WO2018072614A1 - 一种喹啉基取代的羧酸化合物或其药学上可接受的盐、其药物组合物及应用 - Google Patents

一种喹啉基取代的羧酸化合物或其药学上可接受的盐、其药物组合物及应用 Download PDF

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WO2018072614A1
WO2018072614A1 PCT/CN2017/104518 CN2017104518W WO2018072614A1 WO 2018072614 A1 WO2018072614 A1 WO 2018072614A1 CN 2017104518 W CN2017104518 W CN 2017104518W WO 2018072614 A1 WO2018072614 A1 WO 2018072614A1
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Prior art keywords
amino
cyclopropanecarbonyl
phenoxy
carbamoyl
quinoline
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PCT/CN2017/104518
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English (en)
French (fr)
Inventor
张志强
王锡娟
张学辉
邱俊霞
杨结合
张晓凯
姚鹏
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北京康辰药业股份有限公司
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Application filed by 北京康辰药业股份有限公司 filed Critical 北京康辰药业股份有限公司
Priority to KR1020197013884A priority Critical patent/KR102262280B1/ko
Priority to EP17862141.3A priority patent/EP3530654B1/en
Priority to SG11201903463PA priority patent/SG11201903463PA/en
Priority to AU2017346104A priority patent/AU2017346104B2/en
Priority to US16/343,271 priority patent/US10723701B2/en
Priority to JP2019541839A priority patent/JP6875537B2/ja
Priority to CA3040788A priority patent/CA3040788C/en
Priority to CN201780039567.1A priority patent/CN109496212B/zh
Publication of WO2018072614A1 publication Critical patent/WO2018072614A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of organic chemistry and medicinal chemistry, and in particular to a quinolinyl substituted carboxylic acid compound or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, and a pharmaceutical composition containing the same and use thereof.
  • Protein kinases are a class of phosphotransferases that transfer the ⁇ -phosphate group of ATP to specific amino acid residues of the substrate to phosphorylate proteins and exert their physiological and biochemical functions. Protein kinases are an important class of kinases that play a major role in signal transduction: one is to regulate the activity of proteins through phosphorylation; the other is to scale the signal step by step through the phosphorylation of proteins. Cellular response.
  • Abnormal protein kinase activity is not only closely related to tumor proliferation, apoptosis, metastasis, etc., but also to a series of other human diseases related to inflammation or proliferative response. For example, rheumatoid arthritis, cardiovascular and nervous system diseases, asthma, psoriasis and the like. More than 400 human diseases are known to be directly or indirectly related to protein kinases, making protein kinases another important class of drug targets following G-protein coupled receptors.
  • the protein kinase family consists of more than 500 members and is usually classified into protein tyrosine kinases (PTKs) and serine-threonine kinases. According to the position of the kinase in the cell, it can be further divided into receptor kinases and non-receptor kinases, also known as intracellular kinases.
  • Receptor kinases are generally tyrosine kinases, also known as receptor tyrosine kinases (RTKs), which are composed of extracellular, transmembrane, and intracytoplasmic, catalytically active kinases. Part of it is located in the cytoplasm. Most serine-threonine kinases are located in cells and are non-receptor kinases or cytosolic kinases.
  • Typical representatives of the RTKs family are growth factor receptors, with at least 19 subfamilies, and the following are several major subfamilies:
  • HER family tyrosine receptor kinases including EGFR (epithelial growth factor receptor), HER2, HER3 and HER4.
  • EGFR epidermal growth factor receptor
  • HER2 epidermal growth factor receptor
  • HER3 epidermal growth factor receptor
  • HER4 epidermal growth factor receptor
  • EGFR epidermal growth factor receptor
  • IGF-1R insulin-like growth factor I receptor
  • IRR insulin receptor-related receptor
  • IGF-1R insulin receptor-like growth factor I receptor
  • IRR insulin receptor-related receptor Receptor
  • c a family of platelet-derived growth factor receptors (PDGFRs), including PDGFR- ⁇ , PDGFR- ⁇ , CSF1R, c-KIT, and c-fms.
  • PDGFRs platelet-derived growth factor receptors
  • c-KIT is also a leukemia treatment drug.
  • VEGFRs vascular endothelial growth factor receptors
  • FLT1 Fms-like tyrosine kinase 1 or VEGFR1
  • KDR or VEGFR-2
  • FLT4 or VEGFR3
  • FGFRs fibroblast growth factor receptors
  • FGF1, FGF2, FGF3, FGF4, FGF5, FGF6 and FGF7 members of the drug as molecular targets are still in clinical trials.
  • MET family including c-Met or human hepatocyte growth factor receptor (hHGFR) and RON.
  • c-Met plays an important role in the growth and metastasis of initial tumors. Its drug as a molecular target is still in clinical trials.
  • RET is a receptor for members of the GDNF family
  • RET51, RET43 and RET9isoforms are present. Its drug as a molecular target is still in clinical trials.
  • Eph family is the largest family of tyrosine receptor kinases, consisting of 16 receptors (EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4 , EPHB5, EPHB6) and 9 ligands (EFNA1, EFNA2, EFNA3, EFNA4, EFNA5, EFNB1, EFNB2, EFNB3). These members play an important role in the development of animals, and some members play a role in the tumor.
  • AXL is another important tyrosine receptor kinase, also known as UFO/ARK/Tyro, its ligand It is a vitamin K-dependent growth promoting factor GAS6.
  • the first discovery of AXL was as a transforming gene for chronic myeloid leukemia (CML).
  • CML chronic myeloid leukemia
  • AXL is overexpressed in metastatic colon cancer, thyroid cancer, breast cancer, prostate cancer, and melanoma. Inhibition of AXL activity can inhibit tumor growth, spread and metastasis.
  • Non-receptor kinases are absent from the extramembranous and transmembrane regions of the cell, and the entire kinase is in the cytoplasm. At least 24 non-receptor kinases are now known to be divided into 11 subfamilies, which are the Src, Frk, Btk, CsK, Abl, Zap70, Fes, Fps, Fak, Jak and AcK subfamilies.
  • the Src subfamily is the largest, including Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1, AUR2, and Yrk kinase. For more detailed information, see Neet, K.; Hunter, T.
  • non-receptor kinase tyrosine kinases Although there are several non-receptor kinase tyrosine kinases, most non-receptor kinases belong to the serine-threonine kinase. Several of them are leukemia treatments and Molecular targets.
  • receptor kinases and non-receptor kinases have been well demonstrated in clinical and practical applications as anti-tumor targets, and multiple anti-tumor drugs have been approved for market treatment of patients.
  • inhibition of the aberrant activity of receptor kinases and non-receptor kinases can also be used to treat diseases including, but not limited to, psoriasis or psoriasis, cirrhosis, diabetes, diseases involving angiogenesis, and restenosis.
  • An object of the present invention is to provide a quinolinyl-substituted carboxylic acid compound having a protein kinase inhibitory activity, or a pharmaceutically acceptable salt thereof, and a process for producing the same.
  • Another object of the present invention is to provide a use of the above quinolyl-substituted carboxylic acid compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease caused by abnormal activity of a protein kinase.
  • Still another object of the present invention is to provide a pharmaceutical composition capable of treating a disease caused by abnormal activity of a protein kinase comprising the above quinolyl-substituted carboxylic acid compound or a pharmaceutically acceptable salt thereof.
  • a quinolinyl-substituted carboxylic acid compound or a pharmaceutically acceptable salt thereof which has a molecular structural formula as shown in the formula (I):
  • V 1 and V 2 are each independently selected from hydrogen, hydrazine, halogen, C 1-6 alkyl or C 1-6 alkoxy;
  • R represents hydrogen, C 1-12 alkyl, C 1-12 alkoxy, and the hydrogen in R may be optionally substituted by G 1 ;
  • L is a C 1-12 alkylene group, and the hydrogen in L may be optionally substituted by G 2 ;
  • M is selected from:
  • a monovalent, divalent, trivalent or tetravalent metal ion preferably a monovalent and divalent metal ion, more preferably a lithium, sodium, potassium, rubidium, cesium, magnesium, calcium, strontium, barium ion;
  • an ammonium ion or a protonated organic amine including but not limited to a C 1-12 alkyl group, a C 3-12 cycloalkyl group or a C 3-12 heteroalicyclic substituted aliphatic amine, these fats
  • the amine may be optionally substituted with one or more halogen or hydroxyl groups;
  • the present invention is in the structure shown in formula (I):
  • V 1 and V 2 are each independently selected from hydrogen, hydrazine, halogen, C 1-6 alkyl or C 1-6 alkoxy;
  • R represents hydrogen, C 1-12 alkyl, C 1-12 alkoxy
  • L is a C 1-12 alkylene group
  • M is selected from:
  • an ammonium ion or a protonated organic amine comprising a C 1-12 alkyl group, a C 3-12 cycloalkyl group or a C 3-12 heteroalicyclic substituted aliphatic amine, these fatty amines being selectable sexually substituted by one or more halogens or hydroxyl groups.
  • the present invention is in the structure shown in formula (I):
  • V 1 and V 2 are each independently selected from hydrogen, hydrazine or halogen; more preferably, V 1 and V 2 are simultaneously hydrogen, deuterium or halogen; and the substitution sites are at positions 2 and 4 of the respective six-membered ring, respectively.
  • V 1 and V 2 are each independently selected from hydrogen, hydrazine or halogen, R is a C 1-12 alkoxy group, and L is a C 1-12 subunit. alkyl.
  • V 1 and V 2 are each independently selected from hydrogen or halogen; R is methoxy, ethoxy, n-propoxy or isopropoxy; L is a C 1-6 alkylene group.
  • quinolinyl-substituted carboxylic acid compound represented by the formula (I) or a pharmaceutically acceptable salt thereof which is any one of the following:
  • the present invention simultaneously protects the racemate or enantiomer of any of the above-described quinolyl-substituted carboxylic acid compounds or pharmaceutically acceptable salts thereof.
  • the invention simultaneously protects a quinolinyl substituted carboxylic acid compound or a pharmaceutically acceptable salt thereof
  • the method includes, but is not limited to, the experimental steps shown by Scheme 1:
  • Compound A-1 can be synthesized according to the method disclosed in WO2013/040801A1;
  • V 1, V 2, R , L , and M are as hereinbefore refer regarding the quinolinyl substituted carboxylic acid compound, or a pharmaceutically acceptable salt thereof in V 1, V 2, R, L and M Consistent.
  • V 1 and V 2 are each independently selected from hydrogen, hydrazine, halogen, C 1-6 alkyl or C 1-6 alkoxy;
  • R represents hydrogen, C 1-12 alkyl, C 1-12 alkoxy, and the hydrogen in R may be optionally substituted by G 1 ;
  • L is a C 1-12 alkylene group, and the hydrogen in L may be optionally substituted by G 2 ;
  • M is selected from:
  • organic amine including but not limited to a C 1-12 alkyl group, a C 3-12 cycloalkyl group or a C 3-12 heteroalicyclic group substituted Fatty amines, these fatty amines may be optionally substituted by one or more halogen or hydroxyl groups;
  • RR represents hydrogen, C 1-12 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, C 5-12 heteroaryl or C 3-12 heteroalicyclic, and the hydrogen in RR can be selected Substituted by G 4 ;
  • LG stands for the leaving group commonly found in organic chemistry, which is F, Cl, Br, I, CH 3 SO 3 , CH 3 CH 2 SO 3 , CH 3 (CH 2 ) 2 SO 3 , (CH 3 ) 2 CHSO 3 , tert-BuSO 3 , PhSO 3 , o-CH 3 PhSO 3 , m-CH 3 PhSO 3 , p-CH 3 PhSO 3 , oO 2 NPhSO 3 , mO 2 NPhSO 3 , pO 2 NPhSO 3 or CF 3 SO 3 Any one of them;
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a quinolyl substituted carboxylic acid compound or a pharmaceutically acceptable salt thereof.
  • the above pharmaceutical composition comprises, in addition to the quinolyl substituted carboxylic acid compound or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical composition is prepared in the form of an oral preparation, an injection, an anal preparation, a nostril inhalation, an eye drop or a skin patch.
  • a quinolinyl-substituted carboxylic acid compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same is used for the treatment of a disease caused by abnormal activity of a protein kinase.
  • the kinase is AXL or / and VEGFR2.
  • the disease is a tumor, including solid tumors and liquid tumors.
  • the tumors described in the application of the compound of the present invention or/and the pharmaceutical composition comprising the same include: lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer.
  • rectal cancer anal cancer, gastric cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer , Parathyroid carcinoma, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, bladder cancer, kidney or ureteral cancer, renal cancer, central nervous system (CNS) neoplasm, spinal axis tumor, pituitary adenoma
  • CNS central nervous system
  • a medicament for treating a disease caused by abnormal activity of a protein kinase comprising any one or any of the above compounds or a pharmaceutically acceptable salt, solvate, prodrug thereof, or any of the above
  • the racemate, enantiomer or any pharmaceutically acceptable salt, solvate or prodrug thereof of any one or any of several compounds comprising any one or any of the above compounds or a pharmaceutically acceptable salt, solvate, prodrug thereof, or any of the above.
  • the medicament of the present invention comprises, in addition to the quinolyl-substituted carboxylic acid compound or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable carriers or/and diluents.
  • Oral agents (2) injections, (3) anal plugs, (4) nostril inhalers, (5) eye drops or (6) skin patches.
  • the quinolyl-substituted carboxylic acid compound of the present invention or a pharmaceutically acceptable salt thereof has the following beneficial effects after a series of tests (1) By inhibiting the activity of the kinase, it can be seen that the compound of the present invention acts on AXL and VEGFR2 kinase. It has a strong inhibitory effect; (2) It can be seen from the tumor inhibition test on animals that the quinolinyl-substituted carboxylic acid compound or a pharmaceutically acceptable salt thereof can significantly inhibit tumors without obvious toxicity; (3) The compound of the present invention can be used together with other antitumor drugs to achieve a synergistic or additive effect; (4) the compound of the present invention can be combined with other tumor therapies such as radiation therapy.
  • a quinolyl-substituted carboxylic acid compound of the present invention or a pharmaceutically acceptable salt thereof can be used as a medicament for effectively treating a disease caused by abnormal activity of a protein kinase.
  • the compound of the present invention is used for treating diseases caused by abnormal protein kinase activity, wherein the kidney cancer is adrenal cancer, renal cell carcinoma, renal pelvic cancer; glioma is brain stem glioma, neuroendocrine glial tumor , glioma.
  • the compound of the present invention may be psoriasis (or psoriasis), liver cirrhosis, diabetes, diseases involving angiogenesis, diseases involving restenosis, and diseases other than tumors in the treatment of diseases caused by abnormal protein kinase activity.
