细加入甘油适量，研匀后加入已熔化的甘油明胶，研磨均匀，倾入已涂润滑剂的模型中，制得栓剂50颗。
实施例64：膜剂
用含有权利要求1中的化合物(以实施例34化合物为例)10g，将聚乙烯醇、药用甘油、水等搅拌膨胀后加热溶解，80目筛网过滤，再将实施例18化合物加入到滤液中搅拌溶解，涂膜机制膜100片。
实施例65：滴丸剂
用含有权利要求1中的化合物(以实施例34化合物为例)10g，与明胶等基质50g加热熔化混匀后，滴入低温液体石蜡中，共制得滴丸1000丸。
实施例66：外用搽剂
用含有权利要求1中的化合物(以实施例34化合物为例)10g，按照常规药剂学方法与乳化剂等辅料2.5g混合研磨，再加蒸馏水至200mL制得。
实施例67：软膏剂
用含有权利要求1中的化合物(以实施例34化合物为例)10g，研细后与凡士林等油性基质500g研匀制得。
尽管已经通过特定实施方案描述了本发明，但修改和等价变化对于精通此领域的技术人员而言是显见的，且它们都包含在本发明范围。

Claims (10)

  1. 一种通式(I)所示的酰胺/硫代酰胺类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药；
    Figure PCTCN2017117710-appb-100001
    其中，A环部分选自
    Figure PCTCN2017117710-appb-100002
    R 1选自氢、C 1-C 6烷基、被卤素取代的C 1-C 6烷基、C 3-C 6环烷基、被卤素取代的C 3-C 6环烷基、C 1-C 4烷氧基、六元芳基、苄基，其中所述芳基、苄基可进一步被1-6个R x取代；
    B环选自5-6元芳香环、5-6元芳香杂环、5-7元饱和脂肪环、5-7元不饱和脂肪环，B环可进一步被1-4个R 2所取代；
    R 2选自氢、卤素，C 1-C 6烷基，C 1-C 6烷氧基，羟基，卤代的C 1-C 6烷基；
    通式(I)中
    Figure PCTCN2017117710-appb-100003
    部分的Z选自O或S；
    C环为4-7元杂环基、5-7元不饱和杂环基、4-7元双环杂环基，上述环至少含1个氮原子，且该氮原子与酰基或硫代酰基部分
    Figure PCTCN2017117710-appb-100004
    形成酰胺键，该环还包括另外0-2个N,O,或S的杂原子，且该环可进一步被1-4个Rx取代，R x取代后形成的手性碳原子为R构型、S构型或者消旋形式；
    R x为-H、羟基、卤素、硝基、氨基、氰基、(C 1-C 6)烷基、(C 2-C 6)烯基、(C 2-C 6)炔基、(C 1-C 6)烷氧基、任选被羟基、氨基或卤代的(C 1-C 6)烷基或(C 1-C 6)烷氧基、被单或二(C 1-C 6烷基)取代的氨基、(C 1-C 6)烷基酰氨基、游离的、成盐的、酯化的和酰胺化的羧基、(C 1-C 6)烷基亚磺酰基、(C 1-C 6)烷基磺酰基、(C 1-C 6)烷氧基、(C 1-C 6)烷基、(C 1-C 6)烷基酰基、氨基甲酰基、被单或二(C 1-C 6烷基)取代的氨基甲酰基、(C 1-C 3)亚烷基二氧基。
  2. 权利要求1的通式(I)所示的酰胺/硫代酰胺类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
    其中，B环选自5-6元芳香环、5-6元芳香杂环，B环可进一步被1-4个R 2所取代；
    R 2选自氢，卤素，C 1-C 4烷基，C 1-C 4烷氧基，羟基，卤素取代的C 1-C 4烷基，优选为氢、氟，氯，溴，碘，甲基，乙基，甲氧基，乙氧基，羟基，三氟甲基。
  3. 权利要求1或2的通式(I)所示的酰胺/硫代酰胺类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其中
    其中，A环部分选自
    Figure PCTCN2017117710-appb-100005
    R 1选自氢、C 1-C 3烷基、被卤素取代的C 1-C 3烷基、C 3-C 5环烷基、被卤素取代的C 3-C 5环烷基、C 1-C 3烷氧基、苯基、苄基，其中所述苯基、苄基可进一步被1-6个R x取代。
  4. 权利要求1-3任何一项所述的通式(I)所示的酰胺/硫代酰胺类衍生物，及其几何异构体或 其药学上可接受的盐、水合物、溶剂化物或前药，
    其中，C环为6元杂环基，该环至少含1个氮原子，且该氮原子与酰基或硫代酰基部分
    Figure PCTCN2017117710-appb-100006
    形成酰胺键，该环还包括0-1个N,O或S的杂原子，该环可进一步被1-4个R x取代，R x取代后形成的手性碳原子为R构型、S构型或者消旋形式；
    R x为-H、羟基、卤素、硝基、氨基、氰基、(C 1-C 6)烷基、(C 2-C 6)烯基、(C 2-C 6)炔基、(C 1-C 6)烷氧基、任选被羟基、氨基或卤代的(C 1-C 6)烷基或(C 1-C 6)烷氧基、被单或二(C 1-C 6烷基)取代的氨基、(C 1-C 6)烷基酰氨基、游离的、成盐的、酯化的和酰胺化的羧基、(C 1-C 6)烷基亚磺酰基、(C 1-C 6)烷基磺酰基、(C 1-C 6)烷氧基、(C 1-C 6)烷基、(C 1-C 6)烷基酰基、氨基甲酰基、被单或二(C 1-C 6烷基)取代的氨基甲酰基、(C 1-C 3)亚烷基二氧基。
  5. 权利要求1-4中任何一项的通式(I)所示的酰胺/硫代酰胺类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其中
    其中，B环为苯环，所述苯环与相邻环组成的苯并嘧啶环进一步被1-4个R 2所取代，R 2选自氢、氟，氯，溴，碘，甲基，甲氧基，羟基，三氟甲基。
  6. 权利要求1-5中任何一项的通式(I)所示的酰胺/硫代酰胺类衍生物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药,其中
    C环为哌嗪环
    Figure PCTCN2017117710-appb-100007
    且环与酰基或硫代酰基部分
    Figure PCTCN2017117710-appb-100008
