[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2014169845A2 - 4,5-dihydro-pyrazolo [3, 4-c] pyrid-2-ones, preparation method and application thereof - Google Patents

4,5-dihydro-pyrazolo [3, 4-c] pyrid-2-ones, preparation method and application thereof Download PDF

Info

Publication number
WO2014169845A2
WO2014169845A2 PCT/CN2014/075683 CN2014075683W WO2014169845A2 WO 2014169845 A2 WO2014169845 A2 WO 2014169845A2 CN 2014075683 W CN2014075683 W CN 2014075683W WO 2014169845 A2 WO2014169845 A2 WO 2014169845A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
fluorenyl
oxo
phenyl
heterocyclic ring
Prior art date
Application number
PCT/CN2014/075683
Other languages
French (fr)
Chinese (zh)
Other versions
WO2014169845A3 (en
Inventor
魏用刚
邱关鹏
卢泳华
余彦
雷柏林
王松
黄清平
高秋
楚洪柱
祝国智
罗新峰
倪丽军
陈娅姝
邓炳初
Original Assignee
四川海思科制药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 四川海思科制药有限公司 filed Critical 四川海思科制药有限公司
Priority to CN201480003262.1A priority Critical patent/CN105026392B/en
Publication of WO2014169845A2 publication Critical patent/WO2014169845A2/en
Publication of WO2014169845A3 publication Critical patent/WO2014169845A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a 4,5-dihydro-pyrazolo[3,4-c]pyridin-2-one derivative of the formula (I), or a stereoisomer thereof, an oxynitride or a hydrate thereof , solvates, metabolites, pharmaceutically acceptable salts or prodrugs, processes for their preparation, and pharmaceutical compositions containing them and use as coagulation factor Xa inhibitors.
  • Background technique a 4,5-dihydro-pyrazolo[3,4-c]pyridin-2-one derivative of the formula (I), or a stereoisomer thereof, an oxynitride or a hydrate thereof , solvates, metabolites, pharmaceutically acceptable salts or prodrugs, processes for their preparation, and pharmaceutical compositions containing them and use as coagulation factor Xa inhibitors.
  • cardiovascular disease is one of the leading causes of death in humans.
  • thrombosis which is caused by a series of complex reactions.
  • Blood coagulation is a protective mechanism of the organism whereby the defect in the vessel wall can be "sealed” quickly and reliably, thus avoiding blood loss or minimizing it.
  • Maintaining a normal hemostasis, ie hemorrhage and clotting balance, is regulated by a complex mechanism.
  • Unregulated activation of the coagulation system or lack of inhibition of the activation process can lead to a variety of diseases and complications, such as venous thrombosis, deep vein thrombosis, pulmonary embolism, atherosclerosis, acute coronary syndrome, cerebrovascular disease and the like.
  • the endogenous coagulation pathway refers to the process of activating X factor from activation of XII factor to formation of IV a- PF3C a 2+ complex; exogenous The coagulation pathway refers to the process of activating factor X from the activation of a factor to the formation of a Vna-Ca 2+ -TF complex.
  • Activation from factor X to fibrin formation is a common coagulation pathway for endogenous and exogenous coagulation, where blood factor Xa formed by activation of factor X plays a key role.
  • Factor Xa is a member of the trypsin-like serine protease family, and the serine protease family activates prothrombin to be a thrombin.
  • Factor Xa plays an important role in the coagulation pathway and is located at the initial site of the amplification effect.
  • One molecule of coagulation factor X a catalyzes the formation of 1000 molecules of thrombin. Therefore, factor Xa as a target is more effective than anticoagulant in other coagulation factors or downstream thrombin.
  • heparin mainly injectable dosage forms, including unfractionated heparin, low molecular weight heparin (LMWH), Fonda parinux, etc., which are clinically prone to cause severe hemorrhage and heparin-induced thrombocytopenia side effects, requiring clinical testing.
  • LMWH low molecular weight heparin
  • Fonda parinux etc.
  • the new coagulation factor Xa inhibitor has the following advantages: oral, low bleeding risk, high efficiency, no need for individual adjustment and monitoring of patients.
  • Drugs currently on the market or under research include rivaroxaban, apixaban, edoxaban, betrixaban, omeproxaban, eribaxaban, LY517717, YM150, letaxaban, and the like.
  • new clotting factor Xa inhibitors currently on the market or under development also have some disadvantages, such as the poor solubility of rivaroxaban and apixaban.
  • WO00039131 describes nitrogen-containing heterobicyclic derivatives which can be used as trypsin-like serine protease inhibitors, in particular coagulation factor Xa inhibitors, wherein X, Y, ⁇ can be nitrogen and carbon, G selects aromatic or nitrogen-containing heteroaryl Ring, hydrazine is a cyclic group, and B is a basic group or a cyclic group.
  • coagulation factor Xa inhibitors wherein X, Y, ⁇ can be nitrogen and carbon
  • G selects aromatic or nitrogen-containing heteroaryl Ring
  • hydrazine is a cyclic group
  • B is a basic group or a cyclic group.
  • WO00200655 describes heteroaryl-phenylheterobicyclic compounds and derivatives thereof, and uses as coagulation factor Xa inhibitors, wherein A is a 5-6 membered aryl or heteroaryl group, G2 is a phenyl group, a naphthyl group or 5-10 Heteroaryl, Q is a heterobicyclic compound, and the structure of the compound of the present invention is greatly different,
  • WO03026652AK WO03047520, WO03048081, WO03048158, WO03099276, WO2006 047528 describe P4-PM-M4 lactam derivatives including apixaban, wherein ring P may be absent or a 5-7 membered nitrogen or heterocyclic ring, Ring M is a 3-10 membered carbocyclic or heterocyclic ring and is not considered to be a part of the invention as specifically described in this patent.
  • WO2004083174 describes P4-PM-M4 tetrahydropyrimidine and sulfonyl fluorenyl derivatives and their use as serine protease inhibitors, in particular coagulation factor Xa inhibitors, wherein ring P may be absent or is 5-7 members of nitrogen Ring or heterocycle, ring M is a 3-10 membered carbocyclic or heterocyclic ring and is not considered to be a part of the invention as specifically described in this patent.
  • WO2007137801 describes new blood coagulation factor Xa inhibitors of tetrahydropyrrole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine and tetrahydrotriazolopyridine derivatives, which have a large difference in structure from the compounds of the present invention, and the relevant structural formula is as follows :
  • WO2009007028 describes 1-(4-methoxyphenyl)-7-oxo-6[4-(oxoperpiperidin-1-yl)phenyl]-4,6,5,7-tetrahydro-( 1 H)-pyrazolo[3.4,c]pyridine-3-carboxamide derivative, and its use as a factor Xa inhibitor, wherein R1, R2 are a thiol group, L is a substituted amide group or an ester group, The structure is as follows:
  • the present invention is based on a tetrahydropyrazolopyridine compound, and has a compound represented by the general formula to provide a novel factor, a better drug, a higher bioavailability and a better solubility factor Xa.
  • Various diseases and complications caused by thrombosis such as membranous inflammation and cerebrovascular diseases. Summary of the invention
  • the present invention relates to a compound of the formula, or a stereoisomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
  • A is selected from C 6 -14 aryl or 5- to 14-membered heteroaryl, which is optionally further substituted with 0 to 5 R 7 ;
  • any two of RR 2 , R 3 , and R 4 may form a 3 to 6 membered ring together with the atoms to which they are attached, including a spiro ring or a ring, and the 3 to 6 member ring contains 0 to 3 a hetero atom selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ;
  • the rings are each independently optionally further substituted by 0 to 4 R 8 ;
  • R 7 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S,
  • R 8 , ! ⁇ and R 8b are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4 methoxy, C 3 _ 1Q carbon ring or 3 to 10 Metacyclic ring
  • R 8 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S,
  • the compound is not: 1-(2,3-dihydrobenzofuran-5-yl;)-7-oxo-6-[4-(2-oxopiperidin-1-yl;)benzene -4,5, 6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide or 1-(2,3-dihydrobenzofuran-5-yl) -7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c] Ethyl pyridine-3-carboxylate.
  • a in each case is selected from a C 6 - 1Q aryl group or a 5 to 10 membered heteroaryl group, which is optionally further substituted by 0 to 5 R 7 ; Preference is given to phenyl or 5 to 6 heteroaryl, which are optionally further substituted by 0 to 5 R 7 .
  • a in each case is selected from substituted or unsubstituted phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, N-fluorenylpyrrolyl, pyrimidinyl, pyridyl a pyridazinyl, pyridazinyl or imidazolyl group, when substituted, is selected to be substituted with from 1 to 5 R 7 ; preferably substituted or unsubstituted phenyl or pyridyl, when substituted, selected from 1 to 5 R 7 Substituted; Further preferred is a substituted or unsubstituted phenyl group which, when substituted, is optionally substituted with 1 to 5 R 7 ; more preferably a phenyl group or a 1 F substituted phenyl group.
  • any two of RR 2 , R 3 , and R 4 may form a 3 to 6 membered ring together with the atoms to which they are attached, including a spiro ring or a ring, and the 3 to 6 member ring contains 0 to 3 a hetero atom selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ;
  • the rings are each independently optionally further substituted by 0 to 4 R 8 ;
  • R 7 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S,
  • R 8 , ! ⁇ and R 8b are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 4 fluorenyl, d 4 methoxy, C 3 _ 1Q carbon ring or 3 to 10 Heterocycle
  • R 8 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S,
  • X is in each case selected from 0 or S, preferably X is 0.
  • R 5 is, in each case selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, hydroxy, decyl, cyano, amino, methyl, ethyl, propyl, iso Propyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, carbamoyl or aminomethylene, Preference is given to H, F, Cl, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, further preferably 11 or ? .
  • R 7 and 1 are each independently selected from H, d 4 fluorenyl, -(CH 2 ) n -C 3 _ 5 carbocyclic or -(CH 2 ) n -C 3 _ 5 heterocyclic ring, preferably H or embankment d- 4-yl; wherein said R 8 is selected from H, F, Cl, hydroxy, cyano, amino, d- 4 alkyl with or d- 4 embankment group.
  • R 6 is, in each case selected from the group consisting of carbamoyl, 2-isopropanol, 1-cyclopropanol, cyano, trifluoromethyl, 1-fluoroethyl, ethoxy Carbamoyl, 1-fluoromethyl, 1 ,1-difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl, preferably carbamoyl.
  • m is selected from 0 or 1 in each case.
  • a compound of the formula wherein the compound is selected from the group consisting of a compound of the formula (III), or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmacy Acceptable salts, eutectic or prodrugs, of which:
  • any two of the groups RR 2 , R 3 , and R 4 may form a 3 to 6 membered ring with the atoms to which they are attached, including a spiro ring or a ring, and the 3 to 6 member ring contains 0 to 3 a hetero atom selected from N, 0 or S, and the formed 3- to 6-membered ring may be optionally further substituted by 0 to 4 R 7a ;
  • R 7 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S,
  • R 8 , ! ⁇ and R 8b are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 4 fluorenyl, d 4 methoxy, C 3 _ 1Q carbon ring or 3 to 10 Heterocycle
  • R 8 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S,
  • n is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1 or 2.
  • B is preferably a 5- to 6-membered heterocyclic ring, and the heterocyclic ring contains 1 to 4 hetero atoms selected from N, 0 or S, and the heterocyclic ring is optionally further substituted with 0 to 3 substituents, the substitution
  • substituent R 7a is selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, trifluoromethyl, d- 4 fluorenyl, d- 4- decyloxy, -C ⁇ C- D- 5 fluorenyl or -(CH 2 ) n NR 8 R 8a ,
  • R 7a is preferably H, F, trifluoromethyl, d 4 alkyl or -(CH ni ⁇ CM ⁇ fluorenyl),
  • R 7a is more preferably H, F, trifluoromethyl, methyl, ethyl, propyl or isopropyl;
  • R 7a when two R 7a are bonded to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 decyloxy, hydroxy Substituted with a substituent of a thiol, cyano or amide group;
  • the atoms to which they are attached together preferably form a C 3 -5 carbocyclic ring or a 3 to 5 membered heterocyclic ring containing from 1 to 3 selected from N, a hetero atom of 0 or S, which is optionally further substituted with 0 to 4 substituents selected from H, F, d-4 fluorenyl, d-4-methoxy or cyano;
  • R 7a When two R 7a are attached to the same atom, it is more preferred to form a C 3 - 4 carbocyclic ring or 3 to the atoms to which they are attached.
  • B is selected in each case from ,
  • Ring Q is selected from the group consisting of 4 to 8 membered rings, and its composition includes, in addition to the N-E group shown, carbon atoms and 0 to 2
  • R 7a is selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, trifluoromethyl, d_ 4 fluorenyl, d 4 methoxy, -C ⁇ C -d- 5 fluorenyl Or -(CH 2 ) n NR 8 R 8a , preferably H, F, trifluoromethyl, d- 4 fluorenyl or -(CH ⁇ i ⁇ d- 4 yl); 4 fluorenyl), further preferably H, F, trifluoromethyl, methyl, ethylpropyl or isopropyl;
  • R 7a when two R 7a are bonded to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 decyloxy, hydroxy Substituted with a substituent of a thiol, cyano or amide group;
  • the atoms to which they are attached together preferably form a C 3 -5 carbocyclic ring or a 3 to 5 membered heterocyclic ring containing from 1 to 3 selected from N, a hetero atom of 0 or S, which is optionally further substituted with 0 to 4 substituents selected from H, F, d-4 fluorenyl, d-4-methoxy or cyano;
  • the atoms to which they are attached may further preferably form a C 3 - 4 carbocyclic ring or a 3 to 4 membered heterocyclic ring containing 1 to 2 selected from N a hetero atom of 0 or S, which is optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, d-2-indenyl, d-2-indolyl.
  • B is, in each case, selected from substituted or unsubstituted pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, hydrazine Mercapto, benzofuranyl, benzimidazolyl, pyridyl, 2H-pyranyl, 4H-pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiazole base, , N n 3 ⁇ 4 n 3 ⁇ 4
  • a compound of the formula wherein the compound is selected from the group consisting of a compound of the formula (IV), or a stereoisomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically Acceptable salts, eutectic or prodrugs, of which:
  • R 7a when two R 7a are attached to the same atom, they can form a C 3 — 1Q carbocycle together with the atoms to which they are attached.
  • any two of RR 2 , R 3 , and R 4 may form a 3- to 6-membered ring containing a spiro ring or a fused ring, and the 3 to 6 membered ring contains 0 to 3 selected from N, 0. Or a hetero atom of S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ;
  • the heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, the fluorenyl group, the decyloxy group, the carbocyclic ring or the heterocyclic ring
  • R 8 , ! ⁇ and R 8b are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4 methoxy, C 3 _ 1Q carbon ring or 3 to 10 Metacyclic ring
  • R 8 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S,
  • the heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, methyl alkynyl, amino,
  • n is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1 or 2.
  • R 7a is selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, trifluoromethyl, d- 4 fluorenyl, d- 4- decyloxy, -C ⁇ C-d- 5 Mercapto or -(CH 2 ) n NR 8 R 8a , preferably H, F, trifluoromethyl, d- 4 fluorenyl or -(CH ⁇ N ⁇ M fluorenyl XCM fluorenyl), further preferably H, F, Trifluoromethyl, d_ 4 fluorenyl or -CH N w fluorenyl XC ⁇ fluorenyl);
  • R 7a when two R 7a are bonded to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 decyloxy, hydroxy Substituted by a substituent of a mercapto group, a cyano group or an amide group;
  • the atoms to which they are attached together preferably form a C 3 -5 carbocyclic ring or a 3 to 5 membered heterocyclic ring containing from 1 to 3 selected from N, a hetero atom of 0 or S, which is optionally further substituted with 0 to 4 substituents selected from H, F, d-4 fluorenyl, d-4-methoxy or cyano;
  • the atoms to which they are attached may further preferably form a C 3 - 4 carbocyclic ring or
  • a 3- to 4-membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, 0 or S, optionally further 0 to 4 selected from H, F, d - Substituted by a 2 fluorenyl or d-2 oxiranyl substituent.
  • RR 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, in each case.
  • R 1 , R 2 , R 3 and R 4 are each independently preferably 11, F, Cl, Br, I, hydroxy, cyano, amino, d 4 fluorenyl, d 4 methoxy, C 3 _ 5 carbocyclic, a 3- to 5-membered heterocyclic ring, a -0-(CH 2 ) n -C 3 _ 5 carbocyclic ring or a-0-(CH 2 ) n - (3 to 5 membered heterocyclic ring);
  • RR 2 , R 3 and R 4 are each independently further preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 4 fluorenyl, d-4-decyloxy, C 3 - 4 carbocyclic ring. Or -0-C 3 - 4 carbon rings;
  • R 1 , R 2 , R 3 and R 4 are each independently more preferably H, F, Cl, d 2 fluorenyl or d 2 decyloxy;
  • fluorenyl, decyloxy, carbocyclic or heterocyclic ring is each independently optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 Substituted with a substituent of a fluorenyl or d- 4 methoxy group, preferably H, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, methoxy or ethoxy;
  • any two of I 1 , R 2 , R 3 , and R 4 may form a 3 to 6 membered ring together with the atoms to which they are attached, including a spiro ring or a ring, the 3 to 6 membered ring. Containing 0 to 3 heteroatoms selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ;
  • R 1 , R 2 , R 3 , and R 4 may preferably form a 3- to 4-membered ring together with the atoms to which they are attached, and the 3- to 4-membered ring contains 0 to 3 selected from N, 0. Or a hetero atom of S, and the formed 3 to 4 membered ring may be optionally further substituted with 0 to 4 R 7a ;
  • Any two of RR 2 , R 3 , and R 4 may further preferably form a 3-membered ring together with the atoms to which they are attached, the 3-membered ring containing 0 to 1 hetero atom selected from N, 0 or S, And the formed 3-membered ring may be optionally further substituted by 0 to 3 R 7a ;
  • group R 7a is selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, d 4 fluorenyl, d 4 methoxy, preferably H, F, hydroxy, cyano, methyl, Ethyl, methoxy or ethoxy.
  • RR 2 , R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, methyl, ethyl, propyl.
  • any two of RR 2 , R 3 , and R 4 may form a 3 to 6 membered ring together with the atoms to which they are attached, including a spiro ring or a ring, and the 3 to 6 member ring contains 0 to 3 a hetero atom selected from N, 0 or S, and formed
  • the 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ;
  • any two of RR 2 , R 3 , R 4 may form a substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, furyl group together with the atoms to which they are attached.
  • any two of I 1 , R 2 , R 3 , R 4 may further form a cyclopropyl group together with the atoms to which they are attached.
  • R 7 can together form 1 and the atoms to which they are attached form C 3 - 1Q carbocyclic ring or 3 to 10-membered heterocyclic ring, preferably C 3 - 8 carbon ring or 3 to 8-membered heterocyclic ring, more preferably a C a 3 to 5 carbocyclic ring or a 3 to 5 membered heterocyclic ring; wherein the heterocyclic ring contains 1 to 3 hetero atoms selected from N, 0 or S; wherein the heterocyclic ring or carbocyclic ring is optionally further further further from 0 to 4 Substituted from H, F, Cl, Br, I, d-4 fluorenyl, d-4 methoxy, hydroxy, decyl, cyano, amide, methyl alkynyl or amino substituents, preferably H, F, Cl, Br, I, hydroxy, methyl alkynyl, methyl, ethyl, methoxy or ethoxy;
  • R 7a when two R 7a are attached to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, preferably a C 3 - 8 carbocyclic ring or 3 to 8 a heterocyclic ring, further preferably a C 3 - 5 carbocyclic ring or a 3 to 5 -membered hetero a ring; wherein the heterocyclic ring contains 1 to 3 hetero atoms selected from N, 0 or S; wherein the heterocyclic ring or carbocyclic ring is optionally further further further selected from 0 to 4 selected from H, F, Cl, Br, I , d- 4 alkyl with, d- 4 embankment group, a hydroxyl group, a mercapto group, a cyano group, an amide group, an alkynyl group or an amino methyl substituents, preferably H, F, Cl, Br
  • R 7 and R 7a are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, hydroxymethyl, trifluoromethyl, Methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy , cyclopropyloxy, methoxycarbonyl, ethoxycarbonyl, acetyl, carbamoyl, N-ethylaminomethyl, allyl, methylalkynyl, cyclopropyl, cyclopropylmethylene , cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N-methylpyrrolyl, furyl, thienyl, pyrrolyl,
  • R 7 and R 7a are preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, hydroxymethyl, trifluoromethyl, methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, cyclopropoxy, methoxycarbonyl, ethoxycarbonyl, Acetyl, carbamoyl, N-ethylaminomethyl, allyl, methylalkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N - methylpyrrolyl, furyl, thienyl, pyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl
  • R 7 and R 7a are further preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, hydroxymethyl, trifluoromethyl, methyl, ethyl, propyl, isopropyl, isobutyl , methoxy, ethoxy, propoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, carbamoyl, allyl, methylalkynyl, cyclopropyl, cyclo Propylmethylene, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrrolyl, piperidinyl, tetrahydrofuranyl or tetrahydropyrrolyl;
  • R 7 and R 7a are further more preferably H, F, Cl, hydroxy, decyl, cyano, amino, hydroxymethyl, trifluoromethyl, methyl, ethyl, propyl, isopropyl, isobutyl, methyl Oxy, ethoxy, propoxy, isopropoxy, acetyl, carbamoyl, allyl, methylalkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl , cyclohexyl, pyridyl, pyrrolyl, piperidinyl, tetrahydrofuranyl or tetrahydropyrrolyl;
  • R 7 together form a C 3 and may be attached to the atoms to which they - 6 carbocyclic ring or 3 to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0, or S heteroatoms,
  • the heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, d-4 fluorenyl, d-4-decyloxy, hydroxy, amino, decyl, cyano, amide or methyl Alkynyl substituent Replace
  • R 7 and R 7a may form a substituted or unsubstituted cyclopropene, oxetan, cyclobutane, azetidinium, oxetane, cyclopentanthene together with the atoms to which they are attached.
  • pyrrole, piperidine, morpholine or imidazolyldione when substituted, optionally further substituted with 1 to 3 substituents selected from H, F, Cl, hydroxy, methyl, ethyl , methoxy, ethoxy, amino or methoxycarbonyl;
  • R 7 and R 7a may form a cyclopropene, azetidinium, oxetanium, tetrahydropyrrole, piperidine or morpholine together with the atoms to which they are attached;
  • R 7a when two R 7a are connected on the same atom, can atom to which they are attached form a C 3 - 6 carbocyclic ring or 3 to 6-membered heterocyclic ring containing 1 to 3 substituents selected from a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, d- 4 fluorenyl, d- 4- decyloxy, hydroxy, amino, fluorenyl Substituted by a substituent of a cyano group, an amide group or a methyl alkynyl group;
  • R 7a when two R 7a are bonded to the same atom, they may form a substituted or unsubstituted cyclopropene, oxetan, cyclobutane, azetidinium, oroxax together with the atoms to which they are attached.
  • Cyclobutanthene, imidazolyldione, tetrahydropyrrole, piperidine or morpholine when substituted, optionally further substituted with from 1 to 3 substituents selected from H, F, Cl, hydroxy, Methyl, ethyl, methoxy, ethoxy, amino or methoxycarbonyl;
  • R 7a when two R 7a are attached to the same atom, they may form a cyclopropene, azetidinium, oxetanium, tetrahydropyrrole, piperidine or morpholine together with the atoms to which they are attached.
  • R 8 , 1 and R 8b are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, d- 4 fluorenyl, d — 4 ⁇ oxy, C 3 — 1Q carbocyclic or 3 to 10 membered heterocyclic ring, preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d— 4 ⁇ Oxyl group, C 3 -5 carbocyclic ring or 3- to 5-membered heterocyclic ring, further preferably 11, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl or d- 4 fluorenyloxy More preferably H, ? or - 3 fluorenyl;
  • R 8 and the atoms to which they are attached may together form a C 3 - 1Q carbocyclic ring or 3 to 10-membered heterocyclic ring, preferably form C 3 - 8 carbon heterocyclic ring or 3 to 8-membered, more preferably form a C a 3 to 4 carbocyclic ring or a 3 to 4 membered heterocyclic ring; wherein the heterocyclic ring contains 1 to 3 hetero atoms selected from N, 0 or S; wherein the heterocyclic ring or carbocyclic ring is optionally further 0 to 4 Substituted from H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, methyl alkynyl or amino substituents, preferably H, F, Cl, Br, I, hydroxy, methylalkynyl, methyl, ethyl, methoxy or ethoxy; in a preferred
  • R 8 and R 8a may form, together with the atoms to which they are attached, cyclopropene, cyclobutane, oxetan, oxetanium, azetidinium, tetrahydropyrrole, piperidine or Porphyrin, the heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 From H, F, Cl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, hydroxy, decyl, cyano, amide, methyl alkynyl, amino, methoxy Substituted by a carbonyl, ethoxycarbonyl, hydroxymethyl, hydroxyethyl or acetyl substituent; R 8 and 1 together with the atom to which they are attached preferably form a cyclopropene, tetrahydropyrrole or piperidine.
  • a preferred embodiment of the invention a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
  • X is selected from 0 or S ;
  • A is selected from substituted or unsubstituted phenyl groups, and when substituted, is selected to be substituted with 1 to 5 R 7 ;
  • B is selected from one of the following structures substituted or unsubstituted:
  • any two of RR 2 , R 3 , and R 4 may form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyridyl group, a furyl group, a thienyl group, a pyrrolyl group, and an N-fluorene group.
  • R 5 is selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, hydroxy, decyl, cyano, amino, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert Butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, carbamoyl or aminomethylene;
  • R 7 and 1 may form a C 3 - 5 carbocyclic ring or a 3 to 5 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S;
  • R 7a when two R 7a are bonded to the same atom, they may form a C 3 - 5 carbocyclic ring or a 3 to 5 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S;
  • R 8 is selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, Cyclobutyl, oxetanyl, oxetanyl or azetidinyl;
  • a preferred embodiment of the invention a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
  • X is selected from 0;
  • A is selected from phenyl, wherein the phenyl group is optionally further substituted by 0 to 4 F, preferably phenyl or benzene substituted by 1 F
  • R 1 , R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, cyclopropyl, methoxy or ethoxy a group, preferably H , methyl, ethyl, methoxy or ethoxy;
  • any two of the groups RR 2 , R 3 , R 4 may form a cyclopropyl group
  • R 5 is selected from the group consisting of H, F, Cl, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, allyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy a group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group or a tert-butoxy group, preferably H or F;
  • R 6 is selected from the group consisting of carbamoyl, 2-isopropanol, 1-cyclopropanol, cyano, trifluoromethyl 1-fluoroethyl, ethoxycarbonyl
  • the group, 1-fluoromethyl, 1,1-difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl, preferably carbamoyl, cyano or trifluoromethyl is further preferably a carbamoyl group.
  • a preferred embodiment of the invention a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
  • X is 0;
  • A is phenyl, wherein the phenyl group is optionally further substituted by 0 to 4 F;
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from ⁇ F, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, cyclopropyl, methoxy or B.
  • any two of RR 2 , R 3 , and R 4 may form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyridyl group, a furyl group, a thienyl group, a pyrrolyl group, and an N-fluorene group.
  • R 5 is independently selected from H, F, Cl, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy base;
  • R 6 is selected from the group consisting of carbamoyl, 2-isopropanol, 1-cyclopropanol, cyano, trifluoromethyl, 1-fluoroethyl, ethoxycarbonyl, 1-fluoromethyl, 1, 1-difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl;
  • a preferred embodiment of the invention a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
  • X is 0;
  • A is phenyl, wherein the phenyl group is optionally further substituted by 0 to 4 F;
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from ⁇ ⁇ , methyl or ethyl;
  • any two of RR 2 , R 3 , and R 4 may form a cyclopropyl group
  • R 5 is independently selected from the group consisting of g H, F, Cl, trifluoromethyl, hydroxy, methyl or ethyl;
  • R 6 is selected from the group consisting of carbamoyl, 2-isopropanol, 1-cyclopropanol, cyano, trifluoromethyl, 1-fluoroethyl, ethoxycarbonyl, 1-fluoromethyl, 1 . 1-Difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl.
  • a preferred embodiment of the invention a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
  • X is 0;
  • A is phenyl, wherein the phenyl group is optionally further substituted by 0 to 4 F;
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H or methyl;
  • R 5 is independently selected from g H, F, CI or methyl;
  • R 6 is selected from the group consisting of carbamoyl, 2-isopropanol, 1-cyclopropanol, cyano, trifluoromethyl, 1-fluoroethyl, ethoxycarbonyl, 1-fluoromethyl, 1 . 1-Difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl.
  • a preferred embodiment of the invention a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
  • R 5 is selected from H or F ; and R 6 is a carbamoyl group.
  • a preferred embodiment of the invention a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
  • X is 0;
  • A is a phenyl group, wherein the phenyl group may be further substituted by 1 F;
  • B is selected from one of the following structures: ?
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H ;
  • R 5 is independently selected from H or F;
  • R 6 is selected from carbamoyl;
  • m is 1.
  • a preferred embodiment of the invention a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
  • X is 0;
  • A is a phenyl group, wherein the phenyl group may be further substituted by 1 F;
  • R 6 is selected from carbamoyl or trifluoromethyl; m is 1.
  • a preferred embodiment of the invention a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
  • X is 0;
  • A is a phenyl group, wherein the phenyl group may be further substituted by 1 F;
  • R 1 and R 2 are each independently selected from H or methyl; R 3 and R 4 are each independently. ",” is selected from H; R 5 is independently selected from H or F;
  • R 6 is selected from carbamoyl or trifluoromethyl; m is 1.
  • a preferred embodiment of the invention a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
  • X is 0;
  • A is a phenyl group, wherein the phenyl group may be further substituted by 1 F;
  • R 1 , R 2 , R 3 , R 4 are each independently selected from H; R 5 is independently selected from H or F ; R 6 is carbamoyl; m is 1
  • the invention relates to a compound selected from, but not limited to:
  • Suitable pharmaceutically acceptable salts of the compounds of the formula of the invention include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, amber Acid salt, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronide, galactose Acid salt, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, besylate, methanesulfonate, ethanesulfonic acid Salt, triflate or a combination thereof.
  • Preferred pharmaceutically acceptable salts of a compound of the formula include hydrochlorides, sulfates, phosphates, acetates, maleates, succinates, fumarates, Malate, oxalate, tartrate, benzoate, cinnamate, p-toluenesulfonate, besylate, methanesulfonate, triflate or combinations thereof.
  • the present invention relates to a compound of the formula or a pharmaceutically acceptable cocrystal thereof, wherein the eutectic formation comprises valine, phenylalanine, pyroglutamic acid.
  • the present invention relates to a compound represented by the formula (Ib), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is an intermediate for synthesizing a compound of the formula ⁇ , wherein:
  • Z is selected from F, Cl, Br or I;
  • Any two of ⁇ 1 ', R 2 ', R 3 ', R 4 ' may form a 3- to 6-membered ring containing a spiro ring or a ring, and the 3 to 6-membered ring contains 0 to 3 rings. a hetero atom from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ;
  • Carbocycle -C( 0)-(3 to 10 membered heterocyclic), -(CH 2 ) n -(3 to 10 membered heterocyclic), -0-(CH 2 ) n -C 3 _ 1Q carbocyclic or 0-(CH 2 ) n -(3 to 10 membered heterocyclic ring), the heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, the fluorenyl group, the decyloxy group, the carbocyclic ring or the hetero
  • R 7 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S,
  • R 8 , ! ⁇ and R 8b are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 4 fluorenyl, d 4 methoxy, C 3 _ 1Q carbon ring or 3 to 10 Heterocycle
  • R 8 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S,
  • R 9 is selected from d- 12 fluorenyl, which is optionally further substituted with 0 to 4 R 8 .
  • Z is selected from C1;
  • R 9 is, in each case selected from the group consisting of methyl, ethyl, isopropyl, n-butyl or isobutyl.
  • R, R 2 ', R 3 ' and R 4 ' are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, carbamoyl, N-ethylaminomethyl, allyl, Methyl alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N-methylpyrrolyl, furyl, thienyl, pyrrolyl, piperidiny
  • Any two of ⁇ 1 ', R 2 ', R 3 ', R 4 ' may form a 3- to 6-membered ring containing a spiro ring or a ring, and the 3 to 6-membered ring contains 0 to 3 rings.
  • a hetero atom from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a .
  • R 1 ⁇ R 2 ', R 3 ', R 4 ' are independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, methyl, ethyl, cyclopropane a methoxy group, an ethoxy group or a cyclopropoxy group, preferably H or a methyl group;
  • any two of R, R 2 ', R' 3 and R 4 ' may form substituted and unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, pyridyl And a furyl group, a thienyl group, a pyrrolyl group, a N-fluorenylpyrrolyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a tetrahydrofuranyl group or a tetrahydropyrrole group, preferably forms a cyclopropyl group.
  • R 2 ', R 3 ' and R 4 ' are independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, methyl, ethyl, cyclopropyl. , methoxy or ethoxy, preferably H or methyl, further preferably H;
  • any two of R, R 2 ', R 3 ' and R 4 ' may form a cyclopropyl group.
  • R 5 ' is selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, hydroxy, decyl, cyano, amino, methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, carbamoyl or aminomethylene, preferably H or F.
  • R 5 ' is selected from the group consisting of H, F, Cl, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy Or isopropoxy, preferably H or F.
  • Z is selected from the group consisting of Cl ; and R 9 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.
  • the present invention relates to a compound represented by the formula (I-a), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is an intermediate for synthesizing a compound of the formula (I), wherein:
  • Any two of ⁇ 1 ', R 2 ', R 3 ', R 4 ' may form a 3- to 6-membered ring containing a spiro ring or a ring, and the 3 to 6-membered ring contains 0 to 3 rings. a hetero atom from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ; any two of ', R 2 ', R 3 ', R 4 ' Preferably forming a cyclopropyl group;
  • R 7 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S,
  • R 8 , ! ⁇ and R 8b are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 4 fluorenyl, d 4 methoxy, C 3 _ 1Q carbon ring or 3 to 10 Heterocycle
  • R 8 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S,
  • m' is in each case selected from 0 or 1.
  • R, R 2 ', R 3 ' and R 4 ' are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, d --4 alkyl with, d- 4 embankment group, d- 4 alkyl with embankment group, C 3 - 8 carbon ring of 3 to 8-membered heterocyclic, -0- (CH 2) n -C 3 - 8 carbon ring Or -0-(CH 2 ) n -(3 to 8 membered heterocyclic ring), wherein the heterocyclic ring contains 1 to 4 hetero atoms selected from N, 0 or S, wherein the fluorenyl group and the oxime group
  • the radical, carbocyclic or heterocyclic ring are each independently optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4- indolyl
  • R ! ⁇ R 2 ', R 3 ' and R 4 ' are each independently preferably H, F, Cl, Br, I, hydroxy, cyano, amino, d- 4 fluorenyl, CM methoxy, C 3 - 5 Carbocyclic ring, 3 to 5 membered heterocyclic ring, -0-(CH 2 ) n -C 3 - 5 carbocyclic ring or -0-(CH 2 ) n - (3 to 5 membered heterocyclic ring), wherein said heterocyclic ring Containing 1 to 4 hetero atoms selected from N, 0 or S, wherein the fluorenyl, decyloxy, carbocyclic or heterocyclic ring is each independently optionally further selected from 0 to 4 selected from H, F, Cl, Substituted by a substituent of Br, I, hydroxy, decyl, cyano, amino, d- 4 yl or d- 4 methoxy, preferably H,
  • R ! ⁇ R 2 ', R 3 ' and R 4 ' are each independently further preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4 fluorenyloxy a C 3 - 4 carbocyclic ring or an -0-C 3 - 4 carbocyclic ring, wherein the fluorenyl group, the decyloxy group or the carbocyclic ring are each independently optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br Substituted by a substituent of I, hydroxy, decyl, cyano, amino, d- 4 yl or CM methoxy, preferably H, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, methoxy Or an ethoxy group, further preferably H or a methyl group, more preferably H;
  • R 2 ', R 3 ' and R 4 ' are each independently more preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 2 fluorenyl, d- 2- decyloxy, c 3 — a 4 carbocyclic ring or a -oc 3 - 4 carbocyclic ring, wherein said fluorenyl group, decyloxy group or carbocyclic ring are each independently optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, hydroxy, fluorenyl Substituted by a substituent of a cyano group, an amino group, a d- 4 fluorenyl group or a d- 4 methoxy group, preferably H, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, methoxy or B Oxy group, further preferably H or methyl group, more preferably H;
  • any two of R, R 2 ', R 3 ', R 4 ' may form a 3 to 6 membered ring together with the atoms to which they are attached, including a spiro ring or a cis ring, said 3 to 6
  • the ring contains 0 to 3 heteroatoms selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ; 1 , R 2 ', R 3 ⁇ R 4
  • Any two of the 'groups together with the atoms to which they are attached preferably form a 3 to 4 membered ring, and the 3 to 4 membered ring contains 0 to 3 selected from 0 to 3 a hetero atom of N, O or S, and the formed 3- to 4-membered ring may be optionally further substituted by 0 to 4 R 7a ; R h , R 2 ',
  • R 3 ', R 4 ' may further preferably form a 3-membered ring together with the atoms to which they are attached, preferably forming a cyclopropyl group, the 3-membered ring having 0 to 1 selected from N, 0 or a hetero atom of S, and the formed 3-membered ring may be optionally further substituted with 0 to 3 R 7a ; wherein said R 7a is selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, d- 4 -mercapto, d- 4 methoxy, preferably H, F, hydroxy, cyano, methyl, ethyl, methoxy or ethoxy.
  • R 2 ', R 3 ' and R 4 ' are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, methyl , ethyl, propyl, 2-propyl, n-butyl, isobutyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, carbamoyl, N-ethylamino Methyl, allyl, methylalkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N-methylpyrrolyl, furyl, thienyl, pyrrolyl, piperidinyl, Morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyrrolyl, cyclobutoxy, cyclopent
  • Any two of ⁇ 1 ', R 2 ', R 3 ', R 4 ' may form a 3 to 6 membered ring together with the atoms to which they are attached, including a spiro ring or a ring, the 3 to 6 membered ring Containing 0 to 3 heteroatoms selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted by 0 to 4 R 7a , 1 , R 2 ', R 3 ', R 4 ' Any two of the groups may together with the atoms to which they are attached may preferably form substituted and unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, pyridyl, furyl, thienyl, Pyrrolyl, N-fluorenylpyrrolyl, piperidinyl, morpholinyl
  • R 5 ' is, in each case, independently selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, hydroxy, decyl, cyano, amino, methyl, ethyl, Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, carbamoyl or amino Methylene group, preferably H, F, Cl, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy Or isopropoxy group, further preferably H or F ;
  • the present invention relates to a process for the preparation of a compound of the formula of the invention, which process comprises:
  • the compound of the formula (Ia) is reacted with a haloacetoacetate in the presence of an oxidizing agent to give a compound of the formula (Ib), wherein: the haloacetoacetate includes, but is not limited to, methyl 2-chloroacetoacetate or 2-chloroacetyl Ethyl acetate;
  • the compound of the formula (I-b) and the formula (I-f) are ring-closed under basic conditions, and the compound of the formula (I-d) is obtained by demorpholating under acidic conditions;
  • the compound of the formula (Id) is subjected to a coupling reaction under basic conditions to obtain a compound of the formula (Ic);
  • the compound of the formula (I-c) is optionally subjected to aminolysis, hydrolysis, transesterification, substitution, oxidation or reduction to give a compound of the formula 1 wherein:
  • Z is selected from F, Cl, Br or I
  • R 2 ', R 3 ', R 4 ', R 5 ', R 9 , X, and m' are consistent with the definitions of the compounds of the formula (Ib).
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the formula of the present invention, or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite A pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier or excipient.
  • the present invention relates to a compound of the formula: or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug, which is useful in the preparation of a therapeutic serine protease. Use in medicines in disease.
  • the disease associated with the serine protease is selected from the group consisting of a thromboembolic disorder.
  • the thromboembolic disease is selected from the group consisting of an arterial cardiovascular thromboembolic disease, a venous cardiovascular thromboembolic disease, and a cardiac related thromboembolic disease.
  • the thromboembolic disease is selected from the group consisting of venous thrombosis, deep vein thrombosis, deep venous thrombosis of the lower extremity, thrombophlebitis, cerebral arterial thrombosis, arterial embolism, coronary thrombosis, pulmonary embolism, cerebral embolism , renal embolism, hepatic vein thrombosis, portal vein embolization, chronic diffuse intravascular coagulation, extremities and central microvascular arterial embolization, atherosclerosis, acute coronary syndrome, unstable angina, acute coronary syndrome, myocardial infarction, arteries Sclerosis, sudden onset of ischemia, transient ischemia, topical obstructive arterial disease, stroke, aseptic thrombotic endocarditis with arterial embolism, cerebrovascular disease.
  • the invention also relates to a method of treating a thromboembolic disorder.
  • the method comprises administering to the patient a therapeutically effective amount of a pharmaceutical agent comprising a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention may be administered in combination with other therapeutic agents.
  • the present invention relates to a pharmaceutical agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, which may be a combination product, for example comprising administering a therapeutically effective amount of a first and a third to a host in need of such treatment.
  • Two therapeutic agents are a compound of the invention or a stereoisomer thereof, an oxynitride, a hydrate, a solution a drug, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, and a second therapeutic agent selected from the group consisting of a second coagulation factor
  • a factor Xa inhibitor an anticoagulant, an antiplatelet agent, a thrombin inhibitor, a thrombolytic agent, and at least one agent of a fibrin solvate.
  • the second therapeutic agent is selected from the group consisting of warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, water frog, Agaban, acopiline, cloth Lofen, methoxypropionate, sulindac, indomethacin, mefenamic acid, dexamethasone, diclofenac, benzoxazolone, piroxicam, ticlopidine, clopidogrel, tirofiban , eptifibatide, abciximab mecarragine, hirudin disulfate (aka: disulfatohirudin ⁇ tissue plasminogen activator, modified tissue plasminogen activator, complex plasmin streptokinase At least one agent of urokinase and streptokinase.
  • the second therapeutic agent is at least one antiplatelet agent.
  • the antiplatelet agent is aspirin and clopidogrel.
  • the antiplatelet agent is clopidogrel.
  • the pharmaceutical agent of the present invention is a pharmaceutical agent for preparing a thromboembolic disease.
  • the invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a thromboembolic disorder in combination with said second therapeutic agent.
  • the elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the elements and carbons, hydrogen and oxygen involved in the groups and compounds of the present invention.
  • Sulfur or nitrogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 c, 13 c and 14 c, and the hydrogen isotopes include ruthenium (H), ⁇ (D, also known as heavy hydrogen ), ⁇ ( ⁇ , also called super heavy hydrogen), oxygen isotopes include 16 0, 17 0 and 18 0, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N , fluorine isotope 19 F, chlorine isotope includes 35 C1 and 37 C1, and bromine isotopes include 79 Br and 81 Br.
  • mercapto refers to a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms.
  • fluorenyl groups having 1 to 10 carbon atoms and non-limiting examples include, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, and Sulfhydryl, its various branched isomers, etc.; more preferred are lower fluorenyl groups containing from 1 to 4 carbon atoms, non-limiting examples including methyl, ethyl, propyl, isopropyl, positive Butyl, isobutyl or tert-butyl.
  • Alkoxy means a-0-fluorenyl group, wherein the fluorenyl group is as defined herein above.
  • the methoxy group may be substituted or unsubstituted, and non-limiting examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy Or a hexyloxy group, preferably having a 1 to 12 membered decyloxy group.
  • the substituent is preferably from 1 to 5, independently selected from
  • Alkyloxy refers to a fluorenyl group attached to a decyloxy group.
  • Alkenyl is a fluorenyl group as defined in the invention and comprises at least one carbon-carbon double bond, said alkenyl group having 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, further preferably 2 to 8 carbon atoms .
  • alkenyl groups include substituted or unsubstituted vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl , 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-decenyl or 4-nonenyl, etc., when substituted, substituted
  • Alkynyl is a fluorenyl group as defined in the invention and comprises at least one carbon-carbon triple bond, said alkynyl group having 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, further preferably 2 to 8 carbon atoms .
  • Carbocycle means a saturated or unsaturated aromatic ring or a non-aromatic ring.
  • the aromatic ring or non-aromatic may be a single ring of 3 to 8 members, a 4 to 12 membered double ring or a 10 to 15 membered three ring system.
  • Attached to the bridged or spiro ring non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentene, cyclohexadiene, cycloheptane Alkene, phenyl, naphthyl, benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]decyl, tricyclo[5.3.1.1]dodedecyl, adamantyl or Snail [3.3] Geng base and so on.
  • Heterocyclic means a substituted or unsubstituted saturated or unsaturated aromatic ring, a non-aromatic ring, an aromatic ring, a non-aromatic ring which may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered member.
  • a tricyclic system and consists of at least one hetero atom selected from N, 0 or S, preferably a 3 to 10 membered heterocyclic ring, and the optionally substituted N, S in the heterocyclic ring can be oxidized to various oxidation states.
  • the heterocyclic ring can be attached to a hetero atom or a carbon atom.
  • the heterocyclic ring may be attached to a bridged ring or a spiro ring, and non-limiting examples include, ethenyl oxime, azacyclopropyl, oxetanyl, azetidinyl, 1, 3-dioxolane, 1 , 4-dioxolan, 1 ,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, anthracene Azinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazide, dihydrofuran, dihydropyran, dithiapentane, tetrahydrofuran, tetrahydrogen Pyrrole, tetrahydroimid
  • Amino means -NH 2 and may be substituted or unsubstituted. When substituted, the substituent is preferably from 1 to 3, independently selected from decyl, alkenyl, alkynyl, decyloxy, hydrazine.
  • Aryl means a substituted or unsubstituted 6 to 14 membered all-carbon monocyclic or fused polycyclic group having a polycyclic group having a conjugated ⁇ -electron system, preferably a 6 to 10 membered aromatic ring, Non-limiting examples include phenyl or naphthyl; the aryl group may be fused to a heteroaryl, heterocyclyl or cyclodecyl group, and the moiety attached to the parent structure is an aryl group, non-limiting examples of which include benzo Fur Or benzocyclopentenyl or benzothiazole. When substituted, the substituent is preferably from 1 to 5, and the substituents are independently selected from
  • Heteroaryl means a substituted or unsubstituted 5 to 15 membered aromatic ring and contains 1 to 3 heteroatoms selected from N, 0 or S heteroatoms, preferably 5 to 10 membered aromatic rings, non-limiting Examples include pyridyl, furyl, thienyl, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzofuran, benzimidazole, benzopyridine or pyrrolopyridine .
  • “Pharmaceutically acceptable salt” means a pharmaceutically acceptable salt of a non-toxic acid or base, including salts of inorganic acids and bases, organic acids and bases.
  • Salts derived from inorganic bases include, but are not limited to, metal salts formed from Al, Ca, Li, My, K, Na, and Zn;
  • salts derived from organic bases include, but are not limited to, salts of primary, secondary, or tertiary amines, including Naturally occurring substituted or unsubstituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, Dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, phentermine, ethylenediamine, glucosamine, An organic
  • Eutectic refers to a combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, of which API and CCF The pure state is solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-eutectoid formed from a neutral solid with a salt or solvate.
  • the "eutectic former” includes, but is not limited to, various pharmaceutically acceptable acid, base, nonionic compounds, non-limiting examples of which include (Ala), valine (Val), leucine (Leu), isoleucine (lie), proline (Pro), phenylalanine (Phe), tryptophan (Trp), Methionine (Met), glycine (Gly), serine (Ser), threonine (Th), cysteine (Cys), tyrosine (Tyr), asparagine (Asn), glutamine (Gin) Lysine, Lys, Arginine (Arg), Histidine (His), Aspartic Acid (Asp), Glutamate (Glu), Pyroglutamic Acid, Sulfuric Acid, Phosphoric Acid, Nitric Acid, Hydrobromine Acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic
  • Stepoisomer refers to isomers resulting from the arrangement of atoms in a molecule in a spatial arrangement, including cis-trans isomers, enantiomers, and conformational isomers.
  • “Pharmaceutical composition” means one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or mixture of prodrugs thereof with other chemical components, other components such as physiological/pharmaceutically acceptable carriers and excipient.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • Prodrug means a compound of the invention which can be converted to biological activity under physiological conditions or by solvolysis.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compound which can be removed by conventional procedures or in vivo to provide the parent compound.
  • a prodrug includes a compound formed by attaching a hydroxyl group, an amino group or a thiol group to any group in the compound of the present invention.
  • prodrug When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group, respectively. , free amino or free sulfhydryl.
  • Examples of prodrugs include, but are not limited to, compounds formed by the hydroxyl or amino functional groups of the compounds of the invention with formic acid, acetic acid or benzoic acid.
  • aryl group is optionally substituted with a thiol group
  • the thiol group may, but need not, be present, and the description includes the case where the aryl group is substituted by a thiol group and the case where the aryl group is not substituted by a thiol group.
  • the present invention relates to a process for the preparation of a compound of the formula of the invention, the process comprising:
  • the compound of the formula (Ia) is reacted with a haloacetoacetate in the presence of an oxidizing agent to give a compound of the formula (Ib), wherein: the haloacetoacetate includes, but is not limited to, methyl 2-chloroacetoacetate or 2-chloroacetyl Ethyl acetate;
  • the compound of the formula (I-b) (I-e) is ring-closed under basic conditions, and the morpholine is obtained under acidic conditions.
  • the compound of the formula (I-b) and the formula (I-f) are ring-closed under basic conditions, and the compound of the formula (I-d) is obtained by demorpholating under acidic conditions;
  • the compound of the formula (Id) is subjected to a coupling reaction under basic conditions to obtain a compound of the formula (Ic);
  • the compound of the formula (I-c) is optionally subjected to aminolysis, hydrolysis, transesterification, substitution, oxidation or reduction to give a compound of the formula 1 wherein:
  • Z is selected from F, Cl, Br or I
  • R 2 , R 3 , R 4 , R 5 , R 9 , X, and m' are consistent with the definitions of the compounds of the formula (Ib). Detailed ways
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (; and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 - 6 (ppm).
  • NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 X 4.6 mm) » Thin layer chromatography silica gel plate using Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, thin layer chromatography (TLC) using silica gel plate
  • the specification is 0.15 mm ⁇ 0.20 mm, and the specification for thin layer chromatography separation and purification is 0.4 mm ⁇ 0.5 mm.
  • 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 Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume.
  • 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.
  • reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • the reaction temperature is room temperature.
  • the optimum reaction temperature at room temperature is 20 ° C ⁇ 30 ° C.
  • Step 5 ⁇ - ⁇ -Oxopiperidin-1-yl)phenyl 3-morpholine -5,6-dihydropyridine -2 (1H ketone If
  • Triethylamine (10.1 g, 0.10 mol) was dissolved in tetrahydrofuran (200 mL), and 4-iodoaniline 2a (11.00 g, 0.05 mol) was added.
  • the reaction liquid was cooled to 0 ° C, and a solution of 5-chloro-pentanoyl chloride (11.6 g, 0.10 mol) in tetrahydrofuran (50 mL) was added dropwise, and the mixture was allowed to react at room temperature for 3 hours.
  • 2-Methyl-2.3-dihydrobenzofuran 1A (1.0 g, 7.50 mmol) was dissolved in acetic acid (10 mL). Concentrated nitric acid (125 mg, 2.0 mmol) was added at room temperature and then warmed to 70 ° C. Concentrated nitric acid (375 mg, 6.00 mmol) was stirred at 70 ° C for 1 hour. Water (50 mL) and ethyl acetate (50 mL) were added to the mixture and the mixture was evaporated.
  • Step 5 l-(2-Methyl-2,3-dihydropyridylfuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxygen Generation-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide Compound 1
  • Second step l-(2,3-dihydrobenzofuran-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-IH- Pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 2C
  • Second step l-(2,3-dihydrobenzofuran-5-yl)-6-(4-(3-oxothiomorpholine)phenyl)-7-oxo-4,5, 6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide compound 3
  • Ethyl [3,4-c]pyridine-3-carboxylate 3B (130 mg, 0.25 mmol) was dissolved in EtOAc EtOAc (EtOAc) Sodium methoxide (27 mg, 0.50 mmo) was allowed to react to 80 ° C overnight. The reaction mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc.
  • Second step l-(2,3-dihydrobenzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4 ,5,6,7-tetrahydro-1H-pyrazole[3,4-c]pyridine-3-carbonitrile compound 7
  • reaction solution was cooled to 0 ° C, 4N hydrochloric acid (2.5 mL, 10.00 mmol) was added, and the mixture was stirred at room temperature for 1 hour, water (25 mL) was added, and the mixture was extracted with ethyl acetate (25 mL X 2 ) The mixture was washed with brine (30 mL EtOAc).
  • Step 7 l-(7-Fluoro-2,3-dihydrobenzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7 -oxo-4,5,6,7-tetrahydro-1H-pyrazole[3,4-c]pyridine-3-carboxamide compound 8
  • 2-(2-Bromo-5-fluoro-phenoxy)ethanol 9B (8 g, 34 mmol) was dissolved in dichloromethane (100 mL) with stirring under ice-cooling, followed by the addition of carbon tetrabromide (14.1 g, 42.5 mmol) and triphenylphosphine (11.1 g, 42.5 mmol) were reacted for 2 h at room temperature.
  • 6-Fluoro-2,3-dihydrobenzofuran 9D (1.2 g, 8.69 mmol) was dissolved in acetic acid (5 mL), concentrated nitric acid (150 mg, 2.4 mmol) was added at room temperature, and then warmed to 70 ° C, Concentrated nitric acid (450 mg, 7.2 mmol) was added, and the reaction was stirred at 70 ° C for 1 hour. Water (20 mL) and ethyl acetate (50 mL) were added to the mixture and the mixture was evaporated.
  • Step 7 l-(6-Fluoro-dihydrobenzofuran-5-yl;)-6-(4-(2-oxopiperidin-1-yl)phenyl);-7-oxo -4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 9H
  • 3-Methyl-2,3-dihydrobenzofuran 11B (450 mg, 3.35 mmol) was dissolved in acetic acid (5 mL), concentrated nitric acid (56.5 mg, 0.9 mmol) was added at room temperature and warmed to 70 ° C Concentrated nitric acid (169.5 mg, 2.69 mmol) was added, and the reaction was stirred at 70 ° C for 1 h. Water (100 mL) and ethyl acetate (50 mL) were added to the mixture, and the organic layer was washed with saturated brine (50 mL EtOAc).
  • Step 5 l-(3-Methyl-2,3-dihydropyridylfuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxygen Generation-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 11F
  • reaction solution is cooled to 0 ° C, and hydrochloric acid (4N, 2.1 mL, 8.45 mmol), stirred at room temperature for 1 h.
  • hydrochloric acid (4N, 2.1 mL, 8.45 mmol)
  • reaction solution was cooled to room temperature, suction filtered with Celite, and dichloromethane (100 mL) and water (100 mL) were added to the filtrate, and the aqueous phase was extracted with dichloromethane (50 mL X 2 ) The organic phase was combined, and the organic layer was evaporated, evaporated,jjjjjjjjjj Hydroxyphenyl) Ethyl ketone (1B), brown solid, mp.
  • the benzofuran-3 ketone (13C) (134 mg, 1.0 mmol) was dissolved in tetrahydrofuran (15 mL), anhydrous and anaerobic, cooled to -30 ° C, sodium hydride (100 mg, 60%, 2.5 mmol), the reaction was stirred for 20 minutes, potassium iodide (710 mg, 5.0 mmol) was added dropwise, and the reaction was maintained at 0 ° C for 1 hour and at room temperature for 2 hours. A solution of saturated sodium bicarbonate (20 mL) was added, and water (10 mL) and ethyl acetate (50 mL) was evaporated. The organic phase was washed with brine (30 mL EtOAc) 2) The title compound 2,2-dimethylbenzofuran-3-one (13D) was obtained as a yellow oil (70 mg, yield 43%).
  • 2,2-Dimethyl-3H-benzofuran (IF) (2.0 g, 13.4 mmol) was dissolved in acetic acid (40 mL). Concentrated nitric acid (0.4 mL, 4 mmol) was added at room temperature and warmed to 70° C, concentrated nitric acid (1.4 mL, 12 mmol) was added, and the mixture was heated to 70 ° C for 1 hour. The reaction solution was cooled to room temperature, and brine (50 mL) and ethyl acetate (50 mL) was evaporated and evaporated.
  • Step 10 l-(2,2-Dimethyl-3H-benzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7 -oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (compound 13)
  • Step 7 1-(3,3-Dimethyl-3H-benzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7 -oxo-4,5-dihydro-
  • Ethyl [3,4-c]pyridine-3-carboxylate (16G) (210 mg, 0.4 mmol) was dissolved in EtOAc EtOAc (EtOAc) Sodium methoxide (43.2 mg, 0.8 mmol) was heated to 80 ° C overnight. The reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL X 2). The organic phase was combined and the organic phase was washed with saturated brine (50 mL) The title compound 1-(3,3-dimethyl-3H) was obtained.
  • Step 6 -(4-Fluoro-benzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7-oxo-4,5 -Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (18G)
  • Step 7 -(4-Fluoro-benzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7-oxo-4,5 -Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 18)
  • Step 3 1 -(2-Fluoro-4-iodophenyl)piperidin-2-one (21D)
  • N-(2S-2-hydroxypropyl)-2-bromoacetamide (22B) (5.2 g, 26.53 mmol) was dissolved in tert-butanol (200 mL) and potassium tert-butoxide (7.4 g, 66.31 mmol ), react at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture. EtOAc was evaporated, evaporated, evaporated. The residue was purified by silica gel column chromatography (EtOAc:EtOAc: , yield 23%).

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to 4,5-dihydro-pyrazolo [3, 4-c] pyrid-2-ones, as shown in Formula (I), and to a preparation method and an application thereof; the definition of each substituent in the Formula (I) compound is the same as the definition found in the description.

Description

4，5-二氢-吡唑并 [3，4-c】吡啶 -2-酮衍生物、 其制备方法以及应用 技术领域  4,5-dihydro-pyrazolo[3,4-c]pyridine-2-one derivative, preparation method thereof and application thereof
本发明涉及一种通式 （I) 所示 4,5-二氢-吡唑并 [3 ,4-c]吡啶 -2-酮衍生物， 或其立体异构 体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的盐或前药、 其制备方法 以及含有它们的药物组合物以及作为凝血因子 Xa抑制剂的用途。 背景技术  The present invention relates to a 4,5-dihydro-pyrazolo[3,4-c]pyridin-2-one derivative of the formula (I), or a stereoisomer thereof, an oxynitride or a hydrate thereof , solvates, metabolites, pharmaceutically acceptable salts or prodrugs, processes for their preparation, and pharmaceutical compositions containing them and use as coagulation factor Xa inhibitors. Background technique
目前， 心血管疾病是导致人类死亡的主要原因之一， 它的一个主要方面是血栓形成， 血 栓形成是由一系列复杂反应引起凝血而致。 血液凝固是生物体的一种保护机制， 借此可很快 并且可靠地"密封"血管壁的缺损， 因此可以避免失血或将其降到最低限度。 维持正常止血作 用， 即出血和凝血平衡， 受一个复杂机制的调控。 不受调控的活化凝血系统或缺乏活化过程 的抑制作用都可能导致多种疾病和并发症， 例如静脉血栓、 深静脉血栓、 肺栓塞、 动脉粥样 硬化、 急性冠状综合征、 脑血管疾病等。  At present, cardiovascular disease is one of the leading causes of death in humans. One of its main aspects is thrombosis, which is caused by a series of complex reactions. Blood coagulation is a protective mechanism of the organism whereby the defect in the vessel wall can be "sealed" quickly and reliably, thus avoiding blood loss or minimizing it. Maintaining a normal hemostasis, ie hemorrhage and clotting balance, is regulated by a complex mechanism. Unregulated activation of the coagulation system or lack of inhibition of the activation process can lead to a variety of diseases and complications, such as venous thrombosis, deep vein thrombosis, pulmonary embolism, atherosclerosis, acute coronary syndrome, cerebrovascular disease and the like.
在血液凝固中， 传统上分为内源性和外源性系统， 内源性凝血途径是指从 XII 因子激活 到形成 IVa-PF3Ca 2+复合物后激活 X因子的过程； 外源性凝血途径是指从 因子被激活到形成 Vna-Ca2+-TF复合后激活 X因子的过程。 从 X因子被激活至纤维蛋白形成， 是内源、 外源凝血 的共同凝血途径， 这里由 X因子活化形成的血 Xa因子起关键作用。 In blood coagulation, it is traditionally divided into endogenous and exogenous systems. The endogenous coagulation pathway refers to the process of activating X factor from activation of XII factor to formation of IV a- PF3C a 2+ complex; exogenous The coagulation pathway refers to the process of activating factor X from the activation of a factor to the formation of a Vna-Ca 2+ -TF complex. Activation from factor X to fibrin formation is a common coagulation pathway for endogenous and exogenous coagulation, where blood factor Xa formed by activation of factor X plays a key role.
Xa 因子是胰蛋白酶样的丝氨酸蛋白酶家族的一员， 丝氨酸蛋白酶家族激活凝血酶原为凝 血酶。 Xa因子在凝血通路中起重要作用， 而且位于放大效应的初始位点， 一分子凝血因子 X a催化 1000分子凝血酶形成。 因此， Xa因子作为靶点比作用于其他凝血因子或下游凝血酶应 该是抗凝血更有效的策略。  Factor Xa is a member of the trypsin-like serine protease family, and the serine protease family activates prothrombin to be a thrombin. Factor Xa plays an important role in the coagulation pathway and is located at the initial site of the amplification effect. One molecule of coagulation factor X a catalyzes the formation of 1000 molecules of thrombin. Therefore, factor Xa as a target is more effective than anticoagulant in other coagulation factors or downstream thrombin.
临床上常用的传统抗凝药物包括华法林、 肝素、 阿司匹林、 氯比格雷等。 其中涉及凝血 因子 Xa的药物为肝素， 主要为注射剂型， 包括普通肝素、 低分子量肝素 （LMWH) 、 Fonda parinux等， 在临床上容易引起严重出血和肝素诱导的血小板减少副反应， 需要临床检测。 与 传统的凝血药物相比， 新型凝血因子 Xa抑制剂具有以下优点： 口服， 低出血风险， 高效性， 无需个体调整和监控病人。 目前已上市或在研的药物包括利伐沙班、 阿哌沙班、 依度沙班、 贝曲沙班、 奥米沙班、 eribaxaban、 LY517717、 YM150、 letaxaban等。 但是目前上市或在研 的新型凝血因子 Xa抑制剂也有一些缺点， 比如利伐沙班和阿哌沙班的溶解度很差。  Traditional anticoagulant drugs commonly used in clinical practice include warfarin, heparin, aspirin, and clopidogrel. The drug involved in blood coagulation factor Xa is heparin, mainly injectable dosage forms, including unfractionated heparin, low molecular weight heparin (LMWH), Fonda parinux, etc., which are clinically prone to cause severe hemorrhage and heparin-induced thrombocytopenia side effects, requiring clinical testing. Compared with traditional coagulation drugs, the new coagulation factor Xa inhibitor has the following advantages: oral, low bleeding risk, high efficiency, no need for individual adjustment and monitoring of patients. Drugs currently on the market or under research include rivaroxaban, apixaban, edoxaban, betrixaban, omeproxaban, eribaxaban, LY517717, YM150, letaxaban, and the like. However, new clotting factor Xa inhibitors currently on the market or under development also have some disadvantages, such as the poor solubility of rivaroxaban and apixaban.
WO00039131描述了可作为胰蛋白酶样的丝氨酸蛋白酶抑制剂， 特别是凝血因子 Xa抑制 剂的含氮杂双环衍生物， 其中 X、 Y、 Ζ可以为氮和碳， G选择芳环或含氮杂芳环， Α是一个 环状基团， B 是一个碱性基团或者环状基团。 不认为此专利中具体描述是本发明的一部分， 其结构式如下:
Figure imgf000004_0001
WO00039131 describes nitrogen-containing heterobicyclic derivatives which can be used as trypsin-like serine protease inhibitors, in particular coagulation factor Xa inhibitors, wherein X, Y, Ζ can be nitrogen and carbon, G selects aromatic or nitrogen-containing heteroaryl Ring, hydrazine is a cyclic group, and B is a basic group or a cyclic group. The detailed description in this patent is not considered to be part of the present invention. Its structural formula is as follows:
Figure imgf000004_0001
WO00200655 描述了杂芳基 -苯基杂二环化合物及其衍生物， 以及作为凝血因子 Xa抑制 剂的用途， 其中 A为 5-6元芳基或杂芳基、 G2为苯基、 萘基或 5-10杂芳基、 Q为杂二环化 合物， 与本发明的化合物结构差异较大， ：
Figure imgf000004_0002
WO00200655 describes heteroaryl-phenylheterobicyclic compounds and derivatives thereof, and uses as coagulation factor Xa inhibitors, wherein A is a 5-6 membered aryl or heteroaryl group, G2 is a phenyl group, a naphthyl group or 5-10 Heteroaryl, Q is a heterobicyclic compound, and the structure of the compound of the present invention is greatly different,
Figure imgf000004_0002
WO03026652AK WO03047520, WO03048081 , WO03048158, WO03099276, WO2006 047528描述了包括阿哌沙班在内的 P4-P-M-M4 内酰胺衍生物， 其中环 P可以不存在或者为 5-7元的氮环或杂环， 环 M是一个 3-10元的碳环或杂环， 不认为此专利中具体描述是本发明 的一部分。  WO03026652AK WO03047520, WO03048081, WO03048158, WO03099276, WO2006 047528 describe P4-PM-M4 lactam derivatives including apixaban, wherein ring P may be absent or a 5-7 membered nitrogen or heterocyclic ring, Ring M is a 3-10 membered carbocyclic or heterocyclic ring and is not considered to be a part of the invention as specifically described in this patent.
WO2004083174描述了 P4-P-M-M4四氢嘧啶和磺酰基脒基衍生物及其作为丝氨酸蛋白酶 抑制剂， 特别是凝血因子 Xa抑制剂的应用， 其中环 P可以不存在或者为 5-7元的氮环或杂 环， 环 M是一个 3-10元的碳环或杂环， 不认为此专利中具体描述是本发明的一部分。  WO2004083174 describes P4-PM-M4 tetrahydropyrimidine and sulfonyl fluorenyl derivatives and their use as serine protease inhibitors, in particular coagulation factor Xa inhibitors, wherein ring P may be absent or is 5-7 members of nitrogen Ring or heterocycle, ring M is a 3-10 membered carbocyclic or heterocyclic ring and is not considered to be a part of the invention as specifically described in this patent.
WO2007137801 描述了新的四氢吡咯、 四氢吡唑并吡啶、 四氢咪唑并吡啶以及四氢三唑 并吡啶衍生物的凝血因子 Xa抑制剂， 与本发明的化合物结构差异较大， 相关结构式如下：  WO2007137801 describes new blood coagulation factor Xa inhibitors of tetrahydropyrrole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine and tetrahydrotriazolopyridine derivatives, which have a large difference in structure from the compounds of the present invention, and the relevant structural formula is as follows :
Figure imgf000004_0003
Figure imgf000004_0003
WO2009007028描述了 1-(4-甲氧基苯基) -7-氧代 -6[4- (氧代哌啶 -1-基)苯基] -4,6,5,7-四氢 -(1 H)-吡唑并 [3.4,c]吡啶 -3-甲酰胺衍生物， 及其作为凝血因子 Xa抑制剂的用途， 其中 Rl、 R2为 垸基， L为取代酰胺基或酯基， 关结构式如下：  WO2009007028 describes 1-(4-methoxyphenyl)-7-oxo-6[4-(oxoperpiperidin-1-yl)phenyl]-4,6,5,7-tetrahydro-( 1 H)-pyrazolo[3.4,c]pyridine-3-carboxamide derivative, and its use as a factor Xa inhibitor, wherein R1, R2 are a thiol group, L is a substituted amide group or an ester group, The structure is as follows:
Figure imgf000004_0004
Figure imgf000004_0004
本发明是在四氢吡唑并吡啶类化合物的基础上， 设计具有通式 所示的化合物， 以提 供一种结构新颖、 药效更好、 生物利用度高和溶解性更好的凝血因子 Xa抑制剂类化合物， 可 用于治疗静脉血栓形成、 深部静脉血栓形成、 下肢深静脉血栓形成、 血栓性静脉炎、 脑动脉 血栓形成、 动脉栓塞、 冠状动脉血栓形成、 肺栓塞、 脑栓塞、 肾栓塞， 肝静脉栓塞、 门静脉 栓塞、 慢性弥漫性血管内凝血、 四肢和中枢性微血管动脉栓塞、 动脉粥样硬化、 急性冠状综 合征、 不稳定心绞痛、 急性冠状动脉综合征、 心肌梗塞、 动脉硬化症、 局部缺血瘁死、 暂时 性的缺血、 外用阻塞性动脉疾病、 中风、 伴动脉栓塞的无菌性血栓性心内膜炎、 脑血管疾病 等血栓形成引起的多种疾病和并发症。 发明内容 The present invention is based on a tetrahydropyrazolopyridine compound, and has a compound represented by the general formula to provide a novel factor, a better drug, a higher bioavailability and a better solubility factor Xa. Inhibitor compounds for the treatment of venous thrombosis, deep vein thrombosis, deep venous thrombosis of the lower extremities, thrombophlebitis, cerebral arteries Thrombosis, arterial embolism, coronary thrombosis, pulmonary embolism, cerebral embolism, renal embolism, hepatic vein thrombosis, portal vein embolization, chronic diffuse intravascular coagulation, extremities and central microvascular arterial embolization, atherosclerosis, acute coronary syndrome Symptoms, unstable angina, acute coronary syndrome, myocardial infarction, atherosclerosis, ischemic sudden death, transient ischemia, external obstructive arterial disease, stroke, aseptic thrombotic intracardiac with arterial embolism Various diseases and complications caused by thrombosis such as membranous inflammation and cerebrovascular diseases. Summary of the invention
本发明涉及一种通式 所示的化合物， 或者其立体异构体、 氮氧化合物、 水合物、 溶 剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中：  The present invention relates to a compound of the formula, or a stereoisomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
Figure imgf000005_0001
Figure imgf000005_0001
A选自 C6— 14芳基或 5至 14元杂芳基， 所述芳基或杂芳基任选进一步被 0至 5个 R7取 代； A is selected from C 6 -14 aryl or 5- to 14-membered heteroaryl, which is optionally further substituted with 0 to 5 R 7 ;
B选自 3至 10元杂环， 所述的杂环含有 1至 4个选自 N、 0或 S的杂原子， 且所述杂环 任选进一步被 0至 3个取代基所取代， 所述取代基选自 R7a或者 (=0); B is selected from a 3- to 10-membered heterocyclic ring containing 1 to 4 hetero atoms selected from N, 0 or S, and the heterocyclic ring is optionally further substituted with 0 to 3 substituents, Said substituent is selected from R 7a or (=0);
X选自 0或者 S(=0)p; X is selected from 0 or S(=0) p;
R1, R2、 R3和 R4各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d_4垸 基、 d— 4垸氧基、 d— 4垸氧基垸基、 -(CH2)nNR8R8a、 -(CH2)nC(=0)NR8R8\ -OC(=0)NR8R8a、 -OC(=0)OR8、 -OC(=0)R8、 -C(=0)OR8、 -N(R8b)C(=0)NR8R8\ -N(R8)C(=0)OR8a、 -N(R8)C(=0)R8a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 C3_10碳环、 3 至 10 元杂环、 -0-(CH2)n-C3— 1Q碳环或者- 0-(CH2)n-(3至 10元杂环)， 所述的杂环含有 1至 4个选自 N、 0或 S的杂原子， 所述的垸基、 垸氧基、 碳环或杂环各自独立任选进一步被 0至 4个选 自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸基、 d— 4垸氧基或 -NR7R7a的取代基 所取代； R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 4 fluorenyl, d- 4 methoxy, d- 4垸 垸、, -(CH 2 ) n NR 8 R 8a , -(CH 2 ) n C(=0)NR 8 R 8 \ -OC(=0)NR 8 R 8a , -OC(=0) OR 8 , -OC(=0)R 8 , -C(=0)OR 8 , -N(R 8b )C(=0)NR 8 R 8 \ -N(R 8 )C(=0)OR 8a -N(R 8 )C(=0)R 8a , -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 , -(CH 2 ) n - alkynyl-R 8 , C 3 _ 10 carbocyclic ring, 3 to 10 membered heterocyclic ring, -0-(CH 2 ) n -C 3 - 1Q carbocyclic ring or - 0-(CH 2 ) n - (3 to 10 member) a heterocyclic ring, said heterocyclic ring containing 1 to 4 hetero atoms selected from N, 0 or S, said fluorenyl, decyloxy, carbocyclic or heterocyclic ring being each independently optionally further 0 to 4 Substituted with a substituent selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4- decyloxy or -NR 7 R 7a ;
作为选择， R1和 R2可以形成 (=0); Alternatively, R 1 and R 2 may form (=0);
作为选择， R3和 R4可以形成 (=0); Alternatively, R 3 and R 4 may form (=0);
作为选择， R R2、 R3、 R4中任意两个基团可与它们相连的原子一起形成一个 3至 6元 环， 包含螺环或并环， 所述 3至 6元环含有 0至 3个选自 N、 0或者 S的杂原子， 并且形成 的 3至 6元环可以任选进一步被 0至 4个 R7a取代； R5各自独立地选自 H、 F、 Cl、 Br、 I、 三氟甲基、 d_4垸基、 d_4垸氧基、 羟基、 巯基、 氨基、 氰基、 -(CR7R7a)n-C(=0)-NR7R7a或者 -(CR7R7a)nNR7R7a; Alternatively, any two of RR 2 , R 3 , and R 4 may form a 3 to 6 membered ring together with the atoms to which they are attached, including a spiro ring or a ring, and the 3 to 6 member ring contains 0 to 3 a hetero atom selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ; R 5 is each independently selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, d 4 fluorenyl, d 4 methoxy, hydroxy, decyl, amino, cyano, -(CR 7 R 7a ) n -C(=0)-NR 7 R 7a or -(CR 7 R 7a ) n NR 7 R 7a ;
R6选自 -C(=0)NR7R7a、 氰基、 三氟甲基、 -(CH2)nS(=0)pR8、 -C(R7R7a)R8、 -C(R7R7a)OR8、 C3— 1Q碳环或者 3至 10元杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述碳环或 杂环各自独立任选进一步被 0至 4个 R8取代； R 6 is selected from -C(=0)NR 7 R 7a , cyano, trifluoromethyl, -(CH 2 ) n S(=0) p R 8 , -C(R 7 R 7a )R 8 , C(R 7 R 7a )OR 8 , C 3 —1Q carbocyclic or 3 to 10 membered heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, said carbocyclic or heterocyclic The rings are each independently optionally further substituted by 0 to 4 R 8 ;
R7和 1 各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 d— 4垸基、 d— 4垸氧基、 -C(=0)-Ci_s垸基、 -C(=0)OR8、 -N(R8)C(=0)R8a、 -(CR8R8a)nNR8R8a、 -(CH2)nC(=0)NR8R8a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 -(CH2)n-C3— 1()碳环、 -C(=0)-(3至 10元 杂环)、 -(CH2)n-(3至 10元杂环)、 -0-(CH2)n-C3_1Q碳环或者 -0-(CH2)n-(3至 10元杂环)， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述垸基、 垸氧基、 碳环或者杂环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d_4垸基、 d_4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔 基、 氨基、 -C(=0)-(3至 10元杂环)、 -ϋ(=ο)ο- 4垸基、 羟基取代的 d— 3垸基、 -C^C -d— 3 垸基、 C3— 1Q碳环或 3至 10元杂环的取代基所取代； R 7 and 1 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, d- 4 fluorenyl, d- 4- decyloxy, -C(=0)-Ci_s fluorenyl, -C(=0)OR 8 , -N(R 8 )C(=0)R 8a , -(CR 8 R 8a ) n NR 8 R 8a , -(CH 2 ) n C(=0)NR 8 R 8a , -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 , -(CH 2 ) n -alkynyl-R 8 , -(CH 2 ) n - C 3 — 1() carbocyclic ring, —C(=0)—(3 to 10 membered heterocyclic ring), —(CH 2 ) n —(3 to 10 membered heterocyclic ring), —0-(CH 2 ) n — a C 3 _ 1Q carbocyclic ring or a-0-(CH 2 ) n - (3 to 10 membered heterocyclic ring) having 1 to 3 hetero atoms selected from N, 0 or S, the fluorenyl group, The methoxy group, carbocyclic ring or heterocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d_ 4 fluorenyl, d 4 methoxy, hydroxy, decyl, cyano, amide, Methyl alkynyl, amino, -C(=0)-(3 to 10-membered heterocyclic), -ϋ(=ο)ο- 4 fluorenyl, hydroxy-substituted d- 3 fluorenyl, -C^C -d — a substituent substituted with a 3 fluorenyl group, a C 3 —1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring;
作为选择， R7和 1 可以形成 (=0); Alternatively, R 7 and 1 can be formed (=0);
作为选择， R7和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -C(=0)-(3至 10元杂环)、 (=0)0-^4垸基、 羟基取代的 d_3垸基或 -C^C -Cw垸基的取代 基所取代； Alternatively, R 7 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, Methyl alkynyl, amino, -C(=0)-(3 to 10-membered heterocyclic), (=0)0-^4 fluorenyl, hydroxy-substituted d- 3 fluorenyl or -C^C-Cw fluorenyl Substituted by a substituent;
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3—1Q碳环 或 3至 10元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任 选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰 胺基、 甲基炔基、 氨基、 -c(=o)-3至 10元杂环、 -α;=ο)ο- 4垸基、 羟基取代的 d— 3垸基或 -Alternatively, when two R 7a are bonded to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 decyloxy, hydroxy , fluorenyl, cyano, amido, methyl alkynyl, amino, -c(=o)-3 to 10-membered heterocyclic ring, -α;=ο)ο- 4 fluorenyl, hydroxy-substituted d- 3 fluorenyl or-
C(=0)-d.3垸基的取代基所取代； Substituted by a C(=0)-d.3 thiol substituent;
R8、 ！^ 和 R8b各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸 基、 d_4垸氧基、 C3_1Q碳环或 3至 10元杂环； R 8 , ! ^ and R 8b are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4 methoxy, C 3 _ 1Q carbon ring or 3 to 10 Metacyclic ring
作为选择， R8和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -C(=0)-(3至 10元杂环)、 (=0)0-^4垸基、 羟基取代的 d_3垸基或 -C^C -Cw垸基的取代 基所取代； Alternatively, R 8 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, Methyl alkynyl, amino, -C(=0)-(3 to 10-membered heterocyclic), (=0)0-^4 fluorenyl, hydroxy-substituted d- 3 fluorenyl or -C^C-Cw fluorenyl Substituted by a substituent;
m选自 0、 1、 2或者 3 ; n选自 0、 1、 2、 3或者 4; p选自 0、 1或者 2。 条件是该化合物不为： 1-(2,3-二氢苯并呋喃 -5-基；) -7-氧代 -6-[4-(2-氧代哌啶 -1-基;)苯基] -4,5, 6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺或 1-(2,3-二氢苯并呋喃 -5-基) -7-氧代 -6-[4-(2-氧代哌 啶 -1-基)苯基] -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯。 m is selected from 0, 1, 2 or 3; n is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1 or 2. Provided that the compound is not: 1-(2,3-dihydrobenzofuran-5-yl;)-7-oxo-6-[4-(2-oxopiperidin-1-yl;)benzene -4,5, 6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide or 1-(2,3-dihydrobenzofuran-5-yl) -7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c] Ethyl pyridine-3-carboxylate.
