WO2019223704A1 - 一类并环吡唑啉酮甲酰胺类化合物及其制备方法、药物组合物和用途 - Google Patents
一类并环吡唑啉酮甲酰胺类化合物及其制备方法、药物组合物和用途 Download PDFInfo
- Publication number
- WO2019223704A1 WO2019223704A1 PCT/CN2019/087867 CN2019087867W WO2019223704A1 WO 2019223704 A1 WO2019223704 A1 WO 2019223704A1 CN 2019087867 W CN2019087867 W CN 2019087867W WO 2019223704 A1 WO2019223704 A1 WO 2019223704A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- group
- unsubstituted
- chloro
- nitrophenol
- Prior art date
Links
- SIDZXXQYQLBOHZ-UHFFFAOYSA-N COc(c(OC)cc1ncc2)cc1c2Oc(ccc(N)c1)c1F Chemical compound COc(c(OC)cc1ncc2)cc1c2Oc(ccc(N)c1)c1F SIDZXXQYQLBOHZ-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/495—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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to the fields of medicinal chemistry and medicinal therapy, in particular to a class of acylpyrazolone carboxamide compounds, a preparation method thereof, a pharmaceutical composition containing such compounds, and as an AXL inhibitor, especially for preparation for treatment Use of tumor medicine.
- RTK Receptor tyrosine kinase
- AXL receptor is a member of the receptor tyrosine kinase subfamily. It was first discovered in human chronic myeloid leukemia and forms a receptor with Tyro3 (Etk2 or Tif) and Mer (also known as Nyk, Eyk or Tyro12). Tyrosine kinase subfamily.
- AXL through binding to its ligand Gas6, leads to activation of the kinase superfamily, and plays an important regulatory role in regulating the body's inflammatory immune response, maintaining the homeostasis of the phagocytosis, and regulating the differentiation and maturation of NK cells.
- high expression of AXL has been found in a variety of solid tumors, including lung cancer, breast cancer, liver cancer, pancreatic cancer, and prostate cancer, which are closely related to tumor recurrence and poor prognosis.
- AXL abnormal expression activation antagonizes tumor cell apoptosis, promotes tumor cell invasion and metastasis, promotes tumor angiogenesis, and promotes the occurrence and development of tumors.
- AXL expression may mediate acquired resistance to EGFR.
- Clinical studies have shown that up to 20% of EGFR-resistant patients have high AXL expression; pre-clinical studies of the combination of AXL inhibitors Medication can effectively overcome EGFR inhibitor resistance.
- the abnormal activation of AXL overexpression is closely related to the resistance of other targeted inhibitors and chemotherapeutics, suggesting that AXL may have a wide range of applications for combination drugs.
- AXL is highly expressed in macrophages and dendritic cells in the tumor microenvironment, and can interact with tumor cells and other stromal cells to synergistically promote tumor progression. Therefore, in recent years, the development of targeted AXL inhibitors has become the forefront and hotspot of antitumor drug research.
- BGB324 developed by BergenBio is currently the only Axl kinase inhibitor with a high selectivity reported, but it is actually stronger against the same family members Mer and Tyro-3, and against ABL, InsR, EGFR, HER-2 and PDGFR ⁇ inhibition.
- the results of preclinical studies show that BGB324 has good pharmacological and toxicological properties. In two mouse models of metastatic breast cancer, it can prevent breast cancer metastasis and prolong survival. In tumor cells and tumor stromal cells, AXL Signals can regulate breast cancer metastasis at multiple levels, etc., and have now entered clinical II research.
- AXL AXL-specific kinase inhibitor
- Cabozantinib BMS777607
- Ningetinib a small molecule receptor tyrosine kinase inhibitor that target other targets.
- Selection of AXL It is not highly selective and belongs to a multi-target non-selective kinase inhibitor.
- the object of the present invention is to provide a class of small molecule inhibitors that selectively target AXL kinase.
- a benzocyclopyrazolinone carboxamide compound having a structure represented by the following general formula I, or a racemate, R-isomer, S-isomer, Pharmaceutically acceptable salts or mixtures thereof:
- n is an integer from 0 to 2, preferably 0 or 1;
- X, Y and Z are CH or N;
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or Unsubstituted C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, cyano, nitro, amino, hydroxyl, methylol, carboxyl, and -O [(CH 2 ) q O] r R 3 ; Wherein said substitution refers to the replacement of one or more hydrogen atoms on a group with a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, C 1- C 6 alkoxy, halogen-substituted C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloal
- R 3 is selected from hydrogen, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, and hydroxymethyl;
- q 1, 2, 3 or 4;
- r 0, 1, 2, 3, or 4;
- R 1 and its adjacent carbon atoms together form a group selected from the group consisting of a benzene ring and a 5-8 membered heteroaryl ring;
- R 2 and its adjacent carbon atoms together form a group selected from the group consisting of a benzene ring and a 5-8 membered heteroaryl ring;
- the ring is selected from the group consisting of a substituted or unsubstituted 7-20 membered polycyclic heterocyclic ring, a substituted or unsubstituted 7-20 membered polycyclic aromatic ring, a substituted or unsubstituted 7-20 membered polycyclic aromatic heterocycle, wherein
- s is selected from the group: 0, 1, 2, 3, or 4;
- Ar is selected from the group consisting of: substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted 5-12 membered heteroaryl;
- substitution refers to the replacement of one or more hydrogen atoms on a group with a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, halogen-substituted C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, cyano, nitro, amino, hydroxyl, Methylol and carboxyl.
- the halogen is F, Cl, Br or I.
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, cyano, hydroxyl, carboxyl; wherein said substitution refers to the replacement of one or more hydrogen atoms on the group with a substituent selected from the group consisting of: halogen, C 1 -C 6 alkyl, C 1- C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, cyano, amino, hydroxyl, hydroxymethyl, carboxyl; or two R 1 and its adjacent carbon atom together form a group selected from the group consisting of Group: benzene ring, 5-8 membered heteroaryl ring;
- each of R 1 and R 2 is independently 1 to 3 substituents selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl. , C 1 -C 6 alkoxy, cyano, hydroxyl; or two adjacent carbon atoms of R 1 and the atom to which they are attached may together form a group selected from the group consisting of a benzene ring, a 5- to 8-membered hetero Aromatic ring.
- each of R 1 is independently 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, methoxy, trifluoromethyl, or two R 1 The adjacent carbon atoms together form a benzene ring.
- each of R 2 is independently 1 to 3 fluorines.
- said The ring is selected from the group:
- the above group and the atom to which it is attached may together form a structure selected from the group consisting of a substituted or unsubstituted 6-20 membered heterocyclic ring, and the heterocyclic ring may optionally include 1, 2, 3,
- Ar is a substituted or unsubstituted C 6 -C 12 aryl group.
- the acylpyrazolone carboxamide compounds are compounds DC621001-DC621108 appearing in the examples.
- a method for preparing a compound according to the first aspect of the present invention comprising the steps of:
- a compound of formula 1-8 is reacted with a compound of formula 2-4 in an inert solvent to obtain a compound of formula I.
- the compound of formula 1-8 is prepared by the following method:
- a pharmaceutical composition comprising: a therapeutically effective amount of a compound of formula I according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, One or more of a racemate, R-isomer, S-isomer, or a mixture thereof, and optionally a pharmaceutically acceptable carrier, excipient, adjuvant, excipient, and / or dilution Agent.
- a kinase inhibitor comprising: an inhibitory effective amount of a compound of formula I according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, One or more of a gyro, R-isomer, S-isomer, or a mixture thereof, and optionally a pharmaceutically acceptable carrier, excipient, adjuvant, excipient, and / or diluent
- the kinase is selected from the group consisting of AXL, c-Met, or a combination thereof.
- a compound of formula I for one or more aspects selected from the group consisting of: (i) treating or preventing activity or expression with a kinase enzyme Quantity-related diseases; (ii) inhibiting the activity of a kinase, or reducing the expression level of a kinase; (iii) preparing a pharmaceutical composition for treating or preventing a disease related to a kinase activity; (iv) preparing a kinase inhibitor;
- the kinase is selected from the group consisting of AXL, c-Met, or a combination thereof.
- the disease is a tumor, preferably a tumor selected from the group consisting of lung cancer, gastric cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer, prostate cancer, and thyroid cancer. , Esophageal cancer, head and neck cancer, melanoma, glioma, acute myeloid leukemia, etc.
- Figure 1 shows the enzymatic selectivity of compound DC621044.
- the inventors After a long and intensive study, the inventors have designed and prepared a class of cyclic pyrazolinone carboxamide compounds with novel structure.
- the compounds can selectively inhibit kinases such as AXL, c-Met and the like. Based on the above findings, the inventors have completed the present invention.
- An object of the present invention is to provide a benzocyclopyrazolone formamide compound represented by the general formula I, a pharmaceutically acceptable salt thereof, a racemate, an R-isomer, an S-isomer, or Their mixture.
- Another object of the present invention is to provide a method for preparing a benzocyclopyrazolone formamide compound represented by the general formula I.
- Yet another object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of acylpyrazolone carboxamides represented by the above general formula I, a pharmaceutically acceptable salt thereof, and a racemic compound.
- a compound selected from the group consisting of acylpyrazolone carboxamides represented by the above general formula I a pharmaceutically acceptable salt thereof, and a racemic compound.
- Yet another object of the present invention is to provide an AXL inhibitor, which comprises a cyclopyrazolone formamide compound selected from the group consisting of the above-mentioned general formula I, a pharmaceutically acceptable salt thereof, a racemate, R- One or more of the isomers, S-isomers, or mixtures thereof.
- Another object of the present invention is to provide a benzocyclopyrazolone carboxamide compound represented by the above general formula I, a pharmaceutically acceptable salt thereof, a racemate, an R-isomer, an S-isomer or Their mixtures are used to treat malignancies.
- C 1 -C 6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, and includes, without limitation, methyl, ethyl, propyl, isopropyl , Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like; ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl are preferred.
- C 1 -C 6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, methoxy, ethoxy, and propoxy Group, isopropoxy and butoxy.
- C 2 -C 6 alkenyl refers to a straight or branched chain alkenyl group having 2 to 6 carbon atoms and containing one double bond, and includes, without limitation, vinyl, propenyl, butylene Alkenyl, isobutenyl, pentenyl, hexenyl and the like.
- C 2 -C 6 alkynyl refers to a straight or branched chain alkynyl group having a triple bond having 2 to 6 carbon atoms, and includes, without limitation, ethynyl, propynyl, Butynyl, isobutynyl, pentynyl, hexynyl and the like.
- C 3 -C 8 cycloalkyl refers to a cyclic alkyl group having 3 to 8 carbon atoms on the ring, and includes, without limitation, cyclopropyl, cyclobutyl, and cyclopentyl , Cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.
- Other "cycloalkyl” terms have similar meanings.
- C 6 -C 10 aryl group refers to an aromatic ring group having 6 to 10 carbon atoms, such as a phenyl group, a naphthyl group, and the like, which does not contain a hetero atom on the ring.
- C 6 -C 12 aryl has a similar meaning.
- the present invention provides a benzocyclopyrazolone carboxamide compound having the structure shown by the following general formula I, and a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or They mix:
- the compound of the general formula I of the present invention is preferably the following specific compound:
- the present invention provides a pharmaceutically acceptable salt of a compound of the general formula I, specifically a reaction of the compound of the general formula I with an inorganic or organic acid to form a conventional pharmaceutically acceptable salt.
- conventional pharmaceutically acceptable salts can be prepared by reacting a compound of the general formula I with an inorganic or organic acid including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, and phosphoric acid, and the like, and the Organic acids include citric acid, tartaric acid, lactic acid, pyruvate, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid Acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroace
- a method for preparing a compound represented by the general formula I is provided.
- the preparation method is performed according to the following scheme 1, scheme 2 or scheme 3.
- R 1 , R 2 , X, Y, Z and n are the same as the definitions in the general formula I above.
- Step a Dissolve 1-1 (1equiv) in an appropriate amount of DCM, add 10% Na 2 CO 3 aqueous solution (2equiv), and then add 1-2 (1.1equiv) dropwise with stirring at 0 ° C. The reaction was moved to room temperature and stirred overnight;
- Step b Dissolve 1-3 (1equiv) in an appropriate amount of DCM, then add anhydrous Na 2 CO 3 (2equiv), and then add 1-4 (2equiv) dropwise with stirring, and stir the reaction overnight at room temperature;
- Step c Dissolve 1-5 (1equiv) in an appropriate amount of DMF, and then slowly add NaH (3equiv) with stirring at 0 ° C. The reaction is moved to room temperature and stirred for 5h;
- Step d Dissolve 1-6 (1equiv) in an appropriate amount of DBU (4equiv), then raise the temperature to 50 ° C, and stir and heat for 5h;
- Step e Dissolve 1-7 (1equiv) in an appropriate amount of EtOH, and then add 2N KOH aqueous solution (3equiv); stir to reflux for 2h, and then acidify.
- Step f Dissolve 2-1 (1equiv) in an appropriate amount of DMF, and then add 2-2 (1.2equiv), K 2 CO 3 (2.5equiv); then raise the temperature to 100 ° C and stir to the end of the reaction; alkali can be used Potassium carbonate and potassium tert-butoxide, the temperature is between 80-130 °C, and the time is 12-36h;
- Step g Dissolve 2-3 (1equiv) in an appropriate amount of EtOH / H 2 O (1: 1), add iron powder (5equiv), NH 4 Cl (5equiv), and stir under reflux for 2h.
- Step h Dissolve 1-8 (1equiv), 2-3 (1.05equiv) in an appropriate amount of DCM, then add HATU (1.5 equiv), DIPEA (2equiv), and stir at room temperature overnight.
- R 1 , R 2 , X, Y, Z and n are the same as the definitions in the general formula I above.
- Step f Dissolve 3-1 (1equiv) in an appropriate amount of DMF, and then add NaH (3equiv) slowly at 0 ° C. After stirring for half an hour, add 3-2 (1.1equiv), and then move to room temperature. , Stir until the reaction is complete;
- Steps a-e, g-h The specific operations are the same as those in the above scheme 1.
- R 1 , R 2 , X, Y, Z and n are the same as the definitions in the general formula I above.
- Step f PhCl dissolved in an appropriate amount of 4-1 (1equiv), was added 4-2 (1.1equiv), 140 C was stirred at reflux overnight Ji;
- Steps a-e, g-h The specific operations are the same as those in the above scheme 1.
- Another aspect of the present invention provides a pharmaceutical composition containing a therapeutically effective amount of a compound selected from the above-mentioned general formula (I), a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer Or racemates, and optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and / or diluents.
- auxiliary materials are, for example, odorants, flavoring agents, sweeteners, and the like.
- the pharmaceutical composition provided by the present invention preferably contains the active ingredient in a weight ratio of 1-99%, and the preferred ratio is that the compound of the general formula I as the active ingredient accounts for 65% to 99% by weight of the total weight, and the rest is a pharmaceutically acceptable carrier , Diluent or solution or saline solution.
- the compounds and pharmaceutical compositions provided by the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and may be present in suitable solid or liquid carriers or diluents. Neutralize suitable disinfection appliances for injection or drip infusion.
- the various dosage forms of the pharmaceutical composition of the present invention can be prepared according to a conventional preparation method in the pharmaceutical field.
- the unit dosage of the formulation formula generally contains 0.05-400 mg of the compound of the general formula I, and preferably, the unit dosage of the formulation formula contains 1 mg-300 mg of the compound of the general formula I.
- the compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered via the oral, nasal, skin, lung, or gastrointestinal tract. Most preferred is oral. Most preferred is a daily dose of 0.01-400 mg / kg body weight, one-time administration, or 0.01-200 mg / kg body weight in divided doses. Regardless of the method of administration, the optimal dose for an individual should depend on the specific treatment. It usually starts with a small dose and gradually increases the dose until the most suitable dose is found.
- the present invention also provides an AXL kinase inhibitor, which comprises a compound selected from the group consisting of a compound represented by the above-mentioned general formula I, a pharmaceutically acceptable salt thereof, a racemate, an R-isomer, an S-isomer, or the like.
- AXL kinase inhibitor which comprises a compound selected from the group consisting of a compound represented by the above-mentioned general formula I, a pharmaceutically acceptable salt thereof, a racemate, an R-isomer, an S-isomer, or the like.
- One or more of the mixtures, and optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and / or diluents are examples of the mixtures, and optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and / or diluents.
- the compounds and compositions of the invention are used to treat and prevent malignant tumors associated with the AXL kinase pathway.
- the compound represented by the above-mentioned general formula I a pharmaceutically acceptable salt thereof, a racemate, an R-isomer, an S-isomer or a mixture thereof is provided for Treatment of malignancies associated with the AXL kinase pathway.