    形成酰胺键,该环可进一步被1-2个Rx取代，Rx选自氢,(C 1-C 6)烷基,卤代的(C 1-C 6)烷基,(C 3-C 6)环烷基,卤代的(C 3-C 6)环烷基，Rx取代后形成的手性碳原子为R构型、S构型或者消旋形式,所述的C环优选为：
    Figure PCTCN2017117710-appb-100009
  7. 如下的衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药：
    6-氯-2-[1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100010
    2-[1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100011
    2-[1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100012
    2-[1-哌嗪基]甲酰基-4-[1H-3-(5-异丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100013
    2-[1-哌嗪基]甲酰基-4-[1H-3-(5-环丁基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100014
    2-[1-哌嗪基]甲酰基-4-[1H-3-(5-苯基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100015
    2-[1-哌嗪基]甲酰基-4-[1H-3-(5-苄基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100016
    6-氯-2-[1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100017
    6-氯-2-[1-哌嗪基]甲酰基-4-[1H-3-(5-异丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100018
    6-氯-2-[1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100019
    6-氯-2-[4-吗啉基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
    Figure PCTCN2017117710-appb-100020
    6-氯-2-[4-甲基哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
    Figure PCTCN2017117710-appb-100021
    6-氯-2-[哌啶基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
    Figure PCTCN2017117710-appb-100022
    6-氯-2-[1,1-二氧代硫代吗啉基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
    Figure PCTCN2017117710-appb-100023
    6-氯-2-[3-氧代哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
    Figure PCTCN2017117710-appb-100024
    6-氯-2-[4-羟基哌啶基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
    Figure PCTCN2017117710-appb-100025
    6-氯-2-[4-羟基-4-甲基哌啶基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
    Figure PCTCN2017117710-appb-100026
    6-氯-2-[4-氨基哌啶基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100027
    6-氯-2-[4-羟基-4-甲基哌啶基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100028
    6-氯-2-[2,6-二氮杂螺[3.3]庚烷-2-基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100029
    6-氯-2-[3-氨基单杂环丁基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100030
    6-氯-2-[(1R,4R)2,5-二氮双环(2.2.1)庚烷-2-基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100031
    6-氯-2-[(六氢吡咯并[3,4-c]吡咯-2-基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100032
    6-氯-2-[4-氨基哌啶基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100033
    (S)-6-氯-2-[2-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100034
    (R)-6-氯-2-[2-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100035
    (R)-6-氯-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100036
    (S)-6-氯-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100037