本发明优选方案， A在每一种情况下， 选自 C6— 1Q芳基或 5至 10元杂芳基， 所述芳基或 杂芳基任选进一步被 0至 5个 R7取代； 优选苯基或 5至 6杂芳基， 所述苯基或杂芳基任选进 一步被 0至 5个 R7取代。 In a preferred embodiment of the invention, A in each case is selected from a C 6 - 1Q aryl group or a 5 to 10 membered heteroaryl group, which is optionally further substituted by 0 to 5 R 7 ; Preference is given to phenyl or 5 to 6 heteroaryl, which are optionally further substituted by 0 to 5 R 7 .
本发明优选方案， A在每一种情况下， 选自取代的或未取代的苯基、 萘基、 吡啶基、 呋 喃基、 噻吩基、 吡咯基、 N-垸基吡咯基、 嘧啶基、 吡嗪基、 哒嗪基或者咪唑基， 当被取代 时， 选择被 1至 5个 R7取代； 优选取代的或未取代的苯基或吡啶基， 当被取代时， 选择被 1 至 5个 R7取代； 进一步优选取代的或未取代的苯基， 当被取代时， 选择被 1 至 5个 R7取 代； 更优选苯基或 1个 F取代的苯基。 In a preferred embodiment of the invention, A in each case is selected from substituted or unsubstituted phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, N-fluorenylpyrrolyl, pyrimidinyl, pyridyl a pyridazinyl, pyridazinyl or imidazolyl group, when substituted, is selected to be substituted with from 1 to 5 R 7 ; preferably substituted or unsubstituted phenyl or pyridyl, when substituted, selected from 1 to 5 R 7 Substituted; Further preferred is a substituted or unsubstituted phenyl group which, when substituted, is optionally substituted with 1 to 5 R 7 ; more preferably a phenyl group or a 1 F substituted phenyl group.
本发明优选方案， 一种通式 （I) 所示化合物， 其中该化合物选自通式 （II) 所示的化合 物， 或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的 盐、 共晶或前药， 其中：  Preferred Embodiments of the Invention, A compound of the formula (I), wherein the compound is selected from the group consisting of a compound represented by the formula (II), or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite a pharmaceutically acceptable salt, eutectic or prodrug, wherein:
Figure imgf000007_0001
Figure imgf000007_0001
B选自 3至 10元杂环， 所述的杂环含有 1至 4个选自 N、 0或 S的杂原子， 且所述杂环 任选进一步被 0至 3个取代基所取代， 所述取代基选自 R7a或者 (=0); B is selected from a 3- to 10-membered heterocyclic ring containing 1 to 4 hetero atoms selected from N, 0 or S, and the heterocyclic ring is optionally further substituted with 0 to 3 substituents, Said substituent is selected from R 7a or (=0);
X选自 0或者 S(=0)p; X is selected from 0 or S(=0) p;
R1, R2、 R3和 R4各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸 基、 d_4垸氧基、 d_4垸氧基垸基、 -(CH2)nNR8R8a、 -(CH2)nC(=0)NR8R8a、 -OC(=0)NR8R8a、 -OC(=0)OR8、 -OC(=0)R8、 -C(=0)OR8、 -N(R8b)C(=0)NR8R8\ -N(R8)C(=0)OR8a、 -N(R8)C(=0)R8a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 C3— 1()碳环、 3至 10元 杂环、 -0-(CH2)n-C3— 1Q碳环或者 -0-(CH2)n-(3 至 10元杂环)， 所述的杂环含有 1 至 4个选自 N、 0或 S的杂原子， 所述的垸基、 垸氧基、 碳环或杂环各自独立任选进一步被 0至 4个选 自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸基、 d— 4垸氧基或 -NR7R7a的取代基 所取代; R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d 4 methoxy, d 4垸Oxycarbonyl group, -(CH 2 ) n NR 8 R 8a , -(CH 2 ) n C(=0)NR 8 R 8a , -OC(=0)NR 8 R 8a , -OC(=0)OR 8 , -OC(=0)R 8 , -C(=0)OR 8 , -N(R 8b )C(=0)NR 8 R 8 \ -N(R 8 )C(=0)OR 8a , -N(R 8 )C(=0)R 8a , -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 , -(CH 2 ) n -yne -R 8 , C 3 - 1 () carbocyclic ring, 3 to 10 membered heterocyclic ring, -0-(CH 2 ) n -C 3 - 1Q carbocyclic ring or -0-(CH 2 ) n - (3 to 10 a heterocyclic ring), wherein the heterocyclic ring contains 1 to 4 hetero atoms selected from N, 0 or S, and the fluorenyl group, the decyloxy group, the carbocyclic ring or the heterocyclic ring are each independently optionally further 0 to 4 Substituted by a substituent selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4- decyloxy or -NR 7 R 7a ;
作为选择， R1和 R2可以形成 (=0); Alternatively, R 1 and R 2 may form (=0);
作为选择， R3和 R4可以形成 (=0); 作为选择， R R2、 R3、 R4中任意两个基团可与它们相连的原子一起形成一个 3至 6元 环， 包含螺环或并环， 所述 3至 6元环含有 0至 3个选自 N、 0或者 S的杂原子， 并且形成 的 3至 6元环可以任选进一步被 0至 4个 R7a取代； Alternatively, R 3 and R 4 may form (=0); Alternatively, any two of RR 2 , R 3 , and R 4 may form a 3 to 6 membered ring together with the atoms to which they are attached, including a spiro ring or a ring, and the 3 to 6 member ring contains 0 to 3 a hetero atom selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ;
R5各自独立地选自 H、 F、 Cl、 Br、 I、 三氟甲基、 d_4垸基、 d_4垸氧基、 羟基、 巯基、 氨基、 氰基、 -(CR7R7a)n-C(=0)-NR7R7a或者 -(CR7R7a)nNR7R7a; R 5 is each independently selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, d 4 fluorenyl, d 4 methoxy, hydroxy, decyl, amino, cyano, -(CR 7 R 7a ) n -C(=0)-NR 7 R 7a or -(CR 7 R 7a ) n NR 7 R 7a ;
R6选自 -C(=0)NR7R7a、 氰基、 三氟甲基、 -(CH2)nS(=0)pR8、 -C(R7R7a)R8、 -C(R7R7a)OR8、 C3— 1Q碳环或者 3至 10元杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述碳环或 杂环各自独立任选进一步被 0至 4个 R8取代； R 6 is selected from -C(=0)NR 7 R 7a , cyano, trifluoromethyl, -(CH 2 ) n S(=0) p R 8 , -C(R 7 R 7a )R 8 , C(R 7 R 7a )OR 8 , C 3 —1Q carbocyclic or 3 to 10 membered heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, said carbocyclic or heterocyclic The rings are each independently optionally further substituted by 0 to 4 R 8 ;
R7和 1 各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 d_4垸基、 d_4垸氧基、 -C(=0)-Ci_s垸基、 -C(=0)OR8、 -N(R8)C(=0)R8a、 -(CR8R8a)nNR8R8a、 -(CH2)nC(=0)NR8R8a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 -(CH2)n-C3— 1()碳环、 -C(=0)-(3至 10元 杂环)、 -(CH2)n-(3至 10元杂环)、 -0-(CH2)n-C3_1Q碳环或者 -0-(CH2)n-(3至 10元杂环)， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述垸基、 垸氧基、 碳环或者杂环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基 炔基、 氨基、 -C(=0)-(3至 10元杂环)、 (=0)0- 4垸基、 羟基取代的 d— 3垸基、 (=0)- 3 垸基、 C3— 1Q碳环或 3至 10元杂环的取代基所取代； R 7 and 1 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, d 4 fluorenyl, d 4 methoxy, -C(=0)-Ci_s decyl, -C (=0)OR 8 , -N(R 8 )C(=0)R 8a , -(CR 8 R 8a ) n NR 8 R 8a , -(CH 2 ) n C(=0)NR 8 R 8a , -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 , -(CH 2 ) n -alkynyl-R 8 , -(CH 2 ) n -C 3 — 1 () carbocyclic ring, —C(=0)—(3 to 10 membered heterocyclic ring), —(CH 2 ) n —(3 to 10 membered heterocyclic ring), —0-(CH 2 ) n —C 3 _ 1Q carbocyclic ring or -0-(CH 2 ) n - (3 to 10 membered heterocyclic ring), the heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, the fluorenyl group, hydrazine The base, carbocyclic or heterocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4- methoxy, hydroxy, decyl, cyano, amide, methyl alkynyl group, an amino group, -C (= 0) - ( 3 to 10-membered heterocyclyl), (= 0) 0-4 embankment group, a hydroxy-substituted alkyl with d- 3, (= 0) --3 alkyl with Substituting a C 3 —1Q carbocyclic ring or a substituent of a 3 to 10 membered heterocyclic ring;
作为选择， R7和 1 可以形成 (=0) ; Alternatively, R 7 and 1 can form (=0);
作为选择， R7和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -c(=o)-(3至 10元杂环)、 (=ο)ο- 4垸基、 羟基取代的 3垸基或 -C^C -d— 3垸基的取代 基所取代； Alternatively, R 7 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, Methyl alkynyl, amino, -c(=o)-(3 to 10 membered heterocyclic), (=ο)ο- 4 yl, hydroxy substituted 3 fluorenyl or -C^C -d- 3 fluorenyl Substituted by a substituent;
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3— 1Q碳环 或 3至 10元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任 选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰 胺基、 甲基炔基、 氨基、 -C(=0)-3至 10元杂环、 -c^c o-d— 4垸基、 羟基取代的 d— 3垸基
Figure imgf000008_0001
Alternatively, when two R 7a are bonded to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 decyloxy, hydroxy , mercapto, cyano, amido, methyl alkynyl, amino, -C(=0)-3 to 10-membered heterocyclic ring, -c^c od- 4 fluorenyl, hydroxy substituted d- 3 fluorenyl
Figure imgf000008_0001
R8、 ！^ 和 R8b各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d_4垸 基、 d_4垸氧基、 C3_1Q碳环或 3至 10元杂环； R 8 , ! ^ and R 8b are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 4 fluorenyl, d 4 methoxy, C 3 _ 1Q carbon ring or 3 to 10 Heterocycle
作为选择， R8和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -C(=0)-(3至 10元杂环)、 (=ο)ο- 4垸基、 羟基取代的 3垸基或 -c^c -d— 3垸基的取代 基所取代； Alternatively, R 8 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, Methyl alkynyl, amino, Substituted with a substituent of -C(=0)-(3 to 10 membered heterocyclic), (=o)o-4, hydroxy substituted 3 fluorenyl or -c^c-d- 3 fluorenyl;
m选自 0、 1、 2或者 3 ; n选自 0、 1、 2、 3或者 4; p选自 0、 1或者 2。  m is selected from 0, 1, 2 or 3; n is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1 or 2.
本发明优选方案， X在每一种情况下， 选自 0或 S， 优选 X为 0。  In a preferred embodiment of the invention, X is in each case selected from 0 or S, preferably X is 0.
本发明优选方案， R5在每一种情况下， 各自独立地选自 H、 F、 Cl、 Br、 I、 三氟甲基、 羟基、 巯基、 氨基、 氰基、 CM垸基、 d— 4垸氧基或 -(CH2)n-C(=0)-NH2， 优选 H、 F、 Cl、 B r、 I、 三氟甲基、 羟基、 巯基、 氨基、 氰基、 d— 4垸基或 d— 4垸氧基， 进一步优选 H、 F、 C 1、 三氟甲基、 羟基、 氨基、 氰基、 d— 3垸基或 d— 3垸氧基。 In a preferred embodiment of the invention, R 5 is, in each case, independently selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, hydroxy, decyl, amino, cyano, CM thiol, d- 4 Alkoxy or -(CH 2 ) n -C(=0)-NH 2 , preferably H, F, Cl, B r, I, trifluoromethyl, hydroxy, decyl, amino, cyano, d- 4 Or a d- 4 methoxy group, further preferably H, F, C 1, trifluoromethyl, hydroxy, amino, cyano, d- 3 decyl or d- 3 decyloxy.
本发明优选方案， R5在每一种情况下， 选自 H、 F、 Cl、 Br、 I、 三氟甲基、 羟基、 巯 基、 氰基、 氨基、 甲基、 乙基、 丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 甲氧基、 乙氧 基、 丙氧基、 异丙氧基、 丁氧基、 叔丁氧基、 氨基甲酰基或者氨基亚甲基， 优选 H、 F、 Cl、 三氟甲基、 羟基、 氨基、 甲基、 乙基、 丙基、 异丙基、 甲氧基、 乙氧基、 丙氧基或者异丙氧 基， 进一步优选 11或？。 In a preferred embodiment of the invention, R 5 is, in each case selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, hydroxy, decyl, cyano, amino, methyl, ethyl, propyl, iso Propyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, carbamoyl or aminomethylene, Preference is given to H, F, Cl, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, further preferably 11 or ? .
本发明优选方案， R6在每一种情况下， 选自 -C(=0)NR7R7a、 氰基、 三氟甲基、 -(CH2)nS(=0)pR8, -C(R7R7a)R8、 -C(R7R7a)OR8、 C3— 5碳环或者 3至 5元杂环， 其中所述碳环或 杂环各自独立任选进一步被 0至 4个 R8取代， 所述杂环含有 1至 3个选自 N、 0或 S的杂原 子； In a preferred embodiment of the invention, R 6 is, in each case selected from -C(=0)NR 7 R 7a , cyano, trifluoromethyl, -(CH 2 ) n S(=0) p R 8 , -C(R 7 R 7a )R 8 , -C(R 7 R 7a )OR 8 , C 3 -5 carbocyclic or 3- to 5-membered heterocyclic ring, wherein the carbocyclic or heterocyclic ring is independently optionally further 0 to 4 R 8 substituted, the heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S;
R6优选 -C(=0)NR7R7a、 氰基、 三氟甲基、 -(CH2)nS(=0)2R8、 -C(R7R7a)R8、 -C(R7R7a)OR8、 C3— 4碳环或者 3至 4元杂环， 其中所述碳环或杂环各自独立任选进一步被 0至 4个 R8取代， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子； R 6 is preferably -C(=0)NR 7 R 7a , cyano, trifluoromethyl, -(CH 2 ) n S(=0) 2 R 8 , -C(R 7 R 7a )R 8 , -C (R 7 R 7a )OR 8 , C 3 — 4 carbocyclic or 3- to 4-membered heterocyclic ring, wherein the carbocyclic or heterocyclic ring is each independently optionally further substituted by 0 to 4 R 8 , the heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S;
R进一步优选 -C(=0)NR7R7a、 氰基或 -(CH2)nS(=0)2R8; R is further preferably -C(=0)NR 7 R 7a , cyano or -(CH 2 ) n S(=0) 2 R 8 ;
其中所述 R7和 1 各自独立的选自 H、 d_4垸基、 -(CH2)n-C3_5碳环或 -(CH2)n-C3_5杂环， 优选 H或 d— 4垸基； 其中所述 R8选自 H、 F、 Cl、 羟基、 氰基、 氨基、 d— 4垸基或 d— 4垸氧 基。 Wherein R 7 and 1 are each independently selected from H, d 4 fluorenyl, -(CH 2 ) n -C 3 _ 5 carbocyclic or -(CH 2 ) n -C 3 _ 5 heterocyclic ring, preferably H or embankment d- 4-yl; wherein said R 8 is selected from H, F, Cl, hydroxy, cyano, amino, d- 4 alkyl with or d- 4 embankment group.
本发明优选方案， R6在每一种情况下， 选自氨基甲酰基、 2-异丙醇基、 1-环丙醇基、 氰 基、 三氟甲基、 1-氟乙基、 乙氧基甲酰基、 1-氟甲基、 1 ,1-二氟甲基、 1-羟基乙基或 1-羟基甲 基， 优选氨基甲酰基。 In a preferred embodiment of the invention, R 6 is, in each case selected from the group consisting of carbamoyl, 2-isopropanol, 1-cyclopropanol, cyano, trifluoromethyl, 1-fluoroethyl, ethoxy Carbamoyl, 1-fluoromethyl, 1 ,1-difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl, preferably carbamoyl.
本发明优选方案， m在每一种情况下， 选自 0或 1。  In a preferred embodiment of the invention, m is selected from 0 or 1 in each case.
本发明优选方案， 一种通式 © 所示化合物， 其中该化合物选自通式 （III) 所示的化合 物， 或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的 盐、 共晶或前药， 其中：
Figure imgf000010_0001
A preferred embodiment of the invention, a compound of the formula: wherein the compound is selected from the group consisting of a compound of the formula (III), or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmacy Acceptable salts, eutectic or prodrugs, of which:
Figure imgf000010_0001
B选自 3至 10元杂环， 所述的杂环含有 1至 4个选自 N、 0或 S的杂原子， 且所述杂环 任选进一步被 0至 3个取代基所取代， 所述取代基选自 R7a或者 (=0); B is selected from a 3- to 10-membered heterocyclic ring containing 1 to 4 hetero atoms selected from N, 0 or S, and the heterocyclic ring is optionally further substituted with 0 to 3 substituents, Said substituent is selected from R 7a or (=0);
R1, R2、 R3和 R4各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸 基、 d— 4垸氧基、 d— 4垸氧基垸基、 -(CH2)nNR8R8a、 -(CH2)nC(=0)NR8R8a、 -OC(=0)NR8R8a、 -OC(=0)OR8 、 -OC(=0)R8 、 -C(=0)OR8 、 -N(R8b)C(=0)NR8R8a 、 -N(R8)C(=0)OR8a 、 -N(R8)C(=0)R8a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 C3— 1()碳环、 3至 10元 杂环、 -C CH2)n-C3_1Q碳环或者 -0-(CH2)n-(3 至 10元杂环)， 所述的杂环含有 1 至 4个选自 N、 0或 S的杂原子， 所述的垸基、 垸氧基、 碳环或杂环各自独立任选进一步被 0至 4个选 自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸基、 d— 4垸氧基或 -NR7R7a的取代基 所取代； R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4- indolyl, d- 4- decyloxy, d- 4- decyloxycarbonyl, -(CH 2 ) n NR 8 R 8a , -(CH 2 ) n C(=0)NR 8 R 8a , -OC(=0)NR 8 R 8a , -OC(=0 )OR 8 , -OC(=0)R 8 , -C(=0)OR 8 , -N(R 8b )C(=0)NR 8 R 8a , -N(R 8 )C(=0)OR 8a , -N(R 8 )C(=0)R 8a , -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 , -(CH 2 ) n - alkynyl-R 8 , C 3 - 1 () carbocyclic, 3 to 10 membered heterocyclic ring, -C CH 2 ) n -C 3 _ 1Q carbocyclic ring or -0-(CH 2 ) n - (3 to 10 a heterocyclic ring), wherein the heterocyclic ring contains 1 to 4 hetero atoms selected from N, 0 or S, and the fluorenyl group, the decyloxy group, the carbocyclic ring or the heterocyclic ring are each independently optionally further 0 to 4 Substituted by a substituent selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4- decyloxy or -NR 7 R 7a ;
作为选择， R1和 R2可以形成 (=0); Alternatively, R 1 and R 2 may form (=0);
作为选择， R3和 R4可以形成 (=0); Alternatively, R 3 and R 4 may form (=0);
作为选择， R R2、 R3、 R4中任意两个基团可与它们相连的原子形成一个 3至 6元环， 包含螺环或并环， 所述 3至 6元环含有 0至 3个选自 N、 0或者 S的杂原子， 并且形成的 3 至 6元环可以任选进一步被 0至 4个 R7a取代； Alternatively, any two of the groups RR 2 , R 3 , and R 4 may form a 3 to 6 membered ring with the atoms to which they are attached, including a spiro ring or a ring, and the 3 to 6 member ring contains 0 to 3 a hetero atom selected from N, 0 or S, and the formed 3- to 6-membered ring may be optionally further substituted by 0 to 4 R 7a ;
R7和 1 各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 d— 4垸基、 d— 4垸氧 基、 (=0)-^— 5垸基、 -C(=0)OR8、 -N(R8)C(=0)R8a、 -(CR8R8a)nNR8R8a、 -(CH2)nC(=0)NR8R8 a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 -(CH2)n-C3— 10碳环、 -C(=0)-(3 至 10 元杂环)、 -(CH2)n-(3至 10元杂环)、 -0-(CH2)n-C3_1Q碳环或者 -0-(CH2)n-(3至 10元杂环)， 所述 杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述垸基、 垸氧基、 碳环或者杂环任选进一步 被 0至 4个选自 H、 F、 Cl、 Br、 I、 CM垸基、 C14垸氧基、羟基、 巯基、 氰基、 應安基、 甲基炔 基、 氨基、 -C(=0)-(3至 10元杂环)、 (=0)0-^4垸基、 羟基取代的 d_3垸基、 -C^C -d— 3 垸基、 C3— 1Q碳环或 3至 10元杂环的取代基所取代； R 7 and 1 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, d- 4- indolyl, d- 4- decyloxy, (=0)-^- 5 fluorenyl, -C(=0)OR 8 , -N(R 8 )C(=0)R 8a , -(CR 8 R 8a ) n NR 8 R 8a , -(CH 2 ) n C(=0)NR 8 R 8 a , -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 , -(CH 2 ) n -alkynyl-R 8 , -(CH 2 ) n -C 3 - 10 carbocyclic ring, -C(=0)-(3 to 10 membered heterocyclic ring), -(CH 2 ) n -(3 to 10 membered heterocyclic ring), -0-(CH 2 ) n -C 3 _ 1Q carbocyclic ring or -0-(CH 2 ) n - (3 to 10 membered heterocyclic ring), the heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, the fluorenyl group, hydrazine The oxy group, carbocyclic ring or heterocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, C M decyl, C 14 decyloxy, hydroxy, decyl, cyano, acetaminophen, Methyl alkynyl, amino, -C(=0)-(3 to 10-membered heterocyclic), (=0)0-^4 fluorenyl, hydroxy-substituted d- 3 fluorenyl, -C^C-d- 3 Substituted by a substituent of a fluorenyl group, a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring;
作为选择， R7和 1 可以形成 (=0); Alternatively, R 7 and 1 can be formed (=0);
作为选择， R7和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -C(=0)-(3至 10元杂环)、 (=ο)ο- 4垸基、 羟基取代的 3垸基或 -c^c -d— 3垸基的取代 基所取代； Alternatively, R 7 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, Methyl alkynyl, amino, Substituted with a substituent of -C(=0)-(3 to 10 membered heterocyclic), (=o)o-4, hydroxy substituted 3 fluorenyl or -c^c-d- 3 fluorenyl;
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3— 1Q碳环 或 3至 10元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任 选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰 胺基、 甲基炔基、 氨基、 -C(=0)-3至 10元杂环、 -C^C O-d— 4垸基、 羟基取代的 d— 3垸基 或 -Cl^C -d— 3垸基的取代基所取代； Alternatively, when two R 7a are bonded to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 decyloxy, hydroxy , fluorenyl, cyano, amido, methylalkynyl, amino, -C(=0)-3 to 10-membered heterocyclic ring, -C^C Od- 4 fluorenyl, hydroxy substituted d- 3 fluorenyl or Substituted by a substituent of a Cl^C-d- 3 fluorenyl group;
R8、 ！^ 和 R8b各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d_4垸 基、 d_4垸氧基、 C3_1Q碳环或 3至 10元杂环； R 8 , ! ^ and R 8b are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 4 fluorenyl, d 4 methoxy, C 3 _ 1Q carbon ring or 3 to 10 Heterocycle
作为选择， R8和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -C(=0)-(3至 10元杂环)、 -C^C O-CM垸基、 羟基取代的 d_3垸基或 -C^C -Cw垸基的取代 基所取代； Alternatively, R 8 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, Methyl alkynyl, amino, -C(=0)-(3 to 10-membered heterocyclic), -C^C O-CM fluorenyl, hydroxy-substituted d_ 3 fluorenyl or -C^C-Cw fluorenyl Substituted by a substituent;
n选自 0、 1、 2、 3或者 4; p选自 0、 1或者 2。  n is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1 or 2.
本发明优选方案， B在每一种情况下， 选自 3至 8元杂环， 所述的杂环含有 1至 4个选 g N、 0或 S的杂原子， 所述杂环任选进一步被 0至 3个取代基所取代， 所述取代基选自 R7a 或者 (=0); In a preferred embodiment of the invention, B is in each case selected from a 3 to 8 membered heterocyclic ring containing from 1 to 4 heteroatoms selected from g, 0 or S, optionally further Substituted by 0 to 3 substituents selected from R 7a or (=0);
B优选 5至 6元杂环， 所述的杂环含有 1至 4个选自 N、 0或 S的杂原子， 所述杂环任 选进一步被 0至 3个取代基所取代， 所述取代基选自 R7a或者 (=0); B is preferably a 5- to 6-membered heterocyclic ring, and the heterocyclic ring contains 1 to 4 hetero atoms selected from N, 0 or S, and the heterocyclic ring is optionally further substituted with 0 to 3 substituents, the substitution The base is selected from R 7a or (=0);
其中所述的取代基 R7a选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 三氟甲基、 d— 4垸 基、 d— 4垸氧基、 -C^C -d— 5垸基或 -(CH2)nNR8R8a， Wherein the substituent R 7a is selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, trifluoromethyl, d- 4 fluorenyl, d- 4- decyloxy, -C^C- D- 5 fluorenyl or -(CH 2 ) n NR 8 R 8a ,
R7a优选 H、 F、 三氟甲基、 d_4垸基或 -(CH ni^CM垸基 垸基)， R 7a is preferably H, F, trifluoromethyl, d 4 alkyl or -(CH ni^CM垸 fluorenyl),
R7a更优选 H、 F、 三氟甲基、 甲基、 乙基、 丙基或异丙基； R 7a is more preferably H, F, trifluoromethyl, methyl, ethyl, propyl or isopropyl;
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3—1Q碳环 或 3至 10元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任 选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基或酰 胺基的取代基所取代； Alternatively, when two R 7a are bonded to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 decyloxy, hydroxy Substituted with a substituent of a thiol, cyano or amide group;
当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起优选形成 C3— 5碳环或 3至 5 元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步 被 0至 4个选自 H、 F、 d— 4垸基、 d— 4垸氧基或氰基的取代基所取代； When two R 7a are bonded to the same atom, the atoms to which they are attached together preferably form a C 3 -5 carbocyclic ring or a 3 to 5 membered heterocyclic ring containing from 1 to 3 selected from N, a hetero atom of 0 or S, which is optionally further substituted with 0 to 4 substituents selected from H, F, d-4 fluorenyl, d-4-methoxy or cyano;
当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起更优选形成 C3— 4碳环或 3至 4元的杂环， 所述杂环含有 1至 2个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一 步被 0至 4个选自 H、 F、 d_2垸基或 d— 2垸氧 取代。 本发明优选方案， B在每一种情况下， 选自
Figure imgf000012_0001
， When two R 7a are attached to the same atom, it is more preferred to form a C 3 - 4 carbocyclic ring or 3 to the atoms to which they are attached. a 4-membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, 0 or S, optionally further 0 to 4 selected from H, F, d 2 2 Base or d-2 垸 oxygen substitution. In a preferred embodiment of the invention, B is selected in each case from
Figure imgf000012_0001
,
其中 E选自 C=0或 S(=0)2， 优选 C=0; Wherein E is selected from C=0 or S(=0) 2 , preferably C=0;
环 Q选自 4至 8元环， 它的组成除了所示的 N-E基团外， 还包括碳原子和 0至 2个选自 Ring Q is selected from the group consisting of 4 to 8 membered rings, and its composition includes, in addition to the N-E group shown, carbon atoms and 0 to 2
N、 0或 S的杂原子， 其中该环可以任选进一步被 0至 3个取代基所取代， 取代基各自独立 的选自 1 或 （=0); a hetero atom of N, 0 or S, wherein the ring may be optionally further substituted with 0 to 3 substituents, each independently selected from 1 or (=0);
环 Q优选 5至 7元环， 它的组成除了所示的 N-E基团外， 还包括碳原子和 0至 2个选自 N、 0或 S的杂原子， 其中该环可以任选进一步被 0至 3个取代基所取代， 取代基各自独立 的选自 1 或 （=0);  Ring Q is preferably a 5- to 7-membered ring, the composition of which includes, in addition to the NE group shown, a carbon atom and 0 to 2 heteroatoms selected from N, 0 or S, wherein the ring may optionally be further Substituted to 3 substituents, the substituents are each independently selected from 1 or (=0);
环 Q更优选 5至 6元环， 它的组成除了所示的 N-E基团外， 还包括碳原子和 0至 2个选 自 N、 0或 S的杂原子， 其中该环可以任选进一步被 0至 3个取代基所取代， 取代基各自独 立的选自 1 或 （=0；);  The ring Q is more preferably a 5- to 6-membered ring, and its composition includes, in addition to the NE group shown, a carbon atom and 0 to 2 hetero atoms selected from N, 0 or S, wherein the ring may optionally be further Substituted with 0 to 3 substituents, each of which is independently selected from 1 or (=0;);
其中所述 R7a选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 三氟甲基、 d_4垸基、 d_4垸 氧基、 -C^C -d— 5垸基或 -(CH2)nNR8R8a， 优选 H、 F、 三氟甲基、 d— 4垸基或 -(CH^i^d— 4垸 基；) 4垸基 )， 进一步优选 H、 F、 三氟甲基、 甲基、 乙基丙基或异丙基； Wherein R 7a is selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, trifluoromethyl, d_ 4 fluorenyl, d 4 methoxy, -C^C -d- 5 fluorenyl Or -(CH 2 ) n NR 8 R 8a , preferably H, F, trifluoromethyl, d- 4 fluorenyl or -(CH^i^d- 4 yl); 4 fluorenyl), further preferably H, F, trifluoromethyl, methyl, ethylpropyl or isopropyl;
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3— 1Q碳环 或 3至 10元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任 选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基或酰 胺基的取代基所取代； Alternatively, when two R 7a are bonded to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 decyloxy, hydroxy Substituted with a substituent of a thiol, cyano or amide group;
当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起优选形成 C3— 5碳环或 3至 5 元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步 被 0至 4个选自 H、 F、 d— 4垸基、 d— 4垸氧基或氰基的取代基所取代； When two R 7a are bonded to the same atom, the atoms to which they are attached together preferably form a C 3 -5 carbocyclic ring or a 3 to 5 membered heterocyclic ring containing from 1 to 3 selected from N, a hetero atom of 0 or S, which is optionally further substituted with 0 to 4 substituents selected from H, F, d-4 fluorenyl, d-4-methoxy or cyano;
当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起进一步优选形成 C3— 4碳环或 3至 4元的杂环， 所述杂环含有 1至 2个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选 进一步被 0至 4个选自 H、 F、 d— 2垸基、 d— 2垸氧基取代基所取代。 When two R 7a are bonded to the same atom, the atoms to which they are attached may further preferably form a C 3 - 4 carbocyclic ring or a 3 to 4 membered heterocyclic ring containing 1 to 2 selected from N a hetero atom of 0 or S, which is optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, d-2-indenyl, d-2-indolyl.
本发明优选方案， B 在每一种情况下， 选自取代的或未取代的吡咯基、 呋喃基、 噻吩 基、 吡唑基、 咪唑基、 噁唑基、 异噁唑基、 噻唑基、 吲哚基、 苯并呋喃基、 苯并咪唑基、 吡 啶基、 2H-吡喃基、 4H-吡喃基、 哒嗪基、 嘧啶基、 吡嗪基、 四氢呋喃基、 四氢吡咯基、 四氢 噻唑基、 、N n¾ n¾ In a preferred embodiment of the invention, B is, in each case, selected from substituted or unsubstituted pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, hydrazine Mercapto, benzofuranyl, benzimidazolyl, pyridyl, 2H-pyranyl, 4H-pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiazole base, , N n 3⁄4 n 3⁄4
Figure imgf000013_0001
Figure imgf000013_0002
V- 人 ( 一 当被取代时， 任选进一步被 1至 3个取代基所取代， 所述取代基选自 R7a或者 (=0); 优选取代 的或未取代的吡咯基、 呋喃基、 噻吩基、 吡唑基、 咪唑基、 噁唑基、 异噁唑基、 噻唑基、 吲 哚基、 吡啶基、 2H-吡喃基、 4H-吡喃基、 哒嗪基、 嘧啶基、 吡嗪基、 四氢呋喃基、 四氢吡咯 基、 四氢噻唑基、
Figure imgf000013_0001
Figure imgf000013_0002
V-human (when substituted, optionally further substituted with 1 to 3 substituents selected from R 7a or (=0); preferably substituted or unsubstituted pyrrolyl, furyl, Thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, fluorenyl, pyridyl, 2H-pyranyl, 4H-pyranyl, pyridazinyl, pyrimidinyl, pyrazine Base, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiazolyl,
『 『
Figure imgf000013_0003
Figure imgf000013_0003
， 当被取代时， 任选进一步被 1至 3个取代基所取代， 所述取代基选自 R7a或者 (=0)。 When substituted, it is optionally further substituted with from 1 to 3 substituents selected from R 7a or (=0).
本发明优选方案， 一种通式 © 所示化合物， 其中该化合物选自通式 （IV) 所示的化合 物， 或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的 盐、 共晶或前药， 其中：  A preferred embodiment of the invention, a compound of the formula: wherein the compound is selected from the group consisting of a compound of the formula (IV), or a stereoisomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically Acceptable salts, eutectic or prodrugs, of which:
Figure imgf000013_0004
Figure imgf000013_0004
其中 E选自 C=0或 S(=0)2; Wherein E is selected from C=0 or S(=0) 2 ;
环 Q选自 4至 8元环， 它的组成除了所示的 N-E基团外， 还包括碳原子和 0至 1个选自 N、 0或 S的杂原子， 其中该环可以任选进一步被 0至 3个取代基所取代， 取代基各自独立 的选自！ 或(=0)；  Ring Q is selected from the group consisting of 4 to 8 membered rings, the composition of which includes, in addition to the NE group shown, a carbon atom and 0 to 1 hetero atom selected from N, 0 or S, wherein the ring may optionally be further 0 to 3 substituents are substituted, and the substituents are each independently selected from! Or (=0);
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3— 1Q碳环 或 3至 10元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任 选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰 胺基的取代基所取代； Alternatively, when two R 7a are attached to the same atom, they can form a C 3 — 1Q carbocycle together with the atoms to which they are attached. Or a 3 to 10 membered heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, optionally further 0 to 4 selected from H, F, Substituted by a substituent of Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano or amide;
R1, R2、 R3和 R4各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸 基、 CM垸氧基、 CM垸氧基垸基、 -(CH2)nNR8R8a、 -(CH2)nC(=0)NR8R8a、 -OC(=0)NR8R8a、 -OC(=0)OR8、 -OC(=0)R8、 -C(=0)OR8、 -Ν(Κ =0) Ι ¾&、 -N(R8)C(=0)OR8a、 -N(R8)C(=0)R8\ -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 C3— 1()碳环、 3至 10元杂环、 -0-(CH2)n-C3— 10 碳环或者 -0-(CH2)n-(3至 10元杂环 )， 所述的杂环含有 1至 4个选自 N、 0或 S的杂原子， 所 述的垸基、 垸氧基、 碳环或杂环各自独立任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 羟 基、 巯基、 氰基、 氨基、 d— 4垸基、 d— 4垸氧基或 -NR7R7a的取代基所取代； R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, CM methoxy, CM methoxy Mercapto group, -(CH 2 ) n NR 8 R 8a , -(CH 2 ) n C(=0)NR 8 R 8a , -OC(=0)NR 8 R 8a , -OC(=0)OR 8 , -OC(=0)R 8 , -C(=0)OR 8 , -Ν(Κ =0) Ι 3⁄4 & , -N(R 8 )C(=0)OR 8a , -N(R 8 )C (=0) R 8 \ -(CH 2 ) n S(=0)pR 8 , -(CH 2 ) n -alkenyl-R 8 , -(CH 2 )n-alkynyl-R 8 , C 3 — 1 () carbocyclic ring, 3 to 10 membered heterocyclic ring, -0-(CH 2 ) n -C 3 - 10 carbocyclic ring or -0-(CH 2 ) n - (3 to 10 membered heterocyclic ring), The heterocyclic ring contains 1 to 4 hetero atoms selected from N, 0 or S, and the fluorenyl, decyloxy, carbocyclic or heterocyclic ring is each independently optionally further selected from 0 to 4 selected from H, F, Cl. Substituted by a substituent of Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4 decyloxy or -NR 7 R 7a ;
作为选择， R1和 R2可以形成 (=0); Alternatively, R 1 and R 2 may form (=0);
作为选择， R3和 R4可以形成 (=0); Alternatively, R 3 and R 4 may form (=0);
作为选择， R R2、 R3、 R4中任意两个基团可以形成一个 3 至 6元环， 包含螺环或并 环， 所述 3至 6元环含有 0至 3个选自 N、 0或者 S的杂原子， 并且形成的 3至 6元环可以 任选进一步被 0至 4个 R7a取代； Alternatively, any two of RR 2 , R 3 , and R 4 may form a 3- to 6-membered ring containing a spiro ring or a fused ring, and the 3 to 6 membered ring contains 0 to 3 selected from N, 0. Or a hetero atom of S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ;
1 各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 d— 4垸基、 d— 4垸氧基、 -C(=0)-Ci_s垸基、 -C(=0)OR8、 -N(R8)C(=0)R8a、 -(CR8R8a)nNR8R8a、 -(CH2)nC(=0)NR8R8a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 -(CH^-Cw。碳环、 -C(=0)-(3至 10元杂 环)、 -(CH2)n-(3至 10元杂环)、 -0-(CH2)n-C3_1Q碳环或者 -0-(CH2)n-(3至 10元杂环)， 所述杂环 含有 1至 3个选自 N、 0或 S的杂原子， 所述垸基、 垸氧基、 碳环或者杂环任选进一步被 0 至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔 基、 氨基、 -C(=0)-(3至 10元杂环)、 (=0)0-^4垸基、 羟基取代的 d_3垸基、 -C^C -d— 3 垸基、 C3— 1Q碳环或 3至 10元杂环的取代基所取代； 1 each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, d- 4 fluorenyl, d- 4 decyloxy, -C(=0)-Ci_s decyl, -C ( =0)OR 8 , -N(R 8 )C(=0)R 8a , -(CR 8 R 8a ) n NR 8 R 8a , -(CH 2 ) n C(=0)NR 8 R 8a , (CH 2 ) n S(=0) p R 8 , —(CH 2 ) n -alkenyl-R 8 , —(CH 2 ) n -alkynyl-R 8 , —(CH^-Cw. carbocyclic, -C(=0)-(3 to 10 membered heterocyclic), -(CH 2 ) n -(3 to 10 membered heterocyclic), -0-(CH 2 ) n -C 3 _ 1Q carbon ring or -0 -(CH 2 ) n -(3 to 10 membered heterocyclic ring), the heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, the fluorenyl group, the decyloxy group, the carbocyclic ring or the heterocyclic ring Optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, methyl alkynyl, amino, -C (= 0) - (3 to 10-membered heterocyclyl), (= 0) 0- ^ 4 embankment group, a hydroxy-substituted alkyl with d_ 3, -C ^ C -d- 3 embankment group, C 3 - 1Q Substituted by a carbocyclic ring or a substituent of a 3 to 10 membered heterocyclic ring;
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3— 1Q碳环 或 3至 10元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任 选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰 胺基、 甲基炔基、 氨基、 -C(=0)-3至 10元杂环、 -Cl^C O-d— 4垸基、 羟基取代的 d— 3垸基或 -C(=0)-d_3垸基的取代基所取代； Alternatively, when two R 7a are bonded to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 decyloxy, hydroxy , fluorenyl, cyano, amido, methylalkynyl, amino, -C(=0)-3 to 10 membered heterocyclic ring, -Cl^C Od- 4 fluorenyl, hydroxy substituted d- 3 fluorenyl or Substituted by a C(=0)-d- 3 thiol substituent;
R8、 ！^ 和 R8b各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸 基、 d_4垸氧基、 C3_1Q碳环或 3至 10元杂环； R 8 , ! ^ and R 8b are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4 methoxy, C 3 _ 1Q carbon ring or 3 to 10 Metacyclic ring
作为选择， R8和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、Alternatively, R 8 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, methyl alkynyl, amino,
-C(=0)-(3至 10元杂环)、 (=0)0-^4垸基、 羟基取代的 d_3垸基或 -C^C -Cw垸基的取代 基所取代； Substituted with a substituent of -C(=0)-(3 to 10 membered heterocyclic), (=0)0-^4 fluorenyl, hydroxy-substituted d- 3 fluorenyl or -C^C-Cw fluorenyl;
n选自 0、 1、 2、 3或者 4; p选自 0、 1或者 2。  n is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1 or 2.
本发明优选方案， 一种通式 （IV)所示化合物， 其中 E选自 C=0; Preferred Embodiments of the Invention, a compound of the formula (IV), wherein E is selected from C=0 ;
环 Q选自 4至 8元环， 它的组成除了所示的 N-E基团外， 还包括碳原子和 0至 1个选自 N、 0或 S的杂原子， 其中该环可以任选进一步被 0至 3个取代基所取代， 取代基各自独立 的选自 1 或 （=0);  Ring Q is selected from the group consisting of 4 to 8 membered rings, the composition of which includes, in addition to the NE group shown, a carbon atom and 0 to 1 hetero atom selected from N, 0 or S, wherein the ring may optionally be further Substituted with 0 to 3 substituents, each of which is independently selected from 1 or (=0);
环 Q优选 5至 7元环， 它的组成除了所示的 N-E基团外， 还包括碳原子和 0至 1个选自 N、 0或 S的杂原子， 其中该环可以任选进一步被 0至 3个取代基所取代， 取代基各自独立 的选自 1 或 （=0);  Ring Q is preferably a 5- to 7-membered ring, the composition of which includes, in addition to the NE group shown, a carbon atom and 0 to 1 hetero atom selected from N, 0 or S, wherein the ring may optionally be further Substituted to 3 substituents, the substituents are each independently selected from 1 or (=0);
环 Q进一步优选 5至 6元环， 它的组成除了所示的 N-E基团外， 还包括碳原子和 0至 1 个选自 N、 0或 S的杂原子， 其中该环可以任选进一步被 0至 3个取代基所取代， 取代基各 自独立的选自 1 或 （=0);  The ring Q is further preferably a 5- to 6-membered ring, the composition of which includes, in addition to the NE group shown, a carbon atom and 0 to 1 hetero atom selected from N, 0 or S, wherein the ring may optionally be further Substituted with 0 to 3 substituents, each of which is independently selected from 1 or (=0);
其中所述 R7a选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 三氟甲基、 d— 4垸基、 d— 4垸 氧基、 -C^C -d— 5垸基或 -(CH2)nNR8R8a， 优选 H、 F、 三氟甲基、 d— 4垸基或 -(CH^N^M垸 基 XCM垸基)， 进一步优选 H、 F、 三氟甲基、 d_4垸基或 -CH N w垸基 XC^垸基)； Wherein R 7a is selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, trifluoromethyl, d- 4 fluorenyl, d- 4- decyloxy, -C^C-d- 5 Mercapto or -(CH 2 ) n NR 8 R 8a , preferably H, F, trifluoromethyl, d- 4 fluorenyl or -(CH^N^M fluorenyl XCM fluorenyl), further preferably H, F, Trifluoromethyl, d_ 4 fluorenyl or -CH N w fluorenyl XC^ fluorenyl);
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3— 1Q碳环 或 3至 10元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任 选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰 胺基的取代基所取代； Alternatively, when two R 7a are bonded to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 decyloxy, hydroxy Substituted by a substituent of a mercapto group, a cyano group or an amide group;
当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起优选形成 C3— 5碳环或 3至 5 元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步 被 0至 4个选自 H、 F、 d— 4垸基、 d— 4垸氧基或氰基的取代基所取代； When two R 7a are bonded to the same atom, the atoms to which they are attached together preferably form a C 3 -5 carbocyclic ring or a 3 to 5 membered heterocyclic ring containing from 1 to 3 selected from N, a hetero atom of 0 or S, which is optionally further substituted with 0 to 4 substituents selected from H, F, d-4 fluorenyl, d-4-methoxy or cyano;
当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起进一步优选形成 C3—4碳环或When two R 7a are attached to the same atom, the atoms to which they are attached may further preferably form a C 3 - 4 carbocyclic ring or
3至 4元的杂环， 所述杂环含有 1至 2个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选 进一步被 0至 4个选自 H、 F、 d— 2垸基或 d— 2垸氧基取代基所取代。 a 3- to 4-membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, 0 or S, optionally further 0 to 4 selected from H, F, d - Substituted by a 2 fluorenyl or d-2 oxiranyl substituent.
本发明优选方案， R R2、 R3和 R4在每一种情况下， 各自独立地选自 H、 F、 Cl、 Br、In a preferred embodiment of the invention, RR 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, in each case.
I、 羟基、 巯基、 氰基、 氨基、 d— 4垸基、 d— 4垸氧基、 d— 4垸氧基垸基、 C3— 8碳环、 3至 8元 杂环、 -0-(CH2)n-C3_8碳环或者 -0-(CH2)n-(3至 8元杂环)； I, hydroxy, mercapto, cyano, amino, d- 4 alkyl with, d- 4 embankment group, d- 4 alkyl with embankment group, C 3 - 8 carbon ring of 3 to 8-membered heterocyclic, -0- (CH 2 ) n -C 3 -8 carbon ring or -0-(CH 2 ) n - (3 to 8 membered heterocyclic ring);
R1, R2、 R3和 R4各自独立地优选11、 F、 Cl、 Br、 I、 羟基、 氰基、 氨基、 d_4垸基、 d_4 垸氧基、 C3_5碳环、 3至 5元杂环、 -0-(CH2)n-C3_5碳环或者 -0-(CH2)n-(3至 5元杂环)； R R2、 R3和 R4各自独立地进一步优选 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d_4垸基、 d— 4垸氧基、 C3— 4碳环或者 -0-C3— 4碳环； R 1 , R 2 , R 3 and R 4 are each independently preferably 11, F, Cl, Br, I, hydroxy, cyano, amino, d 4 fluorenyl, d 4 methoxy, C 3 _ 5 carbocyclic, a 3- to 5-membered heterocyclic ring, a -0-(CH 2 ) n -C 3 _ 5 carbocyclic ring or a-0-(CH 2 ) n - (3 to 5 membered heterocyclic ring); Further, RR 2 , R 3 and R 4 are each independently further preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 4 fluorenyl, d-4-decyloxy, C 3 - 4 carbocyclic ring. Or -0-C 3 - 4 carbon rings;
R1, R2、 R3和 R4各自独立地更优选 H、 F、 Cl、 d_2垸基或 d_2垸氧基； R 1 , R 2 , R 3 and R 4 are each independently more preferably H, F, Cl, d 2 fluorenyl or d 2 decyloxy;
其中所述的垸基、 垸氧基、 碳环或杂环各自独立任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸基或 d— 4垸氧基的取代基所取代， 优选 H、 F、 Cl、 Br、 I、 羟基、 氨基、 甲基、 乙基、 甲氧基或乙氧基； Wherein the fluorenyl, decyloxy, carbocyclic or heterocyclic ring is each independently optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 Substituted with a substituent of a fluorenyl or d- 4 methoxy group, preferably H, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, methoxy or ethoxy;
作为选择， 其中 R1和 R2可以形成 (=0); Alternatively, wherein R 1 and R 2 may form (=0);
作为选择， 其中 R3和 R4可以形成 (=0); Alternatively, wherein R 3 and R 4 may form (=0);
作为选择， 其中 I 1、 R2、 R3、 R4中任意两个基团可与它们相连的原子一起形成一个 3至 6元环， 包含螺环或并环， 所述 3至 6元环含有 0至 3个选自 N、 0或者 S的杂原子， 并且 形成的 3至 6元环可以任选进一步被 0至 4个 R7a取代； Alternatively, any two of I 1 , R 2 , R 3 , and R 4 may form a 3 to 6 membered ring together with the atoms to which they are attached, including a spiro ring or a ring, the 3 to 6 membered ring. Containing 0 to 3 heteroatoms selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ;
R1, R2、 R3、 R4中任意两个基团可与它们相连的原子一起优选形成一个 3至 4元环， 所 述 3至 4元环含有 0至 3个选自 N、 0或者 S的杂原子， 并且形成的 3至 4元环可以任选进 一步被 0至 4个 R7a取代； Any two of R 1 , R 2 , R 3 , and R 4 may preferably form a 3- to 4-membered ring together with the atoms to which they are attached, and the 3- to 4-membered ring contains 0 to 3 selected from N, 0. Or a hetero atom of S, and the formed 3 to 4 membered ring may be optionally further substituted with 0 to 4 R 7a ;
R R2、 R3、 R4中任意两个基团可与它们相连的原子一起进一步优选形成一个 3元环， 所述 3元环含有 0至 1个选自 N、 0或者 S的杂原子， 并且形成的 3元环可以任选进一步被 0至 3个 R7a取代； Any two of RR 2 , R 3 , and R 4 may further preferably form a 3-membered ring together with the atoms to which they are attached, the 3-membered ring containing 0 to 1 hetero atom selected from N, 0 or S, And the formed 3-membered ring may be optionally further substituted by 0 to 3 R 7a ;
其中所述基团 R7a选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 d_4垸基、 d_4垸氧基， 优选 H、 F、 羟基、 氰基、 甲基、 乙基、 甲氧基或乙氧基。 Wherein the group R 7a is selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, d 4 fluorenyl, d 4 methoxy, preferably H, F, hydroxy, cyano, methyl, Ethyl, methoxy or ethoxy.
本发明优选方案， R R2、 R3和 R4在每一种情况下， 各自独立选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 甲基、 乙基、 丙基、 2-丙基、 正丁基、 异丁基、 甲氧基、 乙氧 基、 丙氧基、 丁氧基、 环丙氧基、 氨基甲酰基、 N-乙基氨基甲基、 烯丙基、 甲基炔基、 环丙 基、 环丁基、 环戊基、 环己基、 吡啶基、 N-甲基吡咯基、 呋喃基、 噻吩基、 吡咯基、 哌啶 基、 吗啉基、 硫代吗啉基， 四氢呋喃基、 四氢吡咯基、 环丁氧基、 环戊氧基、 氧杂环丁基、 氧杂环丁氧基、 氮杂环丁基、 氮杂环丁氧基、 氧杂环戊氧基、 氮杂环戊氧基、 环丙基甲基氧 基、 -OC(=0)NH(CH3)、 -OC(=0)OCH3或 -NH(C=0)NH(CH3)， 优选 H、 F、 Cl、 Br、 I、 羟 基、 巯基、 氰基、 氨基、 甲基、 乙基、 环丙基、 甲氧基、 乙氧基或环丙氧基， 进一步优选 H、 F、 Cl、 甲基、 乙基、 甲氧基或乙氧基； In a preferred embodiment of the invention, RR 2 , R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, methyl, ethyl, propyl. Base, 2-propyl, n-butyl, isobutyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, carbamoyl, N-ethylaminomethyl, allylic , methyl alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N-methylpyrrolyl, furyl, thienyl, pyrrolyl, piperidinyl, morpholinyl, sulfur Dimorpholinyl, tetrahydrofuranyl, tetrahydropyrrolyl, cyclobutoxy, cyclopentyloxy, oxetanyl, oxetanyloxy, azetidinyl, azetidinyloxy, oxygen Heterocyclic pentyloxy, azacyclopentyloxy, cyclopropylmethyloxy, -OC(=0)NH(CH 3 ), -OC(=0)OCH 3 or -NH(C=0)NH (CH 3 ), preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, cyclopropyl, methoxy, ethoxy or cyclopropoxy, further preferably H, F, Cl, Methyl, B , Methoxy or ethoxy;
作为选择， R1和 R2可以形成 (=0); Alternatively, R 1 and R 2 may form (=0);
作为选择， R3和 R4可以形成 (=0); Alternatively, R 3 and R 4 may form (=0);
作为选择， R R2、 R3、 R4中任意两个基团可与它们相连的原子一起形成一个 3至 6元 环， 包含螺环或并环， 所述 3至 6元环含有 0至 3个选自 N、 0或者 S的杂原子， 并且形成 的 3至 6元环可以任选进一步被 0至 4个 R7a取代； Alternatively, any two of RR 2 , R 3 , and R 4 may form a 3 to 6 membered ring together with the atoms to which they are attached, including a spiro ring or a ring, and the 3 to 6 member ring contains 0 to 3 a hetero atom selected from N, 0 or S, and formed The 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ;
优选地， R R2、 R3、 R4中任意两个基团可与它们相连的原子一起形成取代或未取代的 环丙基、 环丁基、 环戊基、 环己基、 吡啶基、 呋喃基、 噻吩基、 吡咯基、 N-垸基吡咯基、 哌 啶基、 吗啉基、 硫代吗啉基、 四氢呋喃基或四氢吡咯基； Preferably, any two of RR 2 , R 3 , R 4 may form a substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, furyl group together with the atoms to which they are attached. , thienyl, pyrrolyl, N-fluorenylpyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl or tetrahydropyrrolyl;
更优选地， I 1、 R2、 R3、 R4中任意两个基团可与它们相连的原子一起进一步形成环丙 基。 More preferably, any two of I 1 , R 2 , R 3 , R 4 may further form a cyclopropyl group together with the atoms to which they are attached.
本发明优选方案， R7和 R7a在每一种情况下， 各自独立地选 g H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 三氟甲基、 4垸基、 d— 4垸氧基、 -C^C -d— 5 垸基、 -C(=0)OR8、 -N(R8)C(=0)R8a、 -(CR8R8a)n R8R8a、 -(CH2)nC(=0)NR8R8a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 -(CH2)n-C3_10碳环、 -C(=0)-(3至 10元杂环)、 -(CH2)n-(3至 10元杂环）、 -0-(CH2)n-C3_1Q碳环或者 -0-(CH2)n-(3至 10元杂环)； In a preferred embodiment of the present invention, R 7 and R 7a are each independently selected from the group consisting of g H, F, Cl, Br, I, hydroxy, decyl, cyano, trifluoromethyl, 4 fluorenyl, d- 4垸oxy, -C^C -d - 5 fluorenyl, -C(=0)OR 8 , -N(R 8 )C(=0)R 8a , -(CR 8 R 8a ) n R 8 R 8a , -(CH 2 ) n C(=0)NR 8 R 8a , -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 , -(CH 2 n - alkynyl-R 8 , -(CH 2 ) n -C 3 _ 10 carbocyclic ring, -C(=0)-(3 to 10 membered heterocyclic ring), -(CH 2 ) n - (3 to 10) a heterocyclic ring), -0-(CH 2 ) n -C 3 _ 1Q carbocyclic ring or -0-(CH 2 ) n - (3 to 10 membered heterocyclic ring);
R7和 R7a各自独立地优选 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 三氟甲基、 d_4垸基、 Ci— 4垸氧基、 -Q^C -d— 2垸基、 (=0)^—2垸氧基、 -(CH2)nC(=0)NH2、 -(CH^i^d— 2垸 基) (d— 2垸基）、 -(CH2)n-烯基、 -(CH2)n-炔基、 -(CH2)n-C3— 6碳环、 -C(=0)-(3 至 6 元杂环）、 -(CH2)n-(3至 6元杂环)、 -0-(CH2)n-C3_6碳环或者 -0-(CH2)n-(3至 6元杂环)， 进一步优选 H、 F、 三氟甲基、 d— 4垸基、 d— 4垸氧基或 -(CH^N ^— 2垸基; ((d— 2垸基； )， 其中所述杂环含有 1至 3个选自 N、 0或 S的杂原子； R 7 and R 7a are each independently preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, trifluoromethyl, d_ 4 fluorenyl, Ci- 4- decyloxy, -Q^C -d- 2 fluorenyl, (=0)^-2 methoxy, -(CH 2 ) n C(=0)NH 2 , -(CH^i^d- 2 yl) (d- 2 fluorenyl), - (CH 2 ) n -alkenyl, -(CH 2 ) n -alkynyl, -(CH 2 ) n -C 3 - 6 carbocyclic ring, -C(=0)-(3 to 6-membered heterocyclic ring), - (CH 2 ) n -(3 to 6-membered heterocyclic ring), -0-(CH 2 ) n -C 3 -6 carbocyclic ring or -0-(CH 2 ) n - (3 to 6-membered heterocyclic ring), further Preferred is H, F, trifluoromethyl, d- 4 fluorenyl, d- 4 decyloxy or -(CH^N^ -2 fluorenyl; ((d- 2 fluorenyl); wherein the heterocyclic ring contains 1 to 3 hetero atoms selected from N, 0 or S;
其中所述垸基、 垸氧基、 烯基、 炔基、 碳环或者杂环任选进一步被 0至 4个取代基所取 代， 取代基各自独立地选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -c(=o;K3至 10元杂环)、 -α;=ο)ο- 4垸基、 羟基取代的 d— 3垸 基、 -C^C -d— 3垸基、 C3— 1Q碳环或 3至 10元杂环， 优选 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰 基、 酰胺基、 甲基炔基、 氨基、 d— 4垸基、 d— 4垸氧基、 C3— 5碳环或 3至 5元杂环， 进一步优 选 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 甲基、 乙基、 甲氧基 或乙氧基； Wherein the fluorenyl, decyloxy, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally further substituted with 0 to 4 substituents each independently selected from the group consisting of H, F, Cl, Br, I , d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, methyl alkynyl, amino, -c (=o; K3 to 10-membered heterocyclic), -α; Ο- 4 fluorenyl, hydroxy-substituted d- 3 fluorenyl, -C^C-d- 3 fluorenyl, C 3 - 1Q carbocyclic or 3 to 10 membered heterocyclic ring, preferably H, F, Cl, Br, I, a hydroxyl group, a decyl group, a cyano group, an amide group, a methyl alkynyl group, an amino group, a d- 4 fluorenyl group, a d- 4 methoxy group, a C 3 -5 carbocyclic ring or a 3- to 5-membered heterocyclic ring, further preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amido, methyl alkynyl, amino, methyl, ethyl, methoxy or ethoxy;
作为选择， 其中 R7和 1 可以形成 (=0) ; Alternatively, where R 7 and 1 can form (=0);
作为选择， 其中 R7和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 优选 C3— 8碳环或 3至 8元的杂环， 更优选 C3— 5碳环或 3至 5元的杂环； 其中所述杂环含有 1 至 3个选自 N、 0或 S的杂原子； 其中所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基或氨基取代基所 取代， 优选 H、 F、 Cl、 Br、 I、 羟基、 甲基炔基、 甲基、 乙基、 甲氧基或乙氧基； Alternatively, where R 7 can together form 1 and the atoms to which they are attached form C 3 - 1Q carbocyclic ring or 3 to 10-membered heterocyclic ring, preferably C 3 - 8 carbon ring or 3 to 8-membered heterocyclic ring, more preferably a C a 3 to 5 carbocyclic ring or a 3 to 5 membered heterocyclic ring; wherein the heterocyclic ring contains 1 to 3 hetero atoms selected from N, 0 or S; wherein the heterocyclic ring or carbocyclic ring is optionally further further from 0 to 4 Substituted from H, F, Cl, Br, I, d-4 fluorenyl, d-4 methoxy, hydroxy, decyl, cyano, amide, methyl alkynyl or amino substituents, preferably H, F, Cl, Br, I, hydroxy, methyl alkynyl, methyl, ethyl, methoxy or ethoxy;
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3— 1Q碳环 或 3至 10元的杂环， 优选 C3—8碳环或 3至 8元的杂环， 进一步优选 C3—5碳环或 3至 5元的杂 环； 其中所述杂环含有 1至 3个选自 N、 0或 S的杂原子； 其中所述杂环或者碳环任选进一 步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基或氨基取代基所取代， 优选 H、 F、 Cl、 Br、 I、 羟基、 甲基炔基、 甲基、 乙基、 甲 氧基或乙氧基。 Alternatively, when two R 7a are attached to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, preferably a C 3 - 8 carbocyclic ring or 3 to 8 a heterocyclic ring, further preferably a C 3 - 5 carbocyclic ring or a 3 to 5 -membered hetero a ring; wherein the heterocyclic ring contains 1 to 3 hetero atoms selected from N, 0 or S; wherein the heterocyclic ring or carbocyclic ring is optionally further further selected from 0 to 4 selected from H, F, Cl, Br, I , d- 4 alkyl with, d- 4 embankment group, a hydroxyl group, a mercapto group, a cyano group, an amide group, an alkynyl group or an amino methyl substituents, preferably H, F, Cl, Br, I, hydroxy, methyl Alkynyl, methyl, ethyl, methoxy or ethoxy.
本发明优选方案， R7和 R7a在每一种情况下， 各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 羟甲基、 三氟甲基、 甲基、 乙基、 丙基、 异丙基、 正丁基、 异丁基、 叔 丁基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基、 丁氧基、 叔丁氧基、 环丙氧基、 甲氧基羰基、 乙氧基羰基、 乙酰基、 氨基甲酰基、 N-乙基氨基甲基、 烯丙基、 甲基炔基、 环丙基、 环丙基 亚甲基、 环丁基、 环戊基、 环己基、 吡啶基、 N-甲基吡咯基、 呋喃基、 噻吩基、 吡咯基、 哌 啶基、 吗啉基、 硫代吗啉基、 四氢呋喃基、 四氢吡咯基、 环丁氧基、 环戊氧基、 氧杂环丁 基、 氧杂环丁氧基、 氮杂环丁基、 氮杂环丁氧基、 氧杂环戊氧基、 氮杂环戊氧基、 氮杂环戊 基亚甲基、 吗啉基羰基、 环丙基甲基氧基或环戊垸乙基氧基； In a preferred embodiment of the invention, R 7 and R 7a are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, hydroxymethyl, trifluoromethyl, Methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy , cyclopropyloxy, methoxycarbonyl, ethoxycarbonyl, acetyl, carbamoyl, N-ethylaminomethyl, allyl, methylalkynyl, cyclopropyl, cyclopropylmethylene , cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N-methylpyrrolyl, furyl, thienyl, pyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrogen Pyrrolyl, cyclobutoxy, cyclopentyloxy, oxetanyl, oxetanyloxy, azetidinyl, azetidinyloxy, oxolyloxy, aziridine Oxyl, azacyclopentylmethylene, morpholinylcarbonyl, cyclopropylmethyloxy or cyclopentanylethyloxy;
R7和 R7a优选 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 羟甲基、 三氟甲基、 甲基、 乙基、 丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基、 丁 氧基、 叔丁氧基、 环丙氧基、 甲氧基羰基、 乙氧基羰基、 乙酰基、 氨基甲酰基、 N-乙基氨基 甲基、 烯丙基、 甲基炔基、 环丙基、 环丙基亚甲基、 环丁基、 环戊基、 环己基、 吡啶基、 N- 甲基吡咯基、 呋喃基、 噻吩基、 吡咯基、 哌啶基、 吗啉基、 硫代吗啉基、 四氢呋喃基、 四氢 吡咯基、 环丁氧基、 环戊氧基、 氧杂环丁基、 氧杂环丁氧基、 氮杂环丁基、 氮杂环丁氧基、 氧杂环戊氧基、 氮杂环戊氧基、 氮杂环戊基亚甲基、 吗啉基羰基、 环丙基甲基氧基或环戊垸 乙基氧基； R 7 and R 7a are preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, hydroxymethyl, trifluoromethyl, methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, cyclopropoxy, methoxycarbonyl, ethoxycarbonyl, Acetyl, carbamoyl, N-ethylaminomethyl, allyl, methylalkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N - methylpyrrolyl, furyl, thienyl, pyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyrrolyl, cyclobutoxy, cyclopentyloxy, oxyheterocycle Butyl, oxetanyloxy, azetidinyl, azetidinoxy, oxetanyloxy, azacyclopentyloxy, azacyclopentylmethylene, morpholinylcarbonyl , cyclopropylmethyloxy or cyclopentanylethyloxy;
R7和 R7a进一步优选 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 羟甲基、 三氟甲基、 甲基、 乙基、 丙基、 异丙基、 异丁基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基、 甲氧基羰基、 乙氧基羰基、 乙酰基、 氨基甲酰基、 烯丙基、 甲基炔基、 环丙基、 环丙基亚甲基、 环丁基、 环戊基、 环己基、 吡啶基、 吡咯基、 哌啶基、 四氢呋喃基或四氢吡咯基； R 7 and R 7a are further preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, hydroxymethyl, trifluoromethyl, methyl, ethyl, propyl, isopropyl, isobutyl , methoxy, ethoxy, propoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, carbamoyl, allyl, methylalkynyl, cyclopropyl, cyclo Propylmethylene, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrrolyl, piperidinyl, tetrahydrofuranyl or tetrahydropyrrolyl;
R7和 R7a更进一步优选 H、 F、 Cl、 羟基、 巯基、 氰基、 氨基、 羟甲基、 三氟甲基、 甲 基、 乙基、 丙基、 异丙基、 异丁基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基、 乙酰基、 氨基甲 酰基、 烯丙基、 甲基炔基、 环丙基、 环丙基亚甲基、 环丁基、 环戊基、 环己基、 吡啶基、 吡 咯基、 哌啶基、 四氢呋喃基或四氢吡咯基； R 7 and R 7a are further more preferably H, F, Cl, hydroxy, decyl, cyano, amino, hydroxymethyl, trifluoromethyl, methyl, ethyl, propyl, isopropyl, isobutyl, methyl Oxy, ethoxy, propoxy, isopropoxy, acetyl, carbamoyl, allyl, methylalkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl , cyclohexyl, pyridyl, pyrrolyl, piperidinyl, tetrahydrofuranyl or tetrahydropyrrolyl;
作为选择， R7和 1 可以形成 (=0); Alternatively, R 7 and 1 can be formed (=0);
作为选择， R7和 1 可与它们相连的原子一起形成 C3— 6碳环或 3至 6元的杂环， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 d— 4垸基、 d— 4垸氧基、 羟基、 氨基、 巯基、 氰基、 酰胺基或甲基炔基的取代基所 取代； Alternatively, R 7 together form a C 3 and may be attached to the atoms to which they - 6 carbocyclic ring or 3 to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0, or S heteroatoms, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, d-4 fluorenyl, d-4-decyloxy, hydroxy, amino, decyl, cyano, amide or methyl Alkynyl substituent Replace
优选地， R7和 R7a可与它们相连的原子一起形成取代或未取代的环丙垸、 氧杂环丙垸、 环丁垸、 氮杂环丁垸、 氧杂环丁垸、 环戊垸、 吡咯、 哌啶、 吗啉或咪唑垸基二酮； 当被取代 时， 任选进一步被 1至 3个取代基所取代， 取代基选自 H、 F、 Cl、 羟基、 甲基、 乙基、 甲氧 基、 乙氧基、 氨基或甲氧基羰基； Preferably, R 7 and R 7a may form a substituted or unsubstituted cyclopropene, oxetan, cyclobutane, azetidinium, oxetane, cyclopentanthene together with the atoms to which they are attached. , pyrrole, piperidine, morpholine or imidazolyldione; when substituted, optionally further substituted with 1 to 3 substituents selected from H, F, Cl, hydroxy, methyl, ethyl , methoxy, ethoxy, amino or methoxycarbonyl;
更优选地， R7和 R7a可与它们相连的原子一起形成环丙垸、 氮杂环丁垸、 氧杂环丁垸、 四氢吡咯、 哌啶或吗啉； More preferably, R 7 and R 7a may form a cyclopropene, azetidinium, oxetanium, tetrahydropyrrole, piperidine or morpholine together with the atoms to which they are attached;
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3—6碳环或 3至 6元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选 进一步被 0至 4个选自 H、 F、 Cl、 d— 4垸基、 d— 4垸氧基、 羟基、 氨基、 巯基、 氰基、 酰胺 基或甲基炔基的取代基所取代； Alternatively, when two R 7a are connected on the same atom, can atom to which they are attached form a C 3 - 6 carbocyclic ring or 3 to 6-membered heterocyclic ring containing 1 to 3 substituents selected from a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, d- 4 fluorenyl, d- 4- decyloxy, hydroxy, amino, fluorenyl Substituted by a substituent of a cyano group, an amide group or a methyl alkynyl group;
优选地， 两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成取代或未取代 的环丙垸、 氧杂环丙垸、 环丁垸、 氮杂环丁垸、 氧杂环丁垸、 咪唑垸基二酮、 四氢吡咯、 哌 啶或吗啉， 当被取代时， 任选进一步被 1 至 3 个取代基所取代， 取代基选自 H、 F、 Cl、 羟 基、 甲基、 乙基、 甲氧基、 乙氧基、 氨基或甲氧基羰基； Preferably, when two R 7a are bonded to the same atom, they may form a substituted or unsubstituted cyclopropene, oxetan, cyclobutane, azetidinium, oroxax together with the atoms to which they are attached. Cyclobutanthene, imidazolyldione, tetrahydropyrrole, piperidine or morpholine, when substituted, optionally further substituted with from 1 to 3 substituents selected from H, F, Cl, hydroxy, Methyl, ethyl, methoxy, ethoxy, amino or methoxycarbonyl;
更优选地， 两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成环丙垸、 氮 杂环丁垸、 氧杂环丁垸、 四氢吡咯、 哌啶或吗啉。 More preferably, when two R 7a are attached to the same atom, they may form a cyclopropene, azetidinium, oxetanium, tetrahydropyrrole, piperidine or morpholine together with the atoms to which they are attached.
本发明优选方案， R8、 1 和 R8b在每一种情况下， 各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸基、 d— 4垸氧基、 C3— 1Q碳环或 3至 10元杂环， 优选 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸基、 d— 4垸氧基、 C3— 5碳环或 3至 5元杂环， 进 一步优选11、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸基或 d— 4垸氧基， 更优选 H、 ?或 — 3垸基； In a preferred embodiment of the invention, R 8 , 1 and R 8b are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, d- 4 fluorenyl, d — 4垸 oxy, C 3 — 1Q carbocyclic or 3 to 10 membered heterocyclic ring, preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d— 4垸Oxyl group, C 3 -5 carbocyclic ring or 3- to 5-membered heterocyclic ring, further preferably 11, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl or d- 4 fluorenyloxy More preferably H, ? or - 3 fluorenyl;
作为选择 R8和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 优选形 成 C3— 8碳环或 3至 8元的杂环， 进一步优选形成 C3— 4碳环或 3至 4元的杂环； 其中所述杂环 含有 1至 3个选自 N、 0或 S的杂原子； 其中所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基或氨基取 代基所取代， 优选 H、 F、 Cl、 Br、 I、 羟基、 甲基炔基、 甲基、 乙基、 甲氧基或乙氧基； 本发明优选方案， R8、 1 和 R8b在每一种情况下， 各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 甲基、 乙基、 异丙基、 甲氧基、 乙氧基、 异丙氧基、 环丙基、 环 丁基、 氧杂环丙基、 氧杂环丁基或氮杂环丁基， 优选 H、 甲基、 乙基和异丙基； Alternatively R 8 and the atoms to which they are attached may together form a C 3 - 1Q carbocyclic ring or 3 to 10-membered heterocyclic ring, preferably form C 3 - 8 carbon heterocyclic ring or 3 to 8-membered, more preferably form a C a 3 to 4 carbocyclic ring or a 3 to 4 membered heterocyclic ring; wherein the heterocyclic ring contains 1 to 3 hetero atoms selected from N, 0 or S; wherein the heterocyclic ring or carbocyclic ring is optionally further 0 to 4 Substituted from H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, methyl alkynyl or amino substituents, preferably H, F, Cl, Br, I, hydroxy, methylalkynyl, methyl, ethyl, methoxy or ethoxy; in a preferred embodiment of the invention, R 8 , 1 and R 8b are each independently independent Selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclo Butyl, oxetanyl, oxetanyl or azetidinyl, preferably H, methyl, ethyl and isopropyl;
作为选择， R8和 R8a可与它们相连的原子一起形成环丙垸、 环丁垸、 氧杂环丙垸、 氧杂 环丁垸、 氮杂环丁垸、 四氢吡咯、 哌啶或吗啉， 所述杂环或者碳环任选进一步被 0至 4个选 自 H、 F、 Cl、 甲基、 乙基、 异丙基、 甲氧基、 乙氧基、 异丙氧基、 羟基、 巯基、 氰基、 酰胺 基、 甲基炔基、 氨基、 甲氧基羰基、 乙氧基羰基、 羟甲基、 羟乙基或乙酰基取代基所取代； R 8和 1 可与它们相连的原子一起优选形成环丙垸、 四氢吡咯或哌啶。 Alternatively, R 8 and R 8a may form, together with the atoms to which they are attached, cyclopropene, cyclobutane, oxetan, oxetanium, azetidinium, tetrahydropyrrole, piperidine or Porphyrin, the heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 From H, F, Cl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, hydroxy, decyl, cyano, amide, methyl alkynyl, amino, methoxy Substituted by a carbonyl, ethoxycarbonyl, hydroxymethyl, hydroxyethyl or acetyl substituent; R 8 and 1 together with the atom to which they are attached preferably form a cyclopropene, tetrahydropyrrole or piperidine.
本发明优选方案， 一种通式 所示化合物或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中：  A preferred embodiment of the invention, a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
X选自 0或 S; A选自取代的或未取代的苯基， 当被取代时， 选择被 1至 5个 R7取代；X is selected from 0 or S ; A is selected from substituted or unsubstituted phenyl groups, and when substituted, is selected to be substituted with 1 to 5 R 7 ;
B选自取代或未取代的如下结构之一： B is selected from one of the following structures substituted or unsubstituted:
Figure imgf000020_0001
Figure imgf000020_0001
当被取代时， 任选进一步被 1至 3个取代基所取代， 所述取代基选自 R7a或者 (=0); R R2、 R3和 R4各自独立选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 甲基、 乙 基、 丙基、 2-丙基、 正丁基、 异丁基、 甲氧基、 乙氧基、 丙氧基、 丁氧基、 环丙氧基、 氨基 甲酰基、 N-乙基氨基甲基、 烯丙基、 甲基炔基、 环丙基、 环丁基、 环戊基、 -OC(=C NH(;CH 3)、 -OC(=0)OCH3或 -NH(C=0)NH(CH3); When substituted, optionally further substituted with 1 to 3 substituents selected from R 7a or (=0); RR 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, methoxy, ethoxy, propoxy, butoxy , cyclopropyloxy, carbamoyl, N-ethylaminomethyl, allyl, methylalkynyl, cyclopropyl, cyclobutyl, cyclopentyl, -OC (=C NH(;CH 3 ) , -OC(=0)OCH 3 or -NH(C=0)NH(CH 3 );
作为选择， R1和 R2可以形成 (=0); Alternatively, R 1 and R 2 may form (=0);
作为选择， R3和 R4可以形成 (=0); Alternatively, R 3 and R 4 may form (=0);
作为选择， 其中 R R2、 R3、 R4中任意两个基团可以形成环丙基、 环丁基、 环戊基、 环 己基、 吡啶基、 呋喃基、 噻吩基、 吡咯基、 N-垸基吡咯基、 哌啶基、 吗啉基、 硫代吗啉基、 四氢呋喃基或四氢吡咯基； Alternatively, any two of RR 2 , R 3 , and R 4 may form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyridyl group, a furyl group, a thienyl group, a pyrrolyl group, and an N-fluorene group. Pyryl pyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl or tetrahydropyrrolyl;
R5选自 H、 F、 Cl、 Br、 I、 三氟甲基、 羟基、 巯基、 氰基、 氨基、 甲基、 乙基、 丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基、 丁氧基、 叔丁氧 基、 氨基甲酰基或者氨基亚甲基； R 5 is selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, hydroxy, decyl, cyano, amino, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert Butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, carbamoyl or aminomethylene;
R6选自 -C(=0)NR7R7a、 氰基、 三氟甲基、 -(CH2)nS(=0)2R8、 -C(R7R7a)R8、 -C(R7R7a)OR8、 C3— 4碳环或者 3至 4元杂环， 所述碳环或杂环各自独立任选进一步被 0至 4个 R8取代， 所述 杂环含有 1至 3个选自 N、 0或 S的杂原子； R 6 is selected from -C(=0)NR 7 R 7a , cyano, trifluoromethyl, -(CH 2 ) n S(=0) 2 R 8 , -C(R 7 R 7a )R 8 , C(R 7 R 7a )OR 8 , C 3 — 4 carbocyclic or 3- to 4-membered heterocyclic ring, each of which is optionally independently further substituted by 0 to 4 R 8 , said heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S;
R7和 1 各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 羟甲基、 三氟甲 基、 甲基、 乙基、 丙基、 异丙基、 异丁基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基、 甲氧基羰 基、 乙氧基羰基、 乙酰基、 氨基甲酰基、 烯丙基、 甲基炔基、 环丙基、 环丙基亚甲基、 环丁 基、 环戊基、 环己基、 吡啶基、 吡咯基、 哌啶基、 四氢呋喃基或四氢吡咯基； 作为选择， R7和 R7a可以形成 (=0)； R 7 and 1 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, hydroxymethyl, trifluoromethyl, methyl, ethyl, propyl, isopropyl, Isobutyl, methoxy, ethoxy, propoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, carbamoyl, allyl, methylalkynyl, cyclopropyl , cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrrolyl, piperidinyl, tetrahydrofuranyl or tetrahydropyrrolyl; Alternatively, R 7 and R 7a can be formed (=0);
作为选择， R7和 1 可与它们相连的原子一起形成 C3— 5碳环或 3至 5元的杂环， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子； Alternatively, R 7 and 1 may form a C 3 - 5 carbocyclic ring or a 3 to 5 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S;
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3—5碳环或 3至 5元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子； Alternatively, when two R 7a are bonded to the same atom, they may form a C 3 - 5 carbocyclic ring or a 3 to 5 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S;
R8选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 甲基、 乙基、 异丙基、 甲氧基、 乙氧基、 异丙氧基、 环丙基、 环丁基、 氧杂环丙基、 氧杂环丁基或氮杂环丁基； R 8 is selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, Cyclobutyl, oxetanyl, oxetanyl or azetidinyl;
m选自 0、 1或者 2; n选自 0、 1或者 2; p选自 0、 1或者 2。  m is selected from 0, 1 or 2; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2.