  • Eye diseases such as AMD, rheumatoid arthritis and other inflammations, immune system diseases such as autoimmune diseases (eg, AIDS, etc.), cardiovascular diseases such as atherosclerosis, kidney disease, epilepsy, neurodegenerative diseases such as Alz Hermes, Huntington's disease, Parkinson's disease, etc.
  • a pharmaceutical composition consisting of a compound of the invention for use in treating a mammal, such as a human patient, A disease caused by abnormal activity of protein kinases.
  • the compounds of the present invention (including racemates, enantiomers and other stereoisomers) or their pharmaceutically acceptable salts, hydrates, solvates or prodrugs are subjected to a formulation process,
  • a pharmaceutical composition suitable for administration is prepared with a suitable pharmaceutically acceptable carrier and a pharmaceutically acceptable adjuvant.
  • the drug administration route composed of the compound of the present invention may be: (1) oral: for example, tablets, capsules, etc.; (2) injection: for example, intravenous injection, subcutaneous injection, intramuscular injection, eye injection, intraperitoneal injection, etc.; Anal plug: for example, suppository, gel, etc.; (4) nostril inhalation: for example, spray, aerosol, etc.; (5) eye drops; (6) skin patch.
  • Drug release systems can also be used, for example, liposome, sustained release techniques, controlled release techniques, and the like, with preferred methods being oral and injectable, with a preferred method being oral.
  • compositions of the present invention consisting of the compounds can be prepared by methods commonly used in the pharmaceutical industry. For example, mixing, dissolving, granulating, grinding, emulsifying, capsule, sugar coating, freeze drying, frozen spray, and the like.
  • the content of the compound of the present invention in the aforementioned pharmaceutical composition ranges from 0.001 to 100%.
  • the pharmaceutical composition is administered to a mammal, including a human, at an effective dose of from 0.1 to 500 mg per kilogram of body weight per day, and an optimized dose of from 1 to 100 mg per kilogram of body weight per day.
  • the compounds of the invention exert their pharmacological effects of inhibiting protein kinase activity and treating diseases (e.g., cancer) caused by abnormal protein kinase activity.
  • the frequency of use of the medicament of the present invention varies depending on the compound to be used or a pharmaceutical composition thereof and the disease to be applied.
  • the pharmaceutical composition of the present invention is usually administered 1-6 times a day, and the optimized administration frequency is per Dosing 1-3 times a day.
  • the packaging and preservation of the medicament of the invention are similar to those of a general western medicine.
  • the solid dosage form of the medicine can be directly loaded into a glass, a plastic, a paper or a metal bottle, and a desiccant or the like is preferably placed in the bottle to maintain the quality of the drug;
  • the dosage form of the drug is generally contained in a glass, plastic or metal bottle or hose;
  • the aerosolized type of drug is generally contained in a metal or plastic container with a pressure-resistant device such as a pressure reducing valve.
  • variable groups used in the present invention such as R a , R b , g, etc., are only applicable to this subsection (ie, the "Definition of Terms” section).
  • the chemical reaction needs to be carried out in a solvent in many cases
  • the solvent (Solvent) commonly used in the preparation of the compound of the present invention includes, but is not limited to, water, methanol, ethanol, isopropanol, n-propanol, n-Butanol, isobutanol, tert-butanol, 2-methoxyethanol, 2,2,2-trifluoroethanol, two Methyl chloride, 1,2-dichloroethane, chloroform, THF, dioxane, DME, ethyl acetate, diethyl ether, methyl tert-butyl ether, hexane, cyclohexane, toluene, acetonitrile, DMF, DMSO or A combination of two or more of these solvents.
  • a base including, but not limited to, an organic base such as MeNH 2 , Me 2 NH, Me 3 N, EtNH 2 , Et 2 NH, Et 3 N, n-PrNH 2 , n-Pr 2 NH, n-Pr 3 N, i-PrNH 2 , i-Pr 2 NH, i-Pr 3 N, n-BuNH 2 , n-Bu 2 NH , n-Bu 3 N, s-BuNH 2 , s-Bu 2 NH, s-Bu 3 N, i-BuNH 2 , i-Bu 2 NH, i-Bu 3 N, t-BuNH 2 , t-Bu 2 NH, t-Bu 3 N, i-Pr 2 NEt, 2-amino-2-(hydroxymethyl)propane-1,3-diol, cyclopropylamine, dicyclopropyl
  • the base also includes, but is not limited to, an inorganic base such as ammonia, ammonia, LiOH, NaOH, KOH, RbOH, CsOH, Cs 2 CO 3 , Rb 2 CO 3 , Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , LiF, NaF, KF, RbF, CsF, K 3 PO 3 , K 2 HPO 4 , KH 2 PO 4 , Na 3 PO 3 , Na 2 HPO 4 , NaH 2 PO 4 , Li 3 PO 3 , Li 2 HPO 4 , LiH 2 PO 4 , NaH, LiH, KH, RbH, CsH, CaO, Ca(OH) 2 , Ca 2 CO 3 , MgO, Mg(OH) 2 , Mg 2 CO 3 , etc., or A combination of two or more of the above bases.
  • an inorganic base such as ammonia, ammonia, LiOH, NaOH, KOH, RbOH
  • a hydrolysis reaction which is generally carried out in the presence of a base or an acid (Acid) having the same meaning as defined above; Including but not limited to HCO 2 H, AcOH, TFA (trifluoroacetic acid), HCl (hydrochloric acid), H 2 SO 4 , HNO 3 , H 3 PO 4 , p-TsOH, PhSO 3 H, CSA, MsOH, etc. or Lewis acid One or several combinations of ZnCl 2 , AlCl 3 , BF 3 .OEt 2 , and the like.
  • a salt formation reaction refers to a process in which the carboxylic acid compound A-3 is reacted with the above base to form a carboxylate compound Ib or Ic.
  • the reaction for preparing the compound of the present invention is usually carried out at room temperature, but sometimes it is required to be lowered to -78 ° C or heated to 200 ° C; the reaction is usually carried out under the aforementioned solvent and temperature under conventional stirring conditions, but sometimes it is required To be carried out in a microwave oven; when the base, reagent, or catalyst used is sensitive to water or oxygen, the reaction is carried out under anhydrous and anaerobic conditions, in which case a protic solvent cannot be used.
  • Solvate means a stable substance formed by a compound of the present invention and a chemically used solvent by covalent bond, hydrogen bond, ionic bond, van der Waals force, complexation, inclusion, etc., and the solvent may be: methanol. , ethanol, propanol, butanol, ethylene glycol, propylene glycol, polyethylene glycol, acetone, acetonitrile, diethyl ether, methyl tert-butyl ether and the like.
  • Hydrophilrate means a solvate wherein the solvent is water.
  • Prodrug means the conversion of a compound of the invention to another compound by chemical synthesis or physical means, and after administration of the compound to a mammal, is converted in the animal to the compound of the invention.
  • the “prodrug” method is generally used to overcome the poor or poor physicochemical properties or drug-forming properties of the drug compound itself.
  • Racemate, enantiomer, cis-trans isomer and other stereoisomers means that the compounds have the same molecular formula and molecular weight, but differ in the manner of different bonding modes and spatial arrangement between the atoms.
  • Compounds, such compounds are called isomers or stereoisomers. When these stereoisomers are mirror images of each other, they look alike, but they do not completely coincide, as with the left and right hands.
  • These compounds are called enantiomers.
  • the absolute configuration of the enantiomers is usually indicated by (R)- and (S)- or R- and S-.
  • Tautomers tautomer
  • rotamers rotamers
  • cis-trans isomers of these concepts can be in J.March “Advanced Organic Chemistry," 4 th edition Found and understood.
  • isomers are also encompassed by the present invention as long as these isomers have the same or similar effects of inhibiting AXL and/or VEGFR2 activity as the compounds of the present invention.
  • a mammal e.g., a human
  • a mammal e.g., a human
  • “Pharmaceutical composition” refers to one or more, pharmaceutically acceptable salts or solvates or hydrates or prodrugs of the compounds described herein, and other chemical ingredients (eg, pharmaceutically acceptable carriers or dilutions) (mixture) prepared by mixing the preparation.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the animal.
  • Combination of the above drugs In addition to including a pharmaceutically acceptable carrier, it may also include adjuvants commonly used in medicine, such as antibacterial agents, antifungal agents, antimicrobial agents, quality assurance agents, toners, and additives. Solvents, thickeners, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, colors, flavors or combinations thereof.
  • “Pharmaceutically acceptable carrier” or “diluent” means an inactive ingredient in a pharmaceutical composition which may be, but is not limited to, calcium carbonate, calcium phosphate, various sugars (eg, lactose, mannitol, etc.), starch, rings Dextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymer, methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil, hydrogenated castor oil, polyethoxylate Hydrogenated castor oil, sesame oil, corn oil, peanut oil, and the like.
  • a pharmaceutical composition which may be, but is not limited to, calcium carbonate, calcium phosphate, various sugars (eg, lactose, mannitol, etc.), starch, rings Dextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymer, methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, ethylene
  • Alkyl means a straight or branched saturated hydrocarbon group having the indicated number of carbon atoms, for example, C 1-12 alkyl means a straight or branched chain group containing at least 1 and up to 12 carbon atoms. . C 0 alkyl represents a covalent single bond.
  • the alkyl groups described in the present invention include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, neopentyl, 2-methyl-1-hexyl and the like.
  • the alkyl group of the present invention is sometimes also referred to as "alkylene", and the alkylene group means a group formed by the loss of one hydrogen atom of the alkyl group.
  • One or all of the hydrogen atoms in the alkyl or alkylene group may be substituted by a cycloalkyl group, an aryl group, a heteroaryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a fluorenyl group.
  • R a and R b are each selected from the group consisting of hydrogen and an alkane A group, a cycloalkyl group, an aryl group, an acetyl group, a carbonyl group, a sulfonyl group, a trifluoromethanesulfonyl group or the like, and R a and R b together with a nitrogen atom may form a 5- or 6-membered heteroalicyclic ring.
  • Cycloalkyl or “cycloalkane” refers to a mono-, di- or polycyclic hydrocarbon group having the indicated number of carbon atoms, which may be fused when bicyclic or polycyclic (two rings or multiple rings share two) a combination of an adjacent carbon atom or a splicing (two or more rings sharing a carbon atom), for example, a C 1-12 cycloalkyl group containing a minimum of one and a maximum of twelve single, double or multiple a hydrocarbon group of the ring.
  • the C 0 cycloalkyl group represents a covalent single bond.
  • the cycloalkyl group may contain an unsaturated double or triple bond, but does not have a fully conjugated ⁇ -electron system.
  • the cycloalkyl group of the present invention sometimes also refers to a cycloalkylene group, that is, a group in which a cycloalkyl group loses one hydrogen atom.
  • the cycloalkyl group of the present invention includes, but is not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentenyl, cycloheptatrienyl, adamantane, etc. (for example, Table A):
  • One or all of the hydrogen atoms in the cycloalkyl or cycloalkane may be substituted by an alkyl group, an aryl group, a heteroaryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a fluorenyl group, Oxy (oxo), alkoxy, aryloxy, alkyl fluorenyl, aryl fluorenyl, carbonyl, thiocarbonyl, C-amido, N-amido, O-aminocarbonyloxy, N-aminocarbonyloxy And O-thioaminocarbonyloxy, N-thioaminocarbonyloxy, C-ester, O-ester and -NR a R b , wherein R a and R b are each selected from the group consisting of hydrogen and alkyl A cycloalkyl
  • Heteroalicyclic or “heteroalicyclic” means a monocyclic, bicyclic or polycyclic ring system consisting of 3 to 12 non-hydrogen ring atoms, wherein at least one of the ring atoms is selected from the group consisting of O, N, S or P Atom, the remaining ring atom is a carbon atom, for example, a C 8 heteroalicyclic group refers to a monocyclic, bicyclic or polycyclic group composed of 8 non-hydrogen ring atoms, wherein at least one ring atom is selected from O, N, S or P.
  • heteroalicyclic group of the present invention sometimes also refers to a heteroalicyclic group, that is, a group in which a heteroalicyclic group loses one hydrogen atom.
  • heteroalicyclic or heteroalicyclic ring in the present invention includes, but is not limited to, piperidine, morpholine, piperazine, pyrrolidine, porphyrin, tetrahydropyridine, tetrahydrofuran, tropinol, etc. (for example, Table B):
  • One or all of the hydrogen atoms in the heteroalicyclic or heteroalicyclic ring may be substituted by an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitrate Base, carboxyl, sulfhydryl, oxo, alkoxy, aryloxy, alkyl fluorenyl, aryl fluorenyl, carbonyl, thiocarbonyl, C-amido, N-amido, O-aminocarbonyloxy, N-aminocarbonyloxy, O-thioaminocarbonyloxy, N-thioaminocarbonyloxy, C-ester, O-ester and -NR a R b , wherein R a and R b are respectively selected From: hydrogen, alkyl, cycloalkyl
  • Alkenyl means a straight or branched hydrocarbon group containing at least two carbon atoms and at least one double bond, for example C 2-12 alkenyl means a straight chain containing at least 2 and up to 12 carbon atoms or An unsaturated group having at least one double bond in a branched chain.
  • the alkenyl group in the present invention includes, but is not limited to, a vinyl group, a 2-propenyl group, a 1-pentenyl group, and the like.
  • Alkynyl means a straight or branched hydrocarbon group containing at least two carbon atoms and at least one triple bond, for example C 2-12 alkynyl refers to a straight chain containing at least 2 and up to 12 carbon atoms or A branched chain contains at least one triple bond of an unsaturated group.
  • the alkynyl group in the present invention includes, but is not limited to, a vinyl group, a 2-propenyl group, a 1-pentenyl group, and the like.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Alkoxy means an alkyl group having the indicated number of carbon atoms attached to the other group through an oxygen atom.
  • Alkoxy groups in the present invention include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopentyloxy, cyclohexyloxy, isopropoxy, neopentyloxy, 2- Methyl-1-hexyloxy and the like.
  • Cycloalkoxy means a cycloalkyl group having the indicated number of carbon atoms attached to the other group through an oxygen atom.
  • the cycloalkoxy group in the present invention includes, but is not limited to, a cyclopropoxy group, a cyclobutoxy group, a cyclohexaneoxy group, and the like.
  • Heteroaliphatic means that a heteroalicyclic group is attached to another group through an oxygen atom.
  • the heteroaliphatic epoxy group in the present invention includes, but is not limited to, piperidin-4-yloxy, oxetan-3-yloxy and the like.
  • Aryl means a monocyclic, bicyclic or polycyclic group consisting of a specified number of carbon atoms, wherein at least one of the rings has a fully conjugated ⁇ -electron system and conforms to the N+2 rule, ie is aromatic, but the entire group Not necessarily all conjugates.