- Example 52 1- (2,5-difluorophenyl) -N- (4-((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy)- 2-fluorophenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a] pyridine-3-carboxamide (DC621054)
- Example 53 (2,5-difluorophenyl) -N- (3-fluoro-4-((5-phenyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy (Phenyl) phenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a] pyridine-3-carboxamide (DC621055)
- Example 62 (2,5-difluorophenyl) -N- (3-chloro-4-((7,8,10,11,13,14-hexahydro- [1,4,7,10 ] Tetraoxanedodecane [2,3-g] quinazolin-4-yl) oxy) phenyl) -2-oxo-1,2,4,5,6,7-hexahydropyridine Zolo [1,5-a] pyridine-3-carboxamide (DC621064)
- Example 80 (2,5-difluorophenyl) -N- (4-((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy)- 3-trifluoromethylphenyl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a] pyridine-3-carboxamide (DC621082)
- Example 82 1- (2,5-difluorophenyl) -N- (4-((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) naphthalene -1-yl) -2-oxo-1,2,4,5,6,7-hexahydropyrazolo [1,5-a] pyridine-3-carboxamide (DC621084)
- ELISA enzyme-linked immunosorbent assay
- Reagents, consumables and instruments The kinases used in the experiment were expressed and purified by the insect baculovirus expression system in our laboratory; the recombinant protein in the protein kinase region was purified; polyglutamic acid-tyrosine peptide [Poly (Glu, Tyr) 4: 1 ] And sodium vanadate were purchased from Sigma; anti-phosphorylated monoclonal antibody PY99 was purchased from Santa Cruz; horseradish peroxidase-labeled goat anti-mouse secondary antibody was purchased from Calbiochem; ATP and OPD were purchased from Shanghai Shenggong; the remaining reagents used All were purchased from Sinopharm Chemical Reagent Co., Ltd.
- Reactive enzyme plate (# 2592) was purchased from Corning.
- the full-wavelength microplate reader for experimental plate reading is a product of Molecular Device, model: SpectraMax 190; the experimental water is distilled water produced by Sinopharm Group.
- Compound preparation The compound was centrifuged at 12000g for 5 minutes, and DMSO was added to prepare a 10-2 M stock solution. After vortexing, the solution was sonicated for 10 minutes and stored at -40 ° C. Compounds were diluted with DMSO from the stock solution to 100 times the concentration tested (DMSO concentration in the system was 1%).
- Poly (Glu, Tyr) substrate for enzyme reaction 4 1 diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 ⁇ g / mL, 125 ⁇ L / well coated enzyme label The plate was left at 37 ° C for 12-16 hours. Discard the liquid in the wells. The plate was washed and washed with T-PBS (potassium-free PBS containing 0.1% Tween-20, 200 ⁇ L / well) three times for 5 minutes each. The plate was dried in an oven at 37 ° C for 1-2 hours.
- potassium-free PBS 10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4
- T-PBS potential-free PBS containing 0.1% Tween-20, 200 ⁇ L / well
- reaction buffer 50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT
- 50 ⁇ L of AXL kinase domain recombinant protein diluted in reaction buffer to start the reaction.
- Two wells without ATP control are required for each experiment. Incubate at 37 ° C (100 rpm) for 1 hour. Discard the liquid in the wells and wash the plate three times with T-PBS.
- the IC 50 value was obtained by a four-parameter regression using the software provided with the microplate reader.
- the compound DC621044 has good selectivity for AXL kinase.
- the compound DC621044 only inhibited MER and TYRO3 kinases of the same family of AXL kinases and c-Met kinases with higher homology, but showed little inhibition on other kinases.
- DC621044 has better selectivity than the AXL inhibitors R428 and Cabozantinib that have been reported in the art, which provides a better basis for the development of selective AXL inhibitors.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明提供了一类并环吡唑啉酮甲酰胺类化合物及其制备方法、药物组合物和用途，具体地，本发明提供了一种具有如式(I)所示结构的化合物(各基团定义如说明书中所述)。该化合物可以作为AXL抑制剂，用于制备治疗肿瘤的药物组合物。
Description
本发明涉及药物化学和药物治疗学领域，具体涉及一类并环吡唑啉酮甲酰胺类化合物、其制备方法、含此类化合物的药物组合物及作为AXL抑制剂，特别是制备用于治疗肿瘤的药物的用途。
恶性肿瘤已经成为严重威胁人类健康的主要疾病之一。《2014年世界癌症报告》指出全球的癌症负担正在急剧加重，中国新增癌症病例已高居全球第一位，其中2012年新增病例约为306万例并造成约220万例死亡，约分别占全球总量的20％和死亡病例的25％。目前，肿瘤已超过心血管疾病，逐步上升为导致死亡的首要病因，对患者造成巨大的生理及心理上的痛苦，给患者家庭及国家来带巨大的经济负担。尽管目前已经有许多抗肿瘤药物面市，但是至今恶性肿瘤仍是难以克服的重大疾病，尤其是耐药等问题的出现。
与传统的细胞毒类化疗药物相比，小分子靶向酪氨酸激酶的抗肿瘤药物凭其优良的特异性和有效性、较好的患者耐受性、以及相对较少的毒副作用等特点，目前已经成为抗肿瘤药物研究的热点。受体酪氨酸激酶(RTK)是一类具有内源性RTK活性的细胞表面跨膜蛋白受体，其结构包括胞外配体结合区、跨膜区和胞内激酶区，通过从细胞外环境转导信号到细胞质和细胞核，调节正常的细胞进程，包括存活、生长、分化、粘附和运动。目前，已发现的受体酪氨酸激酶有58种，根据其激酶域的氨基酸序列的同源性和胞外结构的相似性，可以分为20个亚家族。其中，AXL受体为受体酪氨酸激酶亚家族成员之一，首次在人类慢性髓细胞白血病中发现，与Tyro3(Etk2或Tif)及Mer(又名Nyk，Eyk或Tyro12)共同组成受体酪氨酸激酶亚家族(TAM family)。AXL通过与其配体Gas6的结合，导致激酶超家族活化，在调控机体炎症免疫反应、维持机体吞噬作用的稳态、调节NK细胞的分化成熟等发挥重要的调节作用。目前已在多种实体瘤中发现了AXL的高表达，包括肺癌、乳腺癌、肝癌、胰腺癌、前列腺癌等，与肿瘤复发、不良预后密切相关。AXL异常表达激活拮抗肿瘤细胞凋亡、促进肿瘤细胞侵袭、转移，促进肿瘤血管新生，多环节推动了肿瘤的发生发展。尤其值得关注的是，近年研究显示，AXL的高表达可能介导EGFR的获得性耐药，临床研究表明高达20％的EGFR耐药病人中存在AXL的高表达；临床前研究AXL抑制剂的联合用药可以有效克服EGFR抑制剂耐药。此外，AXL过表达异常激活与其他靶向抑制剂以及化疗药物的耐药也密切相关，提示了AXL可能具有广泛的联合用药的应用空间。与其他激酶不同的是，AXL在肿瘤微环境的巨噬细胞、树突状细胞中高表达，可以通过与肿瘤细胞以及其他基质细胞交互作用，协同促进肿瘤进展。因此，近年来，靶向AXL抑制剂的研发已成为抗肿瘤药物研究的前沿和热点。
目前，在研的AXL抑制剂已经达到32个，其中小分子抑制剂为25个。BergenBio公司开发的化合物BGB324是目前唯一报道具有高选择性的Axl激酶抑制剂，但实际上对同家族成员Mer和Tyro-3、以及对ABL、InsR、EGFR、HER-2和PDGFRβ也有较强 的抑制。临床前研究结果表明，BGB324具有较好的药代和毒理学性质，在两种转移的乳腺癌小鼠模型中，能够阻止乳腺癌转移和延长存活期；在肿瘤细胞和肿瘤基质细胞中，AXL信号能够多水平调节乳腺癌的转移等，目前已经进入了临床II研究。其他的临床研究或上市的化合物尽管对AXL也有较强的抑制作用，如Cabozantinib、BMS777607、Ningetinib等，但均是靶向其他靶点的小分子受体酪氨酸激酶抑制剂，对AXL的选择性不高，属于多靶点的非选择性的激酶抑制剂。
综上所述，本领域尚缺乏一类选择性靶向AXL激酶的小分子抑制剂。
发明内容
本发明的目的是提供一类选择性靶向AXL激酶的小分子抑制剂。
本发明的第一方面，提供了一种具有如下通式I所示结构的并环吡唑啉酮甲酰胺类化合物，或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物：
其中：
n为0～2的整数，优选0或1；
X、Y和Z为CH或N；
R
1和R
2各自独立地选自下组：氢、氘、氚、卤素、取代或未取代的C
1-C
6烷基、取代或未取代的C
1-C
6烷氧基、取代或未取代的C
3-C
8环烷基、C
2-C
6烯基、氰基、硝基、氨基、羟基、羟甲基、羧基、和-O[(CH
2)
qO]
rR
3；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C
1-C
6烷基、卤素取代的C
1-C
6烷基、C
1-C
6烷氧基、卤素取代的C
1-C
6烷氧基、C
1-C
6烷氧基羰基、C
3-C
8环烷基、卤素取代的C
3-C
8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C
6-C
10芳基、和3-12元杂环基；
R
3选自氢、C
1-C
6烷基、卤素取代的C
1-C
6烷基、和羟甲基；
q为1、2、3或4；
r为0、1、2、3或4；
或两个R
1与其相邻的碳原子共同构成选自下组的基团：苯环、5-8元的杂芳环；
或两个R
2与其相邻的碳原子共同构成选自下组的基团：苯环、5-8元的杂芳环；
s选自下组：0、1、2、3或4；
Ar选自下组：取代或未取代的C
6-C
12芳基、取代或未取代的5-12元杂芳基；
除非特别说明，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C
1-C
6烷基、卤素取代的C
1-C
6烷基、C
1-C
6烷氧基、C
1-C
6烷氧基羰基、卤素取代的C
1-C
6烷氧基、C
3-C
8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基。
在另一优选例中，在本发明中，所述卤素为F、Cl、Br或I。
在另一优选例中，R
1和R
2各自独立地选自下组：氢、氘、氚、卤素、取代或未取代的C
1-C
6烷基、取代或未取代的C
1-C
6烷氧基、氰基、羟基、羧基；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C
1-C
6烷基、C
1-C
6烷氧基、C
1-C
6烷氧基羰基、氰基、氨基、羟基、羟甲基、羧基；或两个R
1与其相邻的碳原子共同构成选自下组的基团：苯环、5-8元的杂芳环；
在另一优选例中，其中，
环选自下组：
其中，R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
12分别为1-4个选自下组的取代基：H、D、T、卤素、取代或未取代的C
1-C
6烷基、取代或未取代的C
1-C
6烷氧基、-O[(CH
2)
qO]
rR
3、-NH[(CH
2)
qO]
rR
3、-NH(C＝O)[(CH
2)
qO]
rR
3、-NH(SO
2)[(CH
2)
qO]
rR
3、-O(CH
2)
sAr、取代或未取代的C
3-C
8环烷氧基、取代或未取代的C
3-C
8环烷胺基、取代或未取代的C
3-C
8环氧烷基、取代或未取代的C
3-C
8环胺烷基、氰基、硝基、氨基、胺基(较佳地C
1-C
6胺基)、羟基、羟甲基、羧基、取代或未取代的C
6-C
10芳基、取代或未取代的C
6-C
10芳基氧基、取代或未取代的C
6-C
10芳基胺基、取代或未取代的3-12元杂环基、取代或未取代的3-12元杂环基氧基和取代或未取代的3-12元杂环基胺基；或两个相邻的上述基团与其相连的原子可共同构成选自下组的结构：取代或未取代的6-20元杂环，所述的杂环可任选地包括1、2、3或4个选自N、O或S中的杂原子。
在另一优选例中，所述的R
1和R
2各自独立地为1～3个选自下组的取代基：氢、卤素、C
1-C
6烷基、C
1-C
6卤代烷基、C
1-C
6烷氧基、氰基、羟基；或两个R
1与其相邻的碳原子与其相连的原子可共同构成选自下组的基团：苯环、5-8元的杂芳环。
在另一优选例中，所述的R
1各自独立地为1～3个选自下组的取代基：氟、氯、溴、 碘、甲氧基、三氟甲基，或两个R
1与其相邻的碳原子共同构成苯环。
在另一优选例中，所述的R
2各自独立地为1～3个氟。
在另一优选例中，所述的
环选自下组：
在另一优选例中，R
4、R
5分别为1-4个选自下组的取代基：取代或未取代的C
1-C
6烷氧基、-O[(CH
2)
qO]
rR
3、-NH[(CH
2)
qO]
rR
3、-NH(C＝O)[(CH
2)
qO]
rR
3、-NH(SO
2)[(CH
2)
qO]
rR
3、-O(CH
2)
sAr、取代或未取代的3-12元杂环基氧基和取代或未取代的3-12元杂环基胺基；或两个相邻的上述基团与其相连的原子可共同构成选自下组的结构：取代或未取代的6-20元杂环，所述的杂环可任选地包括1、2、3或4个选自N、O或S中的杂原子。
在另一优选例中，Ar为取代或未取代的C
6-C
12芳基。
在另一优选例中，所述并环吡唑啉酮甲酰胺类化合物为实施例中所出现的化合物DC621001-DC621108。
本发明的第二方面，提供了一种如本发明第一方面所述的化合物的制备方法，所述的方法包括步骤：
在惰性溶剂中，用式1-8化合物与式2-4化合物反应，得到式I化合物。
在另一优选例中，所述式1-8化合物为以下方法制备的：
(b1)在惰性溶剂中，用式1-5化合物进行反应，得到式1-6化合物；
(b2)在惰性溶剂中，用式1-6化合物进行反应，得到式1-7化合物；
(b3)在惰性溶剂中，用式1-7化合物进行反应，得到式1-8化合物。
本发明的第三方面，提供了一种药物组合物，所述的药物组合物包括：治疗有效量的如本发明第一方面所述的式I化合物，或其药学上可接受的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种，以及任选的药学上可接受的载体、赋形剂、佐剂、辅料和/或稀释剂。
本发明的第四方面，提供了一种激酶抑制剂，所述的抑制剂包括：抑制有效量的如本发明第一方面所述的式I化合物，或其药学上可接受的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种，以及任选的药学上可接受的载体、赋形剂、佐剂、辅料和/或稀释剂；且所述的激酶选自下组：AXL、c-Met，或其组合。
本发明的第五方面，提供了一种如本发明第一方面所述的式I化合物用于选自下组的一个或多个方面的用途：(i)治疗或预防与激酶酶活或表达量相关的疾病；(ii)抑制激酶的活性，或降低激酶的表达量；(iii)制备治疗或预防与激酶活性相关的疾病的药物组合物；(iv)制备激酶抑制剂；
其中，所述的激酶选自下组：AXL、c-Met，或其组合。
在另一优选例中，所述的疾病为肿瘤，优选为选自下组的肿瘤：肺癌、胃癌、肝癌、肾癌、乳腺癌、胰腺癌、结直肠癌、卵巢癌、前列腺癌、甲状腺癌、食道癌、头颈癌、黑色素瘤、神经胶质瘤、急性骨髓性白血病等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
图1显示了化合物DC621044的酶谱选择性。
本发明人经过长期而深入的研究，设计制备了一类结构新颖的并环吡唑啉酮甲酰胺类化合物。所述的化合物可以选择性抑制激酶例如AXL，c-Met等。基于上述发现，发明人完成了本发明。
本发明的一个目的在于提供一种通式I所示的并环吡唑啉酮甲酰胺类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物。
本发明的另一个目的在于提供一种上述通式I所示的并环吡唑啉酮甲酰胺类化合物的制备方法。
本发明的再一个目的在于提供一种药物组合物，其包含治疗有效量的选自上述通式I所示的并环吡唑啉酮甲酰胺类化合物、其可药用的盐、外消旋体、R-异构体、S-异构 体或它们的混合物中的一种或多种。
本发明的又一个目的在于提供一种AXL抑制剂，其包含选自上述通式I所示的并环吡唑啉酮甲酰胺类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种。
本发明的又一个目的在于提供上述通式I所示的并环吡唑啉酮甲酰胺类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物用于治疗恶性肿瘤疾病。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“C
1-C
6烷基”是指具有1至6个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等；优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本发明中，术语“C
1-C
6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明中，术语“C
2-C
6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中，术语“C
2-C
6炔基”是指具有2至6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中，术语“C
3-C
8环烷基”是指在环上具有3至8个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基等。其他“环烷基”术语具有类似的含义。
在本发明中，术语“C
6-C
10芳基”是指在环上不含杂原子的具有6至10个碳原子的芳香族环基，如苯基、萘基等。术语“C
6-C
12芳基”具有类似的含义。
并环吡唑啉酮甲酰胺类化合物
本发明提供了一种具有如下通式I所示结构的并环吡唑啉酮甲酰胺类化合物，及其外消旋体、R-异构体、S-异构体、可药用盐或它们混合物：
在本发明更优选的实施方案中，本发明的通式I的化合物优选为如下具体化合物：
本发明提供了通式I化合物的可药用的盐，具体地为通式I化合物与无机酸或有机酸反应形成常规的可药用盐。例如，常规的可药用盐可通过通式I化合物与无机酸或有机酸反应制得，所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、 对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者通式I化合物与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式I化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐。