本发明优选方案， 一种 ©所示化合物或者其立体异构体、 氮氧化合物、 水合物、 溶剂化 物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中：  A preferred embodiment of the invention, a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
X选自 0;  X is selected from 0;
A选自苯基， 其中苯基任选进一步被 0至 4个 F取代， 优选苯基或被 1个 F取代的苯  A is selected from phenyl, wherein the phenyl group is optionally further substituted by 0 to 4 F, preferably phenyl or benzene substituted by 1 F
B B
Figure imgf000021_0001
Figure imgf000021_0001
R1 , R2、 R3和 R4独立的选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 甲基、 乙 基、 环丙基、 甲氧基或乙氧基， 优选 H、 甲基、 乙基、 甲氧基或乙氧基； R 1 , R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, cyclopropyl, methoxy or ethoxy a group, preferably H , methyl, ethyl, methoxy or ethoxy;
作为选择， R1和 R2可以形成 (=0); Alternatively, R 1 and R 2 may form (=0);
作为选择， R3和 R4可以形成 (=0); Alternatively, R 3 and R 4 may form (=0);
作为选择， 其中基团 R R2、 R3、 R4中任意两个可以形成环丙基； Alternatively, wherein any two of the groups RR 2 , R 3 , R 4 may form a cyclopropyl group;
R5选自 H、 F、 Cl、 三氟甲基、 羟基、 氨基、 甲基、 乙基、 丙基、 烯丙基、 异丙基、 正丁 基、 异丁基、 叔丁基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基、 丁氧基或叔丁氧基， 优选 H或 F; R 5 is selected from the group consisting of H, F, Cl, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, allyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy a group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group or a tert-butoxy group, preferably H or F;
R6选自氨基甲酰基、 2-异丙醇基、 1-环丙醇基、 氰基、 三氟甲基 1-氟乙基、 乙氧基甲酰 基、 1-氟甲基、 1,1-二氟甲基、 1-羟基乙基或 1-羟基甲基， 优选氨基甲酰基、 氰基或三氟甲基 进一步优选氨基甲酰基。 R 6 is selected from the group consisting of carbamoyl, 2-isopropanol, 1-cyclopropanol, cyano, trifluoromethyl 1-fluoroethyl, ethoxycarbonyl The group, 1-fluoromethyl, 1,1-difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl, preferably carbamoyl, cyano or trifluoromethyl is further preferably a carbamoyl group.
本发明优选方案， 一种通式 所示化合物或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中：  A preferred embodiment of the invention, a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
X为 0; A为苯基， 其中苯基任选进一步被 0至 4个 F取代；  X is 0; A is phenyl, wherein the phenyl group is optionally further substituted by 0 to 4 F;
B选自如下结构之一：  B is selected from one of the following structures:
Figure imgf000022_0001
Figure imgf000022_0001
R1, R2、 R3、 R4各自独立的选 β Η、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 甲基、 乙 基、 环丙基、 甲氧基或乙氧基； R 1 , R 2 , R 3 , and R 4 are each independently selected from β F, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, cyclopropyl, methoxy or B. Oxylate
作为选择， R1和 R2可以形成 (=0); Alternatively, R 1 and R 2 may form (=0);
作为选择， R3和 R4可以形成 (=0); Alternatively, R 3 and R 4 may form (=0);
作为选择， 其中 R R2、 R3、 R4中任意两个基团可以形成环丙基、 环丁基、 环戊基、 环 己基、 吡啶基、 呋喃基、 噻吩基、 吡咯基、 N-垸基吡咯基、 哌啶基、 吗啉基、 硫代吗啉基、 四氢呋喃基或四氢吡咯基； Alternatively, any two of RR 2 , R 3 , and R 4 may form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyridyl group, a furyl group, a thienyl group, a pyrrolyl group, and an N-fluorene group. Pyryl pyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl or tetrahydropyrrolyl;
R5各自独立的选自 H、 F、 Cl、 三氟甲基、 羟基、 氨基、 甲基、 乙基、 丙基、 异丙基、 甲 氧基、 乙氧基、 丙氧基或者异丙氧基； R 5 is independently selected from H, F, Cl, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy base;
R6选自氨基甲酰基、 2-异丙醇基、 1-环丙醇基、 氰基、 三氟甲基、 1-氟乙基、 乙氧基甲酰 基、 1-氟甲基、 1,1-二氟甲基、 1-羟基乙基或 1-羟基甲基； R 6 is selected from the group consisting of carbamoyl, 2-isopropanol, 1-cyclopropanol, cyano, trifluoromethyl, 1-fluoroethyl, ethoxycarbonyl, 1-fluoromethyl, 1, 1-difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl;
m选自 0、 1或者 2; p选自 0、 1或者 2。  m is selected from 0, 1 or 2; p is selected from 0, 1 or 2.
本发明优选方案， 一种通式 所示化合物或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中：  A preferred embodiment of the invention, a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
X为 0; A为苯基， 其中苯基任选进一步被 0至 4个 F取代；  X is 0; A is phenyl, wherein the phenyl group is optionally further substituted by 0 to 4 F;
B 一：  B one:
Figure imgf000022_0002
Figure imgf000022_0002
R1, R2、 R3、 R4各自独立的选 β Η、 甲基或乙基; R 1 , R 2 , R 3 , and R 4 are each independently selected from β Η, methyl or ethyl;
作为选择， R1和 R2可以形成 (=0); 作为选择， R3和 R4可以形成 (=0); Alternatively, R 1 and R 2 may form (=0); Alternatively, R 3 and R 4 may form (=0);
作为选择， 其中 R R2、 R3、 R4中任意两个基团可以形成环丙基； Alternatively, wherein any two of RR 2 , R 3 , and R 4 may form a cyclopropyl group;
R5各自独立的选 g H、 F、 Cl、 三氟甲基、 羟基、 甲基或者乙基； R 5 is independently selected from the group consisting of g H, F, Cl, trifluoromethyl, hydroxy, methyl or ethyl;
R6选自氨基甲酰基、 2-异丙醇基、 1-环丙醇基、 氰基、 三氟甲基、 1-氟乙基、 乙氧基甲酰 基、 1-氟甲基、 1 ,1-二氟甲基、 1-羟基乙基或 1-羟基甲基。 R 6 is selected from the group consisting of carbamoyl, 2-isopropanol, 1-cyclopropanol, cyano, trifluoromethyl, 1-fluoroethyl, ethoxycarbonyl, 1-fluoromethyl, 1 . 1-Difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl.
本发明优选方案， 一种通式 所示化合物或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中：  A preferred embodiment of the invention, a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
X为 0; A为苯基， 其中苯基任选进一步被 0至 4个 F取代；  X is 0; A is phenyl, wherein the phenyl group is optionally further substituted by 0 to 4 F;
B选自如下结构之一：  B is selected from one of the following structures:
Figure imgf000023_0001
Figure imgf000023_0001
R1 , R2、 R3和 R4各自独立的选自 H或甲基； R5各自独立的选 g H、 F、 CI或者甲基；R 1 , R 2 , R 3 and R 4 are each independently selected from H or methyl; R 5 is independently selected from g H, F, CI or methyl;
R6选自氨基甲酰基、 2-异丙醇基、 1-环丙醇基、 氰基、 三氟甲基、 1-氟乙基、 乙氧基甲酰 基、 1-氟甲基、 1 ,1-二氟甲基、 1-羟基乙基或 1-羟基甲基。 R 6 is selected from the group consisting of carbamoyl, 2-isopropanol, 1-cyclopropanol, cyano, trifluoromethyl, 1-fluoroethyl, ethoxycarbonyl, 1-fluoromethyl, 1 . 1-Difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl.
本发明优选方案， 一种通式 所示化合物或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中：  A preferred embodiment of the invention, a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
R5选自 H或 F; R6为氨基甲酰基。 R 5 is selected from H or F ; and R 6 is a carbamoyl group.
本发明优选方案， 一种通式 所示化合物或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中：  A preferred embodiment of the invention, a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
X为 0; A为苯基， 其中苯基可以进一步被 1个 F取代；  X is 0; A is a phenyl group, wherein the phenyl group may be further substituted by 1 F;
B选自如下结构之一：
Figure imgf000023_0002
? B is selected from one of the following structures:
Figure imgf000023_0002
?
R1 , R2、 R3和 R4各自独立的选自 H; R5各自独立的选自 H或者 F; R6选自氨基甲酰 基； m为 1。 R 1 , R 2 , R 3 and R 4 are each independently selected from H ; R 5 is independently selected from H or F; R 6 is selected from carbamoyl; m is 1.
本发明优选方案， 一种通式 所示化合物或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中：  A preferred embodiment of the invention, a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
X为 0; A为苯基， 其中苯基可以进一步被 1个 F取代；  X is 0; A is a phenyl group, wherein the phenyl group may be further substituted by 1 F;
B选自如下结构之一：
Figure imgf000024_0001
B is selected from one of the following structures:
Figure imgf000024_0001
R1 , R2各自独立的选自 H或者甲基； R3、 R4各自独立的选自 H; R5各自独立的选自 H 或者 F; R 1 , R 2 are each independently selected from H or methyl; R 3 , R 4 are each independently selected from H; R 5 is independently selected from H or F;
R6选自氨基甲酰基或者三氟甲基； m为 1。 R 6 is selected from carbamoyl or trifluoromethyl; m is 1.
本发明优选方案， 一种通式 所示化合物或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中：  A preferred embodiment of the invention, a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
X为 0; A为苯基， 其中苯基可以进一步被 1个 F取代；  X is 0; A is a phenyl group, wherein the phenyl group may be further substituted by 1 F;
B选自 下结构之一：
Figure imgf000024_0002
B is selected from one of the following structures:
Figure imgf000024_0002
R1 , R2各自独立的选自 H或者甲基； R3、 R4各自独。」 ,立的选自 H; R5各自独立的选自 H 或者 F; R 1 and R 2 are each independently selected from H or methyl; R 3 and R 4 are each independently. "," is selected from H; R 5 is independently selected from H or F;
R6选自氨基甲酰基或者三氟甲基； m为 1。 R 6 is selected from carbamoyl or trifluoromethyl; m is 1.
本发明优选方案， 一种通式 所示化合物或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中：  A preferred embodiment of the invention, a compound of the formula or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
X为 0; A为苯基， 其中苯基可以进一步被 1个 F取代；  X is 0; A is a phenyl group, wherein the phenyl group may be further substituted by 1 F;
一：
Figure imgf000024_0003
One:
Figure imgf000024_0003
R1 , R2、 R3、 R4各自独立的选自 H; R5各自独立的选自 H或者 F; R6为氨基甲酰基； m 为 1 R 1 , R 2 , R 3 , R 4 are each independently selected from H; R 5 is independently selected from H or F ; R 6 is carbamoyl; m is 1
案， 本发明涉及化合物选自， 但不限于:  The invention relates to a compound selected from, but not limited to:
Figure imgf000024_0004
Figure imgf000024_0004
Figure imgf000025_0001
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000025_0002
本发明涉及通式 所示化合物的合适的药学上可接受的盐包括， 但不限于盐酸盐、 氢 溴酸盐、 硫酸盐、 硝酸盐、 磷酸盐、 乙酸盐、 马来酸盐、 琥珀酸盐、 扁桃酸盐、 富马酸盐、 丙二酸盐、 苹果酸盐、 2-羟基丙酸盐、 草酸盐、 羟乙酸盐、 水杨酸盐、 葡萄糖醛酸盐、 半乳 糖醛酸盐、 枸橼酸盐、 酒石酸盐、 门冬氨酸盐、 谷氨酸盐、 苯甲酸盐、 肉桂酸盐、 对甲苯磺 酸盐、 苯磺酸盐、 甲磺酸盐、 乙磺酸盐、 三氟甲磺酸盐或它们的组合。  Suitable pharmaceutically acceptable salts of the compounds of the formula of the invention include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, amber Acid salt, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronide, galactose Acid salt, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, besylate, methanesulfonate, ethanesulfonic acid Salt, triflate or a combination thereof.
本发明优选方案， 一种通式 所示化合物的合适的药学上可接受的盐包括盐酸盐、 硫 酸盐、 磷酸盐、 乙酸盐、 马来酸盐、 琥珀酸盐、 富马酸盐、 苹果酸盐、 草酸盐、 酒石酸盐、 苯甲酸盐、 肉桂酸盐、 对甲苯磺酸盐、 苯磺酸盐、 甲磺酸盐、 三氟甲磺酸盐或它们的组合。  Preferred pharmaceutically acceptable salts of a compound of the formula include hydrochlorides, sulfates, phosphates, acetates, maleates, succinates, fumarates, Malate, oxalate, tartrate, benzoate, cinnamate, p-toluenesulfonate, besylate, methanesulfonate, triflate or combinations thereof.
本发明涉及通式 所述的化合物或其药学上可接受的的共晶， 其中共晶形成物包括脯 氨酸、 苯丙氨酸、 焦谷氨酸。  The present invention relates to a compound of the formula or a pharmaceutically acceptable cocrystal thereof, wherein the eutectic formation comprises valine, phenylalanine, pyroglutamic acid.
本发明涉及一种通式 （I-b) 所示的化合物、 其立体异构体或其药学上可接受的盐， 所述 化合物为合成通式 ω所述化合物的中间体， 其中：
Figure imgf000026_0001
The present invention relates to a compound represented by the formula (Ib), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is an intermediate for synthesizing a compound of the formula ω, wherein:
Figure imgf000026_0001
X'选自 O或者 S(=0)p， 优选 O; Z选自 F、 Cl、 Br或 I; X' is selected from O or S(=0) p , preferably O; Z is selected from F, Cl, Br or I;
R 、 R2'、 R3'和 R4'各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d_4 垸基、 d_4垸氧基、 d_4垸氧基垸基、 -(CH2)nNR8R8a、 -(CH2)nC(=0)NR8R8\ -OC(=0)NR8R8\ -OC(=0)OR8、 -OC(=0)R8、 -C(=0)OR8、 -尊 =0) ¾&、 -N(R8)C(=0)OR8\ -雕 8)C(=0)R8a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 C3— 1()碳环、 3至 10元杂环、 -0-(CH2)n-C3— 10 碳环或者 -C CH2;in-(3至 10元杂环 )， 优选 H或者甲基； 所述的垸基、 垸氧基、 碳环或杂环各 自独立任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸基、 4垸氧基或 -NR7R7a的取代基所取代； R, R 2 ', R 3 ' and R 4 ' are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 4 fluorenyl, d 4 methoxy, d 4垸 垸、, -(CH 2 ) n NR 8 R 8a , -(CH 2 ) n C(=0)NR 8 R 8 \ -OC(=0)NR 8 R 8 \ -OC(=0) OR 8 , -OC(=0)R 8 , -C(=0)OR 8 , -尊=0) 3⁄4 & , -N(R 8 )C(=0)OR 8 \ -雕8 )C(= 0) R 8a , -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 , -(CH 2 ) n -alkynyl-R 8 , C 3 - 1 () carbocyclic, 3 to 10 membered heterocyclic ring, -0-(CH 2 ) n -C 3 - 10 carbocyclic ring or -C CH 2 ; i n - (3 to 10 membered heterocyclic ring), preferably H or methyl The thiol, decyloxy, carbocyclic or heterocyclic ring are each independently optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 Substituted by a substituent of a fluorenyl group, a 4-methoxy group or a -NR 7 R 7a ;
作为选择， 1^'和1 2'可以形成(=0); Alternatively, 1^' and 1 2 ' can be formed (=0) ;
作为选择， R3'和 R4'可以形成 (=0); Alternatively, R 3 'and R 4 ' may form (=0);
作为选择， ！^1'、 R2'、 R3'、 R4'中任意两个基团可以形成一个 3至 6元环， 包含螺环或并 环， 所述 3至 6元环含有 0至 3个选自 N、 0或者 S的杂原子， 并且形成的 3至 6元环可以 任选进一步被 0至 4个 R7a取代； As an option, ! Any two of ^ 1 ', R 2 ', R 3 ', R 4 ' may form a 3- to 6-membered ring containing a spiro ring or a ring, and the 3 to 6-membered ring contains 0 to 3 rings. a hetero atom from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ;
R5'各自独立地选自 H、 F、 Cl、 Br、 I、 三氟甲基、 d_4垸基、 d_4垸氧基、 羟基、 巯基、 氨基、 氰基、 -(CR7R7a)n-C(=0)-NR7R7a或者 -(CR7R7a)nNR7R7a， 优选 H或者 F; R 5 ' are each independently selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, d_ 4 fluorenyl, d 4 methoxy, hydroxy, decyl, amino, cyano, -(CR 7 R 7a ) n -C(=0)-NR 7 R 7a or -(CR 7 R 7a ) n NR 7 R 7a , preferably H or F;
R7和 1 各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 d— 4垸基、 d— 4垸氧 基、 -C C -d— 5垸基、 -C(=0)OR8、 -N(R8)C(=0)R8a、 -(CR8R8a)n R8R8a、 -(CH2)nC(=0)NR8R8a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 -(CH^-Cw。碳环、 -C(=0)-(3至 10元杂 环)、 -(CH2)n-(3至 10元杂环)、 -0-(CH2)n-C3_1Q碳环或者 -0-(CH2)n-(3至 10元杂环)， 所述杂环 含有 1至 3个选自 N、 0或 S的杂原子， 所述垸基、 垸氧基、 碳环或者杂环任选进一步被 0 至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔 基、 氨基、 -C(=0)-(3至 10元杂环)、 -ϋ(=ο)ο- 4垸基、 羟基取代的 d— 3垸基、 -C^C -d— 3 垸基、 C3— 1Q碳环或 3至 10元杂环的取代基所取代； R 7 and 1 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, d- 4 fluorenyl, d- 4- decyloxy, -CC-d- 5 fluorenyl, -C (=0)OR 8 , -N(R 8 )C(=0)R 8a , -(CR 8 R 8a ) n R 8 R 8a , -(CH 2 ) n C(=0)NR 8 R 8a , -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 , -(CH 2 ) n -alkynyl-R 8 , -(CH^-Cw. Carbocycle -C(=0)-(3 to 10 membered heterocyclic), -(CH 2 ) n -(3 to 10 membered heterocyclic), -0-(CH 2 ) n -C 3 _ 1Q carbocyclic or 0-(CH 2 ) n -(3 to 10 membered heterocyclic ring), the heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, the fluorenyl group, the decyloxy group, the carbocyclic ring or the hetero The ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, methyl alkynyl, amino -C(=0)-(3 to 10-membered heterocyclic ring), -ϋ(=ο)ο- 4 fluorenyl, hydroxy-substituted d- 3 fluorenyl, -C^C-d- 3 fluorenyl, C Substituted by a substituent of 3 - 1Q carbocyclic or 3 to 10 membered heterocyclic ring;
作为选择， R7和 1 可以形成 (=0); Alternatively, R 7 and 1 can be formed (=0);
作为选择， R7和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -C(=0)-(3至 10元杂环)、 (=ο)ο- 4垸基、 羟基取代的 3垸基或 -c^c -d— 3垸基的取代 基所取代； Alternatively, R 7 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, Methyl alkynyl, amino, Substituted with a substituent of -C(=0)-(3 to 10 membered heterocyclic), (=o)o-4, hydroxy substituted 3 fluorenyl or -c^c-d- 3 fluorenyl;
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3— 1Q碳环 或 3至 10元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任 选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰 胺基、 甲基炔基、 氨基、 -C(=0)-3至 10元杂环、 -Cl^C O-d— 4垸基、 羟基取代的 d— 3垸基或Alternatively, when two R 7a are bonded to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 decyloxy, hydroxy , fluorenyl, cyano, amido, methylalkynyl, amino, -C(=0)-3 to 10-membered heterocyclic ring, -Cl^C Od- 4 fluorenyl, hydroxy substituted d- 3 fluorenyl or
-C(=0)-d.3垸基的取代基所取代； Substituted by a substituent of -C(=0)-d.3 thiol;
R8、 ！^ 和 R8b各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d_4垸 基、 d_4垸氧基、 C3_1Q碳环或 3至 10元杂环； R 8 , ! ^ and R 8b are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 4 fluorenyl, d 4 methoxy, C 3 _ 1Q carbon ring or 3 to 10 Heterocycle
作为选择， R8和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -C(=0)-(3至 10元杂环)、 (=0)0-^4垸基、 羟基取代的 d_3垸基或 -C^C -Cw垸基的取代 基所取代； Alternatively, R 8 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, Methyl alkynyl, amino, -C(=0)-(3 to 10-membered heterocyclic), (=0)0-^4 fluorenyl, hydroxy-substituted d- 3 fluorenyl or -C^C-Cw fluorenyl Substituted by a substituent;
R9选自 d— 12垸基， 所述垸基任选进一步被 0至 4个 R8取代。 R 9 is selected from d- 12 fluorenyl, which is optionally further substituted with 0 to 4 R 8 .
m'选自 0、 1、 2或者 3 ; n选自 0、 1、 2、 3或者 4; p选自 0、 1或者 2。  m' is selected from 0, 1, 2 or 3; n is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1 or 2.
本发明优选方案， Z在每一种情况下， 选自 C1;  Preferably, in each case, Z is selected from C1;
本发明优选方案， R9在每一种情况下， 选自甲基、 乙基、 异丙基、 正丁基或异丁基。 本发明优选方案， R 、 R2'、 R3'和 R4'各自独立选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰 基、 氨基、 甲基、 乙基、 丙基、 2-丙基、 正丁基、 异丁基、 甲氧基、 乙氧基、 丙氧基、 丁氧 基、 环丙氧基、 氨基甲酰基、 N-乙基氨基甲基、 烯丙基、 甲基炔基、 环丙基、 环丁基、 环戊 基、 环己基、 吡啶基、 N-甲基吡咯基、 呋喃基、 噻吩基、 吡咯基、 哌啶基、 吗啉基、 硫代吗 啉基， 四氢呋喃基、 四氢吡咯基、 环丁氧基、 环戊氧基、 氧杂环丁基、 氧杂环丁氧基、 氮杂 环丁基、 氮杂环丁氧基、 氧杂环戊氧基、 氮杂环戊氧基、 环丙基甲基氧基、 -OC(=0)NH(CH3)、 -OC(=0)OCH3或 -NH(C=0)NH(CH3); In a preferred embodiment of the invention, R 9 is, in each case selected from the group consisting of methyl, ethyl, isopropyl, n-butyl or isobutyl. In a preferred embodiment of the invention, R, R 2 ', R 3 ' and R 4 ' are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, carbamoyl, N-ethylaminomethyl, allyl, Methyl alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N-methylpyrrolyl, furyl, thienyl, pyrrolyl, piperidinyl, morpholinyl, thio Polinyl, tetrahydrofuranyl, tetrahydropyrrolyl, cyclobutoxy, cyclopentyloxy, oxetanyl, oxetanyloxy, azetidinyl, azetidinyloxy, oxyheterocycle pentyloxy group, cyclopentyloxy aza, cyclopropylmethyl group, -OC (= 0) NH ( CH 3), -OC (= 0) OCH 3 , or -NH (C = 0) NH ( CH 3 );
作为选择， R1'和 R2'可以形成 (=0); Alternatively, R 1 'and R 2 ' may form (=0);
作为选择， R3'和 R4'可以形成 (=0); Alternatively, R 3 'and R 4 ' may form (=0);
作为选择， ！^1'、 R2'、 R3'、 R4'中任意两个基团可以形成一个 3至 6元环， 包含螺环或并 环， 所述 3至 6元环含有 0至 3个选自 N、 0或者 S的杂原子， 并且形成的 3至 6元环可以 任选进一步被 0至 4个 R7a取代。 As an option, ! Any two of ^ 1 ', R 2 ', R 3 ', R 4 ' may form a 3- to 6-membered ring containing a spiro ring or a ring, and the 3 to 6-membered ring contains 0 to 3 rings. A hetero atom from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a .
本发明优选方案， R1^ R2'、 R3'、 R4'独立的选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰 基、 氨基、 甲基、 乙基、 环丙基、 甲氧基、 乙氧基或环丙氧基， 优选 H或者甲基； 作为选择， R1'和 R2'可以形成 (=0); In a preferred embodiment of the invention, R 1 ^ R 2 ', R 3 ', R 4 ' are independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, methyl, ethyl, cyclopropane a methoxy group, an ethoxy group or a cyclopropoxy group, preferably H or a methyl group; Alternatively, R 1 'and R 2 ' may form (=0) ;
作为选择， R3'和 R4'可以形成 (=0); Alternatively, R 3 'and R 4 ' may form (=0);
作为选择， 其中 R 、 R2'、 R'3和 R4'中任意两个可以形成取代和未取代的环丙基、 环丁 基、 环戊基、 环己基、 环己烯基、 吡啶基、 呋喃基、 噻吩基、 吡咯基、 N-垸基吡咯基、 哌啶 基、 吗啉基、 硫代吗啉基、 四氢呋喃基或四氢吡咯基， 优选形成环丙基。 Alternatively, wherein any two of R, R 2 ', R' 3 and R 4 ' may form substituted and unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, pyridyl And a furyl group, a thienyl group, a pyrrolyl group, a N-fluorenylpyrrolyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a tetrahydrofuranyl group or a tetrahydropyrrole group, preferably forms a cyclopropyl group.
本发明优选方案， '、 R2'、 R3'和 R4'独立的选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰 基、 氨基、 甲基、 乙基、 环丙基、 甲氧基或乙氧基， 优选 H或者甲基， 进一步优选 H; In a preferred embodiment of the invention, ', R 2 ', R 3 ' and R 4 ' are independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, methyl, ethyl, cyclopropyl. , methoxy or ethoxy, preferably H or methyl, further preferably H;
作为选择， R1'和 R2'可以形成 (=0); Alternatively, R 1 'and R 2 ' may form (=0);
作为选择， R3'和 R4'可以形成 (=0); Alternatively, R 3 'and R 4 ' may form (=0);
作为选择， 其中 R 、 R2'、 R3'和 R4'中任意两个可以形成环丙基。 Alternatively, any two of R, R 2 ', R 3 ' and R 4 ' may form a cyclopropyl group.
本发明优选方案， R5'选自 H、 F、 Cl、 Br、 I、 三氟甲基、 羟基、 巯基、 氰基、 氨基、 甲 基、 乙基、 丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 甲氧基、 乙氧基、 丙氧基、 异丙氧 基、 丁氧基、 叔丁氧基、 氨基甲酰基或者氨基亚甲基， 优选 H或者 F。 In a preferred embodiment of the invention, R 5 ' is selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, hydroxy, decyl, cyano, amino, methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, carbamoyl or aminomethylene, preferably H or F.
本发明优选方案， 其中 R5'选自 H、 F、 Cl、 三氟甲基、 羟基、 氨基、 甲基、 乙基、 丙 基、 异丙基、 甲氧基、 乙氧基、 丙氧基或者异丙氧基， 优选 H或者 F。 Preferred Embodiments of the Invention, wherein R 5 ' is selected from the group consisting of H, F, Cl, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy Or isopropoxy, preferably H or F.
本发明优选方案， 其中 Z选自 Cl; R9选自甲基、 乙基、 丙基、 异丙基、 正丁基或异丁 基。 A preferred embodiment of the invention wherein Z is selected from the group consisting of Cl ; and R 9 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.
本发明涉及一种通式 （I-a) 所示的化合物、 其立体异构体或其药学上可接受的盐， 所述 化合物为合成通式（I)所述化合物的中间体， 其中：  The present invention relates to a compound represented by the formula (I-a), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is an intermediate for synthesizing a compound of the formula (I), wherein:
Figure imgf000028_0001
Figure imgf000028_0001
X'选自 0或者 S(=0)p， 优选 0; X' is selected from 0 or S (=0) p , preferably 0;
R 、 R2'、 R3'和 R4'各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d_4 垸基、 CM垸氧基、 d— 4垸氧基垸基、 -(CH2)nNR8R8a、 -(CH2)nC(=0) R8R8a、 -OC(=0)NR8R8a、 -OC(=0)OR8、 -OC(=0)R8、 -C(=0)OR8、 -尊 =0) ¾&、 -N(R8)C(=0)OR8\ -雕 8)C(=0)R8a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 C3— 1()碳环、 3至 10元杂环、 -0-(CH2)n-C3— 10 碳环或者 -0-(CH2)n-(3至 10元杂环)， 优选 H或者甲基， 进一步优选 H; 所述的垸基、 垸氧 基、 碳环或杂环各自独立任选进一步被 0 至 4个选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰 基、 氨基、 d— 4垸基、 d— 4垸氧基或 -NR7R7a的取代基所取代； R, R 2 ', R 3 ' and R 4 ' are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d_ 4 fluorenyl, CM methoxy, d- 4垸 垸、, -(CH 2 ) n NR 8 R 8a , -(CH 2 ) n C(=0) R 8 R 8a , -OC(=0)NR 8 R 8a , -OC(=0) OR 8 , -OC(=0)R 8 , -C(=0)OR 8 , -尊=0) 3⁄4 & , -N(R 8 )C(=0)OR 8 \ -雕8 )C(= 0) R 8a , -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 , -(CH 2 ) n -alkynyl-R 8 , C 3 - 1 () carbocyclic, 3 to 10 membered heterocyclic ring, -0-(CH 2 ) n -C 3 - 10 carbocyclic ring or -0-(CH 2 ) n - (3 to 10 membered heterocyclic ring), preferably H or A Further, H; the fluorenyl group, the decyloxy group, the carbocyclic ring or the heterocyclic ring are each independently optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, Substituted by a substituent of an amino group, d- 4 fluorenyl group, d- 4 methoxy group or -NR 7 R 7a ;
作为选择， R1'和 R2'可以形成 (=0); 作为选择， R3'和 R4'可以形成 (=0); Alternatively, R 1 'and R 2 ' may form (=0); Alternatively, R 3 'and R 4 ' may form (=0) ;
作为选择， ！^1'、 R2'、 R3'、 R4'中任意两个基团可以形成一个 3至 6元环， 包含螺环或并 环， 所述 3至 6元环含有 0至 3个选自 N、 0或者 S的杂原子， 并且形成的 3至 6元环可以 任选进一步被 0至 4个 R7a取代； '、 R2'、 R3'、 R4'中任意两个基团优选形成环丙基； As an option, ! Any two of ^ 1 ', R 2 ', R 3 ', R 4 ' may form a 3- to 6-membered ring containing a spiro ring or a ring, and the 3 to 6-membered ring contains 0 to 3 rings. a hetero atom from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ; any two of ', R 2 ', R 3 ', R 4 ' Preferably forming a cyclopropyl group;
R5'各自独立地选自 H、 F、 Cl、 Br、 I、 三氟甲基、 d_4垸基、 d_4垸氧基、 羟基、 巯基、 氨基、 氰基、 -(CR7R7a)n-C(=0)-NR7R7a或者 -(CR7R7a)nNR7R7a， 优选 H或者甲基， 进一步优选 H; R 5 ' are each independently selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, d_ 4 fluorenyl, d 4 methoxy, hydroxy, decyl, amino, cyano, -(CR 7 R 7a ) n -C(=0)-NR 7 R 7a or -(CR 7 R 7a ) n NR 7 R 7a , preferably H or methyl, further preferably H;
R7和 1 各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 d— 4垸基、 d— 4垸氧 基、 -C(=0)-d— 5垸基、 -C(=0)OR8、 -N(R8)C(=0)R8a、 -(CR8R8a)nNR8R8a、 -(CH2)nC(=0)NR8R8a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 -(CH2)n-C3— 1()碳环、 -C(=0)-(3至 10元 杂环)、 -(CH2)n-(3至 10元杂环)、 -0-(CH2)n-C3_1Q碳环或者 -0-(CH2)n-(3至 10元杂环)， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述垸基、 垸氧基、 碳环或者杂环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基 炔基、 氨基、 -C(=0)-(3至 10元杂环)、 -Q^C O-d— 4垸基、 羟基取代的 d— 3垸基、 -C C -d— 3 垸基、 C3— 1Q碳环或 3至 10元杂环的取代基所取代； R 7 and 1 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, d- 4- indolyl, d- 4- decyloxy, -C(=0)-d- 5垸Base, -C(=0)OR 8 , -N(R 8 )C(=0)R 8a , -(CR 8 R 8a ) n NR 8 R 8a , -(CH 2 ) n C(=0)NR 8 R 8a , -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 , -(CH 2 ) n -alkynyl-R 8 , -(CH 2 ) n -C 3 - 1 () carbocyclic ring, -C (=0) - (3 to 10 membered heterocyclic ring), -(CH 2 ) n - (3 to 10 membered heterocyclic ring), -0-(CH 2 ) n- C 3 _ 1Q carbocyclic ring or-0-(CH 2 ) n - (3 to 10 membered heterocyclic ring) having 1 to 3 hetero atoms selected from N, 0 or S, said hydrazine The group, the methoxy group, the carbocyclic ring or the heterocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano , amide group, methyl alkynyl group, amino group, -C(=0)-(3 to 10-membered heterocyclic ring), -Q^C Od- 4 fluorenyl group, hydroxy-substituted d- 3 fluorenyl group, -CC-d — a substituent substituted with a 3 fluorenyl group, a C 3 —1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring;
作为选择， R7和 1 可以形成 (=0); Alternatively, R 7 and 1 can be formed (=0);
作为选择， R7和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -C(=0)-(3至 10元杂环)、 (=0)0- 4垸基、 羟基取代的 3垸基或 -C^C -d— 3垸基的取代 基所取代； Alternatively, R 7 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, methyl alkynyl group, an amino group, -C (= 0) - ( 3 to 10-membered heterocyclyl), (= 0) 0-4 embankment group, a hydroxy-substituted alkyl with 3 or -C ^ C -d- 3-yl embankment Substituted by a substituent;
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3— 1Q碳环 或 3至 10元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任 选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰 胺基、 甲基炔基、 氨基、 -C(=0)-3至 10元杂环、 -Cl^C O-d— 4垸基、 羟基取代的 d— 3垸基或Alternatively, when two R 7a are bonded to the same atom, they may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 decyloxy, hydroxy , fluorenyl, cyano, amido, methylalkynyl, amino, -C(=0)-3 to 10-membered heterocyclic ring, -Cl^C Od- 4 fluorenyl, hydroxy substituted d- 3 fluorenyl or
-C(=0)-d.3垸基的取代基所取代； Substituted by a substituent of -C(=0)-d.3 thiol;
R8、 ！^ 和 R8b各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d_4垸 基、 d_4垸氧基、 C3_1Q碳环或 3至 10元杂环； R 8 , ! ^ and R 8b are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 4 fluorenyl, d 4 methoxy, C 3 _ 1Q carbon ring or 3 to 10 Heterocycle
作为选择， R8和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 所述杂 环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -C(=0)-(3至 10元杂环)、 -C^C O-CM垸基、 羟基取代的 d_3垸基或 -C^C -Cw垸基的取代 基所取代； Alternatively, R 8 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, Methyl alkynyl, amino, -C(=0)-(3 to 10-membered heterocyclic), -C^C O-CM fluorenyl, hydroxy-substituted d_ 3 fluorenyl or -C^C-Cw fluorenyl Replace Substituted by
m'选自 0、 1、 2或者 3 ; n选自 0、 1、 2、 3或者 4; p选自 0、 1或者 2。  m' is selected from 0, 1, 2 or 3; n is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1 or 2.
本发明优选方案， m'在每一种情况下， 选自 0或 1。  In a preferred embodiment of the invention, m' is in each case selected from 0 or 1.
本发明优选方案， R 、 R2'、 R3'和 R4'在每一种情况下， 各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸基、 d— 4垸氧基、 d— 4垸氧基垸基、 C3— 8碳环、 3至 8 元杂环、 -0-(CH2)n-C3— 8碳环或者 -0-(CH2)n-(3至 8元杂环)， 其中所述的杂环含有 1至 4个选 自 N、 0或 S的杂原子， 其中所述的垸基、 垸氧基、 碳环或杂环各自独立任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸基或 d—4垸氧基的取代基所取 代， 优选 H、 F、 Cl、 Br、 I、 羟基、 氨基、 甲基、 乙基、 甲氧基或乙氧基， 进一步优选 H或 者甲基， 更优选 H; In a preferred embodiment of the invention, R, R 2 ', R 3 ' and R 4 ' are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, d --4 alkyl with, d- 4 embankment group, d- 4 alkyl with embankment group, C 3 - 8 carbon ring of 3 to 8-membered heterocyclic, -0- (CH 2) n -C 3 - 8 carbon ring Or -0-(CH 2 ) n -(3 to 8 membered heterocyclic ring), wherein the heterocyclic ring contains 1 to 4 hetero atoms selected from N, 0 or S, wherein the fluorenyl group and the oxime group The radical, carbocyclic or heterocyclic ring are each independently optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4- indolyl or d- 4 fluorenyloxy Substituted by a substituent, preferably H, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, methoxy or ethoxy, further preferably H or methyl, more preferably H;
R!\ R2'、 R3'和 R4'各自独立地优选 H、 F、 Cl、 Br、 I、 羟基、 氰基、 氨基、 d— 4垸基、 CM垸氧基、 C3— 5碳环、 3至 5元杂环、 -0-(CH2)n-C3— 5碳环或者 -0-(CH2)n-(3至 5元杂环)， 其 中所述的杂环含有 1至 4个选自 N、 0或 S的杂原子， 其中所述的垸基、 垸氧基、 碳环或杂 环各自独立任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d_4垸 基或 d— 4垸氧基的取代基所取代， 优选 H、 F、 Cl、 Br、 I、 羟基、 氨基、 甲基、 乙基、 甲氧 基或乙氧基， 进一步优选 H或者甲基， 更优选 H; R ! \ R 2 ', R 3 ' and R 4 ' are each independently preferably H, F, Cl, Br, I, hydroxy, cyano, amino, d- 4 fluorenyl, CM methoxy, C 3 - 5 Carbocyclic ring, 3 to 5 membered heterocyclic ring, -0-(CH 2 ) n -C 3 - 5 carbocyclic ring or -0-(CH 2 ) n - (3 to 5 membered heterocyclic ring), wherein said heterocyclic ring Containing 1 to 4 hetero atoms selected from N, 0 or S, wherein the fluorenyl, decyloxy, carbocyclic or heterocyclic ring is each independently optionally further selected from 0 to 4 selected from H, F, Cl, Substituted by a substituent of Br, I, hydroxy, decyl, cyano, amino, d- 4 yl or d- 4 methoxy, preferably H, F, Cl, Br, I, hydroxy, amino, methyl, ethyl , methoxy or ethoxy, further preferably H or methyl, more preferably H;
R!\ R2'、 R3'和 R4'各自独立地进一步优选 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨 基、 d— 4垸基、 d— 4垸氧基、 C3— 4碳环或者 -0-C3— 4碳环， 其中所述的垸基、 垸氧基或碳环各自 独立任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d_4垸基或 C M垸氧基的取代基所取代， 优选 H、 F、 Cl、 Br、 I、 羟基、 氨基、 甲基、 乙基、 甲氧基或乙 氧基， 进一步优选 H或者甲基， 更优选 H; R ! \ R 2 ', R 3 ' and R 4 ' are each independently further preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4 fluorenyloxy a C 3 - 4 carbocyclic ring or an -0-C 3 - 4 carbocyclic ring, wherein the fluorenyl group, the decyloxy group or the carbocyclic ring are each independently optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br Substituted by a substituent of I, hydroxy, decyl, cyano, amino, d- 4 yl or CM methoxy, preferably H, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, methoxy Or an ethoxy group, further preferably H or a methyl group, more preferably H;
R2'、 R3'和 R4'各自独立地更优选 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d_2 垸基、 d— 2垸氧基、 c3— 4碳环或者 -o-c3— 4碳环， 其中所述的垸基、 垸氧基或碳环各自独立任选 进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸基或 d— 4垸氧基 的取代基所取代， 优选 H、 F、 Cl、 Br、 I、 羟基、 氨基、 甲基、 乙基、 甲氧基或乙氧基， 进 一步优选 H或者甲基， 更优选 H; R 2 ', R 3 ' and R 4 ' are each independently more preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 2 fluorenyl, d- 2- decyloxy, c 3 — a 4 carbocyclic ring or a -oc 3 - 4 carbocyclic ring, wherein said fluorenyl group, decyloxy group or carbocyclic ring are each independently optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, hydroxy, fluorenyl Substituted by a substituent of a cyano group, an amino group, a d- 4 fluorenyl group or a d- 4 methoxy group, preferably H, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, methoxy or B Oxy group, further preferably H or methyl group, more preferably H;
作为选择， 其中 R1'和 R2'可以形成 (=0); Alternatively, wherein R 1 'and R 2 ' may form (=0);
作为选择， 其中 R3'和 R4'可以形成 (=0); Alternatively, wherein R 3 'and R 4 ' may form (=0);
作为选择， 其中 R 、 R2'、 R3'、 R4'中任意两个基团可与它们相连的原子一起形成一个 3 至 6元环， 包含螺环或并环， 所述 3至 6元环含有 0至 3个选自 N、 0或者 S的杂原子， 并 且形成的 3至 6元环可以任选进一步被 0至 4个 R7a取代； 1 、 R2'、 R3\ R4'中任意两个基 团可与它们相连的原子一起优选形成一个 3至 4元环， 所述 3至 4元环含有 0至 3个选自 N、 O或者 S的杂原子， 并且形成的 3至 4元环可以任选进一步被 0至 4个 R7a取代； Rh, R2'、Alternatively, any two of R, R 2 ', R 3 ', R 4 ' may form a 3 to 6 membered ring together with the atoms to which they are attached, including a spiro ring or a cis ring, said 3 to 6 The ring contains 0 to 3 heteroatoms selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ; 1 , R 2 ', R 3 \ R 4 Any two of the 'groups together with the atoms to which they are attached preferably form a 3 to 4 membered ring, and the 3 to 4 membered ring contains 0 to 3 selected from 0 to 3 a hetero atom of N, O or S, and the formed 3- to 4-membered ring may be optionally further substituted by 0 to 4 R 7a ; R h , R 2 ',
R3'、 R4'中任意两个基团可与它们相连的原子一起进一步优选形成一个 3元环， 优选形成环丙 基， 所述 3元环含有 0至 1个选自 N、 0或者 S的杂原子， 并且形成的 3元环可以任选进一 步被 0至 3个 R7a取代； 其中所述 R7a选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 d— 4垸 基、 d— 4垸氧基， 优选 H、 F、 羟基、 氰基、 甲基、 乙基、 甲氧基或乙氧基。 Any two of R 3 ', R 4 ' may further preferably form a 3-membered ring together with the atoms to which they are attached, preferably forming a cyclopropyl group, the 3-membered ring having 0 to 1 selected from N, 0 or a hetero atom of S, and the formed 3-membered ring may be optionally further substituted with 0 to 3 R 7a ; wherein said R 7a is selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, d- 4 -mercapto, d- 4 methoxy, preferably H, F, hydroxy, cyano, methyl, ethyl, methoxy or ethoxy.
本发明优选方案， '、 R2'、 R3'和 R4'在每一种情况下， 各自独立选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 甲基、 乙基、 丙基、 2-丙基、 正丁基、 异丁基、 甲氧基、 乙氧 基、 丙氧基、 丁氧基、 环丙氧基、 氨基甲酰基、 N-乙基氨基甲基、 烯丙基、 甲基炔基、 环丙 基、 环丁基、 环戊基、 环己基、 吡啶基、 N-甲基吡咯基、 呋喃基、 噻吩基、 吡咯基、 哌啶 基、 吗啉基、 硫代吗啉基， 四氢呋喃基、 四氢吡咯基、 环丁氧基、 环戊氧基、 氧杂环丁基、 氧杂环丁氧基、 氮杂环丁基、 氮杂环丁氧基、 氧杂环戊氧基、 氮杂环戊氧基、 环丙基甲基氧 基、 -OC(=0)NH(CH3)、 -OC(=0)OCH3或 -NH(C=0)NH(CH3)， 优选 H、 F、 Cl、 Br、 I、 羟 基、 巯基、 氰基、 氨基、 甲基、 乙基、 环丙基、 甲氧基、 乙氧基或环丙氧基， 进一步优选 H、 F、 Cl、 甲基、 乙基、 甲氧基或乙氧基， 进一步优选 H或者甲基， 更优选 H; In a preferred embodiment of the invention, ', R 2 ', R 3 ' and R 4 ' are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, thiol, cyano, amino, methyl , ethyl, propyl, 2-propyl, n-butyl, isobutyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, carbamoyl, N-ethylamino Methyl, allyl, methylalkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N-methylpyrrolyl, furyl, thienyl, pyrrolyl, piperidinyl, Morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyrrolyl, cyclobutoxy, cyclopentyloxy, oxetanyl, oxetanyloxy, azetidinyl, nitrogen heterocycle Butoxy, oxolyloxy, azacyclopentyloxy, cyclopropylmethyloxy, -OC(=0)NH(CH 3 ), -OC(=0)OCH 3 or -NH( C=0)NH(CH 3 ), preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, cyclopropyl, methoxy, ethoxy or cyclopropane Oxy group, further preferably H, F, Cl, A , Ethyl, methoxy or ethoxy, more preferably H or methyl, more preferably H;
作为选择， 1^'和1 2'可以形成(=0); Alternatively, 1^' and 1 2 ' can be formed (=0) ;
作为选择， R3'和 R4'可以形成 (=0); Alternatively, R 3 'and R 4 ' may form (=0);
作为选择， ！^1'、 R2'、 R3'、 R4'中任意两个基团可与它们相连的原子一起形成一个 3 至 6 元环， 包含螺环或并环， 所述 3至 6元环含有 0至 3个选自 N、 0或者 S的杂原子， 并且形 成的 3至 6元环可以任选进一步被 0至 4个 R7a取代， 1 、 R2'、 R3'、 R4'中任意两个基团可 与它们相连的原子一起优选可以形成取代和未取代的环丙基、 环丁基、 环戊基、 环己基、 环 己烯基、 吡啶基、 呋喃基、 噻吩基、 吡咯基、 N-垸基吡咯基、 哌啶基、 吗啉基、 硫代吗啉 基、 四氢呋喃基或四氢吡咯基， R1^ R2'、 R3'、 R4'中任意两个基团可与它们相连的原子一起 进一步优选可以形成环丙基。 As an option, ! Any two of ^ 1 ', R 2 ', R 3 ', R 4 ' may form a 3 to 6 membered ring together with the atoms to which they are attached, including a spiro ring or a ring, the 3 to 6 membered ring Containing 0 to 3 heteroatoms selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted by 0 to 4 R 7a , 1 , R 2 ', R 3 ', R 4 ' Any two of the groups may together with the atoms to which they are attached may preferably form substituted and unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, pyridyl, furyl, thienyl, Pyrrolyl, N-fluorenylpyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl or tetrahydropyrrolyl, any of R 1 ^ R 2 ', R 3 ', R 4 ' The groups may further preferably form a cyclopropyl group together with the atoms to which they are attached.
本发明优选方案， R5'在每一种情况下， 各自独立地选自 H、 F、 Cl、 Br、 I、 三氟甲基、 羟基、 巯基、 氨基、 氰基、 d— 4垸基、 d— 4垸氧基、 -(CH2)n-C(=0)-NR7R7a或者 -(CH2)nNR7R7a， 优选 H、 F、 Cl、 Br、 I、 三氟甲基、 羟基、 巯基、 氨基、 氰基、 d— 4垸基或 d— 4垸氧基， 更优 选 H、 F、 Cl、 三氟甲基、 羟基、 氨基、 氰基、 d— 3垸基或 d— 3垸氧基， 进一步优选 H或者 F; In a preferred embodiment of the invention, R 5 ' is, in each case, independently selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, hydroxy, decyl, amino, cyano, d- 4 fluorenyl, D- 4 methoxy, -(CH 2 ) n -C(=0)-NR 7 R 7a or -(CH 2 ) n NR 7 R 7a , preferably H, F, Cl, Br, I, trifluoromethyl a base, a hydroxyl group, a thiol group, an amino group, a cyano group, a d- 4 fluorenyl group or a d- 4 methoxy group, more preferably H, F, Cl, trifluoromethyl, hydroxy, amino, cyano, d- 3 fluorenyl or D- 3 methoxy, further preferably H or F;
本发明优选方案， R5'在每一种情况下， 各自独立地选自 H、 F、 Cl、 Br、 I、 三氟甲基、 羟基、 巯基、 氰基、 氨基、 甲基、 乙基、 丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 甲氧 基、 乙氧基、 丙氧基、 异丙氧基、 丁氧基、 叔丁氧基、 氨基甲酰基或者氨基亚甲基， 优选 H、 F、 Cl、 三氟甲基、 羟基、 氨基、 甲基、 乙基、 丙基、 异丙基、 甲氧基、 乙氧基、 丙氧基 或者异丙氧基， 进一步优选 H或者 F; In a preferred embodiment of the invention, R 5 ' is, in each case, independently selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, hydroxy, decyl, cyano, amino, methyl, ethyl, Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, carbamoyl or amino Methylene group, preferably H, F, Cl, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy Or isopropoxy group, further preferably H or F ;
本发明涉及一种制备本发明通式 的化合物的方法， 该方法包括:  The present invention relates to a process for the preparation of a compound of the formula of the invention, which process comprises:
Figure imgf000032_0001
Figure imgf000032_0001
通式 （I-a)化合物在氧化剂存在下与卤代乙酰乙酸酯反应得到通式 （I-b)化合物， 其中: 卤代乙酰乙酸酯包括但不限于 2-氯乙酰乙酸甲酯或 2-氯乙酰乙酸乙酯；  The compound of the formula (Ia) is reacted with a haloacetoacetate in the presence of an oxidizing agent to give a compound of the formula (Ib), wherein: the haloacetoacetate includes, but is not limited to, methyl 2-chloroacetoacetate or 2-chloroacetyl Ethyl acetate;
Figure imgf000032_0002
Figure imgf000032_0002
通式 （I-b)化合物与通式 （I-e)化合物在碱性条件下关环， 在酸性条件下脱吗啉得到通式 (I-c)化合物；  a compound of the formula (I-b) and a compound of the formula (I-e) are subjected to ring closure under basic conditions, and demorpholine is obtained under acidic conditions to give a compound of the formula (I-c);
Figure imgf000032_0003
Figure imgf000032_0003
或者， 通式 （I-b)化合物与通式 （I-f)在碱性条件下关环， 在酸性条件下脱吗啉制得通式 (I-d)化合物；  Alternatively, the compound of the formula (I-b) and the formula (I-f) are ring-closed under basic conditions, and the compound of the formula (I-d) is obtained by demorpholating under acidic conditions;
Figure imgf000032_0004
Figure imgf000032_0004
通式 （I-d)化合物在碱性条件下发生偶联反应得到通式 (I-c)化合物;
Figure imgf000033_0001
The compound of the formula (Id) is subjected to a coupling reaction under basic conditions to obtain a compound of the formula (Ic);
Figure imgf000033_0001
通式 （I-c) 化合物任选通过氨解、 水解、 酯交换、 取代、 氧化或者还原反应得到通式 ① 化合物， 其中：  The compound of the formula (I-c) is optionally subjected to aminolysis, hydrolysis, transesterification, substitution, oxidation or reduction to give a compound of the formula 1 wherein:
Z选自 F、 Cl、 Br或 I;  Z is selected from F, Cl, Br or I;
A、 B、 R R2、 R3、 R4、 R5、 R6、 X、 m 的定义与通式 （I)化合物所述定义一致， R 、The definitions of A, B, RR 2 , R 3 , R 4 , R 5 , R 6 , X, m are consistent with the definitions of the compounds of formula (I), R,
R2'、 R3'、 R4'、 R5'、 R9、 X、、 m'的定义与通式 （I-b)化合物所述定义一致。 The definitions of R 2 ', R 3 ', R 4 ', R 5 ', R 9 , X, and m' are consistent with the definitions of the compounds of the formula (Ib).
本发明涉及的一种药物组合物， 所述药物组合物含有治疗有效剂量的至少一种本发明通 式 所述化合物， 或其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上 可以接受的盐或前药， 以及药学上可接受的载体或者赋形剂。  The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the formula of the present invention, or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite A pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier or excipient.
进一步， 本发明涉及通式 © 所示化合物， 或其立体异构体、 氮氧化合物、 水合物、 溶 剂化物、 代谢产物、 药学上可以接受的盐或前药， 在制备治疗与丝氨酸蛋白酶有关的疾病中 的药物中的用途。  Further, the present invention relates to a compound of the formula: or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug, which is useful in the preparation of a therapeutic serine protease. Use in medicines in disease.
本发明的优选方案， 其中与丝氨酸蛋白酶有关的疾病选自血栓栓塞疾病。  In a preferred embodiment of the invention, the disease associated with the serine protease is selected from the group consisting of a thromboembolic disorder.
本发明的优选方案， 其中所述丝氨酸蛋白酶选自凝血因子 Xa。  A preferred embodiment of the invention, wherein the serine protease is selected from the group consisting of factor Xa.
本发明的优选方案， 其中血栓栓塞疾病选自动脉心血管血栓栓塞疾病、 静脉心血管血栓 栓塞疾病以及心脏相关血栓栓塞疾病。  Preferably, the thromboembolic disease is selected from the group consisting of an arterial cardiovascular thromboembolic disease, a venous cardiovascular thromboembolic disease, and a cardiac related thromboembolic disease.
本发明的优选方案， 其中血栓栓塞疾病选自静脉血栓形成， 深部静脉血栓形成， 下肢深 静脉血栓形成、 血栓性静脉炎、 脑动脉血栓形成， 动脉栓塞， 冠状动脉血栓形成， 肺栓塞、 脑栓塞、 肾栓塞， 肝静脉栓塞、 门静脉栓塞、 慢性弥漫性血管内凝血、 四肢和中枢性微血管 动脉栓塞、 动脉粥样硬化、 急性冠状综合征、 不稳定心绞痛， 急性冠状动脉综合征、 心肌梗 塞、 动脉硬化症、 局部缺血瘁死、 暂时性的缺血、 外用阻塞性动脉疾病、 中风、 伴动脉栓塞 的无菌性血栓性心内膜炎、 脑血管疾病。  Preferably, the thromboembolic disease is selected from the group consisting of venous thrombosis, deep vein thrombosis, deep venous thrombosis of the lower extremity, thrombophlebitis, cerebral arterial thrombosis, arterial embolism, coronary thrombosis, pulmonary embolism, cerebral embolism , renal embolism, hepatic vein thrombosis, portal vein embolization, chronic diffuse intravascular coagulation, extremities and central microvascular arterial embolization, atherosclerosis, acute coronary syndrome, unstable angina, acute coronary syndrome, myocardial infarction, arteries Sclerosis, sudden onset of ischemia, transient ischemia, topical obstructive arterial disease, stroke, aseptic thrombotic endocarditis with arterial embolism, cerebrovascular disease.
本发明还涉及治疗血栓栓塞疾病的方法。 该方法包括给予患者治疗上有效剂量的包含本 发明所述的化合物或其药学上可以接受的盐的药物试剂。 本发明的所述的化合物可以联合其 他的治疗剂联合给药。  The invention also relates to a method of treating a thromboembolic disorder. The method comprises administering to the patient a therapeutically effective amount of a pharmaceutical agent comprising a compound of the invention or a pharmaceutically acceptable salt thereof. The compounds of the invention may be administered in combination with other therapeutic agents.
本发明涉及含有本发明所述的化合物或其药学上可以接受的盐的药物试剂， 所述药物试 剂可以是联合产品， 例如包括对一个需要这样治疗的宿主施用治疗上有效量的第一和第二种 治疗剂。 其中第一种治疗剂为本发明的化合物或者其立体异构体、 氮氧化合物、 水合物、 溶 剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 第二种治疗剂选自第二种凝血因子The present invention relates to a pharmaceutical agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, which may be a combination product, for example comprising administering a therapeutically effective amount of a first and a third to a host in need of such treatment. Two therapeutic agents. The first therapeutic agent is a compound of the invention or a stereoisomer thereof, an oxynitride, a hydrate, a solution a drug, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, and a second therapeutic agent selected from the group consisting of a second coagulation factor
Xa 因子抑制剂， 一种抗凝剂、 一种抗血小板剂、 一种凝血酶抑制剂、 一种溶血栓剂以及一种 纤维蛋白溶剂剂中的至少一种试剂。 A factor Xa inhibitor, an anticoagulant, an antiplatelet agent, a thrombin inhibitor, a thrombolytic agent, and at least one agent of a fibrin solvate.
本发明的优选方案， 其中所述第二种治疗剂是选自华法林、 未分级肝素、 低分子量肝 索、 合成的五糖、 水蛙素、 阿加由班、 阿可匹林、 布洛芬、 甲氧奈丙酸、 苏灵大、 吲哚美 辛、 甲灭酸、 屈噁昔康、 双氯芬酸、 苯磺唑酮、 吡罗昔康、 噻氯匹定、 氯吡格雷、 替罗非 班、 埃替菲巴肽、 阿昔单抗美加拉群、 二硫酸水蛭素 （又名： disulfatohirudin^ 组织纤溶酶原 激活剂、 修饰的组织型纤溶酶原激活剂、 复合纤溶酶链激酶、 尿激酶和链激酶中的至少一种 试剂。  According to a preferred embodiment of the present invention, the second therapeutic agent is selected from the group consisting of warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, water frog, Agaban, acopiline, cloth Lofen, methoxypropionate, sulindac, indomethacin, mefenamic acid, dexamethasone, diclofenac, benzoxazolone, piroxicam, ticlopidine, clopidogrel, tirofiban , eptifibatide, abciximab mecarragine, hirudin disulfate (aka: disulfatohirudin^ tissue plasminogen activator, modified tissue plasminogen activator, complex plasmin streptokinase At least one agent of urokinase and streptokinase.
本发明的优选方案， 其中所述第二种治疗剂是至少一种抗血小板剂。  In a preferred embodiment of the invention, the second therapeutic agent is at least one antiplatelet agent.
本发明的优选方案， 其中所述抗血小板剂是阿司匹林和氯吡格雷。  In a preferred embodiment of the invention, the antiplatelet agent is aspirin and clopidogrel.
本发明的优选方案， 其中所述抗血小板剂是氯吡格雷。  In a preferred embodiment of the invention, wherein the antiplatelet agent is clopidogrel.
本发明所述药物试剂是用于制备治疗血栓栓塞疾病的药物试剂。  The pharmaceutical agent of the present invention is a pharmaceutical agent for preparing a thromboembolic disease.
本发明还涉及本发明所述的化合物或其药学上可以接受的盐在制备用于与所述第二治疗 剂联合给药治疗血栓栓塞疾病的药物中的用途。  The invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a thromboembolic disorder in combination with said second therapeutic agent.
除非有相反的陈述， 在说明书和权利要求书中使用的术语具有下述含义。  Terms used in the specification and claims have the following meanings unless stated to the contrary.
本发明所述基团和化合物中所涉及的元素碳、 氢、 氧、 硫、 氮或卤素均包括它们的同位 素情况， 及本发明所述基团和化合物中所涉及的元素碳、 氢、 氧、 硫或氮任选进一步被一个 或多个它们对应的同位素所替代， 其中碳的同位素包括 12c、 13c和 14c， 氢的同位素包括氕 (H), 氘 （D， 又叫重氢 )、 氚 （Τ， 又叫超重氢 )， 氧的同位素包括 160、 170和 180， 硫的同位 素包括 32S、 33S、 34S和 36S， 氮的同位素包括 14N和 15N， 氟的同位素 19F， 氯的同位素包括 35C1和 37C1， 溴的同位素包括 79Br和 81Br。 The elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the elements and carbons, hydrogen and oxygen involved in the groups and compounds of the present invention. Sulfur or nitrogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 c, 13 c and 14 c, and the hydrogen isotopes include ruthenium (H), 氘 (D, also known as heavy hydrogen ), 氚 (Τ, also called super heavy hydrogen), oxygen isotopes include 16 0, 17 0 and 18 0, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N , fluorine isotope 19 F, chlorine isotope includes 35 C1 and 37 C1, and bromine isotopes include 79 Br and 81 Br.
术语"垸基"是指饱和的脂肪族烃基团， 包括 1至 20个碳原子的直链和支链基团。 优选含 有 1至 10个碳原子的垸基， 非限制性实施例包括， 甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 正戊基、 正壬基， 及其各种支链异构体等； 更优选的是含有 1 至 4个碳原 子的低级垸基， 非限制性实施例包括甲基、 乙基、 丙基、 异丙基、 正丁基、 异丁基或叔丁基 等。 垸基可以是取代的或未取代的， 当被取代时， 取代基优选为 1至 5个， 独立地选自 F、 C 1、 Br、 I、 =0、 垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 巯基、 羟基、 硝基、 氰 基、 氨基、 垸基酰基氨基、 环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸基巯基、 羟基垸基、 羧酸、 羧酸酯、 杂环垸巯基、 S(=0)pR8、 烯基 -R8或炔基 -R8。 The term "mercapto" refers to a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. Preferred are fluorenyl groups having 1 to 10 carbon atoms, and non-limiting examples include, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, and Sulfhydryl, its various branched isomers, etc.; more preferred are lower fluorenyl groups containing from 1 to 4 carbon atoms, non-limiting examples including methyl, ethyl, propyl, isopropyl, positive Butyl, isobutyl or tert-butyl. The fluorenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably from 1 to 5, independently selected from the group consisting of F, C 1 , Br, I, =0, decyl, alkenyl, alkynyl, Alkoxy, sulfonylthio, decylamino, fluorenyl, hydroxy, nitro, cyano, amino, decyl acylamino, cyclodecyl, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy , cyclodecyl fluorenyl, hydroxy fluorenyl, carboxylic acid, carboxylic acid ester, heterocyclic fluorenyl, S(=0) p R 8 , alkenyl-R 8 or alkynyl-R 8 .
"垸氧基"是指 -0-垸基， 其中垸基如本文上面所定义。 垸氧基可以是取代的或未取代的， 其非限制性实施例包括， 甲氧基、 乙氧基、 丙氧基、 异丙氧基、 丁氧基、 叔丁氧基、 戊氧基 或己氧基， 优选具有 1至 12元垸氧基。 当被取代时， 取代基优选为 1至 5个， 独立地选自"Alkoxy" means a-0-fluorenyl group, wherein the fluorenyl group is as defined herein above. The methoxy group may be substituted or unsubstituted, and non-limiting examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy Or a hexyloxy group, preferably having a 1 to 12 membered decyloxy group. When substituted, the substituent is preferably from 1 to 5, independently selected from
F、 Cl、 Br、 I、 =0、 垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 巯基、 羟基、 硝基、 氰基、 氨基、 垸基酰基氨基、 环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸基巯 基、 羟基垸基、 羧酸、 羧酸酯、 杂环垸基巯基、 S(=0)pR8、 烯基 -R8或炔基 -R8。 F, Cl, Br, I, =0, fluorenyl, alkenyl, alkynyl, decyloxy, sulfonylthio, decylamino, fluorenyl, hydroxy, nitro, cyano, amino, decyl acylamino, ring Mercapto, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecyl fluorenyl, hydroxy fluorenyl, carboxylic acid, carboxylic acid ester, heterocyclic fluorenyl fluorenyl, S(=0) p R 8. Alkenyl-R 8 or alkynyl-R 8 .
"垸氧基垸基 "指与垸氧基相连的垸基。 垸氧基垸基可以是取代的或未取代的， 其非限制性 实施例包括， 甲氧基甲基、 甲氧基乙基、 乙氧基甲基、 乙氧基乙基、 丙氧基甲基、 丙氧基乙 基、 异丙氧基甲基、 丁氧基丙基、 叔丁氧基乙基、 戊氧基乙基、 己氧基乙基、 环丙氧基甲 基、 环丙氧基乙基、 环丙氧基丙基或环己氧基甲基； 当被取代时， 取代基优选为 1 至 5个， 独立地选自 F、 Cl、 Br、 I、 =0、 垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 巯基、 羟 基、 硝基、 氰基、 氨基、 垸基酰基氨基、 环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸基巯基、 羟基垸基、 羧酸、 羧酸酯、 杂环垸基巯基、 S(=0)pR8、 烯基 -R8或炔基 -R8。 "Alkyloxy" refers to a fluorenyl group attached to a decyloxy group. The decyloxy group can be substituted or unsubstituted, non-limiting examples of which include, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxy Base, propoxyethyl, isopropoxymethyl, butoxypropyl, tert-butoxyethyl, pentyloxyethyl, hexyloxyethyl, cyclopropyloxymethyl, cyclopropoxy a ethyl group, a cyclopropoxypropyl group or a cyclohexyloxymethyl group; when substituted, the substituent is preferably from 1 to 5, independently selected from the group consisting of F, Cl, Br, I, =0, fluorenyl, Alkenyl, alkynyl, decyloxy, sulfonylthio, decylamino, fluorenyl, hydroxy, nitro, cyano, amino, decyl acylamino, cyclodecyl, aryl, heteroaryl, cyclodecyloxy , heterocyclomethoxy, cyclodecyl fluorenyl, hydroxy fluorenyl, carboxylic acid, carboxylic acid ester, heterocyclic fluorenyl fluorenyl, S(=0) p R 8 , alkenyl-R 8 or alkynyl-R 8 .
"烯基 "是本发明定义的垸基中， 包含至少一个碳-碳双键， 所述烯基含有 2至 20个碳原 子， 优选 2至 12个碳原子， 进一步优选 2至 8个碳原子。 烯基的非限定实施例包括取代或未 取代的乙烯基、 2-丙烯基、 3-丁烯基、 2-丁烯基、 4-戊烯基、 3-戊烯基、 2-己烯基、 3-己烯 基、 2-庚烯基、 3-庚烯基、 4-庚烯基、 3-辛烯基、 3-壬烯基或 4-癸烯基等， 当被取代时， 取代 基优选为 1至 5个， 独立地选自 F、 Cl、 Br、 I、 =0、 垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 巯基、 羟基、 硝基、 氰基、 氨基、 垸基酰基氨基、 环垸基、 芳基、 杂芳基、 环垸 氧基、 杂环垸氧基、 环垸基巯基、 羟基垸基、 羧酸、 羧酸酯、 杂环垸基巯基、 S(=0)pR8、 烯 基 -R8或炔基 -R8。 "Alkenyl" is a fluorenyl group as defined in the invention and comprises at least one carbon-carbon double bond, said alkenyl group having 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, further preferably 2 to 8 carbon atoms . Non-limiting examples of alkenyl groups include substituted or unsubstituted vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl , 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-decenyl or 4-nonenyl, etc., when substituted, substituted The group is preferably 1 to 5, independently selected from the group consisting of F, Cl, Br, I, =0, decyl, alkenyl, alkynyl, decyloxy, sulfonylthio, decylamino, fluorenyl, hydroxy, nitro , cyano, amino, decyl acylamino, cyclodecyl, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecyl fluorenyl, hydroxy fluorenyl, carboxylic acid, carboxylic acid ester, hetero Cyclodecyl fluorenyl, S(=0) p R 8 , alkenyl-R 8 or alkynyl-R 8 .
"炔基 "是本发明定义的垸基中， 包含至少一个碳-碳三键， 所述炔基含有 2至 20个碳原 子， 优选 2至 12个碳原子， 进一步优选 2至 8个碳原子。 炔基的非限定实施例包括取代或未 取代的乙炔基、 1-丙炔基、 2-丙炔基、 1-丁炔基、 2-丁炔基、 3-丁炔基、 4-戊炔基、 3-戊炔 基、 2-己炔基、 3-己炔基、 3-丁炔基、 2-庚炔基、 3-庚炔基、 4-庚炔基、 3-辛炔基、 3-壬炔基或 4-癸炔基等， 当被取代时， 取代基优选为 1至 5个， 独立地选自 F、 Cl、 Br、 I、 =0、 垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 巯基、 羟基、 硝基、 氰基、 氨基、 垸基酰基氨 基、 环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸基巯基、 羟基垸基、 羧酸、 羧酸 酯、 杂环垸基巯基、 S(=0)pR8、 烯基 -R8或炔基 -R8。 "Alkynyl" is a fluorenyl group as defined in the invention and comprises at least one carbon-carbon triple bond, said alkynyl group having 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, further preferably 2 to 8 carbon atoms . Non-limiting examples of alkynyl groups include substituted or unsubstituted ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 4-pentyne , 3-pentynyl, 2-hexynyl, 3-hexynyl, 3-butynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-decynyl or 4-nonynyl, etc., when substituted, preferably 1 to 5, independently selected from F, Cl, Br, I, =0, decyl, alkenyl, alkynyl , anthracenyloxy, sulfonylthio, decylamino, fluorenyl, hydroxy, nitro, cyano, amino, decyl acylamino, cyclodecyl, aryl, heteroaryl, cyclodecyloxy, heterocyclic oxime A sulfhydryl group, a hydroxy fluorenyl group, a carboxylic acid, a carboxylic acid ester, a heterocyclic fluorenyl fluorenyl group, S(=0) p R 8 , an alkenyl-R 8 or an alkynyl-R 8 group.
"碳环 "是指饱和或者不饱和的芳香环或者非芳香环， 芳香环或者非芳香可以是 3至 8元的 单环， 4至 12元双环或者 10至 15元三环系统， 碳环可以连接有桥环或者螺环， 非限制性实 施例包括环丙基、 环丁基、 环戊基、 环己基、 环己烯基、 环庚基、 环戊烯、 环己二烯、 环庚 三烯、 苯基、 萘基、 苯并环戊基、 二环 [3.2.1]辛垸基、 二环 [5.2.0]壬垸基、 三环 [5.3.1.1]十二 垸基、 金刚垸基或螺 [3.3]庚垸基等。 碳环可以被取代， 当被取代时， 取代基优选为 1 至 5 个， 独立地选自 F、 Cl、 Br、 I、 =0、 垸基、 烯基、 炔基、 垸氧基、 垸巯基、 垸基氨基、 巯 基、 羟基、 硝基、 氰基、 氨基、 垸基酰基氨基、 环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸 氧基、 环垸基巯基、 羟基垸基、 羧酸、 羧酸酯、 杂环垸基巯基、 -(CH2)nS(=0)pR8、 -(CH2)n -烯 基 -R8或 -(CH2)n -炔基 -R8。 "Carbocycle" means a saturated or unsaturated aromatic ring or a non-aromatic ring. The aromatic ring or non-aromatic may be a single ring of 3 to 8 members, a 4 to 12 membered double ring or a 10 to 15 membered three ring system. Attached to the bridged or spiro ring, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentene, cyclohexadiene, cycloheptane Alkene, phenyl, naphthyl, benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]decyl, tricyclo[5.3.1.1]dodedecyl, adamantyl or Snail [3.3] Geng base and so on. The carbocyclic ring may be substituted, and when substituted, the substituent is preferably from 1 to 5 , independently selected from the group consisting of F, Cl, Br, I, =0, decyl, alkenyl, alkynyl, decyloxy, decyl, decylamino, fluorenyl, hydroxy, nitro, cyano, amino, hydrazine Aminoacylamino, cyclodecyl, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecyl fluorenyl, hydroxy fluorenyl, carboxylic acid, carboxylic acid ester, heterocyclic fluorenyl fluorenyl, -( CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 or -(CH 2 ) n -alkynyl-R 8 .
"杂环 "是指取代的或未取代的饱和或者不饱和的芳香环、 非芳香环， 芳香环、 非芳香环可 以是 3至 8元的单环， 4至 12元双环或者 10至 15元三环系统， 且由至少一个选自 N、 0或 S的杂原子组成， 优选 3至 10元杂环， 杂环的环中选择性取代的 N、 S可被氧化成各种氧化 态。 杂环可以连接在杂原子或者碳原子上。 杂环可以连接有桥环或者螺环， 非限制性实施例 包括， 环氧乙垸、 氮杂环丙基、 氧杂环丁垸基、 氮杂环丁垸基、 1 ,3-二氧戊环、 1 ,4-二氧戊 环、 1 ,3-二氧六环、 氮杂环庚基、 吡啶基、 呋喃基、 噻吩基、 吡喃基、 N-垸基吡咯基、 嘧啶 基、 吡嗪基、 哒嗪基、 咪唑基、 哌啶基、 哌叮基、 吗啉基、 硫代吗啉基、 1,3-二噻垸、 二氢呋 喃、 二氢吡喃、 二噻戊环、 四氢呋喃、 四氢吡咯、 四氢咪唑、 四氢噻唑、 四氢吡喃、 苯并咪 唑、 苯并吡啶、 吡咯并吡啶、 苯并二氢呋喃、 氮杂二环 [3.2.1]辛垸基、 氮杂二环 [5.2.0]壬垸 基、 氧杂三环 [5.3.1.1]十二垸基、 氮杂金刚垸基、 氧杂螺 [3.3]庚垸基、  "Heterocyclic" means a substituted or unsubstituted saturated or unsaturated aromatic ring, a non-aromatic ring, an aromatic ring, a non-aromatic ring which may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered member. A tricyclic system, and consists of at least one hetero atom selected from N, 0 or S, preferably a 3 to 10 membered heterocyclic ring, and the optionally substituted N, S in the heterocyclic ring can be oxidized to various oxidation states. The heterocyclic ring can be attached to a hetero atom or a carbon atom. The heterocyclic ring may be attached to a bridged ring or a spiro ring, and non-limiting examples include, ethenyl oxime, azacyclopropyl, oxetanyl, azetidinyl, 1, 3-dioxolane, 1 , 4-dioxolan, 1 ,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, anthracene Azinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazide, dihydrofuran, dihydropyran, dithiapentane, tetrahydrofuran, tetrahydrogen Pyrrole, tetrahydroimidazole, tetrahydrothiazole, tetrahydropyran, benzimidazole, benzopyridine, pyrrolopyridine, benzodihydrofuran, azabicyclo[3.2.1]octyl, azabicyclo[5.2 .0] fluorenyl, oxatricyclo[5.3.1.1] fluorenyl, aza-adalyl, oxaspiro[3.3]heptanyl,
Figure imgf000036_0001
Figure imgf000036_0001
时， 取代基优选为 1至 5个， 取代基独立地选自 F、 Cl、 Br、 I、 =0、 垸基、 烯基、 炔基、 垸 氧基、 垸硫基、 垸基氨基、 巯基、 羟基、 硝基、 氰基、 氨基、 垸基酰基氨基、 杂环垸基、 环 垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸基巯基、 羟基垸基、 羧酸、 羧酸酯、 杂 环垸基巯基、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8或 -(CH2)n-炔基 -R8。 When the substituent is preferably 1 to 5, the substituent is independently selected from the group consisting of F, Cl, Br, I, =0, decyl, alkenyl, alkynyl, decyloxy, sulfonylthio, decylamino, fluorenyl , hydroxy, nitro, cyano, amino, decyl acylamino, heterocycloalkyl, cyclodecyl, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecyl fluorenyl, hydroxy hydrazine a carboxylic acid, a carboxylic acid ester, a heterocyclic fluorenyl fluorenyl group, -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 or -(CH 2 ) n - alkynyl-R 8 .
"氨基 "是指 -NH2， 可以是取代的或未取代的， 当被取代时， 取代基优选为 1至 3个， 独立 地选自垸基、 烯基、 炔基、 垸氧基、 垸硫基、 羟基、 氨基、 垸基氨基、 垸基酰基氨基、 杂环 垸基、 环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 羟基垸基、 羧酸、 羧酸酯、 -(CH2)nS (=0)PR8、 -(CH2)n-烯基 -R8或 -(CH2)n-炔基 -R8。 "Amino" means -NH 2 and may be substituted or unsubstituted. When substituted, the substituent is preferably from 1 to 3, independently selected from decyl, alkenyl, alkynyl, decyloxy, hydrazine. Thio group, hydroxy group, amino group, mercaptoamino group, mercaptoacylamino group, heterocycloalkyl group, cyclodecyl group, aryl group, heteroaryl group, cyclodecyloxy group, heterocyclic methoxy group, hydroxy fluorenyl group, carboxylic acid, Carboxylic acid ester, -(CH 2 ) n S (=0) P R 8 , -(CH 2 ) n -alkenyl-R 8 or -(CH 2 ) n -alkynyl-R 8 .