  • C 6 aryl refers to phenyl.
  • the aryl group may also be present in the form of an arylene group, that is, two or more points of attachment to other groups in the aryl structure.
  • the aryl group in the present invention includes, but is not limited to, a phenyl group, a naphthyl group, an anthracenyl group, an indanyl group, a tetrahydronaphthalene or the like.
  • One or all of the hydrogen atoms in the aryl group may be substituted with an alkyl group, a cycloalkyl group, a heteroaryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a decyl group, an oxy group ( Oxo), alkoxy, aryloxy, alkyl fluorenyl, aryl fluorenyl, carbonyl, thiocarbonyl, C-amido, N-amido, O-aminocarbonyloxy, N-aminocarbonyloxy, O- a thioaminocarbonyloxy group, an N-thioaminocarbonyloxy group, a C-ester group, an O-ester group, and -NR a R b , wherein R a and R b are each selected from the group consisting of hydrogen, an alky
  • Heteroaryl means a monocyclic, bicyclic or polycyclic group consisting of a specified number of non-hydrogen ring atoms, wherein at least one of the ring atoms is a heteroatom selected from O, N, S or P, and the remaining ring atoms are carbon atoms. And wherein at least one of the rings has a fully conjugated ⁇ -electron system and conforms to the N+2 rule, ie, has aromaticity, but the entire group does not have to be fully conjugated, for example, C 5 heteroaryl refers to 5 non- An aromatic ring group composed of a hydrogen ring atom, wherein at least one ring atom is selected from O, N, S or P.
  • the heteroaryl group may also be present in the form of a heteroarylene group having two or more points of attachment to other groups in the heteroaryl structure.
  • the heteroaryl group in the present invention includes, but is not limited to, acridine, anthrone, tetrahydrofurfurone, imidazole, pyrazine, pyridazine, imidazole, thiazole, thiophene, furan, anthracene, azaindole, Benzimidazole, porphyrin, fluorenone, quinone, etc. (for example, Table C):
  • One or all of the hydrogen atoms in the heteroaryl group may be substituted with an alkyl group, a cycloalkyl group, an aryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a decyl group, an oxy group ( Oxo), alkoxy, aryloxy, alkyl fluorenyl, aryl fluorenyl, carbonyl, thiocarbonyl, C-amido, N-amido, O-aminocarbonyloxy, N-aminocarbonyloxy, O- a thioaminocarbonyloxy group, an N-thioaminocarbonyloxy group, a C-ester group, an O-ester group, and -NR a R b , wherein R a and R b are each selected from the group consisting of hydrogen, alkyl,
  • the "nitrogen-containing heteroaryl group” means a heteroaryl group, but the heteroaryl group contains at least one nitrogen atom.
  • the nitrogen atom-containing heteroaryl group in the present invention includes, but is not limited to, a pyridyl group, a quinolyl group, a pyrazinyl group, a pyridazinyl group and the like.
  • Aryloxy means that the aryl group is attached to the other group through an oxygen atom.
  • the aryloxy group in the present invention includes, but is not limited to, a phenoxy group, a naphthyloxy group and the like.
  • Heteroaryloxy means a heteroaryl group attached to another group through an oxygen atom.
  • the heteroaryloxy group in the present invention includes, but is not limited to, 4-acridinyloxy group, 2-thienyloxy group and the like.
  • Amino refers to H 2 N- wherein a hydrogen atom or a substituted H 2 N-, i.e., R a HN- and R a R b N-.
  • the heteroatoms are connected. Examples of substitution by an oxy group include, but are not limited to, those shown in Table D:
  • Niro means -NO 2 .
  • Carboxyl means -CO 2 H.
  • Alkyl fluorenyl means alkyl-S-.
  • Aryl indenyl refers to aryl-S-.
  • Trifluoromethanesulfonyl refers to CF 3 SO 2 -.
  • nM nanomolar (concentration unit)
  • LiOH.H 2 O lithium hydroxide hydrate
  • Nuclear magnetic resonance spectra and carbon spectra were obtained on a Varian 300 or 400 MHz or Bruker 300 or 400 MHz instrument (deuterated DMSO, deuterated chloroform, deuterated methanol, etc., TMS as internal standard).
  • Mass spectrometry was obtained by liquid chromatography-mass spectrometry (using ESI or APCI ion source ZQ4000, Waters, USA).
  • the ultraviolet spectrum was measured by a UV-3010 ultraviolet spectrophotometer from Hitachi, Japan. Infrared spectroscopy A NICOLET 6700 infrared spectrum analyzer (KBr pellet) was used.
  • High performance liquid chromatography was performed using a Waters 2695 ZORBAX high performance liquid chromatograph (Bx-C 8 5 ⁇ 150 x 4.6 mm column) or otherwise stated.
  • the melting point was determined using an Electrothermal digital melting point apparatus IA9100 and was uncorrected.
  • the resulting mixture was stirred at a temperature of 20-25 ° C for 18 h, and the mixture was diluted with water (100 mL) and stirred for 20 min, and pH was adjusted to 3-4 with 1N HCl.
  • the reaction mixture was concentrated under reduced pressure, and about 300 mL of ethanol was distilled off.
  • the compound of the present invention was dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution of 1 ⁇ 10 -3 M for use.
  • DMSO dimethyl sulfoxide
  • Serial semi-logarithmic diluton was used to form 10 different concentrations (1 x 10 5 M to 3 x 10 -10 M).
  • Biochemical activity of AXL and VEGFR2 by radioactive protein kinase assay (33Pan Activity Assay).
  • the reaction mixture was added via a dropper in the following four steps:
  • the reaction was carried out at 30 ° C for 60 minutes, and 50 ⁇ L of 2% (v/v) phosphoric acid was added to terminate the reaction.
  • the reaction mixture in the wells was aspirated and washed twice with 200 ⁇ L of a 0.9% (w/v) NaCl solution.
  • the compound of the present invention has strong inhibitory activity against both AXL and VEGFR2 kinases, and the IC 50 value of inhibiting AXL is between 6.08-55.3 nM, and at the same time, inhibiting the IC 50 of VEGFR2.
  • the value is between 6.56 and 24.5 nM.
  • the compounds of the present invention can be used to treat diseases caused by abnormal activities of these kinases, for example, tumors and the like.
  • Example 21 Pharmaceutical composition and preparation: tablets (mg/tablet)
  • Magnesium stearate 3.0;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 22 Pharmaceutical composition and preparation: tablets (mg/tablet)
  • Example 5 100, other substance content is the same as in Example 21;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 23 Pharmaceutical composition and preparation: tablets (mg/tablet)
  • Polyvinylpyrrolidone (5w/v%): 2.25; magnesium stearate: 3.0;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 24 Pharmaceutical composition and preparation: tablets (mg/tablet)
  • Example 9 The compound prepared in Example 9 was 50, and the other substances were the same as in Example 23;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 25 Pharmaceutical composition and preparation: tablets (mg/tablet)
  • Magnesium stearate 76;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 26 Pharmaceutical composition and preparation: tablets (mg/tablet)
  • Example 13 The compound prepared in Example 13 was 1.0, and the other substances were the same as in Example 25;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 27 Pharmaceutical composition and preparation: capsule (mg/capsule)
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 28 Pharmaceutical composition and preparation: capsule (mg/capsule)
  • Example 2 The compound prepared in Example 2: 10.0, the other substance content is the same as in Example 27;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 29 Drug composition and preparation: injection (50 mg/ml)
  • the water for injection is adjusted to 100%;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 30 Pharmaceutical composition and preparation: injection (50 mg/ml)
  • Example 12 The compound prepared in Example 12: 5%, the other substance content is the same as in Example 29, and finally adjusted to 100% with water for injection;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 31 Drug composition and preparation: injection (10 mg/ml)
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 32 Drug composition and preparation: injection (10 mg/ml)
  • Example 9 The compound prepared in Example 9: 1%, the other substance content is the same as in Example 31, and the water for injection is adjusted to 100%;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 33 Pharmaceutical composition and preparation: injection (1 mg/ml) (pH adjusted to 6)
  • Citric acid 0.38%; polyethylene glycol 400: 3.5%;
  • the water for injection is adjusted to 100%;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 34 Drug composition and preparation: injection (1 mg/ml) (pH adjusted to 6)
  • Example 10 0.1%, the content of other substances is the same as in Example 33, and finally adjusted to 100% with water for injection;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 35 Pharmaceutical Composition and Formulation: Aerosol (mg/ml)
  • Example 2 The compound prepared in Example 1 : 10; sorbitan oleate: 13.5;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 36 Pharmaceutical Composition and Formulation: Aerosol (mg/ml)
  • Example 3 10
  • the other substance content is the same as in Example 35;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 37 Drug Composition and Formulation: Aerosol (mg/ml)
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 38 Pharmaceutical Composition and Formulation: Aerosol (mg/ml)
  • Example 7 The compound prepared in Example 7 was 0.2, and the other substances were the same as in Example 37;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 39 Pharmaceutical Composition and Formulation: Aerosol (mg/ml)
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 40 Pharmaceutical Composition and Formulation: Aerosol (mg/ml)
  • Example 11 The compound prepared in Example 11 was 2.5, and the other substances were the same as in Example 39;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 41 Drug Composition and Formulation: Aerosol (mg/ml)
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 42 Pharmaceutical Composition and Formulation: Aerosol (mg/ml)
  • Example 13 The compound prepared in Example 13 was 2.5, and the other substances were the same as in Example 41;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 43 Drug composition and preparation: ointment (/ml)
  • Propylene glycol to 1 ml
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.
  • Example 44 Drug composition and preparation: ointment (/ml)
  • Example 7 The compound prepared in Example 7 was 40 mg, and the other substances were the same as in Example 43;
  • Applicable people Applicable to a variety of diseases caused by abnormal activity of AXL and / or VEGFR2 protein kinase.

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Abstract

本发明提供了一类如式(I)所示的一种喹啉基取代的羧酸化合物或其药学上可接受的盐，同时还公开了该化合物的制备方法及应用和含所述喹啉基取代的羧酸化合物或其药学上可接受的盐的制剂。这类化合物是蛋白激酶AXL和/或VEGFR2的抑制剂，可用于治疗因这两种激酶活性异常所引起的疾病，例如肿瘤等。

Description

一种喹啉基取代的羧酸化合物或其药学上可接受的盐、其药物组合物及应用
