WO2019218928A1 - 吲哚啉-1-甲酰胺类化合物、其制备方法及其在医药学上的应用 - Google Patents

吲哚啉-1-甲酰胺类化合物、其制备方法及其在医药学上的应用 Download PDF

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WO2019218928A1
WO2019218928A1 PCT/CN2019/086241 CN2019086241W WO2019218928A1 WO 2019218928 A1 WO2019218928 A1 WO 2019218928A1 CN 2019086241 W CN2019086241 W CN 2019086241W WO 2019218928 A1 WO2019218928 A1 WO 2019218928A1
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pharmaceutically acceptable
compound
acceptable salt
alkyl
group
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PCT/CN2019/086241
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English (en)
French (fr)
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陈向阳
庞育成
高英祥
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北京诺诚健华医药科技有限公司
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Priority to KR1020207035577A priority Critical patent/KR20210019012A/ko
Priority to CA3100095A priority patent/CA3100095C/en
Priority to CN201980031818.0A priority patent/CN112384506B/zh
Priority to EP19804493.5A priority patent/EP3795567A4/en
Priority to US17/055,425 priority patent/US20210188806A1/en
Priority to JP2020564103A priority patent/JP7332091B2/ja
Publication of WO2019218928A1 publication Critical patent/WO2019218928A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a novel porphyrin-1-carboxamide compound which modulates or inhibits vascular endothelial growth factor receptor (VEGFR) activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition of a salt, a process for the preparation of the compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of the compound or a pharmaceutically acceptable salt thereof or a compound or a pharmaceutically acceptable salt thereof, for use in the preparation of a pharmaceutical composition Use in the treatment and/or prevention of VEGFR-mediated related disorders, particularly tumors, and methods of use thereof.
  • Angiogenesis is a multifactorial factor including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), angiopoietin (epipoietin), and interleukin-6 (IL-6) and other complex physiological processes stimulated and regulated by different signaling pathways play an important role in tumor growth and metastasis.
  • VEGF vascular endothelial growth factor
  • FGF fibroblast growth factor
  • PDGF platelet-derived growth factor
  • angiopoietin epipoietin
  • IL-6 interleukin-6
  • VEGFR1 FLT1 receptor
  • VEGFR2 KDR/FLK1
  • VEGFR3 FLT4 receptor
  • VEGFR2 is ubiquitously expressed in almost all types of endothelial cells, while expression of VEGFR1/3 is restricted to specific vascular supporting tissues.
  • VEGFR is expressed at low levels in normal human tissues, but is highly expressed in most tumors, and VEGFR is not only expressed in vascular endothelial cells but also in tumor cells. It not only promotes vascular endothelial cell division and proliferation, but also induces tumor angiogenesis and promotes tumor cell growth and metastasis. Therefore, inhibition of VEGFR activity, blocking its signal transduction, and preventing tumor angiogenesis, thereby inhibiting tumor growth and metastasis, and controlling tumor growth, VEGFR is an important target for anti-tumor.
  • VEGFR inhibitors There are several small molecule VEGFR inhibitors on the market, such as sorafenib, sunitinib, levabinib, axitinib, and cabozantini; and some ongoing clinical studies, such as furoquinol Nie, Sandidini, and Deritinib. Most of them are multi-kinase inhibitors with different clinical efficacy and toxic side effects, providing an alternative treatment for cancer patients.
  • immunological checkpoint inhibitors such as PD-1/PD-L1 have shown good curative effect on various tumors in clinical practice, but the response rate needs to be further improved. Whether the combination of PD-1/PD-L1 and a kinase inhibitor such as VEGFR can produce a synergistic effect to improve the efficacy has attracted the attention of many biopharmaceutical companies (WO2015088847, WO2016140717, WO2018068691, etc.), and various combinations have been developed. Clinical Trials. The clinical Ib/II results of PD-1 and levartinib show that combination therapy is superior to monotherapy, in the treatment of metastatic renal cell carcinoma (ESMO 2017 Congress, Abstract No. 8470) and endometrial cancer (2017 ASCO) A higher response rate.
  • ESMO 2017 Congress, Abstract No. 8470 metastatic renal cell carcinoma
  • 2017 ASCO endometrial cancer
  • the present invention contemplates the synthesis of novel compounds having the structure shown in the general formula (I), and finds that compounds having such structures exhibit excellent inhibition.
  • the effect and effect of VEGFR activity are particularly useful.
  • the present invention provides a compound of the formula (I) as a VEGFR inhibitor:
  • R 1 is -OR 7 ;
  • R 2 is independently selected from -OR 8 or -C(O)NHR 8 ;
  • R 3 is an optionally substituted C 1-4 alkyl group, a C 3-7 cycloalkyl group, a 4-7 membered heterocyclic group, a phenyl group, a 5-6 membered heteroaryl group;
  • R 4 is independently selected from the group consisting of H, halogen, CN, C 1-4 alkyl;
  • R 5 and R 6 are each independently selected from H, halogen, C 1-4 alkyl, -OR 7 ; alternatively, R 5 and R 6 together with the attached carbon atom form an optional moiety selected from O, N and S a 3-7 membered ring of a hetero atom;
  • R 7 and R 8 are each independently selected from H or optionally substituted C 1-4 alkyl
  • the optional substitution means substitution with a substituent selected from the group consisting of halogen, -CN, -NO 2 , oxo, -SF 5 , C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 Aromeric heterocyclic group, phenyl group, 5-6 membered heteroaryl group, -OR', -NR'R", -C(O)R', -C(O)OR', -C(O)NR'R ", -C(O)N(R')OR", -OC(O)R', -OC(O)NR'R", -N(R')C(O)OR", -N(R ')C(O)R", -N(R"")C(O)NR'R", -N(R')S(O) 2 R", -S(O) m R', -S (O) 2 NR'R", wherein R', R" and R"" are each independently selected from H,
  • n 1 or 2.
  • One embodiment of the present invention relates to the compound of the above formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof and mixtures thereof, wherein R 2 is independently selected from -OC 1-4 alkyl, -C(O)NH 2 or -C(O)NH-C 1-4 alkyl, preferably R 2 is -OCH 3 , more preferably R 2 is -C(O)NH 2 .
  • One embodiment of the invention relates to a compound of the above formula (I), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and mixtures thereof, wherein R 7 is optionally substituted C 1-4 alkyl, preferably R 7 is C 1-4 alkyl, more preferably R 7 is CH 3 .
  • Another embodiment of the present invention relates to the compound of any one of the above embodiments, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and mixtures thereof, wherein R 4 is H or F, preferably R 4 is H.
  • Another embodiment of the present invention relates to the compound of any one of the above embodiments, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and mixtures thereof, wherein R 5 and R 6 are each independently It is selected from H or F, and preferably R 5 and R 6 are H.
  • One embodiment of the invention relates to a compound of the above formula (I), wherein the compound is selected from, but not limited to:
  • a prodrug thereof a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, and mixtures thereof.
  • VEGFR2 inhibitory effect preferably an IC 50 of less than 10OnM, more preferably IC 50 of less than 10nM.
  • Another aspect of the invention relates to a compound of the formula (I), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof and mixtures thereof, for use as a medicament or for medical use, for use in Treat or prevent VEGFR-mediated related diseases, especially tumors, including but not limited to melanoma, lymphoma, thyroid cancer, kidney cancer, liver cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, brain cancer, bladder cancer , ovarian cancer, head and neck cancer, breast cancer, lung cancer, glioma, etc.
  • tumors including but not limited to melanoma, lymphoma, thyroid cancer, kidney cancer, liver cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, brain cancer, bladder cancer , ovarian cancer, head and neck cancer, breast cancer, lung cancer, glioma, etc.
  • the present invention provides a method of treating or preventing a VEGFR-mediated disease, such as the tumor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable compound thereof Salts, prodrugs, stable isotope derivatives, isomers, and mixtures thereof, or pharmaceutical compositions comprising the compounds.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and mixtures thereof, and a pharmaceutically acceptable carrier And excipients.
  • Another aspect of the invention relates to a compound of the formula (I), or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof and mixtures thereof, or a pharmaceutical composition thereof for use in the preparation of a medicament Use, wherein the medicament is for treating or preventing a VEGFR mediated disease, such as a tumor.
  • a VEGFR mediated disease such as a tumor.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof and mixtures thereof And at least one additional drug, wherein the at least one additional drug is a chemotherapeutic agent or an immunomodulatory agent (such as an immunological checkpoint inhibitor).
  • the medicament may be in any pharmaceutical dosage form including, but not limited to, tablets, capsules, solutions, lyophilized preparations, injections.
  • the pharmaceutical preparation of the present invention can be administered in the form of a dosage unit containing a predetermined amount of the active ingredient per dosage unit.