"芳基 "是指取代的或未取代的 6至 14元全碳单环或稠和多环基团， 具有共轭的 π电子体 系的多环基团， 优选 6至 10元芳香环， 其非限定性实例包括苯基或萘基； 所述芳基可以稠和 与杂芳基、 杂环基或环垸基， 且与母体结构连接的部分为芳基， 其非限定性实例包括苯并呋 喃、 苯并环戊垸基或苯并噻唑等。 当被取代时， 取代基优选为 1 至 5个， 取代基独立地选自"Aryl" means a substituted or unsubstituted 6 to 14 membered all-carbon monocyclic or fused polycyclic group having a polycyclic group having a conjugated π-electron system, preferably a 6 to 10 membered aromatic ring, Non-limiting examples include phenyl or naphthyl; the aryl group may be fused to a heteroaryl, heterocyclyl or cyclodecyl group, and the moiety attached to the parent structure is an aryl group, non-limiting examples of which include benzo Fur Or benzocyclopentenyl or benzothiazole. When substituted, the substituent is preferably from 1 to 5, and the substituents are independently selected from
F、 Cl、 Br、 I、 =0、 垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 巯基、 羟基、 硝基、 氰基、 氨基、 垸基酰基氨基、 环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸基巯 基、 羟基垸基、 羧酸、 羧酸酯、 杂环垸基巯基、 -(CH2)nS(=0)pR8、 -(CH2)n -烯基 -R8或 -(CH2)n - 炔基 -R8。 F, Cl, Br, I, =0, fluorenyl, alkenyl, alkynyl, decyloxy, sulfonylthio, decylamino, fluorenyl, hydroxy, nitro, cyano, amino, decyl acylamino, ring Mercapto, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecyl fluorenyl, hydroxy fluorenyl, carboxylic acid, carboxylic acid ester, heterocyclic fluorenyl fluorenyl, -(CH 2 ) n S (=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 or -(CH 2 ) n -alkynyl-R 8 .
"杂芳基"是指取代或未取代的 5至 15元芳香环， 且含有 1至 3个选自 N、 0或 S杂原 子， 优选 5至 10元芳香环， 杂芳基的非限制性实施例包括吡啶基、 呋喃基、 噻吩基、 N-垸基 吡咯基、 嘧啶基、 吡嗪基、 哒嗪基、 咪唑基、 、 苯并呋喃、 苯并咪唑、 苯并吡啶或吡咯并吡 啶等。 当被取代时， 取代基优选为 1至 5个， 取代基独立地选自 F、 Cl、 Br、 I、 =0、 垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 巯基、 羟基、 硝基、 氰基、 氨基、 垸基酰基氨 基、 环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸基巯基、 羟基垸基、 羧酸、 羧酸 酯、 杂环垸基巯基、 -(CH2)nS(=0)pR8、 -(CH2)n -烯基 -R8或 -(CH2)n -炔基 -R8。 "Heteroaryl" means a substituted or unsubstituted 5 to 15 membered aromatic ring and contains 1 to 3 heteroatoms selected from N, 0 or S heteroatoms, preferably 5 to 10 membered aromatic rings, non-limiting Examples include pyridyl, furyl, thienyl, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzofuran, benzimidazole, benzopyridine or pyrrolopyridine . When substituted, the substituent is preferably from 1 to 5, and the substituent is independently selected from the group consisting of F, Cl, Br, I, =0, fluorenyl, alkenyl, alkynyl, decyloxy, sulfonylthio, fluorenyl Amino, mercapto, hydroxy, nitro, cyano, amino, decyl acylamino, cyclodecyl, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecyl fluorenyl, hydroxy fluorenyl, Carboxylic acid, carboxylic acid ester, heterocyclic fluorenyl fluorenyl, -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 or -(CH 2 ) n -alkynyl -R 8 .
本发明的" =0"为本领域通常习惯用法， 是指以双键相连的氧原子， 譬如羰基中与碳原子 相连的双键氧原子。  The "=0" of the present invention is generally used in the art and refers to an oxygen atom bonded by a double bond, such as a double bond oxygen atom to a carbon atom in a carbonyl group.
"药学上可接受的盐 "是指药学上可接受的无毒酸或碱的盐， 包括无机酸和碱、 有机酸和碱 的盐。 衍生自无机碱的盐包括但不限于 Al、 Ca、 Li、 My、 K、 Na和 Zn形成的金属盐； 衍生 自有机碱的盐包括但不限于伯胺、 仲胺或叔胺的盐， 包括天然存在的取代或未取代的胺、 环 胺和碱性离子交换树脂， 例如氨、 异丙基胺、 三甲基胺、 二乙胺、 三乙胺、 三丙基胺、 二乙 醇胺、 乙醇胺、 二甲基乙醇胺、 2-二甲基氨基乙醇、 2-二乙基氨基乙醇、 二环己基胺、 咖啡 碱、 普鲁卡因、 胆碱、 甜菜碱、 苯明青霉素、 乙二胺、 葡萄糖胺、 甲基葡糖胺、 可可碱、 三 乙醇胺、 氨丁三醇、 嘌吟、 哌嗪、 哌啶、 N-乙基哌啶或聚胺树脂形成的有机盐； 衍生自无机 酸和有机酸的盐包括但不限于硫酸、 磷酸、 硝酸、 氢溴酸、 盐酸、 甲酸、 乙酸、 丙酸、 苯磺 酸、 苯甲酸、 苯乙酸、 水杨酸、 褐藻酸、 氨茴酸、 樟脑酸、 柠檬酸、 乙烯磺酸、 蚁酸、 富马 酸、 糠酸、 葡萄糖酸、 葡萄糖醛酸、 谷氨酸、 乙醇酸、 羟乙磺酸、 乳酸、 马来酸、 苹果酸、 扁桃酸、 粘液酸、 双羟萘酸、 泛酸、 硬脂酸、 琥珀酸、 磺胺酸、 酒石酸、 对甲苯磺酸、 丙二 酸、 2-羟基丙酸、 草酸、 羟乙酸、 葡萄糖醛酸、 半乳糖醛酸、 枸橼酸、 赖氨酸、 精氨酸、 门 冬氨酸、 肉桂酸、 对甲苯磺酸、 甲磺酸、 乙磺酸或三氟甲磺酸等形成的有机盐。  "Pharmaceutically acceptable salt" means a pharmaceutically acceptable salt of a non-toxic acid or base, including salts of inorganic acids and bases, organic acids and bases. Salts derived from inorganic bases include, but are not limited to, metal salts formed from Al, Ca, Li, My, K, Na, and Zn; salts derived from organic bases include, but are not limited to, salts of primary, secondary, or tertiary amines, including Naturally occurring substituted or unsubstituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, Dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, phentermine, ethylenediamine, glucosamine, An organic salt formed by methyl glucosamine, theobromine, triethanolamine, tromethamine, hydrazine, piperazine, piperidine, N-ethylpiperidine or a polyamine resin; a salt derived from a mineral acid and an organic acid Including but not limited to sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, Vinyl sulfonic acid, formic acid, rich Acid, citric acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, Succinic acid, sulfamic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, gate An organic salt formed from a tryptophan, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid.
"共晶 "是指活性药物成分 （ active pharmaceutical ingredient, API) 和共晶形成物 （ cocrystal former, CCF)在氢键或其他非共价键的作用下结合而成的晶体， 其中 API和 CCF 的纯态在 室温下均为固体， 并且各组分间存在固定的化学计量比。 共晶是一种多组分晶体， 既包含两 种中性固体之间形成的二元共晶， 也包含中性固体与盐或溶剂化物形成的多元共晶。 所述"共 晶形成物"包括但不限于各种药学上可接受的酸、 碱、 非离子化合物， 其非限定性实例包括丙 氨酸 （Ala) 、 缬氨酸 （Val) 、 亮氨酸 （Leu) 、 异亮氨酸 （lie) 、 脯氨酸 （Pro ) 、 苯丙氨 酸 （Phe ) 、 色氨酸 （Trp ) 、 蛋氨酸 （Met ) 、 甘氨酸 （Gly ) 、 丝氨酸 （Ser ) 、 苏氨酸 ( Thr) 、 半胱氨酸 （Cys ) 、 酪氨酸 （Tyr) 、 天冬酰胺 （Asn) 、 谷氨酰胺 （Gin) 、 赖氨酸 ( Lys ) 、 精氨酸 （Arg) 、 组氨酸 （His ) 、 天冬氨酸 （Asp) 、 谷氨酸 （Glu) 、 焦谷氨酸、 硫酸、 磷酸、 硝酸、 氢溴酸、 盐酸、 甲酸、 乙酸、 丙酸、 苯磺酸、 苯甲酸、 苯乙酸、 水杨 酸、 褐藻酸、 氨茴酸、 樟脑酸、 柠檬酸、 乙烯磺酸、 蚁酸、 富马酸、 糠酸、 葡萄糖酸、 葡萄 糖醛酸、 谷氨酸、 乙醇酸、 羟乙磺酸、 乳酸、 马来酸、 苹果酸、 扁桃酸、 粘液酸、 双羟萘 酸、 泛酸、 硬脂酸、 琥珀酸、 磺胺酸、 酒石酸、 对甲苯磺酸、 丙二酸、 2-羟基丙酸、 草酸、 羟乙酸、 葡萄糖醛酸、 半乳糖醛酸、 枸橼酸、 赖氨酸、 精氨酸、 门冬氨酸、 肉桂酸、 对甲苯 磺酸、 甲磺酸、 乙磺酸或三氟甲磺酸、 氨、 异丙基胺、 三甲基胺、 二乙胺、 三乙胺、 三丙基 胺、 二乙醇胺、 乙醇胺、 二甲基乙醇胺、 2-二甲基氨基乙醇、 2-二乙基氨基乙醇、 二环己基 胺、 咖啡碱、 普鲁卡因、 胆碱、 甜菜碱、 苯明青霉素、 乙二胺、 葡萄糖胺、 甲基葡糖胺、 可 可碱、 三乙醇胺、 氨丁三醇、 嘌吟、 哌嗪、 哌啶、 N-乙基哌啶。 "eutectic" refers to a combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, of which API and CCF The pure state is solid at room temperature and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-eutectoid formed from a neutral solid with a salt or solvate. The "eutectic former" includes, but is not limited to, various pharmaceutically acceptable acid, base, nonionic compounds, non-limiting examples of which include (Ala), valine (Val), leucine (Leu), isoleucine (lie), proline (Pro), phenylalanine (Phe), tryptophan (Trp), Methionine (Met), glycine (Gly), serine (Ser), threonine (Th), cysteine (Cys), tyrosine (Tyr), asparagine (Asn), glutamine (Gin) Lysine, Lys, Arginine (Arg), Histidine (His), Aspartic Acid (Asp), Glutamate (Glu), Pyroglutamic Acid, Sulfuric Acid, Phosphoric Acid, Nitric Acid, Hydrobromine Acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonic acid, formic acid, fumaric acid, hydrazine Acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionate, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, Sulfamic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid , galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropyl Amine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine , caffeine, procaine, choline, betaine, phenylephrine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, hydrazine, piperazine, piperidine , N-ethyl piperidine.
"立体异构体 "是指由分子中原子在空间上排列方式不同所产生的异构体， 包括顺反异构 体、 对映异构体和构象异构体。  "Stereoisomer" refers to isomers resulting from the arrangement of atoms in a molecule in a spatial arrangement, including cis-trans isomers, enantiomers, and conformational isomers.
"药物组合物 "表示一种或多种文本所述化合物或其生理学 /药学上可接受的盐或前体药物 与其它化学组分的混合物， 其它组分例如生理学 /药学上可接受的载体和赋形剂。 药物组合物 的目的是促进化合物对生物体的给药。  "Pharmaceutical composition" means one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or mixture of prodrugs thereof with other chemical components, other components such as physiological/pharmaceutically acceptable carriers and excipient. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
"前药 "是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。 本发 明的前药通过修饰在该化合物中的功能基团来制备， 该修饰可以按常规的操作或者在体内被 除去， 而得到母体化合物。 前药包括本发明化合物中的一个羟基、 氨基或者巯基连接到任何 基团上所形成的化合物， 当本发明化合物的前药被施予哺乳动物个体时， 前药被割裂而分别 形成游离的羟基、 游离的氨基或者游离的疏基。 前药的例子包括但不限于， 本发明化合物中 的羟基或氨基功能基团与甲酸、 乙酸或苯甲酸所形成的化合物。  "Prodrug" means a compound of the invention which can be converted to biological activity under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying functional groups in the compound which can be removed by conventional procedures or in vivo to provide the parent compound. A prodrug includes a compound formed by attaching a hydroxyl group, an amino group or a thiol group to any group in the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group, respectively. , free amino or free sulfhydryl. Examples of prodrugs include, but are not limited to, compounds formed by the hydroxyl or amino functional groups of the compounds of the invention with formic acid, acetic acid or benzoic acid.
"任选 "或"任选地 "意味着随后所描述地事件或环境可以但不必发生， 包括该事件或环境发 生或不发生的场合。 例如， "芳基任选被垸基取代"意味着垸基可以但不必须存在， 该说明包 括芳基被垸基取代的情形和芳基不被垸基取代的情形。  "Optional" or "optionally" means that the event or environment described subsequently may, but need not, occur, including where the event or environment occurs or does not occur. For example, "the aryl group is optionally substituted with a thiol group" means that the thiol group may, but need not, be present, and the description includes the case where the aryl group is substituted by a thiol group and the case where the aryl group is not substituted by a thiol group.
本发明化合物的合成方法  Method for synthesizing the compound of the present invention
本发明涉及一种制备本发明通式 的化合物的方法， 该方法包括：
Figure imgf000039_0001
The present invention relates to a process for the preparation of a compound of the formula of the invention, the process comprising:
Figure imgf000039_0001
通式 （I-a)化合物在氧化剂存在下与卤代乙酰乙酸酯反应得到通式 （I-b)化合物， 其中: 卤代乙酰乙酸酯包括但不限于 2-氯乙酰乙酸甲酯或 2-氯乙酰乙酸乙酯；  The compound of the formula (Ia) is reacted with a haloacetoacetate in the presence of an oxidizing agent to give a compound of the formula (Ib), wherein: the haloacetoacetate includes, but is not limited to, methyl 2-chloroacetoacetate or 2-chloroacetyl Ethyl acetate;
Figure imgf000039_0002
Figure imgf000039_0002
通式 （I-b)化 （I-e)化合物在碱性条件下关环， 在酸性 件下脱吗啉得到通式 The compound of the formula (I-b) (I-e) is ring-closed under basic conditions, and the morpholine is obtained under acidic conditions.
(I-c)化合物； (I-c) compound;
Figure imgf000039_0003
Figure imgf000039_0003
或者， 通式 （I-b)化合物与通式 （I-f)在碱性条件下关环， 在酸性条件下脱吗啉制得通式 (I-d)化合物；  Alternatively, the compound of the formula (I-b) and the formula (I-f) are ring-closed under basic conditions, and the compound of the formula (I-d) is obtained by demorpholating under acidic conditions;
Figure imgf000039_0004
Figure imgf000039_0004
通式 （I-d)化合物在碱性条件下发生偶联反应得到通式 (I-c)化合物;
Figure imgf000040_0001
The compound of the formula (Id) is subjected to a coupling reaction under basic conditions to obtain a compound of the formula (Ic);
Figure imgf000040_0001
-c  -c
通式 （I-c) 化合物任选通过氨解、 水解、 酯交换、 取代、 氧化或者还原反应得到通式 ① 化合物， 其中：  The compound of the formula (I-c) is optionally subjected to aminolysis, hydrolysis, transesterification, substitution, oxidation or reduction to give a compound of the formula 1 wherein:
Z选自 F、 Cl、 Br或 I;  Z is selected from F, Cl, Br or I;
A、 B、 R R2、 R3、 R4、 R5、 R6、 X、 m 的定义与通式 （I) 化合物所述定义一致， R 、The definitions of A, B, RR 2 , R 3 , R 4 , R 5 , R 6 , X, m are consistent with the definitions of the compounds of formula (I), R,
R2、 R3、 R4、 R5、 R9、 X、、 m'的定义与通式 (I-b)化合物所述定义一致。 具体实施方式 The definitions of R 2 , R 3 , R 4 , R 5 , R 9 , X, and m' are consistent with the definitions of the compounds of the formula (Ib). Detailed ways
以下结合附图及实施例详细说明本发明的技术方案， 但本发明的保护范围包括但是不限 于此。  The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振（NMR) 或 （；和）质谱（MS)来确定的。 NMR位移 （δ) 以 10-6 (ppm) 的单位给出。 NMR的测定是用 (Bruker Avance III 400和 Bruker Avance 300)核磁 仪， 测定溶剂为氘代二甲基亚砜 （DMSO-d6)， 氘代氯仿 （CDC13)， 氘代甲醇 （CD3OD)， 内标 为四甲基硅垸 (TMS)。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or (; and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 - 6 (ppm). NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS).
MS的测定用 (Agilent 6120B(ESI)和 Agilent 6120B(APCI))。  The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC的测定使用安捷伦 1260DAD高压液相色谱仪（Zorbax SB-C18 100 X 4.6 mm) » 薄层层析硅胶板使用烟台黄海 HSGF254 或青岛 GF254硅胶板， 薄层色谱法 （TLC)使 用的硅胶板采用的规格是 0.15 mm~0.20 mm , 薄层层析分离纯化产品采用的规格是 0.4 mm~0.5 mm。  The HPLC was measured using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 X 4.6 mm) » Thin layer chromatography silica gel plate using Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, thin layer chromatography (TLC) using silica gel plate The specification is 0.15 mm~0.20 mm, and the specification for thin layer chromatography separation and purification is 0.4 mm~0.5 mm.
柱层析一般使用烟台黄海硅胶 200~300目硅胶为载体。  Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成， 或可购买于泰坦科 技、 安耐吉化学、 上海德默、 成都科龙化工、 韶远化学科技、 百灵威科技等公司。  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 Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
氮气氛是指反应瓶连接一个约 1L容积的氮气气球。  The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume.
氢气氛是指反应瓶连接一个约 1L容积的氢气气球。  The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
氢化反应通常抽真空， 充入氢气， 反复操作 3次。  The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
实施例中无特殊说明， 反应在氮气氛下进行。  Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.
实施例中无特殊说明， 溶液是指水溶液。 实施例中无特殊说明， 反应的温度为室温。 There is no particular description in the examples, and the solution means an aqueous solution. There is no particular description in the examples, and the reaction temperature is room temperature.
室温为最适宜的反应温度， 为 20°C~ 30°C。  The optimum reaction temperature at room temperature is 20 ° C ~ 30 ° C.
Et， 乙基；  Et, ethyl;
Me, 甲基；  Me, methyl;
Bn， 苄基；  Bn, benzyl;
Bz， 苯甲酰基；  Bz, benzoyl;
中间体 1： 3-吗啉 -1-(4-(2-氧代哌啶 -1-基)苯基) -5,6- Intermediate 1: 3-morpholine-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-
CN101967145) CN101967145)
-morpholino- 1 -(4-(2-oxopiperidin- 1 -yl)phenyl)-5,6-dihydropyridin-2( 1 H)-one (If)  -morpholino-1 -(4-(2-oxopiperidin- 1 -yl)phenyl)-5,6-dihydropyridin-2( 1 H)-one (If)
Figure imgf000041_0001
Figure imgf000041_0001
1e 1f  1e 1f
第一步： l-(4-硝基苯基)哌啶 -2-酮 lb  First step: l-(4-nitrophenyl)piperidin-2-one lb
l-(4-nitrophenyl)piperidin-2-one
Figure imgf000041_0002
L-(4-nitrophenyl)piperidin-2-one
Figure imgf000041_0002
将 4-硝基苯胺 la (11.0 g, 0.08 mol)溶解于四氢呋喃 （200 mL) 中， 冷却至 0°C， 滴加 5- 氯戊酰氯 （16 mL, 0.12 mol) 的四氢呋喃 （50 mL)溶液， 滴加完毕， 升至室温反应 5小时， 冷 却至 0°C， 分批加入氢化钠 （含量： w/w = 60%, 5.8 g, 0.24 mol), 升至室温反应 12小时。 将 反应液冷却至 0°C， 缓慢加入水（60 mL)， 用乙酸乙酯 （50 mL X 3)萃取， 合并有机相， 用 饱和食盐水（30 mL)洗涤， 有机相用无水硫酸钠干燥， 过滤， 浓缩， 残留物用乙酸乙酯 /石油 醚（v/v) =l : 19重结晶， 得到黄色固体状的 1-(4-硝基苯基)哌啶 -2-酮 lb (10.0 g， 产率 58%)。  Dissolve 4-nitroaniline la (11.0 g, 0.08 mol) in tetrahydrofuran (200 mL), cool to 0 ° C, and add dropwise solution of 5-chloropentanoyl chloride (16 mL, 0.12 mol) in tetrahydrofuran (50 mL) After completion of the dropwise addition, the mixture was allowed to react to room temperature for 5 hours, cooled to 0 ° C, sodium hydride (content: w/w = 60%, 5.8 g, 0.24 mol) was added portionwise, and the mixture was allowed to react at room temperature for 12 hours. The reaction solution was cooled to 0 ° C, water (60 mL) was added slowly, and ethyl acetate (50 mL X 3) was evaporated. The organic phase was combined and washed with brine (30 mL) Drying, filtration, EtOAc (EtOAc/EtOAc (EtOAc) 10.0 g, yield 58%).
第二步： 3,3-二氯 -1-(4-硝基苯基)哌啶 -2-酮 lc  Second step: 3,3-dichloro-1-(4-nitrophenyl)piperidin-2-one lc
3 ,3-dichloro- 1 -(4-nitrophenyl)piperidin-2-one
Figure imgf000042_0001
3 ,3-dichloro- 1 -(4-nitrophenyl)piperidin-2-one
Figure imgf000042_0001
将 1-(4-硝基苯基)哌啶 -2-酮 lb (6.6 g, 0.03 mol)溶于氯仿 （30 mL) 中， 10分钟内加入五 氯化磷（18.7 g, 0.09 mol), 加热至回流反应 3小时。 将反应液冷却至室温， 倾倒到冰水（50 mL) 中， 分液， 水相用氯仿 （30 mL X 2)萃取， 合并有机相， 用饱和食盐水（30 mL X 2) 洗涤， 有机相用无水硫酸钠干燥， 过滤， 浓缩得到深黄色固体状的化合物 3,3-二氯 -1-(4-硝基 苯基；)哌啶 -2-酮 lc (8.0 g， 粗品， 未纯化 )。  1-(4-Nitrophenyl)piperidin-2-one lb (6.6 g, 0.03 mol) was dissolved in chloroform (30 mL), and phosphorus pentachloride (18.7 g, 0.09 mol) was added over 10 min. Heat to reflux for 3 hours. The reaction solution was cooled to room temperature, poured into ice water (50 mL), and the mixture was evaporated. EtOAc (EtOAc) Drying over anhydrous sodium sulfate, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ).
第三步 : 1-(4-硝基苯基) -3-吗啉 -5,6-二氢吡啶 -2(1H 酮 Id The third step : 1- (4-nitrophenyl)-3-morpholine-5,6-dihydropyridine-2 (1H ketone Id
3-morpholino-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)-one
Figure imgf000042_0002
3-morpholino-l-(4-nitrophenyl)-5,6-dihydropyridin-2(lH)-one
Figure imgf000042_0002
将 3,3-二氯 -1-(4-硝基苯基)哌啶 -2-酮 lc (8.6 g, 0.03 mol)溶于吗啉溶液（30 mL, 0.30 mol) 中， 升温至 130°C反应 1.5小时。 将反应液冷却至室温， 加入水（50 mL)， 过滤， 滤饼用水淋 洗得到深黄色固体， 用乙酸乙酯重结晶得到深黄色固体状的化合物 1-(4-硝基苯基) -3-吗啉 -5,6- 二氢吡啶 -2(1H)-酮 ld， (6.1 g, 产率 67%)。  3,3-Dichloro-1-(4-nitrophenyl)piperidin-2-one lc (8.6 g, 0.03 mol) dissolved in morpholine solution (30 mL, 0.30 mol), warmed to 130 ° C reacted for 1.5 hours. The reaction mixture was cooled to room temperature, water (50 mL) was evaporated. 3-morpholine-5,6-dihydropyridine-2(1H)-one ld, (6.1 g, yield 67%).
第四步： -(4-氨基苯基) -3-吗啉 -5,6-二氢吡啶 -2(1H)-酮 le  Fourth step: -(4-Aminophenyl)-3-morpholine-5,6-dihydropyridine-2(1H)-one le
l-(4-aminophenyl)-3-morpholino- -dihydropyridin-2(lH)-one
Figure imgf000042_0003
L-(4-aminophenyl)-3-morpholino- -dihydropyridin-2(lH)-one
Figure imgf000042_0003
将 l-(4-硝基苯基) -3-吗啉 -5,6-二氢吡啶 -2(1H)-酮 Id (6.1 g, 0.02mol)溶于乙醇 (60 mL) 中， 加入九水合硫化钠 （9.6 g, 0.04 mol)水（20 mL)溶液， 升温至 70°C反应 2小时。 将反应 液冷却至室温， 浓缩， 残留物中加入乙酸乙酯 （50 mL), 过滤， 滤饼干燥后得到浅黄色固体 状的化合物 1-(4-氨基苯基) -3-吗啉 -5,6-二氢吡啶 -2(1H)-酮 le (3.8 g, 产率 70%)。  1-(4-Nitrophenyl)-3-morpholine-5,6-dihydropyridine-2(1H)-one Id (6.1 g, 0.02 mol) was dissolved in ethanol (60 mL). A solution of sodium sulfide (9.6 g, 0.04 mol) in water (20 mL) was added, and the mixture was heated to 70 ° C for 2 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc m. , 6-dihydropyridine-2(1H)-one le (3.8 g, yield 70%).
第五步： μ -ρ-氧代哌啶 -1-基)苯基 3-吗啉 -5,6-二氢吡啶 -2(1H 酮 If  Step 5: μ -ρ-Oxopiperidin-1-yl)phenyl 3-morpholine -5,6-dihydropyridine -2 (1H ketone If
3 -morpholino- 1 -(4-(2-oxopiperidi - 1 -yl)phenyl)-5,6-dihydropyridin-2( 1 H)-one  3 -morpholino-1 -(4-(2-oxopiperidi - 1 -yl)phenyl)-5,6-dihydropyridin-2( 1 H)-one
Figure imgf000042_0004
Figure imgf000042_0004
将 l-(4-氨基苯基) -3-吗啉 -5,6-二氢吡啶 -2(1H)-酮 le (3.8 g, 13.90 mmol) 溶于四氢呋喃 (100 mL) 中， 加入三乙胺 (4.2 g, 41.70 mmol), 冷却至 0°C， 滴加 5-氯戊酰氯 (3.1 g, 19.50 mmol) 的四氢呋喃 （10 mL)溶液， 滴加完毕， 升至 55°C反应 2小时， 然后冷却至 0°C， 缓慢 加入氢化钠 （含量 60%， 1.7 g, 41.70 mmol), 在 20分钟内加完， 升至室温反应过夜。 将反应 液冷却至 0°C， 缓慢加入水 （10 mL), 减压浓缩， 加入水 （10 mL), 抽滤， 滤饼用乙酸乙酯 (100 mL)洗涤， 得到浅黄色固体， 滤液用二氯甲垸（100 mL X 2)萃取， 合并有机相， 用无 水硫酸钠干燥， 过滤， 浓缩， 残留物与滤饼合并得到浅黄色固体状的化合物 1-(4-(2-氧代哌 啶 -1-基)苯基) -3-吗啉 -5,6-二氢吡啶 -2(1H)-酮 If (3.6 g, 产率 73%)。 1-(4-Aminophenyl)-3-morpholine-5,6-dihydropyridine-2(1H)-one le (3.8 g, 13.90 mmol) was dissolved in tetrahydrofuran (100 mL). Amine (4.2 g, 41.70 mmol), cooled to 0 ° C, and added 5-chloropentanoyl chloride (3.1 g, 19.50) A solution of mmol) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at 55 ° C for 2 hours, then cooled to 0 ° C, slowly adding sodium hydride (content 60%, 1.7 g, 41.70 mmol) in 20 minutes After the addition was completed, the reaction was allowed to rise to room temperature overnight. The reaction mixture was cooled to 0 ° C, EtOAc (EtOAc)EtOAc. Dichloromethane (100 mL X 2 ) was extracted, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated, Piperidin-1-yl)phenyl)-3-morpholine-5,6-dihydropyridine-2(1H)-one If (3.6 g, yield 73%).
中间体 2: 1-(4-碘苯基 )-3-吗啉 -5,6-二氢吡啶 -2(1H)-酮 （2e) (参考文献 CN101967145) Intermediate 2: 1-(4-iodophenyl)-3-morpholine-5,6-dihydropyridine-2(1H)-one (2e) (Reference CN101967145)
1 -(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2( 1 H)-one 1 -(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2( 1 H)-one
Figure imgf000043_0001
第一步： 5-氯 -N-(4-碘苯基;)戊酰胺 2b
Figure imgf000043_0001
First step: 5-chloro-N-(4-iodophenyl;) pentanoamide 2b
5-chloro-N-(4-iodophenyl)pentanamide
Figure imgf000043_0002
5-chloro-N-(4-iodophenyl)pentanamide
Figure imgf000043_0002
将三乙胺 (10.1 g, 0.10 mol)溶于四氢呋喃 (200 mL) 中， 加入 4-碘苯胺 2a (11.00 g, 0.05 mol)。 反应液冷却至 0°C， 滴加 5-氯-戊酰氯（11.6 g, 0.10 mol) 的四氢呋喃 （50 mL)溶液， 滴 加完毕后升至室温反应 3小时。 反应液冷却至 0°C， 缓慢加入水（10 mL), 升至室温， 加入乙 酸乙酯 （100 mL)和水（200 mL), 分液， 有机相用饱和食盐水（100 mL)洗涤， 用无水硫酸 钠干燥， 过滤， 浓缩， 得到黄色固体状的化合物 5-氯 -N-(4-碘苯基)戊酰胺 2b (13.0 g， 产率 77%)。  Triethylamine (10.1 g, 0.10 mol) was dissolved in tetrahydrofuran (200 mL), and 4-iodoaniline 2a (11.00 g, 0.05 mol) was added. The reaction liquid was cooled to 0 ° C, and a solution of 5-chloro-pentanoyl chloride (11.6 g, 0.10 mol) in tetrahydrofuran (50 mL) was added dropwise, and the mixture was allowed to react at room temperature for 3 hours. The reaction mixture was cooled to 0 ° C, and water (10 mL) was added slowly, and the mixture was warmed to room temperature, ethyl acetate (100 mL) and water (200 mL) were added, and the organic phase was washed with saturated brine (100 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4)
MS m/z (ESI): 337.9 [M+l].  MS m/z (ESI): 337.9 [M+l].
第二步： i -(4-碘苯基)哌啶 -2-酮 2c  Second step: i -(4-iodophenyl)piperidin-2-one 2c
1 -(4-iodophenyl)piperidin-2-one
Figure imgf000043_0003
1 -(4-iodophenyl)piperidin-2-one
Figure imgf000043_0003
将 5-氯 -N-(4-碘苯基)戊酰胺 2b(13.0 g, 0.04 mol)溶于四氢呋喃 （100 mL) 中， 冷却至 0 °C， 缓慢加入氢化钠 （含量： w/w = 60%， 3.2 g, 0.08 mol), 升至室温反应 3小时。 反应液冷 却至 0°C， 缓慢加入水（10 mL)， 再加入饱和食盐水溶液（20 mL)， 分液， 有机相用无水硫酸 钠干燥， 过滤， 浓缩， 残留物用乙酸乙酯 /石油醚 i l、 =1 :4 重结晶， 得到浅黄色固体状的化 合物 1-(4-碘苯基)哌啶 -2-酮 2c， (11.0 g, 产率 95%)。 Dissolve 5-chloro-N-(4-iodophenyl)pentanamide 2b (13.0 g, 0.04 mol) in tetrahydrofuran (100 mL) and cool to 0 At ° C, sodium hydride (content: w/w = 60%, 3.2 g, 0.08 mol) was slowly added, and the mixture was allowed to react to room temperature for 3 hours. The reaction mixture was cooled to 0 ° C, then water (10 mL) was added slowly, and then brine (20 mL) was added, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The product was recrystallized from EtOAc to EtOAc (EtOAc: EtOAc)
¾ NMR (300 MHz,CDCl3) δ 1.93-1.99 (m, 4H), 2.55 (t,2H), 3.62-3.60 (m, 2H), 7.02(d, 2H), 7.70 (d, 2H) 3⁄4 NMR (300 MHz, CDCl 3 ) δ 1.93-1.99 (m, 4H), 2.55 (t, 2H), 3.62-3.60 (m, 2H), 7.02 (d, 2H), 7.70 (d, 2H)
MS m/z (ESI): 302.0 [M+l]  MS m/z (ESI): 302.0 [M+l]
第三步： 3,3-二氯 -l-(4-碘苯基)哌啶 -2-酮 2d  The third step: 3,3-dichloro-l-(4-iodophenyl)piperidin-2-one 2d
3,3-dichloro-l-(4-iodophenyl)piperidi -2-one
Figure imgf000044_0001
3,3-dichloro-l-(4-iodophenyl)piperidi -2-one
Figure imgf000044_0001
将 1-( 4-碘苯基)哌啶 -2-酮 2c (11.0 g, 36.50 mmol)溶于氯仿（100 mL)溶液中， 加入五氯 化磷 （22.8 g, 110.00 mmol), 加热至 65°C搅拌反应 4 小时。 反应液冷却至室温， 倒入冰水 中， 分液， 有机相用饱和食盐水溶液（50 mL)洗涤， 无水硫酸钠干燥， 过滤， 浓缩得到红色 粘稠的化合物 3.3-二氯 -1-(4-碘苯基;) -哌啶 -2-酮 2d (13.0 g, 产率 96%)。  1-(4-Iodophenyl)piperidin-2-one 2c (11.0 g, 36.50 mmol) was dissolved in chloroform (100 mL), EtOAc (22.8 g, 110.00 mmol). The reaction was stirred at ° C for 4 hours. The reaction solution was cooled to room temperature, poured into ice water, and then evaporated. EtOAcjjjjjjjjjjj -iodophenyl;)-piperidin-2-one 2d (13.0 g, yield 96%).
MS m/z (ESI): 369.8 [M+l]  MS m/z (ESI): 369.8 [M+l]
第四步： i-(4-碘苯基 )-3-吗啉 -5,6-二氢吡啶 -2(1H)-酮 2e  Fourth step: i-(4-iodophenyl)-3-morpholine-5,6-dihydropyridine-2(1H)-one 2e
1 -(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2( 1 H)-one
Figure imgf000044_0002
1 -(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2( 1 H)-one
Figure imgf000044_0002
将吗啉 (21.2 g, 243.00 mmol)加入 3,3-二氯 -1-(4-碘苯基) -哌啶 -2-酮 2d (16.0 g, 43.36 mmol) 中， 加热至 130°C反应 4小时。 将反应液降温至 30°C， 加入乙酸乙酯（50 mL)和水 (50 mL), 分液， 有机相用饱和食盐水溶液（40 mL X 3)洗涤， 有机相用无水硫酸钠干燥， 过滤， 浓缩， 残留物用硅胶柱色谱法分离 （乙酸乙酯 /正己垸 i N、 =1 : 10-1 :4)得到黄色固体 状的化合物 1-(4-碘苯基 )-3-吗啉 -5,6-二氢吡啶 -2(1H)-酮 2e (6.0 g,产率 65%)。  Add morpholine (21.2 g, 243.00 mmol) to 3,3-dichloro-1-(4-iodophenyl)-piperidin-2-one 2d (16.0 g, 43.36 mmol) and heat to 130 ° C 4 hours. The reaction mixture was cooled to 30 ° C, ethyl acetate (50 mL) and water (50 mL) was evaporated. Filtration, concentrating, and the residue was purified by silica gel column chromatography (ethyl acetate / hexanes / / / / / / / Porphyrin-5,6-dihydropyridine-2(1H)-one 2e (6.0 g, yield 65%).
MS m/z (ESI): 384.9 [M+l] 实施例 1  MS m/z (ESI): 384.9 [M+l] Example 1
l-(2-甲基 -2,3-二氢吡啶呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -1H-吡 唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 1)  L-(2-Methyl-2,3-dihydropyridylfuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 1)
l-(2-methyl-2,3-Dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide
Figure imgf000045_0001
L-(2-methyl-2,3-Dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH -pyrazolo[3,4-c]pyridine-3-carboxamide
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000045_0002
将 2-甲基 -2.3-二氢苯并呋喃 1A (1.0 g, 7.50 mmol )溶于乙酸（10 mL) 中， 室温下加入浓 硝酸 （125 mg, 2.0 mmol), 升温至 70°C， 加入浓硝酸 （375 mg, 6.00 mmol), 维持 70°C搅拌反 应 1小时。 向反应液中加入水（50 mL)和乙酸乙酯 （50 mL)， 分液， 水相用乙酸乙酯 （20 mL X 2) 萃取， 合并有机相， 有机相用饱和食盐水 （50 mL X 2) 洗涤， 无水硫酸钠干燥， 过 滤， 浓缩， 残留物用硅胶柱色谱分离提纯 (石油醚 /乙酸乙酯 （v/v) = 1 :0-1 :9)得到褐色固体状 的化合物 2-甲基 -5-硝基 -2,3-二氢苯并呋喃 1B (170 mg,产率 13%)。  2-Methyl-2.3-dihydrobenzofuran 1A (1.0 g, 7.50 mmol) was dissolved in acetic acid (10 mL). Concentrated nitric acid (125 mg, 2.0 mmol) was added at room temperature and then warmed to 70 ° C. Concentrated nitric acid (375 mg, 6.00 mmol) was stirred at 70 ° C for 1 hour. Water (50 mL) and ethyl acetate (50 mL) were added to the mixture and the mixture was evaporated. 2) Washed, dried over anhydrous sodium sulfate, filtered, EtOAcjjjjjjjjjjjj -Methyl-5-nitro-2,3-dihydrobenzofuran 1B (170 mg, yield 13%).
^ NMR (400 MHz, CDC13) δ 8.09 (dd, 1Η), 8.06 (d, 1H), 6.78 (d, 1H), 5.16-5.07 (m, 1H), 3.41 (dd, 1H), 2.89 (dd, 1H), 1.52 (d, 3H)。 ^ NMR (400 MHz, CDC1 3 ) δ 8.09 (dd, 1Η), 8.06 (d, 1H), 6.78 (d, 1H), 5.16-5.07 (m, 1H), 3.41 (dd, 1H), 2.89 (dd , 1H), 1.52 (d, 3H).
第二步： 2-甲基 -2,3-二氢苯并呋喃 -5-胺 1C  Second step: 2-methyl-2,3-dihydrobenzofuran-5-amine 1C
2-methyl-2,3-dihydrobenzofuran-5-amine  2-methyl-2,3-dihydrobenzofuran-5-amine
Figure imgf000045_0003
Figure imgf000045_0003
将 2-甲基 -5-硝基 -2,3-二氢苯并呋喃 1B (670 mg, 3.74 mmol)溶于乙酸 （30 mL) 中， 加入 九水合硫化钠 （2.7 g, 11.22 mmol) 的水（10 mL)溶液， 升温至 90°C反应 3小时。 浓缩反应 液， 加入水（20 mL)和乙酸乙酯 （30 mL), 分液， 水相用乙酸乙酯 （20 mL X 2)萃取， 合 并有机相， 有机相用饱和食盐水 （20 mL X 2)洗涤， 无水硫酸钠干燥， 过滤， 浓缩得黄色 固体状的化合物 2-甲基 -2,3-二氢苯并呋喃 -5-胺 1C (450 mg, 产率 81%)。  2-Methyl-5-nitro-2,3-dihydrobenzofuran 1B (670 mg, 3.74 mmol) was dissolved in acetic acid (30 mL) and sodium sulfate sulfate (2.7 g, 11.22 mmol) was added. A solution of water (10 mL) was heated to 90 ° C for 3 hours. The reaction mixture was concentrated, EtOAc (EtOAc) (EtOAc) 2) Washed, dried over anhydrous sodium sulfate, filtered and evaporated tolulululululululululululululululululu
^ NMR (400 MHz, CDC13) δ 6.56-6.54 (m, 2Η), 6.45-6.42 (m, 1H), 4.87-4.78 (m, 1H), 3.36 (s, 2H), 3.20 (dd, 1H), 2.72 (dd, 1H), 1.42 (d, 3H)。 ^ NMR (400 MHz, CDC1 3 ) δ 6.56-6.54 (m, 2Η), 6.45-6.42 (m, 1H), 4.87-4.78 (m, 1H), 3.36 (s, 2H), 3.20 (dd, 1H), 2.72 (dd, 1H), 1.42 (d, 3H).
MS m/z (ESI): 150.1 [M+l]  MS m/z (ESI): 150.1 [M+l]
第三步： 2-氯 -2-(2-(2-甲基 1-2,3-二氢苯并呋喃 -5-基)腙基)乙酸乙酯 1D  Step 3: 2-Chloro-2-(2-(2-methyl 1-2,3-dihydrobenzofuran-5-yl)indolyl)acetate 1D
ethyl 2-chloro-2-(2-(2-methyl-2,3-dihy yl)hydrazono)acetate  Ethyl 2-chloro-2-(2-(2-methyl-2,3-dihy yl)hydrazono)acetate
Figure imgf000046_0001
Figure imgf000046_0001
将浓盐酸 （1.7 mL, 20.10 mmol) 的水（3.5 mL)溶液加入到 2-甲基 -2,3-二氢苯并呋喃 -5-胺 1C (1.0 g, 6.70 mmol) 中， 0°C下搅拌反应 15 分钟， 在 0°C下滴加亚硝酸钠 (555 mg, 8.00 mmol) 的水（8 mL)溶液， 维持 0°C搅拌反应 30分钟， 用乙酸钠 （1.1 g, 13.40 mmol)调节反 应液 pH=5~6， 在 0°C下滴加 2-氯乙酰乙酸乙酯（1.1 g, 6.70 mmol) 的甲醇 （10 mL)溶液， 10 分钟加完， 室温反应 1小时。 向反应液中加入乙酸乙酯 （50 mL)和水（20 mL), 分液， 水相 用乙酸乙酯 （20 mL X 2)萃取， 合并有机相， 用饱和食盐水（30 mL)洗涤， 无水硫酸钠干 燥， 过滤， 浓缩， 残留物用硅胶柱色谱分离提纯 (石油醚 /乙酸乙酯 i l、 = 1 :0-1 :9)得到黄色 固体状的化合物 2-氯 -2-(2-(2-甲基 1-2,3-二氢苯并呋喃 -5-基;)腙基)乙酸乙酯 1D (400 mg, 产率 20%)  Add a solution of concentrated hydrochloric acid (1.7 mL, 20.10 mmol) in water (3.5 mL) to 2-methyl-2,3-dihydrobenzofuran-5-amine 1C (1.0 g, 6.70 mmol), 0 ° C The reaction was stirred for 15 minutes, and a solution of sodium nitrite (555 mg, 8.00 mmol) in water (8 mL) was added dropwise at 0 ° C, and the mixture was stirred at 0 ° C for 30 minutes, using sodium acetate (1.1 g, 13.40 mmol) The pH of the reaction mixture was adjusted to 5 to 6, and a solution of ethyl 2-chloroacetoacetate (1.1 g, 6.70 mmol) in methanol (10 mL) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (50 mL) and water (20 mL) were added to the mixture and the mixture was evaporated. Drying over anhydrous sodium sulfate, EtOAc (EtOAc m.) -(2-methyl1-2,3-dihydrobenzofuran-5-yl;) indenyl)ethyl acetate 1D (400 mg, yield 20%)
第四步： 1-(2-甲基 -2,3-二氢吡啶呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5,6,7-四 氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 1E  The fourth step: 1-(2-methyl-2,3-dihydropyridylfuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7 -oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 1E
ethyl l-(2-methyl-2,3-Dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate  Ethyl l-(2-methyl-2,3-Dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]- 4,5,6,7-tetrahydro- lH-pyrazolo[3,4-c]pyridine-3-carboxylate
Figure imgf000046_0002
Figure imgf000046_0002
将 3-吗啉- 1 -(4-(2-氧代哌啶 - 1 -基)苯基) -5,6· 氢吡啶 -2(1H)-酮 (If) (457 mg, 1.28 mmol), 2- 氯 -2-(2-(2-甲基 1-2,3-二氢苯并呋喃 -5-基)腙基)乙酸乙酯 （400 mg, 1.41 mmol) 溶于乙酸乙酯 (30 mL) 中， 加入碘化钾 (22 mg, 0.13 mmol)和三乙胺 (389 mg, 3.84 mmol), 升至 90°C回流 反应 6小时， 反应液冷却至 0°C， 加入盐酸 (4N, 1.6 mL, 6.40 mmol), 室温搅拌反应 1小时。 向反应液中加入水（20 mL)， 分液， 水相用乙酸乙酯 （20 mL X 2)萃取， 合并有机相， 用饱 和食盐水 （30 mL X 2) 洗涤， 无水硫酸钠干燥， 过滤， 浓缩， 残留物用硅胶柱色谱分离提 纯 （乙酸乙酯 /石油醚（v/v) = 1 : 1-1 :0, 甲醇 /乙酸乙酯 （v/v) =1 : 19)得到黄色固体状的化合物 1-(2-甲基 -2,3-二氢吡啶呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 IE (230 mg, 产率 35%)。 3-morpholine-1 -(4-(2-oxopiperidin-1-yl)phenyl)-5,6-hydropyridine-2(1H)-one (If) (457 mg, 1.28 mmol) , 2-Chloro-2-(2-(2-methyl1-2,3-dihydrobenzofuran-5-yl)indolyl)acetate (400 mg, 1.41 mmol). In 30 mL), potassium iodide (22 mg, 0.13 mmol) and triethylamine (389 mg, 3.84 mmol) were added, and the mixture was refluxed to 90 ° C for 6 hours. The reaction solution was cooled to 0 ° C, and hydrochloric acid (4N, 1.6) was added. mL, 6.40 mmol), stir the reaction at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjj Filtration, concentrating, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v/v) = 1 : 1-1 :0, methanol / ethyl acetate (v/v) = 19: 19) Solid 1-(2-methyl-2,3-dihydropyridylfuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo Generation-4,5,6,7-tetrahydro-1H-pyrazole Ethyl [3,4-c]pyridine-3-carboxylate IE (230 mg, yield 35%).
¾ NMR (400 MHz, CDC13) δ 7.36-7.34 (m, 3H), 7.26-7.25 (m, 3H), 6.73 (d, IH), 5.02-4.90 IH), 4.56-4.43 (m, 2H), 4.15-4.10 (m, 2H), 3.60-3.59 (m, 2H), 3.32 (dd, 3H), 2.82 (dd, IH), 2.58 (d, 2H), 1.98 -1.87 (m, 4H), 1.46-1.41 (m, 6H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.36-7.34 (m, 3H), 7.26-7.25 (m, 3H), 6.73 (d, IH), 5.02-4.90 IH), 4.56-4.43 (m, 2H), 4.15-4.10 (m, 2H), 3.60-3.59 (m, 2H), 3.32 (dd, 3H), 2.82 (dd, IH), 2.58 (d, 2H), 1.98 -1.87 (m, 4H), 1.46- 1.41 (m, 6H).
MS m/z (ESI): 515.2 [M+H]  MS m/z (ESI): 515.2 [M+H]
第五步： l-(2-甲基 -2,3-二氢吡啶呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四 氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺化合物 1  Step 5: l-(2-Methyl-2,3-dihydropyridylfuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxygen Generation-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide Compound 1
l-(2-methyl-2,3-Dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-ΙΗ- pyrazolo[3,4-c]pyridi -3-carboxamide  L-(2-methyl-2,3-Dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-ΙΗ - pyrazolo[3,4-c]pyridi -3-carboxamide
Figure imgf000047_0001
Figure imgf000047_0001
将 1-(2-甲基 -2,3-二氢吡啶呋喃 -5-基) -7-氧代 -6-[4-(2-氧代哌啶 -1-基)苯基] -4,5,6,7-四氢 -1H- 吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 1E(230 mg,0.45 mmol) 溶于 Ν,Ν-二甲基甲酰胺 (15 mL) 中， 加入甲酰胺（121 mg, 2.68 mmol), 甲醇钠 （49 mg, 0.90 mmol), 升至 80°C反应 18小时。 向反 应液中加入乙酸乙酯 （30 mL)和水（30 mL), 分液， 水相用乙酸乙酯（30 mL X 2)萃取， 有机相用饱和食盐水 （30 mL X 3) 洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩， 残留物用硅 胶柱色谱分离提纯 （甲醇 /乙酸乙酯 （v/v) = 0: 1-1 : 19) 得到白色固体状的化合物 1-(2-甲基 -2,3- 二氢吡啶呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3- 甲酰胺化合物 1 (80 mg, 产率 37%)。  1-(2-Methyl-2,3-dihydropyridylfuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4 ,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 1E (230 mg, 0.45 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (15 In mL), formamide (121 mg, 2.68 mmol), sodium methoxide (49 mg, 0.90 mmol) was added and the mixture was stirred at 80 ° C for 18 hours. Ethyl acetate (30 mL) and water (30 mL) were added to the mixture and the mixture was evaporated. The residue was dried over anhydrous sodium sulfate (MgSO4jjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -methyl-2,3-dihydropyridylfuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5,6, 7-Tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide Compound 1 (80 mg, yield 37%).
化合物 1:  Compound 1:
O NMR (400 MHz, CDC13) δ 7.36-7.31 (m, 3Η), 7.27-7.25 (m, 3H), 6.84 (s, IH), 6.76 (d, 1H): 5.56 (s, IH), 5.03 - 4.92 (m, IH), 4.11 (t, 2H), 3.60-3.59 (m, 2H), 3.40-3.31 (m, 3H), 2.85 (dd, IH), 2.56 (s, 2H), 1.93 (m 4H), 1.47 (d, 3H)。 O NMR (400 MHz, CDC1 3 ) δ 7.36-7.31 (m, 3Η), 7.27-7.25 (m, 3H), 6.84 (s, IH), 6.76 (d, 1H) : 5.56 (s, IH), 5.03 - 4.92 (m, IH), 4.11 (t, 2H), 3.60-3.59 (m, 2H), 3.40-3.31 (m, 3H), 2.85 (dd, IH), 2.56 (s, 2H), 1.93 (m 4H), 1.47 (d, 3H).
MS m/z (ESI): 486.1 [M+l] 实施例 2  MS m/z (ESI): 486.1 [M+l] Example 2
l-(2,3-二氢苯并呋喃 -5-基) -6-(4-(3-氧代吗啉)苯基) -7-氧代 -4,5,6,7-四氢 -IH-吡唑 [3,4-c]吡 啶 -3-甲酰胺 （；化合物 2)  L-(2,3-Dihydrobenzofuran-5-yl)-6-(4-(3-oxomorpholine)phenyl)-7-oxo-4,5,6,7-tetrahydro -IH-pyrazole [3,4-c]pyridine-3-carboxamide (Compound 2)
l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxomorpholino)phenyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3 ,4-c]pyridine-3-carboxamide 第一歩 L-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxomorpholino)phenyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3 ,4-c Pyridine-3-carboxamide First
ΝΗ2 ΝΗ 2
Figure imgf000048_0001
Figure imgf000048_0001
2Β 2C 2D 化介物 2 第一步： 2-氯 -2-(2-(2,3-二氢苯并呋喃 -5-基)腙基)乙酸乙酯 2B  2Β 2C 2D Chemical 2 Step 1: 2-Chloro-2-(2-(2,3-dihydrobenzofuran-5-yl)indenyl)acetate 2B
ethyl 2-chloro-2-(2-(2,3-dihydrobenzo ono)acetate  Ethyl 2-chloro-2-(2-(2,3-dihydrobenzo ono)acetate
将 2,3-二氢苯并呋喃 -5-胺 2A (2.0 g, 14.80 mmol)加入到盐酸 （14.6 mL, 3N)中， 冷却至 -5 V ,滴加亚硝酸钠 （1.2 g, 17.80 mmol)水（8 mL)溶液， 滴加完毕后， 在 0°C反应 30分钟， 缓慢加入乙酸钠 （2.1 g, 25.6 mmol), 调节反应液至 pH = 5~6， 在 0~5°C下， 滴加 2-氯乙酰乙 酸乙酯 （2.4 g, 14.80 mmol) 的甲醇 （5 mL)溶液， 升至室温反应 2小时， 向反应液中加入乙 酸乙酯 （20 mL), 分液， 有机相用饱和食盐水（30 mL)洗涤， 分液， 有机相用无水硫酸钠干 燥， 过滤， 减压浓缩， 残留物用硅胶柱色谱法纯化（乙酸乙酯 /石油醚（v/V;» = 1 :99 ~ 1 :9)得到 黄色固体状的化合物 2-氯 -2-(2-(2,3-二氢苯并呋喃 -5-基;)腙基)乙酸乙酯 2B (200 mg， 产率 5%)。 2,3-Dihydrobenzofuran-5-amine 2A (2.0 g, 14.80 mmol) was added to hydrochloric acid (14.6 mL, 3 N), cooled to -5 V and sodium nitrite (1.2 g, 17.80 mmol) Water (8 mL) solution, after the addition is completed, react at 0 ° C for 30 minutes, slowly add sodium acetate (2.1 g, 25.6 mmol), adjust the reaction solution to pH = 5~6, at 0~5 °C , a solution of ethyl 2-chloroacetoacetate (2.4 g, 14.80 mmol) in methanol (5 mL) was added dropwise, and the mixture was warmed to room temperature for 2 hr, ethyl acetate (20 mL) was added to the reaction mixture, and the organic phase was separated. with saturated brine (30 mL) was washed, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / V a; »= 1 : 99 ~ 1 : 9) Compound 2-chloro-2-(2-(2,3-dihydrobenzofuran-5-yl;) fluorenyl)acetate 2B (200 mg, Yield 5%).
^ NMR (400 MHz, CDC13) δ 8.27 (s, IH), 7.18 (s, IH), 6.91 (d, IH), 6.73 (d, IH), 4.65-4.54 (m, 2H), 4.38 (q, 2H), 3.22 (t, 2H), 1.40 (t, 3H)。 ^ NMR (400 MHz, CDC1 3 ) δ 8.27 (s, IH), 7.18 (s, IH), 6.91 (d, IH), 6.73 (d, IH), 4.65-4.54 (m, 2H), 4.38 (q , 2H), 3.22 (t, 2H), 1.40 (t, 3H).
第二步： l-(2,3-二氢苯并呋喃 -5-基) -6-(4-碘苯基 )-7-氧代 -4,5,6,7-四氢 -IH-吡唑并 [3,4-c]吡 啶 -3-甲酸乙酯 2C  Second step: l-(2,3-dihydrobenzofuran-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-IH- Pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 2C
ethyl l-(2,3-dihydrobenzofuran-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-lH- pyrazolo[3 ,4-c]pyridine-3-carbox-ylate  Ethyl l-(2,3-dihydrobenzofuran-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3 -carbox-ylate
Figure imgf000048_0003
将 l-(4-碘苯基 )-3-吗啉 -5,6-二氢吡啶 -2(1H)-酮 2e (2.0 g, 5.20 mmol)溶于乙酸乙酯 （20 mL) 中， 加入 2-氯 -2-(2-(2,3-二氢苯并呋喃 -5-基)腙基)乙酸乙酯 2B (1.8 g, 6.70 mmol), 三乙胺 (1.6 g, 15.60 mmol)和碘化钾 （86 mg, 0.52 mmol), 升温至回流反应过夜， 冷却至 0°C， 加入盐酸 (6.5 mL, 26.00 mmol), 室温搅拌反应 1 小时。 向反应液中加入乙酸乙酯 （20 mL)和水（20 mL), 分液， 有机相用饱和食盐水 （30 mL) 洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩， 残留 物用硅胶柱色谱分离提纯 （乙酸乙酯 /石油醚（v/v) = 1 :99-3:7) 得到红棕色固体状的化合物 1- (2,3-二氢苯并呋喃 -5-基) -6-(4-(3-氧代吗啉)苯基) -7-氧代 -4,5,6,7-四氢 -1H-吡唑 [3,4-c]吡啶 -3-甲 酰胺 2C (1.2 g， 产率 44%)。
Figure imgf000048_0003
1-(4-Iodophenyl)-3-morpholine-5,6-dihydropyridine-2(1H)-one 2e (2.0 g, 5.20 mmol) was dissolved in ethyl acetate (20 mL) 2-Chloro-2-(2-(2,3-dihydrobenzofuran-5-yl)indolyl)acetate 2B (1.8 g, 6.70 mmol), triethylamine (1.6 g, 15.60 mmol) Potassium iodide (86 mg, 0.52 mmol) was warmed to reflux overnight, cooled to 0 ° C, then hydrochloric acid (6.5 mL, 26.00 mmol). Ethyl acetate (20 mL) and water (20 mL) were added to the mixture and the mixture was evaporated. Purification by column chromatography (ethyl acetate / petroleum ether (v/v) = 1 : 99 - 3 : 7) to give compound 1- (2, 3-dihydrobenzofuran-5-yl) as a red-brown solid. 6-(4-(3-oxomorpholine)phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazole[3,4-c]pyridine-3-carboxamide 2C (1.2 g, yield 44%).
¾ NMR (400 MHz, CDC13) δ 7.76-7.66 (m, 2H), 7.36(d, 1H), 7.24 (d, 1H), 7.10 (d, 2H), 6.77 (d, 1H), 4.60 (t, 2H), 4.46 (q, 2H), 4.13-4.08 (m, 2H), 3.32 (t, 2H), 3.22 (t, 2H), 1.44-1.41 (m, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.76-7.66 (m, 2H), 7.36 (d, 1H), 7.24 (d, 1H), 7.10 (d, 2H), 6.77 (d, 1H), 4.60 (t , 2H), 4.46 (q, 2H), 4.13-4.08 (m, 2H), 3.32 (t, 2H), 3.22 (t, 2H), 1.44-1.41 (m, 3H).
第三步： l-(2,3-二氢苯并呋喃 -5-基) -6-(4-(3-氧代吗啉)苯基) -7-氧代 -4,5,6,7-四氢 -1H-吡唑 并 [3,4-c]吡啶 -3-甲酸乙酯 2D  The third step: l-(2,3-dihydrobenzofuran-5-yl)-6-(4-(3-oxomorpholine)phenyl)-7-oxo-4,5,6, 7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 2D
ethyl l-(2,3-dihydrobenzofuran-5-yl)-6-(4-(3-oxomorpholino)phenyl)-7-oxo-4,5,6,7-tetrahydro- lH-pyrazolo[3,4-c]pyridine-3-carboxylate  Ethyl l-(2,3-dihydrobenzofuran-5-yl)-6-(4-(3-oxomorpholino)phenyl)-7-oxo-4,5,6,7-tetrahydro- lH-pyrazolo[3,4- c]pyridine-3-carboxylate
Figure imgf000049_0001
Figure imgf000049_0001
将 1-(2,3-二氢苯并呋喃 -5-基) -6-(4-(3-氧代吗啉)苯基) -7-氧代 -4,5,6,7-四氢 -1H-吡唑 [3,4-c] 吡啶 -3-甲酰胺 2C (400 mg, 0.76 mmol), 吗啉 -3-酮 （84 mg, 0.83 mmol)和磷酸钾 (321 mg, 1.51 mmol)溶于 1.4-二氧六环 （20 mL), 在氮气氛围下， 加入碘化亚铜 （14 mg, 0.07 mmol) 和 Ν,Ν-二甲基环己胺 （11 mg, 0.07 mmol), 加热回流反应过夜。 反应液冷却至室温， 加入水 (30 mL) , 用二氯甲垸 （40 mL) 萃取， 有机相用饱和食盐水 （30 mL) 洗涤， 无水硫酸钠干 燥， 过滤， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯 /石油醚（v/V;» = 1 : 1~1 :0)得到 浅黄色固体状的化合物 1-(2,3-二氢苯并呋喃 -5-基;) -6-(4-(3-氧代吗啉;)苯基； 1-7-氧代 -4,5,6,7-四氢- 1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 2D (200 mg,产率 53%)。 1-(2,3-Dihydrobenzofuran-5-yl)-6-(4-(3-oxomorpholine)phenyl)-7-oxo-4,5,6,7-tetra Hydrogen-1H-pyrazole[3,4-c]pyridine-3-carboxamide 2C (400 mg, 0.76 mmol), morpholin-3-one (84 mg, 0.83 mmol) and potassium phosphate (321 mg, 1.51 mmol) Dissolved in 1.4-dioxane (20 mL), adding cuprous iodide (14 mg, 0.07 mmol) and hydrazine, dimethyl-dimethylcyclohexylamine (11 mg, 0.07 mmol) under nitrogen. The reaction was heated to reflux overnight. The reaction mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc. Purification by silica gel column chromatography (ethyl acetate / petroleum ether (v/ v ;) = 1 : 1 to 1 : 0) to give compound 1-(2,3-dihydrobenzofuran-5- (6-(4-(3-oxomorpholine))phenyl; 1-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c Pyridine-3-carboxylic acid ethyl ester 2D (200 mg, yield 53%).
¾ NMR (400 MHz, DMSO-d6) δ 7.40 (m, 5H), 7.26 (d, 1H), 6.82 (d, 1H), 4.60 (t, 2H), 4.34 (q, 2H), 4.21 (s, 2H), 4.08 (t, 2H), 4.02-3.97 (m, 2H), 3.73 (t, 2H), 3.24-3.19 (m, 4H), 1.33 (t, 3H)。 3⁄4 NMR (400 MHz, DMSO-d 6 ) δ 7.40 (m, 5H), 7.26 (d, 1H), 6.82 (d, 1H), 4.60 (t, 2H), 4.34 (q, 2H), 4.21 (s , 2H), 4.08 (t, 2H), 4.02-3.97 (m, 2H), 3.73 (t, 2H), 3.24-3.19 (m, 4H), 1.33 (t, 3H).
第三步： l-(2,3-二氢苯并呋喃 -5-基) -6-(4-(3-氧代吗啉)苯基) -7-氧代 -4,5,6,7-四氢 -1H-吡唑 并 [3,4-c]吡啶 -3-甲酰胺 化合物 2  The third step: l-(2,3-dihydrobenzofuran-5-yl)-6-(4-(3-oxomorpholine)phenyl)-7-oxo-4,5,6, 7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide compound 2
l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxomorpholino)phenyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridine-3-carboxamide
Figure imgf000050_0001
L-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxomorpholino)phenyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c Pyridine-3-carboxamide
Figure imgf000050_0001
将 l-(2,3-二氢苯并呋喃 -5-基;) -6-(4-(3-氧代吗啉;)苯基; 1-7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c 吡啶 -3-甲酸乙酯 2D (200 mg, 0.40 mmol)溶于 Ν,Ν-二甲基甲酰胺 （5 mL) 中， 加入甲酰胺 (179 mg, 3.98 mmol), 甲醇钠 （43 mg, 0.80 mmol), 升至 80°C反应过夜。 将反应液冷却至室 温， 加入水（30 mL)， 用二氯甲垸（30 mL)萃取， 有机相用饱和食盐水（30 mL)洗涤， 无水 硫酸钠干燥， 过滤， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （甲醇 /二氯甲垸 （v/v) = 1 :99-1 : 19) 得到浅黄色固体状的化合物 1-(2,3-二氢苯并呋喃 -5-基;) -6-(4-(3-氧代吗啉；)苯基； 1-7- 氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 化合物 2 (76 mg,产率 40%)。  1-(2,3-Dihydrobenzofuran-5-yl;)-6-(4-(3-oxomorpholine)phenyl; 1-7-oxo-4,5,6, 7-Tetrahydro-1H-pyrazolo[3,4-cpyridine-3-carboxylic acid ethyl ester 2D (200 mg, 0.40 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (5 mL), The amide (179 mg, 3.98 mmol), sodium methoxide (43 mg, 0.80 mmol), was taken up to 80 ° C overnight. The reaction was cooled to room temperature, water (30 mL), and dichloromethane (30 mL) The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate. -1 : 19) The compound 1-(2,3-dihydrobenzofuran-5-yl;)-6-(4-(3-oxomorpholine)phenyl) is obtained as a pale yellow solid. 7-Oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide Compound 2 (76 mg, yield 40%).
^ NMR (400 MHz, CDC13) δ 7.39-7.33 (m, 4Η), 7.28-7.25 (m, 2H), 6.84 (s, 1H), 6.80 (d, 1H), 5.48 (s, 1H), 4.62 (t, 2H), 4.34 (s, 2H), 4.15-4.10(m, 2H), 4.04-4.01 (m, 2H), 3.74-3.72(m, 2H), 3.38 (t, 2H), 3.25 (t, 2H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.39-7.33 (m, 4Η), 7.28-7.25 (m, 2H), 6.84 (s, 1H), 6.80 (d, 1H), 5.48 (s, 1H), 4.62 (t, 2H), 4.34 (s, 2H), 4.15-4.10 (m, 2H), 4.04-4.01 (m, 2H), 3.74-3.72 (m, 2H), 3.38 (t, 2H), 3.25 (t , 2H).
MS m/z (ESI): 474.2 [M+l] 实施例 3  MS m/z (ESI): 474.2 [M+l] Example 3
1-(2,3-二氢苯并呋喃 -5-基;) -6-(4-(3-氧代硫代吗啉)苯基; 1-7-氧代 -4,5,6,7-四氢 -IH-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 3)  1-(2,3-dihydrobenzofuran-5-yl;)-6-(4-(3-oxothiomorpholine)phenyl; 1-7-oxo-4,5,6, 7-tetrahydro-IH-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 3)
l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxothiomorpholino)phenyl)-4,5,6,7-tetrahydro- 1 H- razolo 3 4-c ridine-3-carboxamide  L-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxothiomorpholino)phenyl)-4,5,6,7-tetrahydro- 1 H- razolo 3 4-c ridine -3-carboxamide
Figure imgf000050_0002
第一步： 1-(2,3-二氢苯并呋喃 -5-基;) -6-(4-(3-氧代硫代吗啉)苯基 )- 7-氧代 -4,5,6,7-四氢 -1H- 吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 3A ethyl l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxothiomorpholino)phenyl)-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine- -carboxylate
Figure imgf000050_0002
First step: 1-(2,3-dihydrobenzofuran-5-yl;)-6-(4-(3-oxothiomorpholine)phenyl)-7-oxo-4,5 ,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 3A Ethyl l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxothiomorpholino)phenyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4- c]pyridine- -carboxylate
Figure imgf000051_0001
Figure imgf000051_0001
将 l-(2,3-二氢苯并呋喃 -5-基) -6-(4-碘苯基 )-7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲 酸乙酯 2C (400 mg, 0.76 mmol), 硫代吗啉 -3-酮（97 mg, 0.83 mmol)和磷酸钾 (321 mg, 1.51 mmol)溶于 1.4-二氧六环 （20 mL)中， 在氮气氛围下， 加入碘化亚铜 (14 mg, 0.076 mmol)和 Ν,Ν-二甲基环己胺（11 mg, 0.076 mmol), 加热回流反应过夜。 将反应液冷却至 0°C， 加入水 (40 mL) , 用二氯甲垸 （40 mL) 萃取， 有机相用饱和食盐水 （30 mL) 洗涤， 无水硫酸钠干 燥， 过滤， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯 /石油醚（v/V;» = 1 : 1~1 :0)得到 浅黄色固体状的化合物 1-(2,3-二氢苯并呋喃 -5-基;) -6- (4-P-氧代硫代吗啉；)苯基; 1-7-氧代 -4,5,6,7- 四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 3A (130 mg, 产率 33%)。 1-(2,3-Dihydrobenzofuran-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazole Ethyl [3,4-c]pyridine-3-carboxylate 2C (400 mg, 0.76 mmol), thiomorpholin-3-one (97 mg, 0.83 mmol) and potassium phosphate (321 mg, 1.51 mmol) In 1.4-dioxane (20 mL), copper iodide (14 mg, 0.076 mmol) and hydrazine, hydrazine-dimethylcyclohexylamine (11 mg, 0.076 mmol) were added under a nitrogen atmosphere. The reaction was overnight. The reaction solution was cooled to 0 ° C, EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v/ V ; s = 1 : 1 to 1 : 0) to give compound 1-(2,3-dihydrobenzofuran) as a pale yellow solid. -5-yl;)-6-(4-P-oxothiomorpholine;)phenyl; 1-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3 , 4-c]pyridine-3-carboxylate ethyl ester 3A (130 mg, yield 33%).
^ NMR (400 MHz, CDC13) δ 7.37-7.36 (m, 3Η), 7.26-7.28 (m, 3H), 6.77 (d, 1H), 4.60 (t, 2H), 4.46 (q, 2H), 4.13 (t, 2H), 3.95-3.93 (m, 2H), 3.46 (s, 2H), 3.32 (t, 2H), 3.22 (t, 2H), 3.03-3.00 (m, 2H), 1.43 (t, 3H ^ NMR (400 MHz, CDC1 3 ) δ 7.37-7.36 (m, 3Η), 7.26-7.28 (m, 3H), 6.77 (d, 1H), 4.60 (t, 2H), 4.46 (q, 2H), 4.13 (t, 2H), 3.95-3.93 (m, 2H), 3.46 (s, 2H), 3.32 (t, 2H), 3.22 (t, 2H), 3.03-3.00 (m, 2H), 1.43 (t, 3H
第二步： l-(2,3-二氢苯并呋喃 -5-基 )- 6-(4-(3-氧代硫代吗啉)苯基 )- 7-氧代 -4,5,6,7-四氢 -1H- 吡唑并 [3,4-c]吡啶 -3-甲酰胺化合物 3  Second step: l-(2,3-dihydrobenzofuran-5-yl)-6-(4-(3-oxothiomorpholine)phenyl)-7-oxo-4,5, 6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide compound 3
l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxothiomorpholino)phenyl)-4,5,6,7-tetrahydro- 1 H-pyrazolo[3 ,4-c]pyridi-ne-3 -carboxamide  L-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxothiomorpholino)phenyl)-4,5,6,7-tetrahydro- 1 H-pyrazolo[3 ,4- c]pyridi-ne-3 -carboxamide
Figure imgf000051_0002
Figure imgf000051_0002
将 1-(2,3-二氢苯并呋喃 -5-基;) -7-氧代 -6-(4-(3-氧代硫代吗啉;)苯基; 1-4,5,6,7-四氢 -1H-吡唑并 1-(2,3-dihydrobenzofuran-5-yl;)-7-oxo-6-(4-(3-oxothiomorpholine)phenyl; 1-4,5, 6,7-tetrahydro-1H-pyrazole
[3,4-c]吡啶 -3-甲酸乙酯 3B (130 mg, 0.25 mmol)溶于 Ν,Ν-二甲基甲酰胺 （5 mL) 中， 加入甲酰 胺 （113 mg, 2.50 mmol)、 甲醇钠 （27 mg, 0.50 mmo)， 升至 80°C反应过夜。 将反应液冷却至室 温， 加入水（30 mL)， 用二氯甲垸（30 mL)萃取， 有机相用饱和食盐水（30 mL)洗涤， 无水 硫酸钠干燥， 过滤， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯 /石油醚 （v/v) = 1 : 1-1 :0, 甲醇 /二氯甲垸 =1 :99~1 : 19)得到白色固体状的化合物 1-(2,3-二氢苯并呋喃 -5-基;) -6-(4- (3-氧代硫代吗啉)苯基) -7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺化合物 3 (21 mg, 产率 17 %)。 ¾ NMR (400 MHz, CDC13) δ 7.35-7.36 (m, 3H), 7.26-7.28(m, 3H), 6.83 (s, IH), 6.80 (d, IH) 5.44 (s, IH), 4.62 (t, 2H), 4.12 (t, 2H), 3.96-3.93 (m, 2H), 3.46 (s, 2H), 3.38 (t, 2H), 3.25 (t, 2H) 3.01-3.02 (m, 2H)。 Ethyl [3,4-c]pyridine-3-carboxylate 3B (130 mg, 0.25 mmol) was dissolved in EtOAc EtOAc (EtOAc) Sodium methoxide (27 mg, 0.50 mmo) was allowed to react to 80 ° C overnight. The reaction mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc. The product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v/v) = 1 : 1-1 :0, methanol /dichloromethane = 1 : 99 -1 : 19 ) to give compound 1 as a white solid -(2,3-dihydrobenzofuran-5-yl;)-6-(4-(3-oxothiomorpholine)phenyl)-7-oxo-4,5,6,7- Tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide Compound 3 (21 mg, yield 17%). 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.35-7.36 (m, 3H), 7.26-7.28 (m, 3H), 6.83 (s, IH), 6.80 (d, IH) 5.44 (s, IH), 4.62 ( t, 2H), 4.12 (t, 2H), 3.96-3.93 (m, 2H), 3.46 (s, 2H), 3.38 (t, 2H), 3.25 (t, 2H) 3.01-3.02 (m, 2H).
MS m/z (ESI): 490.1 [M+l] 实施例 4  MS m/z (ESI): 490.1 [M+l] Example 4
1- (苯并呋喃 -5-基;) -6-[4-(4-甲基 -2-氧代哌嗪 -1-基)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c 吡啶 -3-甲酰胺 （化合物 4)  1-(benzofuran-5-yl;)-6-[4-(4-methyl-2-oxopiperin-1-yl)phenyl]-7-oxo-4,5-dihydro -IH-pyrazolo[3,4-cpyridine-3-carboxamide (Compound 4)
l-(benzofuran-5-yl)-7-oxo-6-[4-(4-methyl-2-oxopiperazin-l-yl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[4-(4-methyl-2-oxopiperazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3 -carboxamide
Figure imgf000052_0001
第一步： 1- (苯并呋喃 -5-基) -6-[4-(2-氧代吡嗪 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c 吡啶 -3-甲酸乙酯 (4B)
Figure imgf000052_0001
First step: 1-(benzofuran-5-yl)-6-[4-(2-oxopyrazine-1-yl)phenyl]-7-oxo-4,5-dihydro-1H -pyrazolo[3,4-cpyridine-3-carboxylic acid ethyl ester (4B)
Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-pyrazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxylate  Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-pyrazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3- Carboxylate
Figure imgf000052_0002
Figure imgf000052_0002
在氮气氛围下， 将 1-(2,3-二氢苯并呋喃 -5-基;) -6-(4-碘苯基 )-7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 (2C) (1.0 g, 1.9 mmol)、 吡嗪 -2-酮 （0.36 g, 3.7 mmol)、 磷酸钾 (0.8 g, 3.7 mmol)、 碘化酮（100 mg)和反 -(1R,2R)-N,N'-二甲基 -1,2-环戊二胺 （100 mg)加入到微波 管中， 加入 1,2-二氧六环（40 mL)， 升温至 150°C反应 1.5小时。 将反应液冷却至室温， 加入水 (20 mL), 用乙酸乙酯 （20 mL X 3)萃取， 合并有机相， 有机相用无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （二氯甲垸:甲醇（ν/ν) = 25: 1)得到标题化合物 1- (苯并呋喃 -5- 基) -6-[4-(2-氧代吡嗪 -1-基)苯基] -7-氧代 -4,5-二氢 -1Η-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （4B)， 黄 色固体（0.4 g， 产率 43%)。 1-(2,3-dihydrobenzofuran-5-yl;)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydrogen under a nitrogen atmosphere -1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (2C) (1.0 g, 1.9 mmol), pyrazin-2-one (0.36 g, 3.7 mmol), potassium phosphate (0.8 g) , 3.7 mmol), iodinated ketone (100 mg) and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclopentanediamine (100 mg) were added to the microwave tube, added 1 2-Dioxane (40 mL) was heated to 150 ° C for 1.5 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was evaporated. Dichloromethane:methanol (ν/ν) = 25: 1) The title compound 1-(benzofuran-5-yl)-6-[4-(2-oxopyrazine-1-yl)phenyl -7-oxo-4,5-dihydro-1indole-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (4B), yellow Color solid (0.4 g, yield 43%).
¾ NMR (400 MHz, DMSO-d6) δ 8.12 (d, 1H), 7.66 (m, 1H), 7.53 (m, 4H), 7.42-7.40 (m, 2H), 7.29-7.27 (m, 1H), 6.81 (d, 1H), 4.60 (t, 2H), 4.32 (q, 2H), 4.13 (t, 2H), 3.24-3.20 (m, 4H), 1.33 (t, 3H)。 3⁄4 NMR (400 MHz, DMSO-d 6 ) δ 8.12 (d, 1H), 7.66 (m, 1H), 7.53 (m, 4H), 7.42-7.40 (m, 2H), 7.29-7.27 (m, 1H) , 6.81 (d, 1H), 4.60 (t, 2H), 4.32 (q, 2H), 4.13 (t, 2H), 3.24-3.20 (m, 4H), 1.33 (t, 3H).