相关申请的交叉引用
本申请要求2016年10月18日提交、申请号为201610909448.4的中国专利申请的优先权，其所公开的内容作为参考全文并入本申请。
技术领域
本发明涉及有机化学及药物化学领域，具体涉及喹啉基取代的羧酸化合物或其药学上可接受的盐、其制备方法、以及含有该化合物的药物组合物及其应用。
背景技术
蛋白质激酶是一类磷酸转移酶，其作用是将ATP的γ-磷酸基转移到底物特定的氨基酸残基上，使蛋白质磷酸化，发挥其生理生化功能。蛋白激酶是一类重要的激酶，在信号转导中主要作用有两个方面：其一是通过磷酸化调节蛋白质的活性；其二是通过蛋白质的逐级磷酸化，使信号逐级放大，引起细胞反应。
蛋白激酶活性的异常不仅与肿瘤的增殖、凋亡、转移等与细胞内外的一系列信号传导通路中某个环节的异常密切相关，同时也是导致一系列其他与炎症或增殖反应有关的人类疾病，例如类风湿性关节炎、心血管和神经系统疾病、哮喘、银屑病等的主要原因。目前已知有四百多种人类疾病与蛋白激酶直接或间接相关，这使得蛋白激酶成为继G－蛋白偶联受体之后的另一大类重要药物靶标。
蛋白激酶大家庭由500多个成员组成，通常可分为蛋白酪氨酸激酶(protein tyrosine kinases or PTKs)及丝氨酸-苏氨酸激酶(serine-threonine kinases)两类。按照激酶在细胞中所处的位置，又可分为受体激酶(receptor kinases)及非受体激酶，又称细胞内激酶。受体激酶一般属酪氨酸激酶，也称酪氨酸受体激酶(receptor tyrosine kinases or RTKs)，这类受体激酶由细胞膜外部分、跨膜区及细胞质内部分组成，具有催化活性的激酶部分位于细胞质内。丝氨酸-苏氨酸激酶绝大多数位于细胞内，属非受体激酶或称细胞质激酶(cytosolic kinases)。
RTKs家族中的典型代表为生长因子受体(growth factor receptors)，至少存在19个亚家族，以下是几个主要的亚家族：
(a)HER家族酪氨酸受体激酶，包括EGFR(epithelial growth factor receptor)、HER2、HER3及HER4。EGFR为治疗非小细胞肺癌的合成小分子药
Figure PCTCN2017104518-appb-000001
Figure PCTCN2017104518-appb-000002
及单克隆抗体
Figure PCTCN2017104518-appb-000003
的靶标。
(b)由胰岛素受体(insulin receptor or IR)、像胰岛素的生长因子I型受体(insulin-like growth factor I receptor or IGF-1R)及与胰岛素受体相关的受体(insulin receptor-related receptor or IRR)组成。其中的IGF-1R是公认的抗癌靶标，但由于它与IR太相似，尤其是细胞内的激酶部分，其氨基酸序列为100％相同，抑制IGF-1R的活性，通常也会抑制IR的活性。有证据显示IR也是有效的抗癌靶标，但因为抑制IR有导致血糖升高的风险，IR抑制剂用于抗癌需要找到效益与安全风险的平衡。
(c)血小板源生长因子受体(platelet-derived growth factor receptor or PDGFRs)家族，包括PDGFR-α、PDGFR-β、CSF1R、c-KIT及c-fms。其中c-KIT也是白血病治疗药物
Figure PCTCN2017104518-appb-000004
的分子靶标，用于治疗胃肠间质瘤。
(d)血管内皮生长因子受体(vascular endothelial growth factor receptors or VEGFRs)家族，包括FLT1(Fms-like tyrosine kinase 1或VEGFR1)、KDR(或VEGFR-2)及FLT4(或VEGFR3)。其中的成员为
Figure PCTCN2017104518-appb-000005
和
Figure PCTCN2017104518-appb-000006
的分子靶标。
(e)成纤维细胞生长因子受体(fibroblast growth factor receptors or FGFRs)家族，包括FGFR1、FGFR2、FGFR3及FGFR4及7个配体FGF1、FGF2、FGF3、FGF4、FGF5、FGF6及FGF7。其中的成员作为分子靶标的药物还在临床实验阶段。
(f)MET家族，包括c-Met或称人类肝细胞生长因子受体(human hepatocyte growth factor receptor or hHGFR)及RON。其中c-Met在初始肿瘤的生长及转移中扮演重要的角色。其作为分子靶标的药物还处于临床实验阶段。
(g)RET家族，RET是GDNF家族成员的受体，存在RET51、RET43和RET9isoforms。其作为分子靶标的药物还处于临床实验阶段。
(h)Eph家族是酪氨酸受体激酶中最大的家族，由16个受体(EPHA1、EPHA2、EPHA3,EPHA4、EPHA5、EPHA6、EPHA7、EPHA8、EPHA9、EPHA10、EPHB1、EPHB2、EPHB3、EPHB4、EPHB5、EPHB6)和9个配体(EFNA1、EFNA2、EFNA3、EFNA4、EFNA5、EFNB1、EFNB2、EFNB3)组成。这些成员在动物的发育中起重要作用，有些成员在肿瘤中扮演角色。
AXL是另一个重要的酪氨酸受体激酶，AXL也叫UFO/ARK/Tyro，其配体 是维生素K依赖性的生长促进因子GAS6。AXL的首次发现是作为慢性髓细胞性白血病(CML)的转化基因。AXL在转移性结肠癌、甲状腺癌、乳腺癌、前列腺癌和黑色素瘤中过度表达。抑制AXL的活性可起到抑制肿瘤生长、扩散和转移的目的。
非受体激酶不存在细胞膜外部分及跨膜区部分，整个激酶处于细胞浆中。现在已知至少有24种非受体激酶分为11个亚家族，它们是Src、Frk、Btk、CsK、Abl、Zap70、Fes、Fps、Fak、Jak及AcK亚家族。其中Src亚家族为最大，包括Src、Yes、Fyn、Lyn、Lck、Blk、Hck、Fgr、AUR1、AUR2及Yrk激酶。更详细的资料见Neet,K.；Hunter,T.Genes to Cells 1996,1,147-169及该文引用的文献。虽然有几个非受体激酶属酪氨酸激酶，但绝大多数非受体激酶属于丝氨酸-苏氨酸激酶。其中的几个成员是白血病治疗药物
Figure PCTCN2017104518-appb-000007
及
Figure PCTCN2017104518-appb-000008
的分子靶标。
如上所述，受体激酶及非受体激酶作为抗肿瘤靶标已经在临床上及实际应用中得到充分的证明，多个抗肿瘤药已经批准上市治疗病人。除了肿瘤治疗以外，抑制受体激酶及非受体激酶的异常活性还可用于治疗包括但不限于以下疾病：银屑病或称牛皮癣、肝硬化、糖尿病、涉及血管新生的疾病、涉及再狭窄的疾病、眼睛疾病、与年龄有关的黄斑退化、风湿性关节炎及别的炎症、免疫系统疾病例如自免疫疾病、心血管疾病例如动脉粥样硬化、肾脏疾病等。因此继续研发这些激酶的抑制剂是非常必要的。
发明内容
本发明的目的是提供一种具有蛋白激酶抑制活性的喹啉基取代的羧酸化合物或其药学上可接受的盐和它们的制备方法。
本发明的另一个目的是提供上述喹啉基取代的羧酸化合物或其药学上可接受的盐用于制备治疗因蛋白激酶异常活性引起的疾病的药物的应用。
本发明还有一个目的是提供一种包含上述喹啉基取代的羧酸化合物或其药学上可接受的盐的能够治疗因蛋白激酶异常活性引起的疾病的药物组合物。
本发明所采用的技术方案如下：
一种喹啉基取代的羧酸化合物或其药学上可接受的盐，该化合物分子结构式如式(I)所示：
Figure PCTCN2017104518-appb-000009
式中，
V1和V2分别独立地选自氢、氘、卤素、C1-6烷基或C1-6烷氧基；
R表示氢、C1-12烷基、C1-12烷氧基，且R中的氢可选择性地被G1取代；
L为C1-12亚烷基，且L中的氢可选择性地被G2取代；
M选自：
(a)氢、氘、C2-12烷基、C3-12环烷基、C6-12芳基、C5-12杂芳基或C3-12杂脂环基，且M中的氢可选择性地被G3取代；或
(b)一价、二价、三价或四价金属离子，优选为一价和二价金属离子，更优选为锂、钠、钾、铷、铯、镁、钙、锶、钡离子；或
(c)铵离子或质子化的有机胺，所述有机胺包括但不限于C1-12烷基、C3-12环烷基或C3-12杂脂环基取代的脂肪胺，这些脂肪胺可选择性地被一个或多个卤素或羟基取代；
其中：
G1、G2及G3分别独立地选自氢、氘、-CN、-CF3、-CO2H、卤素、C1-12烷基、C3-12环烷基、C2-12烯基、C2-12炔基、C6-12芳基、C5-12杂芳基、C3-12杂脂环基、R1O-、R1R2N-、R1S(＝O)m-、R1R2NS(＝O)m-、R3C(＝O)-、R1R2NC(＝O)-、R1OC(＝O)-、R3C(＝O)O-、R1R2NC(＝O)O-、R3C(＝O)NR1-、R1R2NC(＝O)NR4-、R1OC(＝O)NR4-、R1S(＝O)mNR4-、R1R2NS(＝O)mNR4-、R1R2NC(＝NR5)NR4-、R1R2NC(＝CHNO2)NR4-、R1R2NC(＝N-CN)NR4-、R1R2NC(＝NR5)-、R1S(＝O)(＝NR5)NR4-或R1R2NS(＝O)(＝NR5)-；
R1、R2、R3、R4及R5分别独立地选自氢、氘、C1-12烷基、C2-12烯基、C2-12炔基、C3-12环烷基、C6-12芳基、C5-12杂芳基或C3-12杂脂环基；当R1和R2连接于同一氮原子上时，可与该氮原子一起形成一个C3-12杂脂环，所述C3-12杂脂环可选择性地包含O、N、S(＝O)m杂原子；且R1、R2、R3、R4及R5中的氢可选择性地被卤素、CN、C1-12烷基或C3-12环烷基取代；
m＝0-2。
优选地，本发明如式(I)所示的结构中：
V1和V2分别独立地选自氢、氘、卤素、C1-6烷基或C1-6烷氧基；
R表示氢、C1-12烷基、C1-12烷氧基；
L为C1-12亚烷基；
M选自：
(a)氢、氘、C2-12烷基；或
(b)锂、钠、钾、铷、铯、镁、钙、锶、钡离子；或
(c)铵离子或质子化的有机胺，所述有机胺包括C1-12烷基、C3-12环烷基或C3-12杂脂环基取代的脂肪胺，这些脂肪胺可选择性地被一个或多个卤素或羟基取代。
优选地，本发明如式(I)所示的结构中：
V1和V2分别独立地选自氢、氘或卤素；更优选V1和V2同时为氢、氘或卤素；且取代位点分别在各自所在六元环的2位和4位。
优选地，本发明如式(I)所示的结构中：V1和V2分别独立地选自氢、氘或卤素时，R为C1-12烷氧基、L为C1-12亚烷基。
优选地，本发明如式(I)所示的结构中：V1和V2分别独立地选自氢或卤素；R为甲氧基、乙氧基、正丙氧基或异丙氧基；L为C1-6亚烷基。
以及，在上述列举的任一种情况下：
本发明所述的如式(I)所示的喹啉基取代的羧酸化合物或其药学上可接受的盐，其中，M选自氢、氘或C2-6烷基；或
如式(I)所示的喹啉基取代的羧酸化合物或其药学上可接受的盐，其中，M选自锂、钠、钾、镁或钙离子；或
如式(I)所示的喹啉基取代的羧酸化合物或其药学上可接受的盐，其中，M选自铵离子或质子化的甲胺、乙胺、正丙胺、异丙胺、正丁胺、异丁胺、仲丁胺、叔丁胺、二甲胺、二乙胺、二正丙胺、二异丙胺、二正丁胺、二异丁胺、二仲丁胺、二叔丁胺、三甲胺、三乙胺、三正丙胺、三异丙胺、三正丁胺、三异丁胺、三仲丁胺、三叔丁胺、二异丙基乙基胺或2-氨基-2-(羟甲基)丙烷-1,3-二醇。
更具体而言，本发明所述如式(I)所示的喹啉基取代的羧酸化合物或其药学上可接受的盐，所述化合物为下列任意一种：
2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基 -7-喹啉基]氧基]乙酸；
2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸锂盐；
2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钠盐；
2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钾盐；
2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸镁盐；
2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钙盐；
2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸铵盐；
2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸三乙基铵盐；
2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸；
3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸锂盐；
3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钠盐；
3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钾盐；
3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸镁盐；
3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钙盐；
3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸铵盐；
3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸三乙基铵盐；
3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸；
4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸锂盐；
4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钠盐；
4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钾盐；
4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸镁盐；
4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钙盐；
4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸铵盐；
4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸三乙基铵盐；
4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸；
5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸锂盐；
5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钠盐；
5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钾盐；
5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基 -7-喹啉基]氧基]戊酸镁盐；
5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钙盐；
5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸铵盐；
5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸三乙基铵盐；
5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸；
6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸锂盐；
6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钠盐；
6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钾盐；
6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸镁盐；
6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钙盐；
6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸铵盐；
6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸三乙基铵盐；
6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸；
7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸锂盐；
7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钠盐；
7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钾盐；
7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸镁盐；
7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钙盐；
7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸铵盐；
7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸三乙基铵盐；
7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸锂盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钠盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钾盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸镁盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钙盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸铵盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸三乙基铵盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基 -7-喹啉基]氧基]乙酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸锂盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钠盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钾盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸镁盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钙盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸铵盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸三乙基铵盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸锂盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钠盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钾盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸镁盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钙盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸铵盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸三乙基铵盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸锂盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钠盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钾盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸镁盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钙盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸铵盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸三乙基铵盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸锂盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钠盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基 -7-喹啉基]氧基]己酸钾盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸镁盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钙盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸铵盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸三乙基铵盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸锂盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钠盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钾盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸镁盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钙盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸铵盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸三乙基铵盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸；
2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸锂盐；
2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钠盐；
2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钾盐；
2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸镁盐；
2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钙盐；
2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸铵盐；
2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸三乙基铵盐；
2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸；
3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸锂盐；
3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钠盐；
3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钾盐；
3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸镁盐；