本发明另一方面提供了一种通式I表示的化合物的制备方法，该制备方法按照如下方案1、方案2或方案3进行。
方案1：
其中，R
1、R
2、X、Y、Z和n的定义与上文通式I中的定义相同。
步骤a：将1-1(1equiv)溶于适量的DCM中，再加入10％的Na
2CO
3水溶液(2equiv)，然后在0℃下搅拌逐滴加入1-2(1.1equiv)。反应移至室温，搅拌过夜；
步骤b：将1-3(1equiv)溶于适量的DCM中，再加入无水Na
2CO
3(2equiv)，然后搅拌逐滴加入1-4(2equiv)，反应室温搅拌过夜；
步骤c：将1-5(1equiv)溶于适量的DMF中，再在0℃下搅拌缓慢加入NaH(3equiv)，反应移至室温，搅拌5h；
步骤d：将1-6(1equiv)溶于适量的DBU(4equiv)中，然后升温至50℃，搅拌加热5h；
步骤e：将1-7(1equiv)溶于适量的EtOH中，再加入2N的KOH水溶液(3equiv)；搅拌回流2h，然后酸化。
步骤f：将2-1(1equiv)溶于适量的DMF中，再加入2-2(1.2equiv)，K
2CO
3(2.5equiv)；然后升温至100℃，搅拌加热至反应结束；碱可用碳酸钾、叔丁醇钾，温度在80-130℃之间，时间在12-36h；
步骤g：将2-3(1equiv)溶于适量的EtOH/H
2O(1:1)中，再加入铁粉(5equiv)，NH
4Cl(5equiv)，然后搅拌回流2h。
步骤h：将1-8(1equiv)，2-3(1.05equiv)溶于适量的DCM中,再加入HATU(1.5 equiv)，DIPEA(2equiv)，然后室温搅拌过夜。
方案2：
其中，R
1、R
2、X、Y、Z和n的定义与上文通式I中的定义相同。
步骤f：将3-1(1equiv)溶于适量的DMF中，再在0℃下搅拌缓慢加入NaH(3equiv)，搅拌半个小时后，再加入3-2(1.1equiv)，然后移至室温，搅拌至反应结束；
步骤a-e,g-h：具体操作同上述方案1。
方案3：
其中，R
1、R
2、X、Y、Z和n的定义与上文通式I中的定义相同。
步骤f：将4-1(1equiv)溶于适量的PhCl中，再加入4-2(1.1equiv)，140
鰶C搅拌回流过夜；
步骤a-e,g-h：具体操作同上述方案1。
本发明的另一方面提供了一种药物组合物，其含有治疗有效量的选自上述通式(Ⅰ)的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体中的一种或多种，以及任选地，一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。所述辅料例如为气味剂、香味剂、甜味剂等。
本发明所提供的药物组合物优选含有重量比为1-99％的活性成份，优选的比例是通式I化合物作为活性成分占总重量的65wt％～99wt％，其余部分为药学可接受的载体、稀释液或溶液或盐溶液。
本发明所提供的化合物和药物组合物可以是多种形式，如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等，并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位计量中通常包含0.05-400mg通式I化合物，优选地，制剂配方的单位计量中包含1mg-300mg通式I化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺或者胃肠道等的给药途径。最优选为口服。最优选日剂量为0.01-400mg/kg体重，一次性服用，或0.01-200mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。
本发明还提供了一种AXL激酶抑制剂，其包含选自上述通式I所示的化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种，以及任选地一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
本发明的化合物和组合物用于治疗和预防与AXL激酶通路相关的恶性肿瘤。
因此，本发明的又一方面提供了上述通式I所示的化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物在制备用于治疗与AXL激酶通路相关的恶性肿瘤。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1 N-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621001)
1.1 5-氯-N’-苯基戊酰肼的合成
向500mL茄形瓶中加入10g苯肼，10％的Na
2CO
3水溶液(180mL)和200mL DCM，0℃下搅拌10min后，再逐滴加入5-氯戊酰氯(11.85mL)，滴加完毕，先在此温度下搅拌10min，然后移至室温，搅拌过夜。用薄层层析(TLC)监测反应。反应结束后，分离 有机层，含水层再用100mL DCM提取3次，合并有机层，有机层依次用饱和食盐水洗涤，无水Na
2SO
4干燥，抽滤，滤液旋干，得红棕色油状液体16g。LRMS(EI)m/z:227(M+H)
+(无需纯化，可直接投下一步)
1.2 3-(2-(5-氯戊酰基)-1-苯基肼基)-3-氧代丙酸乙酯的合成
将16g 5-氯-N’-苯基戊酰肼溶于250mL DCM中，再加入15.0g无水Na
2CO
3，室温搅拌下逐滴加入60mL氯甲酰乙酸乙酯(19.0mL)的DCM溶液，滴加完毕，室温搅拌过夜。用薄层层析(TLC)监测反应。反应结束后，反应液用硅藻土过滤，固体用适量水和DCM洗涤，滤液分离有机层，含水层再用100mL DCM提取3次，合并有机层，有机层依次用饱和食盐水洗涤，无水Na
2SO
4干燥，抽滤，滤液旋干，得黄色油状液体17g。LRMS(EI)m/z:341(M+H)
+(无需纯化，可直接投下一步)
1.3 3-氧代-3-((2-氧代哌啶-1-基)(苯基)氨基)丙酸乙酯的合成
将17g 3-(2-(5-氯戊酰基)-1-苯基肼基)-3-氧代丙酸乙酯溶于250mL DMF中，0℃下搅拌10min后，再缓慢加入6.0g NaH，加完后，先在此温度下搅拌10min，然后移至室温，反应5h。用薄层层析(TLC)监测反应。反应结束后，反应液用饱和NaH
2PO
4调节PH至7，然后过滤，滤液用大量水稀释，然后用100mL EA提取3次，合并有机层，有机层依次用饱和食盐水洗涤，无水Na
2SO
4干燥，抽滤，滤液旋干，得黄色油状液体14g。LRMS(EI)m/z:305(M+H)
+(无需纯化，可直接投下一步)
1.4 2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酸乙酯的合成
将14g 3-氧代-3-((2-氧代哌啶-1-基)(苯基)氨基)丙酸乙酯溶于35mL DBU中，然后升温至50℃，搅拌加热5h。用薄层层析(TLC)监测反应。反应结束后，反应液用饱和NaH
2PO
4调节PH至7，然后用100mL DCM提取3次，合并有机层，有机层依次用饱和食盐水洗涤，无水Na
2SO
4干燥，抽滤，滤液旋干，得黄色油状液体12g。LRMS(EI)m/z:287(M+H)
+(无需纯化，可直接投下一步)
1.5 2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酸的合成
将12g 2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酸乙酯溶于100mL EtOH中，再加入58mL 2N的KOH水溶液，然后搅拌回流2h。用薄层层析(TLC)监测反应。反应结束后，先旋掉部分EtOH，再用EA提取反应液，然后用2N HCl调节含水层的PH至3，析出棕色固体，抽滤，得固体10g。LRMS(EI)m/z:259(M+H)
+
1.6 4-(2-氟-4-硝基苯氧基)-6,7-二甲氧基喹啉的合成
向100mL茄形瓶中加入5g 4-氯-6,7-二甲氧基喹啉，4.2g 2-氟-4-硝基苯酚，7.69g K
2CO
3和50mL DMF，然后100℃搅拌过夜。用薄层层析(TLC)监测反应。反应结束后，向反应液中加入大量水，析出黄色固体，抽滤，得固体6.5g。LRMS(EI)m/z:345(M+H)
+
1.7 4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺的合成
将6.5g 4-(2-氟-4-硝基苯氧基)-6,7-二甲氧基喹啉溶于80mL EtOH/H
2O(1:1)中，再加入5.26g铁粉，5.03g NH
4Cl，然后搅拌回流2h。用薄层层析(TLC)监测反应。反应结束后，反应液用硅藻土过滤，固体用适量EA洗涤，滤液分离有机层，含水层再用100mL EA提取3次，合并有机层，有机层依次用饱和食盐水洗涤，无水Na
2SO
4干燥，抽滤，滤液旋干，得黄色固体5g。LRMS(EI)m/z:315(M+H)
+(无需纯化，可直接投下一步)
1.8 终产物DC621001的合成
向25mL茄形瓶中加入100mg 2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酸，128mg 4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯胺，221mg HATU，0.16mL DIPEA和15mL DCM，然后室温搅拌过夜。用薄层层析(TLC)监测反应。反应结束后，反应液加25mL水稀释，分离有机层，含水层再用25mL DCM提取3次，合并有机层，有机层依次用饱和食盐水洗涤，无水Na
2SO
4干燥，抽滤，滤液旋干，纯化得白色固体180mg，收率84％。
1HNMR(400MHz,DMSO-d6)δ10.83(s,1H),8.51(d,J＝5.3Hz,1H),8.00(dd,J＝13.1,2.3Hz,1H),7.65–7.38(m,8H),7.36(dd,J＝9.0,1.8Hz,1H),6.51(d,J＝5.2Hz,1H),3.96(s,6H),3.59(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.04-1.92(m,2H),1.88–1.78(m,2H).LRMS(EI)m/z:555(M+H)
+.
实施例2 N-(6-((6,7-二甲氧基喹啉-4-基)氧基)吡啶-3-基)-2-氧代-1-苯基-1,2,4,5,6,7-六 氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621002)
2.6 6,7-二甲氧基-4–((5-硝基吡啶-2-基)氧基)喹啉的合成
将5g 6,7-二甲氧基喹啉-4-醇溶于80mL DMF中，再在0℃下搅拌缓慢加入3g NaH，搅拌半个小时后，再加入3.8g 2–氟-5-硝基吡啶，然后移至室温搅拌。用薄层层析(TLC)监测反应。反应结束后，向反应液中加入大量饱和氯化铵水溶液，淬灭过量的NaH，含水层用100mL EA提取3次，合并有机层，有机层依次用饱和食盐水洗涤，无水Na
2SO
4干燥，抽滤，滤液旋干，得黄色固体。LRMS(EI)m/z:328(M+H)
+(无须纯化，可直接进行下一步)
其余步骤如实施例1，得产物DC621002，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.71(s,1H),8.55(d,J＝5.1Hz,1H),8.50(d,J＝2.6Hz,1H),8.27(dd,J＝8.8,2.7Hz,1H),7.59(t,J＝7.5Hz,2H),7.52(d,J＝7.4Hz,1H),7.46(d,J＝7.3Hz,2H),7.40(d,J＝13.1Hz,2H),7.31(d,J＝8.8Hz,1H),6.84(d,J＝5.2Hz,1H),3.95(s,3H),3.88(s,3H),3.58(t,J＝5.7Hz,2H),3.20(t,J＝6.1Hz,2H),2.02–1.93(m,2H),1.88–1.72(m,2H).LRMS(EI)m/z:538(M+H)
+.
实施例3 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621004)
将2-氟-4-硝基苯酚替换成对硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621004，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.68(s,1H),8.55(s,1H),7.70(s,1H),7.68(s,1H),7.65-7.54(m,3H),7.52(d,J＝7.3Hz,1H),7.49–7.44(m,2H),7.39(s,1H),7.27(s,1H),7.25(s,1H),3.99(s,3H),3.98(s,3H),3.57(t,J＝5.8Hz,2H),3.22(t,J＝6.4Hz,2H),2.03–1.95(m,2H),1.86–1.77(m,2H).LRMS(EI)m/z:538(M+H)
+.
实施例4 N-(4-(咪唑并[1,2-a]吡嗪-8-基氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621006)
将2-氟-4-硝基苯酚替换成对硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成8-氯咪唑并[1,2-a]吡嗪，其余所需原料、试剂及制备方法同实施例1，得产物DC621006，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.66(s,1H),8.32(d,J＝4.6Hz,1H),8.16(d,J＝1.0Hz,1H),7.76(d,J＝1.0Hz,1H),7.70–7.63(m,2H),7.62–7.55(m,2H),7.54–7.43(m,3H),7.32(d,J＝4.6Hz,1H),7.28–7.18(m,2H),3.57(t,J＝5.8Hz,2H),3.22(t,J＝6.3Hz,2H),2.02–1.94(m,2H),1.86–1.78(m,2H).LRMS(EI)m/z:467(M+H)
+.
实施例5 N-(4-([1,2,4]三唑并[4,3-b]哒嗪-6-基氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621007)
将2-氟-4-硝基苯酚替换成对硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成6-氯-[1,2,4] 三唑并[4,3-b]哒嗪，其余所需原料、试剂及制备方法同实施例1，得产物DC621007，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.67(s,1H),9.40(d,J＝0.6Hz,1H),8.41(dd,J＝9.8,0.6Hz,1H),7.73–7.63(m,2H),7.59(t,J＝7.5Hz,2H),7.54–7.44(m,3H),7.34–7.25(m,3H),3.57(t,J＝5.8Hz,2H),3.21(t,J＝6.3Hz,2H),2.03–1.94(m,2H),1.88–1.77(m,2H).LRMS(EI)m/z:468(M+H)
+.
实施例6 2-氧代-1-苯基-N-(4-(吡唑并[1,5-a]嘧啶-5-基氧基)苯基)-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621008)
将2-氟-4-硝基苯酚替换成对硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成5-氯吡唑并[1,5-a]嘧啶，其余所需原料、试剂及制备方法同实施例1，得产物DC621008，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.66(s,1H),9.05(d,J＝7.5Hz,1H),8.06(d,J＝2.2Hz,1H),7.67(d,J＝8.9Hz,2H),7.59(t,J＝7.5Hz,2H),7.55–7.43(m,3H),7.21(d,J＝8.9Hz,2H),6.79(d,J＝7.5Hz,1H),6.41–6.27(m,1H),3.57(t,J＝5.8Hz,2H),3.22(t,J＝6.3Hz,2H),2.04–1.95(m,2H),1.88–1.76(m,2H).LRMS(EI)m/z:467(M+H)
+.
实施例7 N-(3-氟-4-(咪唑并[1,2-a]吡啶-8-基氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621009)
将4-氯-6,7-二甲氧基喹啉替换成咪唑并[1,2-a]吡啶-8-醇，将2-氟-4-硝基苯酚替换成1,2–二氟-4-硝基苯，其余所需原料、试剂及制备方法同实施例2，得产物DC621009，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.75(s,1H),8.33(d,J＝6.0Hz,1H),8.03(d,J＝1.1Hz,1H),8.00–7.88(m,1H),7.64–7.55(m,3H),7.54–7.43(m,3H),7.29–7.16(m,2H),6.82–6.76(m,1H),6.52(d,J＝7.5Hz,1H),3.58(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.02–1.95(m,2H),1.87–1.79(m,2H).LRMS(EI)m/z:484(M+H)
+.
实施例8 N-(6-(咪唑并[1,2-a]吡啶-8-基氧基)吡啶-3-基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621010)
将4-氯-6,7-二甲氧基喹啉替换成咪唑并[1,2-a]吡啶-8-醇，将2-氟-4-硝基苯酚替换成2–氟-5-硝基吡啶，其余所需原料、试剂及制备方法同实施例2，得产物DC621010，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.44(dd,J＝6.7,0.9Hz,1H),8.24(d,J＝2.7Hz,1H),8.15(dd,J＝8.8,2.7Hz,1H),7.99(d,J＝1.1Hz,1H),7.58(t,J＝7.5Hz,2H),7.54–7.41(m,4H),7.13(d,J＝8.8Hz,1H),7.03(dd,J＝7.4,0.8Hz,1H),6.89(t,J＝7.1Hz,1H),3.56(t,J＝5.8Hz,2H),3.19(t,J＝6.3Hz,2H),2.13–1.94(m,2H),1.87–1.73(m,2H).LRMS(EI)m/z:467(M+H)
+.
实施例9 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621011)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621011，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.81(s,1H),8.57(s,1H),7.93(dd,J＝12.9,2.3Hz,1H),7.63–7.56(m,3H),7.55–7.46(m, 3H),7.44–7.39(m,2H),7.31(dd,J＝8.8,1.7Hz,1H),4.00(s,3H),3.99(s,3H),3.59(t,J＝5.8Hz,2H),3.22(t,J＝6.2Hz,2H),2.07–1.95(m,2H),1.89–1.77(m,2H).LRMS(EI)m/z:556(M+H)
+.
实施例10 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-氟苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621012)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621012，收率85％。
1HNMR(400MHz,DMSO-d6)δ10.81(s,1H),8.56(s,1H),7.93(dd,J＝12.9,2.2Hz,1H),7.64–7.57(m,3H),7.55–7.38(m,5H),7.31(d,J＝10.2Hz,1H),4.42–4.28(m,4H),3.85–3.69(m,4H),3.59(t,J＝5.8Hz,2H),3.37(s,3H),3.36(s,3H),3.22(t,J＝6.1Hz,2H),2.07–1.95(m,2H),1.89–1.77(m,2H).LRMS(EI)m/z:644(M+H)
+.
实施例11 N-(4-(N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621013)
将2-氟-4-硝基苯酚替换成对硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621013，收率85％。
1HNMR(400MHz,DMSO-d6)δ10.68(s,1H),8.54(s,1H),7.69(d,J＝8.9Hz,2H),7.63–7.56(m,3H),7.55–7.44(m,3H),7.41(s,1H),7.26(d,J＝8.9Hz,2H),4.43–4.26(m,4H),3.81–3.73(m,4H),3.58(t,J＝5.8Hz,2H),3.37(s,3H),3.36(s,3H),3.23(t,J＝6.3Hz,2H),2.05–1.94(m,2H),1.87–1.77(m,2H).LRMS(EI)m/z:626(M+H)
+.
实施例12 N-(4–((7-苄氧基-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621014)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-7-苄氧基-6-甲氧基喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621014，收率85％。
1HNMR(400MHz,DMSO-d6)δ10.81(s,1H),8.57(s,1H),7.93(dd,J＝12.9,2.4Hz,1H),7.60(t,J＝7.4Hz,3H),7.53(t,J＝4.0Hz,3H),7.52–7.41(m 7H),7.32(d,J＝7.2Hz,1H),5.37(s,2H),4.00(s,3H),3.59(t,J＝5.9Hz,2H),3.22(t,J＝6.2Hz,2H),2.04–1.95(m,2H),1.87–1.79(m,2H).LRMS(EI)m/z:632(M+H)
+.