  • a dosage unit may comprise, for example, from 0.5 mg to 1 g, preferably from 1 mg to 700 mg, particularly preferably from 5 mg to 300 mg, of a compound of the invention, depending on the condition being treated, the method of administration and the age, weight and condition of the patient.
  • Preferred dosage unit formulations are those containing the daily or divided doses indicated above or their corresponding fractions of the active ingredient.
  • pharmaceutical preparations of this type can be prepared using methods well known in the pharmaceutical art.
  • the pharmaceutical preparations of the invention may be adapted for administration by any suitable method desired, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral. (including subcutaneous, intramuscular, intravenous or intradermal) methods of administration.
  • Such formulations can be prepared by, for example, combining the active ingredient with one or more excipients or one or more adjuvants, using all methods known in the art of pharmacy.
  • C xy denotes a range of the number of carbon atoms, wherein x and y are both integers, for example, C 3-8 cycloalkyl represents a cycloalkyl group having 3 to 8 carbon atoms, that is, having 3 a cycloalkyl group of 4, 5, 6, 7 or 8 carbon atoms. It should also be understood that “ C3-8 " also encompasses any subranges therein, such as C3-7 , C3-6 , C4-7 , C4-6 , C5-6, and the like.
  • Alkyl means a saturated straight or branched chain hydrocarbon radical containing from 1 to 20 carbon atoms, for example from 1 to 8 carbon atoms, from 1 to 6 carbon atoms or from 1 to 4 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropane 1,1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-Dimethylbutyl and 2-ethylbutyl.
  • the alkyl
  • Cycloalkyl means a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms.
  • the cycloalkyl group may be a single carbon ring and usually contains 3 to 8, 3 to 7, or 3 to 6 carbon ring atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the cycloalkyl group may alternatively be a double or tricyclic ring fused together, such as decahydronaphthyl.
  • the cycloalkyl group can be optionally substituted.
  • Heterocyclyl or heterocyclic refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic group comprising from 3 to 20 ring atoms, for example from 3 to 14, from 3 to 12, from 3 to 10 , 3 to 8, 3 to 6, or 5 to 6 ring atoms, wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but does not include The ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon.
  • It preferably comprises from 3 to 12 ring atoms, more preferably from 3 to 10 ring atoms, more preferably from 4 to 7 ring atoms, most preferably 5 or 6 ring atoms, of which from 1 to 4 are heteroatoms, more preferably from 1 to 3
  • One is a hetero atom, and most preferably one or two are heteroatoms.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl and nitrogen Heterocyclobutane.
  • Polycyclic heterocyclic groups include fused, bridged or spiro polycyclic heterocyclic groups such as octahydrocyclopenta[c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, 3,8-di Azabicyclo[3.2.1]octane, 5-azaspiro[2.4]heptane, 2-oxa-7-azaspiro[3.5]decane.
  • the heterocyclic or heterocyclic ring may be optionally substituted.
  • Aryl or aromatic ring refers to an aromatic monocyclic or fused polycyclic group containing from 6 to 14 carbon atoms, preferably from 6 to 10 members, such as phenyl and naphthyl, most preferably phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples include:
  • the aryl or aromatic ring may be optionally substituted.
  • Heteroaryl or heteroaryl ring refers to a heteroaromatic system containing from 5 to 14 ring atoms, wherein from 1 to 4 ring atoms are selected from heteroatoms including oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably from 5 to 10 members. More preferably, the heteroaryl group is 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include:
  • heteroaryl or heteroaryl ring can be optionally substituted.
  • Halogen means fluoro, chloro, bromo or iodo.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but is not necessarily, present, and the expression includes a case where a heterocyclic group is substituted with an alkyl group and a case where a heterocyclic group is not substituted with an alkyl group.
  • Optionally substituted means that one or more hydrogen atoms in the group, preferably 5, more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • the substituents include, but are not limited to, halogen, -CN, -NO 2 , oxo, -SF 5 , C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -OR', -NR'R", -C(O)R', -C(O)OR', -C(O)NR'R", -C(O)N (R')OR", -OC(O)R', -OC(O)NR'R", -N(R')C(O)OR", -N(R')C(O)R" , -N(R'"'C(O)S(O) 2 R", -S(O) m R' (m is 1 or 2), -S( O) 2 NR'R" and the like, wherein R', R" and R"" are each independently selected from
  • “Isomer” refers to a compound having the same molecular formula but differing in the nature or sequence of its atomic bonding or in the spatial arrangement of its atoms. Isomers whose atomic space is arranged differently are referred to as “stereoisomers”. Stereoisomers include optical isomers, geometric isomers, and conformational isomers.
  • optical isomer form The compounds of the invention may exist in optical isomer form. These optical isomers are in the "R” or “S” configuration depending on the configuration of the substituents around the chiral carbon atom. Optical isomers include enantiomers and diastereomers. Methods of preparing and isolating optical isomers are known in the art.
  • Geometric isomers may also be present in the compounds of the invention.
  • the present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl groups or heterocyclic groups.
  • the substituents around the carbon-carbon double bond or carbon-nitrogen bond are designated as the Z or E configuration, and the substituents around the cycloalkyl or heterocycle are designated in the cis or trans configuration.
  • the compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerization.
  • the invention includes any tautomeric or stereoisomeric forms and mixtures thereof, and is not limited to any one of the tautomeric or stereoisomeric forms used in the nomenclature or chemical structural formula of the compound.
  • isotope includes all isotopes of atoms occurring in the compounds of the invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example but not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples, using the appropriate isotopically labeled reagents in place of the non-isotopically labeled reagents.
  • Such compounds have a variety of potential uses, for example as a standard and reagent in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.
  • Prodrug means that the compound of the invention can be administered in the form of a prodrug.
  • Prodrugs are derivatives which are converted to the biologically active compounds of the invention under physiological conditions in vivo, for example by oxidation, reduction, hydrolysis, etc., each of which is carried out using an enzyme or without the participation of an enzyme.
  • a prodrug is a compound in which an amino group in a compound of the invention is acylated, alkylated or phosphorylated, such as eicosylamino, alanylamino, pivaloyloxymethylamino, or Wherein the hydroxy group is acylated, alkylated, phosphorylated or converted to a borate such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” refers to a salt made from a pharmaceutically acceptable base or acid, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically acceptable salts. Thus, the compounds of the invention containing an acidic group may be present in the form of a salt and may be used according to the invention, for example as an alkali metal salt, an alkaline earth metal salt or as an ammonium salt. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids.
  • the compounds of the invention containing a basic group may be present in the form of a salt and may be used in accordance with the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, and C.
  • the compound of the invention contains both acidic and basic groups in the molecule, the invention includes, in addition to the salt forms mentioned, internal or internal ammonium salts.
  • Each salt can be obtained by conventional methods known to those skilled in the art, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant or by anion exchange or cation exchange with other salts.
  • “Pharmaceutical composition” means a compound containing one or more of the compounds described herein, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and mixtures thereof, and other components such as a pharmaceutically acceptable carrier And a combination of excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • tumor includes benign tumors and malignant tumors (eg, cancer).
  • terapéuticaally effective amount refers to an amount that includes a compound of the invention that is effective to inhibit the function of VEGFR and/or to treat or prevent the disease.
  • the invention also provides methods of making the compounds.
  • the preparation of the compounds of the general formula (I) of the present invention can be carried out by the following exemplary methods and examples, but the methods and examples should not be construed as limiting the scope of the invention in any way.
  • the compounds of the invention may also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and methods of the invention may be employed.
  • the product obtained in each step of the reaction is obtained by separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation and the like.
  • the starting materials and chemical reagents required for the synthesis can be conventionally synthesized or purchased according to the literature (available from SciFinder).
  • porphyrin-1-carboxamide compound of the formula (I) of the present invention can be synthesized according to the route described in Process A: porphyrin A1 is formed into a urea A2 by a conventional condensation method, for example, N,N'-carbonyldiimidazole (CDI) condensing agent, reaction with isocyanate, phenyl porphyrin-1-carboxylate and then reacting with amine; A2 hydrodebenzylation to obtain A3; A3 under base catalysis with 4-chloroquinoline The substitution reaction produces the target product A4.
  • a conventional condensation method for example, N,N'-carbonyldiimidazole (CDI) condensing agent, reaction with isocyanate, phenyl porphyrin-1-carboxylate and then reacting with amine
  • CDI N,N'-carbonyldiimidazole
  • porphyrin-1-carboxamides of the formula (I) of the present invention can also be synthesized according to the route described in Process B: N-Boc-protected porphyrin B1 is subjected to base catalysis with 4-chloroquinoline The substitution reaction produces B2; B2 removes Boc with an acid to obtain B3; and B3 is further subjected to urea condensation to form the target product A4.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR was measured by a Bruker ASCEND-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD), and the internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDC1 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • chemical shifts are given in units of 10 -6 (ppm).
  • the MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, model: 6120).