MS m/z (ESI): 498.1 [M+l]  MS m/z (ESI): 498.1 [M+l]
第二步： 1- (苯并呋喃 -5-基) -6-[4-(2-氧代哌嗪 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c] 吡啶 -3-甲酸乙酯（4C)  The second step: 1-(benzofuran-5-yl)-6-[4-(2-oxopiperin-1-yl;)phenyl]-7-oxo-4,5-dihydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (4C)
Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxylate  Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxylate
Figure imgf000053_0001
Figure imgf000053_0001
1- (苯并呋喃 -5-基) -6-[4-(2-氧代吡嗪 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3- 甲酸乙酯 （4B) (1.4 g, 2.8 mmol), 溶于二氯甲垸 /甲醇混合溶液 （v/v=l :6， 35 mL) 中， 加 入钯碳 （0.2 g), 室温常压， 加氢气反应 4个小时， 过滤钯碳， 浓缩溶剂， 得到标题所示化合 物 1- (苯并呋喃 -5-基;) -6-[4-(2-氧代哌嗪 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲 酸乙酯 (4C)， 黄色固体 (1 g， 产率： 71%)。  1-(benzofuran-5-yl)-6-[4-(2-oxopyrazine-1-yl)phenyl]-7-oxo-4,5-dihydro-1H-pyrazole Ethyl [3,4-c]pyridine-3-carboxylate (4B) (1.4 g, 2.8 mmol), dissolved in methylene chloride / methanol mixture (v / v = 1: 6, 35 mL), Palladium carbon (0.2 g), normal pressure at room temperature, hydrogenation for 4 hours, filtration of palladium on carbon, concentration of solvent, the title compound 1-(benzofuran-5-yl;) -6-[4-(2) -oxopiperazine-1-yl;)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (4C), Yellow solid (1 g, yield: 71%).
¾ NMR (400 MHz, DMSO-d6) δ 7.35 (m, 1H), 7.33-7.27 (m, 4H), 7.25 (m, 1H), 6.81 (d, 1H), 4.60 (t, 2H), 4.31 (q, 2H), 4.07 (t, 2H), 3.58 (t, 2H), 3.39 (s, 2H), 3.17 (m, 4H), 3.01 (t, 2H), 1.33 (t, 3H)。 3⁄4 NMR (400 MHz, DMSO-d 6 ) δ 7.35 (m, 1H), 7.33-7.27 (m, 4H), 7.25 (m, 1H), 6.81 (d, 1H), 4.60 (t, 2H), 4.31 (q, 2H), 4.07 (t, 2H), 3.58 (t, 2H), 3.39 (s, 2H), 3.17 (m, 4H), 3.01 (t, 2H), 1.33 (t, 3H).
MS m/z (ESI): 502.1 [M+l]  MS m/z (ESI): 502.1 [M+l]
第三步： 1- (苯并呋喃 -5-基) -6-[4-(4-甲基 -2-氧代哌嗪 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑 并 [3,4-c]吡啶 -3-甲酸乙酯 4D  The third step: 1-(benzofuran-5-yl)-6-[4-(4-methyl-2-oxopiperin-1-yl)phenyl]-7-oxo-4,5 -Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 4D
Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-(4-methyl-2-oxopiperazin-l-yl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxylate  Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-(4-methyl-2-oxopiperazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine- 3-carboxylate
Figure imgf000053_0002
Figure imgf000053_0002
将 1- (苯并呋喃 -5-基;) -6-[4-(2-氧代哌嗪 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶- 3-甲酸乙酯 (4C) (l.Og , 1.98 mmol) , 甲醛水溶液 (37%) (0.32g , 3.98 mmol) , 乙酸 (0.5 mL), 加入的二氧六环 （10 mL) 中， 最后加入氰基硼氢化钠 （0.25g， 3.9 mmol), 室温反应 2 个小时。 反应液中加入 50 mL水， 用二氯甲垸 50 mL萃取三次， 无水硫酸钠干燥， 浓缩， 用残 留物用硅胶柱色谱分离提纯 （二氯甲垸:甲醇 （v/v) = 25: 1)得到标题化合物 1- (苯并呋喃 -5-基) - 6-[4-(4-甲基 -2-氧代哌嗪 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （4D)， 白色固体（1.4 g， 产率 29%) 1-(Benzofuran-5-yl;)-6-[4-(2-oxopiperin-1-yl;)phenyl]-7-oxo-4,5-dihydro-1H- Pyrazolo[3,4-c]pyridine-3-carboxylate (4C) (1.Og, 1.98 mmol), aqueous formaldehyde (37%) (0.32 g, 3.98 mmol), acetic acid (0.5 mL), In the dioxane (10 mL), the final sodium cyanoborohydride (0.25 g, 3.9 mmol) was added at room temperature. Hours. 50 ml of water was added to the reaction mixture, and the mixture was extracted with EtOAc (EtOAc) (EtOAc m. 1) The title compound 1-(benzofuran-5-yl)-6-[4-(4-methyl-2-oxopipyrazin-1-yl)phenyl]-7-oxo-4 is obtained. 5-Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (4D), white solid (1.4 g, yield 29%)
¾ NMR (400 MHz, DMSO-d6) δ 7.41-7.36 (m, 5H), 7.27-7.25 (m, 1H), 6.81 (d, 1H), 4.60 (t, 2H), 4.31 (q, 2H), 4.08 (t, 2H), 3.87 (t, 2H), 3.61 (dd, 2H), 3.43 (t, 2H), 3.22-3.19 (m, 4H), 2.84 (s, 3H), 1.33 (t, 3H)。 3⁄4 NMR (400 MHz, DMSO-d 6 ) δ 7.41-7.36 (m, 5H), 7.27-7.25 (m, 1H), 6.81 (d, 1H), 4.60 (t, 2H), 4.31 (q, 2H) , 4.08 (t, 2H), 3.87 (t, 2H), 3.61 (dd, 2H), 3.43 (t, 2H), 3.22-3.19 (m, 4H), 2.84 (s, 3H), 1.33 (t, 3H ).
第四步： 1- (苯并呋喃 -5-基；) -6-[4-(4-甲基 -2-氧代哌嗪 -1-基;)苯基] -7-氧代 -4,5-二氢 -IH-吡唑 并 [3,4-c]吡啶 -3-甲酰胺 （化合物 4)  The fourth step: 1-(benzofuran-5-yl;)-6-[4-(4-methyl-2-oxopiperin-1-yl;)phenyl]-7-oxo-4 ,5-Dihydro-IH-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 4)
l-(benzofuran-5-yl)-7-oxo-6-[4-(4-methyl-2-oxopiperazin-l-yl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[4-(4-methyl-2-oxopiperazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3 -carboxamide
Figure imgf000054_0001
Figure imgf000054_0001
将 1 - (苯并呋喃 -5-基;) -6-[4-(4-甲基 -2-氧代哌嗪- 1 -基)苯基] -7-氧代 -4,5-二氢 - 1 H-吡唑并 [3 ,4-c 吡啶 -3-甲酸乙酯 （4C) (0.3g， 0.8 mmol)溶于氨 /甲醇溶液（10 mL) 中， 加入高压反应釜中， 升温至 100'C反应过夜。 将反应液冷却至室温， 过滤， 再将固体用甲醇 （50 mL)加热回流洗 涤， 冷却， 过滤， 得到标题化合物 1- (苯并呋喃 -5-基) -6-[4-(4-甲基 -2-氧代哌嗪 -1-基)苯基] -7-氧 代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 4)， 白色固体（100 mg， 产率 35%)。  1-(benzofuran-5-yl;)-6-[4-(4-methyl-2-oxopiperazine-1-yl)phenyl]-7-oxo-4,5-di Hydrogen - 1 H-pyrazolo[3,4-cpyridine-3-carboxylic acid ethyl ester (4C) (0.3g, 0.8 mmol) dissolved in ammonia / methanol solution (10 mL), added to the autoclave, warmed up React overnight at 100'C. The reaction mixture was cooled to room temperature, filtered, and then evaporated, evaporated, evaporated, evaporated 5-oxopiperazin-1-yl)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 4 ), white solid (100 mg, yield 35%).
¾ NMR (400 MHz, DMSO-de) δ 7.71 (s, 1H), 7.43 (m, 2H), 7.32 (m, 4H), 7.26 (m, 1H), 6.80 (d, 1H), 4.59 (t, 2H), 4.05 (t, 2H), 3.63 (t, 2H), 3.20 (m, 4H), 3.10 (s, 2H), 2.71 (t, 2H), 2.28 (s, 3H)。  3⁄4 NMR (400 MHz, DMSO-de) δ 7.71 (s, 1H), 7.43 (m, 2H), 7.32 (m, 4H), 7.26 (m, 1H), 6.80 (d, 1H), 4.59 (t, 2H), 4.05 (t, 2H), 3.63 (t, 2H), 3.20 (m, 4H), 3.10 (s, 2H), 2.71 (t, 2H), 2.28 (s, 3H).
MS m/z (ESI): 487.1 [M+l]. 实施例 5  MS m/z (ESI): 487.1 [M+l]. Example 5
l-(2,3-二氢苯并呋喃 -5-基) -6-(4-(2-氧代吡啶 -1(2H)-基)苯基) -7-氧代 -4,5,6,7-四氢 -IH-吡唑 并 [3,4-c]吡啶 -3-甲酰胺 （；化合物 5)  L-(2,3-Dihydrobenzofuran-5-yl)-6-(4-(2-oxopyridine-1(2H)-yl)phenyl)-7-oxo-4,5, 6,7-tetrahydro-IH-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 5)
l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopyridin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3 ,4-c]pyridine-3-carboxamide
Figure imgf000055_0001
L-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopyridin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3 ,4-c]pyridine-3-carboxamide
Figure imgf000055_0001
第一步： 1-(2,3-二氢苯并呋喃 -5-基;) -6-(4-(2-氧代吡啶 -1(2H)-基)苯基) -7-氧代 -4,5,6,7-四氢- 1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 5B  First step: 1-(2,3-dihydrobenzofuran-5-yl;)-6-(4-(2-oxopyridine-1(2H)-yl)phenyl)-7-oxo -4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 5B
ethyl l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopyridin-l-yl)phenyl)-4,5,6,7-tetrahydro- lH-pyrazolo[3,4-c]pyridine-3-carboxylate  Ethyl l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopyridin-l-yl)phenyl)-4,5,6,7-tetrahydro- lH-pyrazolo[ 3,4-c]pyridine-3-carboxylate
Figure imgf000055_0002
Figure imgf000055_0002
将 1-(2,3-二氢苯并呋喃 -5-基) -6-(4-碘苯基 )-7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲 酸乙酯 2C (500 mg, 0.94 mmol), 吡啶 -2-醇 （108 mg, 1.14 mmol)和磷酸钾 （400 mg, 1.88 mmol) 溶于 1.4-二氧六环（10 mL) 中， 在氮气氛围下,加入碘化亚铜（18 mg, 0.094 mmol)和 Ν,Ν-二 甲基环己胺 （14 mg, 0.094 mmol), 升至回流反应过夜。 将反应液冷却至 0°C， 加入二氯甲垸 (50 mL) 和水 （50 mL) , 分液， 有机相用饱和食盐水 （50 mL) 洗涤， 无水硫酸钠干燥， 过 滤， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯 /石油醚（v/v) =1 : 1-1 :0)得到浅黄色 固体状的化合物 1-(2,3-二氢苯并呋喃 -5-基;) -6-(4-(2-氧代吡啶 -1(2Η)-基;)苯基; )-7-氧代 -4,5,6,7-四 氢 -1Η-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 5B (180 mg, 产率 39%)。  1-(2,3-Dihydrobenzofuran-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazole [3,4-c]pyridine-3-carboxylic acid ethyl ester 2C (500 mg, 0.94 mmol), pyridin-2-ol (108 mg, 1.14 mmol) and potassium phosphate (400 mg, 1.88 mmol) dissolved in 1.4- In a hexacyclohexane (10 mL), cuprous iodide (18 mg, 0.094 mmol) and hydrazine, dimethyl-dimethylcyclohexylamine (14 mg, 0.094 mmol) were added under a nitrogen atmosphere, and the mixture was refluxed overnight. . The reaction solution was cooled to 0 ° C, chloroform (50 mL) and water (50 mL) were added, and the organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v/v) = 1:1: 1:1) to give the compound 1-(2,3-dihydrobenzofuran as a pale yellow solid. -5-yl;)-6-(4-(2-oxopyridine-1(2Η)-yl;)phenyl; )-7-oxo-4,5,6,7-tetrahydro-1Η- Pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 5B (180 mg, yield 39%).
¾ NMR (400 MHz, CDC13) δ 7.47-7.37 (m, 6H), 7.30-7.26 (m, 2H), 6.78 (d, 1H), 6.70 (d, 1H), 6.27 (t, 1H), 4.61 (t, 2H), 4.49-4.44 (m, 2H), 4.17 (t, 2H), 3.35 (t, 2H), 3.23 (t, 2H), 1.44 (t, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.47-7.37 (m, 6H), 7.30-7.26 (m, 2H), 6.78 (d, 1H), 6.70 (d, 1H), 6.27 (t, 1H), 4.61 (t, 2H), 4.49-4.44 (m, 2H), 4.17 (t, 2H), 3.35 (t, 2H), 3.23 (t, 2H), 1.44 (t, 3H).
第二步： l-(2,3-二氢苯并呋喃 -5-基) -6-(4-(2-氧代吡啶 -1(2H)-基)苯基) -7-氧代 -4,5,6,7-四氢- 1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 化合物 5  The second step: l-(2,3-dihydrobenzofuran-5-yl)-6-(4-(2-oxopyridine-1(2H)-yl)phenyl)-7-oxo- 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide 5
l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopyridin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3 ,4-c]pyridine-3-carboxamide
Figure imgf000056_0001
L-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopyridin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3 ,4-c]pyridine-3-carboxamide
Figure imgf000056_0001
将 l-(2,3-二氢苯并呋喃 -5-基) -6-(4-(2-氧代吡啶 -1-2H-基)苯基) -7-氧代 -4,5,6,7-四氢 -1H-吡 唑并 [3,4-c]吡啶 -3-甲酸乙酯 (180 mg, 0.36 mmol)溶于 Ν,Ν-二甲基甲酰胺 （5 mL) 中， 加入甲 酰胺 (163 mg, 3.63 mmol), 甲醇钠 (39 mg, 0.73 mmol), 升温至 80°C反应 7小时。 将反应液 冷却至室温， 加入水（60 mL)， 用二氯甲垸（40 mL)萃取， 有机相用饱和食盐水（60 mL)洗 涤， 无水硫酸钠干燥， 过滤， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （甲醇 /二氯甲垸（v/v) = 0: 1-3:97)得到浅黄色固体状的化合物 1-(2,3-二氢苯并呋喃 -5-基；) -6-(4-(2-氧代吡啶 -1(2H)-基；) 苯基) -7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺化合物 5 (100 mg, 产率 59%)。  1-(2,3-Dihydrobenzofuran-5-yl)-6-(4-(2-oxopyridine-1-2H-yl)phenyl)-7-oxo-4,5, 6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (180 mg, 0.36 mmol) was dissolved in hydrazine, dimethyl-dimethylformamide (5 mL). Formamide (163 mg, 3.63 mmol), sodium methoxide (39 mg, 0.73 mmol) was added and the mixture was warmed to 80 ° C for 7 hours. The reaction mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc. The product was purified by silica gel column chromatography (methanol / methylene chloride (v/v) = 0: 1-3:97) to give compound 1-(2,3-dihydrobenzofuran-5- ;)-6-(4-(2-oxopyridine-1(2H)-yl;)phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[ 3,4-c]pyridine-3-carboxamide compound 5 (100 mg, yield 59%).
^ NMR (400 MHz, CDC13) δ 7.45-7.35 (m, 6Η), 7.32-7.22 (m, 2H), 6.84 (s, 1H), 6.81 (d, 1H), 6.75 (d, 1H), 6.29 (t, 1H), 5.44(s, 1H), 4.62 (t, 2H), 4.17(t, 2H), 3.41 (t, 2H), 3.25 (t, 2H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.45-7.35 (m, 6Η), 7.32-7.22 (m, 2H), 6.84 (s, 1H), 6.81 (d, 1H), 6.75 (d, 1H), 6.29 (t, 1H), 5.44(s, 1H), 4.62 (t, 2H), 4.17(t, 2H), 3.41 (t, 2H), 3.25 (t, 2H).
MS m/z (ESI): 468.1 [M+l] 实施例 6  MS m/z (ESI): 468.1 [M+l] Example 6
l-(2,3-二氢苯并呋喃 -5-基) -3-(l-羟基 -1-甲基-乙基) -6-(4-(2-氧代吡啶 -1(2H)-基）苯基) - 4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -7-酮 （化合物 6)  L-(2,3-Dihydrobenzofuran-5-yl)-3-(l-hydroxy-1-methyl-ethyl)-6-(4-(2-oxopyridine-1(2H)) -yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-7-one (Compound 6)
1 -(2,3-dihydrobenzofuran-5-yl)-3-(2-hydroxypropan-2-yl)-6-(4-(2-oxopiperidin- 1 -yl)phenyl)- 1-(2,3-dihydrobenzofuran-5-yl)-3-(2-hydroxypropan-2-yl)-6-(4-(2-oxopiperidin- 1 -yl)phenyl)-
6-dihydro-lH-pyrazolo[3,4-c]pyridin-7(4H)-one 6-dihydro-lH-pyrazolo[3,4-c]pyridin-7(4H)-one
Figure imgf000056_0002
Figure imgf000056_0002
第一步： 1-(2,3-二氢苯并呋喃 -5-基;) -7-氧代 -6-[4-(2-氧代哌啶 -1-基;)苯基] -4,5,6,7-四氢 -1H- 吡唑 [3,4-c]吡啶 -3-甲酸乙酯 6B  First step: 1-(2,3-dihydrobenzofuran-5-yl;)-7-oxo-6-[4-(2-oxopiperidin-1-yl;)phenyl] 4,5,6,7-tetrahydro-1H-pyrazole [3,4-c]pyridine-3-carboxylic acid ethyl ester 6B
ethyl l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7- tetrahydro-ΙΗ- pyrazolo[3,4-c] pyridi -3-carboxylate Ethyl l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7- Tetrahydro-ΙΗ- pyrazolo[3,4-c] pyridi -3-carboxylate
Figure imgf000057_0001
Figure imgf000057_0001
将 l-(4-(2-氧代哌啶 -1-基)苯基) -3-吗啉 -5,6-二氢吡啶 -2(1H)-酮 If (220 mg, 0.62 mmol)溶 于乙酸乙酯 （20 mL) 中， 加入 2-氯 -2-(2-(2,3-二氢苯并呋喃 -5-基)腙基)乙酸乙酯 2B (200 mg, 0.68 mmol), 碘化钾 (10 mg, 0.06 mmol)和三乙胺 (190 mg, 1.86 mmol), 升温至回流反应过 夜。 将反应液冷却至 0°C， 加入盐酸 （110 mg, 3.1 mmol), 升至室温搅拌 1小时， 用饱和食盐 水（30 mL)洗涤， 分液， 有机相用无水硫酸钠干燥， 过滤， 减压浓缩， 残留物用硅胶柱色谱 法纯化（乙酸乙酯 /石油醚（v/v) = 1 : 1 ~ 1 :0)得到浅黄色固体状的化合物 1-(2,3-二氢苯并呋喃- 5-基) -7-氧代 -6-[4-(2-氧代哌啶 -1-基)苯基] -4,5,6,7-四氢 -1H-吡唑 [3,4-c]吡啶 -3-甲酸乙酯 6B (230 mg, 产率 74%)。  Dissolve l-(4-(2-oxopiperidin-1-yl)phenyl)-3-morpholine-5,6-dihydropyridine-2(1H)-one If (220 mg, 0.62 mmol) Ethyl 2-chloro-2-(2-(2,3-dihydrobenzofuran-5-yl)indenyl)acetate 2B (200 mg, 0.68 mmol). Potassium iodide (10 mg, 0.06 mmol) and triethylamine (190 mg, 1.86 mmol) were warmed to reflux overnight. The reaction mixture was cooled to 0 ° C, EtOAc (EtOAc (EtOAc) (EtOAc) The organic layer was purified by silica gel chromatography (ethyl acetate / petroleum ether (v/v) = 1 : 1 - 1 : 0) to give compound 1-(2,3-dihydrobenzene) as a pale yellow solid. And furan-5-yl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazole [ Ethyl 3,4-c]pyridine-3-carboxylate 6B (230 mg, yield 74%).
¾ NMR (400 MHz, CDC13) δ 7.33-7.36 (m, 3H), 7.26 (m, 3H), 6.76 (d, 1H), 4.60 (t, 2H), 4.46 (q, 2H), 4.12 (t, 2H), 3.60 (m, 2H), 3.31 (t, 2H), 3.22 (t, 2H), 2.56 (m, 2H), 1.94 (m, 4H), 1.43 (t, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.33-7.36 (m, 3H), 7.26 (m, 3H), 6.76 (d, 1H), 4.60 (t, 2H), 4.46 (q, 2H), 4.12 (t , 2H), 3.60 (m, 2H), 3.31 (t, 2H), 3.22 (t, 2H), 2.56 (m, 2H), 1.94 (m, 4H), 1.43 (t, 3H).
第二步： l-(2,3-二氢苯并呋喃 -5-基) -3-(l-羟基 -1-甲基-乙基) -6-(4-(2-氧代吡啶 -1(2H)-基)苯 基) -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -7-酮化合物 6  The second step: l-(2,3-dihydrobenzofuran-5-yl)-3-(l-hydroxy-1-methyl-ethyl)-6-(4-(2-oxopyridine)- 1(2H)-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-7-one compound 6
1 -(2,3-dihydrobenzofuran-5-yl)-3-(2-hydroxypropan-2-yl)-6-(4-(2-oxopiperidin- 1 -yl)phenyl)- 5,6-dihydro-lH-pyrazolo[3,4-c]pyri  1-(2,3-dihydrobenzofuran-5-yl)-3-(2-hydroxypropan-2-yl)-6-(4-(2-oxopiperidin- 1 -yl)phenyl)- 5,6-dihydro-lH -pyrazolo[3,4-c]pyri
Figure imgf000057_0002
Figure imgf000057_0002
将 1-(2,3-二氢苯并呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -1H-吡唑 [3,4-c]吡啶 -3-甲酸乙酯 6B (200 mg, 0.40 mmol)溶于无水四氢呋喃 （15 mL) 中， 用氮气保 护， 气体置换三次， 降温至 -20。C， 缓慢滴加甲基溴化镁 （ 1.0 mL, 1.0 mmol, 1M) ， 加完后缓 慢升至室温， 室温下搅拌反应 4小时。 将反应液冷却至 0°C， 加入水（20 mL)淬灭反应， 用 乙酸乙酯萃取反应液 （30 mL X l ) ， 有机层用饱和食盐水洗涤 (30 mL X l) , 无水硫酸钠干 燥， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯 /石油醚（v/v) =1 : 1-1 :0)得到浅黄色 固体状的化合物 1-(2,3-二氢苯并呋喃 -5-基) -3-(1-羟基 -1-甲基-乙基) -6-(4-(2-氧代吡啶 -1(2H)-基) 苯基) -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -7-酮化合物 6 (90 mg， 产率 46%)。 Ή NMR (400 MHz, DMSO-d6) δ 7.32-7.35 (m, 2H), 7.25-7.29 (m, 3H), 7.14 (dd, IH), 6.74 (d, IH), 5.13 (s, IH), 4.54 (t, 2H), 4.00 (t, 2H), 3.57 (t, 2H), 3.17 (t, 2H), 3.09 (t, 2H), 2.37 (t, 2H), 1.82 (m, 4H), 1.50 (s, 6H)。 1-(2,3-Dihydrobenzofuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5,6 , 7-tetrahydro-1H-pyrazol [3,4-c]pyridine-3-carboxylic acid ethyl ester 6B (200 mg, 0.40 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), , cool down to -20. C. Methylmagnesium bromide (1.0 mL, 1.0 mmol, 1 M) was added dropwise slowly. After the addition, the mixture was slowly warmed to room temperature, and the reaction was stirred at room temperature for 4 hours. The reaction solution was cooled to 0 ° C, and then the mixture was evaporated to ethyl acetate (20 mL). The residue was dried over EtOAc (EtOAc m. Dihydrobenzofuran-5-yl)-3-(1-hydroxy-1-methyl-ethyl)-6-(4-(2-oxopyridine-1(2H)-yl)phenyl) - 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-7-one compound 6 (90 mg, yield 46%). NMR NMR (400 MHz, DMSO-d6) δ 7.32-7.35 (m, 2H), 7.25-7.29 (m, 3H), 7.14 (dd, IH), 6.74 (d, IH), 5.13 (s, IH), 4.54 (t, 2H), 4.00 (t, 2H), 3.57 (t, 2H), 3.17 (t, 2H), 3.09 (t, 2H), 2.37 (t, 2H), 1.82 (m, 4H), 1.50 (s, 6H).
MS m/z (ESI): 487.2 [M+l] 实施例 7  MS m/z (ESI): 487.2 [M+l] EXAMPLE 7
l-(2,3-二氢苯并呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -IH-吡唑 [3,4-c 吡啶 -3-腈 (化合物 7)  L-(2,3-Dihydrobenzofuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5,6, 7-tetrahydro-IH-pyrazole [3,4-c pyridine-3-carbonitrile (Compound 7)
l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridine-3-carbonitril  L-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3 ,4-c]pyridine-3-carbonitril
Figure imgf000058_0001
Figure imgf000058_0001
第一步： 1-(2,3-二氢苯并呋喃 -5-基;) -7-氧代 -6-[4-(2-氧代哌啶 -1-基;)苯基] -4,5,6,7-四氢 -1H- 吡唑 [3,4-c]吡啶 -3-甲酰胺 7B  First step: 1-(2,3-dihydrobenzofuran-5-yl;)-7-oxo-6-[4-(2-oxopiperidin-1-yl;)phenyl] 4,5,6,7-tetrahydro-1H-pyrazole [3,4-c]pyridine-3-carboxamide 7B
l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH- pyrazolo[3 ,4-c]pyridine-3-carboxamid  L-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH- pyrazolo[3 ,4-c]pyridine-3-carboxamid
Figure imgf000058_0002
Figure imgf000058_0002
将 1-(2,3-二氢苯并呋喃 -5-基) -7-氧代 -6-[4-(2-氧代哌啶 -1-基)苯基] -4,5,6,7-四氢 -1H-吡唑 [3,4-c]吡啶 -3-甲酸乙酯 6B (300 mg, 0.60 mmol)溶于 Ν,Ν-二甲基甲酰胺 (2.5 mL) 中， 加入甲 酰胺 （79 mg, 1.80 mmol)和甲醇钠 （32 mg, 0.60 mmol), 升至 70°C反应 5小时。 浓缩反应 液， 残留物用二氯甲垸（2 mL)溶解， 用硅胶柱色谱法纯化（乙酸乙酯 /石油醚（V/V) = 1 : 1~1 :0) 得到浅黄色固体状的化合物 1-(2,3-二氢苯并呋喃 -5-基) -7-氧代 -6-[4-(2-氧代哌啶 -1-基)苯基] - 4,5,6,7-四氢 -1H-吡唑 [3,4-c]吡啶 -3-甲酰胺 7B (120 mg, 产率 43%)。 ^ NMR (400 MHz, CDC13) δ 7.36-7.33 (m, 3H), 7.26-7.25 (m, 3H), 6.86 (s, 1H), 6.80 (s, 1H), 5.72 (s, 1H), 4.61 (t, 2H), 4.12 (t, 2H), 3.60 (m, 2H), 3.37 (t, 2H), 3.24 (t, 2H), 2.57-2.54 (m, 2H), 1.94-1.93 (m, 4H)0 1-(2,3-Dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6 ,7-tetrahydro-1H-pyrazole [3,4-c]pyridine-3-carboxylic acid ethyl ester 6B (300 mg, 0.60 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (2.5 mL), Formamide (79 mg, 1.80 mmol) and sodium methoxide (32 mg, 0.60 mmol) were reacted to 70 ° C for 5 hours. The reaction solution was concentrated, the residue was dissolved in of dichloromethane (2 mL), purified (ethyl acetate / petroleum ether (V / V) = 1: 1 ~ 1: 0) by silica gel column chromatography to give a pale yellow solid Compound 1-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6 , 7-tetrahydro-1H-pyrazole [3,4-c]pyridine-3-carboxamide 7B (120 mg, yield 43%). ^ NMR (400 MHz, CDC1 3 ) δ 7.36-7.33 (m, 3H), 7.26-7.25 (m, 3H), 6.86 (s, 1H), 6.80 (s, 1H), 5.72 (s, 1H), 4.61 (t, 2H), 4.12 (t, 2H), 3.60 (m, 2H), 3.37 (t, 2H), 3.24 (t, 2H), 2.57-2.54 (m, 2H), 1.94-1.93 (m, 4H ) 0
MS m/z (ESI): 472.1 [M+l].  MS m/z (ESI): 472.1 [M+l].
第二步： l-(2,3-二氢苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -1H- 吡唑 [3,4-c]吡啶 -3-腈化合物 7  Second step: l-(2,3-dihydrobenzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4 ,5,6,7-tetrahydro-1H-pyrazole[3,4-c]pyridine-3-carbonitrile compound 7
l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridine-3-carbonitril  L-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH- pyrazolo[3 ,4-c]pyridine-3-carbonitril
Figure imgf000059_0001
Figure imgf000059_0001
将 1-(2,3-二氢苯并呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -1H-吡唑 1-(2,3-Dihydrobenzofuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5,6 ,7-tetrahydro-1H-pyrazole
[3,4-c]吡啶 -3-甲酰胺 7B (100 mg, 0.21 mmol)、 吡啶 （2.10 g, 26.50 mmol)溶于二氯甲垸 (5 mL) 中， 在氮气保护下， 气体置换三次， 然后冷却到 -20°C。 缓慢滴加三氟乙酸酐 （220 mg, 1.05 mmol) ， 一小时内滴加完毕， -20°C下搅拌反应一小时。 向反应液中慢慢滴加水 （10 mL) ， 升至室温， 加入二氯甲垸 （20 mL) ， 分液， 水相用二氯甲垸 （10 mL) 萃取， 合并有机相， 用 5%HC1 ( 30 mL) 洗涤， 再用饱和食盐水 （30 mL) 洗涤， 有机相用无水硫酸钠干燥， 减压 浓缩， 残留物用硅胶柱色谱分离提纯 （甲醇 /二氯甲垸 iy = 0: 1-1 :49)得到白色固体状化合 物 1-(2,3-二氢苯并呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -1H-吡唑 [3,4-c] 吡啶 -3-腈化合物 7 (60 mg， 产率 63%)。 [3,4-c]pyridine-3-carboxamide 7B (100 mg, 0.21 mmol), pyridine (2.10 g, 26.50 mmol) dissolved in dichloromethane (5 mL). , then cool to -20 ° C. Trifluoroacetic anhydride (220 mg, 1.05 mmol) was slowly added dropwise, and the addition was completed in one hour, and the reaction was stirred at -20 ° C for one hour. Water (10 mL) was slowly added dropwise to the reaction mixture, and the mixture was warmed to room temperature, then dichloromethane (20 mL) was added and the mixture was separated and the aqueous phase was extracted with dichloromethane (10 mL). After washing with HCl (30 mL), EtOAc (3 mL) 1-1:49) Compound 1-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]- 7-oxo-4,5,6,7-tetrahydro-1H-pyrazole[3,4-c]pyridine-3-carbonitrile compound 7 (60 mg, yield 63%).
^ NMR (400 MHz, CDC13) δ 7.32-7.35 (m, 3H), 7.23-7.28 (m, 3H), 6.78 (d, 1H), 4.59 (t, 2H), 4.13 (t, 2H), 3.62 (m, 2H), 3.21 (t, 2H), 3.14 (t, 2H), 2.59 (m, 2H), 1.95 (m, 4H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.32-7.35 (m, 3H), 7.23-7.28 (m, 3H), 6.78 (d, 1H), 4.59 (t, 2H), 4.13 (t, 2H), 3.62 (m, 2H), 3.21 (t, 2H), 3.14 (t, 2H), 2.59 (m, 2H), 1.95 (m, 4H).
MS m/z (ESI): 454.2 [M+l] 实施例 8  MS m/z (ESI): 454.2 [M+l] Example 8
l-(7-氟 -2,3-二氢苯并呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -IH-吡唑 [3,4-c]吡啶 -3-甲酰胺 (化合物 8)  L-(7-Fluoro-2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4, 5,6,7-tetrahydro-IH-pyrazole [3,4-c]pyridine-3-carboxamide (compound 8)
l-(7-fluoro-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide
Figure imgf000060_0001
L-(7-fluoro-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH -pyrazolo[3,4-c]pyridine-3-carboxamide
Figure imgf000060_0001
第一步： 1-溴 -2-(2-溴乙氧基) -3-氟苯 8B  First step: 1-bromo-2-(2-bromoethoxy)-3-fluorobenzene 8B
l-bromo-2-(2-bromoethoxy)-3-fluorobenzene  L-bromo-2-(2-bromoethoxy)-3-fluorobenzene
Br
Figure imgf000060_0002
Br
Figure imgf000060_0002
将 2-溴 -6-氟苯酚 8A (0.5 g, 2.60 mmol ) 、 1,2-二溴乙垸 ( 977 mg, 5.20 mmol) 、 碳酸 钾 （717 mg, 5.20 mmol) 溶于乙腈（5 mL) 中， 加热到 50°C搅拌反应 4小时。 将反应液降 至室温， 加入水 （10 mL) 淬灭反应， 反应液用乙酸乙酯萃取 （20 mL X 2) ， 合并有机相， 用饱和食盐水（20 mLX 2)洗涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （石 油醚 100%)得到无色油状物 1-溴 -2-(2-溴乙氧基) -3-氟苯 8B (340 mg,产率 44%)。  2-Bromo-6-fluorophenol 8A (0.5 g, 2.60 mmol), 1,2-dibromoacetamidine (977 mg, 5.20 mmol), potassium carbonate (717 mg, 5.20 mmol) in acetonitrile (5 mL) The reaction was stirred for 4 hours while heating to 50 °C. The reaction mixture was cooled to room temperature, and then the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The residue was purified by silica gel column chromatography (EtOAc (EtOAc) %).
^ NMR (400 MHz, CDC13) δ 7.31-7.34 (m, 1Η), 7.04-7.09 (m, 1H), 6.91-6.98 (m, 1H), 4.36 (t, 2H), 3.65 (m, 2H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.31-7.34 (m, 1 Η), 7.04-7.09 (m, 1H), 6.91-6.98 (m, 1H), 4.36 (t, 2H), 3.65 (m, 2H) .
第二步： 7-氟 -2,3-二氢苯并呋喃 8C  Second step: 7-fluoro-2,3-dihydrobenzofuran 8C
7-fluoro-2,3-dihydrobenzofuran
Figure imgf000060_0003
7-fluoro-2,3-dihydrobenzofuran
Figure imgf000060_0003
将 1-溴 -2-(2-溴乙氧基) -3-氟苯 8B (340 mg, l.lO mmol)溶于无水四氢呋喃 （5 mL) 中， 降 温至 -78°C， 缓慢加入正丁基锂 （0.75 mL, 1.20 mmol, 1.6M) ， 加完后在该温度下反应 2小 时， 之后逐渐升至室温， 室温下搅拌反应 1小时。 用水 （5 mL) 淬灭反应， 用乙酸乙酯萃取 反应液 （15 mL X 2) ， 合并有机相， 用饱和食盐水 （20 mL X l)洗涤， 无水硫酸钠干燥， 浓 缩， 残留物用硅胶柱色谱分离提纯 （石油醚 100%)得到无色油状物 7-氟 -2,3-二氢苯并呋喃 8C (60 mg, 产率 40%)。 Dissolve 1-bromo-2-(2-bromoethoxy)-3-fluorobenzene 8B (340 mg, 1.0 mmol) in anhydrous tetrahydrofuran (5 mL), cool to -78 ° C, slowly n-Butyllithium (0.75 mL, 1.20 mmol, 1.6 M) was reacted at this temperature for 2 hours after the addition, and then gradually warmed to room temperature, and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (EtOAc:EtOAc)
^ NMR (400 MHz, CDC13) δ 6.96 (dd, 1Η), 6.88-6.92 (m, 1H), 6.75-6.80 (m, 1H), 4.64 (t, 2H) 3.24 (t, 2H ^ NMR (400 MHz, CDC1 3 ) δ 6.96 (dd, 1Η), 6.88-6.92 (m, 1H), 6.75-6.80 (m, 1H), 4.64 (t, 2H) 3.24 (t, 2H
第三步： 5-硝基 -7-氟 -2,3-二氢苯并呋喃 8D  The third step: 5-nitro-7-fluoro-2,3-dihydrobenzofuran 8D
7-fluoro-5-nitro-2,3-dihydrobenzofuran  7-fluoro-5-nitro-2,3-dihydrobenzofuran
Figure imgf000061_0001
Figure imgf000061_0001
将 7-氟 -2,3-二氢苯并呋喃 8C (2.5 g, 18.00 mmol)溶于冰乙酸 （10 mL) 中， 室温下加入浓 硝酸 （0.4 g) ， 搅拌反应 30分钟， 加热升温至 70°C， 再加入浓硝酸 （1.4 g) ， 在该温度下 反应 1 小时。 将反应液降温至 0°C， 加入水 （20 mL), 用乙酸乙酯萃取反应液 （50 mL X 2) ， 合并有机相， 用饱和食盐水（50 mL X l)洗涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶 柱色谱分离提纯 （乙酸乙酯 /石油醚 i N、 = 1 : 100~1 :20)得到淡黄色固体 5-硝基 -7-氟 -2,3-二氢 苯并呋喃 8D (1.3 g， 产率 39%)。  7-Fluoro-2,3-dihydrobenzofuran 8C (2.5 g, 18.00 mmol) was dissolved in glacial acetic acid (10 mL). Concentrated nitric acid (0.4 g) was added at room temperature, and the mixture was stirred for 30 minutes and heated to warm. At 70 ° C, concentrated nitric acid (1.4 g) was added and reacted at this temperature for 1 hour. The reaction solution was cooled to 0 ° C, water (20 mL) was added, and the mixture was evaporated to ethyl acetate (50 mL EtOAc). The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether i N, = 1 : 100 to 1: 20) to give pale yellow solid 5-nitro-7-fluoro-2,3-dihydro Benzofuran 8D (1.3 g, yield 39%).
第四步： 5-氨基 -7-氟 -2,3-二氢苯并呋喃 8E  Fourth step: 5-amino-7-fluoro-2,3-dihydrobenzofuran 8E
-fluoro-2,3-dihydrobenzofuran-5-amin  -fluoro-2,3-dihydrobenzofuran-5-amin
Figure imgf000061_0002
Figure imgf000061_0002
将 5-硝基 -7-氟 -2,3-二氢苯并呋喃 8D (100 mg, 0.50 mmol)溶于无水乙醇 （5 mL) 中， 加 入九水硫化钠 （240 mg， 1.00 mmol) ， 加热升温至 70°C， 搅拌反应 30分钟。 将反应液冷却 至室温， 加入水 （10 mL) ,用乙酸乙酯萃取反应液 （20 mLX l ) ， 合并有机相， 用饱和食盐 水 （20 mL X l) 洗涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚 /二氯 甲垸（v/V) = l : i;i得到黄色固体 5-氨基 -7-氟 -2,3-二氢苯并呋喃 8E (40 mg， 产率 53%)。 Dissolve 5-nitro-7-fluoro-2,3-dihydrobenzofuran 8D (100 mg, 0.50 mmol) in absolute ethanol (5 mL) and add sodium nonahydrate (240 mg, 1.00 mmol) The temperature was raised to 70 ° C by heating, and the reaction was stirred for 30 minutes. The reaction mixture was cooled to room temperature, then water (10 mL), EtOAc (EtOAc (EtOAc) The residue was purified by silica gel column chromatography ( petroleum ether / methylene chloride (v / V ) = 1 : i; i to give a yellow solid 5-amino-7-fluoro-2,3-dihydrobenzofuran 8E ( 40 mg, yield 53%).
lU NMR (400 MHz, CDC13) δ 6.36 (m, 1Η), 6.27 (dd, 1H), 4.56 (t, 2H), 3.46 (s, 2H), 3.14 (t,lU NMR (400 MHz, CDC1 3 ) δ 6.36 (m, 1Η), 6.27 (dd, 1H), 4.56 (t, 2H), 3.46 (s, 2H), 3.14 (t,
2H)。 2H).
MS m/z (ESI): 154.1 [M+H]  MS m/z (ESI): 154.1 [M+H]
第五步： 2-氯 -2-(2-(7-氟 -2,3-二氢苯并呋喃 -5-基)腙基)乙酸乙酯 8F  Step 5: 2-Chloro-2-(2-(7-fluoro-2,3-dihydrobenzofuran-5-yl)indenyl)acetate 8F
ethyl 2-chloro-2-(2-(7-fluoro-2,3-dihydrobenzofuran-5-yl)hydrazono)acetate
Figure imgf000062_0001
Ethyl 2-chloro-2-(2-(7-fluoro-2,3-dihydrobenzofuran-5-yl)hydrazono)acetate
Figure imgf000062_0001
将浓盐酸 （1.2 mL, 15.1 mmol) 的水（2.5 mL)溶液加入到 5-氨基 -7-氟 -2,3-二氢苯并呋喃 8E (800 mg, 5.20 mmol)中， -5~0°C下搅拌反应 30分钟， 在 0°C下滴加亚硝酸钠 （431 mg, 6.24 mmol) 的水（2 mL)溶液， 维持 0°C搅拌反应 30分钟。 在另一反应瓶中， 将乙酸钠 （984 mg, 12.00 mmol)溶于水 ( 3 mL) 中， 再加入 2-氯乙酰乙酸乙酯 (85.6 mg, 5.20 mmol) 的乙酸乙酯 (5 mL) 溶液， 降温至 -5°C， 滴加第一个反应瓶中的反应液， 维持温度在 -5~0°C， 10 分钟加 完， 0°C下搅拌反应 4小时。 向反应液中加入乙酸乙酯 （50 mL)和水（20 mL)， 分液， 水相用 乙酸乙酯 （20 mLX 2) 萃取， 合并有机相， 用饱和食盐水（30 mLX 2)洗涤， 有机相用无水硫 酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯 （v/V;» = 50: l~10: l)得到黄 色固体状的化合物 2-氯 -2-(2-(7-氟 -2,3-二氢苯并呋喃 -5-基;)腙基)乙酸乙酯 8F (700 mg, 产率Add a solution of concentrated hydrochloric acid (1.2 mL, 15.1 mmol) in water (2.5 mL) to 5-amino-7-fluoro-2,3-dihydrobenzofuran 8E (800 mg, 5.20 mmol), -5~0 The reaction was stirred at ° C for 30 minutes, and a solution of sodium nitrite (431 mg, 6.24 mmol) in water (2 mL) was added dropwise at 0 ° C, and the mixture was stirred at 0 ° C for 30 minutes. In a separate reaction flask, sodium acetate (984 mg, 12.00 mmol) was dissolved in water (3 mL) and ethyl 2-chloroacetoacetate (85.6 mg, 5.20 mmol) ethyl acetate (5 mL) The solution was cooled to -5 ° C, and the reaction liquid in the first reaction flask was added dropwise, maintaining the temperature at -5 to 0 ° C, and the addition was completed in 10 minutes, and the reaction was stirred at 0 ° C for 4 hours. Ethyl acetate (50 mL) and water (20 mL) were added to the mixture and the mixture was evaporated. the organic phase was dried over anhydrous sodium sulfate, concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / V; »= 50 : l ~ 10: l) to give a yellow solid compound 2-chloro- 2-(2-(7-fluoro-2,3-dihydrobenzofuran-5-yl;)indolyl)ethyl acetate 8F (700 mg, yield
47%) 47%)
第六步： 1-(7-氟 -2,3-二氢苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5,6,7-四氢- 1H-吡唑 [3,4-c]吡啶 -3-甲酸乙酯 8G  The sixth step: 1-(7-fluoro-2,3-dihydrobenzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7 -oxo-4,5,6,7-tetrahydro-1H-pyrazole [3,4-c]pyridine-3-carboxylic acid ethyl ester 8G
ethyl l-(7-fluoro-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7- tetrahydro- lH-pyrazolo[3,4-c]pyri  Ethyl l-(7-fluoro-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro- lH-pyrazolo[3,4-c]pyri
Figure imgf000062_0002
Figure imgf000062_0002
将 1-(4-(2-氧代哌啶 -1-基)苯基) -3-吗啉 -5,6-二氢吡啶 -2(1H)-酮 If (700 mg, 2.00 mmol)溶 于乙酸乙酯 （15 mL) 中， 加入 2-氯 -2-(2-(5-氨基 -7-氟 -2,3-二氢苯并呋喃 -5-基;)腙基)乙酸乙酯 8F (574 mg, 2.00 mmol), 碘化钾 (33 mg, 0.20 mmol)和三乙胺 (607 mg, 6.00 mmol), 升温至 回流反应过夜。 将反应液冷却至 0°C， 加入 4N盐酸 （2.5 mL, 10.00 mmol), 升至常温搅拌 1 小时， 加入水 （25 mL) ， 用乙酸乙酯萃取反应液 （25 mL X 2) ， 合并有机相， 用饱和食盐 水（30 mLX l)洗涤， 有机相用无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸 乙酯 /石油醚 （v/v) = 1 : 1~1 :0)得到黄褐色固体 1-(7-氟 -2,3-二氢苯并呋喃 -5-基;) -6-[4-(2-氧代哌 啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -1H-吡唑 [3,4-c]吡啶 -3-甲酸乙酯 8G (260 mg, 产率 26%)。  Dissolve 1-(4-(2-oxopiperidin-1-yl)phenyl)-3-morpholine-5,6-dihydropyridine-2(1H)-one If (700 mg, 2.00 mmol) Ethyl 2-chloro-2-(2-(5-amino-7-fluoro-2,3-dihydrobenzofuran-5-yl;) fluorenyl)acetate was added to ethyl acetate (15 mL) 8F (574 mg, 2.00 mmol), potassium iodide (33 mg, 0.20 mmol) and triethylamine (607 mg, 6.00 mmol). The reaction solution was cooled to 0 ° C, 4N hydrochloric acid (2.5 mL, 10.00 mmol) was added, and the mixture was stirred at room temperature for 1 hour, water (25 mL) was added, and the mixture was extracted with ethyl acetate (25 mL X 2 ) The mixture was washed with brine (30 mL EtOAc). :0) Obtained a yellow-brown solid 1-(7-fluoro-2,3-dihydrobenzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl)phenyl] Ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazo[3,4-c]pyridine-3-carboxylate 8G (260 mg, yield 26%).
¾ NMR (400 MHz, CDC13) δ 7.34 (d, 2H), 7.26 (d, 2H), 7.20 (m, 1H), 7.16-7.17 (m, 1H), 4.683⁄4 NMR (400 MHz, CDC1 3 ) δ 7.34 (d, 2H), 7.26 (d, 2H), 7.20 (m, 1H), 7.16-7.17 (m, 1H), 4.68
(t, 2H), 4.45 (q, 2H), 4.08 (t, 2H), 3.61 (t, 2H), 3.30 (t, 2H), 3.26 (t, 2H), 2.56 (t, 2H), 1.94 (m, 4H),(t, 2H), 4.45 (q, 2H), 4.08 (t, 2H), 3.61 (t, 2H), 3.30 (t, 2H), 3.26 (t, 2H), 2.56 (t, 2H), 1.94 ( m, 4H),
1.42 (t, 3H MS m/z (ESI): 519.2 [M+l] 1.42 (t, 3H MS m/z (ESI): 519.2 [M+l]
第七步 : l-(7-氟 -2,3-二氢苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5,6,7-四氢- 1H-吡唑 [3,4-c]吡啶 -3-甲酰胺 化合物 8  Step 7: l-(7-Fluoro-2,3-dihydrobenzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7 -oxo-4,5,6,7-tetrahydro-1H-pyrazole[3,4-c]pyridine-3-carboxamide compound 8
l-(7-fluoro-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyri  L-(7-fluoro-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH -pyrazolo[3,4-c]pyri
Figure imgf000063_0001
Figure imgf000063_0001
将 1-(7-氟 -2,3-二氢苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5,6,7-四氢 -1H-吡 唑 [3,4-c]吡啶 -3-甲酸乙酯 8G (260 mg, 0.50 mmol)溶于 Ν,Ν-二甲基甲酰胺 （5 mL) 中， 加入 甲酰胺 （225 mg, 5.00 mmol)和甲醇钠 （108 mg, 2.00 mmol), 升温至 70°C反应 6小时。 浓缩 反应液， 残留物用二氯甲垸（2 mL)溶解， 用饱和食盐水（30 mLX 2)洗涤， 有机相用无水硫 酸钠干燥， 浓缩， 用硅胶柱色谱法纯化（乙酸乙酯 /石油醚（v/v) = 1 : 1~1 :0)得到黄色固体状的 化合物 1-(7-氟 -2,3-二氢苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5,6,7-四氢 -1H-吡 唑 [3,4-c]吡啶 -3-甲酰胺化合物 8 (25 mg， 产率 10%)。 1-(7-Fluoro-2,3-dihydrobenzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7-oxo -4,5,6,7-tetrahydro-1H-pyrazole [3,4-c]pyridine-3-carboxylic acid ethyl ester 8G (260 mg, 0.50 mmol) dissolved in hydrazine, hydrazine-dimethylformamide ( To 5 mL), formamide ( 22 5 mg, 5.00 mmol) and sodium methoxide (108 mg, 2.00 mmol) were added, and the mixture was warmed to 70 ° C for 6 hours. The reaction mixture was concentrated, EtOAc m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Petroleum ether (v/v) = 1 : 1~1 : 0) Compound 1-(7-fluoro-2,3-dihydrobenzofuran-5-yl;) -6-[4- (2-oxopiperidin-1-yl;)phenyl]-7-oxo-4,5,6,7-tetrahydro-1H-pyrazole[3,4-c]pyridine-3-carboxamide Compound 8 (25 mg, 10% yield).
¾ NMR (400 MHz, CDC13) δ 7.33 (d, 2H), 7.26 (d, 2H), 7.14-7.19 (m, 2H), 6.81 (s, IH), 5.48 (s, IH), 4.69 (t, 2H), 4.08 (t, 2H), 3.61 (m, 2H), 3.36 (t, 2H), 3.27 (t, 2H), 2.56 (m, 2H), 1.93 (m, 4H)。  3⁄4 NMR (400 MHz, CDC13) δ 7.33 (d, 2H), 7.26 (d, 2H), 7.14-7.19 (m, 2H), 6.81 (s, IH), 5.48 (s, IH), 4.69 (t, 2H), 4.08 (t, 2H), 3.61 (m, 2H), 3.36 (t, 2H), 3.27 (t, 2H), 2.56 (m, 2H), 1.93 (m, 4H).
MS m/z (ESI): 490.2 [M+l] 实施例 9  MS m/z (ESI): 490.2 [M+l] EXAMPLE 9
l-(6-氟-二氢苯并呋喃 -5-基;) -6-(4-(2-氧代哌啶 -1-基;)苯基; )-7-氧代 -4,5,6,7-四氢 -IH-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 9)  1-(6-Fluoro-dihydrobenzofuran-5-yl;)-6-(4-(2-oxopiperidin-1-yl;)phenyl; )-7-oxo-4,5 ,6,7-tetrahydro-IH-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 9)
l-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyri  L-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH -pyrazolo[3,4-c]pyri
Figure imgf000063_0002
Figure imgf000063_0002
化合物 9 Compound 9
Figure imgf000064_0001
Figure imgf000064_0001
第一步： 2-(2-溴 -5-氟-苯氧基)乙醇 9B  First step: 2-(2-bromo-5-fluoro-phenoxy)ethanol 9B
2-(2-bromo-5-fluorophenoxy)ethanol  2-(2-bromo-5-fluorophenoxy)ethanol
Figure imgf000064_0002
Figure imgf000064_0002
用乙醇 （150 mL)溶解 2,4-二氟溴苯（15 g, 77.7 mmol), 加入 N-甲基吡咯垸酮 （15 mL), 分四次加入叔丁醇钾 （30.54 g 272 mmol), 然后在 100°C 反应 6h。 反应结束， 加入水（200 mL), 用乙酸乙酯（150 mL x 3)萃取， 合并有机相， 有机相用饱和食盐水（100 mL x 2)洗 涤， 无水硫酸钠干燥， 过滤， 浓缩； 用硅胶柱色谱分离提纯 （石油醚 /乙酸乙酯 （v/v) = 10: 1-3: 1)得到化合物 2-(2-溴 -5-氟-苯氧基)乙醇 9B (9.0 g， 产率 49%)。  2,4-Difluorobromobenzene (15 g, 77.7 mmol) was dissolved in ethanol (150 mL), N-methylpyrrolidone (15 mL) was added, and potassium t-butoxide (30.54 g 272 mmol) was added in four portions. And then react at 100 ° C for 6 h. After the reaction was completed, water (200 mL), EtOAc (EtOAc (EtOAc) Purification by silica gel column chromatography (petroleum ether / ethyl acetate (v/v) = 10: 1-3: 1) to give compound 2-(2-bromo-5-fluoro-phenoxy)ethanol 9B (9.0 g, Yield 49%).
第二步： 1-溴 -2-(2-溴乙氧基) -4-氟苯 9C  Second step: 1-bromo-2-(2-bromoethoxy)-4-fluorobenzene 9C
l-bromo-2-(2-bromoethoxy)-4-fluorobenzene  L-bromo-2-(2-bromoethoxy)-4-fluorobenzene
Figure imgf000064_0003
Figure imgf000064_0003
在冰浴下， 将 2-(2-溴 -5-氟-苯氧基)乙醇 9B (8 g, 34 mmol)搅拌下溶解于二氯甲垸（100 mL) 中， 依次加入四溴化碳（14.1 g, 42.5 mmol)和 三苯基膦（11.1 g, 42.5 mmol), 室温下反 应 2h。 反应结束， 减压浓缩， 用硅胶柱色谱分离提纯 （石油醚）得到化合物 1-溴 -2-(2-溴乙氧 基) -4-氟苯 9C (8.0 g， 产率 79%)。  2-(2-Bromo-5-fluoro-phenoxy)ethanol 9B (8 g, 34 mmol) was dissolved in dichloromethane (100 mL) with stirring under ice-cooling, followed by the addition of carbon tetrabromide (14.1 g, 42.5 mmol) and triphenylphosphine (11.1 g, 42.5 mmol) were reacted for 2 h at room temperature. After completion of the reaction, the residue was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
第三步： 6-氟 -2,3-二氢苯并呋喃 9D  The third step: 6-fluoro-2,3-dihydrobenzofuran 9D
6-fluoro-2,3-dihydrobenzofuran  6-fluoro-2,3-dihydrobenzofuran
Figure imgf000064_0004
在氮气保护下， 干冰丙酮浴中， 将 1-溴 -2-(2-溴乙氧基) -4-氟苯 9C (2.72 g, 9.1 mmol)搅拌 下溶解于四氢呋喃 （20 mL) 中， 滴加正丁基锂 （1.6 M, 6.26 mL) 的正己垸溶液， -78°C反应 2h, 反应结束滴加水 （20 mL), 用乙酸乙酯 （30 mL x 3) 萃取， 合并有机相， 无水硫酸钠干 燥， 过滤， 浓缩； 用硅胶柱色谱分离提纯 （石油醚） 得到化合物 6-氟 -2,3-二氢苯并呋喃 9D (0.8 g, 产率 63%)。
Figure imgf000064_0004
Dissolve 1-bromo-2-(2-bromoethoxy)-4-fluorobenzene 9C (2.72 g, 9.1 mmol) in tetrahydrofuran (20 mL) with stirring under a nitrogen atmosphere. Add n-butyl lithium (1.6 M, 6.26 mL) in n-hexane solution, react at -78 °C for 2 h, add water (20 mL) at the end of the reaction, extract with ethyl acetate (30 mL x 3), and combine organic phases. The aqueous solution was dried over sodium sulfate, filtered and evaporated.]]]]]]]]]
第四步： 5-硝基 -6-氟 -2,3-二氢苯并呋喃 9E  Fourth step: 5-nitro-6-fluoro-2,3-dihydrobenzofuran 9E
6-fluoro-5-nitro-2,3-dihydrobenzofuran  6-fluoro-5-nitro-2,3-dihydrobenzofuran
Figure imgf000065_0001
Figure imgf000065_0001
将 6-氟 -2,3-二氢苯并呋喃 9D (1.2 g, 8.69 mmol )溶于乙酸（5 mL) 中， 室温下加入浓硝 酸 （150 mg, 2.4 mmol), 升温至 70°C， 加入浓硝酸 （450 mg, 7.2 mmol), 维持 70°C搅拌反应 1 小时。 向反应液中加入水（20 mL)和乙酸乙酯（50 mL), 分液， 水相用乙酸乙酯 （50 mL X 3)萃取， 合并有机相， 有机相用饱和食盐水 （50 mL X 2)洗涤， 无水硫酸钠干燥， 过滤， 浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚 /乙酸乙酯 （v/V;» = 20: l~10: l)得到浅黄色固体状 的化合物 5-硝基 -6-氟 -2,3-二氢苯并呋喃 9E (700 mg,产率 44%)。 6-Fluoro-2,3-dihydrobenzofuran 9D (1.2 g, 8.69 mmol) was dissolved in acetic acid (5 mL), concentrated nitric acid (150 mg, 2.4 mmol) was added at room temperature, and then warmed to 70 ° C, Concentrated nitric acid (450 mg, 7.2 mmol) was added, and the reaction was stirred at 70 ° C for 1 hour. Water (20 mL) and ethyl acetate (50 mL) were added to the mixture and the mixture was evaporated. 2), dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / V; »= 20 : l ~ 10: l) to give a pale yellow solid Compound 5-nitro-6-fluoro-2,3-dihydrobenzofuran 9E (700 mg, yield 44%).
^ NMR (400 MHz, CDC13) δ 7.79 (d, 1Η), 6.63 (d, 1H), 4.77 (t, 2H), 3.27 (t, 2H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.79 (d, 1 Η), 6.63 (d, 1H), 4.77 (t, 2H), 3.27 (t, 2H).
第五步： 6-氟 -2,3-二氢苯并呋喃 -5-胺 9F  Step 5: 6-Fluoro-2,3-dihydrobenzofuran-5-amine 9F
6-fluoro-2,3-dihydrobenzofuran-5-amine  6-fluoro-2,3-dihydrobenzofuran-5-amine
Figure imgf000065_0002
Figure imgf000065_0002
将 6-氟 -5-硝基 -2,3-二氢苯并呋喃 9E (550 mg, 3.0 mmol)溶于甲醇 （20 mL) 中， 加入钯炭 (82.5 mg, 钯含量 w/w = 10%)在氢气氛下， 置换气体三次， 在是室温下反应 4h。 反应结 束， 过滤固体， 浓缩反应液， 残留物用硅胶柱色谱分离提纯 （石油醚 /乙酸乙酯 i N、 =5: 1-1 : 1) 得到浅黄色固体状的化合物 6-氟 -2,3-二氢苯并呋喃 -5-胺 9F (460 mg,产率 100%)。  6-Fluoro-5-nitro-2,3-dihydrobenzofuran 9E (550 mg, 3.0 mmol) was dissolved in methanol (20 mL) and palladium charcoal (82.5 mg, palladium content w/w = 10) %) The gas was replaced three times under a hydrogen atmosphere and reacted at room temperature for 4 h. After the completion of the reaction, the solid was filtered, and the residue was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjj 3-Dihydrobenzofuran-5-amine 9F (460 mg, yield 100%).
¾ NMR (400 MHz, CDC13) δ 6.66 (d, 1H), 6.51 (d, 1H), 4.52 (t, 2H), 3.30 (br, 2H), 3.10 (t,3⁄4 NMR (400 MHz, CDC1 3 ) δ 6.66 (d, 1H), 6.51 (d, 1H), 4.52 (t, 2H), 3.30 (br, 2H), 3.10 (t,
2H)。 2H).
第六步： 2-氯 -2-(2-(6-氟 -2,3-二氢苯并呋喃 -5-基)腙基)乙酸乙酯 9G  Step 6: 2-Chloro-2-(2-(6-fluoro-2,3-dihydrobenzofuran-5-yl)indenyl)acetate 9G
ethyl 2-chloro-2-(2-(6-fluoro-2,3-dihydrobenzofuran-5-yl)hydrazono)acetate
Figure imgf000066_0001
Ethyl 2-chloro-2-(2-(6-fluoro-2,3-dihydrobenzofuran-5-yl)hydrazono)acetate
Figure imgf000066_0001
将浓盐酸 （0.72 mL, 8.7 mmol) 的水（2 mL)溶液加入到 6-氟 -2,3-二氢苯并呋喃 -5-胺 9F (460 mg, 3 mmol) 中， 0°C下搅拌反应 15分钟， 在 0°C下滴加亚硝酸钠 （248 mg, 3.6 mmol) 的 水（3 mL)溶液， 维持 0°C搅拌反应 lh， 用乙酸钠 （566 mg, 6.9 mmol)调节反应液 pH=5~6， 在 0°C下滴加 2-氯乙酰乙酸乙酯 （494 mg, 3 mmol) 的乙酸乙酯（3 mL)溶液， 10 min加完， 在 0 °C下反应 30min， 升温到室温反应 lh。 向反应液中加入乙酸乙酯 （30 mL) 和水 （10 mL), 分液， 水相用乙酸乙酯 （20 mL X 2) 萃取， 合并有机相， 用饱和食盐水（20 mL)洗 涤， 无水硫酸钠干燥， 过滤， 浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚 /乙酸乙酯 i N、 = 10: 1-5: 1)得到黄色固体状的化合物 2-氯 -2-(2-(6-氟 -2,3-二氢苯并呋喃 -5-基；)腙基)乙酸乙酯 9G (200 mg, 产率 23%)。  Add concentrated hydrochloric acid (0.72 mL, 8.7 mmol) in water (2 mL) to 6-fluoro-2,3-dihydrobenzofuran-5-amine 9F (460 mg, 3 mmol) at 0 ° C The reaction was stirred for 15 minutes, and a solution of sodium nitrite (248 mg, 3.6 mmol) in water (3 mL) was added dropwise at 0 ° C, and the mixture was stirred at 0 ° C for 1 h, and the reaction was adjusted with sodium acetate (566 mg, 6.9 mmol). Liquid pH=5~6, a solution of ethyl 2-chloroacetoacetate (494 mg, 3 mmol) in ethyl acetate (3 mL) was added dropwise at 0 ° C, and the mixture was stirred at 10 ° C for 30 min. , warmed to room temperature for 1 h. Ethyl acetate (30 mL) and water (10 mL) were added to the mixture and the mixture was evaporated. Drying over anhydrous sodium sulfate, EtOAc~~~~~~~~~~~~~~~~~~~ 2-(6-Fluoro-2,3-dihydrobenzofuran-5-yl;)indenyl)acetate 9G (200 mg, yield 23%).
¾ NMR (400 MHz, CDC13) δ 8.34 (s, 1H), 7.43 (d, 1H), 6.56 (d, 1H), 4.60 (t, 2H), 4.39 (q, 2H), 3.20 (t, 2H), 1.40 (t, 3H 3⁄4 NMR (400 MHz, CDC1 3 ) δ 8.34 (s, 1H), 7.43 (d, 1H), 6.56 (d, 1H), 4.60 (t, 2H), 4.39 (q, 2H), 3.20 (t, 2H ), 1.40 (t, 3H)
第七步： l-(6-氟-二氢苯并呋喃 -5-基;) -6-(4-(2-氧代哌啶 -1-基;)苯基； )-7-氧代 -4,5,6,7-四氢 -1H- 吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 9H  Step 7: l-(6-Fluoro-dihydrobenzofuran-5-yl;)-6-(4-(2-oxopiperidin-1-yl)phenyl);-7-oxo -4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 9H
Ethyl 1 -(6-fluoro-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin- 1 -yl)phenyl)- Ethyl 1 -(6-fluoro-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin- 1 -yl)phenyl)-
4,5,6,7-tetrahydro- lH-pyrazolo[3,4-c]pyridine-3-carboxylate 4,5,6,7-tetrahydro- lH-pyrazolo[3,4-c]pyridine-3-carboxylate
Figure imgf000066_0002
Figure imgf000066_0002
将 2-氯 -2-(2-(6-氟 -2,3-二氢苯并呋喃 -5-基)腙基)乙酸乙酯 9G (150 mg, 0.52 mmol), 3-吗 啉 -1-(4-(2-氧代哌啶 -1-基)苯基) -5,6-二氢吡啶 -2(1H)-酮 (If) (222 mg, 0.62 mmol), 溶于乙酸乙酯 (5 mL) 中， 加入碘化钾 （8.6 mg, 0.052 mmol)和三乙胺 （158 mg, 1.56 mmol), 升至 90°C回流 过夜， 反应液冷却至 0°C， 加入盐酸 (4N, 0.65 mL, 2.6 mmol), 室温搅拌反应 lh。 向反应液中 加入水 （10 mL), 分液， 水相用乙酸乙酯 （20 mL X 2) 萃取， 合并有机相， 无水硫酸钠干 燥， 过滤， 浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯）得到黄色固体状的化合物 1-(6- 氟-二氢苯并呋喃 -5-基) -6-(4-(2-氧代哌啶 -1-基)苯基) -7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶- 3-甲酸乙酯 9H (180 mg， 产率 67%)。  2-Chloro-2-(2-(6-fluoro-2,3-dihydrobenzofuran-5-yl)indolyl)acetate 9G (150 mg, 0.52 mmol), 3-morpholine-1 -(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridine-2(1H)-one (If) (222 mg, 0.62 mmol), dissolved in ethyl acetate (5 mL), add potassium iodide (8.6 mg, 0.052 mmol) and triethylamine (158 mg, 1.56 mmol), reflux to 90 ° C overnight, cool the reaction to 0 ° C, add hydrochloric acid (4N, 0.65 mL) , 2.6 mmol), stir the reaction at room temperature for 1 h. Water (10 mL) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, (Ethyl acetate) gave the compound 1-(6-fluoro-dihydrobenzofuran-5-yl)-6-(4-(2-oxopiperidin-1-yl)phenyl) as a yellow solid. 7-Oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate 9H (180 mg, yield 67%).
¾ NMR (400 MHz, CDC13) δ 7.35-7.24 (m, 5H), 6.57 (d, 1H), 4.64 (t, 2H), 4.46 (t, 2H), 4.13 (t 2H), 3.59 (m, 2H), 3.32 (t, 2H), 3.19 (t, 2H), 2.56 (m, 2H), 1.94 (m, 4H), 1.43 (t, 3H)。 第八步： 1-(6-氟-二氢苯并呋喃 -5-基;) -6-(4-(2-氧代哌啶 -1-基;)苯基) -7-氧代 -4,5,6,7-四氢 -1H- 吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 9 ) 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.35-7.24 (m, 5H), 6.57 (d, 1H), 4.64 (t, 2H), 4.46 (t, 2H), 4.13 (t 2H), 3.59 (m, 2H), 3.32 (t, 2H), 3.19 (t, 2H), 2.56 (m, 2H), 1.94 (m, 4H), 1.43 (t, 3H). The eighth step: 1-(6-fluoro-dihydrobenzofuran-5-yl;)-6-(4-(2-oxopiperidin-1-yl;)phenyl)-7-oxo- 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (compound 9)
l-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyri  L-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH -pyrazolo[3,4-c]pyri
Figure imgf000067_0001
Figure imgf000067_0001
1-(6-氟-二氢苯并呋喃 -5-基;) -7-氧代 -6-(4-(2-氧代哌啶 -1-基;)苯基 )-4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 9H (180 mg, 0.347 mmol)溶于 Ν,Ν-二甲基甲酰胺 （5 mL) 中， 加入甲 酰胺 （124.9 mg, 2.8 mmol), 甲醇钠 （54 mg, 1.04 mmol), 升温至 80°C反应过夜。 将反应液冷 却至室温， 减压除去溶剂， 然后用二氯甲垸溶解加入硅胶（lg) 拌样， 用硅胶柱色谱分离提纯 (乙酸乙酯）得到浅黄色固体状的化合物 1-(6-氟-二氢苯并呋喃 -5-基) -6-(4-(2-氧代哌啶 -1-基)苯 基) -7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 化合物 9 (95 mg, 产率 56 %)。  1-(6-fluoro-dihydrobenzofuran-5-yl;)-7-oxo-6-(4-(2-oxopiperidin-1-yl;)phenyl)-4,5, 6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 9H (180 mg, 0.347 mmol) dissolved in hydrazine, hexane-dimethylformamide (5 mL) Add formamide (124.9 mg, 2.8 mmol), sodium methoxide (54 mg, 1.04 mmol), and warm to 80 ° C overnight. The reaction solution was cooled to room temperature, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated. Fluoro-dihydrobenzofuran-5-yl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-7-oxo-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide compound 9 (95 mg, yield 56%).
¾ NMR (400 MHz, CDC13) δ 7.35-7.24 (m, 5H), 6.80 (s, IH), 6.60 (d, IH), 5.46 (s, 2H), 4.65 (t, 2H), 4.12 (t, 2H), 3.59 (m, 2H), 3.59 (m, 2H), 3.37 (t, 2H), 3.22 (t, 2H), 2.56 (m, 2H), 1.93 (m, 4H)。 实施例 10 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.35-7.24 (m, 5H), 6.80 (s, IH), 6.60 (d, IH), 5.46 (s, 2H), 4.65 (t, 2H), 4.12 (t , 2H), 3.59 (m, 2H), 3.59 (m, 2H), 3.37 (t, 2H), 3.22 (t, 2H), 2.56 (m, 2H), 1.93 (m, 4H). Example 10
l-(2,3-二氢苯并呋喃 -5-基) -6-(4-(2- ((二甲基胺基)甲基) -IH-咪唑 -1-基)苯基) -7-氧代 -4,5,6,7- 四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 10)  L-(2,3-Dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino)methyl)-IH-imidazol-1-yl)phenyl) - 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 10)
1 -(2,3-dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino)methyl)- 1 H-imidazol- 1 -yl)phenyl)-7- oxo-4,5,6,7-tetrahydro-lH-pyrazol -c] pyridine -3-carboxamide  1-(2,3-dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino)methyl)- 1 H-imidazol- 1 -yl)phenyl)-7- oxo-4,5,6 ,7-tetrahydro-lH-pyrazol -c] pyridine -3-carboxamide
Figure imgf000067_0002
Figure imgf000067_0002
化合物 10
Figure imgf000068_0001
第一步： 1-(2,3-二氢苯并呋喃 -5-基) -6-(4-(2- ((二甲基胺基)甲基) -1H-咪唑 -1-基)苯基) -7-氧 代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 10B Compound 10
Figure imgf000068_0001
First step: 1-(2,3-dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino)methyl))-1H-imidazol-1-yl) Phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 10B
ethyl l-(2,3-dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino)methyl)-lH-imidazol-l- yl)phenyl)-7-oxo-4,5,6,7-tetrahydro- -pyrazolo[3,4-c]pyridine-3-carboxylate  Ethyl l-(2,3-dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino)methyl)-lH-imidazol-l-yl)phenyl)-7-oxo-4,5,6 ,7-tetrahydro- -pyrazolo[3,4-c]pyridine-3-carboxylate
Figure imgf000068_0002
Figure imgf000068_0002
将 1-(2,3-二氢苯并呋喃 -5-基) -6-(4-碘苯基 )-7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲 酸乙酯 2B (1.2 g, 2.27 mmol)、 1-(111-咪唑-2-基)^^-二甲基甲基胺 （284 mg, 2.27 mmol)和碳 酸钾 （627 mg, 4.54 mmol)溶于 1.4-二氧六环 （30 mL) 中， 在氮气氛围下,加入碘化亚铜 (86.4 mg, 0.45 mmol) 升至 120°C 反应 2h。 将反应液冷却至室温， 加入乙酸乙酯（50 mL)和水（50 mL), 分液， 有机相用饱和食盐水 （30 mL) 洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩， 残留 物用硅胶柱色谱分离提纯 （甲醇 /二氯甲垸 （v/v) = 0: 1-4:96) 得到浅黄色固体状的化合物 1- (2,3-二氢苯并呋喃 -5-基) -6-(4-(2-((二甲基胺基)甲基) -1H-咪唑 -1-基)苯基) -7-氧代 -4,5,6,7-四氢- 1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 10B (400 mg， 产率 34%)。  1-(2,3-Dihydrobenzofuran-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazole Ethyl [3,4-c]pyridine-3-carboxylate 2B (1.2 g, 2.27 mmol), 1-(111-imidazol-2-yl)^^-dimethylmethylamine (284 mg, 2.27 mmol) Potassium carbonate (627 mg, 4.54 mmol) was dissolved in 1.4-dioxane (30 mL). Under a nitrogen atmosphere, cuprous iodide (86.4 mg, 0.45 mmol) was added and the mixture was stirred at 120 ° C for 2 h. The reaction mixture was cooled to room temperature, ethyl acetate (50 mL) and water (50 mL) was evaporated. The product was purified by silica gel column chromatography (methanol / methylene chloride (v/v) = 0: 1-4:96) to give compound 1-(2,3-dihydrobenzofuran-5- -6-(4-(2-((Dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-7-oxo-4,5,6,7-tetrahydro - 1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 10B (400 mg, yield 34%).
¾ NMR (400 MHz, CDC13) δ 7.55-7.53 (m, 2H), 7.46-7.44 (m, 2H), 7.37 (s, IH), 7.28-7.26 (m,3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.55-7.53 (m, 2H), 7.46-7.44 (m, 2H), 7.37 (s, IH), 7.28-7.26 (m,
IH), 7.12-7.07 (m, 2H), 6.80-6.77 (d, IH), 4.61 (t, 2H), 4.47 (q, 2H), 4.19 (t, 2H), 3.54 (m, 2H), 3.39-3.36 (m, 2H), 3.26-3.21 (m, 2H), 2.37 (m, 6H), 1.44 (t, 3H)。 IH), 7.12-7.07 (m, 2H), 6.80-6.77 (d, IH), 4.61 (t, 2H), 4.47 (q, 2H), 4.19 (t, 2H), 3.54 (m, 2H), 3.39 -3.36 (m, 2H), 3.26-3.21 (m, 2H), 2.37 (m, 6H), 1.44 (t, 3H).
第二步： l-(2,3-二氢苯并呋喃 -5-基) -6-(4-(2- ((二甲基胺基)甲基) -IH-咪唑 -1-基)苯基) -7-氧 代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 10)  The second step: l-(2,3-dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino)methyl)-IH-imidazol-1-yl) Phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 10)
1 -(2,3-dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino)methyl)- 1 H-imidazol- 1 -yl)phenyl)-7- oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]5-3-carboxamide
Figure imgf000069_0001
1-(2,3-dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino)methyl)- 1 H-imidazol- 1 -yl)phenyl)-7- oxo-4,5,6 ,7-tetrahydro-lH-pyrazolo[3,4-c]5-3-carboxamide
Figure imgf000069_0001
将 l-(2,3-二氢苯并呋喃 -5-基) -6-(4-(2- ((二甲基胺基）甲基) -IH-咪唑 -1-基)苯基) -7-氧代- 4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （400 mg, 0.76 mmol)溶于 Ν,Ν-二甲基甲酰胺 (10 mL) 中， 加入甲酰胺 (340 mg, 7.6 mmol), 甲醇钠 (80 mg, 1.52 mmol), 升温至 80°C反应 过夜。 将反应液冷却至室温， 减压除去溶剂， 然后用二氯甲垸溶解加入硅胶（lg) 拌样， 用硅 胶柱色谱分离提纯（甲醇 /二氯甲垸（v/v) = 0: 1-6:94)得到浅黄色固体状的化合物 1-(2,3-二氢 苯并呋喃 -5-基) -6-(4-(2-((二甲基胺基)甲基) -1H-咪唑 -1-基)苯基) -7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 化合物 10 (180 mg， 产率 48 %)。  1-(2,3-Dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino)methyl)-IH-imidazol-1-yl)phenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (400 mg, 0.76 mmol) dissolved in hydrazine, hydrazine To the methylformamide (10 mL), formamide (340 mg, 7.6 mmol), sodium methoxide (80 mg, 1.52 mmol), and warmed to 80 ° C overnight. The reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure. Then, the mixture was dissolved in dichloromethane (g), and the mixture was purified by silica gel column chromatography (methanol/dichloromethane (v/v) = 0: 1- 6:94) Obtained the compound 1-(2,3-dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino))methyl) - 1H as a pale yellow solid -imidazol-1-yl)phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide Compound 10 (180 mg , yield 48%).
^ NMR (400 MHz, CDC13) δ 7.55-7.53 (m, 2Η), 7.46-7.44 (m, 2H), 7.36 (s, IH), 7.28-7.26 (m, IH), 7.11-7.07 (m, 2H), 6.85 (s, IH) , 6.83-6.81 (m, IH), 5.45 (s, IH), 4.63 (t, 2H), 4.18 (t, 2H), 3.51 (s, 2H), 3.43 (t, 2H), 3.26 (t, 2H), 2.35 (m, 6H)。 实施例 11 ^ NMR (400 MHz, CDC1 3 ) δ 7.55-7.53 (m, 2Η), 7.46-7.44 (m, 2H), 7.36 (s, IH), 7.28-7.26 (m, IH), 7.11-7.07 (m, 2H), 6.85 (s, IH), 6.83-6.81 (m, IH), 5.45 (s, IH), 4.63 (t, 2H), 4.18 (t, 2H), 3.51 (s, 2H), 3.43 (t , 2H), 3.26 (t, 2H), 2.35 (m, 6H). Example 11
l-(3-甲基 -2,3-二氢吡啶呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -IH-吡 唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 11)  L-(3-Methyl-2,3-dihydropyridylfuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4, 5,6,7-tetrahydro-IH-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 11)
l-(3-methyl-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7- tetrahyd  L-(3-methyl-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahyd
Figure imgf000069_0002
Figure imgf000069_0002
化合物 1 1 第一步： 3-甲基 -2 3-二氢苯并呋喃 11B Compound 1 1 First step: 3-methyl-2 3-dihydrobenzofuran 11B
Figure imgf000070_0001
Figure imgf000070_0001
将 3-甲基苯并呋喃 11A (500 mg, 3.78 mmol)溶于乙酸乙酯 （20 mL) 中， 加入钯炭（50 mg, 钯含量 w/w = 10%)在氢气氛下， 置换气体三次， 在是室温下反应 48h。 反应结束， 过 滤固体， 浓缩反应液， 得到无色液体化合物 3-甲基 -2,3-二氢苯并呋喃 11B (450 mg, 产率 89%)  Dissolve 3-methylbenzofuran 11A (500 mg, 3.78 mmol) in ethyl acetate (20 mL), add palladium charcoal (50 mg, palladium content w/w = 10%) under hydrogen atmosphere, replace the gas Three times, it was reacted at room temperature for 48 h. After completion of the reaction, the solid was filtered, and the reaction mixture was evaporated to ethylamine.