实施例13 N-(4–((7-苄氧基-6-甲氧基喹唑啉-4-基)氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621015)
将2-氟-4-硝基苯酚替换成对硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-7-苄氧基-6-甲氧基喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621015，收率85％。
1HNMR(400MHz,DMSO-d6)δ10.68(s,1H),8.54(s,1H),7.73–7.66(m,2H),7.65-7.57(m,3H),7.55–7.41(m,8H),7.39–7.35(m,1H),7.29–7.23(m,2H),5.35(s,2H),3.98(s,3H),3.57(t,J＝5.8Hz,2H),3.22(t,J＝6.3Hz,2H),2.03–1.94(m,2H),1.87 –1.76(m,2H).LRMS(EI)m/z:614(M+H)
+.
实施例14 N-(3-氟-4-(喹啉-4-基氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621016)
将4-氯-6,7-二甲氧基喹啉替换成4-氯喹啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621016，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.80(s,1H),8.87(d,J＝2.9Hz,1H),8.05-7.88(m,3H),7.70–7.64(m,2H),7.62–7.54(m,3H),7.53–7.43(m,3H),7.40–7.29(m,2H),3.58(t,J＝5.8Hz,2H),3.21(t,J＝6.3Hz,2H),2.04–1.94(m,2H),1.87–1.78(m,2H).LRMS(EI)m/z:495(M+H)
+.
实施例15 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-甲氧基苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621017)
将2-氟-4-硝基苯酚替换成2-甲氧基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621017，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.71(s,1H),8.51(s,1H),7.63–7.55(m,3H),7.54–7.50(m,2H),7.49–7.45(m,2H),7.38(s,1H),7.19(s,2H),3.99(s,3H),3.97(s,3H),3.68(s,3H),3.58(t,J＝5.8Hz,2H),3.23(t,J＝6.2Hz,2H),2.05–1.96(m,2H),1.87–1.77(m,2H).LRMS(EI)m/z:568(M+H)
+.
实施例16 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-甲氧基苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621018)
将2-氟-4-硝基苯酚替换成2-甲氧基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621018，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.71(s,1H),8.50(s,1H),7.62–7.54(m,4H),7.53–7.44(m,3H),7.40(s,1H),7.18(s,2H),4.39–4.26(m,4H),3.80–3.73(m,4H),3.68(s,3H),3.58(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.23(t,J＝6.3Hz,2H),2.07–1.93(m,2H),1.88–1.77(m,2H).LRMS(EI)m/z:656(M+H)
+.
实施例17 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-甲基苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621019)
将2-氟-4-硝基苯酚替换成2-甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621019，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.64(s,1H),8.52(s,1H),7.63–7.56(m,4H),7.55–7.50(m,2H),7.49–7.45(m,2H),7.39(s,1H),7.16(d,J＝8.7Hz,1H),3.99(s,3H),3.98(s,3H),3.57(t,J＝5.8Hz,2H),3.22(t,J＝6.3Hz,2H),2.07(s,3H),2.02–1.95(m,2H),1.86–1.79(m,2H).LRMS(EI)m/z:552(M+H)
+.
实施例18 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-甲基苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621020)
将2-氟-4-硝基苯酚替换成2-甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621020，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.64(s,1H),8.51(s,1H),7.64(s,1H),7.63–7.56(m,3H),7.55–7.50(m,2H),7.49–7.44(m,2H),7.42(s,1H),7.16(d,J＝8.7Hz,1H),4.39–4.29(m,4H),3.79–3.75(m,4H),3.57(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.22(t,J＝6.3Hz,2H),2.07(s,3H),2.03–1.94(m,2H),1.88–1.77(m,2H).LRMS(EI)m/z:640(M+H)
+.
实施例19 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-2-氟苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621021)
3.6 4-(3-氟-4-硝基苯氧基)-6,7-二甲氧基喹唑啉的合成
向100mL茄形瓶中加入5g 4-氯-6,7-二甲氧基喹啉，4.2g 3-氟-4-硝基苯酚，50mL PhCl，然后140℃搅拌过夜。用薄层层析(TLC)监测反应。反应结束后，旋掉PhCl，析出黄色固体，抽滤，得固体6.5g。LRMS(EI)m/z 346(M+H)
+
其余步骤如实施例1，得产物DC621021，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.89(s,1H),8.57(s,1H),8.50(t,J＝9.0Hz,1H),7.59(t,J＝7.5Hz,2H),7.56–7.51(m,2H),7.50–7.46(m,2H),7.44–7.39(m,2H),7.16(d,J＝9.0Hz,1H),3.99(s,3H),3.97(s,3H),3.58(t,J＝5.8Hz,2H),3.22(t,J＝6.2Hz,2H),2.04–1.94(m,2H),1.88–1.78(m,2H).LRMS(EI)m/z:556(M+H)
+.
实施例20 1-(2,5-二氟苯基)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621022)
将2-氟-4-硝基苯酚替换成对硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621022，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.46(s,1H),8.55(s,1H),7.67–7.60(m,4H),7.59–7.51(m,2H),7.39(s,1H),7.26(d,J＝8.9Hz,2H),3.99(s,3H),3.98(s,3H),3.58(t,J＝5.8Hz,2H),3.21(t,J＝6.1Hz,2H),2.06–1.93(m,2H),1.89–1.75(m,2H).LRMS(EI)m/z:574(M+H)
+.
实施例21 1-(2,5-二氟苯基)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621023)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621023，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.57(s,1H),7.92(dd,J＝12.9,2.4Hz,1H),7.69–7.52(m,4H),7.45–7.37(m,2H),7.35–7.28(m,1H),4.00(s,3H),3.98(s,3H),3.60(t,J＝ 5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.05–1.93(m,2H),1.89–1.75(m,2H).LRMS(EI)m/z:592(M+H)
+.
实施例22 1-(2,5-二氟苯基)-N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621024)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621024，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.56(s,1H),7.92(dd,J＝12.8,2.4Hz,1H),7.68–7.52(m,5H),7.44(s,1H),7.40(d,J＝8.8Hz,1H),7.35–7.28(m,1H),4.38–4.31(m,4H),3.80-3.72(m,4H),3.53(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.2Hz,2H),2.04–1.95(m,2H),1.87–1.77(m,2H).LRMS(EI)m/z:680(M+H)
+.
实施例23 1-(2,5-二氟苯基)-N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621025)
将2-氟-4-硝基苯酚替换成对硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621025，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.46(s,1H),8.54(s,1H),7.73–7.49(m,6H),7.41(s,1H),7.34–7.21(m,2H),4.37–4.28(m,4H),3.79–3.73(m,4H),3.59(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.2Hz,2H),2.04–1.93(m,2H),1.87–1.76(m,2H).LRMS(EI)m/z:662(M+H)
+.
实施例24 1-(2,5-二氟苯基)-N-(4–((7-苄氧基-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621026)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-7-苄氧基-6-甲氧基喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621026，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.56(s,1H),7.92(dd,J＝12.8,2.3Hz,1H),7.69–7.59(m,3H),7.58–7.51(m,4H),7.47–7.37(m,4H),7.35-7.29(m,1H),5.36(s,2H),3.99(s,3H),3.58(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.05–1.93(m,2H),1.87–1.75(m,2H).LRMS(EI)m/z:668(M+H)
+.
实施例25 1-(2,5-二氟苯基)-N-(4–((7-苄氧基-6-甲氧基喹唑啉-4-基)氧基)苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621027)
将2-氟-4-硝基苯酚替换成对硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-7-苄氧基-6-甲氧基喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621027，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.46(s,1H),8.54(s,1H),7.73–7.49(m,9H),7.44(t,J＝7.3Hz,2H),7.41–7.34(m,1H),7.26(d,J＝8.9Hz,2H),5.35(s,2H),3.98(s,3H),3.58(t,J＝5.8Hz,2H),3.21(t,J＝6.1Hz,2H),2.06–1.91(m,2H),1.88–1.76(m,2H).LRMS(EI)m/z:650(M+H)
+.
实施例26 1-(2,5-二氟苯基)-N-(3-氟-4-(喹啉-4-基氧基)苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621028)
将4-氯-6,7-二甲氧基喹啉替换成4-氯喹啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621028，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.87(d,J＝2.9Hz,1H),8.05-7.91(m,3H),7.76–7.49(m,6H),7.45–7.24(m,2H),3.59(t,J＝5.8Hz,2H),3.20(t,J＝6.2Hz,2H),2.04–1.94(m,2H),1.86–1.75(m,2H).LRMS(EI)m/z:531(M+H)
+.
实施例27 1-(2,5-二氟苯基)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-甲氧基苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621029)
将2-氟-4-硝基苯酚替换成2-甲氧基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621029，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.49(s,1H),8.51(s,1H),7.70–7.51(m,5H),7.38(s,1H),7.19(s,2H),3.99(s,3H),3.97(s,3H),3.68(s,3H),3.53(t,J＝5.8Hz,2H),3.22(t,J＝6.2Hz,2H),2.03–1.95(m,2H),1.86–1.78(m,2H).LRMS(EI)m/z:604(M+H)
+.
实施例28 1-(2,5-二氟苯基)-N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-甲氧基苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621030)
将2-氟-4-硝基苯酚替换成2-甲氧基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621030，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.49(s,1H),8.50(s,1H),7.71–7.51(m,5H),7.40(s,1H),7.19(s,2H),4.43–4.26(m,4H),3.79-3.71(m,4H),3.68(s,3H),3.52(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.22(t,J＝6.2Hz,2H),2.05–1.93(m,2H),1.87–1.76(m,2H).LRMS(EI)m/z:692(M+H)
+.
实施例29 1-(2,5-二氟苯基)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-甲基苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621031)
将2-氟-4-硝基苯酚替换成2-甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621031，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.42(s,1H),8.52(s,1H),7.70–7.48(m,6H),7.39(s,1H),7.16(d,J＝8.7Hz,1H),3.99(s,3H),3.98(s,3H),3.58(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.07(s,3H),2.02–1.95(m,2H),1.88-1,76(m,2H).LRMS(EI)m/z:588(M+H)
+.
实施例30 1-(2,5-二氟苯基)-N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-甲基苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621032)
将2-氟-4-硝基苯酚替换成2-甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂 及制备方法同实施例1，得产物DC621032，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.42(s,1H),8.52(s,1H),7.67–7.50(m,6H),7.42(s,1H),7.17(d,J＝8.7Hz,1H),4.39-4.31(m,4H),3.80–3.73(m,4H),3.59(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.2Hz,2H),2.07(s,3H),2.01–1.93(m,2H),1.88–1.72(m,2H).LRMS(EI)m/z:676(M+H)
+.
实施例31N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621033)
将2-氟-4-硝基苯酚替换成对硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621033，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.54(s,1H),8.55(s,1H),7.72–7.60(m,4H),7.58–7.50(m,2H),7.47–7.41(m,1H),7.39(s,1H),7.30–7.23(m,2H),3.99(s,3H),3.98(s,3H),3.56(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.04-1.93(m,2H),1.86–1.78(m,2H).LRMS(EI)m/z:556(M+H)
+.
实施例32 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621034)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621034，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.66(s,1H),8.57(s,1H),7.92(dd,J＝12.9,2.4Hz,1H),7.69–7.60(m,2H),7.58–7.50(m,2H),7.47–7.38(m,3H),7.33–7.28(m,1H),4.00(s,3H),3.98(s,3H),3.57(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.02–1.94(m,2H),1.86–1.77(m,2H).LRMS(EI)m/z:574(M+H)
+.
实施例33 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-氟苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621035)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621035，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.66(s,1H),8.56(s,1H),7.92(dd,J＝12.9,2.4Hz,1H),7.69–7.59(m,3H),7.54(t,J＝8.7Hz,1H),7.48–7.38(m,3H),7.33–7.28(m,1H),4.42–4.27(m,4H),3.79–3.72(m,4H),3.58(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.2Hz,2H),2.02–1.92(m,2H),1.85–1.78(m,2H).LRMS(EI)m/z:662(M+H)
+..
实施例34 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621036)
将2-氟-4-硝基苯酚替换成对硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621036，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.54(s,1H),8.54(s,1H),7.71–7.59(m,5H),7.53(t,J＝9.2Hz,1H),7.47–7.40(m,2H),7.26(d,J＝ 8.9Hz,2H),4.39–4.24(m,4H),3.79–3.73(m,4H),3.53(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.1Hz,2H),2.03–1.94(m,2H),1.86–1.76(m,2H).LRMS(EI)m/z:644(M+H)
+.
实施例35 N-(4–((7-苄氧基-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621037)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-7-苄氧基-6-甲氧基喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621037，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.66(s,1H),8.56(s,1H),7.92(dd,J＝12.8,2.4Hz,1H),7.69–7.58(m,3H),7.57–7.51(m,4H),7.47–7.35(m,5H),7.33–7.28(m,1H),5.36(s,2H),3.99(s,3H),3.60(t,J＝5.8Hz,2H),3.20(t,J＝6.1Hz,2H),2.02–1.93(m,2H),1.86–1.77(m,2H).LRMS(EI)m/z:650(M+H)
+.
实施例36 N-(3-氟-4-(喹啉-3-基氧基)苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621038)
将4-氯-6,7-二甲氧基喹啉替换成4-氯喹啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621038，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.65(s,1H),8.87(d,J＝2.9Hz,1H),8.05–7.89(m,3H),7.70–7.50(m,6H),7.44(t,J＝7.6Hz,1H),7.39–7.28(m,2H),3.54(t,J＝5.8Hz,2H),3.20(t,J＝6.2Hz,2H),2.01–1.93(m,2H),1.86–1.76(m,2H).LRMS(EI)m/z:513(M+H)
+.
实施例37 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-甲氧基苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621039)
将2-氟-4-硝基苯酚替换成2-甲氧基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621039，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.51(s,1H),7.67–7.60(m,2H),7.53(t,J＝9.0Hz,3H),7.44(t,J＝7.7Hz,1H),7.38(s,1H),7.19(s,2H),3.99(s,3H),3.97(s,3H),3.68(s,3H),3.50(t,J＝5.8Hz,2H),3.22(t,J＝6.2Hz,2H),2.02–1.95(m,2H),1.84–1.77(m,2H).LRMS(EI)m/z:586(M+H)
+.
实施例38 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-甲氧基苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621040)
将2-氟-4-硝基苯酚替换成2-甲氧基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621040，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.50(s,1H),7.70–7.60(m,2H),7.58–7.50(m,3H),7.48–7.38(m,2H),7.18(s,2H),4.38–4.27(m,4H),3.80–3.72(m,4H),3.68(s,3H),3.50(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.22(t,J＝6.1Hz,2H),2.03–1.93(m,2H),1.86–1.76(m,2H).LRMS(EI)m/z:674(M+H)
+.
实施例39 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-甲基苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621041)
将2-氟-4-硝基苯酚替换成2-甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621041，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.50(s,1H),8.53(s,1H),7.69–7.58(m,4H),7.57–7.49(m,2H),7.44(t,J＝7.7Hz,1H),7.39(s,1H),7.16(d,J＝8.7Hz,1H),3.99(s,3H),3.98(s,3H),3.54(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.07(s,3H),2.01–1.96(m,2H),1.86–1.78(m,2H).LRMS(EI)m/z:570(M+H)
+.
实施例40 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-甲基苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621042)
将2-氟-4-硝基苯酚替换成2-甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621042，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.50(s,1H),8.52(s,1H),7.68–7.58(m,4H),7.56–7.49(m,2H),7.47–7.40(m,2H),7.16(d,J＝8.7Hz,1H),4.40–4.29(m,4H),3.79–3.73(m,4H),3.54(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.2Hz,2H),2.07(s,3H),2.02–1.93(m,2H),1.83–1.77(m,2H).LRMS(EI)m/z:658(M+H)
+.
实施例41 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621043)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621043，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.66(s,1H),8.57(s,1H),7.92(dd,J＝12.9,2.4Hz,1H),7.69–7.60(m,2H),7.58–7.50(m,2H),7.47–7.38(m,3H),7.33–7.28(m,1H),4.00(s,3H),3.98(s,3H),3.57(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.03–1.93(m,2H),1.86–1.77(m,2H).LRMS(EI)m/z:574(M+H)
+.
实施例42 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621044)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621044，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.77(s,1H),8.56(s,1H),7.92(dd,J＝12.9,2.3Hz,1H),7.61(s,1H),7.59–7.50(m,2H),7.48–7.37(m,4H),7.34–7.27(m,1H),4.40–4.29(m,4H),3.79–3.73(m,4H),3.56(t,J＝5.7Hz,2H),3.36(s,3H),3.36(s,3H),3.20(t,J＝6.2Hz,2H),2.01–1.93(m,2H),1.86–1.77(m,2H).LRMS(EI)m/z:662(M+H)
+.
实施例43 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)苯基)-1-(4-氟苯基)-2-氧 代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621045)
将2-氟-4-硝基苯酚替换成对硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621045，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.65(s,1H),8.52(d,J＝12.9Hz,1H),7.71–7.65(m,2H),7.60(s,1H),7.57–7.52(m,2H),7.48–7.39(m,3H),7.29–7.23(m,2H),4.45–4.22(m,4H),3.79–3.74(m,4H),3.56(t,J＝5.9Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.2Hz,2H),2.03–1.94(m,2H),1.85–1.78(m,2H).LRMS(EI)m/z:644(M+H)
+.