  • ESI Agilent SQD
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Poroshell 120 EC-C18, 50 x 3.0 mm, 2.7 ⁇ m column) or a Waters Arc high pressure liquid chromatograph (Sunfirc C18, 150 x 4.6 mm, 5 ⁇ m column).
  • Thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15 ⁇ 0.2mm.
  • the specification of thin layer chromatography separation and purification product is 0.4 ⁇ 0.5mm silica gel plate. .
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Beijing. Coupling chemicals and other companies.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-SP type microwave reactor.
  • the temperature of the reaction is room temperature, and the temperature range is from 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored using an Agilent LC/MS (1260/6120).
  • the progress of the reaction can also be monitored by thin layer chromatography (TLC).
  • the system used for the developing agent is A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system, the volume ratio of the solvent is based on the polarity of the compound. Adjust differently.
  • the system for purifying the compound using the column chromatography eluent and the system for developing the thin layer chromatography include A: dichloromethane and methanol systems; B: petroleum ether and ethyl acetate system, the volume ratio of the solvent according to the compound The polarity is adjusted differently, and a small amount of triethylamine and an acidic or alkaline reagent may be added for adjustment, or other solvent systems may be used.
  • the purified compound was also subjected to a Waters mass spectrometric automated preparation system (mass spectrometer: SQD2) with appropriate acetonitrile/water (containing 0.1% trifluoroacetic acid or formic acid) or acetonitrile/water (containing 0.05% aqueous ammonia) depending on the polarity of the compound.
  • the reverse phase high pressure column (XBridge-C18, 19 x 150 mm, 5 ⁇ m) was eluted with a gradient at a flow rate of 20 mL/min.
  • the in vitro activity of VEGFR1 was determined by measuring the phosphorylation level of the substrate in the kinase reaction using a homogeneous time-resolved fluorescence (HTRF) kinase assay kit (Cisbio, Cat. No. 62TK0PEC).
  • the reaction buffer contains the following components: the kit comes with enzymatic reaction buffer (1 ⁇ ), 5 mM MgCl 2 , 1 mM MnCl 2 , 1 mM DTT; human recombinant VEGFR 1 protein (Cat. No. PV3666) is purchased from ThermoFish, using reaction buffer.
  • kinase solution Diluted to 0.3 ng/ ⁇ L of kinase solution; substrate reaction solution including dilution with reaction buffer to 1 ⁇ M biotinylated tyrosine kinase substrate and 0.8 ⁇ M ATP; assay buffer including dilution with reaction buffer to 0.1 ng/ ⁇ L Eu 3+ labeled cage antibody and 0.125 ⁇ M streptavidin-labeled XL665.
  • the ratio of 665/620 is positively correlated with the degree of phosphorylation of the substrate, thereby detecting the activity of VEGFR1 kinase.
  • the VEGFR1 kinase protein group was not added as a negative control (100% inhibition), and the VEGFR1 kinase protein was added but the compound group was not added as a positive control (0% inhibition).
  • the percent inhibition of VEGFR1 activity by a compound can be calculated using the following formula:
  • Y is the percent inhibition
  • X is the logarithm of the concentration of the test compound
  • Bottom is the maximum percent inhibition
  • Top is the minimum percent inhibition
  • slope factor is the slope coefficient of the curve.
  • the in vitro activity of VEGFR2 was determined by measuring the phosphorylation level of the substrate in the kinase reaction using a homogeneous time-resolved fluorescence (HTRF) kinase assay kit (Cisbio, Cat. No. 62TK0PEC).
  • the reaction buffer contains the following components: the kit comes with enzymatic reaction buffer (1 ⁇ ), 5 mM MgCl 2 , 1 mM MnCl 2 , 1 mM DTT, 0.01% BSA and 0.005% Tween 20; human recombinant VEGFR 2 protein (Cat. No.
  • 10012-H20B1) purchased from Yishen Shenzhou, diluted to 0.3 ng / ⁇ L of kinase solution with reaction buffer; substrate reaction solution including dilution with reaction buffer to 0.3 ⁇ M biotin-labeled tyrosine kinase substrate and 3.5 ⁇ M ATP; detection Buffers included dilution with reaction buffer to 0.1 ng/ ⁇ L Eu 3+ labeled cage antibody and 18.75 nM streptavidin labeled XL665 (Cisbio, Cat. No. 610SAXLB).
  • the ratio of 665/620 is positively correlated with the degree of phosphorylation of the substrate, thereby detecting the activity of VEGFR2 kinase.
  • the VEGFR2 kinase protein group was not added as a negative control (100% inhibition), and the VEGFR2 kinase protein was added but the compound group was not added as a positive control (0% inhibition).
  • the percent inhibition of VEGFR2 activity by a compound can be calculated using the following formula:
  • Percent inhibition 100-100* (signal value at a specific concentration of the test compound - negative control signal value) / (positive control signal value - negative control signal value)
  • Y is the percent inhibition
  • X is the logarithm of the concentration of the test compound
  • Bottom is the maximum percent inhibition
  • Top is the minimum percent inhibition
  • Slope factor is the slope slope factor
  • the in vitro activity of VEGFR3 was determined by measuring the phosphorylation level of the substrate in the kinase reaction using the HTRF Kinase Assay Kit (Cisbio, Cat. No. 62TK0PEC).
  • the reaction buffer contains the following components: the kit comes with enzymatic reaction buffer (1 ⁇ ), 5 mM MgCl 2 , 1 mM MnCl 2 , 1 mM DTT and 0.01% Tween 20 ; human recombinant VEGFR 3 protein (Cat. No. 08-190) was purchased from Carna Biosciences.
  • reaction buffer Diluted into 0.05 ng/ ⁇ L of kinase solution with reaction buffer; substrate reaction solution including dilution with reaction buffer to 0.13 ⁇ M biotinylated tyrosine kinase substrate and 0.4 ⁇ M ATP; detection buffer including reaction buffer The solution was diluted to 0.1 ng/ ⁇ L Eu 3+ labeled cage antibody and 8.13 nM streptavidin labeled XL665.
  • the ratio of 665/620 is positively correlated with the degree of phosphorylation of the substrate, thereby detecting the activity of VEGFR3 kinase.
  • the VEGFR3 kinase protein group was not added as a negative control (100% inhibition), and the VEGFR3 kinase protein was added but the compound group was not added as a positive control (0% inhibition).
  • the percent inhibition of VEGFR3 activity by a compound can be calculated using the following formula:
  • Percent inhibition 100-100* (signal value at a specific concentration of the test compound - negative control signal value) / (positive control signal value - negative control signal value)
  • Y is the percent inhibition
  • X is the logarithm of the concentration of the test compound
  • Bottom is the maximum percent inhibition
  • Top is the minimum percent inhibition
  • slope factor is the slope coefficient of the curve.
  • the compounds of the examples of the present invention have a significant inhibitory effect on the activity of VEGFR, respectively.