3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钙盐；
3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸铵盐；
3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基 -7-喹啉基]氧基]丙酸三乙基铵盐；
3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸；
4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸锂盐；
4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钠盐；
4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钾盐；
4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸镁盐；
4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钙盐；
4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸铵盐；
4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸三乙基铵盐；
4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸；
5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸锂盐；
5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钠盐；
5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钾盐；
5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸镁盐；
5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钙盐；
5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸铵盐；
5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸三乙基铵盐；
5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸；
6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸锂盐；
6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钠盐；
6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钾盐；
6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸镁盐；
6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钙盐；
6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸铵盐；
6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸三乙基铵盐；
6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸；
7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸锂盐；
7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基 -7-喹啉基]氧基]庚酸钠盐；
7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钾盐；
7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸镁盐；
7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钙盐；
7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸铵盐；
7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸三乙基铵盐；
7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸锂盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸钠盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸钾盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸镁盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸钙盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸铵盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸三乙基铵盐；
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸锂盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸钠盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸钾盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸镁盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸钙盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸铵盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸三乙基铵盐；
3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸锂盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸钠盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸钾盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸镁盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸钙盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基 -7-喹啉基]氧基]丁酸铵盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸三乙基铵盐；
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸锂盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸钠盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸钾盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸镁盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸钙盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸铵盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸三乙基铵盐；
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸锂盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸钠盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸钾盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸镁盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸钙盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸铵盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸三乙基铵盐；
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸1,3-二羟基-2-(羟甲基)丙-2-铵盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸锂盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸钠盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸钾盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸镁盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸钙盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸铵盐；
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸三乙基铵盐；或
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸1,3-二羟基-2-(羟甲基)丙-2-铵盐。
本发明同时保护上述的任意一种喹啉基取代的羧酸化合物或其药学上可接受的盐的消旋体或对映异构体。
本发明同时保护一种喹啉基取代的羧酸化合物或其药学上可接受的盐的制 备方法，该方法包括，但不限于由Scheme 1所示的实验步骤：
Figure PCTCN2017104518-appb-000010
其中，
化合物A-1可以按照WO2013/040801A1所公开的方法合成；
其中，V1、V2、R、L和M的指代同上文中关于所述喹啉基取代的羧酸化合物或其药学上可接受的盐中V1、V2、R、L和M的限定一致。
如：V1和V2分别独立地选自氢、氘、卤素、C1-6烷基或C1-6烷氧基；
R表示氢、C1-12烷基、C1-12烷氧基，且R中的氢可选择性地被G1取代；
L为C1-12亚烷基，且L中的氢可选择性地被G2取代；
M选自：
(a)氢、氘、C2-12烷基、C3-12环烷基、C6-12芳基、C5-12杂芳基或C3-12杂脂环基，且M中的氢可选择性地被G3取代；或
(b)一价、二价、三价或四价金属离子，优选为一价和二价金属离子，更优选为锂、钠、钾、铷、铯、镁、钙、锶、钡离子，给出化合物Ib；
或
(c)铵离子或质子化的有机胺，给出化合物Ic；所述有机胺包括但不限于C1-12烷基、C3-12环烷基或C3-12杂脂环基取代的脂肪胺，这些脂肪胺可选择性地被一个或多个卤素或羟基取代；
RR表示氢、C1-12烷基、C3-12环烷基、C6-12芳基、C5-12杂芳基或C3-12杂脂环基，且RR中的氢可选择性地被G4取代；
LG表示有机化学中常见的离去基团，为F、Cl、Br、I、CH3SO3、CH3CH2SO3、CH3(CH2)2SO3、(CH3)2CHSO3、tert-BuSO3、PhSO3、 o-CH3PhSO3、m-CH3PhSO3、p-CH3PhSO3、o-O2NPhSO3、m-O2NPhSO3、p-O2NPhSO3或CF3SO3中的任意一个；
其中：
G1、G2、G3及G4分别独立地选自氢、氘、-CN、-CF3、-CO2H、卤素、C1-12烷基、C3-12环烷基、C2-12烯基、C2-12炔基、C6-12芳基、C5-12杂芳基、C3-12杂脂环基、R1O-、R1R2N-、R1S(＝O)m-、R1R2NS(＝O)m-、R3C(＝O)-、R1R2NC(＝O)-、R1OC(＝O)-、R3C(＝O)O-、R1R2NC(＝O)O-、R3C(＝O)NR1-、R1R2NC(＝O)NR4-、R1OC(＝O)NR4-、R1S(＝O)mNR4-、R1R2NS(＝O)mNR4-、R1R2NC(＝NR5)NR4-、R1R2NC(＝CHNO2)NR4-、R1R2NC(＝N-CN)NR4-、R1R2NC(＝NR5)-、R1S(＝O)(＝NR5)NR4-或R1R2NS(＝O)(＝NR5)-；
R1、R2、R3、R4及R5分别独立地选自氢、氘、C1-12烷基、C2-12烯基、C2-12炔基、C3-12环烷基、C6-12芳基、C5-12杂芳基或C3-12杂脂环基；当R1和R2连接于同一氮原子上时，可与该氮原子一起形成一个C3-12杂脂环，所述C3-12杂脂环可选择性地包含O、N、S(＝O)m杂原子；且R1、R2、R3、R4及R5中的氢可选择性地被卤素、CN、C1-12烷基或C3-12环烷基取代；
m＝0-2。
Base、Solvent、Hydrolysis和Salt formation的意思见“术语定义”部分，不构成对制备历程保护范围的限定。
本发明还涉及了一种包含喹啉基取代的羧酸化合物或其药学上可接受的盐的药物组合物。
上述药物组合物除了喹啉基取代的羧酸化合物或其药学上可接受的盐以外，还包含一种或几种药学上可接受的载体或稀释剂。
上述药物组合物的制剂形式为：口服剂、注射剂、肛塞剂、鼻孔吸入剂、滴眼剂或皮肤贴剂。
如式(I)所示喹啉基取代的羧酸化合物或其药学上可接受的盐或包含该化合物的药物组合物的应用，在于用于治疗因蛋白激酶异常活性所引起的疾病。所述激酶为AXL或/及VEGFR2。所述疾病为肿瘤，包括实体瘤和液体肿瘤。
本发明化合物或/及包含该化合物的药物组合物的应用中所述的肿瘤具体包括：肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌、胃癌、结肠癌、乳腺癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、阴户癌、何杰金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、 甲状旁腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、膀胱癌、肾或输尿管癌、肾癌、中枢神经中枢系统(CNS)赘生物、脊柱轴肿瘤、垂体腺瘤、胃肠间质肿瘤、结肠直肠癌、非小细胞肺癌、小细胞肺癌、肥大细胞增多症、胶质瘤、肉瘤、淋巴瘤中的一种或任意几种的组合。
一种治疗因蛋白激酶异常活性所引起的疾病的药物，包含上述任意一种或任意几种化合物或其在药学上可接受的盐、溶剂合物、前药，或上述任意一项中所述的任意一种或任意几种化合物的消旋体、对映异构体或其在药学上可接受的盐、溶剂合物或前药。
本发明所述的药物，除了喹啉基取代的羧酸化合物或其药学上可接受的盐以外，还包含一种或几种药学上可接受的载体或/及稀释剂。
本发明上述任意一种药物的制剂形式如下：
(1)口服剂、(2)注射剂、(3)肛塞剂、(4)鼻孔吸入剂、(5)滴眼剂或(6)皮肤贴剂。
经过一系列的试验证明，本发明喹啉基取代的羧酸化合物或其药学上可接受的盐具有如下有益效果(1)通过抑制激酶活性的试验，可以看出本发明化合物对AXL和VEGFR2激酶具有很强的抑制作用；(2)通过对动物的肿瘤抑制试验可以看到，该类喹啉基取代的羧酸化合物或其药学上可接受的盐可以显著抑制肿瘤，且没有明显的毒性；(3)本发明所述的化合物可与其他抗肿瘤药物共同使用从而起到协同(synergistic)或加合(additive)效应；(4)本发明中的化合物可以与其他的肿瘤疗法，例如放射线疗法、介入疗法等一同使用。由此可见，本发明一种喹啉基取代的羧酸化合物或其药学上可接受的盐可以作为一种有效治疗因蛋白激酶异常活性所引起的疾病的药物。
本发明所述化合物在治疗因蛋白激酶活性异常所引起的疾病中，所述的肾癌为肾上腺癌、肾细胞癌、肾盂癌；胶质瘤为脑干神经胶质瘤、神经内分泌胶质肿瘤、神经胶质瘤。
本发明所述化合物在治疗因蛋白激酶活性异常所引起的疾病中，除肿瘤外还可以为银屑病(或称牛皮癣)、肝硬化、糖尿病、涉及血管新生的疾病、涉及再狭窄的疾病、眼睛疾病例如AMD、风湿性关节炎及别的炎症、免疫系统疾病例如自免疫疾病(例如，爱滋病等)、心血管疾病例如动脉粥样硬化、肾脏疾病、癫痫、神经退行性疾病，比如阿尔茨海默氏病、亨廷顿氏病、帕金森氏症等。
由本发明所述化合物组成的药物组合物用于治疗哺乳动物，如人类病人，因 蛋白激酶异常活性引起的疾病。
本发明所述化合物(包括消旋体、对映异构体及别的立体异构体)或其在药学上可接受的盐、水合物、溶剂合物或前药通过制剂(formulation)过程，与适合的药学上可接受的载体及药学上常用的辅剂制备成利于给药的药物组合物。
本发明所述化合物组成的药物给药途径可以为：(1)口服：例如片剂、胶囊等；(2)注射：例如静脉注射、皮下注射、肌肉注射、眼球注射、腹腔注射等；(3)肛塞：例如栓剂、凝胶剂等；(4)鼻孔吸入：例如喷雾剂、气雾剂等；(5)滴眼剂；(6)皮肤贴剂。也可使用药物释放系统，例如，脂质体(liposome)、缓释技术、控释技术等，其中优先选用的方法为口服及注射，更优先选用的方法为口服。
本发明由所述化合物组成的药物组合物的各种剂型可以采用医药工业常用的方法制备。例如，混合、溶解、制粒、研磨、乳化、胶囊、糖衣、冷冻干燥、冷冻喷雾等。
本发明中的化合物在前述药物组合物中的含量范围为0.001－100％。该药物组合物施用于包括人在内的哺乳动物的有效剂量为每日每千克体重0.1－500毫克，优化的剂量为每日每千克体重使用1－100毫克。在这个有效剂量范围内，本发明中的化合物发挥其抑制蛋白激酶活性及治疗因异常蛋白激酶活性异常引起的疾病(例如癌症)的药理作用。
本发明药物的使用频率依所使用的化合物或其药物组合物及应用的疾病而有所变化，本发明中的药物组合物通常是每日给药1－6次，优化的给药频率为每日给药1－3次。
本发明所述药物的包装和保存和一般西药类似，例如固体剂型的药物可直接装入玻璃、塑料、纸质或金属瓶中，瓶内最好放入干燥剂等以保持药物的质量；液体剂型的药物一般装入玻璃、塑料或金属瓶或软管中；起雾剂型的药物一般装入耐压的附有减压阀等装置的金属或塑料容器中。
术语的定义
以下为本发明中所涉及的术语定义。在本发明中使用的可变基团，例如Ra、Rb、g等只适用于本小节(即“术语的定义”部分)。
根据本领域普通技术人员的公知常识，化学反应多数情况下需要在溶剂中进行，制备本发明的化合物常用的溶剂(Solvent)包括但不限于水、甲醇、乙醇、异丙醇、正丙醇、正丁醇、异丁醇、叔丁醇、2-甲氧基乙醇、2,2,2-三氟乙醇、二 氯甲烷、1,2-二氯乙烷、氯仿、THF、二氧六环、DME、乙酸乙酯、乙醚、甲基叔丁醚、己烷、环己烷、甲苯、乙腈、DMF、DMSO或这些溶剂中的两种或几种的组合。
本发明化合物的制备过程中，有些步骤需要在碱(Base)的存在发生反应，所述的碱包括但不限于有机碱，例如，MeNH2、Me2NH、Me3N、EtNH2、Et2NH、Et3N、n-PrNH2、n-Pr2NH、n-Pr3N、i-PrNH2、i-Pr2NH、i-Pr3N、n-BuNH2、n-Bu2NH、n-Bu3N、s-BuNH2、s-Bu2NH、s-Bu3N、i-BuNH2、i-Bu2NH、i-Bu3N、t-BuNH2、t-Bu2NH、t-Bu3N、i-Pr2NEt、2-氨基-2-(羟甲基)丙烷-1,3-二醇、环丙胺、二环丙胺、环丁胺、二环丁胺、环戊胺、二环戊胺、环己胺、二环己胺、吡啶、DBU、DABCO、四甲基胍、五甲基胍、四乙基胍、五乙基胍、吗啉、1-甲基吗啉、哌啶、1-甲基哌啶、1-乙基哌啶、哌嗪、1-甲基哌嗪、1-乙基哌嗪、1,4-二甲基哌嗪、1,4-二乙基哌嗪、吡咯烷、1-甲基吡咯烷、1-乙基吡咯烷、MeONa、MeOK、MeOLi、EtOLi、EtONa、EtOK、n-PrOLi、n-PrONa、n-PrOK、i-PrOLi、i-PrONa、i-PrOK、n-BuOLi、n-BuONa、n-BuOK、i-BuOLi、i-BuONa、i-BuOK、s-BuOLi、s-BuONa、s-BuOK、t-BuOLi、t-BuONa、t-BuOK、n-BuLi、s-BuLi、t-BuLi、NaN(SiMe3)2、LiN(SiMe3)2、KN(SiMe3)2等。所述的碱也包括但不限于无机碱，例如，氨气、氨水、LiOH、NaOH、KOH、RbOH、CsOH、Cs2CO3、Rb2CO3、Li2CO3、Na2CO3、K2CO3、NaHCO3、LiF、NaF、KF、RbF、CsF、K3PO3、K2HPO4、KH2PO4、Na3PO3、Na2HPO4、NaH2PO4、Li3PO3、Li2HPO4、LiH2PO4、NaH、LiH、KH、RbH、CsH、CaO、Ca(OH)2、Ca2CO3、MgO、Mg(OH)2、Mg2CO3等，或上述碱中的两种或几种的组合。
本发明化合物的制备过程中，有些步骤需要用到水解反应(Hydrolysis)，所述反应一般是在碱(Base)或酸(Acid)的存在下进行，所述的碱的定义同上；所述酸包括但不限于HCO2H、AcOH、TFA(三氟醋酸)、HCl(盐酸)、H2SO4、HNO3、H3PO4、p-TsOH、PhSO3H、CSA、MsOH等或Lewis酸ZnCl2、AlCl3、BF3.OEt2等的一种或几种组合。
本发明化合物的制备过程中，有些步骤需要用到成盐反应(Salt formation)，该反应是指羧酸化合物A-3与上述碱(Base)发生反应生成羧酸盐化合物Ib或Ic的过程。
制备本发明的化合物的反应通常在室温下进行，但有时需要降低至-78℃或加热至200℃；反应通常在前述的溶剂及温度及常规搅拌条件下进行，但有时需 要在微波炉中进行；当使用的碱、试剂、催化剂对水或氧气敏感时，反应需在无水无氧条件下进行，在这种情况下，不能使用质子性溶剂。
“溶剂合物”指本发明所述化合物与化学上常用的溶剂以共价键、氢键、离子键、范德华力、络合、包合等形成的稳定物质，所述的溶剂可以为：甲醇、乙醇、丙醇、丁醇、乙二醇、丙二醇、聚乙二醇、丙酮、乙腈、乙醚、甲基叔丁醚等。
“水合物”指溶剂合物，其中的溶剂为水。
“前药”指通过化学合成或物理的方法将本发明中的化合物转化为另一种化合物，并将该化合物给予哺乳动物后，在动物体内被转化成本发明所述的化合物。利用“前药”方法通常是为了克服药物化合物本身不良或欠佳的物理化学性质或成药性。
“消旋体、对映异构体、顺反异构体及别的立体异构体”指化合物具有相同的分子式及分子量，然而由于原子之间的不同键合方式及空间安排顺序而形成不同的化合物，这样的化合物叫异构体或称立体异构体。当这些立体异构体互为镜像关系，即看起来很像，却不能完全重合，就如左手与右手，这些化合物叫对映异构体。对映异构体的绝对构型通常用(R)-及(S)-或R-及S-来标示。具体确定对映异构体的绝对构型的规则见Chapter 4 of“Advanced Organic Chemistry,”4th edition(by J.March,John Wiley and Sons,New York,1992)。(R)-及(S)-对映异构体对偏振光具有相反的旋转作用，即左旋和右旋。当(R)-及(S)-对映异构体按1:1的比例混合或存在时，该混合物对偏振光没有旋转作用，这时该混合物称为消旋体。
本发明所述化合物还可能存在互变异构体(tautomers)、旋转异构体(rotamers)、顺反异构体等，这些概念都可在J.March的“Advanced Organic Chemistry,”4th edition中找到并得到理解。只要这些异构体具有与本发明所述化合物相同或类似的抑制AXL和/或VEGFR2活性的作用，这些异构体也涵盖于本发明中。
本发明中的化合物被给予哺乳动物(例如人)后，据本领域的常识，有可能在动物体内被不同的酶代谢成各种代谢产物，只要这些代谢产物具有与本发明所述化合物类似的抑制AXL和/或VEGFR2活性的作用，这些代谢产物也涵盖于本发明中。
“药物组合物”指将本发明所述化合物中的一个、多个、药学上可接受的盐或溶剂合物或水合物或前药与别的化学成分(例如药学上可接受的载体或稀释剂)混合制得的制剂。药物组合物的目的是促进给动物给药的过程。上述的药物组合 物中，除了包括药学上可接受的载体外，还可以包括在药(剂)学上常用的辅剂，例如：抗细菌剂、抗真菌剂、抗微生物剂、保质剂、调色剂、增溶剂、增稠剂、表面活性剂、络合剂、蛋白质、氨基酸、脂肪、糖类、维生素、矿物质、微量元素、甜味剂、色素、香精或它们的结合等。