实施例44 N-(4–((7-苄氧基-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621046)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-7-苄氧基-6-甲氧基喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621046，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.77(s,1H),8.56(s,1H),7.92(dd,J＝12.9,2.4Hz,1H),7.59(s,1H),7.58–7.51(m,5H),7.47–7.37(m,7H),7.31–7.21(m,1H),5.36(s,2H),3.99(s,3H),3.56(t,J＝5.8Hz,2H),3.20(t,J＝6.2Hz,2H),2.03–1.93(m,2H),1.85–1.77(m,2H).LRMS(EI)m/z:650(M+H)
+.
实施例45 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-甲氧基苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621047)
将2-氟-4-硝基苯酚替换成2-甲氧基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621047，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.68(s,1H),8.51(s,1H),7.58–7.52(m,4H),7.48–7.40(m,2H),7.38(s,1H),7.21–7.15(m,2H),3.99(s,3H),3.97(s,3H),3.68(s,3H),3.56(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.02–1.92(m,2H),1.86–1.74(m,2H).LRMS(EI)m/z:586(M+H)
+.
实施例46 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-甲氧基苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621048)
将2-氟-4-硝基苯酚替换成2-甲氧基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621048，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.68(s,1H),8.50(s,1H),7.58–7.51(m,4H),7.48–7.38(m,3H),7.18(s,2H),4.37–4.30(m,4H),3.81–3.73(m,4H),3.68(s,3H),3.56(t,J＝5.7Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.2Hz,2H),2.04–1.92(m,2H),1.87–1.76(m,2H).LRMS(EI)m/z:674(M+H)
+.
实施例47 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-甲基苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621049)
将2-氟-4-硝基苯酚替换成2-甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621049，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.61(s,1H),8.52(s,1H),7.59(d,J＝3.1Hz,2H),7.57–7.49(m,3H),7.44(t,J＝8.8Hz,2H),7.39(s,1H),7.16(d,J＝8.7Hz,1H),3.99(s,3H),3.98(s,3H),3.56(t,J＝5.8Hz,2H),3.21(t,J＝6.3Hz,2H),2.07(s,3H),2.02–1.95(m,2H),1.85–1.77(m,2H).LRMS(EI)m/z:570(M+H)
+.
实施例48 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-甲基苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621050)
将2-氟-4-硝基苯酚替换成2-甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621050，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.61(s,1H),8.51(s,1H),7.64(s,1H),7.59(d,J＝2.3Hz,1H),7.58–7.50(m,3H),7.48–7.40(m,3H),7.16(d,J＝8.7Hz,1H),4.38–4.30(m,4H),3.79–3.73(m,4H),3.56(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.3Hz,2H),2.07(s,3H),2.02–1.95(m,2H),1.86–1.76(m,2H).LRMS(EI)m/z:658(M+H)
+.
实施例49 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-2-氟苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621051)
将2-氟-4-硝基苯酚替换成3-氟-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，其余所需原料、试剂及制备方法同实施例21，得产物DC621051，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.89(s,1H),8.57(s,1H),8.50(t,J＝9.0Hz,1H),7.63–7.56(m,3H),7.53(d,J＝7.3Hz,1H),7.51–7.45(m,2H),7.44–7.39(m,2H),7.21–7.11(m,1H),4.40–4.26(m,4H),3.79–3.73(m,4H),3.58(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.22(t,J＝6.2Hz,2H),2.03–1.95(m,2H),1.87–1.77(m,2H).LRMS(EI)m/z:644(M+H)
+.
实施例50 N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621052)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-5-苯基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1，得产物DC621052，收率80％。
1HNMR(400MHz,DMSO-d6)δ12.54(s,1H),10.78(s,1H),8.33(s,1H),7.89(dd,J＝12.8,2.3Hz,1H),7.79–7.75(m,3H),7.59(t,J＝7.5Hz,2H),7.54–7.44(m,3H),7.43–7.35(m,3H),7.30–7.23(m,2H),3.57(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.03–1.95(m,2H),1.86–1.78(m,2H).LRMS(EI)m/z:561(M+H)
+.
实施例51 1-(2,5-二氟苯基)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621053)
将2-氟-4-硝基苯酚替换成3-氟-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例21，得产物DC621053，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.45(s,1H),8.52(s,1H),7.67–7.50(m,6H),7.42(s,1H),7.17(d,J＝8.7Hz,1H),3.99(s,3H),3.98(s,3H),3.55(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.01–1.95(m,2H),1.88-1.74(m,2H).LRMS(EI)m/z:592(M+H)
+.
实施例52 1-(2,5-二氟苯基)-N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621054)
将2-氟-4-硝基苯酚替换成3-氟-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例21，得产物DC621054，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.67(s,1H),8.57(s,1H),8.48(t,J＝9.0Hz,1H),7.69–7.54(m,4H),7.46–7.39(m,2H),7.20–7.13(m,1H),4.38–4.29(m,4H),3.79–3.73(m,4H),3.53(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.3Hz,2H),2.05–1.93(m,2H),1.89–1.75(m,2H).LRMS(EI)m/z:680(M+H)
+.
实施例53 1-(2,5-二氟苯基)-N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621055)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-5-苯基-7H-吡咯并[2,3-d]嘧啶，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621055，收率80％。
1HNMR(400MHz,DMSO-d6)δ12.54(s,1H),10.55(s,1H),8.33(s,1H),7.88(dd,J＝12.8,2.2Hz,1H),7.82–7.74(m,3H),7.68–7.53(m,3H),7.45–7.35(m,3H),7.28(d,J＝7.5Hz,2H),3.57(t,J＝5.8Hz,2H),3.21(t,J＝6.0Hz,2H),2.07–1.96(m,2H),1.88–1.76(m,2H).LRMS(EI)m/z:597(M+H)
+.
实施例54 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-2-氟苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621056)
将2-氟-4-硝基苯酚替换成3-氟-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例21，得产物DC621056，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.75(s,1H),8.58(s,1H),8.50(t,J＝9.0Hz,1H),7.70–7.60(m,2H),7.57–7.50(m,2H),7.47–7.38(m,3H),7.19–7.14(m,1H),3.99(s,3H),3.97(s,3H),3.52(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.03–1.93(m,2H),1.87–1.77(m,2H).LRMS(EI)m/z:574(M+H)
+.
实施例55 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-2-氟苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621057)
将2-氟-4-硝基苯酚替换成3-氟-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备 方法同实施例21，得产物DC621057，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.74(s,1H),8.57(s,1H),8.49(t,J＝9.0Hz,1H),7.69–7.61(m,2H),7.59(s,1H),7.58–7.50(m,1H),7.47–7.39(m,3H),7.20–7.13(m,1H),4.38–4.26(m,4H),3.79–3.73(m,4H),3.52(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.1Hz,2H),2.03–1.93(m,2H),1.86–1.77(m,2H).LRMS(EI)m/z:662(M+H)
+.
实施例56 N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621058)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-5-苯基-7H-吡咯并[2,3-d]嘧啶，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621058，收率80％。
1HNMR(400MHz,DMSO-d6)δ12.54(s,1H),10.63(s,1H),8.33(s,1H),7.88(dd,J＝12.8,2.3Hz,1H),7.77(d,J＝6.9Hz,3H),7.70–7.58(m,2H),7.53(t,J＝8.7Hz,1H),7.46–7.34(m,4H),7.27(t,J＝7.4Hz,2H),3.54(t,J＝5.8Hz,2H),3.20(t,J＝6.1Hz,2H),2.02–1.93(m,2H),1.86–1.76(m,2H).LRMS(EI)m/z:579(M+H)
+.
实施例57 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-2-氟苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621059)
将2-氟-4-硝基苯酚替换成3-氟-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例21，得产物DC621059，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.75(s,1H),8.58(s,1H),8.50(t,J＝9.0Hz,1H),7.70–7.60(m,2H),7.57–7.50(m,2H),7.47–7.38(m,3H),7.19–7.14(m,1H),3.99(s,3H),3.97(s,3H),3.53(t,J＝5.8Hz,2H),3.22(t,J＝6.2Hz,2H),2.03–1.96(m,2H),1.87-1.75(m,2H).LRMS(EI)m/z:574(M+H)
+.
实施例58 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-4-氟苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621060)
将2-氟-4-硝基苯酚替换成3-氟-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例21，得产物DC621060，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.85(s,1H),8.56(s,1H),8.50(t,J＝9.0Hz,1H),7.61–7.50(m,3H),7.47–7.39(m,4H),7.21–7.12(m,1H),4.37–4.29(m,4H),3.79–3.73(m,4H),3.56(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.20(t,J＝6.3Hz,2H),2.03–1.94(m,2H),1.87–1.77(m,2H).LRMS(EI)m/z:662(M+H)
+.
实施例59 N-(3-氟-4-((7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉-4-基)氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621061)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621061，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.80(s,1H),8.59(s,1H),7.93(dd,J＝12.9,2.4Hz, 1H),7.83(s,1H),7.59(t,J＝7.4Hz,2H),7.54–7.44(m,4H),7.41(t,J＝8.8Hz,1H),7.31(dd,J＝8.9,1.5Hz,1H),4.40–4.30(m,4H),3.84–3.79(m,2H),3.76–3.72(m,2H),3.64(s,4H),3.58(t,J＝5.9Hz,2H),3.21(t,J＝6.3Hz,2H),2.02–1.94(m,2H),1.86–1.78(m,2H).LRMS(EI)m/z:642(M+H)
+.
实施例60 N-(3-氯-4-((7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉-4-基)氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621062)
将2-氟-4-硝基苯酚替换成2-氯-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621062，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.79(s,1H),8.57(s,1H),8.12(d,J＝2.3Hz,1H),7.83(s,1H),7.62–7.56(m,3H),7.55–7.41(m,5H),4.41–4.29(m,4H),3.85–3.79(m,2H),3.77–3.72(m,2H),3.65(s,4H),3.49(t,J＝5.9Hz,2H),3.21(t,J＝6.3Hz,2H),2.02–1.95(m,2H),1.86–1.78(m,2H).LRMS(EI)m/z:658(M+H)
+.
实施例61 1-(2,5-二氟苯基)-N-(3-氟-4-((7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉-4-基)氧基)苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621063)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621063，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.59(s,1H),7.92(dd,J＝12.7,1.9Hz,1H),7.83(s,1H),7.69–7.50(m,4H),7.42(t,J＝8.7Hz,1H),7.32(dd,J＝8.7,1.3Hz,1H),4.42–4.26(m,4H),3.84–3.78(m,2H),3.77–3.70(m,2H),3.64(s,4H),3.47(t,J＝5.9Hz,2H),3.21(t,J＝5.9Hz,2H),2.04–1.94(m,2H),1.87–1.77(m,2H).LRMS(EI)m/z:678(M+H)
+.
实施例62 1-(2,5-二氟苯基)-N-(3-氯-4-((7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉-4-基)氧基)苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621064)
将2-氟-4-硝基苯酚替换成2-氯-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621064，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.56(s,1H),8.57(s,1H),8.12(d,J＝2.3Hz,1H),7.83(s,1H),7.69–7.52(m,4H),7.50–7.41(m,2H),4.39–4.30(m,4H),3.84–3.79(m,2H),3.77–3.72(m,2H),3.65(s,4H),3.49(t,J＝5.9Hz,2H),3.21(t,J＝6.3Hz,2H),2.03–1.95(m,2H),1.86–1.77(m,2H).LRMS(EI)m/z:694(M+H)
+.
实施例63 N-(3-氟-4-((7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉-4-基)氧基)苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺 (DC621065)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621065，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.66(s,1H),8.59(s,1H),7.92(dd,J＝12.9,2.1Hz,1H),7.83(s,1H),7.73–7.61(m,2H),7.57–7.51(m,2H),7.43(dd,J＝18.6,8.4Hz,2H),7.31(d,J＝8.6Hz,1H),4.41–4.29(m,4H),3.85–3.79(m,2H),3.77–3.72(m,2H),3.65(s,4H),3.47(t,J＝5.8Hz,2H),3.21(t,J＝6.1Hz,2H),2.04–1.92(m,2H),1.86–1.77(m,2H).LRMS(EI)m/z:660(M+H)
+.
实施例64 N-(3-氯-4-((7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉-4-基)氧基)苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621066)
将2-氟-4-硝基苯酚替换成2-氯-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621066，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.64(s,1H),8.57(s,1H),8.12(d,J＝2.3Hz,1H),7.83(s,1H),7.70–7.59(m,2H),7.57–7.50(m,2H),7.49–7.41(m,3H),4.40–4.29(m,4H),3.86–3.79(m,2H),3.78–3.71(m,2H),3.65(s,4H),3.48(t,J＝5.8Hz,2H),3.20(t,J＝6.1Hz,2H),2.03–1.94(m,2H),1.87–1.76(m,2H).LRMS(EI)m/z:676(M+H)
+.
实施例65 N-(3-氟-4-((7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉-4-基)氧基)苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621067)
将4-氯-6,7-二甲氧基喹啉替换成4-氯-7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621067，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.77(s,1H),8.58(s,1H),7.92(dd,J＝12.9,2.4Hz,1H),7.83(s,1H),7.58–7.52(m,3H),7.48–7.37(m,3H),7.33–7.28(m,1H),4.39–4.31(m,4H),3.84–3.79(m,2H),3.77–3.72(m,2H),3.64(s,4H),3.56(t,J＝5.8Hz,2H),3.20(t,J＝6.2Hz,2H),2.01–1.94(m,2H),1.87–1.78(m,2H).LRMS(EI)m/z:660(M+H)
+.
实施例66 N-(3-氯-4-((7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉-4-基)氧基)苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621068)
将2-氟-4-硝基苯酚替换成2-氯-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-7,8,10,11,13,14-六氢-[1,4,7,10]四氧杂环十二烷[2,3-g]喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621068，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.76(s,1H),8.57(s,1H),8.12(d,J＝2.2Hz,1H),7.83(s,1H),7.58–7.51(m,3H),7.49–7.41(m,4H),4.38–4.30(m,4H),3.85–3.78(m,2H),3.77–3.71(m, 2H),3.65(s,4H),3.56(t,J＝5.8Hz,2H),3.20(t,J＝6.3Hz,2H),2.01–1.94(m,2H),1.86–1.78(m,2H).LRMS(EI)m/z:676(M+H)
+.
实施例67 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氯苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621069)
将2-氟-4-硝基苯酚替换成2-氯-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621069，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.79(s,1H),8.55(s,1H),8.12(d,J＝2.4Hz,1H),7.62–7.56(m,3H),7.54–7.50(m,1H),7.49–7.41(m,5H),4.00(s,3H),3.98(s,3H),3.58(t,J＝5.8Hz,2H),3.21(t,J＝6.3Hz,2H),2.02–1.96(m,2H),1.87–1.79(m,2H).LRMS(EI)m/z:572(M+H)
+.
实施例68 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-氯苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621070)
将2-氟-4-硝基苯酚替换成2-氯-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621070，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.81(s,1H),8.46(s,1H),8.05(s,1H),7.72(d,J＝2.9Hz,1H),7.60–7.46(m,3H),7.41–7.31(m,3H),7.29–7.23(m,1H),7.03(d,J＝15.0Hz,1H),4.43–4.29(m,4H),3.84–3.67(m,4H),3.58(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.1Hz,2H),2.06–1.96(m,2H),1.88–1.76(m,2H).LRMS(EI)m/z:660(M+H)
+.
实施例69 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-三氟甲基苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621071)
将2-氟-4-硝基苯酚替换成2-三氟甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621071，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.81(s,1H),8.45(s,1H),7.87(s,1H),7.85(d,J＝3.1Hz,1H),7.56–7.46(m,3H),7.41–7.28(m,4H),6.80(d,J＝15.0Hz,1H),3.99(s,3H),3.98(s,3H),3.58(t,J＝5.8Hz,2H),3.22(t,J＝6.2Hz,2H),2.06–1.95(m,2H),1.88–1.77(m,2H).LRMS(EI)m/z:606(M+H)
+.
实施例70 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-三氟甲基苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621072)
将2-氟-4-硝基苯酚替换成2-三氟甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621072，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.64(s,1H),8.46(s,1H),7.86(d,J＝3.1Hz,1H),7.77(s,1H),7.64–7.46(m,2H),7.44–7.27(m,5H),6.81(d,J＝15.0Hz,1H),4.37–4.26(m,4H),3.80–3.75(m,4H),3.59(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.22(t,J＝6.3Hz,2H),2.07–1.93(m,2H),1.88–1.77(m,2H).LRMS(EI) m/z:694(M+H)
+.
实施例71 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)萘-1-基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621073)
将2-氟-4-硝基苯酚替换成4-硝基-1-萘酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，其余所需原料、试剂及制备方法同实施例21，得产物DC621073，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.64(s,1H),8.45(s,1H),8.24(dd,J＝14.9,3.0Hz,1H),7.97(dd,J＝14.8,3.1Hz,1H),7.80(s,1H),7.69–7.46(m,3H),7.44–7.28(m,5H),6.81(d,J＝15.0Hz,1H),6.05(d,J＝14.8Hz,1H),3.99(s,3H),3.97(s,3H),3.58(t,J＝5.8Hz,2H),3.23(t,J＝6.3Hz,2H),2.03–1.95(m,2H),1.87–1.78(m,2H).LRMS(EI)m/z:588(M+H)
+.