    6-氯-2-[3,5-二甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100038
    6-氯-2-[3,3’-二甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100039
    6-氯-2-[3,3’-二甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100040
    (S)-6-氯-2-[2-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100041
    (R)-6-氯-2-[2-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100042
    (R)-6-氯-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100043
    (S)-6-氯-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100044
    6-氯-2-[3,5-二甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100045
    (R)-6-氯-2-[3-乙基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100046
    (R)-6-氯-2-[3-异丙基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100047
    (R)-6-氯-2-[3-异丙基-1-哌嗪基]甲酰基-4-[1H-3-(5-苯基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100048
    6-氯-2-[1-哌嗪基]硫代甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
    Figure PCTCN2017117710-appb-100049
    6-氯-2-[1-哌嗪基]硫代甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉
    Figure PCTCN2017117710-appb-100050
    (R)-6-氯-2-[3-甲基-1-哌嗪基]硫代甲酰基-4-[1H-3-(5-甲基)吡唑基]胺基喹唑啉
    Figure PCTCN2017117710-appb-100051
    (R)-6-氯-2-[3-甲基-1-哌嗪基]硫代甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉
    Figure PCTCN2017117710-appb-100052
    (R)-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100053
    (R)-6-氟-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100054
    (R)-6-溴-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100055
    (R)-6-甲基-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100056
    (R)-6-甲氧基-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100057
    (R)-7-氯-2-[3-甲基-1-哌嗪基]甲酰基-4-[1H-3-(5-环丙基)吡唑基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100058
    6-氯-2-[1-哌嗪基]甲酰基-4-[1-甲基-1H-咪唑4-基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100059
    6-氯-2-[1-哌嗪基]甲酰基-4-[1-环丙基-1H-咪唑4-基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100060
    6-氯-2-[1-哌嗪基]甲酰基-4-[1-三氟乙基-1H-咪唑4-基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100061
    6-氯-2-[1-哌嗪基]甲酰基-4-[1-环丙甲基-1H-咪唑4-基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100062
    6-氯-2-[1-哌嗪基]甲酰基-4-[1-异丙基-1H-咪唑4-基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100063
    6-氯-2-[1-哌嗪基]甲酰基-4-[1-异丙基-1H-咪唑4-基]胺基喹唑啉盐酸盐
    Figure PCTCN2017117710-appb-100064
  8. 一种药用组合物，包含权利要求1至7中任何一项的衍生物及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。
  9. 权利要求1-7任何一项所述的衍生物及其药学上可接受的盐、水合物、溶剂化物或前药或权利要求8所述的药用组合物在制备预防或治疗与PAK4激酶的表达或活性有关的疾病的药物中的应用。
  10. 权利要求1-7任何一项所述的衍生物及其药学上可接受的盐、水合物、溶剂化物或前药或权利要求8所述的药用组合物在制备预防或治疗抗肿瘤药物中的应用。
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