“药学上可接受的载体”或”稀释剂”指药物组合物中的非活性成分，可以是但不限于：碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物、甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油、氢化蓖麻油、多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
“烷基”指具有指定数目碳原子的直链或支链的饱和碳氢化合物基团，例如C1-12烷基指含最少1个，最多12个碳原子的直链或支链基团。C0烷基代表一个共价单键。本发明所述的烷基包括但不限于：甲基、乙基、丙基、丁基、异丙基、新戊基、2-甲基-1-己基等。本发明所述的烷基有时也指“亚烷基”，亚烷基是指烷基失去一个氢原子形成的基团。烷基或亚烷基中的一个或全部氢原子可被下列基团取代：环烷基、芳基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NRaRb，其中，Ra及Rb分别选自：氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“环烷基”或“环烷”指具有指定数目碳原子的单、双或多环的碳氢化合物基团，双环或多环时，可以以稠合(两个环或多个环共用两个相邻的碳原子)或螺合(两个环或多个环共用一个碳原子)的形式结合，例如C1-12环烷基指含最少1个，最多12个的单、双或多环的碳氢化合物基团。C0环烷基代表一个共价单键。环烷基中可以含有不饱和的双键或三键，但不具有完全共轭的π电子体系。本发明所述的环烷基有时也指亚环烷基，即环烷基失去一个氢原子形成的基团。本发明所述的环烷基包括但不限于：环丙基、环丁基、环己基、环戊烯基、环庚三烯基、金刚烷等(举例如表A)：
表A
Figure PCTCN2017104518-appb-000011
环烷基或环烷中的一个或全部氢原子可被下列基团取代：烷基、芳基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NRaRb，其中，Ra及Rb分别选自：氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“杂脂环基”或“杂脂环”指由3至12个非氢环原子组成的单环、双环或多环体系，其中至少一个环原子为选自O、N、S或P的杂原子，其余环原子为碳原子，例如，C8杂脂环基指的是由8个非氢环原子构成的单环、双环或多环基团，其中至少一个环原子选自O、N、S或P。这种环中除单键外，还可含有双键或叁键，但这些双键或叁键不构成全部共轭的芳香结构。这些单环、双环或多环体系可以以稠环、桥环或螺环的形式存在。本发明所述的杂脂环基有时也指亚杂脂环基，即杂脂环基失去一个氢原子形成的基团。本发明中的杂脂环基或杂脂环包括但不限于：哌啶、吗啉、哌嗪、吡咯烷、吲哚啉、四氢吡啶、四氢呋喃、托品醇等(举例如表B)：
表B
Figure PCTCN2017104518-appb-000012
杂脂环基或杂脂环中的一个或全部氢原子可被下列基团取代：烷基、环烷基、芳基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯 基及-NRaRb，其中，Ra及Rb分别选自：氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“烯基”指含有至少两个碳原子及至少一个双键的直链或支链碳氢化合物基团，例如C2-12烯基指含最少2个，最多12个碳原子的直链或支链含至少一个双键的不饱和基团。本发明中的烯基包括但不限于：乙烯基、2-丙烯基、1-戊烯基等。
“炔基”指含有至少两个碳原子及至少一个三键的直链或支链碳氢化合物基团，例如C2-12炔基指含最少2个，最多12个碳原子的直链或支链含至少一个三键的不饱和基团。本发明中的炔基包括但不限于：乙烯基、2-丙烯基、1-戊烯基等。
“卤素”指氟、氯、溴或碘。
“烷氧基”指具有指定数目碳原子的烷基通过氧原子与其他基团相连。本发明中的烷氧基包括但不限于：甲氧基、乙氧基、丙氧基、丁氧基、环戊氧基、环己氧基、异丙氧基、新戊氧基、2-甲基-1-己氧基等。
“环烷氧基”指具有指定数目碳原子的环烷基通过氧原子与其他基团相连。本发明中的环烷氧基包括但不限于：环丙烷氧基、环丁烷氧基、环己烷氧基等。
“杂脂环氧基”指杂脂环基通过氧原子与其他基团相连。本发明中的杂脂环氧基包括但不限于：哌啶-4基氧基、氧杂环丁烷-3-基氧基等。
“芳基”指由指定数目碳原子组成的单环、双环或多环基团，其中至少一个环具有完全共轭的π电子体系并符合N+2规则，即具有芳香性，但整个基团不必全部共轭。例如，C6芳基指苯基。芳基也可以以亚芳基的形式出现，即芳基结构中与其他基团有两个或以上的连接点。本发明中的芳基包括但不限于：苯基、萘基、茚基、二氢化茚基、四氢化萘等。芳基中的一个或全部氢原子可被下列基团取代：烷基、环烷基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NRaRb，其中，Ra及Rb分别选自：氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“杂芳基”指由指定数目非氢环原子组成的单环、双环或多环基团，其中至少一个环原子为选自O、N、S或P的杂原子，其余环原子为碳原子，并且，其中 至少一个环具有完全共轭的π电子体系并符合N+2规则，即具有芳香性，但整个基团不必全部共轭，例如，C5杂芳基指的是由5个非氢环原子构成的芳香环基团，其中至少一个环原子选自O、N、S或P。杂芳基也可以以亚杂芳基的形式出现，即杂芳基结构中与其他基团有两个或以上的连接点。本发明中的杂芳基包括但不限于：砒啶、砒碇酮、四氢砒碇酮、咪啶、吡嗪、哒嗪、咪唑、噻唑、噻吩、呋喃、吲哚、氮杂吲哚、苯并咪唑、吲哚啉、吲哚酮、喹咛等(举例如表C)：
表C
Figure PCTCN2017104518-appb-000013
杂芳基中的一个或全部氢原子可被下列基团取代：烷基、环烷基、芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NRaRb，其中，Ra及Rb分别选自氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“含氮原子杂芳基”指杂芳基，但是该杂芳基中包含至少一个氮原子。本发明中的含氮原子杂芳基包括但不限于：吡啶基、喹啉基、吡嗪基、哒嗪基等。
“芳氧基”指芳基通过氧原子与其他基团相连。本发明中的芳氧基包括但不限于：苯氧基、萘氧基等。
“杂芳氧基”指杂芳基通过氧原子与其他基团相连。本发明中的杂芳氧基包括但不限于：4-砒啶氧基、2-噻吩氧基等。
“N-氧化物”指分子中的N原子与O原子通过双键相连，形成N＝O或N+-O-结构。
“氨基”指H2N-或其中氢原子被取代的H2N-，即RaHN-及RaRbN-。
“oxo”或“氧基”指＝O或-O-，即氧原子通过双键或单键与碳或N、S、P等 杂原子相连接。被氧基取代的例子包括但不限于表D中所示物质：
表D
Figure PCTCN2017104518-appb-000014
“羟基”指-OH。
“硝基”指-NO2。
“羧基”指-CO2H。
“巯基”指-SH。
“烷基巯基”指烷基-S-。
“芳基巯基”指芳基-S-。
“羰基”指-C(＝O)-。
“硫羰基”指-C(＝S)-。
“C-酰胺基”指-C(＝O)NRaRb。
“N-酰胺基”指C(＝O)NRa-。
“O-氨羰氧基”指-O-C(＝O)NRaRb。
“N-氨羰氧基”指O-C(＝O)NRa-。
“O-硫代氨羰氧基”指-O-C(＝S)NRaRb。
“N-硫代氨羰氧基”指O-C(＝S)NRa-。
“C-酯基”指-C(＝O)ORa。
“N-酯基”指C(＝O)O-。
“乙酰基”指CH3C(＝O)-。
“磺酰基”指-SO2Ra。
“三氟甲磺酰基”指CF3SO2-。
具体实施方式
以下结合具体实施例对本发明作进一步详细说明，以便读者进一步理解本发明所述化合物、其制备方法及有益效果等，但本发明的具体实施方式对本发明要求保护的内容不具有限制作用。
下面列出在实施例中出现的英文缩写及相应的中文含义。如果实施例中出现没有列于此的缩写，则代表普遍接受的含义。
HPLC：高效液相色谱
g：克
mg：毫克
mol：摩尔
mmol：毫摩尔
nM：纳摩尔(浓度单位)
μM：微摩尔(浓度单位)
M：摩尔(浓度单位)
N：当量浓度
L：升
μL：微升
[M+H]+：质谱中的分子离子峰
m/z：质荷比
δ：化学位移
MeOH：甲醇
EtOH：乙醇
DMSO-d6：六氘代二甲基亚砜
CDCl3：氘代氯仿
CD3OD：氘代甲醇
TMS：四甲基硅烷
HCl：氯化氢或盐酸
LiOH.H2O：氢氧化锂水合物
Ca(OH)2：氢氧化钙
KOH：氢氧化钾
NaOH：氢氧化钠
DBU：1,8-二氮杂二环[5.4.0]十一碳-7-烯
DABCO：1,4-二氮杂二环[2.2.2]辛烷
一般实验条件：
核磁共振氢谱及碳谱于Varian 300或400MHz或Bruker 300或400MHz仪器上获得(氘代DMSO，氘代氯仿，氘代甲醇等为溶剂，TMS为内标)。质谱由液相色谱-质谱联用仪获得(采用ESI或APCI离子源ZQ4000，美国Waters公司)。紫外光谱由日本日立公司的UV-3010紫外分光光度计测得。红外光谱 使用NICOLET6700红外光谱分析仪(KBr压片)。高效液相色谱使用Waters 2695 ZORBAX高效液相色谱仪(Bx-C8 5μ 150×4.6mm色谱柱)或另外说明。熔点的测定使用Electrothermal数字式熔点仪IA9100，并且未校正。
起始原料、试剂及溶剂从下列供应商购买：Beta-Pharma；Shanghai PI Chemicals；AndaChem；Taiyuan；Shanghai FWD Chemicals；Sigma-Aldrich,Milwaukee,WI,USA；Acros,Morris Plains,NJ,USA；Frontier Scientific,Logan,Utah,USA；Alfa Aesar,Ward Hill,MA,USA等或利用文献报道的方法合成。除非特别指出，溶剂一般不经干燥，而直接使用供应商的产品或经过分子筛干燥。
实施例1
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸(I-2)的制备，反应式如下：
Figure PCTCN2017104518-appb-000015
往2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基羰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸甲酯(I-1,60mg,0.104mmol，按照WO2013/040801A1中描述的方法制备)的甲醇(1.0mL)和水(0.3mL)溶液中加入LiOH.H2O(44mg,1.04mmol)。所得混合物在室温下搅拌1h，反应液用水稀释、并用1N的HCl调节pH至4。过滤收集固体产物，并用乙腈洗，得到2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸(I-2)，26mg(产率：44％)。分析数据：1H-NMR(400MHz,DMSO-d6)：δ＝13.29(s,br,1H),10.44(s,1H),10.00(s,1H),8.63(s,1H),7.94(d,J＝12.8Hz,1H),7.66-7.46(m,5H),7.37(s,1H),7.18-7.14(m,2H),6.66-6.62(m,1H),4.97(s,2H),4.02(s,3H),1.49(d,J＝6.8Hz,4H)。质谱(ESI)m/z：564.1[M+H]+。
实施例2
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钙盐(1:1)(I-3)的制备，反应式如下：
Figure PCTCN2017104518-appb-000016
往2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸(I-2,35mg,0.062mmol)的甲醇溶液(0.5mL)中，加入Ca(OH)2的水溶液(0.031N,1mL,0.031mmol)，所得混合物在室温下搅拌16h，用水稀释，冷冻干燥得到2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钙盐(1:1)(I-3)，29mg(产率：80％)。分析数据：1H-NMR(400MHz,DMSO-d6)：δ＝10.49(s,1H),10.11(s,1H),8.42(d,J＝4.5Hz,1H),7.91-7.86(m,1H),7.67-7.62(m,2H),7.49-7.34(m,4H),7.19-7.12(m,3H),6.35(d,J＝5.1Hz,1H),4.40(s,2H),3.94(s,3H),1.46(s,4H)。质谱(ESI)m/z：564.1[M+H]+。
实施例3
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸(II-2)的制备，反应式如下：
Figure PCTCN2017104518-appb-000017
往4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸甲酯(II-1,280mg,0.463mmol，按照WO2013/040801A1中描述的方法制备)的甲醇(3.0mL)和水(1.0mL)溶液中加入LiOH.H2O(194mg,4.628mmol)。所得混合物在室温下搅拌1h，反应液用水稀释、并用1N的HCl调节pH至4。过滤收集固体产物，并用乙腈洗，得到4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸(II-2)，191.3mg(产率：70％)。分析数据：1H-NMR(400MHz,DMSO-d6)：δ＝12.22(s,1H),10.49(s,1H),10.00(s,1H),8.75(d,J＝6.0Hz,1H),7.97(d,J＝12.8Hz,1H),7.71(s,1H),7.67-7.50(m,5H),7.18-7.14(m,2H),6.83(d,J＝6.4Hz,1H),4.25(t,J＝6.4Hz,2H),4.03(s,3H),2.51-2.45(m,2H),2.12-2.05(m,2H),1.49(d,J＝9.6Hz,4H)。质谱(ESI)m/z：592.1[M+H]+。
实施例4
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钠盐(II-3)的制备，反应式如下：
Figure PCTCN2017104518-appb-000018
往4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸(II-2,24mg,0.041mmol)的甲醇溶液(0.5mL)中，加入NaOH的水溶液(0.041N,1mL,0.041mmol)，所得混合物在室温下搅拌16h，用水稀释，冷冻干燥得到4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钠盐(II-3)，23mg(产率：92％)，。分析数据：1H-NMR(400MHz,DMSO-d6)：δ＝10.45(s,1H),10.10(s,1H),8.47(d,J＝5.4Hz,1H),7.92(d,J＝11.1Hz,1H),7.69-7.40(m,6H),7.20-7.12(m,2H),6.42-6.40(m,1H),4.18(t,J＝6.6Hz,2H),3.96(s,3H),2.37(d,J＝6.9Hz,2H),2.07-1.98(m,2H),1.48(s,4H)。质谱(ESI)m/z：592.1[M+H]+。
实施例5
4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸1,3-二羟基-2-(羟甲基)丙-2-铵盐(II-4)的制备，反应式如下：
Figure PCTCN2017104518-appb-000019
往4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸(II-2,24mg,0.041mmol)的甲醇溶液(0.5mL)中，加入2-氨基-2-(羟甲基)丙烷-1,3-二醇的甲醇溶液(0.041N,1mL,0.041mmol)，所得混合物在室温下搅拌16h，用水稀释，冷冻干燥得到4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸1,3-二羟基-2-(羟甲基)丙-2-铵盐(II-4)，27mg(产率：93％)。分析数据：1H-NMR(400MHz,DMSO-d6)：δ＝10.41(s,1H),10.03(s,1H),8.47(d,J＝5.1Hz,1H), 7.94-7.87(m,1H),7.68-7.39(m,6H),7.19-7.12(m,2H),6.43-6.41(m,1H),5.12(br,2H),4.18(t,J＝6.3Hz,2H),3.96(s,3H),3.44(s,6H),2.50-2.42(m,2H),2.09-2.00(m,2H),1.48(s,4H)。质谱(ESI)m/z：592.1[M+H]+。
实施例6
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸(III-2)的制备，反应式如下：
Figure PCTCN2017104518-appb-000020
往5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸甲酯(III-1,220mg,0.354mmol，按照WO2013/040801A1中描述的方法制备)的甲醇(3.0mL)和水(1.0mL)溶液中加入LiOH.H2O(149mg,3.54mmol)。所得混合物在室温下搅拌1h，反应液用水稀释、并用1N的HCl调节pH至4。过滤收集固体产物，并用乙腈洗，得到5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸(III-2)，184mg(产率：85％)。分析数据：1H-NMR(400MHz,DMSO-d6)：δ＝12.12(s,1H),10.51(s,1H),10.01(s,1H),8.76(d,J＝6.0Hz,1H),8.00-7.96(m,1H),7.71(s,1H),7.67-7.51(m,5H),7.19-7.15(m,2H),6.83(d,J＝6.4Hz,1H),4.24(t,J＝6.4Hz,2H),4.03(s,3H),2.37-2.33(m,2H),1.90-1.86(m,2H),1.76-1.70(m,2H),1.53-1.47(m,4H)。质谱(ESI)m/z：606.1[M+H]+。
实施例7
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钾盐(III-3)的制备，反应式如下：
Figure PCTCN2017104518-appb-000021
往5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸(III-2,24mg,0.040mmol)的甲醇溶液(0.5mL)中，加入KOH的水溶液(0.040N,1mL,0.040mmol)，所得混合物在室温下搅拌16h， 用水稀释，冷冻干燥得到5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钾盐(III-3)，24mg(产率：94％)。分析数据：1H-NMR(400MHz,DMSO-d6)：δ＝10.35(s,br,2H),8.47(d,J＝5.4Hz,1H),7.94-7.89(m,1H),7.68-7.38(m,6H),7.19-7.13(m,2H),6.42-6.40(m,1H),4.15(t,J＝6.3Hz,2H),3.95(s,3H),2.28-2.21(m,2H),1.87-1.66(m,4H),1.47(m,4H)。质谱(ESI)m/z：606.1[M+H]+。
实施例8
5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸三乙基铵盐(III-4)的制备，反应式如下：
Figure PCTCN2017104518-appb-000022
往5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸(III-2,24mg,0.040mmol)的甲醇(0.3mL)及水(0.5mL)溶液中，加入三乙基胺的乙腈溶液(0.040N,1mL,0.040mmol)，所得混合物在室温下搅拌16h，用水稀释，冷冻干燥得到5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸三乙基铵盐(III-4)，24mg(产率：86％)。分析数据：1H-NMR(400MHz,DMSO-d6)：δ＝12.07(s,1H),10.40(s,1H),10.02(s,1H),8.49(d,J＝5.1Hz,1H),7.94-7.89(m,1H),7.67-7.40(m,6H),7.19-7.13(m,2H),6.44(d,J＝4.5Hz,1H),4.17(t,J＝6.3Hz,2H),3.96(s,3H),3.12-3.06(m,2.5H),2.34(d,J＝6.9Hz,1H),2.28-2.21(m,2H),1.87-1.68(m,4H),1.48(m,4H),1.19(t,J＝7.2Hz,2.5H)。质谱(ESI)m/z：606.1[M+H]+。
实施例9
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸(IV-2)的制备，反应式如下：
Figure PCTCN2017104518-appb-000023
在搅拌下，往6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸甲酯(IV-1,35.0g,55.2mmol，按照WO2013/040801A1中描述的方法制备)的乙醇(350mL)溶液中滴加NaOH(4.4g,110mmol)，滴加完成后，加入水(50mL)。所得混合物在20-25℃温度下搅拌18h，反应液用水(100mL)稀释、搅拌20min，用1N的HCl调节pH至3-4。减压浓缩反应混合物，蒸馏出大约300mL的乙醇。过滤收集固体产物，得到28.4g粗产物，用硅胶柱色谱纯化(洗脱剂：乙酸乙酯:甲醇＝1:1,v/v)得到6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸(IV-2)，9.6g(产率：28.1％)。分析数据：1H-NMR(400MHz,DMSO-d6)：δ＝8.17(d,J＝8.0Hz,1H),7.81(dd,J＝2.8,13.4Hz,1H)7.62(m,2H),7.51(m,4H),7.39(t,J＝2.4Hz,2H),6.44(d,J＝20.0Hz,1H),4.13(t,J＝8.5Hz,2H),3.85(s,3H),2.27(t,J＝4.0Hz,2H),1.83(m,2H),1.68-1.46(m,8H)。质谱(ESI)m/z：620.2[M+H]+。
实施例10
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钠盐(IV-3)的制备，反应式如下：
Figure PCTCN2017104518-appb-000024
往6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸(IV-2,500mg,0.807mmol)的乙醇溶液(20mL)中，加入NaOH(34.29mg,0.857mmol)的水溶液(5mL)，所得混合物在室温下搅拌30min，减压蒸馏(温度控制在40℃)得到6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钠盐(IV-3)，617.2mg(产率：96％)。质谱(ESI)m/z：620.2[M+H]+。
实施例11
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钾盐(IV-4)的制备，反应式如下：
Figure PCTCN2017104518-appb-000025
往6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸(IV-2,500mg,0.807mmol)的乙醇溶液(20mL)中，加入KOH(55.44mg,0.988mmol)的水溶液(5mL)，所得混合物在室温下搅拌30min，减压蒸馏(温度控制在40℃)得到6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钾盐(IV-4)，555.46mg(产率：100％)。质谱(ESI)m/z：620.2[M+H]+。
实施例12
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钙盐(1:1)(IV-5)的制备，反应式如下：
Figure PCTCN2017104518-appb-000026