实施例72 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-三氟甲基苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621074)
将2-氟-4-硝基苯酚替换成4-硝基-1-萘酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，其余所需原料、试剂及制备方法同实施例21，得产物DC621074，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.64(s,1H),8.46(s,1H),8.25(dd,J＝14.9,3.0Hz,1H),8.10(s,1H),7.98(dd,J＝14.9,3.0Hz,1H),7.68–7.47(m,3H),7.44–7.30(m,5H),6.82(d,J＝15.0Hz,1H),6.06(d,J＝15.0Hz,1H),4.38–4.27(m,4H),3.78–3.71(m,4H),3.56(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.3Hz,2H),2.04–1.95(m,2H),1.86–1.77(m,2H).LRMS(EI)m/z:676(M+H)
+.
实施例73 N-(5-(6,7-二甲氧基喹唑啉-4-基)氧基)吡啶-2-基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621075)
将2-氟-4-硝基苯酚替换成5-羟基-2-硝基吡啶，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621075，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.89(s,1H),8.82(d,J＝15.0Hz,1H),8.42(s,1H),8.12(d,J＝2.9Hz,1H),7.66(s,1H),7.58–7.41(m,2H),7.35–7.29(m,4H),7.28–7.23(m,1H),3.99(s,3H),3.98(s,3H),3.59(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.04–1.94(m,2H),1.88–1.78(m,2H).LRMS(EI)m/z:539(M+H)
+.
实施例74 N-(5-(6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)吡啶-2-基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621076)
将2-氟-4-硝基苯酚替换成5-羟基-2-硝基吡啶，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621076，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.89(s,1H),8.84(d,J＝14.8Hz,1H),8.44(s,1H),8.14(d,J＝3.1Hz,1H),8.02(s,1H),7.69(s,1H),7.55–7.46(m,2H),7.40–7.24(m,4H),4.39–4.25(m,4H),3.78–3.71(m,4H),3.59(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.2Hz,2H),2.02–1.95(m,2H),1.88–1.76(m,2H). LRMS(EI)m/z:627(M+H)
+.
实施例75 (R)-N-(3-氟-4-((6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉-4-基)氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621077)
将4-氯-6,7-二甲氧基喹啉替换成(R)-4-氯-6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621077，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.89(s,1H),8.44(s,1H),7.81(s,1H),7.65–7.42(m,3H),7.39–7.28(m,4H),7.13(dd,J＝15.0,3.0Hz,1H),6.84(dd,J＝14.9,10.0Hz,1H),5.03–4.95(m,1H),4.23–4.13(m,1H),4.07–4.01(m,1H),3.91(s,3H)3.87–3.80(m,1H),3.78–3.73(m,1H),3.58(t,J＝5.8Hz,2H),3.22(t,J＝6.2Hz,2H),2.44–2.31(m,1H),2.19–2.10(m,1H),2.02–1.95(m,2H),1.88–1.76(m,2H).LRMS(EI)m/z:612(M+H)
+.
实施例76 (S)-N-(3-氟-4-((6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉-4-基)氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621078)
将4-氯-6,7-二甲氧基喹啉替换成(S)-4-氯-6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉，其余所需原料、试剂及制备方法同实施例1，得产物DC621078，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.89(s,1H),8.42(s,1H),7.82(s,1H),7.66–7.41(m,3H),7.37–7.27(m,4H),7.15(dd,J＝15.0,3.0Hz,1H),6.86(dd,J＝14.9,10.0Hz,1H),5.05–4.97(m,1H),4.21–4.12(m,1H),4.06–4.02(m,1H),3.93(s,3H)3.86–3.80(m,1H),3.77–3.72(m,1H),3.59(t,J＝5.8Hz,2H),3.23(t,J＝6.2Hz,2H),2.45–2.30(m,1H),2.18–2.11(m,1H),2.04–1.93(m,2H),1.85–1.75(m,2H).LRMS(EI)m/z:612(M+H)
+.
施例77 1-(2,5-二氟苯基)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氯苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621079)
将2-氟-4-硝基苯酚替换成2-氯-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621079，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.56(s,1H),8.56(s,1H),8.12(d,J＝2.4Hz,1H),7.68–7.53(m,4H),7.50–7.45(m,1H),7.44–7.39(m,2H),4.00(s,3H),3.98(s,3H),3.55(t,J＝5.8Hz,2H),3.21(t,J＝6.3Hz,2H),2.04–1.94(m,2H),1.89–1.76(m,2H).LRMS(EI)m/z:608(M+H)
+.
实施例78 1-(2,5-二氟苯基)-N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-氯苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621080)
将2-氟-4-硝基苯酚替换成2-氯-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621080，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.46(s,1H),8.05(s,1H),7.72(d,J＝3.1Hz,1H),7.51(s,1H),7.26(dd,J＝15.0,2.9Hz,1H),7.18–7.07(m,1H),7.05–6.92(m,2H),6.64–6.54(m,1H),4.39–4.32(m,4H),3.82-3.74(m,4H),3.55(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.24(t,J＝6.2 Hz,2H),2.06–1.97(m,2H),1.85–1.76(m,2H).LRMS(EI)m/z:696(M+H)
+.
实施例79 1-(2,5-二氟苯基)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-三氟甲基苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621081)
将2-氟-4-硝基苯酚替换成2-三氟甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621081，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.46(s,1H),7.86(d,J＝3.1Hz,1H),7.76(s,1H),7.38(dd,J＝14.9,3.0Hz,1H),7.35(s,1H),7.16–7.07(m,1H),7.03–6.95(m,1H),6.81(d,J＝15.0Hz,1H),6.67–6.52(m,1H),3.99(s,3H),3.98(s,3H),3.58(t,J＝5.8Hz,2H),3.23(t,J＝6.2Hz,2H),2.06–1.95(m,2H),1.88–1.73(m,2H).LRMS(EI)m/z:642(M+H)
+.
实施例80 1-(2,5-二氟苯基)-N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-三氟甲基苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621082)
将2-氟-4-硝基苯酚替换成2-三氟甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621082，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.68(s,1H),8.45(s,1H),7.85(d,J＝3.1Hz,1H),7.79(s,1H),7.43(s,1H),7.37(dd,J＝15.0,2.9Hz,1H),7.17–7.07(m,1H),7.02–6.93(m,1H),6.80(d,J＝15.0Hz,1H),6.63–6.54(m,1H),4.38–4.30(m,4H),3.83–3.74(m,4H),3.58(t,J＝5.7Hz,2H),3.36(s,3H),3.36(s,3H),3.24(t,J＝6.2Hz,2H),2.05–1.93(m,2H),1.88–1.76(m,2H).LRMS(EI)m/z:730(M+H)
+.
实施例81 1-(2,5-二氟苯基)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)萘-1-基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621083)
将2-氟-4-硝基苯酚替换成4-硝基-1-萘酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例21，得产物DC621083，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.42(s,1H),8.44(s,1H),8.24(dd,J＝14.9,3.0Hz,1H),7.97(dd,J＝14.9,3.0Hz,1H),7.82(s,1H),7.67–7.55(m,2H),7.43–7.32(m,1H),7.17–7.08(m,1H),7.02–6.93(m,1H),6.81(d,J＝15.0Hz,1H),6.63–6.52(m,1H),6.05(d,J＝15.0Hz,1H),4.00(s,3H),3.98(s,3H),3.56(t,J＝5.8Hz,2H),3.22(t,J＝6.2Hz,2H),2.03–1.94(m,2H),1.89-1,78(m,2H).LRMS(EI)m/z:624(M+H)
+.
实施例82 1-(2,5-二氟苯基)-N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)萘-1-基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621084)
将2-氟-4-硝基苯酚替换成4-硝基-1-萘酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例21，得产物DC621084，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.42 (s,1H),8.46(s,1H),8.25(dd,J＝14.9,3.0Hz,1H),8.10(s,1H),7.98(dd,J＝14.9,3.1Hz,1H),7.67–7.58(m,1H),7.48–7.31(m,2H),7.18–7.08(m,1H),7.03–6.94(m,1H),6.82(d,J＝15.0Hz,1H),6.64–6.53(m,1H),6.06(d,J＝15.0Hz,1H),4.38-4.30(m,4H),3.80–3.72(m,4H),3.58(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.23(t,J＝6.2Hz,2H),2.03–1.95(m,2H),1.85–1.71(m,2H).LRMS(EI)m/z:712(M+H)
+.
实施例83 1-(2,5-二氟苯基)-N-(5-(6,7-二甲氧基喹唑啉-4-基)氧基)吡啶-2-基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621085)
将2-氟-4-硝基苯酚替换成5-羟基-2-硝基吡啶，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621085，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.45(s,1H),8.85(d,J＝15.0Hz,1H),8.45(s,1H),8.15(d,J＝2.9Hz,1H),7.68(s,1H),7.35(s,1H),7.28(dd,J＝15.0,3.1Hz,1H),7.16–7.07(m,1H),7.02–6.93(m,1H),6.63–6.52(m,1H),4.00(s,3H),3.98(s,3H),3.57(t,J＝5.8Hz,2H),3.22(t,J＝6.2Hz,2H),2.02–1.94(m,2H),1.87-1.75(m,2H).LRMS(EI)m/z:575(M+H)
+.
实施例84 1-(2,5-二氟苯基)-N-(5-(6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)吡啶-2-基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621086)
将2-氟-4-硝基苯酚替换成5-羟基-2-硝基吡啶，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621086，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.67(s,1H),8.86(d,J＝15.0Hz,1H),8.46(s,1H),8.16(d,J＝3.1Hz,1H),8.02(s,1H),7.53(s,1H),7.29(dd,J＝15.0,3.1Hz,1H),7.18–7.08(m,1H),7.03-6.92(m,1H),6.64–6.54(m,1H),4.37–4.29(m,4H),3.78–3.72(m,4H),3.55(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.23(t,J＝6.3Hz,2H),2.02–1.93(m,2H),1.86–1.75(m,2H).LRMS(EI)m/z:663(M+H)
+.
实施例85 (R)-1-(2,5-二氟苯基)-N-(3-氟-4-((6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉-4-基)氧基)苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621087)
将4-氯-6,7-二甲氧基喹啉替换成(R)-4-氯-6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621087，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.89(s,1H),8.45(s,1H),7.77(s,1H),7.61(s,1H),7.57(dd,J＝15.9,2.9Hz,1H),7.18–7.06(m,2H),7.02-6.93(m,1H),6.85(dd,J＝15.0,10.1Hz,1H),6.64-6.53(m,1H),5.04–4.96(m,1H),4.22–4.13(m,1H),4.07–4.02(m,1H),3.93(s,3H)3.86–3.80(m,1H),3.79–3.73(m,1H),3.56(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.42–2.31(m,1H),2.18–2.10(m,1H),2.02–1.94(m,2H),1.88–1.79(m,2H).LRMS(EI)m/z:648(M+H)
+.
实施例86 (S)-1-(2,5-二氟苯基)-N-(3-氟-4-((6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉 -4-基)氧基)苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621088)
将4-氯-6,7-二甲氧基喹啉替换成(S)-4-氯-6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉，将苯肼替换成2,5-二氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621088，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.88(s,1H),8.43(s,1H),7.75(s,1H),7.63(s,1H),7.59(dd,J＝15.9,2.9Hz,1H),7.17–7.07(m,2H),7.01-6.93(m,1H),6.86(dd,J＝15.0,10.1Hz,1H),6.62-6.53(m,1H),5.03–4.96(m,1H),4.21–4.13(m,1H),4.08–4.02(m,1H),3.95(s,3H)3.87–3.80(m,1H),3.79–3.71(m,1H),3.54(t,J＝5.8Hz,2H),3.23(t,J＝6.2Hz,2H),2.42–2.33(m,1H),2.18–2.11(m,1H),2.02–1.95(m,2H),1.89–1.79(m,2H).LRMS(EI)m/z:648(M+H)
+.
实施例87 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氯苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621089)
将2-氟-4-硝基苯酚替换成2-氯-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621089，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.64(s,1H),8.56(s,1H),8.12(d,J＝2.3Hz,1H),7.70–7.60(m,2H),7.58–7.50(m,2H),7.49–7.40(m,4H),4.00(s,3H),3.98(s,3H),3.56(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.03–1.93(m,2H),1.86–1.77(m,2H).LRMS(EI)m/z:590(M+H)
+.
实施例88 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-氯苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621090)
将2-氟-4-硝基苯酚替换成2-氯-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621090，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.66(s,1H),8.44(s,1H),8.01(s,1H),7.70(d,J＝2.9Hz,1H),7.41(s,1H),7.24(dd,J＝15.0,2.9Hz,1H),7.06–6.93(m,3H),6.92–6.82(m,1H),6.70–6.55(m,1H),4.41–4.27(m,4H),3.79–3.71(m,4H),3.58(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.2Hz,2H),2.01–1.92(m,2H),1.86–1.78(m,2H).LRMS(EI)m/z:678(M+H)
+.
实施例89 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-三氟甲基苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621091)
将2-氟-4-硝基苯酚替换成2-三氟甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621091，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.45(s,1H),8.04–7.73(m,2H),7.57(s,1H),7.37(dd,J＝14.9,3.0Hz,1H),7.10–6.95(m,2H),6.93–6.83(m,1H),6.80(d,J＝15.0Hz,1H),6.68–6.56(m,1H),3.99(s,3H),3.97(s,3H),3.50(t,J＝5.8Hz,2H),3.22(t,J＝6.2Hz,2H),2.02–1.95(m,2H),1.84–1.77(m,2H).LRMS(EI)m/z:624(M+H)
+.
实施例90 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-三氟甲基苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621092)
将2-氟-4-硝基苯酚替换成2-三氟甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621092，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.50(s,1H),8.45(s,1H),8.01(s,1H),7.85(d,J＝3.1Hz,1H),7.40(s,1H),7.37(dd,J＝15.0,3.1Hz,1H),7.06–6.95(m,2H),6.92–6.83(m,1H),6.80(d,J＝15.0Hz,1H),6.67-6.56(m,1H),4.40–4.28(m,4H),3.79–3.73(m,4H),3.56(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.23(t,J＝6.2Hz,2H),2.02–1.94(m,2H),1.83–1.75(m,2H).LRMS(EI)m/z:712(M+H)
+.
实施例91 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)萘-1-基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621093)
将2-氟-4-硝基苯酚替换成4-硝基-1-萘酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例21，得产物DC621093，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.45(s,1H),8.24(dd,J＝14.9,3.0Hz,1H),7.97(dd,J＝14.9,3.0Hz,1H),7.89(s,1H),7.68–7.53(m,2H),7.42–7.34(m,1H),7.08–6.94(m,2H),6.92–6.84(m,1H),6.81(d,J＝15.0Hz,1H),6.65–6.56(m,1H),6.05(d,J＝15.0Hz,1H),3.98(s,3H),3.97(s,3H),3.54(t,J＝5.8Hz,2H),3.23(t,J＝6.2Hz,2H),2.03–1.95(m,2H),1.84–1.75(m,2H).LRMS(EI)m/z:606(M+H)
+.
实施例92 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)萘-1-基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621094)
将2-氟-4-硝基苯酚替换成4-硝基-1-萘酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例21，得产物DC621094，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.45(s,1H),8.24(dd,J＝14.9,3.0Hz,1H),8.07(s,1H),7.97(dd,J＝14.9,3.0Hz,1H),7.66–7.58(m,1H),7.47–7.29(m,2H),7.06–6.95(m,2H),6.92–6.83(m,1H),6.81(d,J＝15.0Hz,1H),6.70–6.56(m,1H),6.05(d,J＝15.0Hz,1H),4.39–4.27(m,4H),3.81–3.72(m,4H),3.53(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.24(t,J＝6.1Hz,2H),2.02–1.93(m,2H),1.85–1.76(m,2H).LRMS(EI)m/z:694(M+H)
+.
实施例93 N-(5-(6,7-二甲氧基喹唑啉-4-基)氧基)吡啶-2-基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621095)
将2-氟-4-硝基苯酚替换成5-羟基-2-硝基吡啶，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621095，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.75(s,1H),8.85(d,J＝15.0Hz,1H),8.45(s,1H),8.15(d,J＝2.9Hz,1H),7.83(s,1H),7.72(s,1H),7.28 (dd,J＝15.0,2.9Hz,1H),7.07–6.94(m,2H),6.91–6.85(m,1H),6.67–6.56(m,1H),3.99(s,3H),3.98(s,3H),3.54(t,J＝5.8Hz,2H),3.24(t,J＝6.2Hz,2H),2.02–1.93(m,2H),1.85–1.77(m,2H).LRMS(EI)m/z:557(M+H)
+.
实施例94 N-(5-(6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)吡啶-2-基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621096)
将2-氟-4-硝基苯酚替换成5-羟基-2-硝基吡啶，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621096，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.74(s,1H),8.86(d,J＝15.0Hz,1H),8.46(s,1H),8.16(d,J＝3.1Hz,1H),7.85(s,1H),7.40(s,1H),7.29(dd,J＝14.9,3.0Hz,1H),7.15–6.95(m,2H),6.94–6.79(m,1H),6.67–6.56(m,1H),4.36–4.26(m,4H),3.79–3.74(m,4H),3.55(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.23(t,J＝6.1Hz,2H),2.02–1.93(m,2H),1.86–1.75(m,2H).LRMS(EI)m/z:645(M+H)
+.