Abstract

一种新的调控或抑制血管内皮细胞生长因子受体(VEGFR)活性的吲哚啉-1-甲酰胺类化合物，其制备方法及其在医药学上的应用。具体而言，涉及一种通式(I)所示的化合物及其可药用的盐、含有所述化合物或其可药用的盐的药物组合物、应用所述化合物或其可药用的盐治疗和/或预防VEGFR介导的相关性病症、特别是肿瘤的方法以及所述化合物或其可药用的盐的制备方法。还涉及所述化合物或其可药用的盐或含有所述化合物或其可药用的盐的药物组合物在制备用于治疗和/或预防VEGFR介导的相关性病症、特别是肿瘤的药物中的用途。其中通式(I)的各取代基与说明书中的定义相同。

Description

吲哚啉-1-甲酰胺类化合物、其制备方法及其在医药学上的应用 技术领域
本发明涉及一种新的调控或抑制血管内皮细胞生长因子受体(VEGFR)活性的吲哚啉-1-甲酰胺类化合物或其可药用的盐、含有所述化合物或其可药用的盐的药物组合物、所述化合物或其可药用的盐的制备方法以及所述化合物或其可药用的盐或含有所述化合物或其可药用的盐的药物组合物在制备用于治疗和/或预防VEGFR介导的相关性病症、特别是肿瘤的药物中的用途和其使用方法。
背景技术
血管新生(angiogenesis)是一个受多种因子，包括血管内皮生长因子(VEGF)、成纤维细胞生长因子(FGF)、血小板衍生生长因子(PDGF)、血管生成素(angiopoietin)、白细胞介素6(IL-6)等通过不同的信号通路激发和调控的复杂生理过程，对肿瘤的生长和转移起着重要的作用。比如VEGF与其受体VEGFR1/2/3结合，引发下游的信号级联反应，促进内皮细胞增殖、存活、迁移、血管通透等。VEGFR1(FLT1受体)和VEGFR2(KDR/FLK1)主要与血管生成相关，而VEGFR3(FLT4受体)主要与***生成相关。VEGFR2普遍表达于几乎所有类型的内皮细胞中，而VEGFR1/3的表达被限制在特定的血管支持组织中。
VEGFR在正常人体组织中呈低水平表达，而在绝大多数肿瘤中呈现高表达，且VEGFR不单表达于血管内皮细胞，还表达于肿瘤细胞。它不仅促进血管内皮细胞***、增殖，且诱导肿瘤血管增生，并促使其肿瘤细胞生长转移。因此，抑制VEGFR活性，阻断其信号转导，又达到阻止肿瘤血管新生的作用，进而抑制肿瘤生长及转移，控制肿瘤生长，因此VEGFR是抗肿瘤的一个重要靶标。市场上已有几个小分子VEGFR抑制剂，比如索拉非尼、舒尼替尼、乐伐替尼、阿西替尼、卡博替尼；还有一些正在进行临床研究，比如呋喹替尼、西地尼布、德立替尼。大多为多激酶抑制剂，具有不同的临床疗效和毒副作用，为肿瘤患者提供了可供选择的治疗手段。
当前PD-1/PD-L1等免疫检查点抑制剂在临床上对多种肿瘤显示了良好的疗效，但应答率有待进一步提高。PD-1/PD-L1与VEGFR等激酶抑制剂的联用能否产生协同作用以提高疗效吸引了众多生物制药公司的关注(WO2015088847、WO2016140717、WO2018068691等)，现已展开了多种联合用药的临床试验。PD-1与乐伐替尼的临床Ib/II结果显示联合疗法优于单药治疗，在转移性肾细胞癌(ESMO 2017 Congress,Abstract No.8470)和子宫内膜癌(2017 ASCO)治疗取得了更高的应 答率。
基于VEGFR抑制剂在单独和免疫联合治疗多种肿瘤中所展示的前景，本发明设计合成了具有通式(I)所示结构的新颖化合物，并发现具有此类结构的化合物表现出优异的抑制VEGFR活性的效果和作用。
发明内容
本发明提供作为VEGFR抑制剂的一种通式(I)所示的化合物：
Figure PCTCN2019086241-appb-000001
或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，
其中：
R 1为-OR 7；
R 2独立地选自-OR 8或-C(O)NHR 8；
R 3为任选取代的C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基；
R 4独立地选自H、卤素、CN、C 1-4烷基；
R 5和R 6各自独立地选自H、卤素、C 1-4烷基、-OR 7；或者，R 5和R 6与连接的碳原子共同形成一任选含有选自O、N和S的杂原子的3-7元环；
R 7和R 8各自独立地选自H或任选取代的C 1-4烷基；
所述任选取代是指被选自以下的取代基取代：卤素、-CN、-NO 2、氧代、-SF 5、C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基、-OR′、-NR′R″、-C(O)R′、-C(O)OR′、-C(O)NR′R″、-C(O)N(R′)OR″、-OC(O)R′、-OC(O)NR′R″、-N(R′)C(O)OR″、-N(R′)C(O)R″、-N(R′″)C(O)NR′R″、-N(R′)S(O) 2R″、-S(O) mR′、-S(O) 2NR′R″，其中R′、R″和R′″各自独立地选自H、C 1-4烷基、C 3-7环烷基、卤代C 1-4烷基、4-7元杂环基、C 6-10芳基、5-10元杂芳基；在同一个氮原子上的R′和R″任选与它们连接的氮原子共同形成一任选含有另外的选自O、S和N的杂原子的4-7元杂环，且
m为1或2。
本发明的一个实施方案涉及上述通式(I)所示的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中R 2独立地选自-OC 1-4烷基、-C(O)NH 2或-C(O)NH-C 1-4烷基，优选R 2为-OCH 3，更优选R 2为-C(O)NH 2。
本发明的一个实施方案涉及上述通式(I)所示的化合物或其可药用 的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中R 7为任选取代的C 1-4烷基，优选R 7为C 1-4烷基，更优选R 7为CH 3。
本发明的另一个实施方案涉及上述任一实施方案所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中R 4为H或F，优选R 4为H。
本发明的另一个实施方案涉及上述任一实施方案所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中R 5和R 6各自独立地选自H或F，优选R 5和R 6为H。
本发明的一个实施方案涉及上述通式(I)所示的化合物，其中所述化合物选自但不限于：
Figure PCTCN2019086241-appb-000002
Figure PCTCN2019086241-appb-000003
或其前药、稳定同位素衍生物、可药用的盐、异构体及其混合物形式。
本发明化合物对VEGFR2的酶活性具有显著抑制效应，优选其IC 50小于100nM，更优选IC 50小于10nM。
本发明的另一方面涉及作为药物或者用于医药用途的通式(I)所示的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物，其用于治疗或者预防VEGFR介导的相关性疾病，特别是肿瘤，包括但不限于黑色素瘤、淋巴瘤、甲状腺癌、肾癌、肝癌、***癌、结肠癌、直肠癌、胃癌、脑癌、膀肮癌、卵巢癌、头颈癌、乳腺癌、肺癌、神经胶质瘤等。因此，再一方面，本发明提供一种治疗或者预防VEGFR介导的疾病(例如所述肿瘤)的方法，其包括给予有需要的患者治疗有效量的本发明所述化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物、或包含所述化合物的药物组合物。
本发明进一步涉及一种药物组合物，所述药物组合物包含本发明所述化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物及药学上可接受的载体和赋形剂。
本发明的另一方面涉及通式(I)所示的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物、或所述药物组合物在制备药物中的用途，其中所述药物用于治疗或者预防VEGFR介导的疾病，例如肿瘤。
本发明的另一方面涉及一种药物组合物，所述药物组合物包含通式(I)所示的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物和至少一种额外的药物，其中所述至少一种额外的药物为化学治疗剂或免疫调节剂(比如免疫检查点抑制剂)。
根据本发明，所述药物可以是任何药物剂型，包括但不限于片剂、胶囊剂、溶液剂、冻干制剂、注射剂。
本发明的药物制剂可以以每剂量单位包含预定量的活性成分的剂 量单位形式给药。这种单位可根据治疗的病症、给药方法和患者的年龄、体重和状况包含例如0.5毫克至1克，优选1毫克至700毫克，特别优选5毫克至300毫克的本发明的化合物。优选剂量单位制剂是包含如上指示的日剂量或分剂量或其相应分数的活性成分的那些。此外，可以使用制药领域中公知的方法制备这种类型的药物制剂。
本发明药物制剂可适于通过任何所需的合适方法给药，例如通过经口(包括口腔或舌下)、直肠、经鼻、局部(包括口腔、舌下或经皮)、***或肠道外(包括皮下、肌内、静脉内或皮内)方法给药。可以使用制药领域中已知的所有方法通过例如将活性成分与一种或多种赋形剂或一种或多种辅助剂合并来制备这样的制剂。
具体实施方式
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。
在本文中使用的表示方式“C x-y”表示碳原子数的范围，其中x和y均为整数，例如C 3-8环烷基表示具有3-8个碳原子的环烷基，即具有3、4、5、6、7或8个碳原子的环烷基。还应理解，“C 3-8”还包含其中的任意亚范围，例如C 3-7、C 3-6、C 4-7、C 4-6、C 5-6等。