¾ NMR (400 MHz, CDC13) δ 7.16-7.10 (m, 2H), 6.89-6.85 (m, 1H), 6.80-6.78 (m, 1H), 4.70- 4.66 (m, 1H), 4.13-4.05 (m, 1H), 3.50-3.59 (m, 1H), 1.33 (d, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.16-7.10 (m, 2H), 6.89-6.85 (m, 1H), 6.80-6.78 (m, 1H), 4.70- 4.66 (m, 1H), 4.13-4.05 ( m, 1H), 3.50-3.59 (m, 1H), 1.33 (d, 3H).
第二步： 3-甲基 -5-硝基 -2,3-二氢苯并呋喃 11C  Second step: 3-methyl-5-nitro-2,3-dihydrobenzofuran 11C
3-methyl-5-nitro-2,3-dihydrobenzofura  3-methyl-5-nitro-2,3-dihydrobenzofura
Figure imgf000070_0002
Figure imgf000070_0002
将 3-甲基 -2,3-二氢苯并呋喃 11B (450 mg, 3.35 mmol )溶于乙酸 （5 mL) 中， 室温下加入 浓硝酸 (56.5 mg, 0.9 mmol), 升温至 70°C， 加入浓硝酸 (169.5 mg, 2.69 mmol), 维持 70°C 搅 拌反应 lh。 向反应液中加入水（100 mL)和乙酸乙酯 （50 mL), 分液， 有机相用饱和食盐水 (50 mL X 2)洗涤， 无水硫酸钠干燥， 过滤， 浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚 / 乙酸乙酯 （v/v) = 1 :0-98:2) 得到浅黄色油状的化合物 3-甲基 -5-硝基 -2,3-二氢苯并呋喃 11C (300 mg,产率 50%)。  3-Methyl-2,3-dihydrobenzofuran 11B (450 mg, 3.35 mmol) was dissolved in acetic acid (5 mL), concentrated nitric acid (56.5 mg, 0.9 mmol) was added at room temperature and warmed to 70 ° C Concentrated nitric acid (169.5 mg, 2.69 mmol) was added, and the reaction was stirred at 70 ° C for 1 h. Water (100 mL) and ethyl acetate (50 mL) were added to the mixture, and the organic layer was washed with saturated brine (50 mL EtOAc). Purification by column chromatography (petroleum ether / ethyl acetate (v/v) = 1 : 0 - 98: 2) to give the compound 3-methyl-5-nitro-2,3-dihydrobenzofuran as a pale yellow oil. 11C (300 mg, yield 50%).
^ NMR (400 MHz, CDC13) δ 8.13-8.10 (m, 1H), 8.06 (s, 1H), 6.83-6.81(m, 1H), 4.88-4.84 (m, 1H), 4.31-4.24 (m, 1H), 3.67-3.58 (m, 1H), 1.40 (d, 3H)。 ^ NMR (400 MHz, CDC1 3 ) δ 8.13-8.10 (m, 1H), 8.06 (s, 1H), 6.83-6.81 (m, 1H), 4.88-4.84 (m, 1H), 4.31-4.24 (m, 1H), 3.67-3.58 (m, 1H), 1.40 (d, 3H).
第三步： 3-甲基 -2,3-二氢苯并呋喃 -5-胺 11D  The third step: 3-methyl-2,3-dihydrobenzofuran-5-amine 11D
3-methyl-2,3-dihydrobenzofuran-5-ami  3-methyl-2,3-dihydrobenzofuran-5-ami
Figure imgf000070_0003
Figure imgf000070_0003
将 3-甲基 -5-硝基 -2,3-二氢苯并呋喃 1 1C (2.5 g, 14 mmol) 溶于乙醇 （50 mL) 中， 加入 九水合硫化钠 （8.4 g, 35 mmol) 的水（50 mL)溶液， 升温至 90°C反应 3小时。 浓缩反应液， 加入水（50 mL)和乙酸乙酯 （80 mL), 分液， 水相用乙酸乙酯 （40 mL X 2)萃取， 合并有 机相， 有机相用饱和食盐水 （40 mL X 2) 洗涤， 无水硫酸钠干燥， 过滤， 浓缩得黄色固体 状的化合物 3-甲基 -2,3-二氢苯并呋喃 -5-胺 11D (1.1 g, 产率 52%)。 3-Methyl-5-nitro-2,3-dihydrobenzofuran 1 1C (2.5 g, 14 mmol) was dissolved in ethanol (50 mL) and sodium sulfate sulphate (8.4 g, 35 mmol) was added. A solution of water (50 mL) was heated to 90 ° C for 3 hours. The reaction mixture was concentrated, EtOAc (EtOAc) (EtOAc) The organic phase was washed with saturated brine (40 mL EtOAc). 11D (1.1 g, yield 52%).
¾ NMR (400 MHz, CDC13) δ 6.83-6.60 (m, 2H), 6.55-6.52 (m, 1H), 4.65-4.61 (m, 1H), 4.03-3⁄4 NMR (400 MHz, CDC1 3 ) δ 6.83-6.60 (m, 2H), 6.55-6.52 (m, 1H), 4.65-4.61 (m, 1H), 4.03-
3.99 (m, 1H), 3.50-3.44 (m, 1H), 1.29 (d, 3H)。 3.99 (m, 1H), 3.50-3.44 (m, 1H), 1.29 (d, 3H).
第四步： 2-氯 -2-(2-(3-甲基 -2,3-二氢苯并呋喃 -5-基)腙基)乙酸乙酯 11E  Fourth step: ethyl 2-chloro-2-(2-(3-methyl-2,3-dihydrobenzofuran-5-yl)indenyl) 11E
ethyl 2-chloro-2-(2-(3-methyl-2,3-dih robenzofuran-5-yl)hydrazono)acetate  Ethyl 2-chloro-2-(2-(3-methyl-2,3-dih robenzofuran-5-yl)hydrazono)acetate
Figure imgf000071_0001
Figure imgf000071_0001
将浓盐酸 （0.96 mL, 11.66 mmol) 的水（2 mL)溶液加入到 3-甲基 -2,3-二氢苯并呋喃 -5-胺 11D (0.6 g, 4.02 mmol) 中， 0°C下搅拌反应 15分钟， 在 0°C下滴加亚硝酸钠 (333 mg, 4.82 mmol) 的水（2 mL)溶液， 维持 0°C搅拌反应 1.5h， 用乙酸钠 （758 mg, 9.25 mmol)调节反应 液 pH=5~6， 在 0°C下滴加 2-氯乙酰乙酸乙酯 （661 mg, 4.02 mmol) 的乙酸乙酯 （4 mL)溶 液， lOmin加完， 室温反应 lh。 向反应液中加入乙酸乙酯 （30 mL)和水（20 mL), 分液， 水 相用乙酸乙酯 （20 mL X 2)萃取， 合并有机相， 用饱和食盐水（30 mL)洗涤， 无水硫酸钠 干燥， 过滤， 浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚 /乙酸乙酯（v/V;» = 1 :0~9: 1)得到黄 色油状的化合物 2-氯 -2-(2-(3-甲基 -2,3-二氢苯并呋喃 -5-基;)腙基)乙酸乙酯 11E (660 mg, 产率 58%) Add a solution of concentrated hydrochloric acid (0.96 mL, 11.66 mmol) in water (2 mL) to 3-methyl-2,3-dihydrobenzofuran-5-amine 11D (0.6 g, 4.02 mmol), 0 ° C The reaction was stirred for 15 minutes, and a solution of sodium nitrite (333 mg, 4.82 mmol) in water (2 mL) was added dropwise at 0 ° C, and the mixture was stirred at 0 ° C for 1.5 h with sodium acetate (758 mg, 9.25 mmol) The pH of the reaction mixture was adjusted to 5~6, and a solution of ethyl 2-chloroacetoacetate (661 mg, 4.02 mmol) in ethyl acetate (4 mL) was added dropwise at 0 ° C. Ethyl acetate (30 mL) and water (20 mL) were added to the mixture and the mixture was evaporated. dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / V; »= 1 : 0 ~ 9: 1) to give a yellow oil of compound 2-chloro-2 -(2-(3-methyl-2,3-dihydrobenzofuran-5-yl;)indolyl)ethyl acetate 11E (660 mg, yield 58%)
^ NMR (400 MHz, CDC13) δ 8.28 (s, 1H), 7.11 (s, 1H), 6.94-6.91 (m, 1H), 6.77-6.72 (m, 1H), 4.73-4.67 (m, 1H), 4.38 (q, 2H), 4.11-4.07 (m, 1H), 3.59-3.50 (m, 1H), 1.40 (t, 3H), 1.35 (d, 3H)。 ^ NMR (400 MHz, CDC1 3 ) δ 8.28 (s, 1H), 7.11 (s, 1H), 6.94-6.91 (m, 1H), 6.77-6.72 (m, 1H), 4.73-4.67 (m, 1H) , 4.38 (q, 2H), 4.11-4.07 (m, 1H), 3.59-3.50 (m, 1H), 1.40 (t, 3H), 1.35 (d, 3H).
第五步： l-(3-甲基 -2,3-二氢吡啶呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四 氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 11F  Step 5: l-(3-Methyl-2,3-dihydropyridylfuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxygen Generation-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 11F
Ethyl l-(3-methyl-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)- 4,5,6,7-tetrahydro- lH-pyrazolo[3, -c]pyridine-3-carboxylate  Ethyl l-(3-methyl-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro- lH-pyrazolo[3, -c]pyridine-3-carboxylate
Figure imgf000071_0002
Figure imgf000071_0002
将 3-吗啉 -1-(4-(2-氧代哌啶 -1-基)苯基) -5,6-二氢吡啶 -2(1H)-酮（If) (600 mg, 1.69 mmol), 2-氯 -2-(2-(3-甲基 -2,3-二氢苯并呋喃 -5-基)腙基)乙酸乙酯 11E (573 mg, 2.03 mmol)溶于乙酸乙 酯 (20 mL) 中， 加入碘化钾 (28 mg, 0.169 mmol)和三乙胺 (513 mg, 5.07 mmol), 升至 90°C 回流反应过夜， 反应液冷却至 0°C， 加入盐酸 （4N, 2.1 mL, 8.45 mmol), 室温搅拌反应 lh。 向 反应液中加入水（30 mL)， 分液， 水相用乙酸乙酯 （20 mL X 2)萃取， 合并有机相， 用饱和 食盐水 （30 mL X 2)洗涤， 无水硫酸钠干燥， 过滤， 浓缩， 残留物用硅胶柱色谱分离提纯 (乙酸乙酯 /石油醚（v/v) = 1 :99-1 :0)得到黄色固体状的化合物 1-(3-甲基 -2,3-二氢吡啶呋喃 -5- 基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 11F (380 mg, 产率 44%)。 3-morpholine-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridine-2(1H)-one (If) (600 mg, 1.69 mmol , 2-chloro-2-(2-(3-methyl-2,3-dihydrobenzofuran-5-yl)indolyl)ethyl acetate 11E (573 mg, 2.03 mmol) dissolved in ethyl acetate (20 mL), add potassium iodide (28 mg, 0.169 mmol) and triethylamine (513 mg, 5.07 mmol), and bring to reflux at 90 ° C overnight. The reaction solution is cooled to 0 ° C, and hydrochloric acid (4N, 2.1 mL, 8.45 mmol), stirred at room temperature for 1 h. To Water (30 mL) was added to the reaction mixture and the mixture was evaporated. EtOAcjjjjjjjjjjjj The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v/v) = 1 : 99-1 : 0) to give compound 1-(3-methyl-2,3- Dihydropyridylfuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5,6,7-tetrahydro-1H-pyridyl Ethylzolo[3,4-c]pyridine-3-carboxylate 11F (380 mg, yield 44%).
¾ NMR (400 MHz, CDC13) δ 7.35-7.33 (m, 2H), 7.28-7.24 (m, 5H), 6.76 (d, IH), 4.73-4.69 IH), 4.76 (q, 2H), 4.14-4.07 (m, 3H), 3.60-3.54 (m, 2H), 3.33-3.30 (m, 2H), 2.56 (m, 2H), 1.94-1.93 (m, 4H), 1.43 (t, 3H), 1.32 (d, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.35-7.33 (m, 2H), 7.28-7.24 (m, 5H), 6.76 (d, IH), 4.73-4.69 IH), 4.76 (q, 2H), 4.14- 4.07 (m, 3H), 3.60-3.54 (m, 2H), 3.33-3.30 (m, 2H), 2.56 (m, 2H), 1.94-1.93 (m, 4H), 1.43 (t, 3H), 1.32 ( d, 3H).
第六步： l-(3-甲基 -2,3-二氢吡啶呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5,6,7-四 氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 11 )  The sixth step: l-(3-methyl-2,3-dihydropyridylfuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7 -oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 11)
l-(3-methyl-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyr  L-(3-methyl-2,3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro-lH -pyrazolo[3,4-c]pyr
Figure imgf000072_0001
Figure imgf000072_0001
将 1-(3-甲基 -2,3-二氢吡啶呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -1H- 吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 11F (380 mg,0.74 mmol)溶于 Ν,Ν-二甲基甲酰胺（10 mL) 中， 加入甲酰胺 (332 mg, 7.4 mmol)、 甲醇钠 （80 mg, 1.48 mmol), 升至 80°C反应过夜。 向反应液 中加入水（50 mL), 水相用乙酸乙酯 （50 mL X 2)萃取， 有机相用饱和食盐水（50 mL)洗 涤， 无水硫酸钠干燥， 过滤， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （甲醇 /二氯甲垸（v/v) = 0: 1-2:98)得到浅黄色固体状的化合物 1-P-甲基 -2,3-二氢吡啶呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1- 基）苯基] -7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 化合物 11 (150 mg , 产率 1-(3-Methyl-2,3-dihydropyridin-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4 ,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 11F (380 mg, 0.74 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (10 In mL), formamide (332 mg, 7.4 mmol), sodium methoxide (80 mg, 1.48 mmol) was added, and the mixture was allowed to react at 80 ° C overnight. Water (50 mL) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated. The product was purified by silica gel column chromatography (methanol / methylene chloride (v/v) = 0: 1-2: 98) to give the compound 1-P-methyl-2,3-dihydropyridinefuran as a pale yellow solid. -5-yl;)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[ 3,4-c]pyridine-3-carboxamide compound 11 (150 mg, yield
42%) 42%)
O NMR (400 MHz, CDC13) δ 7.36-7.25 (m, 6Η), 6.85 (s, IH), 6.79 (d, IH), 5.46 (s, IH), 4.75- 4.71 (m, IH), 4.15-4.08 (m, 3H), 3.61 (m, 3H), 3.39-3.36 (m, 2H), 2.57 (m, 2H), 1.94(m 4H), 1.34(d, 3H)。 实施例 12 O NMR (400 MHz, CDC1 3 ) δ 7.36-7.25 (m, 6Η), 6.85 (s, IH), 6.79 (d, IH), 5.46 (s, IH), 4.75- 4.71 (m, IH), 4.15 -4.08 (m, 3H), 3.61 (m, 3H), 3.39-3.36 (m, 2H), 2.57 (m, 2H), 1.94 (m 4H), 1.34 (d, 3H). Example 12
l-(2,3-二氢苯并呋喃 -5-基) -6-[4-(2-甲基 -3-氧代 -吗啉 -4-基)苯基] -7-氧代 -4,5-二氢吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 12)  L-(2,3-Dihydrobenzofuran-5-yl)-6-[4-(2-methyl-3-oxo-morpholin-4-yl)phenyl]-7-oxo- 4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxamide (compound 12)
l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-methyl-3-oxo-morpholin-4-yl)phenyl]-7-oxo-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxamide L-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-methyl-3-oxo-morpholin-4-yl)phenyl]-7-oxo-4,5-dihydropyrazolo[3,4 -c]pyridine-3-carboxamide
Figure imgf000073_0001
Figure imgf000073_0001
第一步： 2-甲基吗啉 -3-酮 (12B) First step: 2-methylmorpholine-3-one (12B)
2-methylmorpholin-3-one
Figure imgf000073_0002
2-methylmorpholin-3-one
Figure imgf000073_0002
将 2-氨基乙醇 (10.0 g, 73.5 mmol)溶于 1,4-二氧六环 (100 mL) 中， 加入钠 (1.7 g, 73.5 mmol), 升温至 110°C反应 7小时， 缓慢加入 2-氯丙酸乙酯 （10.0 g， 73.5 mmol)， 继续回流反应 3小时。 将反应液过滤除去沉淀， 浓缩， 残留物中加入水（100 mL), 用乙酸乙酯 （100 mL X 2)萃取， 用二氯甲垸（100 mL X 2)萃取， 合并有机相， 无水硫酸钠干燥， 浓缩， 残留物用 硅胶柱色谱分离提纯 （二氯甲垸 /甲醇 （v/v) = 70: 1)得到标题化合物 2-甲基吗啉 -3-酮 （12B)， 白色固体（4.3 g, 产率 51%)。  2-Aminoethanol (10.0 g, 73.5 mmol) was dissolved in 1,4-dioxane (100 mL), sodium (1.7 g, 73.5 mmol) was added, and the mixture was heated to 110 ° C for 7 hours, slowly added 2 Ethyl chloropropionate (10.0 g, 73.5 mmol) was refluxed for 3 hours. The reaction mixture was filtered and evaporated to dryness crystals crystals crystals crystals crystalsssssssssssssssssssssssssssssssssssssss Drying over sodium sulfate, EtOAc (EtOAc m.) (4.3 g, yield 51%).
^ NMR (400 MHz, CDC13) δ 7.05 (s, IH), 4.23-4.17 (m, IH), 3.99-3.96 (m, IH), 3.78-3.70 IH), 3.59-3.52 (m, IH), 3.32-3.27 (m, IH), 1.46 (dd, 3H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.05 (s, IH), 4.23-4.17 (m, IH), 3.99-3.96 (m, IH), 3.78-3.70 IH), 3.59-3.52 (m, IH), 3.32-3.27 (m, IH), 1.46 (dd, 3H).
MS m/z (ESI): 116.2 [M+l] MS m/z (ESI): 116.2 [M+l]
第二步： l-(2,3-二氢苯并呋喃 -5-基) -6-[4-(2-甲基 -3-氧代 -吗啉 -4-基)苯基] -7-氧代 -4,5-二氢 吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （12C)  The second step: l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-methyl-3-oxo-morpholin-4-yl)phenyl]-7 -oxo-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (12C)
ethyl l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-methyl-3-oxo-morpholin-4-yl)phenyl]-7-oxo-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxylate  Ethyl l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-methyl-3-oxo-morpholin-4-yl)phenyl]-7-oxo-4,5-dihydropyrazolo[3, 4-c]pyridine-3-carboxylate
Figure imgf000073_0003
Figure imgf000073_0003
将 l-(2,3-二氢苯并呋喃 -5-基) -6-(4-碘苯基 )-7-氧代 -4,5,6,7-四氢 -IH-吡唑并 [3,4-c]吡啶 -3-甲 酸乙酯 (2C) (2.0 g, 产率 3.6 mmol) 溶于 1,2-二氧六环 (30 mL) 中， 加入 2-甲基吗啉 -3-酮 (12B) (815 mg, 7.2 mmol), 磷酸钾 （1.5 g, 7.2 mmol), 碘化酮 （100 mg) 和反 -(1R,2R)-N, Ν'-二甲基 -1 ,2-环戊二胺 （100 mg), 升温至 80°C反应 10小时。 将反应液冷却至室温， 加入水 (30 mL), 用乙酸乙酯 （50 mL X 2)萃取， 合并有机相， 有机相用无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯） 得到标题化合物 1-(2,3-二氢苯并呋喃 -5-基;) -6-[4-(2- 甲基 -3-氧代 -吗啉 -4-基)苯基] -7-氧代 -4,5-二氢吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （12C)， 白色固体 (1.2 g, 产率 65%)。 1-(2,3-Dihydrobenzofuran-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-IH-pyrazole [3,4-c]pyridine-3-methyl Ethyl acetate (2C) (2.0 g, yield 3.6 mmol) was dissolved in 1,2-dioxane (30 mL), and 2-methylmorpholin-3-one (12B) (815 mg, 7.2 Methyl), potassium phosphate (1.5 g, 7.2 mmol), iodinated ketone (100 mg) and trans-(1R,2R)-N, Ν'-dimethyl-1,2-cyclopentanediamine (100 mg) , the temperature was raised to 80 ° C for 10 hours. The reaction mixture was cooled to room temperature, and water (30 mL) was evaporated. Ethyl acetate) gave the title compound 1-(2,3-dihydrobenzofuran-5-yl;)-6-[4-(2-methyl-3-oxo-morpholin-4-yl)benzene Ethyl]-7-oxo-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (12C), white solid (1.2 g, yield 65%).
¾ NMR (400 MHz, CDC13) δ 7.31 - 7.22 (m, 5H), 7.19 (dd, IH), 6.69 (d, IH), 4.52 (t, 2H), 4.38 (q, 2H), 4.30 (q, IH), 4.05 (m, 2H), 3.88 (m, 2H), 3.46 (m, 2H), 3.25 (t, 2H), 3.15 (t, 2H), 1.47
Figure imgf000074_0001
3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.31 - 7.22 (m, 5H), 7.19 (dd, IH), 6.69 (d, IH), 4.52 (t, 2H), 4.38 (q, 2H), 4.30 (q , IH), 4.05 (m, 2H), 3.88 (m, 2H), 3.46 (m, 2H), 3.25 (t, 2H), 3.15 (t, 2H), 1.47
Figure imgf000074_0001
MS m/z (ESI): 517.3 [M+l]  MS m/z (ESI): 517.3 [M+l]
第三步： l-(2,3-二氢苯并呋喃 -5-基) -6-[4-(2-甲基 -3-氧代 -吗啉 -4-基)苯基] -7-氧代 -4,5-二氢 吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 12)  The third step: l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-methyl-3-oxo-morpholin-4-yl)phenyl]-7 -oxo-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxamide (compound 12)
l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-methyl-3-oxo-morpholin-4-yl)phenyl]-7-oxo-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxamide  L-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-methyl-3-oxo-morpholin-4-yl)phenyl]-7-oxo-4,5-dihydropyrazolo[3,4 -c]pyridine-3-carboxamide
Figure imgf000074_0002
Figure imgf000074_0002
将 1-(2,3-二氢苯并呋喃 -5-基;) -6-[4-(2-甲基 -3-氧代 -吗啉 -4-基;)苯基] -7-氧代 -4,5-二氢吡唑并 [3,4-c]吡啶 -3-甲酸乙酯（12C) (100 mg, 0.19 mmol)溶于 Ν,Ν-二甲基甲酰胺 （20 mL) 中， 加 入甲酰胺 （1.0 mg, 23 mmol), 甲醇钠 （502 mg, 9.3 mmol), 升温至 80°C反应 3小时。 将反应 液冷却至室温， 加入水 （10 mL), 浓缩， 向残留物中加入水 （20 mL), 用二氯甲垸 （30 mL X 2)萃取， 合并有机相， 有机相无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯（二 氯甲垸 /甲醇 (v/v) =100: 1) 得到标题化合物 1-(2,3-二氢苯并呋喃 -5-基；) -6-[4-(2-甲基 -3-氧代-吗 啉 -4-基)苯基] -7-氧代 -4,5-二氢吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 12)， 白色固体 （400 mg, 产率 36 %)。  1-(2,3-Dihydrobenzofuran-5-yl;)-6-[4-(2-methyl-3-oxo-morpholin-4-yl;)phenyl]-7- Ethyl oxo-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxylate (12C) (100 mg, 0.19 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (20 mL) Wherein, formamide (1.0 mg, 23 mmol), sodium methoxide (502 mg, 9.3 mmol) was added, and the mixture was heated to 80 ° C for 3 hours. The reaction solution was cooled to room temperature, water (10 mL) was evaporated, evaporated, evaporated, evaporated. The title compound 1-(2,3-dihydrobenzofuran-5-yl;) was obtained as the title compound (m.). -6-[4-(2-methyl-3-oxo-morpholin-4-yl)phenyl]-7-oxo-4,5-dihydropyrazolo[3,4-c]pyridine -3-carboxamide (Compound 12), white solid (400 mg, yield 36%).
¾ NMR (400 MHz, CDC13) δ 7.42 - 7.30 (m, 5H), 7.30 - 7.22 (m, IH), 6.84 (s, IH), 6.79 (d,3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.42 - 7.30 (m, 5H), 7.30 - 7.22 (m, IH), 6.84 (s, IH), 6.79 (d,
IH), 5.56 (s, IH), 4.61 (t, 2H), 4.37 (q, IH), 4.15 - 4.04 (m, 3H), 4.00 - 3.86 (m, 2H), 3.59 - 3.50 (m, IH), 3.38 (t, 2H), 3.24 (t, 2H), 1.54 (d, 3H)。 MS m/z (ESI): 488.3 [M+l] 实施例 13 (I, IH) , 3.38 (t, 2H), 3.24 (t, 2H), 1.54 (d, 3H). MS m/z (ESI): 488.3 [M+l] EXAMPLE 13
l-(2,2-二甲基 -3H-苯并呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡啶 -3-甲酰胺 (化合物 13) L-(2,2-Dimethyl-3H-benzofuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4, 5-dihydro-IH-pyrazole [3,4-c]pyridine-3-carboxamide (compound 13)
l-(2,2-dimethyl-3H-benzofuran-5-y l)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxamide  L-(2,2-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c Pyridine-3-carboxamide
Figure imgf000075_0001
第一步： 2-溴 -1(2-羟基苯基)乙酮 (IB)
Figure imgf000075_0001
First step: 2-bromo-1(2-hydroxyphenyl)ethanone (IB)
2-bromo- 1 -(2-hydroxyphenyl)ethanone
Figure imgf000075_0002
2-bromo-1 -(2-hydroxyphenyl)ethanone
Figure imgf000075_0002
将 2-乙酰基苯酚 (10.0 g, 13.4 mmol)和溴化铜 (27.9 g, 124.9 mmol)溶于氯仿 (60 mL) 中， 加入乙酸乙酯 （40 mL) , 升温至 90°C反应 8小时。 将反应液冷却至室温， 用硅藻土抽 滤， 向滤液中加入二氯甲垸 （100 mL) 和水 （100 mL), 分液， 水相用二氯甲垸（50 mL X 2) 萃取， 合并有机相， 有机相用饱和食盐水 （100 mL X 2) 洗涤， 无水硫酸钠干燥， 浓 缩， 残留物用硅胶柱色谱分离提纯 （石油醚）得到标题化合物 2-溴 -1(2-羟基苯基)乙酮 (1B)， 褐 色固体， 未计算产率， 直接用于下一步。  2-Acetylphenol (10.0 g, 13.4 mmol) and copper bromide (27.9 g, 124.9 mmol) were dissolved in chloroform (60 mL), ethyl acetate (40 mL) was added, and the mixture was warmed to 90 ° C for 8 hours. . The reaction solution was cooled to room temperature, suction filtered with Celite, and dichloromethane (100 mL) and water (100 mL) were added to the filtrate, and the aqueous phase was extracted with dichloromethane (50 mL X 2 ) The organic phase was combined, and the organic layer was evaporated, evaporated,jjjjjjjjjjjjjj Hydroxyphenyl) Ethyl ketone (1B), brown solid, mp.
^ NMR (400 MHz, CDC13) δ 11.73 (s, 1Η), 7.75 (dd, 1H), 7.53 (dd, 1H), 7.02 (d, 1H), 6.94 (t, 1H), 4.45 (s, 2H)。 ^ NMR (400 MHz, CDC1 3 ) δ 11.73 (s, 1Η), 7.75 (dd, 1H), 7.53 (dd, 1H), 7.02 (d, 1H), 6.94 (t, 1H), 4.45 (s, 2H ).
第二步： 苯并呋喃 -3酮 (13C)  Step 2: Benzofuran-3 Ketone (13C)
benzofuran-3-one
Figure imgf000076_0001
Benzofuran-3-one
Figure imgf000076_0001
将 2-溴 -1(2-羟基苯基)乙酮 (IB) (1.0 g, 4.7 mmol)加入到甲醇 （40 mL) 中， 加入乙酸钠 (1.2 g, 14.1 mmol), 室温搅拌反应 3小时。 向反应液中加入乙酸乙酯 （30 mL)和饱和食盐水 (50 mL), 分液， 水相用乙酸乙酯 （30 mL X 2) 萃取， 合并有机相， 有机相用饱和食盐水 (50 mL X 3)洗涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯（石油醚:乙酸乙 酯 （v/v) = 1 :0-98:2) 得到标题化合物苯并呋喃 -3酮 （13C)， 浅黄色固体 （240 mg, 产率 38 %)。  2-Bromo-1(2-hydroxyphenyl)ethanone (IB) (1.0 g, 4.7 mmol) was added to methanol (40 mL), sodium acetate (1.2 g, 14.1 mmol) was added, and the mixture was stirred at room temperature for 3 hours. . Ethyl acetate (30 mL) and saturated brine (50 mL) were added to the mixture, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (30 mL EtOAc). The title compound benzofuran was obtained by chromatography, eluting with EtOAc EtOAc (EtOAc (EtOAc) 3 ketone (13C), light yellow solid (240 mg, yield 38%).
^ NMR (400 MHz, CDC13) δ 7.68 (d, 1Η), 7.65 - 7.58 (m, 1H), 7.15 (d, 1H), 7.10 (t, 1H), 4.63 (s, 2H ^ NMR (400 MHz, CDC1 3 ) δ 7.68 (d, 1Η), 7.65 - 7.58 (m, 1H), 7.15 (d, 1H), 7.10 (t, 1H), 4.63 (s, 2H
第三步： 2 2—二甲基苯并呋喃 -3-酮 (13D)  The third step: 2 2 -dimethylbenzofuran-3-one (13D)
Figure imgf000076_0002
Figure imgf000076_0002
将苯并呋喃 -3酮 (13C) (134 mg, 1.0 mmol) 溶于四氢呋喃 （15 mL) 溶液中， 无水无氧 处理， 冷却至 -30°C， 加入氢化钠 （100 mg, 60%, 2.5 mmol), 搅拌反应 20分钟， 滴加碘化 钾 （710 mg, 5.0 mmol), 维持 0°C反应 1小时， 室温反应 2小时。 向反应液中加入饱和碳酸氢 钠 （20 mL) 溶液， 加入水 （10 mL) 和乙酸乙酯 （50 mL), 分液， 水相用乙酸乙酯 （20 mL X 2) 萃取， 合并有机相， 有机相用饱和食盐水 （30 mL X 2) 洗涤， 无水硫酸钠干燥， 浓 缩， 残留物用硅胶柱色谱分离提纯 （石油醚:乙酸乙酯 （v/v) = 1 :0-98:2) 得到标题化合物 2, 2—二甲基苯并呋喃 -3-酮（13D)， 黄色油状物 （70 mg, 产率 43%)。  The benzofuran-3 ketone (13C) (134 mg, 1.0 mmol) was dissolved in tetrahydrofuran (15 mL), anhydrous and anaerobic, cooled to -30 ° C, sodium hydride (100 mg, 60%, 2.5 mmol), the reaction was stirred for 20 minutes, potassium iodide (710 mg, 5.0 mmol) was added dropwise, and the reaction was maintained at 0 ° C for 1 hour and at room temperature for 2 hours. A solution of saturated sodium bicarbonate (20 mL) was added, and water (10 mL) and ethyl acetate (50 mL) was evaporated. The organic phase was washed with brine (30 mL EtOAc) 2) The title compound 2,2-dimethylbenzofuran-3-one (13D) was obtained as a yellow oil (70 mg, yield 43%).
^ NMR (400 MHz, CDC13) δ 7.67 (d, 1Η), 7.65 - 7.59 (m, 1H), 7.08 (dd, 2H), 1.47 (s, 6H)。 四步： 2,2-甲基 -3H-苯并呋喃 -3-醇 (13E) ^ NMR (400 MHz, CDC1 3 ) δ 7.67 (d, 1 Η), 7.65 - 7.59 (m, 1H), 7.08 (dd, 2H), 1.47 (s, 6H). Four steps: 2,2-methyl-3H-benzofuran-3-ol (13E)
Figure imgf000076_0003
Figure imgf000076_0003
将 2,2-二甲基苯并呋喃 -3-酮 (13D) (1.0 g, 6.2 mmol) 溶于甲醇 （40 mL) 中， 冷却至 0 V , 加入硼氢化钠 （1.2 g, 30.8 mmol), 室温搅拌反应 2小时。 向反应液中加入水 （30 mL) 和乙酸乙酯 （30 mL), 分液， 水相用乙酸乙酯 （30 mL X 2) 萃取， 合并有机相， 有机相用 饱和食盐水 （30 mL X 2) 洗涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 (石油醚:乙酸乙酯 （v/v) = 1 :0-9: 1) 得到标题化合物 2,2-甲基 -3H-苯并呋喃 -3-醇 (1E)， 白色固 体（400 mg, 产率 40%)。 2,2-Dimethylbenzofuran-3-one (13D) (1.0 g, 6.2 mmol) was dissolved in methanol (40 mL), cooled to 0 V, and sodium borohydride (1.2 g, 30.8 mmol) The reaction was stirred at room temperature for 2 hours. Water (30 mL) and ethyl acetate (30 mL) were added to the reaction mixture, and the mixture was evaporated. EtOAc (30 mL?? 2) Washing, drying over anhydrous sodium sulfate, EtOAc (EtOAc m.) -3H-benzofuran-3-ol (1E), white solid Body (400 mg, yield 40%).
^ NMR (400 MHz, CDC13) δ 7.40 (d, 1H), 7.26 - 7.22 (m, 1H), 6.91 (t, 1H), 6.79 (d, 1H), 4.75 (s, 1H), 1.69 (s, 1H), 1.49 (s, 3H), 1.35 (s, 3H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.40 (d, 1H), 7.26 - 7.22 (m, 1H), 6.91 (t, 1H), 6.79 (d, 1H), 4.75 (s, 1H), 1.69 (s , 1H), 1.49 (s, 3H), 1.35 (s, 3H).
第五步： 2,2-二甲基 -3H-苯并呋喃 (13F)  Step 5: 2,2-Dimethyl-3H-benzofuran (13F)
2,2-dimethyl-3H-benzofuran
Figure imgf000077_0001
2,2-dimethyl-3H-benzofuran
Figure imgf000077_0001
将 2,2-甲基 -3H-苯并呋喃 -3-醇 (IE) (82 mg, 0.5 mmol)和三乙基硅垸 (70 mg, 0.6 mmol) 溶于无水二氯甲垸 （15 mL) 中， 氮气保护下， 冷却反应液至 -78°C， 滴加 BF3.Et20 (85 mg, 0.6 mmol), 室温搅拌反应 3小时。 向反应液中加入饱和碳酸氢钠 （10 mL) 溶液， 搅拌 10分 钟， 加入二氯甲垸 （10 mL), 分液， 水相用二氯甲垸 （10 mL X 2) 萃取， 合并有机相， 有 机相用饱和食盐水 （10 mL X 2) 洗涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离 提纯 （ 乙酸乙酯： 石油醚 （v/v) =2:8) 得到标题化合物 2,2-二甲基 -3H-苯并呋喃 (1F)， 无水液 体（10 mg, 产率 14%)。 2,2-Methyl-3H-benzofuran-3-ol (IE) (82 mg, 0.5 mmol) and triethylsilyl (70 mg, 0.6 mmol) were dissolved in anhydrous dichloromethane. In mL), the reaction solution was cooled to -78 ° C under a nitrogen atmosphere, and BF 3 .Et 2 0 (85 mg, 0.6 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 hours. Add saturated sodium bicarbonate (10 mL) solution to the reaction solution, stir for 10 minutes, add dichloromethane (10 mL), and separate the mixture. The aqueous phase is extracted with dichloromethane (10 mL X 2 ). The organic phase was washed with saturated brine (10 mL EtOAc) (mjjjjjjjj Compound 2,2-Dimethyl-3H-benzofuran (1F), anhydrous liquid (10 mg, yield 14%).
^ NMR (400 MHz, CDC13) δ 7.11 (dd, 2Η), 6.82 (dd, 1H), 6.73 (d, 1H), 3.01 (s, 2H), 1.48 (s,^ NMR (400 MHz, CDC1 3 ) δ 7.11 (dd, 2Η), 6.82 (dd, 1H), 6.73 (d, 1H), 3.01 (s, 2H), 1.48 (s,
6H)。 6H).
第六步： 2,2-二甲基 -5-硝基 -3H-苯并呋喃 （13G)  Step 6: 2,2-Dimethyl-5-nitro-3H-benzofuran (13G)
2,2-dimethyl-5-nitro-3H-benzofuran
Figure imgf000077_0002
2,2-dimethyl-5-nitro-3H-benzofuran
Figure imgf000077_0002
将 2,2-二甲基 -3H-苯并呋喃 (IF) (2.0 g, 13.4 mmol)溶于乙酸 （40 mL) 中， 室温下加入 浓硝酸 （0.4 mL, 4 mmol), 升温至 70°C， 加入浓硝酸 （1.4 mL, 12 mmol), 升温至 70°C反 应 1小时。 将反应液冷去至室温， 加入饱和食盐水 （50 mL) 和乙酸乙酯 （50 mL), 分液， 水 相用乙酸乙酯 （50 mL X 2) 萃取， 合并有机相， 有机相用饱和食盐水 （50 mL X 2) 洗 涤， 无水硫酸钠干燥， 浓缩， 残留物用原制备板制备 （乙酸乙酯： 石油醚 （v/v) = 1： 9) 得 到标题化合物 2,2-二甲基 -5-硝基 -3H-苯并呋喃 （13G)， 浅黄色固体， 直接投入下一步反应， 不 计算产率。  2,2-Dimethyl-3H-benzofuran (IF) (2.0 g, 13.4 mmol) was dissolved in acetic acid (40 mL). Concentrated nitric acid (0.4 mL, 4 mmol) was added at room temperature and warmed to 70° C, concentrated nitric acid (1.4 mL, 12 mmol) was added, and the mixture was heated to 70 ° C for 1 hour. The reaction solution was cooled to room temperature, and brine (50 mL) and ethyl acetate (50 mL) was evaporated and evaporated. Washed with brine (50 mL EtOAc), dried over anhydrous sodium sulfate, evaporated, evaporated,jjjjjjjjjjjjjjj Methyl-5-nitro-3H-benzofuran (13G), as a pale yellow solid, was taken directly to the next reaction.
^ NMR (400 MHz, CDC13) δ 8.10 (dd, 1Η), 8.07 - 8.04 (m, 1H), 6.75 (d, 1H), 3.08 (s, 2H), 1.53 (s, 6H)。 ^ NMR (400 MHz, CDC1 3 ) δ 8.10 (dd, 1Η), 8.07 - 8.04 (m, 1H), 6.75 (d, 1H), 3.08 (s, 2H), 1.53 (s, 6H).
第七步： 2,2-二甲基 -5-氨基 -3H-苯并呋喃 （13H)  Step 7: 2,2-Dimethyl-5-amino-3H-benzofuran (13H)
2,2-dimethyl-3H-benzofuran-5-amine
Figure imgf000077_0003
将 2,2-二甲基 -5-硝基 -3H-苯并呋喃 (13G) (2.6 g, 13.4 mmol) 溶于无水乙醇 (40 mL) 中， 加入九水硫化钠 （9.7 g, 40.2 mmol) 的水（20 mL)溶液， 升温至 90°C反应 2小时。 将反 应液浓缩， 残留物中加入饱和食盐水（20 mL)和乙酸乙酯 （50 mL), 分液， 水相用乙酸乙酯 (30 mL X 2) 萃取， 合并有机相， 有机相用饱和食盐水 （20 mL X 3) 洗涤， 无水硫酸钠 干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯： 石油醚（v/v) = 1： 9 ~ 3:7)得到标 题化合物 2,2-二甲基 -5-氨基 -3H-苯并呋喃 (13H)， 棕黄色固体（730 mg， 产率 34%)。 2,2-dimethyl-3H-benzofuran-5-amine
Figure imgf000077_0003
2,2-Dimethyl-5-nitro-3H-benzofuran (13G) (2.6 g, 13.4 mmol) was dissolved in absolute ethanol (40 mL), and sodium sulphate (9.7 g, 40.2 A solution of water (20 mL) was heated to 90 ° C for 2 hours. The reaction mixture was concentrated, and brine (20 mL) and ethyl acetate (50 mL) was evaporated. Washed with brine (20 mL EtOAc), EtOAc (mjjjjjjj 2,2-Dimethyl-5-amino-3H-benzofuran (13H), tan solid (730 mg, yield 34%).
^ NMR (400 MHz, CDC13) δ 6.53 (m, 3Η), 2.93 (s, 2H), 1.44 (s, 6H)。 ^ NMR (400 MHz, CDC1 3 ) δ 6.53 (m, 3 Η), 2.93 (s, 2H), 1.44 (s, 6H).
MS m/z (ESI): 164.1 [M+l] MS m/z (ESI): 164.1 [M+l]
第八步： 2-氯 -2[(2,2-二甲基 -3H-苯并呋喃 -5-基)腙基]乙酸乙酯 (131)  Step 8: 2-Chloro-2[(2,2-dimethyl-3H-benzofuran-5-yl)indenyl]acetate (131)
Ethyl 2-chloro-2-[(2,2-dimethyl-3H-b azono]acetate  Ethyl 2-chloro-2-[(2,2-dimethyl-3H-b azono]acetate
Figure imgf000078_0001
Figure imgf000078_0001
在第一个反应瓶中将 2,2-二甲基 -5-氨基 -3H-苯并呋喃 (13H) (630 mg, 4.0 mmol) 加入浓 盐酸 （1 mL) 和水（2 mL) 的混合溶液中， 冷却反应液至 -5°C-0°C， 滴加亚硝酸钠 （331 mg, 4.80 mmol) 的水 （4 mL) 溶液， 维持 0°C搅拌反应 1小时。 在另一反应瓶中， 将乙酸钠 （755 mg, 9.20 mmol)溶于水（5 mL) 中， 再加入 2-氯乙酰乙酸乙酯 （658 mg, 4.00 mmol) 的乙酸 乙酯 （10 mL) 溶液， 降温至 0°C， 滴加第一个反应瓶中的反应液， 0°C下搅拌反应 1小时， 室 温搅拌反应 1小时。 将反应液分液， 水相用乙酸乙酯 （15 mL X 2)萃取， 合并有机相， 用饱和 食盐水（20 mL X 2) 洗涤， 有机相用无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 (石油醚 /乙酸乙酯 （v/v) = 1 :0 - 9: 1) 得标题化合物 2-氯 -2[(2,2-二甲基 -3H-苯并呋喃 -5-基)腙 基]乙酸乙酯 （131)， 黑色油状物 （500 mg, 产率 42%)。  In a first reaction flask, 2,2-dimethyl-5-amino-3H-benzofuran (13H) (630 mg, 4.0 mmol) was added to a mixture of concentrated hydrochloric acid (1 mL) and water (2 mL) In the solution, the reaction solution was cooled to -5 ° C - 0 ° C, and a solution of sodium nitrite (331 mg, 4.80 mmol) in water (4 mL) was added dropwise, and the mixture was stirred at 0 ° C for 1 hour. In a separate reaction flask, sodium acetate (755 mg, 9.20 mmol) was dissolved in water (5 mL) and ethyl 2-chloroacetate (658 mg, 4.00 mmol) ethyl acetate (10 mL) The solution was cooled to 0 ° C, and the reaction liquid in the first reaction flask was added dropwise, and the reaction was stirred at 0 ° C for 1 hour, and the reaction was stirred at room temperature for 1 hour. The reaction mixture was separated, EtOAc (EtOAc) (EtOAc m. The title compound 2-chloro-2[(2,2-dimethyl-3H-benzofuran-) was obtained from silica gel column chromatography (EtOAc/EtOAc (EtOAc) 5-yl) fluorenyl]ethyl acetate (131), m.p. (500 mg, yield 42%).
第九步： 1-(2,2-二甲基 -3H-苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5-二氢- 1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （13J)  The ninth step: 1-(2,2-dimethyl-3H-benzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7 -oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (13J)
ethyl l-(2,2-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4 dihydropyrazolo[3,4-c]pyridine-3-carboxylate  Ethyl l-(2,2-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4 dihydropyrazolo[3,4-c]pyridine -3-carboxylate
Figure imgf000078_0002
将 2-氯 -2[(2,2-二甲基 -3H-苯并呋喃 -5-基)腙基]乙酸乙酯 (131) (500, 1.70 mmol), 3-吗啉 -1- (4-(2-氧代哌啶 -1 -基)苯基) -5,6-二氢吡啶 -2(1H)-酮 (If) (400 mg, 1.10 mmol), 溶于乙酸乙酯 (50 mL) 中， 加入碘化钾 （18 mg, 0.1 1 mmol)和三乙胺 （334 mg, 3.30 mmol), 升至 90°C反 应 24小时， 将反应液冷却至 0°C， 加入盐酸 (4N, 1.4 mL, 5.50 mmol), 室温搅拌反应 lh。 向反 应液中加入水 （20 mL) , 分液， 水相用乙酸乙酯 （15 mL X 2) 萃取， 合并有机相， 无水硫 酸钠干燥， 过滤， 浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯： 石油醚 i l、 = 2:8 -1 :0) 得标题化合物 1-(2,2-二甲基 -3H-苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1 -基;)苯基] -7-氧代 -4,5-二氢- 1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 (13J)， 灰色固体（100mg， 产率 17%)。
Figure imgf000078_0002
2-Chloro-2[(2,2-dimethyl-3H-benzofuran-5-yl)indolyl]acetate (131) (500, 1.70 mmol), 3-morpholin-1-( 4-(2-Oxopiperidin-1-yl)phenyl)-5,6-dihydropyridine-2(1H)-one (If) (400 mg, 1.10 mmol), EtOAc (50) In mL), add potassium iodide (18 mg, 0.1 1 mmol) and triethylamine (334 mg, 3.30 mmol), and raise to 90 ° C for 24 hours. Cool the reaction to 0 ° C and add hydrochloric acid (4N, 1.4). mL, 5.50 mmol), stirred at room temperature for 1 h. Water (20 mL) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated (ethyl acetate: petroleum ether il, = 2:8 -1:0) to give the title compound 1-(2,2-dimethyl-3H-benzofuran-5-yl;) -6-[4-( 2-oxo piperidin-1-yl;)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (13J) , gray solid (100 mg, yield 17%).
¾ NMR (400 MHz, CDC13) δ 7.33 (m, 3H), 7.26 (m, 3H), 6.70 (d, 1H), 4.45 (q, 2H), 4.1 1 (t, 2H), 3.59 (t, 2H), 3.31 (t, 2H), 3.01 (s, 2H), 2.55 (t, 2H), 1.98 - 1.88 (m, 4H), 1.46 (s, 6H), 1.42 (t, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.33 (m, 3H), 7.26 (m, 3H), 6.70 (d, 1H), 4.45 (q, 2H), 4.1 1 (t, 2H), 3.59 (t, 2H), 3.31 (t, 2H), 3.01 (s, 2H), 2.55 (t, 2H), 1.98 - 1.88 (m, 4H), 1.46 (s, 6H), 1.42 (t, 3H).
MS m/z (ESI): 529.4 [M+l]  MS m/z (ESI): 529.4 [M+l]
第十步： l-(2,2-二甲基 -3H-苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5-二氢- 1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 (化合物 13)  Step 10: l-(2,2-Dimethyl-3H-benzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7 -oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (compound 13)
l-(2,2-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxamide  L-(2,2-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c Pyridine-3-carboxamide
Figure imgf000079_0001
Figure imgf000079_0001
1-(2,2-二甲基 -3H-苯并呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯（13J) (100 mg, 0.19 mmol) 溶于 Ν,Ν-二甲基甲酰胺 (10 mL) 中， 加 入甲酰胺 （51 mg, 1.14 mmol), 甲醇钠 （31 mg, 0.57 mmol), 升温至 80°C反应 16小时。 将反 应液冷却至室温， 减压除去溶剂， 向残留物中加入二氯甲垸（20 mL)和水（20 mL), 分液， 水相用二氯甲垸（10 mL X 2) 萃取， 合并有机相， 有机相用饱和食盐水 （20 mL X 3) 洗 涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （甲醇 /石油醚 /乙酸乙酯 （v/v) = 0:5:5 -5:0:95) 得到标题化合物 1-(2,2-二甲基 -3H-苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 - 1-基;)苯基] - 7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 (化合物 13) (60 mg, 产率 63 %)。  1-(2,2-dimethyl-3H-benzofuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4, Ethyl 5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (13J) (100 mg, 0.19 mmol) dissolved in hydrazine, dimethyl-dimethylformamide (10 mL) Formamide (51 mg, 1.14 mmol), sodium methoxide (31 mg, 0.57 mmol), and warmed to 80 ° C for 16 hours. The reaction solution was cooled to room temperature, and then the solvent was evaporated, and then, then, the mixture was evaporated to the residue, and the mixture was partitioned with chloroform (20 mL) The combined organic phase was washed with brine (20 mL EtOAc)EtOAc. :5:5 -5:0:95) The title compound 1-(2,2-dimethyl-3H-benzofuran-5-yl;)-6-[4-(2-oxopiperidine- 1-yl;)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 13) (60 mg, yield 63 %).
^ NMR (400 MHz, CDC13) δ 7.38 - 7.28 (m, 3H), 7.26 (m, 3H), 6.82 (s, 1H), 6.73 (d, 1H), 5.45 (s, 1H), 4.1 1 (t, 2H), 3.60 (m, 2H), 3.37 (t, 2H), 3.04 (s, 2H), 2.56 (t, 2H), 1.97 - 1.88 (m, 4H), 1.47 (s, 6H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.38 - 7.28 (m, 3H), 7.26 (m, 3H), 6.82 (s, 1H), 6.73 (d, 1H), 5.45 (s, 1H), 4.1 1 ( t, 2H), 3.60 (m, 2H), 3.37 (t, 2H), 3.04 (s, 2H), 2.56 (t, 2H), 1.97 - 1.88 (m, 4H), 1.47 (s, 6H).
MS m/z (ESI): 500.5 [M+l] 实施例 14和 实施例 15 MS m/z (ESI): 500.5 [M+l] Example 14 and Example 15
将 1-(2-甲基 -2,3-二氢吡啶呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5,6,7-四氢 -1H- 吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 1)进行手性拆分， 采用 HPLC法， 用制备设备和手性柱对 手性异构体进行分离得到两个异构体 化合物 1-1 (化合物 1异构体 1， 实施例 14) (ee > 99% , RT: 12.563 min)和化合物 1-2 (化合物 1异构体 2， 实施例 15) (ee>99%, RT: 14.795 min) (手 性拆分条件： 色谱柱： ChiralCN OD (4.6 mmx250 mm, 5μηι), 测试仪器： SSI Series III， 检测 波长： 210nm， 进样量： 20μ1， 流动相： 乙醇， 柱温箱 /°C : 常温， 流速： 0.7 mL.min- ^。  1-(2-Methyl-2,3-dihydropyridin-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4 ,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 1) for chiral resolution, using HPLC method, preparation equipment and chiral column The isomers were separated to give two isomer compounds 1-1 (Compound 1 isomer 1, Example 14) (ee > 99%, RT: 12.563 min) and Compound 1-2 (Compound 1 isomer) 2, Example 15) (ee>99%, RT: 14.795 min) (Chiral separation conditions: Column: ChiralCN OD (4.6 mm x 250 mm, 5μηι), Test instrument: SSI Series III, Detection wavelength: 210 nm, Sample size: 20μ1, mobile phase: ethanol, column oven/°C: normal temperature, flow rate: 0.7 mL.min- ^.
化合物 1-1  Compound 1-1
O NMR (400 MHz, CDC13) δ 7.39 - 7.29 (m, 3H), 7.26 (d, 3H), 6.84 (s, IH), 6.76 (d, IH), 5.50 (s, IH), 5.03 - 4.91 (m, IH), 4.1 1 (t, 2H), 3.60 (s, 2H), 3.45 - 3.25 (m, 3H), 2.85 (dd, IH), 2.56 (s, 2H), 1.94 (s, 4H), 1.47 (d, 3H)。 O NMR (400 MHz, CDC1 3 ) δ 7.39 - 7.29 (m, 3H), 7.26 (d, 3H), 6.84 (s, IH), 6.76 (d, IH), 5.50 (s, IH), 5.03 - 4.91 (m, IH), 4.1 1 (t, 2H), 3.60 (s, 2H), 3.45 - 3.25 (m, 3H), 2.85 (dd, IH), 2.56 (s, 2H), 1.94 (s, 4H) , 1.47 (d, 3H).
LCMS m/z =486.2 [M+H]  LCMS m/z =486.2 [M+H]
化合物 1-2  Compound 1-2
¾ NMR (400 MHz, CDC13) δ 7.33 (t, 3H), 7.25 (d, 3H), 6.85 (s, IH), 6.76 (d, IH), 5.56 (s, 1H): 5.05 - 4.89 (m, IH), 4.1 1 (t, 2H), 3.59 (d, 2H), 3.43 - 3.29 (m, 3H), 2.85 (dd, IH), 2.56 (d, 2H), 1.99 - 1.82 (m, 4H), 1.47 (d, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.33 (t, 3H), 7.25 (d, 3H), 6.85 (s, IH), 6.76 (d, IH), 5.56 (s, 1H) : 5.05 - 4.89 (m , IH), 4.1 1 (t, 2H), 3.59 (d, 2H), 3.43 - 3.29 (m, 3H), 2.85 (dd, IH), 2.56 (d, 2H), 1.99 - 1.82 (m, 4H) , 1.47 (d, 3H).
LCMS m/z =486.2 [M+H] 实施例 16  LCMS m/z = 486.2 [M+H] Example 16
l-(3,3-二甲基 -3H-苯并呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 16)  L-(3,3-Dimethyl-3H-benzofuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4, 5-dihydro-IH-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 16)
l-(3,3-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxamide  L-(3,3-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c Pyridine-3-carboxamide
Figure imgf000080_0001
Figure imgf000080_0001
化合物 16  Compound 16
Figure imgf000080_0002
Figure imgf000081_0001
Figure imgf000080_0002
Figure imgf000081_0001
第一步： 1-溴 -2-(2-甲基烯丙氧基)苯（16B)  First step: 1-bromo-2-(2-methylallyloxy)benzene (16B)
l-bromo-2-(2-methylallyloxy)benzene  L-bromo-2-(2-methylallyloxy)benzene
Figure imgf000081_0002
Figure imgf000081_0002
将 2-溴丙烯 (20.2 g, 0.15 mol) 和 2-溴苯酚 (17.3 g, 0.1 mol), 溶于丙酮 (200 mL) 中 ， 加入碳酸钾 （34 g, 0.25 mol), 回流反应过夜。 将反应液过滤， 滤饼用乙酸乙酯洗涤， 合 并滤液， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚） 得到标题化合物 1-溴 -2-(2-甲基 烯丙氧基)苯（16B)， 无色油状物 （20 g,产率 88%)。  2-Bromopropene (20.2 g, 0.15 mol) and 2-bromophenol (17.3 g, 0.1 mol) were dissolved in acetone (200 mL), and potassium carbonate (34 g, 0.25 mol) was added and refluxed overnight. The reaction mixture was filtered, and EtOAc was evaporated,jjjjjjjjjjjjjj Benzene (16B), colorless oil (20 g, yield 88%).
¾ NMR (400 MHz, CDC13) δ 7.54 (dd, 1H), 7.23-7.21 (m, 1H), 6.89-6.81 (m, 2H), 5.16 (s, 1H), 5.01 (s, 1H), 4.49 (s, 2H), 1.86 (s, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.54 (dd, 1H), 7.23-7.21 (m, 1H), 6.89-6.81 (m, 2H), 5.16 (s, 1H), 5.01 (s, 1H), 4.49 (s, 2H), 1.86 (s, 3H).
第二步： 3,3-二甲基 -3H-苯并呋喃 （16C)  Second step: 3,3-dimethyl-3H-benzofuran (16C)
3,3-dimethyl-3H-benzofuran
Figure imgf000081_0003
3,3-dimethyl-3H-benzofuran
Figure imgf000081_0003
将 1-溴 -2-(2-甲基烯丙氧基)苯 (16B) (25 g, 0.11 mol) 溶于甲苯 (300 mL)中， 加入三叔 丁基锡垸 （48 g, 0.165 mol) 和偶氮二异丁腈 （2.5g)， 在氮气氛围下， 升温至 1 10°C反应过 夜。 将反应液冷却至常温， 加入 10%氟化甲溶液 （300 mL), 剧烈搅拌 3小时， 分液， 有机相 用饱和食盐水 （200 mL) 洗涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （石 油醚）得到标题化合物 3,3-二甲基 -3H-苯并呋喃 （16C)， 浅黄色油状物 （1.4 g, 产率 9%)。  1-Bromo-2-(2-methylallyloxy)benzene (16B) (25 g, 0.11 mol) was dissolved in toluene (300 mL), and tri-tert-butyltin sulfonium (48 g, 0.165 mol) and Azobisisobutyronitrile (2.5 g) was heated to 110 ° C overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and a 10% fluorinated solution (300 mL) was added, and the mixture was stirred for 3 hours. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and evaporated. The title compound (3,3-dimethyl-3H-benzofuran (16C), m.p.
¾ NMR (400 MHz, CDC13) δ 7.10-7.06 (m, 2H), 6.90-6.86 (m, 1H), 6.79 (d, 1H), 4.18 (m, 2H): 1.34 (s, 6H 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.10-7.06 (m, 2H), 6.90-6.86 (m, 1H), 6.79 (d, 1H), 4.18 (m, 2H) : 1.34 (s, 6H
第三步： 3,3-二甲基 -5-硝基 -3H-苯并呋喃 （16D)  The third step: 3,3-dimethyl-5-nitro-3H-benzofuran (16D)
3,3-dimethyl-5-nitro-3H-benzofuran
Figure imgf000081_0004
3,3-dimethyl-5-nitro-3H-benzofuran
Figure imgf000081_0004
甲基 -3H-苯并呋喃 (16C) (1.4 g, 9.44 mmol)溶于乙酸 (20 mL) 中， 加入硝酸 (68%, 0.24 g, 2.6 mmol), 升温至 70°C， 滴加硝酸 （68%, 0.72 g, 0.78 mmol), 搅拌反应 2小 时。 将反应液冷却至常温， 加入水 （100 mL) 和乙酸乙酯 （50 mL), 分液， 有机层用饱和食 盐水 （50 mL)洗涤， 无水硫酸钠干燥， 浓缩， 残留物用柱色谱分离提纯 （乙酸乙酯： 石油醚Methyl-3H-benzofuran (16C) (1.4 g, 9.44 mmol) was dissolved in acetic acid (20 mL). (68%, 0.24 g, 2.6 mmol), warmed to 70 ° C, nitric acid (68%, 0.72 g, 0.78 mmol) was added dropwise, and the reaction was stirred for 2 hours. The reaction solution was cooled to room temperature, and water (100 mL) and ethyl acetate (50 mL) was added, and the organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate Separation and purification (ethyl acetate: petroleum ether)
(v/v) = 0: 1- 1 :9)得到标题化合物 3,3-二甲基 -5-硝基 -3H-苯并呋喃 （16D)， 浅黄色固体（0.7 g， 产率 39%)。 (v/v) = 0: 1- 1 :9) gave the title compound 3,3-dimethyl-5-nitro-3H-benzofuran (16D) as a pale yellow solid (0.7 g, yield 39%) ).
¾ NMR (400 MHz, CDC13) δ 8.11 (dd, 1H), 8.00 (d, 1H), 6.83 (d, 1H), 4.40 (s, 2H), 1.40 (s,3⁄4 NMR (400 MHz, CDC1 3 ) δ 8.11 (dd, 1H), 8.00 (d, 1H), 6.83 (d, 1H), 4.40 (s, 2H), 1.40 (s,
6H)。 6H).
第四步： 3,3-二甲基 -5-氨基 -3H-苯并呋喃 （16E)  Fourth step: 3,3-dimethyl-5-amino-3H-benzofuran (16E)
3,3-dimethyl-3H-benzofuran-5-amine
Figure imgf000082_0001
3,3-dimethyl-3H-benzofuran-5-amine
Figure imgf000082_0001
将 3,3-二甲基 -5-硝基 -3H-苯并呋喃 (16D) (0.7 g, 3.6 mmol)溶于甲醇 (20 mL) 中， 加入 钯碳 （20 mg), 在氢气氛围下反应过夜。 将反应液碘硅藻土过滤， 滤液浓缩得到标题化合物 3,3-二甲基 -5-氨基 -3H-苯并呋喃 （16E)， 浅褐色固体（0.56 g， 产率 95%)。  3,3-Dimethyl-5-nitro-3H-benzofuran (16D) (0.7 g, 3.6 mmol) was dissolved in methanol (20 mL), palladium carbon (20 mg) The reaction was overnight. The reaction mixture was filtered with EtOAc EtOAc (EtOAc m.)
¾ NMR (400 MHz, CDC13) δ 6.62-6.59 (m, 1H), 6.51-6.48 (m, 2H), 4.16 (s, 2H), 3.60 (br, 2H): 1.30 (s, 6H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 6.62-6.59 (m, 1H), 6.51-6.48 (m, 2H), 4.16 (s, 2H), 3.60 (br, 2H) : 1.30 (s, 6H).
第五步： 2-氯 -2-[(3,3-二甲基 -3H-苯并呋喃 -5-基)腙基]乙酸乙酯 （16F)  Step 5: 2-Chloro-2-[(3,3-dimethyl-3H-benzofuran-5-yl)indolyl]acetate (16F)
ethyl 2-chloro-2-[(3,3-dimethyl-3H- zono]acetate  Ethyl 2-chloro-2-[(3,3-dimethyl-3H- zono]acetate
Figure imgf000082_0002
Figure imgf000082_0002
将 3,3-二甲基 -5-氨基 -3H-苯并呋喃 （16E) (0.56 g, 3.43 mmol)加入到浓盐酸 （0.82 mL)的 水 (1.4 mL)溶液中， 冷却至 0~-5°C ,滴加亚硝酸钠 (284 mg, 4.12 mmol)水 (0.7 mL)溶液， 滴加完毕后， 在 0°C反应 60分钟， 将该重氮盐溶液滴加到已冷却至 0°C的 2-氯乙酰乙酸乙酯 (565 mg, 3.43 mmol)的乙酸乙酯 (2.7 mL)溶液和乙酸钠 (647 mg, 7.89 mmol) 的水溶液 (1.4 mL) 混合溶液中， 滴加完毕后， 维持 0°C反应 30分钟， 升至室温反应 3小时。 向反应液中加入 乙酸乙酯 （20 mL)和饱和食盐水（30 mL)， 分液， 有机相用无水硫酸钠干燥， 过滤， 减压浓 缩， 残留物用硅胶柱色谱法纯化（乙酸乙酯 /石油醚（v/v) = 0: 1 ~ 1 :9)得到标题化合物 2-氯 -2- [(3,3-二甲基 -3H-苯并呋喃 -5-基)腙基]乙酸乙酯 （16F)， 浅黄色油状物 （300 mg， 产率 30%)。  Add 3,3-dimethyl-5-amino-3H-benzofuran (16E) (0.56 g, 3.43 mmol) to a solution of concentrated hydrochloric acid (0.82 mL) in water (1.4 mL). At 5 ° C, a solution of sodium nitrite (284 mg, 4.12 mmol) in water (0.7 mL) was added dropwise. After the addition was completed, the reaction was carried out at 0 ° C for 60 minutes, and the diazonium salt solution was added dropwise to the cooled to 0 °. a mixed solution of ethyl 2-chloroacetoacetate (565 mg, 3.43 mmol) in ethyl acetate (2.7 mL) and sodium acetate (647 mg, 7.89 mmol) in water (1.4 mL). The reaction was maintained at 0 ° C for 30 minutes and allowed to react to room temperature for 3 hours. Ethyl acetate (20 mL) and saturated aqueous sodium chloride (30 mL) were added to the mixture, and the mixture was evaporated. Ester/petroleum ether (v/v) = 0: 1 ~ 1 : 9) to give the title compound 2-chloro-2-[(3,3-dimethyl-3H-benzofuran-5-yl)indolyl] Ethyl acetate (16F), light yellow oil (300 mg, yield 30%).
第六步： 1-(3,3-二甲基 -3H-苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5-二氢- 1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （16G) ethyl l-(3,3-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4 dihydropyrazolo[3,4-c]pyridine-3-carboxylate The sixth step: 1-(3,3-dimethyl-3H-benzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7 -oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (16G) Ethyl l-(3,3-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4 dihydropyrazolo[3,4-c]pyridine -3-carboxylate
Figure imgf000083_0001
Figure imgf000083_0001
将 2-氯 -2-[(3,3-二甲基 -3H-苯并呋喃 -5-基)腙基]乙酸乙酯 （16F) (300, 1.0 mmol), 3-吗啉- 1-(4-(2-氧代哌啶 -1-基)苯基) -5,6-二氢吡啶 -2(1H)-酮 (If) (500 mg, 1.41 mmol), 碘化钾 （23.4 mg, 0.14 mmol) 和三乙胺 （428 mg, 4.23 mmol), 溶于乙酸乙酯 （50 mL) 中， 升至 80°C反 应过夜， 将反应液冷却至 0°C， 加入盐酸 （4N, 1.8 mL, 7.05 mmol), 室温搅拌反应 lh。 向反 应液中加入饱和食盐水 （30 mL), 分液， 有机相用无水硫酸钠干燥， 过滤， 浓缩， 残留物用 硅胶柱色谱分离提纯 （乙酸乙酯： 石油醚 （v/v) = 1 : 1 -1 :0) 得标题化合物 1-(3,3-二甲基 -3H- 苯并呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 (16G), 浅黄色固体（210mg， 产率 28%)。  2-Chloro-2-[(3,3-dimethyl-3H-benzofuran-5-yl)indolyl]ethyl acetate (16F) (300, 1.0 mmol), 3-morpholine-1 (4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridine-2(1H)-one (If) (500 mg, 1.41 mmol), potassium iodide (23.4 mg, 0.14 Methyl acetate (428 mg, 4.23 mmol), dissolved in ethyl acetate (50 mL), EtOAc (EtOAc) (EtOAc) 7.05 mmol), stir the reaction at room temperature for 1 h. Saturated brine (30 mL) was added to the mixture, and the mixture was evaporated, evaporated, evaporated, evaporated 1 : 1 -1 :0) The title compound 1-(3,3-dimethyl-3H-benzofuran-5-yl)-6-[4-(2-oxopiperidin-1-yl) Phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (16G), pale yellow solid (210 mg, yield 28%) .
^ NMR (400 MHz, CDC13) δ 7.35-7.33 (m, 2Η), 7.29-7.22 (m, 4H), 6.75 (d, 1H), 4.49-4.41 (m: 2H), 4.26 (s, 2H), 4.12 (t, 2H), 3.60-3.56 (m, 2H), 3.31 (t, 2H), 2.57-2.55 (m, 2H), 1.95-1.93 (m, 4H), 1.46-1.42 (m, 3H), 1.35 (s, 6H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.35-7.33 (m, 2Η), 7.29-7.22 (m, 4H), 6.75 (d, 1H), 4.49-4.41 (m : 2H), 4.26 (s, 2H) , 4.12 (t, 2H), 3.60-3.56 (m, 2H), 3.31 (t, 2H), 2.57-2.55 (m, 2H), 1.95-1.93 (m, 4H), 1.46-1.42 (m, 3H) , 1.35 (s, 6H).
第七步： 1-(3,3-二甲基 -3H-苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5-二氢- Step 7: 1-(3,3-Dimethyl-3H-benzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7 -oxo-4,5-dihydro-
1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 16) 1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 16)
l-(3,3-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxamide  L-(3,3-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c Pyridine-3-carboxamide
Figure imgf000083_0002
Figure imgf000083_0002
1-(3,3-二甲基 -3H-苯并呋喃 -5-基) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 1-(3,3-Dimethyl-3H-benzofuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4, 5-dihydro-1H-pyrazole
[3,4-c]吡啶 -3-甲酸乙酯 (16G) (210 mg, 0.4 mmol)溶于 Ν,Ν-二甲基甲酰胺 (5 mL) 中， 加入 甲酰胺 （180 mg, 4 mmol), 甲醇钠 （43.2 mg, 0.8 mmol), 升温至 80°C反应过夜。 将反应液 冷却至室温， 加入水（50 mL), 分液， 水相用乙酸乙酯 （50 mL X 2)萃取， 合并有机相， 有 机相用饱和食盐水 （50 mL) 洗涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 (；甲醇 /二氯甲垸 （v/v) = 0: 1-1 : 19) 得到标题化合物 1-(3,3-二甲基 -3H-苯并呋喃 -5-基;) -6-[4-(2- 氧代哌啶 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 16)， 白色固体 (70 mg, 产率 36 %)。 Ethyl [3,4-c]pyridine-3-carboxylate (16G) (210 mg, 0.4 mmol) was dissolved in EtOAc EtOAc (EtOAc) Sodium methoxide (43.2 mg, 0.8 mmol) was heated to 80 ° C overnight. The reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL X 2). The organic phase was combined and the organic phase was washed with saturated brine (50 mL) The title compound 1-(3,3-dimethyl-3H) was obtained. mjjjjjjjjjj -benzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7-oxo-4,5-dihydro-1H-pyrazole [3,4-c]pyridine-3-carboxamide (compound 16), white solid (70 mg, yield 36%).
^ NMR (400 MHz, CDC13) δ 7.35 (m, 2H), 7.27-725 (m, 4H), 6.86 (s, 1H), 6.79 (d, 1H), 5.46 (s, 1H), 4.29 (s, 2H), 4.11 (t, 2H), 3.61 (m, 2H), 3.37 (t, 2H), 2.57 (m, 2H), 1.94 (m, 4H), 1.37 (s, 6H)。 实施例 17 ^ NMR (400 MHz, CDC1 3 ) δ 7.35 (m, 2H), 7.27-725 (m, 4H), 6.86 (s, 1H), 6.79 (d, 1H), 5.46 (s, 1H), 4.29 (s , 2H), 4.11 (t, 2H), 3.61 (m, 2H), 3.37 (t, 2H), 2.57 (m, 2H), 1.94 (m, 4H), 1.37 (s, 6H). Example 17
1- (苯并呋喃 -5-基) -6-[4-(5-三氟甲基 -2-氧代 -吡啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 17)  1-(benzofuran-5-yl)-6-[4-(5-trifluoromethyl-2-oxo-pyridin-1-yl)phenyl]-7-oxo-4,5-di Hydrogen-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 17)
l-(benzofuran-5-yl)-7-oxo-6-[4-(5-trifluoromethyl-2-oxo-pyridin-2-yl)phenyl]-4,5- dih dro razolo 3 4-c ridine-3-carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[4-(5-trifluoromethyl-2-oxo-pyridin-2-yl)phenyl]-4,5-dih dro razolo 3 4-c ridine- 3-carboxamide
Figure imgf000084_0001
Figure imgf000084_0001
第一步： 1- (苯并呋喃 -5-基) -6-[4-(5-三氟甲基 -2-氧代 -吡啶 -1-基;)苯基] -7-氧代 -4,5-二氢 -1Η- 吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （17B)  First step: 1-(benzofuran-5-yl)-6-[4-(5-trifluoromethyl-2-oxo-pyridin-1-yl;)phenyl]-7-oxo- 4,5-Dihydro-1Η-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (17B)
Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-(5-trifluoromethyl-2-oxo-pyridin-2-yl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxylate  Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-(5-trifluoromethyl-2-oxo-pyridin-2-yl)phenyl]-4,5-dihydropyrazolo[3,4-c] Pyridine-3-carboxylate
Figure imgf000084_0002
Figure imgf000084_0002
将 1-(2,3-二氢苯并呋喃 -5-基) -6-(4-碘苯基 )-7-氧代 -4,5,6,7-四氢 -1Η-吡唑并 [3,4-c]吡啶 -3-甲 酸乙酯 (2C) (2.0 g, 3.78 mmol) 溶于 1,2-二氧六环 (50 mL) 中， 加入 5-三氟甲基吡啶 -2-酮 (1.2 g, 7.56 mmol), 磷酸钾 (1.6 g, 7.56 mmol), 碘化酮 (100 mg)和反 -(1R,2R)-N,N'-二甲基- 1,2-环戊二胺 （100 mg), 在氮气氛围下， 升温至 80°C反应 10小时。 将反应液冷却至室温， 加 入水（50 mL)， 用乙酸乙酯 （50 mL X 2)萃取， 合并有机相， 有机相用无水硫酸钠干燥， 浓 缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯）得到标题化合物 1- (苯并呋喃 -5-基;) -6-[4-(5-三 氟甲基 -2-氧代 -吡啶 -1-基)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （17B)， 白 色固体（1.0 g， 产率 48%)。 1-(2,3-Dihydrobenzofuran-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-1Η-pyrazole Ethyl [3,4-c]pyridine-3-carboxylate (2C) (2.0 g, 3.78 mmol) dissolved in 1,2-dioxane (50 mL). -ketone (1.2 g, 7.56 mmol), potassium phosphate (1.6 g, 7.56 mmol), iodinated ketone (100 mg) and trans-(1R,2R)-N,N'-dimethyl-1,2-ring Pentamethylenediamine (100 mg) was heated to 80 ° C for 10 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc. Ethyl acetate) gave the title compound 1- (benzofuran-5-yl;) -6-[4-(5- Ethyl fluoromethyl-2-oxo-pyridin-1-yl)phenyl]-7-oxo-4,5-dihydro-IH-pyrazolo[3,4-c]pyridine-3-carboxylate (17B), White solid (1.0 g, yield 48%).
第二步： 1- (苯并呋喃 -5-基) -6-[4-(5-三氟甲基 -2-氧代 -吡啶 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H- 吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 17)  The second step: 1-(benzofuran-5-yl)-6-[4-(5-trifluoromethyl-2-oxo-pyridin-1-yl;)phenyl]-7-oxo- 4,5-Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 17)
l-(benzofuran-5-yl)-7-oxo-6-[4-(5-trifluoromethyl-2-oxo-pyridin-2-yl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[4-(5-trifluoromethyl-2-oxo-pyridin-2-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine -3-carboxamide
Figure imgf000085_0001
Figure imgf000085_0001
1- (苯并呋喃 -5-基) -6-[4-(5-三氟甲基 -2-氧代 -吡啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3, 4-c]吡啶 -3-甲酸乙酯 (17B) (950 mg, 1.68 mmol)溶于 Ν,Ν-二甲基甲酰胺 (10 mL) 中， 加入 甲酰胺 （757 mg, 16.8 mmol), 甲醇钠 （364 mg, 6.72 mmol), 升温至 80°C反应 3小时。 将反 应液冷却至室温， 加入水 （50 mL), 分液， 水相用乙酸乙酯 （50 mL X 2)萃取， 合并有机 相， 有机相用饱和食盐水（50 mL)洗涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离 提纯 （甲醇 /二氯甲垸 （v/v) = 0: 1-1 : 19) 得到标题化合物 1-(3,3-二甲基 -3H-苯并呋喃 -5-基) -6- [4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 16)， 白色 固体（200 mg, 产率 22%)。  1-(benzofuran-5-yl)-6-[4-(5-trifluoromethyl-2-oxo-pyridin-1-yl)phenyl]-7-oxo-4,5-di Hydrogen-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (17B) (950 mg, 1.68 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (10 mL) The amide (757 mg, 16.8 mmol), sodium methoxide (364 mg, 6.72 mmol) was warmed to 80 ° C for 3 hours. The reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL X 2). The organic phase was combined and the organic phase was washed with saturated brine (50 mL) The title compound 1-(3,3-dimethyl-3H- was obtained as the title compound (m.p.). Benzofuran-5-yl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3, 4-c]pyridine-3-carboxamide (Compound 16), white solid (200 mg, yield 22%).
¾ NMR (400 MHz, CDC13) δ 7.63 (s, IH), 7.44-7.42 (m, 3H), 7.34-7.29 (m, 3H), 7.28 (m, 1H): 6.85 (s, IH), 6.80 (d, IH), 6.72 (d, IH), 5.50 (s, IH), 4.62 (t, 2H), 4.17 (t, 2H), 3.42 (t, 2H), 3.26 (t, 2H)。 实施例 18 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.63 (s, IH), 7.44-7.42 (m, 3H), 7.34-7.29 (m, 3H), 7.28 (m, 1H) : 6.85 (s, IH), 6.80 (d, IH), 6.72 (d, IH), 5.50 (s, IH), 4.62 (t, 2H), 4.17 (t, 2H), 3.42 (t, 2H), 3.26 (t, 2H). Example 18
l-(4-氟-苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡 啶 -3-甲酰胺 （化合物 18)  1-(4-Fluoro-benzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5-dihydro- IH-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 18)
l-(4-fluorobenzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide  L-(4-fluorobenzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide
Figure imgf000085_0002
Figure imgf000085_0002
Figure imgf000086_0001
第一步： 2-溴 -1-(2-溴乙氧基) -3-氟苯（18B)
Figure imgf000086_0001
First step: 2-bromo-1-(2-bromoethoxy)-3-fluorobenzene (18B)
2-bromo- 1 -(2-bromoethoxy)-3-fluorobenzene
Figure imgf000086_0002
2-bromo-1 -(2-bromoethoxy)-3-fluorobenzene
Figure imgf000086_0002
将 3-氟 -2-溴苯酚 (10.0 g, 0.05 mol) 加入乙腈 (100 mL) 溶液中， 加入碳酸钾 (15.2 g, 0.11 mol)和 1,2-二溴乙垸 (19.7 g, 0.11 mol), 升至 50°C反应 32小时。 将反应液抽滤， 滤饼用 乙酸乙酯 (20 mL X 3)洗涤， 合并滤液， 加入水（50 mL), 分液， 水相用乙酸乙酯 （50 mL) 萃取， 合并有机相， 有机相用饱和食盐水 （50 mL X 2) 洗涤， 无水硫酸钠干燥， 浓缩， 残 留物用硅胶柱色谱分离提纯 （石油醚）得到标题化合物 2-溴 -1-(2-溴乙氧基) -3-氟苯 （18B)， 无 水液体（9.0 g， 产率 60%)。  Add 3-fluoro-2-bromophenol (10.0 g, 0.05 mol) to acetonitrile (100 mL), add potassium carbonate (15.2 g, 0.11 mol) and 1,2-dibromoacetamidine (19.7 g, 0.11 mol) ), raised to 50 ° C for 32 hours. The reaction mixture was filtered with EtOAc (EtOAc) (EtOAc)EtOAc. The mixture was washed with EtOAc (EtOAc m. 3-fluorobenzene (18B), anhydrous liquid (9.0 g, yield 60%).