往6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸(IV-2,500mg,0.807mmol)的乙醇溶液(20mL)中，加入Ca(OH)2(30.245mg,0.408mmol)的水溶液(5mL)，所得混合物在室温下搅拌30min，减压蒸馏(温度控制在40℃)得到6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钙盐(1:1)(IV-5)，309.19mg(产率：58％)。质谱(ESI)m/z：620.2[M+H]+。
实施例13
6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸1,3-二羟基-2-(羟甲基)丙-2-铵盐(IV-6)的制备，反应式如下：
Figure PCTCN2017104518-appb-000027
往6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸(IV-2,500mg,0.807mmol)的乙醇溶液(20mL)中，加入2-氨基-2-(羟甲基)丙烷-1,3-二醇的(102.75mg,0.848mmol)的水溶液(5mL)，所得混合物在室温下搅拌1h，减压蒸馏(温度控制在40℃)得到浅黄色油状物，干燥得到6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸1,3-二羟基-2-(羟甲基)丙-2-铵盐(IV-6)，394.11mg(产率：66％)。质谱(ESI)m/z：620.2[M+H]+。
实施例14
7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸的制备，反应式如下：
Figure PCTCN2017104518-appb-000028
将7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸甲酯(VI-1，1.0g,1.53mmol)的乙醇(10mL)溶液，加入氢氧化钾(86.4mg)的水(2mL)溶液，所得混合物于室温搅拌5小时。调节反应液pH值至3左右。乙酸乙酯萃取反应液，萃取液减压蒸干既得目标产物(VI-2)，715mg，收率74％。质谱(ESI)m/z：635.4[M+H]+。
实施例15
7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸的制备，反应式如下：
Figure PCTCN2017104518-appb-000029
将7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸甲酯(VII-1，1.0g,1.51mmol)的乙醇(10mL)溶液，加入氢氧化钾(84.3mg)的水(2mL)溶液，所得混合物于室温搅拌4.5小时。调节反应液pH值至3左右。乙酸乙酯萃取反应液，萃取液减压蒸干既得目标产 物(VII-2)，700mg，收率71％。质谱(ESI)m/z：651.1[M+H]+。
实施例16
7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钙的制备，反应式如下：
Figure PCTCN2017104518-appb-000030
将7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸(VIII-1，1.0g,1.54mmol)的乙醇(10ml)溶液，加入氢氧化钙(43.1mg)的水(5mL)溶液，所得混合物于50℃左右搅拌4小时。反应液减压蒸干既得目标产物(VIII-2)，909mg，收率90％。
实施例17
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-异丙氧基-7-喹啉基]氧基]乙酸的制备，反应式如下：
Figure PCTCN2017104518-appb-000031
将2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-异丙氧基-7-喹啉基]氧基]乙酸甲酯(IX-1，800mg,1.32mmol)的乙醇(12mL)溶液，加入氢氧化钾(147.8mg)的水(5mL)溶液，所得混合物于室温搅拌4小时。调节反应液pH值至3左右。乙酸乙酯萃取反应液，萃取液减压蒸干既得目标产物(IX-2)，633mg，收率81％。质谱(ESI)m/z：593.3[M+H]+。
实施例18
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸钾的制备，反应式如下：
Figure PCTCN2017104518-appb-000032
将2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸(X-1，500mg,0.865mmol)的乙醇(10mL)溶液，加入氢氧化钾(57.0mg)的水(5mL)溶液，所得混合物于室温搅拌4小时。反应液减压蒸干既得目标产物(X-2)，513mg，收率96％。
实施例19
2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸铵盐的制备，反应式如下：
Figure PCTCN2017104518-appb-000033
往2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸(XI-1,500mg,0.865mmol)的乙醇溶液(15mL)中，加入2-氨基-2-(羟甲基)丙烷-1,3-二醇(105mg,0.865mmol)的水溶液(5mL)，所得混合物在室温下搅拌3h。反应液减压蒸干，得目标产物(XI-2)，450mg(产率：74％)。
实施例20
对AXL和VEGFR2激酶的生化抑制活性：本发明中化合物抑制AXL和VEGFR2激酶的生化IC50值由ProQinase GmbH公司(Breisacher Str.117,D-79106Freiburg,Germany.www.proqinase.com)测定。具体步骤如下：
首先，将本发明所述的化合物溶解于二甲基亚砜(DMSO)中，配制成1×10-3M的原液备用。采用半-对数系列稀释(serial semi-logarithmic diluton)成10个不同的浓度(1×105M至3×10-10M)。
AXL和VEGFR2的生化活性由放射性蛋白激酶测定方法(33Pan
Figure PCTCN2017104518-appb-000034
Activity Assay)测定。试验使用Perkin Elmer(Boston,MA,USA)生产的FlashPlatesTM 96孔板进行，反应体积50μL。反应混合物由以下四步通过滴管加 入：
(1)20μL的缓冲液(标准缓冲液)；
(2)5μL的ATP水溶液；
(3)5μL的化合物(10％DMSO溶液)；
(4)10μL的底物/10μL的激酶溶液。
测定溶液含70mM的HEPES-NaOH，pH＝7.5、3mM的MgCl2、3mM的MnCl2、3μM的原钒酸钠(Na-orthovanadate)、1.2mM的DTT、50μg/mL的PEG20000、ATP(其浓度与激酶的Km相同，并且因不同的激酶而不同)、[γ-33P]-ATP(大约4×105cpm/孔)、激酶和底物。
每一孔中激酶和底物的用量总结在表1中：
表1、测定参数：
Figure PCTCN2017104518-appb-000035
反应在30℃进行60分钟，加入50μL的2％(v/v)磷酸终止反应。板孔中的反应混合物吸出，用200μL的0.9％(w/v)NaCl溶液洗两次。参入33P的量(incoporation of 33P)用微孔板闪烁计数器(microplate scintillation counter)测定。
测定结果总结于表2中：
表2、本发明化合物对两种激酶抑制的生化活性：
Figure PCTCN2017104518-appb-000036
Figure PCTCN2017104518-appb-000037
由上述数据可看出，本发明所述的化合物对AXL和VEGFR2两种激酶具有很强的抑制活性，其抑制AXL的IC50值介于6.08-55.3nM之间，同时，抑制VEGFR2的IC50值介于6.56-24.5nM之间。因而，本发明中的化合物可以用于治疗因这些激酶的异常活性引起的疾病，例如，肿瘤等。
实施例21：药物组成及制剂：片剂(毫克/片)
实施例1制备的化合物：100；     乳糖，Ph EUR：182.75；
羧甲基纤维素钠：12.0；     玉米淀粉浆(5w/v％)：2.25；
硬脂酸镁：3.0；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例22：药物组成及制剂：片剂(毫克/片)
实施例5制备的化合物：100，其它物质含量同实施例21；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例23：药物组成及制剂：片剂(毫克/片)
实施例9制备的化合物：50；     乳糖，Ph EUR：223.75；
羧甲基纤维素钠：6.0；     玉米淀粉：15.0；
聚乙烯吡咯烷酮(5w/v％)：2.25；     硬脂酸镁：3.0；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例24：药物组成及制剂：片剂(毫克/片)
实施例9制备的化合物：50，其它物质含量与实施例23相同；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例25：药物组成及制剂：片剂(毫克/片)
实施例13制备的化合物：1.0；     乳糖，Ph EUR：93.25；
羧甲基纤维素钠：4.0；     玉米淀粉浆(5w/v％)：0.75；
硬脂酸镁：76；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例26：药物组成及制剂：片剂(毫克/片)
实施例13制备的化合物：1.0，其它物质含量与实施例25相同；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例27：药物组成及制剂：胶囊(毫克/胶囊)
实施例7制备的化合物：10.0；乳糖，Ph EUR：488.5；镁：1.5；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例28：药物组成及制剂：胶囊(毫克/胶囊)
实施例2制备的化合物：10.0，其它物质含量与实施例27相同；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例29：药物组成及制剂：注射剂(50毫克/毫升)
实施例6制备的化合物：5％；     1M氢氧化钠溶液:15％；
0.1M盐酸溶液(调节pH＝7.6)；      聚乙二醇400：5％；
注射用水调节至100％；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例30：药物组成及制剂：注射剂(50毫克/毫升)
实施例12制备的化合物：5％，其它物质含量与实施例29相同，最后用注射用水调节至100％；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例31：药物组成及制剂：注射剂(10毫克/毫升)
实施例11制备的化合物：1％；     磷酸氢二钠BP：3.6％；
0.1M氢氧化钠溶液：15％；     注射用水调节至100％；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例32：药物组成及制剂：注射剂(10毫克/毫升)
实施例9制备的化合物：1％，其它物质含量与实施例31相同，注射用水调节至100％；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例33：药物组成及制剂：注射剂(1毫克/毫升)       (pH调节至6)
实施例6制备的化合物：0.1％；     磷酸氢二钠BP：2.26％；
柠檬酸：0.38％；     聚乙二醇400：3.5％；
注射用水调节至100％；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例34：药物组成及制剂：注射剂(1毫克/毫升)      (pH调节至6)
实施例10制备的化合物：0.1％，其它物质的含量与实施例33相同，最后用注射用水调节至100％；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例35：药物组成及制剂：气雾剂(毫克/毫升)
实施例1制备的化合物：10；     失水山梨醇油酸酯：13.5；
三氯氟甲烷：910.0；     二氯二氟甲烷：490.0；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例36：药物组成及制剂：气雾剂(毫克/毫升)
实施例3制备的化合物：10，其它物质含量与实施例35相同；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例37：药物组成及制剂：气雾剂(毫克/毫升)
实施例4制备的化合物：0.2；     失水山梨醇油酸酯：0.27；
三氯氟甲烷：70.0；     二氯二氟甲烷：280.0；
二氯四氟乙烷：1094.0；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例38：药物组成及制剂：气雾剂(毫克/毫升)
实施例7制备的化合物：0.2，其它物质含量与实施例37相同；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例39：药物组成及制剂：气雾剂(毫克/毫升)
实施例8制备的化合物：2.5；     失水山梨醇油酸酯：3.38；
三氯氟甲烷：67.5；     二氯二氟甲烷：1086.0；
二氯四氟乙烷：191.60；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例40：药物组成及制剂：气雾剂(毫克/毫升)
实施例11制备的化合物：2.5，其它物质含量与实施例39相同；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例41：药物组成及制剂：气雾剂(毫克/毫升)
实施例4制备的化合物：2.5；     大豆卵磷脂：2.7；
三氯氟甲烷：67.5；     二氯二氟甲烷：1086.0；
二氯四氟乙烷：191.60；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例42：药物组成及制剂：气雾剂(毫克/毫升)
实施例13制备的化合物：2.5，其它物质含量与实施例41相同；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例43：药物组成及制剂：软膏(/毫升)
实施例1制备的化合物：40毫克；     乙醇：300微升；
水：300微升；     1-十二烷基氮杂环庚酮：50微升；
丙二醇：至1毫升；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
实施例44：药物组成及制剂：软膏(/毫升)
实施例7制备的化合物：40毫克，其它物质含量与实施例43相同；
适用人群：适用于各种因AXL和/或VEGFR2蛋白激酶活性异常所引起的疾病人群。
上述实施例中的实施方案可以进一步组合或者替换，且实施例仅仅是对本发明的优选实施例进行描述，并非对本发明的构思和范围进行限定，在不脱离本发明设计思想的前提下，本领域中专业技术人员对本发明的技术方案作出的各种变化和改进，均属于本发明的保护范围。

Claims (13)

  1. 一种喹啉基取代的羧酸化合物或其药学上可接受的盐，该化合物分子结构式如式(I)所示：
    Figure PCTCN2017104518-appb-100001
    式中，
    V1和V2分别独立地选自氢、氘、卤素、C1-6烷基或C1-6烷氧基；
    R表示氢、C1-12烷基、C1-12烷氧基，且R中的氢可选择性地被G1取代；
    L为C1-12亚烷基，且L中的氢可选择性地被G2取代；
    M选自：
    (a)氢、氘、C2-12烷基、C3-12环烷基、C6-12芳基、C5-12杂芳基或C3-12杂脂环基，且M中的氢可选择性地被G3取代；或
    (b)一价、二价、三价或四价金属离子，优选为一价和二价金属离子，更优选为锂、钠、钾、铷、铯、镁、钙、锶、钡离子；或
    (c)铵离子或质子化的有机胺，所述有机胺包括但不限于C1-12烷基、C3-12环烷基或C3-12杂脂环基取代的脂肪胺，这些脂肪胺可选择性地被一个或多个卤素或羟基取代；
    其中：
    G1、G2及G3分别独立地选自氢、氘、-CN、-CF3、-CO2H、卤素、C1-12烷基、C3-12环烷基、C2-12烯基、C2-12炔基、C6-12芳基、C5-12杂芳基、C3-12杂脂环基、R1O-、R1R2N-、R1S(＝O)m-、R1R2NS(＝O)m-、R3C(＝O)-、R1R2NC(＝O)-、R1OC(＝O)-、R3C(＝O)O-、R1R2NC(＝O)O-、R3C(＝O)NR1-、R1R2NC(＝O)NR4-、R1OC(＝O)NR4-、R1S(＝O)mNR4-、R1R2NS(＝O)mNR4-、R1R2NC(＝NR5)NR4-、R1R2NC(＝CHNO2)NR4-、R1R2NC(＝N-CN)NR4-、R1R2NC(＝NR5)-、R1S(＝O)(＝NR5)NR4-或R1R2NS(＝O)(＝NR5)-；
    R1、R2、R3、R4及R5分别独立地选自氢、氘、C1-12烷基、C2-12烯基、C2-12炔基、C3-12环烷基、C6-12芳基、C5-12杂芳基或C3-12杂脂环基；当R1和R2连接 于同一氮原子上时，可与该氮原子一起形成一个C3-12杂脂环，所述C3-12杂脂环可选择性地包含O、N、S(＝O)m杂原子；且R1、R2、R3、R4及R5中的氢可选择性地被卤素、CN、C1-12烷基或C3-12环烷基取代；
    m＝0-2。
  2. 根据权利要求1所述的喹啉基取代的羧酸化合物或其药学上可接受的盐，其特征在于：其中，V1和V2分别独立地选自氢、氘、卤素、C1-6烷基或C1-6烷氧基；
    R表示氢、C1-12烷基、C1-12烷氧基；
    L为C1-12亚烷基；
    M选自：
    (a)氢、氘、C2-12烷基；或
    (b)锂、钠、钾、铷、铯、镁、钙、锶、钡离子；或
    (c)铵离子或质子化的有机胺，所述有机胺包括C1-12烷基、C3-12环烷基或C3-12杂脂环基取代的脂肪胺，这些脂肪胺可选择性地被一个或多个卤素或羟基取代。
  3. 根据权利要求1或2所述的喹啉基取代的羧酸化合物或其药学上可接受的盐，其特征在于：其中，V1和V2分别独立地选自氢、氘或卤素；
    优选V1和V2同时为氢、氘或卤素；且取代位点分别在各自所在六元环的2位和4位。
  4. 根据权利要求1-3任一项所述的喹啉基取代的羧酸化合物或其药学上可接受的盐，其特征在于：其中，V1和V2分别独立地选自氢、氘或卤素时，R为C1-12烷氧基、L为C1-12亚烷基。
  5. 根据权利要求1-3任一项所述的喹啉基取代的羧酸化合物或其药学上可接受的盐，其中，V1和V2分别独立地选自氢或卤素；R为甲氧基、乙氧基、正丙氧基或异丙氧基；L为C1-6亚烷基。
  6. 根据权利要求1-5任一项所述的喹啉基取代的羧酸化合物或其药学上可接受的盐，其中，M选自氢、氘或C2-6烷基；
    或，M选自锂、钠、钾、镁或钙离子；
    或，M选自铵离子或质子化的甲胺、乙胺、正丙胺、异丙胺、正丁胺、异丁胺、仲丁胺、叔丁胺、二甲胺、二乙胺、二正丙胺、二异丙胺、二正丁胺、二异丁胺、二仲丁胺、二叔丁胺、三甲胺、三乙胺、三正丙胺、三异丙胺、三正丁胺、三异丁胺、三仲丁胺、三叔丁胺、二异丙基乙基胺或2-氨基-2-(羟甲基) 丙烷-1,3-二醇。
  7. 根据权利要求1所述的喹啉基取代的羧酸化合物或其药学上可接受的盐，所述化合物为下列任意一种：
    2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸；
    2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸锂盐；
    2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钠盐；
    2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钾盐；
    2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸镁盐；
    2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钙盐；
    2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸铵盐；
    2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸 三乙基铵盐；
    2-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸；
    3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸锂盐；
    3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钠盐；
    3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钾盐；
    3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸镁盐；
    3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钙盐；
    3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸铵盐；
    3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸 三乙基铵盐；
    3-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸；
    4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸锂盐；
    4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钠盐；
    4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钾盐；
    4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸镁盐；
    4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钙盐；
    4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸铵盐；
    4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸 三乙基铵盐；
    4-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸；
    5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸锂盐；
    5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基 -7-喹啉基]氧基]戊酸钠盐；
    5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钾盐；
    5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸镁盐；
    5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钙盐；
    5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸铵盐；
    5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸 三乙基铵盐；
    5-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸；
    6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸锂盐；
    6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钠盐；
    6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钾盐；
    6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸镁盐；