“烷基”指含有1至20个碳原子，例如1至8个碳原子、1至6个碳原子或1至4个碳原子的饱和的直链或支链的烃基基团。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基和2-乙基丁基。所述烷基可以是任选取代的。
“环烷基”指含有3至14个碳环原子的饱和环形烃基取代基。环烷基可以是单碳环，通常含有3至8个、3至7个或3至6个碳环原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环己基和环庚基。环烷基可选择地可以是稠合到一起的双或三环，如十氢萘基。所述环烷基可以是任选取代的。
“杂环基或杂环”指饱和或部分不饱和的单环或多环环状基团，其包括3至20个环原子，例如可以是3至14个、3至12个、3至10个、3至8个、3至6个或5至6个环原子，其中一个或多个环原子选自氮、氧或S(O) m(其中m是整数0至2)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个环原子，更优选3至10个环原子，更优选4至7个环原子，最优选5或6个环原子，其中1～4个是杂原子，更优选1～3个是杂原子，最优选1～2个是杂原子。单环杂环基的非限制性实例包含吡咯烷基、哌啶基、哌嗪基、吡喃基、吗啉基、硫代吗啉基、高哌嗪基、氧杂环己烷基和氮杂环丁烷基。多环 杂环基包括稠合、桥接或螺多环杂环基，如八氢环戊二烯并[c]吡咯、八氢吡咯并[1,2-a]吡嗪、3,8-二氮杂二环[3.2.1]辛烷、5-氮杂螺[2.4]庚烷、2-氧杂-7-氮杂螺[3.5]壬烷。所述杂环基或杂环可以是任选取代的。
“芳基或芳环”指含有6至14个碳原子的芳香族单环或稠合多环基团，优选为6至10元，例如苯基和萘基，最优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，非限制性实例包括:
Figure PCTCN2019086241-appb-000004
所述芳基或芳环可以是任选取代的。
“杂芳基或杂芳环”指包含5至14个环原子的杂芳族体系，其中1至4个环原子选自包括氧、硫和氮的杂原子。杂芳基优选为5至10元。更优选杂芳基是5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、吡唑基、咪唑基、四唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、喹啉基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实例包括:
Figure PCTCN2019086241-appb-000005
所述杂芳基或杂芳环可以是任选取代的。
“卤素”指氟、氯、溴或碘。
“氰基”指-CN。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该表述包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该表述包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“任选取代的”指基团中的一个或多个氢原子，优选为5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。所述取代基包括但不限于卤素、-CN、-NO 2、氧代、-SF 5、C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基、-OR′、-NR′R″、-C(O)R′、-C(O)OR′、-C(O)NR′R″、-C(O)N(R′)OR″、-OC(O)R′、-OC(O)NR′R″、-N(R′)C(O)OR″、-N(R′)C(O)R″、-N(R′″)C(O)NR′R″、- N(R′)S(O) 2R″、-S(O) mR′(m为1或2)、-S(O) 2NR′R″等，其中R′、R″和R′″各自独立地选自H、C 1-4烷基、C 3-7环烷基、卤代C 1-4烷基、4-7元杂环基、C 6-10芳基、5-10元杂芳基等；在同一个氮原子上的R′和R″任选与它们连接的氮原子共同形成一任选含有另外的选自O、S和N的杂原子的4-7元杂环。
“异构体”指具有相同分子式但其原子结合的性质或顺序或其原子的空间排列不同的化合物。其原子空间排列不同的异构体称为“立体异构体”。立体异构体包括光学异构体、几何异构体和构象异构体。
本发明的化合物可以以光学异构体形式存在。根据手性碳原子周围取代基的构型，这些光学异构体是“R”或“S”构型。光学异构体包括对映异构体和非对映异构体。制备和分离光学异构体的方法是本领域中已知的。
本发明的化合物也可以存在几何异构体。本发明考虑由碳-碳双键、碳-氮双键、环烷基或杂环基团周围的取代基的分布所产生的各种几何异构体和其混合物。碳-碳双键或碳-氮键周围的取代基指定为Z或E构型，环烷基或杂环周围的取代基指定为顺式或反式构型。
本发明的化合物还可能显示互变异构现象，例如酮-烯醇互变异构。
应该理解，本发明包括任何互变异构或立体异构形式和其混合物，并且不仅仅限于化合物的命名或化学结构式中所使用的任何一个互变异构或立体异构形式。
“同位素”包括在本发明化合物中出现的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。适合并入本发明化合物中的同位素的实例是氢、碳、氮、氧、磷、氟和氯，分别例如但不限于 2H、 3H、 13C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明的同位素标记化合物通常可通过本领域技术人员已知的传统技术或通过与所附实施例中描述的那些类似的方法使用适当的同位素标记的试剂代替非同位素标记的试剂来制备。这样的化合物具有各种潜在用途，例如作为测定生物活性中的标样和试剂。在稳定同位素的情况下，这样的化合物具有有利地改变生物、药理学或药代动力学性质的潜力。
“前药”是指本发明的化合物可以以前药的形式给予。前药是指在活体内的生理条件下例如通过氧化、还原、水解等(它们各自利用酶或在没有酶参与下进行)转化成本发明的生物活性化合物的衍生物。前药的实例是下述化合物：其中本发明的化合物中的氨基被酰化、烷基化或磷酸化，例如二十烷酰基氨基、丙氨酰氨基、新戊酰氧基甲基氨基，或其中羟基被酰化、烷基化、磷酸化或转化成硼酸盐，例如乙酰氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基、丙氨酰氧基，或其中羧基被酯化或酰胺化，或其中巯基与选择性地向靶和/或向细胞的胞质溶胶递送药物的载体分子，例如肽形成二硫桥键。这些化合物可以由 本发明的化合物根据公知方法制备。
“可药用的盐”或者“药学上可接受的盐”是指由可药用的碱或酸，包括无机碱或酸和有机碱或酸制成的盐。在本发明的化合物含有一个或多个酸性或碱性基团的情况下，本发明还包含它们相应的可药用盐。因此，含有酸性基团的本发明的化合物可以以盐形式存在并可根据本发明使用，例如作为碱金属盐、碱土金属盐或作为铵盐。这样的盐的更确切实例包括钠盐、钾盐、钙盐、镁盐或与氨或有机胺，例如乙胺、乙醇胺、三乙醇胺或氨基酸的盐。含有碱性基团的本发明的化合物可以以盐形式存在并可根据本发明以它们与无机或有机酸的加成盐的形式使用。合适的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、特戊酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和本领域技术人员已知的其它酸。如果本发明的化合物在分子中同时含有酸性和碱性基团，本发明除所提到的盐形式外还包括内盐或内铵盐。各盐可通过本领域技术人员已知的常规方法获得，例如通过在溶剂或分散剂中使这些与有机或无机酸或碱接触或通过与其它盐阴离子交换或阳离子交换。
“药物组合物”指含有一种或多种本文所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式以及其他组分例如可药用的载体和赋形剂的组合物。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
因此，在本申请中当提及“化合物”、“本发明化合物”或“本发明所述化合物”时，包括所有所述化合物形式，例如其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物。
在本文中，术语“肿瘤”包括良性肿瘤和恶性肿瘤(例如癌症)。
在本文中，术语“治疗有效量”是指包括可有效抑制VEGFR的功能和/或治疗或防止所述疾病的本发明化合物的量。
合成方法
本发明还提供制备所述化合物的方法。本发明通式(I)所述化合物的制备，可通过以下示例性方法和实施例完成，但这些方法和实施例不应以任何方式被认为是对本发明范围的限制。也可通过本领域技术人员所知的合成技术合成本发明所述的化合物，或者综合使用本领域已知方法和本发明所述方法。每步反应所得的产物用本领域已知的分离技术得到，包括但不限于萃取、过滤、蒸馏、结晶、色谱分离等。合成所需的起始原料和化学试剂可以根据文献(可从SciFinder上查询)常规合成或购买。
本发明通式(I)所述吲哚啉-1-甲酰胺类化合物可按照方法A所述 路线合成：吲哚啉A1通过常规缩合方法生成脲A2，比如用N,N'-羰基二咪唑(CDI)缩合剂、与异氰酸酯反应、先生成苯基吲哚啉-1-羧酸酯再与胺反应等；A2氢化脱苄基得到A3；A3在碱催化下与4-氯代喹啉进行取代反应生成目标产物A4。
方法A：
Figure PCTCN2019086241-appb-000006
本发明通式(I)所述吲哚啉-1-甲酰胺类化合物也可按照方法B所述路线合成：N-Boc保护的吲哚啉B1在碱催化下与4-氯代喹啉进行取代反应生成B2；B2用酸脱Boc得到B3；B3再经过脲缩合生成目标产物A4。