¾ NMR (400 MHz, CDC13) δ 7.25 (m, 1H), 6.82 (m, 1H), 6.78 (m, 1H), 4.35 (t, 2H), 3.68 (t,3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.25 (m, 1H), 6.82 (m, 1H), 6.78 (m, 1H), 4.35 (t, 2H), 3.68 (t,
2H)。 2H).
第二步： 4-氟苯并呋喃 （18C)  Second step: 4-fluorobenzofuran (18C)
4-fluorobenzofuran
Figure imgf000086_0003
4-fluorobenzofuran
Figure imgf000086_0003
将 2-溴 - 1-(2-溴乙氧基) -3-氟苯 （18B) (4 g, 13.4 mmol) 溶于四氢呋喃溶液 （20 mL) 中， 冷却至 -78 °C， 在氮气氛围下， 滴加丁基锂 （9.2 mL, 14.7 mmol) , 维持 -78°C反应 2小 时。 在 -78°C下， 向反应液中加入水（10 mL) 淬灭反应， 分液， 水相用乙酸乙酯 （10 mL X 3) 萃取， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚） 得到标题化合物 4-氟苯并呋喃 （18C)， 无水液体（1.4 g, 产率 76%)。  2-Bromo-1-(2-bromoethoxy)-3-fluorobenzene (18B) (4 g, 13.4 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to -78 ° C Then, butyllithium (9.2 mL, 14.7 mmol) was added dropwise, and the reaction was maintained at -78 °C for 2 hours. The reaction mixture was quenched with water (10 mL). Column chromatography purification (petroleum ether) gave the title compound 4-fluorobenzofuran (18C) as an anhydrous liquid (1.4 g, yield 76%).
第三步： 4-氟 -5-溴苯并呋喃 （18D)  Step 3: 4-Fluoro-5-bromobenzofuran (18D)
4-fluoro-5-bromobenzofuran
Figure imgf000087_0001
4-fluoro-5-bromobenzofuran
Figure imgf000087_0001
将 4-氟苯并呋喃 (18C) (3.4 g, 24.6 mmol) 溶于乙腈 (30 mL)溶液中， 冷却至 0°C， 加入 N-溴代丁二酰亚胺 （4.8 g, 27.1 mmol), 保持 0°C反应 30分钟， 再升至室温反应 2小时。 将反应 液浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚）得到标题化合物 4-氟 -5-溴苯并呋喃 （18D)， 浅黄色固体（5.2 g， 产率 97%)。  4-Fluorobenzofuran (18C) (3.4 g, 24.6 mmol) was dissolved in acetonitrile (30 mL), cooled to 0 ° C, then N-bromosuccinimide (4.8 g, 27.1 mmol) The reaction was kept at 0 ° C for 30 minutes and then raised to room temperature for 2 hours. The reaction mixture was concentrated and purified mjjjjlililililililililililililili
^ NMR (400 MHz, CDC13) δ 7.26-7.24 (m, 1Η), 6.49 (d, 1H), 4.64 (t, 2H), 3.28 (t, 2H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.26-7.24 (m, 1 Η), 6.49 (d, 1H), 4.64 (t, 2H), 3.28 (t, 2H).
第四步： 4-氟 -5-氨基苯并呋喃 （18E)  Step 4: 4-Fluoro-5-aminobenzofuran (18E)
4-fluoro-5-aminobenzofuran  4-fluoro-5-aminobenzofuran
Figure imgf000087_0002
Figure imgf000087_0002
将 4-氟 -5-溴苯并呋喃 (18D) (5.2 g, 24 mmol) 溶于氨水 (4.08 g, 240 mmol) 中， 加入 铜 （1.82 g, 28.9 mmol), 在封管中， 升至 100°C反应过夜。 将反应液过滤， 得固体 4-氟 -5-氨 基苯并呋喃 （18E)， 将滤液浓缩， 无水硫酸钠干燥， 残留物用硅胶柱色谱分离提纯 （石油醚： 乙酸乙酯 (v/v) = 10: 1-5: 1)得标题化合物 4-氟 -5-氨基苯并呋喃 (18E), 浅黄色固体 （共计 1.6 g， 产率 44%)。  Dissolve 4-fluoro-5-bromobenzofuran (18D) (5.2 g, 24 mmol) in aqueous ammonia (4.08 g, 240 mmol), add copper (1.82 g, 28.9 mmol), in a sealed tube, to The reaction was carried out at 100 ° C overnight. The reaction mixture was filtered to give EtOAc (EtOAc) (EtOAc). = 10: 1-5: 1) The title compound 4-fluoro-5-aminobenzofuran (18E) was obtained as pale yellow solid (yield: 1.6 g, yield 44%).
¾ NMR (400 MHz, CDC13) δ 6.62 (t, 1H), 6.42 (d, 1H), 4.56 (t, 2H), 3.86 (br, 2H), 3.22 (t,3⁄4 NMR (400 MHz, CDC1 3 ) δ 6.62 (t, 1H), 6.42 (d, 1H), 4.56 (t, 2H), 3.86 (br, 2H), 3.22 (t,
2H)。 2H).
第五步： 2-氯 -2-(2-(4-氟苯并呋喃 -5-基)腙基)乙酸乙酯 （18F)  Step 5: 2-Chloro-2-(2-(4-fluorobenzofuran-5-yl)indolyl)acetate (18F)
ethyl 2-chloro-2-(2-(4-fluorobenzofuran-5-yl) hydrazono)acetate  Ethyl 2-chloro-2-(2-(4-fluorobenzofuran-5-yl) hydrazono)acetate
Figure imgf000087_0003
Figure imgf000087_0003
在第一个反应瓶中， 加入 4-氟 -5-氨基苯并呋喃 （18E) (500 mg, 3.26 mmol), 水（10 mL) 和浓盐酸 (0.79 mL, 9.45 mmol )， 冷却反应液至 -5°C -0°C， 滴加亚硝酸钠 (269.9 mg, 3.91 mmol) 的水 （5 mL) 溶液， 维持 0°C搅拌反应半小时； 在另一反应瓶中， 加入 2-氯乙酰乙酸乙 酯 (536.6 mg, 3.26 mmol), 乙酸钠 (615 mg, 7.50 mmol), 水 (5 mL)和乙酸乙酯 (5 mL), 降 温至 0°C， 滴加第一个反应瓶中的反应液， 0°C下搅拌反应 2小时。 向反应液中加入乙酸乙酯 (10 mL) , 分液， 水相用乙酸乙酯 （10 mL X 2) 萃取， 合并有机相， 用无水硫酸钠干燥， 浓 缩， 残留物用硅胶柱色谱分离提纯 （石油醚 /乙酸乙酯 （v/v) = 10: 1 ~ 5: 1)得标题化合物 2-氯 -2- (2-(4-氟苯并呋喃 -5-基;)腙基)乙酸乙酯 （18F)， 浅黄色油状物 （600 mg， 产率 64%)。 In the first reaction flask, add 4-fluoro-5-aminobenzofuran (18E) (500 mg, 3.26 mmol), water (10 mL) and concentrated hydrochloric acid (0.79 mL, 9.45 mmol). -5 ° C -0 ° C, dropwise addition of sodium nitrite (269.9 mg, 3.91 mmol) in water (5 mL), stirring at 0 ° C for half an hour; in another reaction bottle, adding 2-chloroacetyl Ethyl acetate (536.6 mg, 3.26 mmol), sodium acetate (615 mg, 7.50 mmol), water (5 mL) and ethyl acetate (5 mL), cooled to 0 ° C, and added dropwise to the first reaction flask The reaction solution was stirred at 0 ° C for 2 hours. Adding ethyl acetate to the reaction solution (10 mL), EtOAc (EtOAc) (EtOAc (EtOAc) (v/v) = 10: 1 ~ 5: 1) The title compound 2-chloro-2-(2-(4-fluorobenzofuran-5-yl)-yl)acetate (18F), Yellow oil (600 mg, yield 64%).
第六步： -(4-氟-苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （18G)  Step 6: -(4-Fluoro-benzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7-oxo-4,5 -Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (18G)
Ethyl l-(4-fluorobenzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxylate  Ethyl l-(4-fluorobenzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3- Carboxylate
Figure imgf000088_0001
Figure imgf000088_0001
将 2-氯 -2-(2-(4-氟苯并呋喃 -5-基)腙基)乙酸乙酯 （18F) (600, 2.1 mmol)溶于乙酸乙酯 （30 mL) 中， 加入 3-吗啉 -1-(4-(2-氧代哌啶 -1-基)苯基) -5,6-二氢吡啶 -2(1H)-酮 （If) (892.6 mg, 2.52 mmol), 碘化钾 (34.9 mg, 0.21 mmol)和三乙胺 (637.5 mg, 6.3 mmol), 在氮气氛围下， 升温 至回流， 反应 20小时， 将反应液冷却至 0°C， 加入盐酸 （4N, 20 mL), 室温搅拌反应 2h。 将反 应液分液， 有机相用无水硫酸钠干燥， 过滤， 浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙 酯） 得标题化合物 1-(4-氟-苯并呋喃 -5-基；) -6-[4-(2-氧代哌啶 -1-基；)苯基] -7-氧代 -4,5-二氢 -1H-吡 唑并 [3,4-c]吡啶 -3-甲酸乙酯 （18G)， 浅黄色固体（180 mg， 产率 15%)。  Ethyl 2-chloro-2-(2-(4-fluorobenzofuran-5-yl)indenyl)acetate (18F) (600, 2.1 mmol) was dissolved in ethyl acetate (30 mL) -morpholin-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridine-2(1H)-one (If) (892.6 mg, 2.52 mmol), Potassium iodide (34.9 mg, 0.21 mmol) and triethylamine (637.5 mg, 6.3 mmol) were heated to reflux under a nitrogen atmosphere for 20 hours. The reaction mixture was cooled to 0 ° C, and hydrochloric acid (4N, 20 mL) was added. The reaction was stirred at room temperature for 2 h. The reaction mixture was separated, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -6-[4-(2-oxopiperidin-1-yl;)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine- Ethyl 3-carboxylate (18G), light yellow solid (180 mg, yield 15%).
^ NMR (400 MHz, CDC13) δ 7.35-7.33 (m, 2Η), 7.25-7.23 (m, 3H), 6.61 (d, 1H), 4.65 (t, 2H), 4.46 (q, 2H), 4.13 (t, 2H), 3.60 (m, 2H), 3.29 (m, 4H), 2.57 (m, 2H), 1.94 (m, 4H), 1.43 (m, 3H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.35-7.33 (m, 2Η), 7.25-7.23 (m, 3H), 6.61 (d, 1H), 4.65 (t, 2H), 4.46 (q, 2H), 4.13 (t, 2H), 3.60 (m, 2H), 3.29 (m, 4H), 2.57 (m, 2H), 1.94 (m, 4H), 1.43 (m, 3H).
第七步： -(4-氟-苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 18)  Step 7: -(4-Fluoro-benzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7-oxo-4,5 -Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 18)
l-(4-fluorobenzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide  L-(4-fluorobenzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide
Figure imgf000088_0002
Figure imgf000088_0002
将 1-(4-氟-苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c] 吡啶 -3-甲酸乙酯 (18G) (180 mg, 0.347 mmol) 溶于 Ν,Ν-二甲基甲酰胺 (5 mL) 中， 加入甲 酰胺 （125 mg, 2.78 mmol), 甲醇钠 （56.3 mg, 1.04 mmol), 在氮气氛围下， 升温至 80°C反 应 6小时。 将反应液浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯） 得到标题化合物 1-(4-氟- 苯并呋喃 -5-基;) -6-[4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 (化合物 18)， 白色固体（80 mg, 产率 47 %)。 1-(4-Fluoro-benzofuran-5-yl;)-6-[4-(2-oxopiperidin-1-yl;)phenyl]-7-oxo-4,5-di Hydrogen-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (18G) (180 mg, 0.347 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (5 mL) Amide (125 mg, 2.78 mmol), sodium methoxide (56.3 mg, 1.04 mmol), heated to 80 ° C under nitrogen It should be 6 hours. The reaction mixture was concentrated, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -1-yl;)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 18), white solid (80 mg , yield 47%).
^ NMR (400 MHz, CDC13) δ 7.36-7.33 (m, 2Η), 7.25-7.20 (m, 3H), 6.81 (br, 1H), 6.64 (d, 1H) 5.44 (br, 1H), 4.67 (t, 2H), 4.12 (t, 2H), 3.60 (m, 2H), 3.40-3.26 (m, 4H), 2.59 (m, 2H), 1.94 (m, 4H)。 实施例 19 ^ NMR (400 MHz, CDC1 3 ) δ 7.36-7.33 (m, 2Η), 7.25-7.20 (m, 3H), 6.81 (br, 1H), 6.64 (d, 1H) 5.44 (br, 1H), 4.67 ( t, 2H), 4.12 (t, 2H), 3.60 (m, 2H), 3.40-3.26 (m, 4H), 2.59 (m, 2H), 1.94 (m, 4H). Example 19
l-(2,3-二氢苯并呋喃 -5-基) -3- (羟甲基) -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c]吡 啶 -7-酮 （化合物 19)  L-(2,3-Dihydrobenzofuran-5-yl)-3-(hydroxymethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5- Dihydropyrazolo[3,4-c]pyridine-7-one (Compound 19)
l-(2,3-dihydrobenzofuran-5-yl)-3-(hydroxymethyl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin-7-one  L-(2,3-dihydrobenzofuran-5-yl)-3-(hydroxymethyl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin -7-one
Figure imgf000089_0001
Figure imgf000089_0001
7B 化合物 19  7B Compound 19
第一步： 1-(2,3-二氢苯并呋喃 -5-基) -3- (羟甲基) -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 First step: 1-(2,3-dihydrobenzofuran-5-yl)-3-(hydroxymethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl] 4,5-dihydropyrazole
[3,4-c]吡啶 -7-酮 （化合物 19) [3,4-c]pyridine-7-one (Compound 19)
l-(2,3-dihydrobenzofuran-5-yl)-3-(hydroxymethyl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin-7-one  L-(2,3-dihydrobenzofuran-5-yl)-3-(hydroxymethyl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin -7-one
Figure imgf000089_0002
Figure imgf000089_0002
将 1-(2,3-二氢苯并呋喃 -5-基) -7-氧代 -6-[4-(2-氧代哌啶 -1-基)苯基] -4,5,6,7-四氢 -1H-吡唑 [3,4-c]吡啶 -3-甲酸乙酯 （7B) (2 g, 4 mmol)悬浮于无水甲醇 （20 mL) 中， 分批加入硼氢化钠 (2.57 g, 68 mmol), 完成后加热至 40°C反应 3h,冰浴冷却， 滴加饱和氯化铵 （100 mL), 依次用 乙酸乙酯 （50 mL), 二氯甲垸 （20 mL X 2) 萃取， 合并有机层， 有机相用饱和氯化钠 （20 mL X 2) 洗涤， 无水硫酸钠干燥， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯）得 标题化合物 1-(2,3-二氢苯并呋喃 -5-基) -3- (羟甲基) -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c]吡啶 -7-酮 (化合物 19)， 浅黄色固体 (1.2g, 产率 66%)。 1-(2,3-Dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6 , 7-tetrahydro-1H-pyrazole [3,4-c]pyridine-3-carboxylic acid ethyl ester (7B) (2 g, 4 mmol) was suspended in anhydrous methanol (20 mL). Sodium (2.57 g, 68 mmol), heated to 40 ° C for 3 h after completion, cooled in an ice bath, and saturated ammonium chloride (100 mL) was added dropwise. Ethyl acetate (50 mL), EtOAc (EtOAc (EtOAc)EtOAc. The title compound (1-ethyl acetate) was purified by silica gel column chromatography to give the title compound 1-(2,3-dihydrobenzofuran-5-yl)-3-(hydroxymethyl)-6-[4-(2-oxygen) 1-(Piperidine)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin-7-one (Compound 19), pale yellow solid (1.2 g, yield 66%).
¾ NMR (400 MHz, CDC13) δ 7.33-7.35 (m, 3H), 7.26-7.21 (m, 3H), 6.77 (d, 1H), 4.79 (s, 2H), 4.59 (t, 2H), 4.15-4.08 (m, 2H), 3.59-3.60 (m, 2H), 3.22 (t, 2H), 3.05 (t, 2H), 2.56-2.58 (m, 2H), 2.05 (m, 1H), 1.98-1.89 (m, 4H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.33-7.35 (m, 3H), 7.26-7.21 (m, 3H), 6.77 (d, 1H), 4.79 (s, 2H), 4.59 (t, 2H), 4.15 -4.08 (m, 2H), 3.59-3.60 (m, 2H), 3.22 (t, 2H), 3.05 (t, 2H), 2.56-2.58 (m, 2H), 2.05 (m, 1H), 1.98-1.89 (m, 4H).
LC-MS:[M+1] 459.3 实施例 20  LC-MS: [M+1] 459.3 Example 20
l-(2,3-二氢苯并呋喃 -5-基) -3-(l-羟乙基 )-6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c] 吡啶 -7-酮 （化合物 20)  L-(2,3-Dihydrobenzofuran-5-yl)-3-(l-hydroxyethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-4, 5-dihydropyrazolo[3,4-c]pyridin-7-one (Compound 20)
l-(2,3-dihydrobenzofuran-5-yl)-3-(l-hydroxyethyl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin-7-one  L-(2,3-dihydrobenzofuran-5-yl)-3-(l-hydroxyethyl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c ]pyridin-7-one
Figure imgf000090_0001
第一步： 1-(2,3-二氢苯并呋喃 -5-基;) -7-氧代 -6-[4-(2-氧代 -1-哌啶)苯基] -4,5- c]吡啶 -3-醛（20B)
Figure imgf000090_0001
First step: 1-(2,3-dihydrobenzofuran-5-yl;)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4, 5- c]pyridine-3-aldehyde (20B)
l-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carbaldehyde  L-(2,3-dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3 -carbaldehyde
Figure imgf000090_0002
Figure imgf000090_0002
将 1-(2,3-二氢苯并呋喃 -5-基) -3- (羟甲基) -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c 吡啶 -7-酮 （1 g, 2.18 mmol)溶于干燥的二氯甲垸（20 mL) 中， 在氮气保护下， 冰浴冷却至 0 V， 加入戴斯 -马丁氧化剂 （1.02 g, 2.40 mmol)， 0°C反应 2h， 加入饱和碳酸氢钠 （10 mL)， 分 液， 水层用二氯甲垸 （20 mL X 2)萃取， 合并有机层， 硅藻土过滤， 无水硫酸钠干燥， 减 压浓缩得粗品用硅胶柱色谱分离提纯 （乙酸乙酯）得标题化合物 1-(2,3-二氢苯并呋喃 -5-基；) -7- 氧代 -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c]吡啶 -3-醛 （20B)， 白色固体 （600 mg, 产率 60%)。 1-(2,3-Dihydrobenzofuran-5-yl)-3-(hydroxymethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5 -dihydropyrazolo[3,4-c Pyridine-7-one (1 g, 2.18 mmol) was dissolved in dry methylene chloride (20 mL). The reaction was carried out at 0 ° C for 2 h. EtOAc (EtOAc) (EtOAc) The residue was concentrated to give purified crystals eluted eluted eluted elut elut elut elut elut elut elut 2-oxo-1-piperidine)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3-aldehyde (20B), white solid (600 mg, yield 60%) .
¾ NMR (400 MHz, CDC13) δ 10.13 (s, 1H), 7.40-7.39 (m, 1H), 7.36-7.24 (m, 5H), 6.81 (d, 1H), 4.62 (t, 2H), 4.13 (t, 2H), 3.60-3.58 (m, 2H), 3.33 (t, 2H), 3.25 (t, 2H), 2.57-2.54 (m, 2H), 1.99- 1.88 (m, 4H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 10.13 (s, 1H), 7.40-7.39 (m, 1H), 7.36-7.24 (m, 5H), 6.81 (d, 1H), 4.62 (t, 2H), 4.13 (t, 2H), 3.60-3.58 (m, 2H), 3.33 (t, 2H), 3.25 (t, 2H), 2.57-2.54 (m, 2H), 1.99- 1.88 (m, 4H).
LC-MS: [M+l] 457.1  LC-MS: [M+l] 457.1
第二步： l-(2,3-二氢苯并呋喃 -5-基) -3-(l-羟乙基 )-6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑 并 [3,4-c]吡啶 -7-酮（化合物 20)  Second step: l-(2,3-dihydrobenzofuran-5-yl)-3-(l-hydroxyethyl)-6-[4-(2-oxo-1-piperidine)phenyl -4,5-Dihydropyrazolo[3,4-c]pyridin-7-one (Compound 20)
l-(2,3-dihydrobenzofuran-5-yl)-3-(l-hydroxyethyl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin-7-one  L-(2,3-dihydrobenzofuran-5-yl)-3-(l-hydroxyethyl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c ]pyridin-7-one
Figure imgf000091_0001
Figure imgf000091_0001
将 1-(2,3-二氢苯并呋喃 -5-基;) -7-氧代 -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c]吡 啶 -3-酸 （4 g, 8.76 mmol) 溶于干燥的二氯甲垸 （150 mL) 中， 氮气保护下用干冰丙酮冷却 至 -40°C， 慢慢滴加甲基溴化镁 （1N的四氢呋喃溶液 10.5 mL, 10.5 mmol), 滴完后自然升温 至室温反应 2h, 加入饱和氯化铵溶液 （10 mL) , 分液， 水层用二氯甲垸 （50 mL X 2) 萃 取， 合并有机层， 饱和氯化钠 （30 mL X 2) 洗涤， 无水硫酸钠干燥， 减压浓缩， 残留物用 硅胶柱色谱分离提纯 （乙酸乙酯）得标题化合物 1-(2,3-二氢苯并呋喃 -5-基) -3-(1-羟乙基 )-6-[4- (2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c]吡啶 -7-酮 （化合物 20)， 浅黄色固体（2.8g， 产率 68 %)。  1-(2,3-Dihydrobenzofuran-5-yl;)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5-di Hydropyrazolo[3,4-c]pyridine-3-acid (4 g, 8.76 mmol) was dissolved in dry methylene chloride (150 mL) and cooled to -40 ° C with dry ice acetone. Add methyl magnesium bromide (10.5 mL of 1N tetrahydrofuran solution, 10.5 mmol), and then warm to room temperature for 2 h. Add saturated ammonium chloride solution (10 mL). The guanidine (50 mL X 2 ) was extracted, and the combined organic layer was evaporated. The title compound 1-(2,3-dihydrobenzofuran-5-yl)-3-(1-hydroxyethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl] 4,5-Dihydropyrazolo[3,4-c]pyridin-7-one (Compound 20), pale yellow solid (2.8 g, yield 68%).
^ NMR (400 MHz, CDC13) δ 7.35-7.33 (m, 3Η), 7.26-7.19 (m, 3H), 6.76 (d, 1H), 5.09 (q, 1H), 4.58 (t, 2H), 4.10 (t, 2H), 3.60 (m, 2H), 3.22 (t, 2H), 3.15-3.04 (m, 2H), 2.56 (m, 2H), 1.94-1.93 (m, 5H), 1.63 (d, 3H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.35-7.33 (m, 3Η), 7.26-7.19 (m, 3H), 6.76 (d, 1H), 5.09 (q, 1H), 4.58 (t, 2H), 4.10 (t, 2H), 3.60 (m, 2H), 3.22 (t, 2H), 3.15-3.04 (m, 2H), 2.56 (m, 2H), 1.94-1.93 (m, 5H), 1.63 (d, 3H ).
LC-MS: [M+l] 473.1 实施例 21  LC-MS: [M+l] 473.1 Example 21
1- (苯并呋喃 -5-基) -6-[3-氟 -4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡 啶 -3-甲酰胺 l-(benzofuran-5-yl)-7-oxo-6-[3-fluoro-4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide 1-(benzofuran-5-yl)-6-[3-fluoro-4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5-dihydro-IH -pyrazolo[3,4-c]pyridine-3-carboxamide L-(benzofuran-5-yl)-7-oxo-6-[3-fluoro-4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3 -carboxamide
Figure imgf000092_0001
Figure imgf000092_0001
第一步： l-(2-氟 -4-硝基苯基)哌啶 -2-酮 （21B)  First step: l-(2-Fluoro-4-nitrophenyl)piperidin-2-one (21B)
l-(2-fluoro-4-nitrophenyl)piperidin-2-
Figure imgf000092_0002
L-(2-fluoro-4-nitrophenyl)piperidin-2-
Figure imgf000092_0002
将哌啶-酮 （4.4 g, 0.11 mol)溶于 N-甲基吡咯垸酮 （300 mL) 中， 冷却至 0°C， 分批加入 氰化钠 （9.9 g, 0.1 mol), 搅拌反应半小时， 滴加 3,4-二氟硝基苯 （15.9 g, 0.1 mol), 升至常 温反应过夜。 向反应液中缓慢加入水（300 mL)和乙酸乙酯 （500 mL), 分液， 有机层用饱和 食盐水 （300 mL) 洗涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙 酯： 石油醚（v/v) = 1 :9-1 :3) 的到标题化合物 1-(2-氟 -4-硝基苯基；)哌啶 -2-酮 （21B)， 浅黄色固 体（4.5 g, 产率 19%)。  Piperidine-ketone (4.4 g, 0.11 mol) was dissolved in N-methylpyrrolidone (300 mL), cooled to 0 ° C, sodium cyanide (9.9 g, 0.1 mol) was added in portions, and the reaction was stirred half. In an hour, 3,4-difluoronitrobenzene (15.9 g, 0.1 mol) was added dropwise, and the mixture was allowed to react to room temperature overnight. Water (300 mL) and ethyl acetate (500 mL) were added to the reaction mixture, and the mixture was evaporated. Purification (ethyl acetate: petroleum ether (v/v) = 1 : 9-1 : 3) to the title compound 1-(2-fluoro-4-nitrophenyl;)piperidin-2-one (21B) , pale yellow solid (4.5 g, yield 19%).
^ NMR (400 MHz, CDC13) δ 8.10-8.03 (m, 2Η), 7.52-7.48 (m, 1H), 3.65 (t, 2H), 2.62-2.59 (m, 2H), 2.05-1.96 (m, 4H)0 ^ NMR (400 MHz, CDC1 3 ) δ 8.10-8.03 (m, 2Η), 7.52-7.48 (m, 1H), 3.65 (t, 2H), 2.62-2.59 (m, 2H), 2.05-1.96 (m, 4H) 0
第二步： l-(2-氟 -4-氨基苯基)哌啶 -2-酮 （21C)  Step 2: l-(2-Fluoro-4-aminophenyl)piperidin-2-one (21C)
l-(2-fluoro-4-aminophenyl)piperidin-2-one  L-(2-fluoro-4-aminophenyl)piperidin-2-one
Figure imgf000092_0003
Figure imgf000092_0003
将 1-(2-氟 -4-硝基苯基)哌啶 -2-酮 （21B) (3.5 g, 14.7mmol) 溶于乙醇 （30 mL) 中， 加入 九水硫化钠 （12.6 g, 36.7mmol), 升温至 80°C， 反应 1小时。 将反应液冷却至常温， 加入水 (100 mL) 和乙酸乙酯 （50 mL), 分液， 有机层用饱和食盐水（50 mL) 洗涤， 无水硫酸钠干 燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯： 石油醚（v/v) = 1 :99-2:3) 的到标题化 合物 1 -(2-氟 -4-氨基苯基;)哌啶 -2-酮 （21C)， 浅黄色固体（1.1 g， 产率 37%)。 1-(2-Fluoro-4-nitrophenyl)piperidin-2-one (21B) (3.5 g, 14.7 mmol) was dissolved in ethanol (30 mL) Sodium sulfide nonahydrate (12.6 g, 36.7 mmol) was heated to 80 ° C for 1 hour. The reaction solution was cooled to room temperature, and water (100 mL) and ethyl acetate (50 mL) was added, and the organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate Purification by chromatography (ethyl acetate: petroleum ether (v/v) = 1 : 99-2:3) to the title compound 1-(2-fluoro-4-aminophenyl;)piperidin-2-one (21C ), pale yellow solid (1.1 g, yield 37%).
^ NMR (400 MHz, CDC13) δ 6.97 (t, 1Η), 6.44 (d, 2H), 3.53 (m, 2H), 2.54 (m, 2H), 1.93-1.92 (m, 4H)。 ^ NMR (400 MHz, CDC1 3 ) δ 6.97 (t, 1 Η), 6.44 (d, 2H), 3.53 (m, 2H), 2.54 (m, 2H), 1.93-1.92 (m, 4H).
第三步： 1 -(2-氟 -4-碘苯基)哌啶 -2-酮 （21D)  Step 3: 1 -(2-Fluoro-4-iodophenyl)piperidin-2-one (21D)
l-(2-fluoro-4-iodophenyl)piperidin-2-o  L-(2-fluoro-4-iodophenyl)piperidin-2-o
Figure imgf000093_0001
Figure imgf000093_0001
将 1-(2-氟 -4-氨基苯基)哌啶 -2-酮 （21C) (1.1 g, 5.28 mmol)溶于盐酸 （1.32 mL, 15.84 mmol) 的水（3 mL) 溶液中， 冷却至 0~-5°C， 滴加亚硝酸钠 （546 mg, 7.92 mmol) 的水（3 mL)溶 液， 保持 0°C搅拌反应半小时， 加入碘化钾 （4.38 g, 26.40 mmol) 的水（15 mL)溶液， 升至 常温反应 1小时。 向反应液中加入水（50 mL)和乙酸乙酯 （50 mL)， 分液， 有机层依次用 10% 氢氧化钠溶（50 mL), 饱和食盐水（50 mL)洗涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱 色谱分离提纯 （乙酸乙酯： 石油醚（v/v) = 1 :99-1 :9) 的到标题化合物 1-(2-氟 -4-碘苯基；)哌啶 -2- 酮 （21D)， 暗色固体（1.1 g, 产率 66%)。  1-(2-Fluoro-4-aminophenyl)piperidin-2-one (21C) (1.1 g, 5.28 mmol) was dissolved in water (3 mL) (3 mL) To 0~-5 ° C, a solution of sodium nitrite (546 mg, 7.92 mmol) in water (3 mL) was added dropwise, and the mixture was stirred at 0 ° C for half an hour, and potassium iodide (4.38 g, 26.40 mmol) was added. (mL) solution, raised to room temperature for 1 hour. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the mixture was separated, and then organic layer was washed with 10% sodium hydroxide (50 mL) and brine (50 mL) The title compound 1-(2-fluoro-4-iodophenyl) was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) = 1:99-1:9). Piperidin-2-one (21D), dark solid (1.1 g, yield 66%).
^ NMR (400 MHz, CDC13) δ 7.52-7.50 (m, 2Η), 6.99 (t, 1H), 3.58-3.55 (m, 2H), 2.56 (m, 2H), 1.96-1.95 (m, 4H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.52-7.50 (m, 2Η), 6.99 (t, 1H), 3.58-3.55 (m, 2H), 2.56 (m, 2H), 1.96-1.95 (m, 4H) .
第四步： 1- (苯并呋喃 -5-基;) -6-[3-氟 -4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （21E)  The fourth step: 1-(benzofuran-5-yl;)-6-[3-fluoro-4-(2-oxopiperidin-1-yl;)phenyl]-7-oxo-4, 5-Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (21E)
Ethyl l-(benzofuran-5-yl)-7-oxo-6-[3-fluoro-4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxylate  Ethyl l-(benzofuran-5-yl)-7-oxo-6-[3-fluoro-4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine- 3-carboxylate
Figure imgf000093_0002
Figure imgf000093_0002
在微波反应其中， 将 1-(2,3-二氢吡啶呋喃 -5-基) -7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡 啶 -3-甲酸乙酯 （31) (960 mg, 3 mmol)溶于 1.4-二氧六环 （20 mL)， 加入 1-(2-氟 -4-碘苯基)哌啶- 2-酮 (21D) (935 mg, 3 mmol)和磷酸钾 (1.3 g, 6 mmol), 氮气鼓泡， 加入碘化亚铜 (57 mg, 0.3 mmol)和 Ν,Ν-二甲基环己胺 (43.5 mg, 0.3 mmol), 加热至 150°C， 微波反应 6小时。 将反应 液冷却至常温， 过滤， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯 /石油醚 i N =1 : 1-1 :0) 得到浅黄色固体状的化合物 1-(苯并呋喃 -5-基;) -6-[3-氟 -4-(2-氧代哌啶 -1-基；)苯基] -7- 氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （21E) (300 mg， 产率 19%)。 In the microwave reaction, 1-(2,3-dihydropyridylfuran-5-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c Pyridine-3-carboxylic acid ethyl ester (31) (960 mg, 3 mmol) dissolved in 1.4-dioxane (20 mL), 1-(2-fluoro-4-iodophenyl)piperidine-2- Ketone (21D) (935 mg, 3 mmol) and potassium phosphate (1.3 g, 6 mmol), nitrogen bubbling, adding cuprous iodide (57 mg, 0.3 mmol) and hydrazine, hydrazine-dimethylcyclohexylamine ( 43.5 mg, 0.3 mmol), heated to 150 ° C, microwaved for 6 hours. Will react The solution was cooled to room temperature, filtered, and evaporated to dryness crystals crystals crystalssssssssssssssssss -5-yl;)-6-[3-fluoro-4-(2-oxopiperidin-1-yl;)phenyl]-7-oxo-4,5-dihydro-1H-pyrazole Ethyl [3,4-c]pyridine-3-carboxylate (21E) (300 mg, yield 19%).
¾ NMR (400 MHz, CDC13) δ 7.36 (s, 1H), 7.20-7.13 (m, 4H), 6.78 (d, 1H), 4.61 (t, 2H), 4.46 (q, 2H), 4.12 (t, 2H), 3.55 (m, 2H), 3.32 (t, 2H), 3.23 (t, 2H), 2.57 (m, 2H), 1.95 (m, 4H), 1.45-1.41 (m, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.36 (s, 1H), 7.20-7.13 (m, 4H), 6.78 (d, 1H), 4.61 (t, 2H), 4.46 (q, 2H), 4.12 (t , 2H), 3.55 (m, 2H), 3.32 (t, 2H), 3.23 (t, 2H), 2.57 (m, 2H), 1.95 (m, 4H), 1.45-1.41 (m, 3H).
第五步： 1- (苯并呋喃 -5-基) -6-[3-氟 -4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 21)  The fifth step: 1-(benzofuran-5-yl)-6-[3-fluoro-4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5- Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 21)
l-(benzofuran-5-yl)-7-oxo-6-[3-fluoro-4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[3-fluoro-4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3 -carboxamide
Figure imgf000094_0001
Figure imgf000094_0001
将 1 - (苯并呋喃 -5-基;) -6-[3-氟 -4-(2-氧代哌啶 -1 -基)苯基] -7-氧代 -4,5-二氢 - 1H-吡唑并 [3,4-c] 吡啶 -3-甲酸乙酯 （21E) (300 mg, 0.578 mmol) 溶于 Ν,Ν-二甲基甲酰胺 （10 mL) 中， 加入甲 酰胺 （260 mg, 5.78 mmol), 甲醇钠 （62 mg, 1.156 mmol), 升温至 90°C反应过夜。 将反应液 冷却至 0°C， 加入水（50 mL), 用乙酸乙酯 （50 mL X 2)萃取， 合并有机相， 有机相用饱和 食盐水（100 mL) 洗涤， 无水硫酸钠干燥， 浓缩， 残留物用二氯甲垸 /乙酸乙酯重结晶得到标 题化合物 1- (苯并呋喃 -5-基;) -6-[3-氟 -4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c 吡啶 -3-甲酰胺 （化合物 21) (70 mg, 产率 25 %)。  1-(Benzofuran-5-yl;)-6-[3-fluoro-4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5-dihydro - 1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (21E) (300 mg, 0.578 mmol) dissolved in hydrazine, dimethyl-dimethylformamide (10 mL) (260 mg, 5.78 mmol), sodium methoxide (62 mg, 1.156 mmol), warmed to 90 ° C overnight. The reaction mixture was cooled to 0 ° C, EtOAc (EtOAc)EtOAc. Concentration, the residue was crystallised eluted eluted eluted eluted eluted ;) phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-cpyridine-3-carboxamide (Compound 21) (70 mg, yield 25%).
^ NMR (400 MHz, CDC13) δ 7.34 (s, 1Η), 7.24-7.19 (m, 4H), 6.82-6.80 (m, 2H), 5.44 (s, 1H), 4.62 (t, 2H), 4.1 1 (t, 2H), 3.54 (m, 2H), 3.38 (t, 2H), 3.25 (t, 2H), 2.57 (m, 2H), 1.95 (m, 4H)。 实施例 22 ^ NMR (400 MHz, CDC1 3 ) δ 7.34 (s, 1Η), 7.24-7.19 (m, 4H), 6.82-6.80 (m, 2H), 5.44 (s, 1H), 4.62 (t, 2H), 4.1 1 (t, 2H), 3.54 (m, 2H), 3.38 (t, 2H), 3.25 (t, 2H), 2.57 (m, 2H), 1.95 (m, 4H). Example 22
1- (苯并呋喃 -5-基) -6-[4-((2R)-2-甲基 -5-氧代吗啉 -4-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3 4-c]吡啶 -3-甲酰胺（化合物 22)  1-(benzofuran-5-yl)-6-[4-((2R)-2-methyl-5-oxomorpholin-4-yl)phenyl]-7-oxo-4,5 -Dihydro-1H-pyrazolo[3 4-c]pyridine-3-carboxamide (Compound 22)
l-(benzofuran-5-yl)-7-oxo-6-[4-((2R)-2-methyl-5-oxo-morpholin-4-yl)phenyl]-4,5- dihydropyrazolo [3 ,4-c]pyridine-3 - carboxamide
Figure imgf000095_0001
L-(benzofuran-5-yl)-7-oxo-6-[4-((2R)-2-methyl-5-oxo-morpholin-4-yl)phenyl]-4,5- dihydropyrazolo [3 ,4 -c]pyridine-3 - carboxamide
Figure imgf000095_0001
o  o
第一步： N-(2S-2-羟基丙基) -2-溴乙酰胺 H（22B)  First step: N-(2S-2-hydroxypropyl)-2-bromoacetamide H(22B)
N-(2S-2-hydroxypropyl)-2-bromoacetamide HN  N-(2S-2-hydroxypropyl)-2-bromoacetamide HN
Br Br
0  0
将 2S-2-羟基丙胺 （6.8 g, 90.5 mmol)溶于乙酸乙酯 （100 mL) 中， 加入碳酸氢钠 （11.4 g, 136 mmol) 和水 (10 mL), 冷却至 0°C， 滴加溴乙酰溴 (20.2 g, 99.6 mmol), 室温反应 3 小时。 将反应液用乙酸乙酯 （100 mL X 4) 萃取， 合并有机相， 有机相用无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚： 乙酸乙酯 （v/v) = 3:2) 得到标题化合物 N-(2 S-2-羟基丙基) -2-溴乙酰胺 （22B)， 黄色固体（5.0 g,产率 28%)。  2S-2-Hydroxypropylamine (6.8 g, 90.5 mmol) was dissolved in ethyl acetate (100 mL), sodium bicarbonate (11.4 g, 136 mmol) and water (10 mL) were added and cooled to 0 ° C Bromoacetyl bromide (20.2 g, 99.6 mmol) was added and allowed to react at room temperature for 3 hours. The reaction mixture was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) The title compound N-(2S-2-hydroxypropyl)-2-bromoacetamide (22B) was obtained as a yellow solid (5.0 g, yield 28%).
第二步： （2R)-2-甲基 -吗啉 -5-酮 （22C)  Step 2: (2R)-2-Methyl-morpholine-5-one (22C)
(2R)-2-methyl-morpholin-5-one
Figure imgf000095_0002
(2R)-2-methyl-morpholin-5-one
Figure imgf000095_0002
将 N-(2S-2-羟基丙基) -2-溴乙酰胺 (22B) (5.2 g, 26.53 mmol) 溶于叔丁醇 (200 mL) 中， 加入叔丁醇钾 （7.4 g, 66.31 mmol), 室温下反应 2小时。 向反应液中加入水 （10 mL), 浓缩除去大部分溶剂， 加入水（50 mL), 用乙酸乙酯 （100 mL X 2) 萃取， 合并有机相， 有 机相用无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚： 乙酸乙酯 iyl = 1 : 2)得到标题化合物 （2R;»-2-甲基 -吗啉 -5-酮（22C)， 白色固体（700 mg,产率 23%)。  N-(2S-2-hydroxypropyl)-2-bromoacetamide (22B) (5.2 g, 26.53 mmol) was dissolved in tert-butanol (200 mL) and potassium tert-butoxide (7.4 g, 66.31 mmol ), react at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture. EtOAc was evaporated, evaporated, evaporated. The residue was purified by silica gel column chromatography (EtOAc:EtOAc: , yield 23%).
¾ NMR (400 MHz, CDC13) δ 6.97 (s, 1H), 4.21 (dd, 2H), 3.90 - 3.77 (m, 1H), 3.32 - 3.20 (m, 2H), 1.27 (t, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 6.97 (s, 1H), 4.21 (dd, 2H), 3.90 - 3.77 (m, 1H), 3.32 - 3.20 (m, 2H), 1.27 (t, 3H).
第三步： 1- (苯并呋喃 -5-基） -6-[4-((2R)-2-甲基 -5-氧代吗啉 -4-基)苯基] -7-氧代 -4,5-二氢 -1H- 吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （22D)
Figure imgf000096_0001
The third step: 1-(benzofuran-5-yl)-6-[4-((2R)-2-methyl-5-oxomorpholin-4-yl)phenyl]-7-oxo -4,5-Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (22D)
Figure imgf000096_0001
将 l-(2,3-二氢吡啶呋喃 -5-基) -7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （31) (10.0 g, 30.6 mmol) 溶于 1.4-二氧六环 (500 mL)， 加入 （2R)-2-甲基 -吗啉 -5-酮 (22C) (720 mg, 6.25 mmol), 碘化亚铜 (100 mg) 和磷酸钾 (2.65 mg, 12.6 mmol)和 Ν,Ν-二甲基环己胺 (100 mg), 在氮气氛围下， 室温至 110°C， 反应 10小时。 将反应液冷却至常温， 加入水 （50 mL)， 用二氯甲垸 （50 mL X 2) 洗涤， 合并有机相， 用无水硫酸钠干燥， 减压浓缩， 残留 物用硅胶柱色谱分离提纯 （乙酸乙酯）得到标题化合物 1- (苯并呋喃 -5-基） -6-[4-((2R)-2-甲基 -5- 氧代吗啉 -4-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （22D)， 白色粉末 （0.6 g， 产率 18%)。  1-(2,3-Dihydropyridylfuran-5-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3- Ethyl formate (31) (10.0 g, 30.6 mmol) dissolved in 1.4-dioxane (500 mL), (2R)-2-methyl-morpholin-5-one (22C) (720 mg, 6.25 Methyl) cuprous iodide (100 mg) and potassium phosphate (2.65 mg, 12.6 mmol) and hydrazine, hydrazine-dimethylcyclohexylamine (100 mg), under nitrogen atmosphere, room temperature to 110 ° C, reaction 10 hour. The reaction mixture was cooled to room temperature, water (50 mL), EtOAc (EtOAc) (ethyl acetate) the title compound 1-(benzofuran-5-yl)-6-[4-((2R)-2-methyl-5-oxomorpholin-4-yl)phenyl]- Ethyl 7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (22D), white powder (0.6 g, yield 18%).
^ NMR (400 MHz, CDC13) δ 7.31-7.27 (m, 5Η), 7.18-7.21 (m, 1H), 6.70 (d, 1H), 4.53 (t, 2H), 4.38 (q, 2H), 4.27 (dd, 2H), 4.05 (t, 2H), 3.99 (m, 1H), 3.56 (m, 1H), 3.40 (dd, 1H), 3.25 (t, 2H), 3.15 (t, 2H), 1.36 (t, 3H), 1.25 (d, 3H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.31-7.27 (m, 5Η), 7.18-7.21 (m, 1H), 6.70 (d, 1H), 4.53 (t, 2H), 4.38 (q, 2H), 4.27 (dd, 2H), 4.05 (t, 2H), 3.99 (m, 1H), 3.56 (m, 1H), 3.40 (dd, 1H), 3.25 (t, 2H), 3.15 (t, 2H), 1.36 ( t, 3H), 1.25 (d, 3H).
MS m/z (ESI): 517.2 [M+l]  MS m/z (ESI): 517.2 [M+l]
第四步： 1- (苯并呋喃 -5-基） -6-[4- ;2Ε 2-甲基 -5-氧代吗啉 -4-基;)苯基] -7-氧代 -4,5-二氢 -1H- 吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 22)  The fourth step: 1-(benzofuran-5-yl)-6-[4-; 2Ε 2-methyl-5-oxomorpholin-4-yl;)phenyl]-7-oxo-4 ,5-Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 22)
l-(benzofuran-5-yl)-7-oxo-6-[4-((2R)-2-methyl-5-oxo-morpholin-4-yl)phenyl]-4,5- dihydropyrazolo [3 ,4-c]pyridine-3 - carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[4-((2R)-2-methyl-5-oxo-morpholin-4-yl)phenyl]-4,5- dihydropyrazolo [3 ,4 -c]pyridine-3 - carboxamide
Figure imgf000096_0002
Figure imgf000096_0002
将 1- (苯并呋喃 -5-基） -6-[4-((2R)-2-甲基 -5-氧代吗啉 -4-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑 并 [3,4-c]吡啶 -3-甲酸乙酯 (22D) (600 mg, 1.16 mmol)溶于 Ν,Ν-二甲基甲酰胺 (10 mL) 中， 加入甲酰胺 (522 mg, 11.6 mmol), 甲醇钠 (251 mg, 4.65 mmol), 升温至 80°C反应 3小时。 向反应液中加入水 （15 mL), 用二氯甲垸 （20 mL X 2) 萃取， 合并有机相， 有机相用无水 硫酸钠干燥， 浓缩， 残留物硅胶柱色谱分离提纯（二氯甲垸： 甲醇 （v/v) = 80: 1) 得到标题化 合物 1- (苯并呋喃 -5-基） -6-[4-((2R)-2-甲基 -5-氧代吗啉 -4-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3, 4-c]吡啶 -3-甲酰胺（化合物 22)， 白色固体（200 mg, 产率 35 %)。 1-(Benzofuran-5-yl)-6-[4-((2R)-2-methyl-5-oxomorpholin-4-yl)phenyl]-7-oxo-4, Ethyl 5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (22D) (600 mg, 1.16 mmol) dissolved in hydrazine, dimethyl-dimethylformamide (10 mL) Formamide (522 mg, 11.6 mmol), sodium methoxide (251 mg, 4.65 mmol), and warmed to 80 ° C for 3 hours. Water (15 mL) was added to the reaction mixture, and the mixture was combined with methylene chloride (20 mL EtOAc).垸: Methanol (v/v) = 80: 1) The title compound 1-(benzofuran-5-yl)-6-[4-((2R)-2-methyl-5-oxomorpholine- 4-yl)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3, 4-c]pyridine-3-carboxamide (Compound 22), white solid (200 mg, yield: 35 %).
¾ NMR (400 MHz, CDC13) δ 7.38-7.32 (m, 5H), 7.26 (m, 1H),6.84 (s, IH), 6.79 (d, IH), 5.50 (s, IH), 4.62 (t, 2H), 4.36 (dd, 2H), 4.11 (t, 2H), 4.05 (m, IH), 3.63 (m, IH), 3.47 (dd, IH), 3.38 (t, 2H), 3.25 (t, 2H), 1.32 (d, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.38-7.32 (m, 5H), 7.26 (m, 1H), 6.84 (s, IH), 6.79 (d, IH), 5.50 (s, IH), 4.62 (t , 2H), 4.36 (dd, 2H), 4.11 (t, 2H), 4.05 (m, IH), 3.63 (m, IH), 3.47 (dd, IH), 3.38 (t, 2H), 3.25 (t, 2H), 1.32 (d, 3H).
MS m/z (ESI): 488.1 [M+l] 实施例 23  MS m/z (ESI): 488.1 [M+l] EXAMPLE 23
l-(2,3-二氢苯并呋喃 -5-基) -6-[4-[(2S)-2-甲基 -5-氧代 -吗啉 -4-基]苯基] -7-氧代 -4,5-二氢吡唑 并 [3,4-c]吡啶 -3-甲酰胺 （化合物 23)  L-(2,3-Dihydrobenzofuran-5-yl)-6-[4-[(2S)-2-methyl-5-oxo-morpholin-4-yl]phenyl]-7 -oxo-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxamide (Compound 23)
l-(2,3-dihydrobenzofuran-5-yl)-6-[4-[(2R)-2-methyl-5-oxo-morpholin-4-yl]phenyl]-7-oxo-4,5- dih dro razolo 3 4-c ridine-3-carboxamide  L-(2,3-dihydrobenzofuran-5-yl)-6-[4-[(2R)-2-methyl-5-oxo-morpholin-4-yl]phenyl]-7-oxo-4,5-dih Dro razolo 3 4-c ridine-3-carboxamide
Figure imgf000097_0001
第一步： 2-溴 -N-[(2R)-2-羟基丙基]乙酰胺 (23B)
Figure imgf000097_0001
First step: 2-bromo-N-[(2R)-2-hydroxypropyl]acetamide (23B)
2-bromo-N-[(2R)-2-hydroxypropyl] acetamide  2-bromo-N-[(2R)-2-hydroxypropyl] acetamide
?H H ? H H
人 N^ Br Human N ^ Br
O  O
将 2R-2-羟基丙胺 （10 g, 0.133 mol) 溶于乙酸乙酯 （500 mL) 中， 加入碳酸氢钠 （16.7 g, 0.2 mol) 的水 (300 mL) 溶液， 冷却至 0°C滴加溴乙酰溴 (29.6 g, 0.146 mol),滴完后 0°C反 应 3h。 将反应液分液， 水层用乙酸乙酯 （200 mL X 2) 萃取， 合并有机层， 无水硫酸钠干 燥， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚 /乙酸乙酯 （v/v) =1 : 1-3:7)得到标题化 合物 2-溴 -N-[(2R)-2-羟基丙基]乙酰胺 （23B)， 白色固体（22B) (2.0 g, 产率 8%)。  2R-2-hydroxypropylamine (10 g, 0.133 mol) was dissolved in ethyl acetate (500 mL), sodium bicarbonate (16.7 g, 0.2 mol) in water (300 mL) was added and cooled to 0 ° C Bromoacetyl bromide (29.6 g, 0.146 mol) was added, and the reaction was carried out at 0 ° C for 3 h after the completion of the dropwise addition. The reaction mixture was separated, EtOAcjjjjjjjjjjjjjj v/v) =1 : 1-3:7) gave the title compound 2-bromo-N-[(2R)-2-hydroxypropyl]acetamide (23B) as a white solid (22B) (2.0 g, yield 8%).
^ NMR (400 MHz, CDC13) δ 6.91 (br, IH), 3.92-3.88 (m, IH), 3.84 (s, 2H), 3.44-3.38 (m, 1H): 3.13-3.05 (m, IH), 2.48 (br, IH), 1.15 (d, 3H)。 ^ NMR (400 MHz, CDC1 3 ) δ 6.91 (br, IH), 3.92-3.88 (m, IH), 3.84 (s, 2H), 3.44-3.38 (m, 1H) : 3.13-3.05 (m, IH) , 2.48 (br, IH), 1.15 (d, 3H).
LC-MS:[M+1] 198.1.  LC-MS: [M+1] 198.1.
第二步： （6S)-6-甲基吗啉 -3-酮 (23C) (6S)-6-methylmorpholin-3-one Step 2: (6S)-6-Methylmorpholine-3-one (23C) (6S)-6-methylmorpholin-3-one
Figure imgf000098_0001
Figure imgf000098_0001
将 2-溴 -N-[(2R)-2-羟基丙基]乙酰胺 （2 g, 10.2 mmol)溶于叔丁醇（150 mL) 中， 加入叔丁 醇钾 （2.86 g, 25.5 mmol), 室温反应 2h， 加入水（50 mL)、 二氯甲垸（100 mL)和 4N盐酸调 节 pH=6， 分液， 水层用二氯甲垸（50 mL)萃取， 合并有机层， 有机层用饱和氯化钠 （50 mL) 洗涤， 无水硫酸钠干燥， 减压浓缩的标题化合物 （6S 6-甲基吗啉 -3-酮 （23C)， (740 mg, 产 率 63%)， 直接用于下一步。  2-Bromo-N-[(2R)-2-hydroxypropyl]acetamide (2 g, 10.2 mmol) was dissolved in tert-butanol (150 mL) and potassium t-butoxide (2.86 g, 25.5 mmol) After reacting at room temperature for 2 h, add water (50 mL), dichloromethane (100 mL) and 4N hydrochloric acid to adjust pH=6, partition, and the aqueous layer is extracted with dichloromethane (50 mL), organic layer, organic layer The title compound (6S 6-methylmorpholin-3-one (23C), (740 mg, yield 63%) Used in the next step.
第三步： 1-(2,3-二氢苯并呋喃 -5-基) -6-[4-[(2S)-2-甲基 -5-氧代 -吗啉 -4-基]苯基] -7-氧代 -4,5- 二氢吡唑并 [3,4-c]吡啶 -3-甲酸乙酯（23D)  The third step: 1-(2,3-dihydrobenzofuran-5-yl)-6-[4-[(2S)-2-methyl-5-oxo-morpholin-4-yl]benzene Ethyl]-7-oxo-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (23D)
ethyl l-(2,3-dihydrobenzofuran-5-yl)-6-[4-[(2R)-2-methyl-5-oxo-morpholin-4-yl]phenyl]-7- oxo-4,5-dihydropyrazolo[3,4-c]pyridi -3-carboxylate  Ethyl l-(2,3-dihydrobenzofuran-5-yl)-6-[4-[(2R)-2-methyl-5-oxo-morpholin-4-yl]phenyl]-7-oxo-4,5- Dihydropyrazolo[3,4-c]pyridi -3-carboxylate
Figure imgf000098_0002
Figure imgf000098_0002
将 l-(2,3-二氢苯并呋喃 -5-基) -6-(4-碘苯基 )-7-氧代 -4,5,6,7-四氢 -IH-吡唑并 [3,4-c]吡啶 -3-甲 酸乙酯 （1.66 g, 3.13 mmol)溶于 1,4-二氧六环 （15 mL) 中， 加入 (6S)-6-甲基吗啉 -3-酮 （23C) (740 mg, 6.43 mmol), 磷酸钾 (1.33 g, 6.26 mmol), Ν,Ν-二甲基环己胺 (44.5 mg, 0.313 mmol), 氮气氛围下加入碘化亚铜 （60 mg, 0.313 mmol), 加热至 110°C反应过夜。 将反应液 冷却至室温， 加入水 （30 mL), 用二氯甲垸 （40 mL) 萃取， 有机相用饱和食盐水 （30 mL) 洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯 /石油醚 (v/v) = 1 : 1-1 :0) 得到标题化合物 1-(2,3-二氢苯并呋喃 -5-基) -6-[4-[(2S)-2-甲基 -5-氧代 -吗啉 -4- 基]苯基] -7-氧代 -4,5-二氢吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （23D)， 浅黄色固体 （890 mg,产率 55 %)。  1-(2,3-Dihydrobenzofuran-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-IH-pyrazole Ethyl [3,4-c]pyridine-3-carboxylate (1.66 g, 3.13 mmol) was dissolved in 1,4-dioxane (15 mL) and (6S)-6-methylmorpholine-3 was added. -ketone (23C) (740 mg, 6.43 mmol), potassium phosphate (1.33 g, 6.26 mmol), hydrazine, hydrazine-dimethylcyclohexylamine (44.5 mg, 0.313 mmol), added cuprous iodide under nitrogen atmosphere ( 60 mg, 0.313 mmol), heated to 110 ° C overnight. The reaction mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc. The product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v/v) = 1 : 1-1 : 0) to give the title compound 1-(2,3-dihydrobenzofuran-5-yl)-6 -[4-[(2S)-2-methyl-5-oxo-morpholin-4-yl]phenyl]-7-oxo-4,5-dihydropyrazolo[3,4-c Pyridine-3-carboxylic acid ethyl ester (23D), light yellow solid (890 mg, yield 55%).
^ NMR (400 MHz, CDC13) δ 7.33-7.23 (m, 5Η), 7.21-7.18 (m, IH), 6.69 (d, IH), 4.53 (t, 2H), 4.41-4.38 (m, 2H), 4.33-4.21 (m, 2H), 4.02-3.94 (m, IH), 3.60-3.51 (m, IH), 3.42-3.38 (m, IH), 3.25 (t, 2H), 3.15 (t, 2H), 1.36 (t, 3H), 1.25 (d, 3H), 1.19-1.15 (m, 2H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.33-7.23 (m, 5Η), 7.21-7.18 (m, IH), 6.69 (d, IH), 4.53 (t, 2H), 4.41-4.38 (m, 2H) , 4.33-4.21 (m, 2H), 4.02-3.94 (m, IH), 3.60-3.51 (m, IH), 3.42-3.38 (m, IH), 3.25 (t, 2H), 3.15 (t, 2H) , 1.36 (t, 3H), 1.25 (d, 3H), 1.19-1.15 (m, 2H).
LC-MS:[M+1] 517.3.  LC-MS: [M+1] 517.3.
第四步： l-(2,3-二氢苯并呋喃 -5-基) -6-[4-[(2S)-2-甲基 -5-氧代 -吗啉 -4-基]苯基] -7-氧代 -4,5- 二氢吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 23)  The fourth step: l-(2,3-dihydrobenzofuran-5-yl)-6-[4-[(2S)-2-methyl-5-oxo-morpholin-4-yl]benzene -7-oxo-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxamide (compound 23)
l-(2,3-dihydrobenzofuran-5-yl)-6-[4-[(2R)-2-methyl-5-oxo-morpholin-4-yl]phenyl]-7-oxo-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxamide L-(2,3-dihydrobenzofuran-5-yl)-6-[4-[(2R)-2-methyl-5-oxo-morpholin-4-yl]phenyl]-7-oxo-4,5- Dihydropyrazolo[3,4-c]pyridine-3-carboxamide
Figure imgf000099_0001
Figure imgf000099_0001
将 l-(2,3-二氢苯并呋喃 -5-基) -6-[4-[(2S)-2-甲基 -5-氧代 -吗啉 -4-基]苯基] -7-氧代 -4,5-二氢吡 唑并 [3,4-c]吡啶 -3-甲酸乙酯 (23D) (880 mg, 1.7 mmol) 溶于 Ν,Ν-二甲基甲酰胺 (10 mL) 中， 加入甲酰胺 （766 mg, 17 mmol), 甲醇钠 （367 mg, 6.80 mmol), 升至 80°C反应过夜。 减压除去 Ν,Ν-二甲基甲酰胺， 残留物用二氯甲垸 （50 mL) 溶解， 用水 （100 mL) 洗涤， 分 液， 有机层用饱和氯化钠 （30 mL)洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩， 残留物用硅胶 柱色谱分离提纯 （石油醚 /乙酸乙酯 =1 : 1-0: 1甲醇 /二氯甲垸 （v/v) = 1 : 19) 得到标题化合物 1-(2, 3-二氢苯并呋喃 -5-基) -6-[4-[(2S)-2-甲基 -5-氧代 -吗啉 -4-基]苯基] -7-氧代 -4,5-二氢吡唑并 [3,4-c] 吡啶 -3-甲酰胺 （化合物 23)， 浅黄色固体（480 mg, 产率 55%)。  1-(2,3-Dihydrobenzofuran-5-yl)-6-[4-[(2S)-2-methyl-5-oxo-morpholin-4-yl]phenyl] - Ethyl 7-oxo-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxylate (23D) (880 mg, 1.7 mmol) dissolved in hydrazine, hydrazine-dimethylformamide In 10 mL), formamide (766 mg, 17 mmol), sodium methoxide (367 mg, 6.80 mmol) was added, and the mixture was stirred at 80 ° C overnight. The hydrazine, hydrazine-dimethylformamide was removed under reduced pressure. The residue was crystallised eluted eluted eluted eluted eluted eluted eluted The organic layer was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated,363363363363363363363363363363363363363363363363363363363363363 The title compound 1-(2,3-dihydrobenzofuran-5-yl)-6-[4-[(2S)-2-methyl-5-oxo-morpholin-4-yl]phenyl 7-oxo-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxamide (Compound 23), pale yellow solid (480 mg, yield 55%).
¾ NMR (400 MHz, 6-DMSO) δ 7.71 (br, 1H), 7.42-7.36 (m, 6H), 7.29-7.26 (m, 1H), 6.77 (d, 1H), 4.59 (t, 2H), 4.22-4.20 (m, 2H), 4.08-3.94 (m, 3H), 3.60-3.52 (m, 2H), 3.28-3.19 (m, 4H), 1.25 (d, 3H)。 3⁄4 NMR (400 MHz, 6 -DMSO) δ 7.71 (br, 1H), 7.42-7.36 (m, 6H), 7.29-7.26 (m, 1H), 6.77 (d, 1H), 4.59 (t, 2H), 4.22-4.20 (m, 2H), 4.08-3.94 (m, 3H), 3.60-3.52 (m, 2H), 3.28-3.19 (m, 4H), 1.25 (d, 3H).
LC-MS:[M+1] 488.2 实施例 24  LC-MS: [M+1] 488.2 Example 24
1- (苯并呋喃 -5-基) -3-三氟甲基 -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 （化合物 24)  1-(benzofuran-5-yl)-3-trifluoromethyl-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5-di Hydrogen-1H-pyrazolo[3,4-c]pyridine (Compound 24)
l-(benzofuran-5-yl)-3-trifluoromethyl-7-oxo-6-[4-(l,2,3,4-tetrazole-5-yl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine  L-(benzofuran-5-yl)-3-trifluoromethyl-7-oxo-6-[4-(l,2,3,4-tetrazole-5-yl)phenyl]-4,5-dihydropyrazolo[3,4 -c]pyridine
Figure imgf000099_0002
第一步： 苯并呋喃 -5-肼盐酸盐（24B)
Figure imgf000100_0001
Figure imgf000099_0002
First step: benzofuran-5-indole hydrochloride (24B)
Figure imgf000100_0001
将 5-氨基苯并呋喃 （5.5 g, 40.7 mmol) 加入浓盐酸 （10 mL) 和水 （20 mL) 的混合物 中， 冷却至 -5~0°C， 滴加亚硝酸钠 （3.4 g, 48.8 mmol) 的水 （10 mL) 溶液， 维持 0°C搅拌反 应 1小时， 在 0°C下， 滴加二水氯化锡 （27.6 g, 122.1 mmol) 的浓盐酸 （15 mL) 溶液， 10分 钟滴完， 维持 0°C反应 2小时。 向反应液中加入乙酸乙酯 （100 mL), 加入 10%氢氧化钠溶液调 节 pH=8~ 9， 抽滤， 将滤液分液， 水相用乙酸乙酯 （50 mL X 2) 萃取， 合并有机相， 有机 相用饱和食盐水 （50 mL X 2) 洗涤， 无水硫酸钠干燥， 减压浓缩， 放置过夜， 有固体析 出， 过滤， 干燥滤饼得到标题化合物苯并呋喃 -5-肼盐酸盐 （24B)， 灰色固体 （1.3 g， 产率 17 %)。  5-Aminobenzofuran (5.5 g, 40.7 mmol) was added to a mixture of concentrated hydrochloric acid (10 mL) and water (20 mL), cooled to -5~0 ° C, and sodium nitrite (3.4 g, 48.8) Methyl alcohol (10 mL) solution was stirred at 0 ° C for 1 hour. At 0 ° C, a solution of tin chloride dihydrate (27.6 g, 122.1 mmol) in concentrated hydrochloric acid (15 mL) was added dropwise for 10 min. After the completion of the dropwise addition, the reaction was maintained at 0 ° C for 2 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and 10% sodium hydroxide solution was added thereto to adjust pH = 8-9, and the filtrate was separated. The filtrate was separated and the aqueous phase was extracted with ethyl acetate (50 mL X 2 ). The organic phase was washed with brine (50 mL EtOAc) EtOAc. Acid salt (24B), grey solid (1.3 g, yield 17%).
第二步： 2-溴 -2-(2- (苯并呋喃 -5-基)腙 -1,1,1-三氟乙垸（24C)  Second step: 2-bromo-2-(2-(benzofuran-5-yl)indole-1,1,1-trifluoroacetamidine (24C)
Figure imgf000100_0002
Figure imgf000100_0002
将苯并呋喃 -5-肼盐酸盐 (24B) (1.3 g, 7.0 mmol)和 1-甲氧基 -2,2,2,-三氟乙醇 (1.1 g, 9.0 mmol) 溶于乙醇 （40 mL) 中， 升温至 85 °C反应 4小时， 将反应液冷却， 浓缩出去乙醇， 残留 物中加入 Ν,Ν-二甲基甲酰胺 （20 mL) , 冷却至 0 °C， 加入 N-溴代丁二酰亚胺 （1.2 g , 7.0 mmol), 室温反应 2小时。 向反应液中加入水（100 mL)和乙酸乙酯 （100 mL), 分液， 水相用 乙酸乙酯 （50 mL X 2) 萃取， 合并有机相， 有机相依次用水 （80 mL X 2)、 饱和食盐水 (50 mL X 2)洗涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚： 乙酸 乙酯 (v/v) = 1 :0 ~ 19: 1) 得到标题化合物 2-溴 -2-(2- (苯并呋喃 -5-基)腙基) -1,1,1-三氟乙垸 (24C), 棕红色固体（700 mg， 33%)。  Benzofuran-5-indole hydrochloride (24B) (1.3 g, 7.0 mmol) and 1-methoxy-2,2,2,-trifluoroethanol (1.1 g, 9.0 mmol) were dissolved in ethanol (40) In mL), the temperature was raised to 85 °C for 4 hours, the reaction solution was cooled, and the ethanol was concentrated. The residue was added with hydrazine, hydrazine-dimethylformamide (20 mL), cooled to 0 ° C, and N-bromine was added. Desuccinimide (1.2 g, 7.0 mmol) was reacted at room temperature for 2 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the mixture and the mixture was evaporated. The mixture was washed with saturated brine (50 mL EtOAc) (EtOAc) The title compound 2-bromo-2-(2-(benzofuran-5-yl)indolyl)-1,1,1-trifluoroacetamidine (24C), m.p.
¾ NMR (400 MHz, CDC13) δ 7.93 (s, 1Η), 7.10 - 7.06 (m, 1H), 6.87 - 6.81 (m, 1H), 6.72 (d,3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.93 (s, 1Η), 7.10 - 7.06 (m, 1H), 6.87 - 6.81 (m, 1H), 6.72 (d,
1H), 4.57 (t, 2H), 3.21 (t, 2H)。 1H), 4.57 (t, 2H), 3.21 (t, 2H).
第三步： 1- (苯并呋喃 -5-基) -3-三氟甲基 -6-[4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H- 吡唑并 [3,4-c]吡啶 （化合物 24)  The third step: 1-(benzofuran-5-yl)-3-trifluoromethyl-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4 ,5-Dihydro-1H-pyrazolo[3,4-c]pyridine (Compound 24)
l-(benzofuran-5-yl)-3-trifluoromethyl-7-oxo-6-[4-(l,2,3,4-tetrazole-5-yl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine
Figure imgf000101_0001
L-(benzofuran-5-yl)-3-trifluoromethyl-7-oxo-6-[4-(l,2,3,4-tetrazole-5-yl)phenyl]-4,5-dihydropyrazolo[3,4 -c]pyridine
Figure imgf000101_0001
将 3—吗啉 -l-(4-(2-氧代哌啶 -1-基)苯基) -5,6-二氢吡啶 -2(1H)-酮 (If) (391 mg, 1.1 mmol), 3-morpholine-l-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridine-2(1H)-one (If) (391 mg, 1.1 mmol ),
2-溴 -2-(2- (苯并呋喃 -5-基)腙基) -1,1,1-三氟乙垸 （24C) (309 mg, 1.0 mmol)溶于乙酸乙酯 （50 mL) 中， 加入碘化钾 （17 mg, 0.1 mmol) 和三乙胺 （304 mg, 3.0 mmol), 升至 85°C回流反 应 16小时， 反应液冷却至 0°C， 加入盐酸 (4N, 1.25 mL, 5.0 mmol), 室温搅拌反应 1小时。 向 反应液中加入水（30 mL), 分液， 水相用乙酸乙酯 （20 mL X 2) 萃取， 合并有机相， 用饱 和食盐水 （30 mL X 2) 洗涤， 无水硫酸钠干燥， 过滤， 浓缩， 残留物用硅胶柱色谱分离提 纯 （乙酸乙酯 /石油醚（v/v) = 1: 1-1 :0) 得到标题化合物 1- (苯并呋喃 -5-基) -3-三氟甲基 -6-[4-(2- 氧代哌啶 -1 -基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 （化合物 24) (370 mg, 产率 74 %)。 2-Bromo-2-(2-(benzofuran-5-yl)indolyl)-1,1,1-trifluoroacetamidine (24C) (309 mg, 1.0 mmol) dissolved in ethyl acetate (50 mL Add potassium iodide (17 mg, 0.1 mmol) and triethylamine (304 mg, 3.0 mmol), reflux to 85 ° C for 16 hours, cool the reaction to 0 ° C, add hydrochloric acid (4N, 1.25 mL, 5.0 mmol), the reaction was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjj Filtration, concentrating, and EtOAc (EtOAc/EtOAc (EtOAc) Trifluoromethyl-6-[4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c] Pyridine (Compound 24) (370 mg, yield 74%).
¾ NMR (400 MHz, CDC13) δ 7.36 - 7.31 (m, 3H), 7.28 - 7.24 (m, 3H), 6.78 (d, 1H), 4.60 (t, 2H), 4.14 (t, 2H), 3.60 (t, 2H), 3.23 (t, 2H), 3.15 (t, 2H), 2.57 (t, 2H), 1.96 - 1.92 (m, 4H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.36 - 7.31 (m, 3H), 7.28 - 7.24 (m, 3H), 6.78 (d, 1H), 4.60 (t, 2H), 4.14 (t, 2H), 3.60 (t, 2H), 3.23 (t, 2H), 3.15 (t, 2H), 2.57 (t, 2H), 1.96 - 1.92 (m, 4H).
LC-MS:[M+1] 497.1 实施例 25  LC-MS: [M+1] 497.1 Example 25
1- (苯并呋喃 -5-基) -6-[4-(l,2,3,4-戊四唑 -5-基)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡啶- 1-(benzofuran-5-yl)-6-[4-(l,2,3,4-pentetazol-5-yl)phenyl]-7-oxo-4,5-dihydro- IH-pyrazolo[3,4-c]pyridine-
3-甲酰胺 （化合物 25) 3-formamide (compound 25)
l-(benzofuran-5-yl)-7-oxo-6-[4-(l,2,3,4-tetrazole-5-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[4-(l,2,3,4-tetrazole-5-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine -3-carboxamide
Figure imgf000101_0002
第一步： 1- (苯并呋喃 -5-基) -6-[4-氰基苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸 乙酯 （25B) Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-Cyanophenyl]-4,5-dihydropyrazolo[3,4-c]pyridine carboxylate
Figure imgf000101_0002
First step: 1-(benzofuran-5-yl)-6-[4-cyanophenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c Pyridine-3-carboxylic acid ethyl ester (25B) Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-Cyanophenyl]-4,5-dihydropyrazolo[3,4-c]pyridine carboxylate
Figure imgf000102_0001
Figure imgf000102_0001
将 l -(2,3-二氢吡啶呋喃 -5-基) -7-氧代 -4,5,6,7-四氢 - IH-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （3f) (10.0 g, 30.6 mmol) 和 4-氰基 -1碘苯 (14.0 g, 61.1 mmol) 溶于 1.4-二氧六环 （100 mL)， 加 入碘化亚铜 (583 mg, 3.0 mmol) 和磷酸钾 (13.0 g, 61.1 mmol), 在氮气氛围下， 加入 Ν,Ν- 二甲基环己胺 （427 mg, 3.0 mmol) , 加热至 1 10°C， 反应 16小时。 将反应液冷却至常温， 加 入二氯甲垸 （100 mL) , 过滤， 滤饼用二氯甲垸 （50 mL X 2) 洗涤， 合并有机相， 减压浓 缩， 残留物用硅胶柱色谱分离提纯 （二氯甲垸： 乙酸乙酯 （v/v) =1 :0-9: 1) 得到浅黄色固体状 的化合物 1- (苯并呋喃 -5-基) -6-[4-氰基苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 (25B) (9.0 g, 产率 69%)。  1-(2,3-Dihydropyridylfuran-5-yl)-7-oxo-4,5,6,7-tetrahydro-IH-pyrazolo[3,4-c]pyridine-3- Ethyl formate (3f) (10.0 g, 30.6 mmol) and 4-cyano-1iodobenzene (14.0 g, 61.1 mmol) dissolved in 1.4-dioxane (100 mL), added cuprous iodide (583 mg) , 3.0 mmol) and potassium phosphate (13.0 g, 61.1 mmol) were added to hydrazine, hydrazine-dimethylcyclohexylamine (427 mg, 3.0 mmol) under nitrogen, and heated to 10 ° C for 16 hours. The reaction solution was cooled to room temperature, then dichloromethane (100 mL) was added, filtered, and the filter cake was washed with methylene chloride (50 mL EtOAc). (Dichloromethane: ethyl acetate (v/v) = 1: 0-9: 1) Compound 1- (benzofuran-5-yl)-6-[4-cyanobenzene obtained as a pale yellow solid Ethyl 7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (25B) (9.0 g, yield 69%).
¾ NMR (400 MHz, CDC13) δ 7.68 - 7.63 (m,2H), 7.49 - 7.44 (m, 2H), 7.36 - 7.33 (m, IH), 7.24 (dd, IH), 6.78 (d, IH), 4.61 (t, 2H), 4.46 (q, 2H), 4.16 (t, 2H), 3.35 (t, 2H), 3.23 (t, 2H), 1.43 (t, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.68 - 7.63 (m, 2H), 7.49 - 7.44 (m, 2H), 7.36 - 7.33 (m, IH), 7.24 (dd, IH), 6.78 (d, IH) , 4.61 (t, 2H), 4.46 (q, 2H), 4.16 (t, 2H), 3.35 (t, 2H), 3.23 (t, 2H), 1.43 (t, 3H).
第二步： 1- (苯并呋喃 -5-基;) -6-[4-氰基苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡啶 -3-甲酰 胺 （25C)  Second step: 1-(benzofuran-5-yl;)-6-[4-cyanophenyl]-7-oxo-4,5-dihydro-IH-pyrazolo[3,4- c]pyridine-3-carboxamide (25C)
l-(benzofuran-5-yl)-7-oxo-6-[4-Cyanophenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3- carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[4-Cyanophenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3- carboxamide
Figure imgf000102_0002
Figure imgf000102_0002
在封管中加入 1- (苯并呋喃 -5-基;) -6-[4-氰基苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3- 甲酸乙酯 (25B) (1.4 g, 3.3 mmol) , 加入甲醇 (8 mL) 和氨水 (25%, 0.56 g, 33.0 mmol) , 升温至 90°C反应 24小时。 将反应液冷却至 室温， 加入二氯甲垸 （50 mL) 和水（50 mL), 分 液， 水相用二氯甲垸（20 mL X 2)萃取， 合并有机相， 有机层用饱和食盐水（30 mL X 2) 洗涤， 无水硫酸钠干燥， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯： 石油醚 i N、 =1 : 19-2:4) 得到标题化合物 1- (苯并呋喃 -5-基;) -6-[4-氰基苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3, 4-c]吡啶 -3-甲酰胺（25C)， 白色固体（760 mg, 产率 58%)。 ¾ NMR (400 MHz, CDC13) δ 7.65 (d, 2H), 7.46 (d, 2H), 7.33 (s, IH), 7.24 (dd, IH), 6.85 (s, IH), 6.81 (d, IH), 5.65 (s, IH), 4.63 (t, 2H), 4.15 (t, 2H), 3.41 (t, 2H), 3.25 (t, 2H)。 Add 1-(benzofuran-5-yl;)-6-[4-cyanophenyl]-7-oxo-4,5-dihydro-1H-pyrazole[3,4] to the sealed tube. -c]Pyridine-3-carboxylic acid ethyl ester (25B) (1.4 g, 3.3 mmol), methanol (8 mL) and aqueous ammonia (25%, 0.56 g, 33.0 mmol) were added and the mixture was warmed to 90 ° C for 24 hours. The reaction solution was cooled to room temperature, and dichloromethane (50 mL) and water (50 mL) were added, and the mixture was separated. The aqueous phase was extracted with methylene chloride (20 mL), and the organic phase was combined. The mixture was washed with water (30 mL EtOAc) (EtOAcjjjjjj -(benzofuran-5-yl;)-6-[4-cyanophenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3 -carboxamide (25C), white solid (760 mg, yield 58%). 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.65 (d, 2H), 7.46 (d, 2H), 7.33 (s, IH), 7.24 (dd, IH), 6.85 (s, IH), 6.81 (d, IH ), 5.65 (s, IH), 4.63 (t, 2H), 4.15 (t, 2H), 3.41 (t, 2H), 3.25 (t, 2H).