    6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钙盐；
    6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸铵盐；
    6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸 三乙基铵盐；
    6-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸；
    7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸锂盐；
    7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钠盐；
    7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钾盐；
    7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸镁盐；
    7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钙盐；
    7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸铵盐；
    7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸 三乙基铵盐；
    7-[[4-[2-氟-4-[[1-[(3-氯苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸锂盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钠盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钾盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸镁盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钙盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基 -7-喹啉基]氧基]乙酸铵盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸 三乙基铵盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸锂盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钠盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钾盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸镁盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钙盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸铵盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸 三乙基铵盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸锂盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钠盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钾盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸镁盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钙盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸铵盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸 三乙基铵盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸锂盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钠盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钾盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸镁盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钙盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸铵盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸 三乙基铵盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基 -7-喹啉基]氧基]己酸锂盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钠盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钾盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸镁盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钙盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸铵盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸 三乙基铵盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸锂盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钠盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钾盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸镁盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钙盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸铵盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸 三乙基铵盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸；
    2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸锂盐；
    2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钠盐；
    2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钾盐；
    2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸镁盐；
    2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸钙盐；
    2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸铵盐；
    2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸 三乙基铵盐；
    2-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]乙酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸；
    3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸锂盐；
    3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钠盐；
    3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸钾盐；
    3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸镁盐；
    3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基 -7-喹啉基]氧基]丙酸钙盐；
    3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸铵盐；
    3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸 三乙基铵盐；
    3-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丙酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸；
    4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸锂盐；
    4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钠盐；
    4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钾盐；
    4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸镁盐；
    4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸钙盐；
    4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸铵盐；
    4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸 三乙基铵盐；
    4-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]丁酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸；
    5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸锂盐；
    5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钠盐；
    5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钾盐；
    5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸镁盐；
    5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸钙盐；
    5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸铵盐；
    5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸 三乙基铵盐；
    5-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]戊酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸；
    6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸锂盐；
    6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钠盐；
    6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钾盐；
    6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸镁盐；
    6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸钙盐；
    6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸铵盐；
    6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸 三乙基铵盐；
    6-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]己酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基 -7-喹啉基]氧基]庚酸；
    7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸锂盐；
    7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钠盐；
    7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钾盐；
    7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸镁盐；
    7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸钙盐；
    7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸铵盐；
    7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸 三乙基铵盐；
    7-[[4-[2-氯-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-甲氧基-7-喹啉基]氧基]庚酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸锂盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸钠盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸钾盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸镁盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸钙盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸铵盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸 三乙基铵盐；
    2-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]乙酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸锂盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸钠盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸钾盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸镁盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸钙盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸铵盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸 三乙基铵盐；
    3-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丙酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸锂盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸钠盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸钾盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基 -7-喹啉基]氧基]丁酸镁盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸钙盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸铵盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸 三乙基铵盐；
    4-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]丁酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸锂盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸钠盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸钾盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸镁盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸钙盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸铵盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸 三乙基铵盐；
    5-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]戊酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸锂盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸钠盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸钾盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸镁盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸钙盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸铵盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸 三乙基铵盐；
    6-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]己酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸锂盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸钠盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸钾盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸镁盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸钙盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸铵盐；
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基-7-喹啉基]氧基]庚酸 三乙基铵盐；或
    7-[[4-[2-氟-4-[[1-[(4-氟苯基)氨基甲酰基]环丙烷羰基]氨基]苯氧基]-6-乙氧基 -7-喹啉基]氧基]庚酸 1,3-二羟基-2-(羟甲基)丙-2-铵盐。
  8. 权利要求1-7任一项所述喹啉基取代的羧酸化合物或其药学上可接受的盐的消旋体或对映异构体。
  9. 权利要求1-7任一项所述喹啉基取代的羧酸化合物或其药学上可接受的盐的制备方法，包括但不限于如下步骤：
    Figure PCTCN2017104518-appb-100002
    其中，V1、V2、R、L和M的指代同权利要求1-7任一项；
    RR表示氢、C1-12烷基、C3-12环烷基、C6-12芳基、C5-12杂芳基或C3-12杂脂环基，且RR中的氢可选择性地被G4取代；
    LG表示F、Cl、Br、I、CH3SO3、CH3CH2SO3、CH3(CH2)2SO3、(CH3)2CHSO3、tert-BuSO3、PhSO3、o-CH3PhSO3、m-CH3PhSO3、p-CH3PhSO3、o-O2NPhSO3、m-O2NPhSO3、p-O2NPhSO3或CF3SO3中的任意一个；
    其中：
    G4选自氢、氘、-CN、-CF3、-CO2H、卤素、C1-12烷基、C3-12环烷基、C2-12烯基、C2-12炔基、C6-12芳基、C5-12杂芳基、C3-12杂脂环基、R1O-、R1R2N-、R1S(＝O)m-、R1R2NS(＝O)m-、R3C(＝O)-、R1R2NC(＝O)-、R1OC(＝O)-、R3C(＝O)O-、R1R2NC(＝O)O-、R3C(＝O)NR1-、R1R2NC(＝O)NR4-、R1OC(＝O)NR4-、R1S(＝O)mNR4-、R1R2NS(＝O)mNR4-、R1R2NC(＝NR5)NR4-、R1R2NC(＝CHNO2)NR4-、R1R2NC(＝N-CN)NR4-、R1R2NC(＝NR5)-、R1S(＝O)(＝NR5)NR4-或R1R2NS(＝O)(＝NR5)-；
    R1、R2、R3、R4及R5分别独立地选自氢、氘、C1-12烷基、C2-12烯基、C2-12炔基、C3-12环烷基、C6-12芳基、C5-12杂芳基或C3-12杂脂环基；当R1和R2连接 于同一氮原子上时，可与该氮原子一起形成一个C3-12杂脂环，所述C3-12杂脂环可选择性地包含O、N、S(＝O)m杂原子；且R1、R2、R3、R4及R5中的氢可选择性地被卤素、CN、C1-12烷基或C3-12环烷基取代；
    m＝0-2。
  10. 包含权利要求1～7任一项所述喹啉基取代的羧酸化合物或其药学上可接受的盐，或权利要求8所述消旋体或对映异构体的药物组合物；
    优选，所述药物组合物除了包含喹啉基取代的羧酸化合物或其药学上可接受的盐或所述消旋体或对映异构体以外，还包含一种或几种药学上可接受的载体或稀释剂；
    更优选所述药物组合物的制剂形式为：口服剂、注射剂、肛塞剂、鼻孔吸入剂、滴眼剂或皮肤贴剂。
  11. 权利要求1～7任一项所述喹啉基取代的羧酸化合物或其药学上可接受的盐，权利要求8所述消旋体或对映异构体或权利要求10所述药物组合物在治疗因蛋白激酶异常活性所引起的疾病中的应用；
    优选所述的蛋白激酶为AXL或/及VEGFR2。
  12. 权利要求11所述的应用，其特征在于所述的疾病为肿瘤，优选所述肿瘤包括实体瘤和液体瘤。
  13. 权利要求12所述的应用，其特征在于所述的肿瘤包括：肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌、胃癌、结肠癌、乳腺癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、阴户癌、何杰金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、膀胱癌、肾或输尿管癌、肾癌、中枢神经中枢系统赘生物、脊柱轴肿瘤、垂体腺瘤、胃肠间质肿瘤、结肠直肠癌、非小细胞肺癌、小细胞肺癌、肥大细胞增多症、胶质瘤、肉瘤和淋巴瘤中的一种或任意几种的组合。
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