方法B：
Figure PCTCN2019086241-appb-000007
实施例
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR的测定是用Bruker ASCEND-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDC1 3)、氘代甲醇(CD 3OD)，内标为四甲基甲硅烷(TMS)，化学位移是以10 -6(ppm)作为单位给出。
MS的测定用Agilent SQD(ESI)质谱仪(生产商：Agilent，型号：6120)。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Poroshell 120 EC-C18，50×3.0mm，2.7μm色谱柱)或Waters Arc高压液相色谱仪(Sunfirc C18，150×4.6mm，5μm色谱柱)。
薄层层析硅胶板使用青岛海洋GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15～0.2mm，薄层层析分离纯化产品采用的规格是0.4～0.5mm硅胶板。
柱层析一般使用青岛海洋200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc.)、北京耦合化学品等公司。
实施例中如无特殊说明，反应均在氩气气氛或氮气气氛下进行。
氩气气氛或氮气气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-SP型微波反应器。
实施例中如无特殊说明，反应的温度为室温，温度范围是20℃-30℃。
实施例中的反应进程的监测使用安捷伦的液质联用仪(1260/6120)。反应进程的监测也可采用薄层色谱法(TLC)，展开剂所使用的体系有A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和酸性或碱性试剂等进行调节，或者采用其它的溶剂体系。纯化化合物还采用Waters的质谱导向自动制备***(质谱检测器：SQD2)，根据化合物的极性用适当的乙腈/水(含0.1％三氟乙酸或甲酸)或乙腈/水(含0.05％氨水)梯度于20mL/min的流速洗脱反相高压柱(XBridge-C18，19×150mm，5μm)。
实施例1和2
4-((1-(环丙基氨基甲酰)吲哚啉-5-基)氧基)-7-甲氧基喹啉-6-甲酰胺1
4-((1-(环丙基氨基甲酰)吲哚啉-5-基)氧基)-7-羟基喹啉-6-甲酰胺2
Figure PCTCN2019086241-appb-000008
Figure PCTCN2019086241-appb-000009
第一步
5-(苄氧基)吲哚啉
将化合物5-(苄氧基)吲哚1a(1.06g，4.75mmol)溶于乙酸(10mL)，然后加入氰基硼氢化钠(447mg，7.12mmol)。室温下搅拌1小时后，用1N氢氧化锂溶液调节至pH＝8，然后用乙酸乙酯萃取(50mL×3)。有机相合并后用无水硫酸钠干燥，过滤后滤液在减压条件下除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝20/1)纯化，得到目标产物5-(苄氧基)吲哚啉1b(883mg，黄色油状物)，产率：88％。
MS m/z(ESI):226[M+1]
1H NMR(400MHz,CDCl 3)δ7.45–7.28(m,5H),6.85–6.81(m,1H),6.68(dd,J＝8.4,2.5Hz,1H),6.63(d,J＝8.4Hz,1H),4.99(s,2H),3.56(t,J＝8.3Hz,2H),3.01(t,J＝8.3Hz,2H)。
第二步
5-(苄氧基)-N-环丙基吲哚啉-1-甲酰胺
将环丙胺(46mg，0.8mmol)溶于N,N-二甲基甲酰胺(2mL)后，加入N,N'-羰基二咪唑(156mg，0.96mmol)，然后加热至65℃并搅拌2小时。冷却到室温后，加入5-(苄氧基)吲哚啉1b(113mg，0.5mmol)，然后再次升温到65℃并搅拌2小时。冷却到室温后，用水淬灭，然后用乙酸乙酯萃取(20mL×3)。有机相合并后依次用水(20mL×2)和饱和食盐水(20mL)洗涤，然后用无水硫酸钠干燥。过滤后，滤液在减压条件下除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝1/1至1/2)纯化，得到目标产物5-(苄氧基)-N-环丙基吲哚啉-1-甲酰胺1c(124mg，白色固体)，产率：80％。
MS m/z(ESI):309[M+1]
1H NMR(400MHz,CDCl 3)δ7.79(d,J＝8.5Hz,1H),7.45–7.28(m,5H),6.82–6.74(m,2H),5.01(s,2H),4.75(s,1H),3.83(t,J＝8.6Hz,2H),3.11(t,J＝8.5Hz,2H),2.72(tt,J＝7.0,3.7Hz,1H),0.81–0.75(m,2H),0.57–0.51(m,2H)。
第三步
N-环丙基-5-羟基吲哚啉-1-甲酰胺
将化合物5-(苄氧基)-N-环丙基吲哚啉-1-甲酰胺1c(530mg，1.72mmol)溶于甲醇(30mL)，然后加入10％钯碳(110mg)并在氢气气 氛下室温搅拌2小时。反应完成后过滤，滤液在减压条件下除去溶剂，得到目标产物N-环丙基-5-羟基吲哚啉-1-甲酰胺1d(308mg，白色固体)，产率：82％。
MS m/z(ESI):219[M+1]
第四步
4-((1-(环丙基氨基甲酰)吲哚啉-5-基)氧基)-7-甲氧基喹啉-6-甲酰胺和4-((1-(环丙基氨基甲酰)吲哚啉-5-基)氧基)-7-羟基喹啉-6-甲酰胺
将化合物N-环丙基-5-羟基吲哚啉-1-甲酰胺1d(110mg，0.5mmol)、4-氯-7-甲氧基喹啉-6-甲酰胺(118mg，0.5mmol)、二异丙基乙基胺(97mg，0.75mmol)和N-甲基吡咯烷酮(0.2mL)混合，在微波反应器中加热到130℃并搅拌35分钟。冷却室温后，用反相制备高效液相色谱纯化，得到目标产物4-((1-(环丙基氨基甲酰)吲哚啉-5-基)氧基)-7-甲氧基喹啉-6-甲酰胺1(64mg，橙色固体)，产率：14％；以及4-((1-(环丙基氨基甲酰)吲哚啉-5-基)氧基)-7-羟基喹啉-6-甲酰胺2(22.3mg，橙色固体)，产率：5％。
4-((1-(环丙基氨基甲酰)吲哚啉-5-基)氧基)-7-甲氧基喹啉-6-甲酰胺1
MS m/z(ESI):419[M+1]
1H NMR(400MHz,CD 3OD)δ9.05(s,1H),8.86(d,J＝6.8Hz,1H),8.07(d,J＝8.7Hz,1H),7.59(s,1H),7.20(d,J＝2.3Hz,1H),7.13(dd,J＝8.7,2.5Hz,1H),6.98(d,J＝6.8Hz,1H),4.22(s,3H),4.00(t,J＝8.7Hz,2H),3.27(t,J＝8.7Hz,2H),2.70–2.63(m,1H),0.80-0.75(m,2H),0.63–0.56(m,2H)。
4-((1-(环丙基氨基甲酰)吲哚啉-5-基)氧基)-7-羟基喹啉-6-甲酰胺2
MS m/z(ESI):405[M+H]
1H NMR(400MHz,CD 3OD)δ9.26(s,1H),8.81(d,J＝6.8Hz,1H),8.08(d,J＝8.8Hz,1H),7.45(s,1H),7.21(s,1H),7.14(dd,J＝8.8,2.5Hz,1H),6.90(t,J＝5.5Hz,1H),4.00(t,J＝8.7Hz,2H),3.27(t,J＝8.7Hz,2H),2.70–2.63(m,1H),0.81–0.74(m,2H),0.62–0.56(m,2H)。
实施例3
7-甲氧基-4-((1-(甲基氨基甲酰)吲哚啉-5-基)氧基)喹啉-6-甲酰胺
Figure PCTCN2019086241-appb-000010
Figure PCTCN2019086241-appb-000011
第一步
5-(苄氧基)吲哚啉-1-羧酸叔丁酯
将化合物5-(苄氧基)吲哚啉1b(2g，8.88mmol)溶于二氯甲烷(80mL)，冷却到0℃后依次加入三乙胺(1.35g，13.32mmol)、4-二甲氨基吡啶(217mg，1.776mmol)、二碳酸二叔丁酯(2.13g，9.76mmol)。0℃下搅拌2小时后，减压除去溶剂，残余物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到目标产物5-(苄氧基)吲哚啉-1-羧酸叔丁酯3a(2.42g，白色固体)，产率：42％。
MS m/z(ESI):270[M+1-56]
1H NMR(400MHz,CDCl 3)δ7.74(s,1H),7.44–7.28(m,5H),6.80(s,1H),6.77(d,J＝8.7Hz,1H),5.02(s,2H),3.96(s,2H),3.04(t,J＝8.7Hz,2H),1.55(s,9H)。
第二步
5-羟基吲哚啉-1-羧酸叔丁酯
将化合物5-(苄氧基)吲哚啉-1-羧酸叔丁酯3a(2.42g，7.44mmol)溶于甲醇(80mL)，然后加入10％钯碳(1.2g)并在氢气气氛下室温搅拌2小时。反应完成后过滤，滤液在减压条件下除去溶剂，得到目标产物5-羟基吲哚啉-1-羧酸叔丁酯3b(1.65g，灰色固体)，产率：95％。
MS m/z(ESI):180[M+1-56]
1H NMR(400MHz,CDCl 3)δ7.69(s,1H),6.67(s,1H),6.62(dd,J＝8.6,2.2Hz,1H),4.81(s,1H),3.96(s,2H),3.03(t,J＝8.6Hz,2H),1.55(s,9H)。
第三步