实施例95 (R)-N-(3-氟-4-((6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉-4-基)氧基)苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621097)
将4-氯-6,7-二甲氧基喹啉替换成(R)-4-氯-6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉，将苯肼替换成2-苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621097，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.89(s,1H),8.46(s,1H),7.72(s,1H),7.58(dd,J＝16.0,3.0Hz,1H),7.42(s,1H),7.15(dd,J＝15.0,3.0Hz,1H),7.09–6.95(m,2H),6.93–6.81(m,2H),6.67–6.57(m,1H),5.05–4.96(m,1H),4.21–4.13(m,1H),4.06–4.02(m,1H),3.94(s,3H),3.85–3.80(m,1H),3.78–3.73(m,1H),3.54(t,J＝5.8Hz,2H),3.20(t,J＝6.2Hz,2H),2.44–2.31(m,1H),2.18–2.11(m,1H),2.02–1.95(m,2H),1.88–1.77(m,2H).LRMS(EI)m/z:630(M+H)
+.
实施例96 (S)-N-(3-氟-4-((6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉-4-基)氧基)苯基)-1-(2-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621098)
将4-氯-6,7-二甲氧基喹啉替换成(S)-4-氯-6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉，将苯肼替换成2-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621098，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.88(s,1H),8.45(s,1H),7.73(s,1H),7.56(dd,J＝16.0,3.0Hz,1H),7.44(s,1H),7.13(dd,J＝15.0,3.0Hz,1H),7.09–6.97(m,2H),6.93–6.84(m,2H),6.67–6.59(m,1H),5.07–4.96(m,1H),4.23–4.13(m,1H),4.06–4.01(m,1H),3.96(s,3H),3.86–3.80(m,1H),3.78–3.71(m,1H),3.56(t,J＝5.8Hz,2H),3.22(t,J＝6.2Hz,2H),2.42–2.31(m,1H),2.18–2.11(m,1H),2.04–1.95(m,2H),1.89–1.77(m,2H).LRMS(EI)m/z:630(M+H)
+.
实施例97 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氯苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621099)
将2-氟-4-硝基苯酚替换成2-氯-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621099，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.76(s,1H),8.55(s,1H),8.12(d,J＝2.3Hz,1H),7.58–7.53(m,3H),7.49–7.40(m,5H),4.00(s,3H),3.98(s,3H),3.56(t,J＝5.8Hz,2H),3.20(t,J＝6.3Hz,2H),2.02–1.94(m,2H),1.85–1.78(m,2H).LRMS(EI)m/z:590(M+H)
+.
实施例98 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-氯苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621100)
将2-氟-4-硝基苯酚替换成2-氯-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621100，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.66(s,1H),8.46(s,1H),8.04(s,1H),7.72(d,J＝3.1Hz,1H),7.41(s,1H),7.26(dd,J＝14.9,3.0Hz,1H),7.07–6.95(m,3H),6.88(dd,J＝15.0,10.0Hz,2H),4.42–4.27(m,4H),3.79–3.72(m,4H),3.57(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.22(t,J＝6.2Hz,2H),2.02–1.92(m,2H),1.87–1.78(m,2H).LRMS(EI)m/z:678(M+H)
+.
实施例99 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-三氟甲基苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621101)
将2-氟-4-硝基苯酚替换成2-三氟甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621101，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.46(s,1H),7.90(s,1H),7.86(d,J＝3.1Hz,1H),7.66(s,1H),7.38(dd,J＝14.9,3.0Hz,1H),7.05–6.95(m,2H),6.94–6.75(m,3H),3.98(s,3H),3.97(s,3H),3.53(t,J＝5.8Hz,2H),3.20(t,J＝6.2Hz,2H),2.01–1.95(m,2H),1.85–1.77(m,2H).LRMS(EI)m/z:624(M+H)
+.
实施例100 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)-3-三氟甲基苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621102)
将2-氟-4-硝基苯酚替换成2-三氟甲基-4-硝基苯酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621102，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.50(s,1H),8.46(s,1H),8.02(s,1H),7.86(d,J＝3.1Hz,1H),7.45–7.32(m,2H),7.15–6.95(m,2H),6.94–6.70(m,3H),4.40–4.29(m,4H),3.79–3.72(m,4H),3.58(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.24(t,J＝6.2Hz,2H),2.03–1.94(m,2H),1.84–1.75(m,2H).LRMS(EI)m/z:712(M+H)
+.
实施例101 N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)萘-1-基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621103)
将2-氟-4-硝基苯酚替换成4-硝基-1-萘酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例21，得产物DC621103，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.44(s,1H),8.23(dd,J＝14.9,3.0Hz,1H),7.96(dd,J＝14.9,3.0Hz,1H),7.83(s,1H),7.66–7.48(m,2H),7.42–7.33(m,1H),7.04-6.95(m,2H),6.89–6.78(m,3H),6.04(d,J＝14.8Hz,1H),3.99(s,3H),3.97(s,3H),3.56(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.02–1.95(m,2H),1.86–1.75(m,2H).LRMS(EI)m/z:606(M+H)
+.
实施例102 N-(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氧基)萘-1-基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621104)
将2-氟-4-硝基苯酚替换成4-硝基-1-萘酚，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例21，得产物DC621104，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.46(s,1H),8.25(dd,J＝14.9,3.0Hz,1H),8.06(s,1H),7.98(dd,J＝14.8,3.1Hz,1H),7.62(d,J＝3.1Hz,1H),7.49–7.26(m,2H),7.09–6.95(m,2H),6.94–6.74(m,3H),6.06(d,J＝15.0Hz,1H),4.38–4.27(m,4H),3.83–3.72(m,4H),3.51(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.22(t,J＝6.1Hz,2H),2.02–1.94(m,2H),1.87–1.76(m,2H).LRMS(EI)m/z 694(M+H)
+.
实施例103 N-(5-(6,7-二甲氧基喹唑啉-4-基)氧基)吡啶-2-基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621105)
将2-氟-4-硝基苯酚替换成5-羟基-2-硝基吡啶，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二甲氧基喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621105，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.75(s,1H),8.86(d,J＝15.0Hz,1H),8.46(s,1H),8.16(d,J＝3.1Hz,1H),7.85(s,1H),7.62(s,1H),7.29(dd,J＝15.0,3.1Hz,1H),7.12–6.95(m,2H),6.94–6.81(m,2H),3.99(s,3H),3.97(s,3H),3.56(t,J＝5.8Hz,2H),3.23(t,J＝6.2Hz,2H),2.02–1.94(m,2H),1.85–1.76(m,2H).LRMS(EI)m/z:557(M+H)
+.
实施例104 N-(5-(6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)吡啶-2-基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621106)
将2-氟-4-硝基苯酚替换成5-羟基-2-硝基吡啶，将4-氯-6,7-二甲氧基喹啉替换成4-氯-6,7-二((2-甲氧基乙氧基)喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621106，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.74(s,1H),8.85(d,J＝15.0Hz,1H),8.45(s,1H),8.15(d,J＝3.1Hz,1H),7.84(s,1H),7.40(s,1H),7.28(dd,J＝15.0,2.9Hz,1H),7.11–6.94(m,2H),6.92–6.82(m,2H),4.36–4.25(m,4H),3.79–3.73(m,4H),3.57(t,J＝5.8Hz,2H),3.36(s,3H),3.36(s,3H),3.21(t,J＝6.1Hz,2H),2.02–1.94(m,2H),1.86–1.77(m,2H).LRMS(EI)m/z:645(M+H)
+.
实施例105 (R)-N-(3-氟-4-((6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉-4-基)氧基)苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621107)
将4-氯-6,7-二甲氧基喹啉替换成(R)-4-氯-6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉，将苯肼替换成4-苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621107，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.89(s,1H),8.44(s,1H),7.76(d,J＝8.8Hz,2H),7.57(dd,J＝15.9,2.9Hz,1H),7.14(dd,J＝15.0,3.1Hz,1H),7.07–6.93(m,2H),6.91–6.77(m,3H),5.05–4.97(m,1H),4.22–4.13(m,1H),4.06–4.01(m,1H),3.95(s,3H),3.86–3.80(m,1H),3.78–3.72(m,1H),3.56(t,J＝5.8Hz,2H),3.22(t,J＝6.2Hz,2H),2.44–2.33(m,1H),2.19–2.11(m,1H),2.02–1.96(m,2H),1.88–1.76(m,2H).LRMS(EI)m/z:630(M+H)
+.
实施例106 (S)-N-(3-氟-4-((6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉-4-基)氧基)苯基)-1-(4-氟苯基)-2-氧代-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(DC621108)
将4-氯-6,7-二甲氧基喹啉替换成(S)-4-氯-6-甲氧基-7-((四氢呋喃-3-基)氧基)喹唑啉，将苯肼替换成4-氟苯肼，其余所需原料、试剂及制备方法同实施例1，得产物DC621108，收率80％。
1HNMR(400MHz,DMSO-d6)δ10.88(s,1H),8.45(s,1H),7.75(d,J＝8.8Hz,2H),7.56(dd,J＝15.9,2.9Hz,1H),7.15(dd,J＝15.0,3.1Hz,1H),7.05–6.93(m,2H),6.92–6.78(m,3H),5.06–4.97(m,1H),4.21–4.13(m,1H),4.07–4.01(m,1H),3.93(s,3H),3.87–3.80(m,1H),3.78–3.73(m,1H),3.56(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.42–2.33(m,1H),2.18–2.11(m,1H),2.03–1.96(m,2H),1.88–1.78(m,2H).LRMS(EI)m/z:630(M+H)
+.
对比例1 N-(4-((4,6-二甲氧基-1,3,5-三嗪-2-基)氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢[1,5-a]吡啶-3-甲酰胺(DC621003)
关键中间体2,4-二甲氧基-6-(4-硝基苯氧基)-1,3,5-三嗪的合成
向100mL茄形瓶中加入5g 2-氯-4,6-二甲氧基-1,3,5-三嗪，4.4g对硝基苯酚，18.6g Cs
2CO
3和75mL DMF，然后室温搅拌过夜。用薄层层析(TLC)监测反应。反应结束后， 向反应液中加入大量水，析出黄色固体，抽滤，得固体7g。LRMS(EI)m/z:279(M+H)
+。(无须纯化，可直接进行下一步)
其余步骤如实施例1，得产物DC621003，收率82％。
1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),7.69–7.62(m,2H),7.62–7.55(m,2H),7.53–7.43(m,3H),7.21–7.13(m,2H),3.90(s,6H),3.56(t,J＝5.8Hz,2H),3.21(t,J＝6.3Hz,2H),2.01–1.95(m,2H),1.87–1.74(m,2H).
13C NMR(101MHz,DMSO-d6)δ173.7,173.3,163.1,161.5,153.9,147.1,137.1,133.1,129.8,129.3,127.7,122.4,120.1,96.5,55.7,46.8,23.8,22.2,19.0.LRMS(EI)m/z 489(M+H)
+.
对比例2 N-(4-((2-甲基嘧啶-4-基)氧基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢[1,5-α]吡啶-3-甲酰胺(DC621005)
将2-氯-4,6-二甲氧基-1,3,5-三嗪替换成4-氯-2-甲基嘧啶，其余所需原料、试剂及制备方法同实施例107，得产物DC621005，收率83％。
1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.53(d,J＝5.8Hz,1H),7.67(d,J＝8.9Hz,2H),7.58(t,J＝7.5Hz,2H),7.54–7.44(m,3H),7.16(d,J＝8.9Hz,2H),6.84(d,J＝5.8Hz,1H),3.56(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.44(s,3H),2.04–1.92(m,2H),1.87–1.73(m,2H).
13C NMR(101MHz,DMSO-d6)δ169.4,168.1,163.1,161.5,159.5,153.9,147.6,136.8,133.1,129.8,129.3,127.7,122.5,120.6,105.4,96.5,46.8,25.9,23.9,22.2,19.1.LRMS(EI)m/z 442(M+H)
+.
药理活性试验实施例
实验实施例1：化合物对受体酪氨酸激酶AXL酶活影响筛选
检测方法：酶联免疫吸附测定(ELISA)
受试受体酪氨酸激酶：AXL
试验批次：2批次
试剂、耗材与仪器：实验中所用激酶由本实验室利用昆虫杆状病毒表达系统表达纯化蛋白激酶区重组蛋白；多聚谷氨酸-酪氨酸肽段【Poly(Glu,Tyr)
4:1】及钒酸钠购自Sigma公司；抗磷酸化单抗PY99购自Santa Cruz公司；辣根过氧化物酶标记羊抗鼠二抗购自Calbiochem公司；ATP及OPD购自上海生工；其余所用试剂均购自国药集团化学试剂有限公司。反应酶标板(#2592)购自Corning公司。实验读板用全波长型酶标仪为Molecular Device公司产品，型号：SpectraMax 190；实验用水为国药集团产蒸馏水。
化合物配制：化合物12000g离心5min，加入DMSO配制成10
-2M储液,涡旋均匀后超声10min待用，-40℃保存。测试时将化合物用DMSO从储液稀释到所测试浓度的100倍(体系中DMSO浓度为1％)。
试验方法：
1、酶反应底物Poly(Glu,Tyr)4:1用无钾离子的PBS(10mM磷酸钠缓冲液，150mM NaCl，pH7.2-7.4)稀释成20μg/mL，125μL/孔包被酶标板，置37℃反应12-16小时。弃去孔中液体。洗板，用T-PBS(含0.1％Tween-20的无钾离子的PBS，200μL/孔)洗板三次，每次5分钟。于37℃烘箱中干燥酶标板1-2小时。
2、每孔加入以反应缓冲液(50mM HEPES pH 7.4,50mM MgCl
2,0.5mM MnCl
2,0.2mM Na
3VO
4,1mM DTT)稀释的ATP溶液49μL，每孔中加入1μL待测试化合物，再加入50μL以反应缓冲液稀释的AXL激酶域重组蛋白启动反应，每次实验需设无ATP对照孔两孔。置37℃摇床(100rpm)反应1小时。弃去孔中液体，T-PBS洗板三次。
3、加入抗体PY99稀释液(抗体用含BSA 5mg/mL的T-PBS 1:500稀释)，100μL/孔，37℃摇床反应0.5小时。弃去孔中液体，T-PBS洗板三次。
4、加入辣根过氧化物酶标记的羊抗鼠二抗稀释液(抗体用含BSA 5mg/ml的T-PBS1:2000稀释)，100μL/孔，37℃摇床反应0.5小时。弃去孔中液体，T-PBS洗板三次。
5、加入2mg/ml的OPD显色液100μL/孔【用含有0.03％H
2O
2的0.1M柠檬酸-柠檬酸钠缓冲液(pH＝5.4)稀释】，25℃避光反应1-10分钟。
6、加入2M H
2SO
4 50μL/孔中止反应，用可调波长式微孔板酶标仪VERSAmax读数，波长为490nm。
7、结果分析
IC
50值采用酶标仪随机附带软件以四参数法回归求得。
表1.化合物对受体酪氨酸激酶AXL酶活抑制率(％)
注：“/”未测。
结论：申请人发现，A环为双环的化合物活性更优，当A环为单环时，如对照化合物DC621003和DC621005，在1000、100、10nM几乎没有活性。经初步的体外酶活抑制检测，共发现有25个化合物具有良好的AXL激酶抑制活性，其10nM浓度下对AXL的抑制率超过50％(表1所示)。我们完成DC621001等8个化合物的IC
50测定，发现其抑制IC
50低于10nM，具有强效的AXL抑制活性，优于阳性药R428和Cabozantinib。
实验实施例2：化合物的激酶谱选择性研究
鉴于化合物对AXL强效抑制活性，我们挑选了其中一个化合物DC621044进行了369种激酶谱的筛选，以期考察化合物对激酶谱的选择性。
结果如图1和下表中所示：
研究结果发现，化合物DC621044具有良好的对于AXL激酶的选择性。在筛选的369种激酶中，化合物DC621044仅对AXL激酶同家族的MER和TYRO3激酶，以及同源性较高的c-Met激酶有较一定的抑制，而对其他激酶基本没有抑制作用，展现出了良好的激酶谱选择性。DC621044比本领域中已经报道的AXL抑制剂R428和Cabozantinib具有更好的选择性，这为选择性的AXL抑制剂的开发提供了较好的基础。
实验实施例3：体外c-Met激酶抑制活性研究
基于化合物DC621044进行了369种激酶谱的筛选结果，发现该化合物对c-Met有一定的抑制活性，我们进一步筛选部分化合物对c-Met激酶的抑制活性。如表2所示，有18个化合物在10nM浓度下对c-Met激酶的抑制率超过50％，表现出良好的c-Met抑制活性。
表2.化合物对受体酪氨酸激酶c-Met酶活抑制
实验实施例4：化合物对BaF3/TEL-AXL细胞增殖效应的影响
在上述酶活性研究结果的基础上，我们进一步探索了化合物对受体酪氨酸激酶AXL介导的细胞增殖影响。如表3所示，化合物DC621024、DC621044、DC621051等多个化合物在1nM浓度下对BaF3/TEL-AXL细胞增殖抑制率>70％，表现出强效的细胞增值抑制作用。
表3.化合物对BaF3/TEL-AXL细胞的增殖抑制
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
- 一种具有如下通式I所示结构的并环吡唑啉酮甲酰胺类化合物，或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物：