5-((6-氨基甲酰-7-甲氧基喹啉-4-基)氧基)吲哚啉-1-羧酸叔丁酯
将化合物5-羟基吲哚啉-1-羧酸叔丁酯3b(590mg，2.5mmol)、4-氯-7-甲氧基喹啉-6-甲酰胺(590mg，2.5mmol)、叔丁醇钾(340mg，3mmol)和二甲基亚砜(10mL)混合，加热到65℃并搅拌16小时。冷却到室温后，加入水(50mL)。搅拌20分钟后过滤，固体空气中干燥后得到目标产物5-((6-氨基甲酰-7-甲氧基喹啉-4-基)氧基)吲哚啉- 1-羧酸叔丁酯3c(1.01g，灰色固体)，产率：93％。
MS m/z(ESI):436[M+1]
1H NMR(400MHz,CDCl 3)δ9.31(s,1H),8.62(d,J＝5.4Hz,1H),7.92(s,1H),7.77(s,1H),7.59(s,1H),6.97(d,J＝6.4Hz,2H),6.47(d,J＝5.4Hz,1H),5.91(s,1H),4.13(s,3H),4.06(t,J＝8.4Hz,2H),3.13(t,J＝8.7Hz,2H),1.58(s,9H)。
第四步
4-(吲哚啉-5-氧基)-7-甲氧基喹啉-6-甲酰胺
将化合物5-((6-氨基甲酰-7-甲氧基喹啉-4-基)氧基)吲哚啉-1-羧酸叔丁酯3c(1.01g，2.32mmol)溶于二氯甲烷(20mL)，然后逐滴加入三氟乙酸(8mL)。室温下搅拌2小时后，减压条件下除去溶剂。残余物分散到饱和碳酸氢钠溶液(50mL)中，然后用二氯甲烷萃取(50mL×3)。有机相合并后，用无水硫酸钠干燥，过滤后滤液在减压条件下除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化，得到目标产物4-(吲哚啉-5-氧基)-7-甲氧基喹啉-6-甲酰胺3d(713mg，黄色固体)，产率：92％。
MS m/z(ESI):336[M+1]
第五步
5-((6-氨基甲酰-7-甲氧基喹啉-4-基)氧基)吲哚啉-1-羧酸-4-硝基苯酯
将化合物4-(吲哚啉-5-氧基)-7-甲氧基喹啉-6-甲酰胺3d(107mg，0.32mmol)溶于四氢呋喃(5mL)，冷却到0℃后，加入对硝基苯基氯甲酸酯(64mg，0.32mmol)。室温下搅拌30分钟后，用饱和碳酸氢钠溶液(20mL)淬灭反应，然后用二氯甲烷萃取(20mL×2)。有机相合并后，用无水硫酸钠干燥，过滤后滤液在减压条件下除去溶剂，残余物用硅胶柱层析(二氯甲烷/甲醇＝50/1)纯化，得到目标产物5-((6-氨基甲酰-7-甲氧基喹啉-4-基)氧基)吲哚啉-1-羧酸-4-硝基苯酯3e(110mg，白色固体)，产率：69％。
MS m/z(ESI):501[M+1]
第六步
7-甲氧基-4-((1-(甲基氨基甲酰)吲哚啉-5-基)氧基)喹啉-6-甲酰胺
将化合物5-((6-氨基甲酰-7-甲氧基喹啉-4-基)氧基)吲哚啉-1-羧酸-4-硝基苯酯3e(110mg，0.22mmol)溶于四氢呋喃(8mL)，然后加入甲胺的四氢呋喃溶液(2M，2mL，4mmol)并在封管中于80℃下加热1小时。冷却到室温，减压除去溶剂，残余物用反相高效制备液相色谱纯化，得到目标产物7-甲氧基-4-((1-(甲基氨基甲酰)吲哚啉-5-基)氧基)喹啉-6-甲酰胺3(42mg，黄色固体)，产率：44％。
MS m/z(ESI):393[M+1]
1H NMR(400MHz,CD 3OD)δ9.06(s,1H),8.87(d,J＝6.8Hz,1H),8.06(d,J＝8.7Hz,1H),7.58(s,1H),7.21(s,1H),7.13(dd,J＝8.6,2.3Hz,1H),7.00(d,J＝6.8Hz,1H),4.23(s,3H),4.03(t,J＝8.7Hz,2H),3.28(d, J＝8.7Hz,2H),2.86(s,3H)
实施例4
4-((1-((4-氟苯基)氨基甲酰)吲哚啉-5-基)氧基)-7-甲氧基喹啉-6-甲酰胺
Figure PCTCN2019086241-appb-000012
将化合物对硝基苯基氯甲酸酯(40mg，0.2mmol)溶于四氢呋喃(5mL)，冷却到0℃后加入4-氟苯胺(22mg，0.2mmol)。升温到室温并搅拌1小时后，加入4-(吲哚啉-5-氧基)-7-甲氧基喹啉-6-甲酰胺3d(70mg，0.21mmol)和二异丙基乙基胺(97mg，0.75mmol)，然后在微波反应器中加热到80℃并搅拌1小时。冷却到室温后，减压除去溶剂，残余物用反相高效制备液相色谱纯化，得到目标产物4-((1-((4-氟苯基)氨基甲酰)吲哚啉-5-基)氧基)-7-甲氧基喹啉-6-甲酰胺4(24mg，黄色固体)，产率：23％。
MS m/z(ESI):473[M+1]
1H NMR(400MHz,CD 3OD)δ9.06(s,1H),8.89(d,J＝6.8Hz,1H),8.09(d,J＝8.8Hz,1H),7.60(s,1H),7.54–7.47(m,2H),7.26(d,J＝2.1Hz,1H),7.16(dd,J＝8.8,2.5Hz,1H),7.09(t,J＝8.8Hz,2H),7.02(d,J＝6.8Hz,1H),4.27(t,J＝8.7Hz,2H),4.23(s,3H),3.37(t,J＝8.6Hz,2H)。
实施例5
N-环丙基-5-((6,7-二甲氧基喹啉-4-基)氧基)吲哚啉-1-甲酰胺
Figure PCTCN2019086241-appb-000013
将化合物N-环丙基-5-羟基吲哚啉-1-甲酰胺1d(200mg，0.917mmol)、4-氯-6,7-二甲氧基喹啉(200mg，0.897mmol)、叔丁醇钾(300mg，2.75mmol)和N,N-二甲基甲酰胺(3mL)混合，加热到70℃并 搅拌12小时。冷却室温后，用反相制备高效液相色谱纯化，得到目标产物N-环丙基-5-((6,7-二甲氧基喹啉-4-基)氧基)吲哚啉-1-甲酰胺1(50mg，黄色固体)，产率：13％。
MS m/z(ESI):406[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.80(d,J＝6.7Hz,1H),8.00(d,J＝8.7Hz,1H),7.74(s,1H),7.73–7.68(m,1H),7.22(d,J＝2.4Hz,1H),7.12(dd,J＝8.7,2.5Hz,1H),6.85(s,1H),6.84(s,1H),4.04(s,3H),4.04(s,3H),3.93(t,J＝8.7Hz,2H),3.16(t,J＝8.6Hz,2H),2.66–2.57(m,1H),0.67–0.60(m,2H),0.54–0.47(m,2H)。
实施例6
7-甲氧基-4-((1-((5-甲基异恶唑-3-基)氨基甲酰)吲哚啉-5-基)氧基)喹啉-6-甲酰胺
Figure PCTCN2019086241-appb-000014
将化合物5-甲基异恶唑-3-胺(98mg，1.0mmol)溶于无水四氢呋喃(2mL)，然后依次加入吡啶(0.2mL)和氯甲酸苯酯(156mg，1.0mmol)。室温下搅拌2小时后，在减压条件下除去溶剂。残余物溶于乙酸乙酯(20mL)，用水洗涤(5mL×2)后用无水硫酸钠干燥。过滤后，滤液在减压条件下除去溶剂，得到一灰白色固体。将此固体和4-(吲哚啉-5-氧基)-7-甲氧基喹啉-6-甲酰胺3d(80mg，0.24mmol)一起溶于N,N-二甲基甲酰胺(1mL)中，然后加入4-二甲氨基吡啶(1mg，0.082mmol)。室温下搅拌40小时后，在减压条件下除去溶剂，残余物用反相制备高效液相色谱纯化，得到目标产物7-甲氧基-4-((1-((5-甲基异恶唑-3-基)氨基甲酰)吲哚啉-5-基)氧基)喹啉-6-甲酰胺6(47mg，黄色固体)，产率：43％。
MS m/z(ESI):460[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.80(s,1H),8.96(d,J＝6.4Hz,1H),8.75(s,1H),8.02(d,J＝8.7Hz,1H),7.97(s,1H),7.90(s,1H),7.76(s,1H),7.30(s,1H),7.20(d,J＝7.9Hz,1H),6.86(d,J＝6.4Hz,1H),6.61(s,1H),4.23(t,J＝8.3Hz,2H),4.09(s,3H),3.24(t,J＝8.1Hz,2H),2.39(s,3H)。
生物学实验
VEGFR1的活性抑制测试
使用体外激酶检测实验评估本发明的化合物对VEGFR1活性的影响
实验方法概述如下：
使用均相时间分辨荧光(HTRF)激酶检测试剂盒(Cisbio，货号62TK0PEC)，通过检测激酶反应中底物的磷酸化水平来测定VEGFR1的体外活性。反应缓冲液包含以下组分：试剂盒自带酶反应缓冲液(1×)、5mM MgCl 2、1mM MnCl 2、1mM DTT；人源重组VEGFR1蛋白(货号PV3666)购自ThermoFish公司，用反应缓冲液稀释成0.3ng/μL的激酶溶液；底物反应溶液包括用反应缓冲液稀释成1μM生物素标记的酪氨酸激酶底物和0.8μM ATP；检测缓冲液包括用反应缓冲液稀释成0.1ng/μL Eu 3+标记的笼状抗体和0.125μM链霉亲和素标记的XL665。
将化合物在100％DMSO中溶解稀释至10μM，然后用DMSO进行4倍的系列稀释至最低浓度为0.61nM，每个浓度点再使用反应缓冲液稀释40倍。
向384孔检测板(Corning，货号4512)中添加4μL化合物溶液和2μL VEGFR1激酶溶液，混合均匀后室温孵育15分钟。随后加入4μL底物反应溶液，将反应混合物在室温孵育50分钟。随后加入与反应等体积的10μL检测缓冲液，混合均匀并在室温条件下静置30分钟后，用Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。665/620的比值与底物的磷酸化程度呈正相关性，从而检测出VEGFR1激酶的活性。该实验中，未加VEGFR1激酶蛋白组作为阴性对照(100％抑制)，加VEGFR1激酶蛋白但是未加化合物组作为阳性对照(0％抑制)。化合物对VEGFR1活性抑制百分比可以用以下公式计算：
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算：
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)*slope factor))
其中Y为抑制百分比，X为待测化合物浓度的对数值，Bottom为最大抑制百分比，Top为最小抑制百分比，slope factor为曲线斜率系数。
VEGFR2的活性抑制测试
使用体外激酶检测实验评估本发明的化合物对VEGFR2活性的影响
实验方法概述如下：
使用均相时间分辨荧光(HTRF)激酶检测试剂盒(Cisbio，货号62TK0PEC)，通过检测激酶反应中底物的磷酸化水平来测定VEGFR2的体外活性。反应缓冲液包含以下组分：试剂盒自带酶反应缓冲液(1×)、5mM MgCl 2、1mM MnCl 2、1mM DTT、0.01％BSA和0.005％Tween20； 人源重组VEGFR2蛋白(货号10012-H20B1)购自义翘神州，用反应缓冲液稀释成0.3ng/μL的激酶溶液；底物反应溶液包括用反应缓冲液稀释成0.3μM生物素标记的酪氨酸激酶底物和3.5μM ATP；检测缓冲液包括用反应缓冲液稀释成0.1ng/μL Eu 3+标记的笼状抗体和18.75nM链霉亲和素标记的XL665(Cisbio，货号610SAXLB)。
将化合物在100％DMSO中溶解稀释至10μM，然后用DMSO进行4倍的系列稀释至最低浓度为0.61nM，每个浓度点再使用反应缓冲液稀释40倍。
向384孔检测板(Corning，货号4512)中添加4μL化合物溶液和2μL VEGFR2激酶溶液，混合均匀后室温孵育15分钟。随后加入4μL底物反应溶液，将反应混合物在室温孵育30分钟。随后加入与反应等体积的10μL检测缓冲液，混合均匀并在室温条件下静置30分钟后，用Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。665/620的比值与底物的磷酸化程度呈正相关性，从而检测出VEGFR2激酶的活性。该实验中，未加VEGFR2激酶蛋白组作为阴性对照(100％抑制)，加VEGFR2激酶蛋白但是未加化合物组作为阳性对照(0％抑制)。化合物对VEGFR2活性抑制百分比可以用以下公式计算：
抑制百分比＝100-100*(待测化合物特定浓度下信号值-阴性对照信号值)/(阳性对照信号值-阴性对照信号值)
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算：
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)*slope factor))
其中Y为抑制百分比，X为待测化合物浓度的对数值，Bottom为最大抑制百分比，Top为最小抑制百分比，Slope factor为曲线斜率系数。
VEGFR3的活性抑制测试
使用体外激酶检测实验评估本发明的化合物对VEGFR3活性的影响
实验方法概述如下：
使用HTRF激酶检测试剂盒(Cisbio，货号62TK0PEC)，通过检测激酶反应中底物的磷酸化水平来测定VEGFR3的体外活性。反应缓冲液包含以下组分：试剂盒自带酶反应缓冲液(1×)、5mM MgCl 2、1mM MnCl2、1mM DTT和0.01％Tween20；人源重组VEGFR3蛋白(货号08-190)购自Carna Biosciences，用反应缓冲液稀释成0.05ng/μL的激酶溶液；底物反应溶液包括用反应缓冲液稀释成0.13μM生物素标记的酪氨酸激酶底物和0.4μM ATP；检测缓冲液包括用反应缓冲液稀释成0.1ng/μL Eu 3+标记的笼状抗体和8.13nM链霉亲和素标记的XL665。
将化合物在100％DMSO中溶解稀释至10μM，然后用DMSO进行4倍的系列稀释至最低浓度为0.61nM，每个浓度点再使用反应缓冲液稀释40倍。
向384孔检测板(Corning，货号4512)中添加4μL化合物溶液和2μL VEGFR3激酶溶液，混合均匀后室温孵育15分钟。随后加入4μL底物反应溶液，将反应混合物在室温孵育40分钟。随后加入与反应等体积的10μL检测缓冲液，混合均匀并在室温条件下静置30分钟后，用Envision读板机(Perkin Elmer)在620nm和665nm波长下检测反应进程。665/620的比值与底物的磷酸化程度呈正相关性，从而检测出VEGFR3激酶的活性。该实验中，未加VEGFR3激酶蛋白组作为阴性对照(100％抑制)，加VEGFR3激酶蛋白但是未加化合物组作为阳性对照(0％抑制)。化合物对VEGFR3活性抑制百分比可以用以下公式计算：
抑制百分比＝100-100*(待测化合物特定浓度下信号值-阴性对照信号值)/(阳性对照信号值-阴性对照信号值)
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算：
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)*slope factor))
其中Y为抑制百分比，X为待测化合物浓度的对数值，Bottom为最大抑制百分比，Top为最小抑制百分比，slope factor为曲线斜率系数。
部分代表性实施例化合物的活性数据如下：
Figure PCTCN2019086241-appb-000015
A<10nM；10nM≤B<100nM
本发明的实施例化合物分别对VEGFR的活性具有显著抑制效应。

Claims (9)

  1. 通式(I)所示的化合物：
    Figure PCTCN2019086241-appb-100001
    或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，
    其中：
    R 1为-OR 7；
    R 2独立地选自-OR 8或-C(O)NHR 8；
    R 3为任选取代的C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基；
    R 4独立地选自H、卤素、CN、C 1-4烷基；
    R 5和R 6各自独立地选自H、卤素、C 1-4烷基、-OR 7；或者，R 5和R 6与连接的碳原子共同形成一任选含有选自O、N和S的杂原子的3-7元环；
    R 7和R 8各自独立地选自H或任选取代的C 1-4烷基；
    所述任选取代是指被选自以下的取代基取代：卤素、-CN、-NO 2、氧代、-SF 5、C 1-4烷基、C 3-7环烷基、4-7元杂环基、苯基、5-6元杂芳基、-OR′、-NR′R″、-C(O)R′、-C(O)OR′、-C(O)NR′R″、-C(O)N(R′)OR″、-OC(O)R′、-OC(O)NR′R″、-N(R′)C(O)OR″、-N(R′)C(O)R″、-N(R′″)C(O)NR′R″、-N(R′)S(O) 2R″、-S(O) mR′、-S(O) 2NR′R″，其中R′、R″和R′″各自独立地选自H、C 1-4烷基、C 3-7环烷基、卤代C 1-4烷基、4-7元杂环基、C 6-10芳基、5-10元杂芳基；在同一个氮原子上的R′和R″任选与它们连接的氮原子共同形成一任选含有另外的选自O、S和N的杂原子的4-7元杂环，且
    m为1或2。
  2. 根据权利要求1所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中R 2独立地选自-OC 1-4烷基、-C(O)NH 2或-C(O)NH-C 1-4烷基，优选R 2为-OCH 3，更优选R 2为-C(O)NH 2。
  3. 根据权利要求1或2所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中R 7为任选取代的C 1-4烷基，优选R 7为C 1-4烷基，更优选R 7为CH 3。
  4. 根据前述权利要求任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中R 4为H或F，优选R 4为H。
  5. 根据前述权利要求任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，其中R 5和R 6各自独立地选自H或F，优选R 5和R 6为H。
  6. 前述权利要求任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式，所述化合物选自但不限于：
    Figure PCTCN2019086241-appb-100002
  7. 药物组合物，所述药物组合物包含根据权利要求1-6任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式和药学上可接受的载体和赋形剂。
  8. 药物组合物，所述药物组合物包含根据权利要求1-6任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式和至少一种额外的药物，其中所述至少一种额外的药物为化学治疗剂或免疫调节剂(比如免疫检查点抑制剂)。
  9. 根据权利要求1-6任一项所述的化合物或其可药用的盐、前药、稳定同位素衍生物、异构体及其混合物形式或根据权利要求7-8任一项所述的药物组合物在制备用于治疗和/或预防VEGFR介导的相关性疾病，特别是肿瘤的药物中的用途。
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