其中：n为0～2的整数，优选0或1；X、Y和Z为CH或N；R 1和R 2各自独立地选自下组：氢、氘、氚、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 3-C 8环烷基、C 2-C 6烯基、氰基、硝基、氨基、羟基、羟甲基、羧基和-O[(CH 2) qO] rR 3；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C 1-C 6烷基、卤素取代的C 1-C 6烷基、C 1-C 6烷氧基、卤素取代的C 1-C 6烷氧基、C 1-C 6烷氧基羰基、C 3-C 8环烷基、卤素取代的C 3-C 8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C 6-C 10芳基、和3-12元杂环基；R 3选自氢、C 1-C 6烷基、卤素取代的C 1-C 6烷基、和羟甲基；q为1、2、3或4；r为0、1、2、3或4；或两个R 1与其相邻的碳原子共同构成选自下组的基团：苯环、5-8元的杂芳环；或两个R 2与其相邻的碳原子共同构成选自下组的基团：苯环、5-8元的杂芳环；环选自下组：取代或未取代的7-20元多环杂环、取代或未取代的7-20元多环芳环、取代或未取代的7-20元多环芳杂环，其中，所述的取代指基团上的氢原子被1、2、3或4个选自下组的取代基取代：氘(D)、氚(T)、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、-O[(CH 2) qO] rR 3、-NH[(CH 2) qO] rR 3、-NH(C＝O)[(CH 2) qO] rR 3、-NH(SO 2)[(CH 2) qO] rR 3、-O(CH 2) sAr、取代或未取代的C 3-C 8环烷氧基、取代或未取代的C 3-C 8环烷胺基、取代或未取代的C 3-C 8环氧烷基、取代或未取代的C 3-C 8环胺烷基、氰基、硝基、氨基、胺基(较佳地C 1-C 6胺基)、羟基、羟甲基、羧基、C 6-C 10芳基、C 6-C 10芳基氧基、取代或未取代的3-12元杂环基、取代或未取代的3-12元杂环基氧基和取代或未取代的3-12元杂环基胺基；其中，所述的芳杂环(基)、杂环(基)各自独立地含有1～4个选自氧、硫和氮中的杂原子；或两个相邻的取代基与其相连的原子可共同构成选自下组的结构：取代或未取代的6-20元杂环，所述的杂环可任选地包括1、2、3或4个选自N、O或S中的杂原子；
s选自下组：0、1、2、3或4；Ar选自下组：取代或未取代的C 6-C 12芳基、取代或未取代的5-12元杂芳基；除非特别说明，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C 1-C 6烷基、卤素取代的C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氧基羰基、卤素取代的C 1-C 6烷氧基、C 3-C 8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基。 - 如权利要求1所述的并环吡唑啉酮甲酰胺类化合物，或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物，其中，R 1和R 2各自独立地选自下组：氢、氘、氚、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、氰基、羟基、羧基；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氧基羰基、氰基、氨基、羟基、羟甲基、羧基；或两个R 1与其相邻的碳原子共同构成选自下组的基团：苯环、5-8元的杂芳环。
- 如权利要求1所述的并环吡唑啉酮甲酰胺类化合物，或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物，其中，环选自下组：
其中，R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12分别为1-4个选自下组的取代基：H、D、T、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、-O[(CH 2) qO] rR 3、-NH[(CH 2) qO] rR 3、-NH(C＝O)[(CH 2) qO] rR 3、-NH(SO 2)[(CH 2) qO] rR 3、-O(CH 2) sAr、取代或未取代的C 3-C 8环烷氧基、取代或未取代的C 3-C 8环烷胺基、取代或未取代的C 3-C 8环氧烷基、取代或未取代的C 3-C 8环胺烷基、氰基、硝基、氨基、胺基(较佳地C 1-C 6胺基)、羟基、羟甲基、羧基、C 6-C 10芳基、C 6-C 10芳基氧基、取代或未取代的3-12元杂环基、取代或未取代的3-12元杂环基氧基和取代或未取代的3-12元杂环基胺基；或两个相邻的上述基团与其相连的原子可共同构成选自下组的结构：取代或未取代的6-20元杂环，所述的杂环可任选地包括1、2、3或4个选自N、O或S中的杂原子。 - 如权利要求2所述的并环吡唑啉酮甲酰胺类化合物或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物，其特征在于，所述的环选自下组：
- 如权利要求4所述的并环吡唑啉酮甲酰胺类化合物或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物，其特征在于：R 4、R 5分别为1-4个选自下组的取代基：取代或未取代的C 1-C 6烷氧基、-O[(CH 2) qO] rR 3、-NH[(CH 2) qO] rR 3、-NH(C＝O)[(CH 2) qO] rR 3、-NH(SO 2)[(CH 2) qO] rR 3、-O(CH 2) sAr、取代或未取代的3-12元杂环基氧基和取代或未取代的3-12元杂环基胺基；或两个相邻的上述基团与其相连的原子可共同构成选自下组的结构：取代或未取代的6-20元杂环，所述的杂环可任选地包括1、 2、3或4个选自N、O或S中的杂原子。
- 如权利要求1所述的并环吡唑啉酮甲酰胺类化合物或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物，其中，所述并环吡唑啉酮甲酰胺类化合物选自如下化合物：
- 如权利要求1所述的化合物的制备方法，其特征在于，所述的方法包括步骤：
在惰性溶剂中，用式1-8化合物与式2-4化合物反应，得到式I化合物。 - 一种药物组合物，其特征在于，所述的药物组合物包括：治疗有效量的如权利要求1所述的式I化合物，或其药学上可接受的盐、外消旋体、R-异构体、S-异构体或它 们的混合物中的一种或多种，以及任选的药学上可接受的载体、赋形剂、佐剂、辅料和/或稀释剂。
- 一种激酶抑制剂，其特征在于，所述的抑制剂包括：抑制有效量的如权利要求1-6任一所述的式I化合物，或其药学上可接受的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种，以及任选的药学上可接受的载体、赋形剂、佐剂、辅料和/或稀释剂；且所述的激酶选自下组：AXL、c-Met，或其组合。
- 如权利要求1所述的式I化合物的用途，其特征在于，用于选自下组的一个或多个用途：(i)治疗或预防与激酶酶活或表达量相关的疾病；(ii)抑制激酶的活性，或降低激酶的表达量；(iii)制备治疗或预防与激酶活性相关的疾病的药物组合物；(iv)制备激酶抑制剂；其中，所述的激酶选自下组：AXL、c-Met，或其组合。
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201980034774.7A CN112236430B (zh) | 2018-05-21 | 2019-05-21 | 一类并环吡唑啉酮甲酰胺类化合物及其制备方法、药物组合物和用途 |
| SG11202011638WA SG11202011638WA (en) | 2018-05-21 | 2019-05-21 | Fused-cyclic pyrazolone formamide compound and preparation method therefor, pharmaceutical composition and use thereof |
| US17/057,199 US20210221807A1 (en) | 2018-05-21 | 2019-05-21 | Fused-cyclic pyrazolone formamide compound and preparation method therefor, pharmaceutical composition and use thereof |
| KR1020207036703A KR102658011B1 (ko) | 2018-05-21 | 2019-05-21 | 융합된 시클릭 피라졸론포름아미드계 화합물 및 이의 제조 방법, 약학 조성물 및 용도 |
| EA202092766A EA202092766A1 (ru) | 2018-05-21 | 2019-05-21 | Конденсированные циклические производные пиразолона формамида, способ их получения, фармацевтическая композиция и их применение |
| CA3101223A CA3101223A1 (en) | 2018-05-21 | 2019-05-21 | Fused-cyclic pyrazolone formamide compound and preparation method therefor, pharmaceutical composition and use thereof |
| JP2020565414A JP7339282B2 (ja) | 2018-05-21 | 2019-05-21 | 縮合環式ピラゾロンホルムアミド系化合物およびその調製方法、医薬組成物と使用 |
| AU2019273337A AU2019273337B2 (en) | 2018-05-21 | 2019-05-21 | Fused-cyclic pyrazolone formamide compound and preparation method therefor, pharmaceutical composition and use thereof |
| BR112020023870-8A BR112020023870A2 (pt) | 2018-05-21 | 2019-05-21 | composto de pirazolona formamida cíclico fundido e método de preparação para o mesmo, composição farmacêutica e uso do mesmo |
| EP19806732.4A EP3798218A4 (en) | 2018-05-21 | 2019-05-21 | FUSED CYCLIC FORMAMIDE PYRAZOLONE COMPOUND, METHOD FOR PREPARATION, PHARMACEUTICAL COMPOSITION AND USE THEREOF |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810491115.3A CN110511218A (zh) | 2018-05-21 | 2018-05-21 | 一类并环吡唑啉酮甲酰胺类化合物及其制备方法、药物组合物和用途 |
| CN201810491115.3 | 2018-05-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2019223704A1 true WO2019223704A1 (zh) | 2019-11-28 |
Family
ID=68615979
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2019/087867 WO2019223704A1 (zh) | 2018-05-21 | 2019-05-21 | 一类并环吡唑啉酮甲酰胺类化合物及其制备方法、药物组合物和用途 |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20210221807A1 (zh) |
| EP (1) | EP3798218A4 (zh) |
| JP (1) | JP7339282B2 (zh) |
| KR (1) | KR102658011B1 (zh) |
| CN (2) | CN110511218A (zh) |
| AU (1) | AU2019273337B2 (zh) |
| BR (1) | BR112020023870A2 (zh) |
| CA (1) | CA3101223A1 (zh) |
| EA (1) | EA202092766A1 (zh) |
| SG (1) | SG11202011638WA (zh) |
| WO (1) | WO2019223704A1 (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JOP20180094A1 (ar) | 2017-10-18 | 2019-04-18 | Hk Inno N Corp | مركب حلقي غير متجانس كمثبط بروتين كيناز |
| CN113683629B (zh) * | 2020-05-18 | 2023-07-04 | 北京范恩柯尔生物科技有限公司 | 取代的杂芳基化合物及其组合物和用途 |
| WO2024039842A2 (en) * | 2022-08-19 | 2024-02-22 | National Health Research Institutes | Inhibitors of tam receptors |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101248059A (zh) * | 2005-04-27 | 2008-08-20 | 安姆根有限公司 | 作为蛋白激酶抑制剂的取代的酰胺衍生物 |
| WO2010039248A1 (en) * | 2008-10-01 | 2010-04-08 | Ludwig Institute For Cancer Research | Methods for the treatment of cancer |
| CN102086211A (zh) * | 2009-12-08 | 2011-06-08 | 深圳市东阳光实业发展有限公司 | 作为蛋白激酶抑制剂的芳杂环化合物 |
| CN102245595A (zh) * | 2008-10-14 | 2011-11-16 | 株式会社新药 | 作为蛋白质激酶抑制剂的杂环化合物 |
| CN104974162A (zh) * | 2014-04-09 | 2015-10-14 | 广东东阳光药业有限公司 | 双环吡唑酮化合物及其使用方法和用途 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2012339640B2 (en) * | 2011-11-14 | 2017-01-05 | Ignyta, Inc. | Uracil derivatives as AXL and c-MET kinase inhibitors |
| US10208034B2 (en) * | 2014-12-25 | 2019-02-19 | Ono Pharmaceutical Co., Ltd. | Quinoline derivative |
-
2018
- 2018-05-21 CN CN201810491115.3A patent/CN110511218A/zh active Pending
-
2019
- 2019-05-21 AU AU2019273337A patent/AU2019273337B2/en active Active
- 2019-05-21 SG SG11202011638WA patent/SG11202011638WA/en unknown
- 2019-05-21 WO PCT/CN2019/087867 patent/WO2019223704A1/zh unknown
- 2019-05-21 EP EP19806732.4A patent/EP3798218A4/en active Pending
- 2019-05-21 EA EA202092766A patent/EA202092766A1/ru unknown
- 2019-05-21 US US17/057,199 patent/US20210221807A1/en active Pending
- 2019-05-21 BR BR112020023870-8A patent/BR112020023870A2/pt unknown
- 2019-05-21 KR KR1020207036703A patent/KR102658011B1/ko active IP Right Grant
- 2019-05-21 JP JP2020565414A patent/JP7339282B2/ja active Active
- 2019-05-21 CA CA3101223A patent/CA3101223A1/en active Pending
- 2019-05-21 CN CN201980034774.7A patent/CN112236430B/zh active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101248059A (zh) * | 2005-04-27 | 2008-08-20 | 安姆根有限公司 | 作为蛋白激酶抑制剂的取代的酰胺衍生物 |
| WO2010039248A1 (en) * | 2008-10-01 | 2010-04-08 | Ludwig Institute For Cancer Research | Methods for the treatment of cancer |
| CN102245595A (zh) * | 2008-10-14 | 2011-11-16 | 株式会社新药 | 作为蛋白质激酶抑制剂的杂环化合物 |
| CN102086211A (zh) * | 2009-12-08 | 2011-06-08 | 深圳市东阳光实业发展有限公司 | 作为蛋白激酶抑制剂的芳杂环化合物 |
| CN104974162A (zh) * | 2014-04-09 | 2015-10-14 | 广东东阳光药业有限公司 | 双环吡唑酮化合物及其使用方法和用途 |
Non-Patent Citations (1)
| Title |
|---|
| THE WORLD CANCER REPORT, 2014 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3798218A4 (en) | 2022-03-02 |
| AU2019273337A1 (en) | 2021-01-21 |
| CN112236430B (zh) | 2023-02-17 |
| KR20210011988A (ko) | 2021-02-02 |
| JP2021524471A (ja) | 2021-09-13 |
| EA202092766A1 (ru) | 2021-07-08 |
| KR102658011B1 (ko) | 2024-04-17 |
| SG11202011638WA (en) | 2020-12-30 |
| BR112020023870A2 (pt) | 2021-02-09 |
| CN112236430A (zh) | 2021-01-15 |
| CN110511218A (zh) | 2019-11-29 |
| CA3101223A1 (en) | 2019-11-28 |
| US20210221807A1 (en) | 2021-07-22 |
| EP3798218A1 (en) | 2021-03-31 |
| JP7339282B2 (ja) | 2023-09-05 |
| AU2019273337B2 (en) | 2022-02-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102237707B1 (ko) | 퀴놀론계를 대체하는 유도체 또는 그의 약학적으로 수용가능한 염 또는 입체이성체 및 이들의 의약용 조성물과 응용 | |
| TWI644909B (zh) | 磷脂酸肌醇３－激酶抑制劑 | |
| TWI525093B (zh) | 用作為３'磷酸肌醇依賴性激酶１（ｐｄｋ１）抑制劑之雜環化合物 | |
| WO2021073439A1 (zh) | 用于抑制shp2活性的吡嗪衍生物 | |
| TWI527800B (zh) | 作為聚（二磷酸腺苷酸－核醣）聚合酶（ｐａｒｐ）之抑制劑之１－（芳基甲基）喹唑啉－２，４（１ｈ，３ｈ）－二酮及其應用 | |
| WO2016184434A1 (zh) | 一种吡啶并氮杂环化合物及其制备方法和用途 | |
| EP2995618B1 (en) | [1,2,4]triazol [4,3-a]pyridine derivate, preparation method therefor or medical application thereof | |
| WO2019223704A1 (zh) | 一类并环吡唑啉酮甲酰胺类化合物及其制备方法、药物组合物和用途 | |
| WO2013033981A1 (zh) | 一类2,7-萘啶衍生物及其制备方法和应用 | |
| BR112013018212A2 (pt) | Hidrazida diarila acetileno contendo inibidores de tirosina-cinase | |
| TW200529846A (en) | 3-quinolinecarbonitrile protein kinase inhibitors | |
| JP2015503528A (ja) | キノリン類およびシンノリン類化合物、およびその応用 | |
| TWI523856B (zh) | BCR-ABL kinase inhibitor and its application | |
| TW200916458A (en) | Heterocyclic compounds and methods of use thereof | |
| US11427559B2 (en) | Substituted quinolines useful as kinase inhibitors | |
| CN112236422B (zh) | 喹唑啉类化合物作为egfr三突变抑制剂及其应用 | |
| CN112351971B (zh) | 喹啉或喹唑啉类化合物及其应用 | |
| TWI565698B (zh) | 喹啉化合物，其製造方法及用途 | |
| CN112313213B (zh) | 3-氨基吡唑类化合物及其应用 | |
| US10202374B2 (en) | 6-aryl-4-phenylamino-quinazoline analogs as phosphoinositide-3-kinase inhibitors | |
| CN106146464A (zh) | 喹啉酮类化合物及其制备方法和用途 |
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: 19806732 Country of ref document: EP Kind code of ref document: A1 |
|
| ENP | Entry into the national phase |
Ref document number: 2020565414 Country of ref document: JP Kind code of ref document: A |
|
| ENP | Entry into the national phase |
Ref document number: 3101223 Country of ref document: CA |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112020023870 Country of ref document: BR |
|
| ENP | Entry into the national phase |
Ref document number: 20207036703 Country of ref document: KR Kind code of ref document: A |
|
| ENP | Entry into the national phase |
Ref document number: 2019806732 Country of ref document: EP Effective date: 20201221 |
|
| ENP | Entry into the national phase |
Ref document number: 2019273337 Country of ref document: AU Date of ref document: 20190521 Kind code of ref document: A |
|
| ENP | Entry into the national phase |
Ref document number: 112020023870 Country of ref document: BR Kind code of ref document: A2 Effective date: 20201123 |