LCMS m/z =400.1 [M+l]  LCMS m/z = 400.1 [M+l]
第三步： 1- (苯并呋喃 -5-基) -6-[4-(l ,2,3,4-戊四唑 -5-基)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 25)  The third step: 1-(benzofuran-5-yl)-6-[4-(l,2,3,4-pentetazol-5-yl)phenyl]-7-oxo-4,5 -dihydro-IH-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 25)
l-(benzofuran-5-yl)-7-oxo-6-[4-(l ,2,3,4-tetrazole-5-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[4-(l,2,3,4-tetrazole-5-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine -3-carboxamide
Figure imgf000103_0001
Figure imgf000103_0001
在封管中， 加入 1- (苯并呋喃 -5-基;) -6-[4-氰基苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶- 3-甲酰胺 （25C) (300 mg, 0.75 mmol)、 叠氮钠 （73 mg, 1.13 mmol)、 三乙胺盐酸盐（156 mg, 1.13 mmol)和三乙胺 （759 mg, 7.5 mmol), 升温至 130°C密闭反应 12小时。 将反应液冷却至室 温， 加入二氯甲垸（30 mL)和水（30 mL)， 分液， 水相用二氯甲垸（10 mL)洗涤， 水相中加 入 NaOH溶液调节溶液 pH=13~14， 用二氯甲垸 （20 mL X 2)洗涤， 将水层减压浓缩， 残留 物用硅胶柱色谱分离提纯 （甲醇： 二氯甲垸（v/v) = 1 : 19 ~2:23)得到标题化合物 25， 黄色固体 (70 mg, 产率 21%)。  In the sealed tube, 1-(benzofuran-5-yl;)-6-[4-cyanophenyl]-7-oxo-4,5-dihydro-1H-pyrazole[3, 4-c]pyridine-3-carbamide (25C) (300 mg, 0.75 mmol), sodium azide (73 mg, 1.13 mmol), triethylamine hydrochloride (156 mg, 1.13 mmol) and triethylamine ( 759 mg, 7.5 mmol), warmed to 130 ° C for 12 hours. The reaction solution was cooled to room temperature, dichloromethane (30 mL) and water (30 mL) were added, and the mixture was separated. The aqueous phase was washed with dichloromethane (10 mL). ~14, Washing with dichloromethane (20 mL X 2), the aqueous layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: chloroform (v/v) = 1: 19~2: 23) The title compound 25 was obtained (yield: 70 mg, yield 21%).
¾ NMR (400 MHz, DMSO) δ 8.05 (d, 2H), 7.73 (s, IH), 7.60 (d, 2H), 7.45 (d, 2H), 7.29 (d, IH), 6.82 (d, IH), 4.60 (t, 2H), 4.14 (t, 2H), 3.21 (m, 4H)。  3⁄4 NMR (400 MHz, DMSO) δ 8.05 (d, 2H), 7.73 (s, IH), 7.60 (d, 2H), 7.45 (d, 2H), 7.29 (d, IH), 6.82 (d, IH) , 4.60 (t, 2H), 4.14 (t, 2H), 3.21 (m, 4H).
LCMS m/z =443.1 [M+l] 实施例 26  LCMS m/z = 443.1 [M+l] Example 26
l-(2,3-二氢苯并呋喃 -5-基) -3-(l-羟基环丙基) -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 L-(2,3-Dihydrobenzofuran-5-yl)-3-(l-hydroxycyclopropyl)-6-[4-(2-oxo-1-piperidinyl)phenyl] -4 5-dihydropyrazole
[3,4-c]吡啶 -7-酮 （化合物 26) [3,4-c]pyridine-7-one (Compound 26)
l-(2,3-dihydrobenzofuran-5-yl)-3-(l-hydroxycyclopropyl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin-7-one  L-(2,3-dihydrobenzofuran-5-yl)-3-(l-hydroxycyclopropyl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c ]pyridin-7-one
Figure imgf000103_0002
Figure imgf000104_0001
第一步： l-(2,3-二氢苯并呋喃 -5-基) -3-乙酰基 -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c]吡啶 -7-酮 （26B)
Figure imgf000103_0002
Figure imgf000104_0001
First step: l-(2,3-Dihydrobenzofuran-5-yl)-3-acetyl-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5 -dihydropyrazolo[3,4-c]pyridine-7-one (26B)
3-acetyl-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin-7-one  3-acetyl-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin-7 -one
Figure imgf000104_0002
Figure imgf000104_0002
将原料 1-(2,3-二氢苯并呋喃 -5-基) -3-(1-羟乙基 )-6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c]吡啶 -7-酮 （化合物 20) (500 mg, 1.06 mmol)溶于干燥二氯甲垸 (10 mL) 中， 氮气保护 下冷却至 0°C， 加入戴斯 -马丁氧化剂 （539 mg, 1 ,27 mmol), (TC搅拌 10分钟后升至室温反应 过夜。 加入饱和碳酸氢钠 （10 mL), 分液， 水层用二氯甲垸 （20 mL X 2) 萃取， 合并有机 层， 有机相用饱和氯化钠 （10 mL X 2)洗涤， 无水硫酸钠干燥， 减压浓缩， 残留物用硅胶 柱色谱分离提纯 （石油醚： 乙酸乙酯 i N、 =1 : 1-0: 1) 得到标题化合物 1-(2,3-二氢苯并呋喃 -5- 基) -3 -乙酰基 -6- [4-(2-氧代 - 1 -哌啶）苯基] -4,5-二氢吡唑并 [3 ,4-c]吡啶 -7-酮 （26B)， 白色固体 (400 mg, 产率 80%)。  The starting material 1-(2,3-dihydrobenzofuran-5-yl)-3-(1-hydroxyethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl] - 4,5-Dihydropyrazolo[3,4-c]pyridin-7-one (Compound 20) (500 mg, 1.06 mmol) was dissolved in dry dichloromethane (10 mL). At 0 ° C, Add Dess-Martin Oxidizer (539 mg, 1 ,27 mmol), (TC stirred for 10 minutes, then allowed to react to room temperature overnight. Add saturated sodium bicarbonate (10 mL), separate the liquid, dichloro The hydrazine (20 mL X 2 ) was extracted and the organic layer was combined. The organic layer was washed with saturated sodium chloride (10 mL EtOAc) : ethyl acetate i N, =1 : 1-0: 1) The title compound 1-(2,3-dihydrobenzofuran-5-yl)-3-acetyl-6-[4-(2- Oxo- 1 -piperidinyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin-7-one (26B), white solid (400 mg, yield 80%).
^ NMR (400 MHz, CDC13) δ 7.53-7.24 (m, 6Η), 6.80 (d, 1H), 4.61 (t, 2H), 4.12-4.08 (m, 2H), 3.60-3.59 (m, 2H), 3.29 (dt, 4H), 2.65 (s, 3H), 2.57-2.54 (m, 2H), 1.94-1.93 (m, 4H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.53-7.24 (m, 6Η), 6.80 (d, 1H), 4.61 (t, 2H), 4.12-4.08 (m, 2H), 3.60-3.59 (m, 2H) , 3.29 (dt, 4H), 2.65 (s, 3H), 2.57-2.54 (m, 2H), 1.94-1.93 (m, 4H).
LC-MS:[M+1] 471.1  LC-MS: [M+1] 471.1
第二步： l-(2,3-二氢苯并呋喃 -5-基) -3-(l-叔丁基二甲基硅氧基乙烯基 )-6-[4-(2-氧代 -1-哌啶) 苯基] -4,5-二氢吡唑并 [3,4-c]吡啶 -7-酮 （26C)  The second step: l-(2,3-dihydrobenzofuran-5-yl)-3-(l-tert-butyldimethylsilyloxy)-6-[4-(2-oxo) 1-piperidinyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin-7-one (26C)
3-[l-[tert-butyl(dimethyl)silyl]oxyvinyl]-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l- piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin-7-one
Figure imgf000105_0001
3-[l-[tert-butyl(dimethyl)silyl]oxyvinyl]-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4, 5-dihydropyrazolo[3,4-c]pyridin-7-one
Figure imgf000105_0001
将 l-(2,3-二氢苯并呋喃 -5-基) -3-乙酰基 -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c]吡 啶 -7-酮 （26B) (370 mg， 0.79 mmol)溶于干燥的二氯甲垸（10 mL) 中， 氮气保护下加入 2,6-二 甲基吡啶 （126 mg, 1.18 mmol), 冷却至 0°C， 滴加叔丁基二甲硅基三氟甲磺酸酯 （270 mg, 1.02 mmol), 滴完后自然升温至室温反应过夜， 冰浴冷却， 滴加饱和碳酸氢钠 （ 5 mL)， 二氯 甲垸（10 mL X 3)萃取， 合并有机层， 有机相用饱和氯化钠 （10 mL X 2)洗涤， 无水硫酸 钠干燥， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚： 乙酸乙酯 （v/v) =3: 1-0: 1)得到 标题化合物 1-(2,3-二氢苯并呋喃 -5-基) -3-(1-叔丁基二甲基硅氧基乙烯基 )-6-[4-(2-氧代 -1-哌啶) 苯基] -4,5-二氢吡唑并 [3,4-c]吡啶 -7-酮 （26C)， 白色固体（370 mg， 产率 80%)。  1-(2,3-Dihydrobenzofuran-5-yl)-3-acetyl-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5-dihydro Pyrazolo[3,4-c]pyridin-7-one (26B) (370 mg, 0.79 mmol) was dissolved in dry dichloromethane (10 mL), and 2,6-dimethyl Pyridine (126 mg, 1.18 mmol), cooled to 0 ° C, tert-butyldimethylsilyl trifluoromethanesulfonate (270 mg, 1.02 mmol) was added dropwise, and then warmed to room temperature overnight, ice bath The organic layer was washed with saturated sodium chloride (10 mL×2) and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. EtOAcjjjjjjjjjj -yl)-3-(1-tert-butyldimethylsilyloxy)-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5-dihydropyrazole And [3,4-c]pyridine-7-one (26C), white solid (370 mg, yield 80%).
¾ NMR (400 MHz, CDC13) δ 7.32-7.02 (m, 8H), 6.71 (dd, 1H), 5.00-4.96 (m, 1H), 4.54-4.493⁄4 NMR (400 MHz, CDC1 3 ) δ 7.32-7.02 (m, 8H), 6.71 (dd, 1H), 5.00-4.96 (m, 1H), 4.54-4.49
(m, 2H), 4.45-3.99 (m, 1H), 3.53 (m, 2H), 3.28-3.06 (m, 4H), 2.50-2.48 (m, 2H), 1.87-1.86 (m, 4H), 1.04-0.79 (m, 9H), 0.17 (s, 3H), 0.01 -0.03 (m, 3H)» (m, 2H), 4.45-3.99 (m, 1H), 3.53 (m, 2H), 3.28-3.06 (m, 4H), 2.50-2.48 (m, 2H), 1.87-1.86 (m, 4H), 1.04 -0.79 (m, 9H), 0.17 (s, 3H), 0.01 -0.03 (m, 3H)»
LC-MS:[M+1] 585.3  LC-MS: [M+1] 585.3
第三步 l-(2,3-二氢苯并呋喃 -5-基 3-(l-叔丁基二甲基硅氧基环丙基 )-6-[4-(2-氧代 -1-哌啶) 苯基] -4,5-二氢吡唑并 [3,4-c]吡啶 -7-酮 （26D)  The third step l-(2,3-dihydrobenzofuran-5-yl 3-(l-tert-butyldimethylsilylcyclopropyl)-6-[4-(2-oxo-1 - piperidine) phenyl] -4,5-dihydropyrazolo[3,4-c]pyridin-7-one (26D)
3 - [ 1 - [tert-butyl(dimethyl)silyl] oxycyclopropyl] - 1 -(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo- 1 - piperidyl)phenyl]-4,5-dihydropyrazol -c]pyridin-7-one  3 - [ 1 - [tert-butyl(dimethyl)silyl] oxycyclopropyl] - 1 -(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo- 1 - piperidyl)phenyl]-4, 5-dihydropyrazol -c]pyridin-7-one
Figure imgf000105_0002
Figure imgf000105_0002
将 1-(2,3-二氢苯并呋喃 -5-基) -3-(1-叔丁基二甲基硅氧基乙烯基 )-6-[4-(2-氧代 -1-哌啶)苯基] - 4,5-二氢吡唑并 [3,4-c]吡啶 -7-酮 (26C) (100 mg, 0.17 mmol) 溶于干燥的二氯甲垸 (2 mL) 中， 氮气保护下冷却至 0°C， 加入二乙基锌 （2N的甲苯溶液 0.17 mL， 0.34 mmol), 搅拌 10分钟 再加入二碘甲垸（91 mg, 0.34 mmol)加完后， 0°C搅拌 5分钟再升至室温反应 20分钟， 加入饱 和氯化铵 （5 mL)， 分液， 水层用二氯甲垸（5 mL X 2)萃取， 合并有机层， 有机相用饱和氯 化钠 （5 mL)洗涤， 无水硫酸钠干燥， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚： 乙 酸乙酯 （v/v) =7:3-0: 1)得到标题化合物 1-(2,3-二氢苯并呋喃 -5-基) -3-(1-叔丁基二甲基硅氧基环 丙基) -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c]吡啶 -7-酮 （26D)， 白色固体 （50 mg, 产率 49%)。 1-(2,3-Dihydrobenzofuran-5-yl)-3-(1-tert-butyldimethylsiloxyvinyl)-6-[4-(2-oxo-1- Piperidine)Phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin-7-one (26C) (100 mg, 0.17 mmol) dissolved in dry dichloromethane (2 mL) Cool to 0 ° C under nitrogen, add diethylzinc (2N in toluene solution 0.17 mL, 0.34 mmol), stir for 10 minutes and then add diiodoguanidine (91 mg, 0.34 mmol), 0 ° C was stirred for 5 minutes and then allowed to react to room temperature for 20 minutes. Saturated ammonium chloride (5 mL) was added and the mixture was separated. The aqueous layer was extracted with methylene chloride (5 mL EtOAc). The residue was washed with EtOAc (EtOAc) (EtOAc. -(2,3-dihydrobenzofuran-5-yl)-3-(1-tert-butyldimethylsilylcyclopropyl)-6-[4-(2-oxo-1-piperidin Pyridinium phenyl] -4,5-dihydropyrazolo[3,4-c]pyridin-7-one (26D), white solid (50 mg, Yield 49%).
O NMR (400 MHz, CDC13) δ 7.34 (m, 3H), 7.22 (m, 3H), 6.75 (d, 1H), 4.57 (t, 2H), 4.10-4.08 (m, 2H), 3.61 (m, 2H), 3.21 (t, 2H), 3.13 (t, 2H), 2.62 (m, 2H), 1.94 (m, 4H), 1.10-1.06 (m, 4H), 0.85 (s, 9H), 0.05 (s, 6H)。 O NMR (400 MHz, CDC1 3 ) δ 7.34 (m, 3H), 7.22 (m, 3H), 6.75 (d, 1H), 4.57 (t, 2H), 4.10-4.08 (m, 2H), 3.61 (m , 2H), 3.21 (t, 2H), 3.13 (t, 2H), 2.62 (m, 2H), 1.94 (m, 4H), 1.10-1.06 (m, 4H), 0.85 (s, 9H), 0.05 ( s, 6H).
第四步： l-(2,3-二氢苯并呋喃 -5-基) -3-(l-羟基环丙基) -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢 吡唑并 [3,4-c]吡啶 -7-酮 （化合物 26)  The fourth step: l-(2,3-dihydrobenzofuran-5-yl)-3-(l-hydroxycyclopropyl)-6-[4-(2-oxo-1-piperidine)benzene -4,5-Dihydropyrazolo[3,4-c]pyridin-7-one (Compound 26)
l-(2,3-dihydrobenzofuran-5-yl)-3-(l-hydroxycyclopropyl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin-7-one  L-(2,3-dihydrobenzofuran-5-yl)-3-(l-hydroxycyclopropyl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c ]pyridin-7-one
Figure imgf000106_0001
Figure imgf000106_0001
将 1-(2,3-二氢苯并呋喃 -5-基) -3-(1-叔丁基二甲基硅氧基环丙基 6-[4-(2-氧代 -1-哌啶)苯基] - 4,5-二氢吡唑并 [3,4-c]吡啶 -7-酮 （26D) (45 mg, 0.075 mmol) 溶于二氯甲垸与四氢呋喃的混 合溶剂 (v/v = 1/1 , 2 mL) 中，加入四丁基氟化铵 （196 mg, 0.75 mmol), 室温反应 2h， 加入 水（5 mL), 二氯甲垸（5 mL), 分液， 有机层用饱和氯化钠 （2 mL X 3)洗涤， 无水硫酸钠 干燥， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚： 乙酸乙酯 （v/v) =1 : 1-0: 1) 得到标 题化合物 1-(2,3-二氢苯并呋喃 -5-基) -3-(1-羟基环丙基) -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑 并 [3,4-c]吡啶 -7-酮（化合物 26)， 白色固体。  1-(2,3-Dihydrobenzofuran-5-yl)-3-(1-tert-butyldimethylsilylcyclopropyl 6-[4-(2-oxo-1-piperidin) Pyridinium phenyl] - 4,5-dihydropyrazolo[3,4-c]pyridin-7-one (26D) (45 mg, 0.075 mmol) in a mixed solvent of dichloromethane and tetrahydrofuran (v /v = 1/1 , 2 mL), add tetrabutylammonium fluoride (196 mg, 0.75 mmol), react at room temperature for 2 h, add water (5 mL), dichloromethane (5 mL), and separate. The organic layer was washed with EtOAc EtOAc (EtOAc m. 0: 1) The title compound 1-(2,3-dihydrobenzofuran-5-yl)-3-(1-hydroxycyclopropyl)-6-[4-(2-oxo-1-piperidine) was obtained. Acridine)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin-7-one (Compound 26), white solid.
^ NMR (400 MHz, CDC13) δ 7.34-7.30 (m, 3Η), 7.25-7.18 (m, 3H), 6.75 (d, 1H), 4.57 (t, 2H), 4.07 (t, 2H), 3.59-3.58 (m, 2H), 3.21 (t, 2H), 3.12 (t, 2H), 2.57-2.48 (m, 3H), 1.97-1.88 (m, 4H), 1.20 (m, 4H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.34-7.30 (m, 3Η), 7.25-7.18 (m, 3H), 6.75 (d, 1H), 4.57 (t, 2H), 4.07 (t, 2H), 3.59 -3.58 (m, 2H), 3.21 (t, 2H), 3.12 (t, 2H), 2.57-2.48 (m, 3H), 1.97-1.88 (m, 4H), 1.20 (m, 4H).
LC-MS:[M+1] 485.1 实施例 27  LC-MS: [M+1] 485.1 Example 27
l-(2,3-二氢苯并呋喃 -5-基) -3- (二氟甲基) -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c 吡啶 -7-酮 （化合物 27)  L-(2,3-Dihydrobenzofuran-5-yl)-3-(difluoromethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl] -4,5 -dihydropyrazolo[3,4-cpyridine-7-one (Compound 27)
3-(difluoromethyl)-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin-7-one  3-(difluoromethyl)-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin -7-one
Figure imgf000106_0002
Figure imgf000107_0001
Figure imgf000106_0002
Figure imgf000107_0001
第一步： l-(2,3-二氢苯并呋喃 -5-基;) -3- (二氟甲基; )-6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡 并 [3,4-c]吡啶 -7-酮（化合物 27)  First step: l-(2,3-dihydrobenzofuran-5-yl;)-3-(difluoromethyl; )-6-[4-(2-oxo-1-piperidine)benzene -4,5-dihydropyrazo[3,4-c]pyridin-7-one (Compound 27)
3-(difluoromethyl)-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin-7-one  3-(difluoromethyl)-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin -7-one
Figure imgf000107_0002
Figure imgf000107_0002
将 1 -(2,3-二氢苯并呋喃 -5-基;) -7-氧代 -6-[4-(2-氧代 - 1 -哌啶)苯基] -4,5-二氢吡唑并 [3,4-c]吡 啶 -3-醛 （500 mg, 1.09 mmol) 溶于干燥的二氯甲垸 （5 mL) 中， 氮气保护下， 干冰-丙酮冷 却至 -78 °C， 慢慢滴加二乙胺基三氟化硫 （DAST) (396 mg, 2.19 mmol), 加完后自然升温至 室温反应过夜， 加入饱和碳酸氢钠 （10 mL) , 分液， 水层用二氯甲垸 （15 mL X 2) 萃取， 合并有机层， 用饱和氯化钠 （10 mL X 2) 洗涤， 无水硫酸钠干燥， 减压浓缩， 残留物用硅 胶柱色谱分离提纯 （石油醚： 乙酸乙酯 （v/v) =1 : 1 -0: 1) 得到标题化合物 1 -(2,3-二氢苯并呋喃- 5-基) -3- (二氟甲基) -6-[4-(2-氧代 -1 -哌啶)苯基] -4,5-二氢吡唑并 [3,4-c]吡啶 -7-酮 （化合物 27)， 白 色固体（120 mg, 产率 23%)。  1-(2,3-dihydrobenzofuran-5-yl;)-7-oxo-6-[4-(2-oxo- 1 -piperidinyl)phenyl] -4,5-di Hydropyrazolo[3,4-c]pyridine-3-aldehyde (500 mg, 1.09 mmol) dissolved in dry methylene chloride (5 mL), cooled with nitrogen and evaporated to -78 ° C Diethylaminosulfur trifluoride (DAST) (396 mg, 2.19 mmol) was added dropwise slowly. After the addition, the mixture was warmed to room temperature overnight, then added saturated sodium bicarbonate (10 mL). The mixture was extracted with chloroform (15 mL EtOAc). EtOAc (EtOAc m. Ethyl acetate (v/v) =1 : 1 -0: 1) The title compound 1-(2,3-dihydrobenzofuran-5-yl)-3-(difluoromethyl)-6- [4-(2-oxo-1 -piperidinyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin-7-one (Compound 27), white solid (120 mg, Yield 23%).
¾ NMR (400 MHz, CDC13) δ 7.35-7.33 (m, 3H), 7.28-7.27 (m, IH), 7.25-7.22 (m, 2H), 6.93-3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.35-7.33 (m, 3H), 7.28-7.27 (m, IH), 7.25-7.22 (m, 2H), 6.93-
6.66 (t, IH), 6.79 (s, IH), 4.60 (t, 2H), 4.13 (t, 2H), 3.61 (m, 2H), 3.25-3.16 (m, 4H), 2.59 (m, 2H), 1.94 (m, 4H)。 6.66 (t, IH), 6.79 (s, IH), 4.60 (t, 2H), 4.13 (t, 2H), 3.61 (m, 2H), 3.25-3.16 (m, 4H), 2.59 (m, 2H) , 1.94 (m, 4H).
19F NMR (376 MHz, CDC13) δ -1 12.16. 19 F NMR (376 MHz, CDC1 3 ) δ -1 12.16.
LC-MS:[M+1] 479.1 实施例 28  LC-MS: [M+1] 479.1 Example 28
l-(2,3-二氢苯并呋喃 -5-基) -3- (—氟甲基) -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c] 吡啶 -7-酮 （化合物 28)  L-(2,3-Dihydrobenzofuran-5-yl)-3-(-fluoromethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl] -4,5 -Dihydropyrazolo[3,4-c]pyridin-7-one (Compound 28)
3-(fluoromethyl)-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin-7-one
Figure imgf000108_0001
3-(fluoromethyl)-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin -7-one
Figure imgf000108_0001
第一步： l-(2,3-二氢苯并呋喃 -5-基) -3- (—氟甲基) -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑 并 [3,4-c]吡啶 -7-酮（化合物 28)  First step: l-(2,3-dihydrobenzofuran-5-yl)-3-(-fluoromethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl] -4,5-dihydropyrazolo[3,4-c]pyridin-7-one (Compound 28)
3-(fluoromethyl)-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin-7-one  3-(fluoromethyl)-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin -7-one
Figure imgf000108_0002
Figure imgf000108_0002
将 1-(2,3-二氢苯并呋喃 -5-基) -3- (羟甲基) -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c] 吡啶 -7-酮 (600 mg， 1.3 mmol)溶于干燥的二氯甲垸（10 mL) 中， 氮气保护下， 干冰-丙酮冷 却至 -78 °C， 慢慢滴加二乙胺基三氟化硫 （DAST) (356 mg, 1.96 mmol),加完后 -78 °C反应 lh, 升至室温， 加入饱和碳酸氢钠 （10 mL)， 分液， 水层用二氯甲垸（10 mL X 2)萃取， 合并有 机层， 用饱和氯化钠 （10 mL)洗涤， 无水硫酸钠干燥， 减压浓缩， 残留物用硅胶柱色谱分离 提纯 （石油醚： 乙酸乙酯 （v/v) =1 : 1-0: 1)得到标题化合物 1-(2,3-二氢苯并呋喃 -5-基;) -3- (—氟甲 基) -6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c]吡啶 -7-酮 （化合物 28)， 白色固体 （250 mg, 产率 42%)。  1-(2,3-Dihydrobenzofuran-5-yl)-3-(hydroxymethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5 -Dihydropyrazolo[3,4-c]pyridin-7-one (600 mg, 1.3 mmol) dissolved in dry dichloromethane (10 mL). °C, slowly add dropwise diethylamine trifluoride (DAST) (356 mg, 1.96 mmol), add -78 °C for 1 h, add to room temperature, add saturated sodium bicarbonate (10 mL), The mixture was separated with EtOAc (EtOAc) (EtOAc m. Purification (petroleum ether: ethyl acetate (v/v) = 1 : 1 - 0: 1) to give the title compound 1-(2,3-dihydrobenzofuran-5-yl; -6-[4-(2-Oxo-1-piperidine)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin-7-one (Compound 28), white Solid (250 mg, yield 42%).
¾ NMR (400 MHz, CDC13) δ 7.37-7.31 (m, 3H), 7.26-7.25 (m, 3H), 6.77 (d, 1H), 5.50 (d, 2H), 4.59 (t, 2H), 4.12 (t, 2H), 3.60-3.59 (m, 2H), 3.22 (t, 2H), 3.09 (t, 2H), 2.57-2.55 (m, 2H), 1.94 -1.93 (m, 4H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.37-7.31 (m, 3H), 7.26-7.25 (m, 3H), 6.77 (d, 1H), 5.50 (d, 2H), 4.59 (t, 2H), 4.12 (t, 2H), 3.60-3.59 (m, 2H), 3.22 (t, 2H), 3.09 (t, 2H), 2.57-2.55 (m, 2H), 1.94 -1.93 (m, 4H).
9F NMR (376 MHz, CDC13) δ -21 1.24 9 F NMR (376 MHz, CDC1 3 ) δ -21 1.24
LC-MS:[M+1] 461.1 实施例 29  LC-MS: [M+1] 461.1 Example 29
1- (苯并呋喃 -5-基;) -6-[2-氟 -4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡 啶 -3-甲酰胺 （化合物 22) 1-(benzofuran-5-yl;)-6-[2-fluoro-4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5-dihydro- 1H-pyrazolo[3,4-c]pyridyl Pyridine-3-carboxamide (compound 22)
l-(benzof mn-5-yl)-7-oxo-6-[2-fluoro-4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropymzolo[3，4- c]pyridine-3-carboxamide  L-(benzof mn-5-yl)-7-oxo-6-[2-fluoro-4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropymzolo[3,4- c]pyridine- 3-carboxamide
Figure imgf000109_0001
第一步： N-(3-氟 -4溴苯基 )-5-氯戊酰胺 (29B)
Figure imgf000109_0001
First step: N-(3-fluoro-4-bromophenyl)-5-chloropentanamide (29B)
N-(3-fluoro-4-bromophenyl)-5-chloropentanamide  N-(3-fluoro-4-bromophenyl)-5-chloropentanamide
Figure imgf000109_0002
将 3-氟 -4-溴苯胺 (5.7 g, 0.03 mol)溶于二氯甲垸 (100 mL) 中， 加入三乙胺 (8.3 mL, 0.06 mol), 冷却至 0°C， 滴加 5-氯戊酰氯 （6 mL, 0.045 mol)， 升至室温反应 3小时。 向反应液中 加入水（200 mL), 分液， 有机相用饱和食盐水（100 mL)洗涤， 无水硫酸钠干燥， 浓缩， 得 标题化合物 N-(3-氟 -4溴苯基 )-5-氯戊酰胺 （29B)， 浅黄色固体 （9.2 g,产率 100%)。
Figure imgf000109_0002
3-Fluoro-4-bromoaniline (5.7 g, 0.03 mol) was dissolved in dichloromethane (100 mL), triethylamine (8.3 mL, 0.06 mol) was added, cooled to 0 ° C, and added dropwise 5- Chloropentanoyl chloride (6 mL, 0.045 mol) was allowed to react to room temperature for 3 hours. Water (200 mL) was added to the reaction mixture and the mixture was evaporated. 5-chloropentanamide (29B), light yellow solid (9.2 g, yield 100%).
'Η NMR (400 MHz, CDC13) δ 7.62 (dd, 1Η), 7.47-7.40 (m, 2H), 7.08 (dd, 1H), 3.60-3.48 (m, 2H), 2.45-2.40 (m, 2H), 1.88 (m, 2H), 1.28-1.25 (m, 2H)。 'Η NMR (400 MHz, CDC1 3 ) δ 7.62 (dd, 1Η), 7.47-7.40 (m, 2H), 7.08 (dd, 1H), 3.60-3.48 (m, 2H), 2.45-2.40 (m, 2H ), 1.88 (m, 2H), 1.28-1.25 (m, 2H).
第二步： l-(3-氟 -4溴苯基)哌啶 -2-酮 （29C)  Step 2: l-(3-Fluoro- 4 bromophenyl)piperidin-2-one (29C)
l-(3-fluoro-4-bromophenyl)piperidin- -one  L-(3-fluoro-4-bromophenyl)piperidin- -one
Figure imgf000109_0003
Figure imgf000109_0003
将 N-(3-氟 -4溴苯基 )-5-氯戊酰胺 （29B) (9.2 g, 0.03 mol) 溶于四氢呋喃 （50 mL) 中， 冷 却至 0°C， 分批加入氢化钠 （2.4 g, 0.06 mol), 升至常温反应 4小时。 将反应液冷却至 (TC， 滴 加水 （10 mL), 加入饱和食盐水 （100 mL), 分液， 有机层用乙酸乙酯萃取 （100 mL) , 合并 有机相， 有机相用饱和食盐水 （100 mL) 洗涤， 无水硫酸钠干燥， 浓缩， 残留物用 30%乙酸 乙酯 /石油醚重结晶得到标题化合物 l-(3-氟 -4溴苯基)哌啶 -2-酮 （29C)， 浅黄色固体（7.3 g, 产 率 90%)。 N-(3-Fluoro-4-bromophenyl)-5-chloropentanamide (29B) (9.2 g, 0.03 mol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0 ° C. 2.4 g, 0.06 mol), raised to room temperature for 4 hours. The reaction mixture was cooled to EtOAc (EtOAc (EtOAc) (EtOAc) 100 mL) Wash, dry over anhydrous sodium sulfate, concentrate, residue with 30% acetic acid The ethyl ester/petroleum ether was recrystallized to give the title compound l-(3-fluoro-4-bromophenyl)piperidin-2-one (29C) as a pale yellow solid (7.3 g, yield 90%).
^ NMR (400 MHz, CDC13) δ 7.55 (dd, 1Η), 7.11 (dd, 1H), 6.98 (ddd, 1H), 3.65-3.62 (m, 2H), 2.56 (t , 2H), 1.99-1.94 (m, 4H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.55 (dd, 1Η), 7.11 (dd, 1H), 6.98 (ddd, 1H), 3.65-3.62 (m, 2H), 2.56 (t , 2H), 1.99-1.94 (m, 4H).
第三步： 1- (苯并呋喃 -5-基) -6-[2-氟 -4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （22D)  The third step: 1-(benzofuran-5-yl)-6-[2-fluoro-4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5- Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (22D)
Ethyl l-(benzofuran-5-yl)-7-oxo-6-[2-fluoro-4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxylate  Ethyl l-(benzofuran-5-yl)-7-oxo-6-[2-fluoro-4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine- 3-carboxylate
Figure imgf000110_0001
Figure imgf000110_0001
将 l-(2,3-二氢吡啶呋喃 -5-基) -7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （3f) (1.96 g, 6 mmol)和 1-(3-氟 -4溴苯基)哌啶 -2-酮 (29C) (1.63 g, 6 mmol)溶于 1.4-二氧六环 (50 mL) 中， 加入磷酸钾 (2.54 g, 12 mmol), 在氮气氛围下， 加入碘化亚铜 (114 mg, 0.6 mmol) 和 Ν,Ν-二甲基环己胺 （87 mg, 0.6 mmol), 加热至 110°C反应 2天。 将反应液冷却至常温， 垫硅 藻土过滤， 滤液减压浓缩， 残留物用硅胶柱色谱分离提纯 （甲醇 /二氯甲垸 （v/v) =0: 1-2:98) 得到浅黄色固体状的化合物 1- (苯并呋喃 -5-基) -6-[2-氟 -4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二 氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （22D) (140 mg， 产率 5%)。  1-(2,3-Dihydropyridylfuran-5-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3- Ethyl formate (3f) (1.96 g, 6 mmol) and 1-(3-fluoro-4-bromophenyl)piperidin-2-one (29C) (1.63 g, 6 mmol) dissolved in 1.4-dioxane (50 mL), potassium phosphate (2.54 g, 12 mmol) was added, and copper iodide (114 mg, 0.6 mmol) and hydrazine, hydrazine-dimethylcyclohexylamine (87 mg, 0.6) were added under a nitrogen atmosphere. Methyl), heated to 110 ° C for 2 days. The reaction liquid was cooled to room temperature, and the mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / methylene chloride (v/v) =0: 1-2:98) Solid compound 1-(benzofuran-5-yl)-6-[2-fluoro-4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5- Ethyl dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (22D) (140 mg, 5% yield).
^ NMR (400 MHz, CDC13) δ 7.37-7.32 (m, 3Η), 7.13-7.06 (m, 2H), 6.77 (d, 1H), 4.60 (t, 2H), 4.46 (q, 2H), 4.03 (t, 2H), 3.60 (m, 2H), 3.34 (t, 2H), 3.22 (t, 2H), 2.58 (m, 2H), 1.94 (m, 4H), 1.43 (m, 3H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.37-7.32 (m, 3Η), 7.13-7.06 (m, 2H), 6.77 (d, 1H), 4.60 (t, 2H), 4.46 (q, 2H), 4.03 (t, 2H), 3.60 (m, 2H), 3.34 (t, 2H), 3.22 (t, 2H), 2.58 (m, 2H), 1.94 (m, 4H), 1.43 (m, 3H).
第四步： 1- (苯并呋喃 -5-基;) -6-[2-氟 -4-(2-氧代哌啶 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 22)  The fourth step: 1-(benzofuran-5-yl;)-6-[2-fluoro-4-(2-oxopiperidin-1-yl;)phenyl]-7-oxo-4, 5-Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 22)
l-(benzofuran-5-yl)-7-oxo-6-[2-fluoro-4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[2-fluoro-4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3 -carboxamide
Figure imgf000110_0002
Figure imgf000110_0002
将 1- (苯并呋喃 -5-基;) -6-[2-氟 -4-(2-氧代哌啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c] 吡啶 -3-甲酸乙酯 (22D) (140mg, 0.27 mmol) 溶于 Ν,Ν-二甲基甲酰胺 (5 mL) 中， 加入甲酰 胺 （121 mg, 2.7 mmol), 甲醇钠 （29 mg, 0.54 mmol), 升温至 90°C反应过夜。 将反应液冷却 至常温， 加入水 （50 mL) , 用乙酸乙酯 （50 mL) 萃取， 合并有机相， 有机相用饱和食盐水 (50 mL)洗涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （二氯甲垸 /甲醇 （v/v) = 1 :0-98:2)得到标题化合物 1 - (苯并呋喃 -5-基;) -6-[2-氟 -4-(2-氧代哌啶 -1 -基;)苯基] -7-氧代 -4,5- 二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 22) (50 mg, 产率 38%)。 1-(benzofuran-5-yl;)-6-[2-fluoro-4-(2-oxopiperidin-1-yl)phenyl]-7-oxo-4,5-dihydro -1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (22D) (140 mg, 0.27 mmol) dissolved in hydrazine, dimethyl-dimethylformamide (5 mL) Amine (121 mg, 2.7 mmol), sodium methoxide (29 mg, 0.54 mmol). The reaction mixture was cooled to room temperature, EtOAc (EtOAc) (EtOAc)EtOAc. Purification by silica gel column chromatography (dichloromethane/methanol (v/v) = 1 : 0 - 98: 2) to give the title compound 1 - (benzofuran-5-yl;) -6-[2-fluoro- 4-(2-oxopiperidin-1-yl;)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide ( Compound 22) (50 mg, yield 38%).
¾ NMR (400 MHz, CDC13) δ 7.37-7.29 (m, 3H), 7.13-7.07 (m, 2H), 6.84 (s, 1H), 6.80 (d, 1H), 5.46 (s, 1H), 4.62 (m, 2H), 4.02 (t, 2H), 3.60 (m, 2H), 3.40 (t, 2H), 3.25 (t, 2H), 2.57 (t, 2H), 1.95- 1.93 (m, 4H)。 实施例 30 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.37-7.29 (m, 3H), 7.13-7.07 (m, 2H), 6.84 (s, 1H), 6.80 (d, 1H), 5.46 (s, 1H), 4.62 (m, 2H), 4.02 (t, 2H), 3.60 (m, 2H), 3.40 (t, 2H), 3.25 (t, 2H), 2.57 (t, 2H), 1.95- 1.93 (m, 4H). Example 30
l-(2,3-二氢苯并呋喃 -5-基) -3-(l-氟乙基 )-6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c] 吡啶 -7-酮 （化合物 30)  L-(2,3-Dihydrobenzofuran-5-yl)-3-(l-fluoroethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-4, 5-dihydropyrazolo[3,4-c]pyridin-7-one (Compound 30)
3-(l-fluoroethyl)-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[ -c]pyridin-7-one  3-(l-fluoroethyl)-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[-c]pyridin- 7-one
Figure imgf000111_0001
Figure imgf000111_0001
第一步： 1-(2,3-二氢苯并呋喃 -5-基) -3-(1-氟乙基 )-6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑 并 [3,4-c]吡啶 -7-酮（化合物 30)  First step: 1-(2,3-dihydrobenzofuran-5-yl)-3-(1-fluoroethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl -4,5-Dihydropyrazolo[3,4-c]pyridin-7-one (Compound 30)
3-(l-fluoroethyl)-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridin-7-one  3-(l-fluoroethyl)-l-(2,3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-l-piperidyl)phenyl]-4,5-dihydropyrazolo[3,4-c ]pyridin-7-one
Figure imgf000111_0002
Figure imgf000111_0002
将 1-(2,3-二氢苯并呋喃 -5-基) -3-(1-羟乙基 )-6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c 吡啶 -7-酮 (600 mg, 1.27 mmol) 溶于干燥的二氯甲垸 （10 mL) 中， 氮气保护下， 干冰 -丙酮 冷却至 -78 °C， 慢慢滴加二乙胺基三氟化硫 （DAST) (276 mg， 1.52 mmol), 加完后 -78。C反应 lh， 升至室温， 加入饱和碳酸氢钠 （5 mL), 分液， 水层用二氯甲烷 （20 mL X 2)萃取， 合 并有机层， 用饱和氯化钠 （10 mL X 2) 洗涤， 无水硫酸钠干燥， 减压浓缩， 残留物用硅胶 柱色谱分离提纯 （石油醚： 乙酸乙酯 （v/v) =1 : 1-0: 1) 得到标题化合物 1 -(2,3-二氢苯并呋喃 -5- 基) -3-(1 -氟乙基 )-6-[4-(2-氧代 -1-哌啶)苯基] -4,5-二氢吡唑并 [3,4-c]吡啶 -7-酮 （化合物 30)， 白色 固体（250 mg, 产率 42%)。 1-(2,3-Dihydrobenzofuran-5-yl)-3-(1-hydroxyethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-4 ,5-Dihydropyrazolo[3,4-c-pyridin-7-one (600 mg, 1.27 mmol) dissolved in dry dichloromethane (10 mL), dry ice-acetone After cooling to -78 °C, diethylamine trifluoride (DAST) (276 mg, 1.52 mmol) was added dropwise, and -78 after the addition. After reacting for 1 h, it was taken to room temperature. EtOAc (5 mL) was evaporated. The organic layer was dried (MgSO4jjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -dihydrobenzofuran-5-yl)-3-(1-fluoroethyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5-dihydropyrazole And [3,4-c]pyridine-7-one (Compound 30), white solid (250 mg, yield 42%).
lR NMR (400 MHz, CDC13) δ 7.35-7.33 (m, 3Η), 7.26-7.22 (m, 3H), 6.76 (d, 1H), 5.82 (dq, 1H), 4.58 (t, 2H), 4.18-4.05 (m, 2H), 3.60 (m, 2H), 3.22 (t, 2H), 3.14-3.1 1 (m, 2H), 2.56 (m, 2H), 1.93 (m, 4H), 1.79 (dd, 3H)。 lR NMR (400 MHz, CDC1 3 ) δ 7.35-7.33 (m, 3Η), 7.26-7.22 (m, 3H), 6.76 (d, 1H), 5.82 (dq, 1H), 4.58 (t, 2H), 4.18 -4.05 (m, 2H), 3.60 (m, 2H), 3.22 (t, 2H), 3.14-3.1 1 (m, 2H), 2.56 (m, 2H), 1.93 (m, 4H), 1.79 (dd, 3H).
1 F NMR (376 MHz, CDC13) δ -169.94 1 F NMR (376 MHz, CDC1 3 ) δ -169.94
LC-MS:[M+1] 475.1 实施例 31  LC-MS: [M+1] 475.1 Example 31
1- (苯并呋喃 -5-基) -6-[4-(5-氟 -2-氧代 -吡啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡 啶 -3-甲酰胺 （化合物 31)  1-(benzofuran-5-yl)-6-[4-(5-fluoro-2-oxo-pyridin-1-yl)phenyl]-7-oxo-4,5-dihydro-1H -pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 31)
l -(benzofuran-5-yl)-7-oxo-6-[4-(5-fluoro-2-oxo-pyridin-2-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide  l -(benzofuran-5-yl)-7-oxo-6-[4-(5-fluoro-2-oxo-pyridin-2-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine -3-carboxamide
Figure imgf000112_0001
Figure imgf000112_0001
第一步： 1- (苯并呋喃 -5-基) -6-[4-(5-氟 -2-氧代 -吡啶 -1 -基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （31B)  First step: 1-(benzofuran-5-yl)-6-[4-(5-fluoro-2-oxo-pyridin-1-yl)phenyl]-7-oxo-4,5- Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (31B)
l-(benzofuran-5-yl)-7-oxo-6-[4-(5-fluoro-2-oxo-pyridin-2-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxyalte
Figure imgf000113_0001
L-(benzofuran-5-yl)-7-oxo-6-[4-(5-fluoro-2-oxo-pyridin-2-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine -3-carboxyalte
Figure imgf000113_0001
将 l-(2,3-二氢吡啶呋喃 -5-基) -7-氧代 -4,5,6,7-四氢 -IH-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （31) (1.0 g, 1.9 mmol)溶于 1.4-二氧六环 (10 mL), 加入 5-氟吡啶 -2-酮 (236 mg, 2.1 mmol)和磷酸 钾 (806 g, 3.8 mmol) , 碘化亚铜 (36 mg, 0.19 mmol) 和 Ν,Ν-二甲基环己胺 (22 mg, 0.19 mmol) , 加热至 150°C， 反应 5小时。 将反应液冷却至常温， 倒入水 （30 mL) 中， 用乙酸乙酯 (30 mL X 2)萃取， 合并有机相， 有机相用饱和食盐水（30 mL)洗涤， 无水硫酸钠干燥， 过 滤， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （乙酸乙酯 /石油醚（v/v) =1 : 1-1 :0)得到浅黄色 固体状的化合物 1-(苯并呋喃 -5-基;) -6-[4-(5-氟 -2-氧代 -吡啶 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡唑 并 [3,4-c]吡啶 -3-甲酸乙酯 (31B) (700 mg, 产率 71%)。  1-(2,3-Dihydropyridylfuran-5-yl)-7-oxo-4,5,6,7-tetrahydro-IH-pyrazolo[3,4-c]pyridine-3- Ethyl formate (31) (1.0 g, 1.9 mmol) was dissolved in 1.4-dioxane (10 mL), and 5-fluoropyridin-2-one (236 mg, 2.1 mmol) and potassium phosphate (806 g, 3.8) Methyl iodide (36 mg, 0.19 mmol) and hydrazine, hydrazine-dimethylcyclohexylamine (22 mg, 0.19 mmol), heated to 150 ° C for 5 hours. The reaction solution was cooled to room temperature, poured into water (30 mL), EtOAc (EtOAc (EtOAc) Filtration, concentrating under reduced pressure, EtOAc (EtOAc/EtOAc (EtOAc) -yl;)-6-[4-(5-fluoro-2-oxo-pyridin-1-yl;)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3 , 4-c]pyridine-3-carboxylic acid ethyl ester (31B) (700 mg, yield 71%).
¾ NMR (400 MHz, CDC13) δ 7.50 - 7.43 (m, 2H), 7.43 - 7.34 (m, 4H), 7.25 (m, 2H), 6.77 (d, IH), 6.64 (dd, IH), 4.61 (t, 2H), 4.46 (q, 2H), 4.24 - 4.07 (m, 2H), 3.35 (t, 2H), 3.23 (t, 2H), 1.43 (t, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.50 - 7.43 (m, 2H), 7.43 - 7.34 (m, 4H), 7.25 (m, 2H), 6.77 (d, IH), 6.64 (dd, IH), 4.61 (t, 2H), 4.46 (q, 2H), 4.24 - 4.07 (m, 2H), 3.35 (t, 2H), 3.23 (t, 2H), 1.43 (t, 3H).
MS m/z (ESI): 515.1 [M+l]  MS m/z (ESI): 515.1 [M+l]
第二步 : The second step :
1- (苯并呋喃 -5-基) -6-[4-(5-氟 -2-氧代 -吡啶 -1-基)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡 啶 -3-甲酰胺 （化合物 31)  1-(benzofuran-5-yl)-6-[4-(5-fluoro-2-oxo-pyridin-1-yl)phenyl]-7-oxo-4,5-dihydro-IH -pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 31)
l-(benzofuran-5-yl)-7-oxo-6-[4-(5-fluoro-2-oxo-pyridin-2-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[4-(5-fluoro-2-oxo-pyridin-2-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine -3-carboxamide
Figure imgf000113_0002
Figure imgf000113_0002
将 1 - (苯并呋喃 -5-基) -6-[4-(5-氟 -2-氧代 -吡啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c] 吡啶 -3-甲酸乙酯 (31B) (700 mg, 1.66 mmol) 溶于 Ν,Ν-二甲基甲酰胺 (10 mL) 中， 加入甲 酰胺 （612 mg, 13.6 mmol), 甲醇钠 （294 mg, 5.44 mmol) , 升温至 80°C反应 4小时。 将反应 液浓缩， 残留物中加入二氯甲垸 （30 mL) , 依次用水 （30 mL X 2)、 饱和食盐水 （30 mL X 2) 洗涤， 无水硫酸钠干燥， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （二氯甲垸： 甲醇 (v/v) = 50: 1 ~ 20: 1)得到标题化合物 1- (苯并呋喃 -5-基；) -6-[4-(5-氟 -2-氧代 -吡啶 -1 -基)苯基] -7- 氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡啶 -3-甲酰胺（化合物 31) (110 mg, 产率 17 %)。 1-(Benzofuran-5-yl)-6-[4-(5-fluoro-2-oxo-pyridin-1-yl)phenyl]-7-oxo-4,5-dihydro- Ethyl 1H-pyrazolo[3,4-c]pyridine-3-carboxylate (31B) (700 mg, 1.66 mmol) dissolved in hydrazine, hexane-dimethylformamide (10 mL) 612 mg, 13.6 mmol), sodium methoxide (294 mg, 5.44 mmol), warmed to 80 ° C for 4 h. The reaction mixture was concentrated, and dichloromethane (30 mL) was evaporated, evaporated, evaporated, Purification by silica gel column chromatography (dichloromethane:methanol (v/v) = 50:1 to 20:1) to give the title compound 1- (benzofuran-5-yl;) -6-[4-(5 -fluoro-2-oxo-pyridin-1-yl)phenyl]-7- Oxo-4,5-dihydro-IH-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 31) (110 mg, yield 17%).
^ NMR (400 MHz, DMSO) δ 7.93 (dd, IH), 7.68 (m, 2H), 7.52 - 7.41 (m, 6H), 7.30 (dd, IH), 6.81 (d, IH), 6.52 (dd, IH), 4.60 (t, 2H), 4.09 (t, 2H), 3.26 - 3.15 (m, 4H)。  ^ NMR (400 MHz, DMSO) δ 7.93 (dd, IH), 7.68 (m, 2H), 7.52 - 7.41 (m, 6H), 7.30 (dd, IH), 6.81 (d, IH), 6.52 (dd, IH), 4.60 (t, 2H), 4.09 (t, 2H), 3.26 - 3.15 (m, 4H).
MS m/z (ESI): 486.1 [M+l] 实施例 32  MS m/z (ESI): 486.1 [M+l] EXAMPLE 32
1- (苯并呋喃 -5-基) -6-[4-(3-氟 -2-氧代 -吡啶 -1-基)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡 啶 -3-甲酰胺 （化合物 32)  1-(benzofuran-5-yl)-6-[4-(3-fluoro-2-oxo-pyridin-1-yl)phenyl]-7-oxo-4,5-dihydro-IH -pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 32)
l-(benzofuran-5-yl)-7-oxo-6-[4-(3-fluoro-2-oxo-pyridin-2-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[4-(3-fluoro-2-oxo-pyridin-2-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine -3-carboxamide
Figure imgf000114_0001
Figure imgf000114_0001
第一步：  The first step:
1- (苯并呋喃 -5-基) -6-[4-(3-氟 -2-氧代 -吡啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡 啶 -3-甲酸乙酯 （32B)  1-(benzofuran-5-yl)-6-[4-(3-fluoro-2-oxo-pyridin-1-yl)phenyl]-7-oxo-4,5-dihydro-1H -pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (32B)
Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-(3-fluoro-2-oxo-pyridin-2-yl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxylate  Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-(3-fluoro-2-oxo-pyridin-2-yl)phenyl]-4,5- dihydropyrazolo[3,4-c] Pyridine-3-carboxylate
Figure imgf000114_0002
Figure imgf000114_0002
将 l-(2,3-二氢苯并呋喃 -5-基) -6-(4-碘苯基 )-7-氧 -4,5,6,7-四氢 -IH-吡唑 [3,4-c]吡啶 -3-甲酸乙 酯 （1.0g， 1.9 mmol)溶于 1,4-二氧六环 （10 mL) 中， 氮气保护下加入 3-氟吡啶 -2-醇 （236 mg 1-(2,3-Dihydrobenzofuran-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-IH-pyrazole [3] , 4-c]pyridine-3-carboxylic acid ethyl ester (1.0 g, 1.9 mmol) dissolved in 1,4-dioxane (10 mL), 3-fluoropyridin-2-ol (236 mg)
2.1 mmol), 磷酸钾 (806 mg 3.8 mmol), 碘化亚铜 (36 mg 0.19 mmol), 反 -(1R,2R)-N,N'-二甲 基 1,2-环己垸二胺（27 mg 0.19 mmol), 微波 150度反应 4小时。 反应结束后， 加入 20 mL EA， 水洗 2次（20 mL X 2), 饱和食盐水洗涤 1次（20 mL x 1), 无水硫酸钠干燥， 减压浓缩， 残留 物用硅胶柱柱色谱分离提纯 （乙酸乙酯： 石油醚（v/v) =1 :5-1 :2) 的标题化合物 1- (苯并呋喃 -5- 基) -6-[4-(3-氟 -2-氧代 -吡啶 - 1 -基)苯基] -7-氧代 -4,5-二氢 - 1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 (32B), 灰白的固体（0.7g， 产率 71.4%)。 2.1 mmol), potassium phosphate (806 mg 3.8 mmol), cuprous iodide (36 mg 0.19 mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexyl diamine ( 27 mg 0.19 mmol), microwave reaction at 150 ° for 4 hours. After the reaction was completed, 20 mL of EA was added, washed twice with water (20 mL X 2), and washed once with brine (20 mL×1), dried over anhydrous sodium sulfate The title compound 1-(benzofuran-5-yl)-6-[4-(ethyl acetate: petroleum ether (v/v) = 1 : 5-1 : 2) was purified by silica gel column chromatography. Ethyl 3-fluoro-2-oxo-pyridine-1-yl)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (32B), off-white solid (0.7 g, yield 71.4%).
¾ NMR (400 MHz, CDC13) δ 7.47 (d, 2H), 7.41 (d, 2H), 7.37 (s, IH), 7.28 (d, IH), 7.18 (dd, IH), 7.14 (dd, IH), 6.78 (d, IH), 6.18 (dd, IH), 4.61 (t, 2H), 4.47 (q, 2H), 4.18 (t, 2H), 3.35 (t, 2H), 3.23 (t, 2H), 1.49 - 1.39 (m, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.47 (d, 2H), 7.41 (d, 2H), 7.37 (s, IH), 7.28 (d, IH), 7.18 (dd, IH), 7.14 (dd, IH ), 6.78 (d, IH), 6.18 (dd, IH), 4.61 (t, 2H), 4.47 (q, 2H), 4.18 (t, 2H), 3.35 (t, 2H), 3.23 (t, 2H) , 1.49 - 1.39 (m, 3H).
MS m/z (ESI): 515.1 [M+l]  MS m/z (ESI): 515.1 [M+l]
第二步： 1- (苯并呋喃 -5-基) -6-[4-(3-氟 -2-氧代 -吡啶 -1-基;)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 32)  The second step: 1-(benzofuran-5-yl)-6-[4-(3-fluoro-2-oxo-pyridin-1-yl;)phenyl]-7-oxo-4,5 -dihydro-IH-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 32)
l-(benzofuran-5-yl)-7-oxo-6-[4-(3-fluoro-2-oxo-pyridin-2-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[4-(3-fluoro-2-oxo-pyridin-2-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine -3-carboxamide
Figure imgf000115_0001
Figure imgf000115_0001
将 1- (苯并呋喃 -5-基) -6-[4-(3-氟 -2-氧代 -吡啶 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c] 吡啶 -3-甲酸乙酯（32B) (0.7g 1.36 mmol)溶于 Ν,Ν-二甲基甲酰胺 （10 mL) 中， 加入甲醇钠 (294 mg 5.44 mmol), 甲酰胺 （612 mg 13.6 mmol), 80度反应过夜。 将反应液减压除去 Ν,Ν- 二甲基甲酰胺， 加入二氯甲垸 （30 mL) 溶解残留物， 依次用水 （30 mL x 2)、 饱和食盐水 (30 mL X 2) 洗涤， 无水硫酸钠干燥， 减压浓缩， 残留物用硅胶柱柱色谱分离提纯 （乙酸乙 酯： 石油醚（v/v) =1 :5-1 :)得标题化合物 1- (苯并呋喃 -5-基;) -6-[4-(3-氟 -2-氧代 -吡啶 -1-基；)苯基] - 7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合物 32)， 类白色固体（0.2g 30.3%)。  1-(Benzofuran-5-yl)-6-[4-(3-fluoro-2-oxo-pyridin-1-yl)phenyl]-7-oxo-4,5-dihydro- Ethyl 1H-pyrazolo[3,4-c]pyridine-3-carboxylate (32B) (0.7 g 1.36 mmol) was dissolved in hydrazine, hexane-dimethylformamide (10 mL). Mg 5.44 mmol), formamide (612 mg 13.6 mmol), reacted overnight at 80 °C. The reaction solution was dehydrated to remove hydrazine, hydrazine-dimethylformamide, and the residue was dissolved in dichloromethane (30 mL), and washed with water (30 mL x 2) and saturated brine (30 mL X 2 ) The residue was dried over EtOAc (EtOAc m. ;; 6-[4-(3-fluoro-2-oxo-pyridin-1-yl;)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3, 4-c]pyridine-3-carboxamide (Compound 32), off-white solid (0.2 g 30.3%).
^ NMR (400 MHz, CDC13) δ 7.47 (d, 2H), 7.41 (d, 2H), 7.36 (s, IH), 7.31 - 7.26 (m, IH), 7.21^ NMR (400 MHz, CDC1 3 ) δ 7.47 (d, 2H), 7.41 (d, 2H), 7.36 (s, IH), 7.31 - 7.26 (m, IH), 7.21
- 7.15 (m, IH), 7.15 - 7.10 (m, IH), 6.82 (m, 2H), 6.18 (m, IH), 5.50 (s, IH), 4.62 (t, 2H), 4.17 (t, 2H), 3.41 (t, 2H), 3.25 (t, 2H)。 - 7.15 (m, IH), 7.15 - 7.10 (m, IH), 6.82 (m, 2H), 6.18 (m, IH), 5.50 (s, IH), 4.62 (t, 2H), 4.17 (t, 2H ), 3.41 (t, 2H), 3.25 (t, 2H).
MS m/z (ESI): 486.0 [M+l] 实施例 33  MS m/z (ESI): 486.0 [M+l] EXAMPLE 33
1- (苯并呋喃 -5-基) -6-[4-(2-氧代吡嗪 -1-基)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡啶 -3- 甲酰胺 （化合物 33)  1-(benzofuran-5-yl)-6-[4-(2-oxopyrazine-1-yl)phenyl]-7-oxo-4,5-dihydro-IH-pyrazole [3,4-c]pyridine-3-carboxamide (compound 33)
l-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-pyrazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide
Figure imgf000116_0001
L-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-pyrazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide
Figure imgf000116_0001
第一步： 1- (苯并呋喃 -5-基) -6-[4-(2-氧代吡嗪 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c] 吡啶 -3-甲酰胺 （化合物 33)  First step: 1-(benzofuran-5-yl)-6-[4-(2-oxopyrazine-1-yl)phenyl]-7-oxo-4,5-dihydro-1H -pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 33)
l-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-pyrazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-pyrazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide
Figure imgf000116_0002
Figure imgf000116_0002
1- (苯并呋喃 -5-基) -6-[4-(2-氧代吡嗪 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3- 甲酸乙酯 （4B) (0.4 g, 0.8 mmol)溶于氨 /甲醇溶液（10 mL) 中升温至 100°C反应过夜。 将反 应液冷却至室温， 用乙酸乙酯 （50 mL X 3)萃取， 合并有机相， 有机相用无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （甲醇 /二氯甲垸 （v/v) = 1 :50) 得到标题化合物 1- (苯并 呋喃 -5-基) -6-[4-(2-氧代吡嗪 -1-基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （化合 物 33)， 白色固体（200 mg, 产率 54%)。  1-(benzofuran-5-yl)-6-[4-(2-oxopyrazine-1-yl)phenyl]-7-oxo-4,5-dihydro-1H-pyrazole Ethyl [3,4-c]pyridine-3-carboxylate (4B) (0.4 g, 0.8 mmol) was dissolved in ammonia/methanol (10 mL) and warmed to 100 ° C overnight. The reaction mixture was cooled to room temperature, EtOAc (EtOAc (EtOAc)EtOAc. v/v) = 1 :50) The title compound 1-(benzofuran-5-yl)-6-[4-(2-oxopyrazine-1-yl)phenyl]-7-oxo- 4,5-Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 33), white solid (200 mg, yield 54%).
¾ NMR (400 MHz, DMSO-d6) δ 8.12 (d, IH), 7.72 (s, IH), 7.66 (dd, IH), 7.55-7.50 (m, 4H), 7.43-7.44 (m, 2H), 7.40 (dd, IH), 7.28 (dd, IH), 6.81 (d, IH), 4.60 (t, 2H), 4.02 (t, 2H), 3.22-3.19 4H)。 3⁄4 NMR (400 MHz, DMSO-d 6 ) δ 8.12 (d, IH), 7.72 (s, IH), 7.66 (dd, IH), 7.55-7.50 (m, 4H), 7.43-7.44 (m, 2H) , 7.40 (dd, IH), 7.28 (dd, IH), 6.81 (d, IH), 4.60 (t, 2H), 4.02 (t, 2H), 3.22-3.19 4H).
MS m/z (ESI): 469.0 [M+l] 实施例 34  MS m/z (ESI): 469.0 [M+l] EXAMPLE 34
1- (苯并呋喃 -5-基) -6-[4-(2-氧代哌嗪 -1-基)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c]吡啶 -3- 甲酰胺 （化合物 34)  1-(benzofuran-5-yl)-6-[4-(2-oxopiperin-1-yl)phenyl]-7-oxo-4,5-dihydro-IH-pyrazole [3,4-c]pyridine-3-carboxamide (compound 34)
l-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-piperazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide
Figure imgf000117_0001
L-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-piperazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide
Figure imgf000117_0001
第一步： 4-叔丁氧羰基哌嗪 -2-酮 （34B)  First step: 4-tert-butoxycarbonylpiperazine-2-one (34B)
4-tert-butoxycarbonyl-2-oxo-piperazine
Figure imgf000117_0002
4-tert-butoxycarbonyl-2-oxo-piperazine
Figure imgf000117_0002
将哌嗪 -2-酮（1.0 g, 1 mmol), 二碳酸二叔丁酯 （2.3 g, 1.1 mmol), 三乙胺 （1.21 g, 1.2 mmol) 加入到二氯甲垸溶液（60 mL) 中， 室温反应过夜。 将反应液用水（30 mL X 2) 洗 涤， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚： 乙酸乙酯 （v/v) = 1 :2) 得到标题化合物 4-叔丁氧羰基哌嗪 -2-酮 （34B)， 白色固体（1.0 g, 产率 50%)。  Piperazine-2-one (1.0 g, 1 mmol), di-tert-butyl dicarbonate (2.3 g, 1.1 mmol), triethylamine (1.21 g, 1.2 mmol) was added to dichloromethane (60 mL) In the reaction at room temperature overnight. The reaction mixture was washed with EtOAcqqqqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH tert-Butoxycarbonylpiperazin-2-one (34B), white solid (1.0 g, yield 50%).
^ NMR (400 MHz, DMSO-d6) δ 3.81 (s, 2Η), 3.45 (t, 2H), 3.17 (t, 2H), 1.41 (s, 9H)。 ^ NMR (400 MHz, DMSO-d 6 ) δ 3.81 (s, 2 Η), 3.45 (t, 2H), 3.17 (t, 2H), 1.41 (s, 9H).
第二步： 1- (苯并呋喃 -5-基；) -6-[4-(4-叔丁氧基羰基 -2-氧代哌嗪 -1-基;)苯基] -7-氧代 -4,5-二氢- 1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （34C)  The second step: 1-(benzofuran-5-yl;)-6-[4-(4-tert-butoxycarbonyl-2-oxopiperazine-1-yl;)phenyl]-7-oxygen Generation of 4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (34C)
Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-(4-tertbutoxycarbonyl-2-oxo-piperazin-l-yl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxylate  Ethyl l-(benzofuran-5-yl)-7-oxo-6-[4-(4-tertbutoxycarbonyl-2-oxo-piperazin-l-yl)phenyl]-4,5- dihydropyrazolo[3,4-c] Pyridine-3-carboxylate
Figure imgf000117_0003
Figure imgf000117_0003
在氮气氛围下， 将 1-(2,3-二氢苯并呋喃 -5-基;) -6-(4-碘苯基 )-7-氧代 -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （2C) (1.0 g, 1.9 mmol), 4-叔丁氧羰基哌嗪 -2-酮 （34B) (0.75 g, 3.78 mmol), 磷酸钾 (0.8 g, 3.78 mmol), 碘化酮 (100 mg, 0.19 mmol)和反 -(1R,2R)-N,N'-二甲 基 -1,2-环戊二胺 (100 mg, 0.19 mmol) 加入到微波管中， 加入 1,2-二氧六环 （40 mL), 升温 至 150°C反应 1.5小时。 将反应液冷却至室温， 加入水（50mL)， 用乙酸乙酯 （50 mL X 3) 萃 取， 合并有机相， 有机相用无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯 （二氯甲 垸:甲醇 （v/v) = 100: 1)得到标题化合物 1-(苯并呋喃 -5-基;) -6-[4-(4-叔丁氧基羰基 -2-氧代哌嗪- 1 -基)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯 （34C)， 白色固体（0.6 g, 产率 53%) 1-(2,3-dihydrobenzofuran-5-yl;)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydrogen under a nitrogen atmosphere -1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (2C) (1.0 g, 1.9 mmol), 4-tert-butoxycarbonylpiperazin-2-one (34B) (0.75 g, 3.78 mmol), potassium phosphate (0.8 g, 3.78 mmol), iodinated ketone (100 mg, 0.19 mmol) and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclopentanediamine (100 mg, 0.19 mmol) was added to a microwave tube, and 1,2-dioxane (40 mL) was added, and the mixture was heated to 150 ° C for 1.5 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was evaporated. Chlorine 垸:methanol (v/v) = 100: 1) The title compound 1-(benzofuran-5-yl;)-6-[4-(4-tert-butoxycarbonyl-2-oxopiperazine- Ethyl 1-phenyl)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (34C), white solid (0.6 g, yield Rate 53%)
^ NMR (400 MHz, CDC13) δ 7.39-7.30 (m, 3Η), 7.28-7.25 (m, 3H), 6.76 (d, IH), 4.60 (t, 2H), 4.45 (t, 2H), 4.25 (s, 2H), 4.13 (q, 2H), 3.77 (t, 2H), 3.68 (t, 2H), 3.32 (t, 2H), 3.22 (t, 2H), 1.50 (s, 9H), 1.43 (t, 3H)。 ^ NMR (400 MHz, CDC1 3 ) δ 7.39-7.30 (m, 3Η), 7.28-7.25 (m, 3H), 6.76 (d, IH), 4.60 (t, 2H), 4.45 (t, 2H), 4.25 (s, 2H), 4.13 (q, 2H), 3.77 (t, 2H), 3.68 (t, 2H), 3.32 (t, 2H), 3.22 (t, 2H), 1.50 (s, 9H), 1.43 ( t, 3H).
MS m/z (ESI): 602.2 [M+l]  MS m/z (ESI): 602.2 [M+l]
第三步： 1- (苯并呋喃 -5-基 6-[4-(4-叔丁氧基羰基 -2-氧代哌嗪 -1-基)苯基] -7-氧代 -4,5-二氢- 1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （34D)  The third step: 1-(benzofuran-5-yl 6-[4-(4-tert-butoxycarbonyl-2-oxopipyrazin-1-yl)phenyl]-7-oxo-4, 5-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (34D)
l-(benzofuran-5-yl)-7-oxo-6-[4-(4-tertbutoxycarbonyl-2-oxo-piperazin-l-yl)phenyl]-4,5- dihydropyrazolo[3,4-c]pyridine-3-carboxamide  L-(benzofuran-5-yl)-7-oxo-6-[4-(4-tertbutoxycarbonyl-2-oxo-piperazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine -3-carboxamide
Figure imgf000118_0001
Figure imgf000118_0001
将 1-(苯并呋喃 -5-基;) -6-[4-(4-叔丁氧基羰基 -2-氧代哌嗪 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡 唑并 [3,4-c]吡啶 -3-甲酸乙酯 （34C) (700 mg)溶于 Ν,Ν-二甲基甲酰胺 （20 mL)中， 加入甲醇钠 (251 mg, 4.65 mmol),甲酰胺 （522 mg,l 1.6 mmol), 80度反应 4个小时， 冷却到室温， 加入 20 mL 水， 用乙酸乙酯 50 mL萃取三次， 无水硫酸钠干燥， 浓缩， 残留物用硅胶柱色谱分离提纯（二 氯甲垸：甲醇 i l、 = 100: 1)得到标题化合物 1-(苯并呋喃 -5-基;) -6-[4-(4-叔丁氧基羰基 -2-氧代哌 嗪 -1-基；)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺 （34D)， 黄色固体（0.4 g, 产率 60%)  1-(benzofuran-5-yl;)-6-[4-(4-tert-butoxycarbonyl-2-oxopiperazine-1-yl;)phenyl]-7-oxo-4 ,5-Dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (34C) (700 mg) dissolved in hydrazine, hydrazine-dimethylformamide (20 mL), Sodium methoxide (251 mg, 4.65 mmol), formamide (522 mg, l 1.6 mmol), reacted at 80 °C for 4 hours, cooled to room temperature, added with 20 mL of water and extracted three times with 50 mL of ethyl acetate. The title compound 1-(benzofuran-5-yl;) -6-[4-(4-) was purified by silica gel column chromatography (dichloromethane:m. tert-Butoxycarbonyl-2-oxopiperazine-1-yl;)phenyl]-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-3- Formamide (34D), yellow solid (0.4 g, yield 60%)
¾ NMR (400 MHz, DMSO-d6) δ 7.71 (s, IH), 7.42 (m, 2H), 7.37 (m, 4H), 7.29-7.26 (m, IH),3⁄4 NMR (400 MHz, DMSO-d 6 ) δ 7.71 (s, IH), 7.42 (m, 2H), 7.37 (m, 4H), 7.29-7.26 (m, IH),
6.79 (d, IH), 4.59 (t, 2H), 4.07-4.03 (m, 4H), 3.69 (m, 4H), 3.22-3.18 (m, 4H), 1.41 (s, 9H)。 6.79 (d, IH), 4.59 (t, 2H), 4.07-4.03 (m, 4H), 3.69 (m, 4H), 3.22-3.18 (m, 4H), 1.41 (s, 9H).
MS m/z (ESI): 573.2 [M+l]  MS m/z (ESI): 573.2 [M+l]
第四步： 1- (苯并呋喃 -5-基) -6-[4-(2-氧代哌嗪 -1-基)苯基] -7-氧代 -4,5-二氢 -IH-吡唑并 [3,4-c] 吡啶 -3-甲酰胺 （化合物 34)  Fourth step: 1-(benzofuran-5-yl)-6-[4-(2-oxopiperin-1-yl)phenyl]-7-oxo-4,5-dihydro-IH -pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 34)
l-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-piperazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide
Figure imgf000119_0001
L-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-piperazin-l-yl)phenyl]-4,5-dihydropyrazolo[3,4- c]pyridine-3-carboxamide
Figure imgf000119_0001
将 1- (苯并呋喃 -5-基;) -6-[4-(4-叔丁氧基羰基 -2-氧代哌嗪 -1-基;)苯基] -7-氧代 -4,5-二氢 -IH-吡 唑并 [3,4-c]吡啶 -3-甲酰胺 (34D) (0.4 g, 8.7 mmol) 溶于三氟乙酸 (9.9g) 和 20mL二氯甲垸 中， 室温反应 5个小时。 将二氯甲垸和三氟乙酸浓缩干， 加入 50毫升水和碳酸钾固体， 调 PH 为 9左右， 用乙酸乙酯 50 mL萃取三次， 无水硫酸钠干燥浓缩， 粗品用 50 mL乙醇重结晶得到 标题化合物 1- (苯并呋喃 -5-基;) -6-[4-(2-氧代哌嗪 -1-基;)苯基] -7-氧代 -4,5-二氢 -1H-吡唑并 [3,4-c]吡 啶 -3-甲酰胺 （化合物 34)， 白色固体（0.10g， 产率： 30%)。  1-(Benzofuran-5-yl;)-6-[4-(4-tert-butoxycarbonyl-2-oxopiperazine-1-yl;)phenyl]-7-oxo-4 ,5-Dihydro-IH-pyrazolo[3,4-c]pyridine-3-carboxamide (34D) (0.4 g, 8.7 mmol) dissolved in trifluoroacetic acid (9.9 g) and 20 mL of dichloromethane , react at room temperature for 5 hours. Dichloromethane and trifluoroacetic acid were concentrated to dryness, and 50 ml of water and potassium carbonate solid were added, and the pH was adjusted to about 9, and extracted three times with ethyl acetate 50 mL, dried over anhydrous sodium sulfate and concentrated. The title compound 1-(benzofuran-5-yl;)-6-[4-(2-oxopiperin-1-yl;)phenyl]-7-oxo-4,5-dihydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Compound 34), white solid (0.10 g, yield: 30%).
¾ NMR (400 MHz, DMSO-de) δ 7.71 (s, IH), 7.37 (m, 2H), 7.31 (m, 4H), 7.26 (m, IH), 6.79 (d, IH), 4.59 (t, 2H), 4.05 (m, 2H), 3.57 (t, 2H), 3.38 (s, 2H), 3.18 (m, 4H), 3.00 (t, 2H), 2.76 (s, 1H)。  3⁄4 NMR (400 MHz, DMSO-de) δ 7.71 (s, IH), 7.37 (m, 2H), 7.31 (m, 4H), 7.26 (m, IH), 6.79 (d, IH), 4.59 (t, 2H), 4.05 (m, 2H), 3.57 (t, 2H), 3.38 (s, 2H), 3.18 (m, 4H), 3.00 (t, 2H), 2.76 (s, 1H).
MS m/z (ESI): 473.1 [M+l] 测试例： 测试例 1、 化合物溶解度测定  MS m/z (ESI): 473.1 [M+l] Test Example: Test Example 1. Determination of Compound Solubility
(1)标准曲线溶液的配制  (1) Preparation of standard curve solution
称取干燥恒重后的供试品适量于容量瓶中， 选取适当溶剂将样品完全溶解定容， 配成一 系列浓度梯度的标准曲线溶液， 用 0.45 mm的滤膜过滤后， 进 HPLC, 记录峰面积， 以峰面 积为纵坐标， 进样体积所含药物的质量为横坐标进行线性回归， 即得该化合物的标准曲线方 程。  Weigh the dry constant weight of the test sample in the volumetric flask, select the appropriate solvent to completely dissolve the sample, prepare a series of concentration gradient standard curve solution, filter with 0.45 mm filter, enter HPLC, record The peak area, with the peak area as the ordinate, and the mass of the drug contained in the injection volume is linearly regressioned on the abscissa, that is, the standard curve equation of the compound is obtained.
(2)供试品溶液的配制与测定  (2) Preparation and determination of the test solution
称取适量供试品 （一般 1~2 mg) ， 加入适量待测溶剂 （一般 1~2 mL) ， 用涡旋振荡器 每隔 5分钟强力振摇 30秒， 观察 30分钟内的溶解情况， 若不溶解则为样品的饱和溶液； 若 溶解， 则继续加入样品， 直至不再溶解。 然后将此饱和溶液置于水浴箱中， 在要求的温度下 不断振摇， 并于 4、 24小时抽取上层液体， 经 0.45 mm的滤头过滤后， 取续滤液进 HPLC测 定； 若 4小时和 24小时测定结果一致， 则说明溶液已达平衡， 所测结果即为溶解度结果， 若 不一致， 说明未达平衡， 则继续取点测定， 直至平衡； 测定过程中若供试品溶液的浓度太 大， 已超出标准曲线范围， 则需精确稀释后再测定。  Weigh the appropriate amount of test sample (generally 1~2 mg), add appropriate amount of solvent to be tested (generally 1~2 mL), shake vigorously for 30 seconds every 5 minutes with vortex shaker, observe the dissolution within 30 minutes. If not dissolved, it is a saturated solution of the sample; if dissolved, continue to add the sample until it is no longer dissolved. Then, the saturated solution is placed in a water bath, shaken continuously at the required temperature, and the upper liquid is taken at 4, 24 hours, filtered through a 0.45 mm filter, and the filtrate is taken for HPLC determination; if 4 hours and If the results are consistent for 24 hours, the solution has reached equilibrium, and the measured result is the solubility result. If it is inconsistent, it means that the balance is not reached, then continue to take the measurement until equilibrium; if the concentration of the test solution is too large during the measurement If the standard curve range has been exceeded, it needs to be diluted accurately before measurement.
(3) 实验结果的计算  (3) Calculation of experimental results
将测定的供试品溶液的峰面积代入标准曲线方程， 计算出所测饱和平衡溶液的浓度 ( mg/ mL) ，即为溶解度， 结果如表 1所示。 称取干燥恒重后的供试品适量， 配成一系列浓度梯度的标准曲线溶液， 过滤后进 HPLC, 以峰面积为纵坐标， 进样体积所含药物的质量为横坐标进行线性回归， 即得该化合物 的标准曲线方程。 The peak area of the measured test solution was substituted into the standard curve equation, and the concentration (mg/mL) of the measured saturated equilibrium solution was calculated, which is the solubility. The results are shown in Table 1. Weigh the amount of the test sample after drying and constant weight, and prepare a series of concentration curve standard curve solution, filter and then enter HPLC, the peak area is the ordinate, and the mass of the drug contained in the injection volume is linearly regression, ie The standard curve equation for this compound is obtained.
配制供试品饱和溶液置于待测温度恒温水浴箱中， 不断振摇， 并于 4、 24 小时抽取上层 液体， 过滤后进 HPLC测定； 若 4小时和 24小时测定结果不一致， 则继续取点测定， 直至一 致。  Prepare the saturated solution of the test sample in a constant temperature water bath at the temperature to be tested, shake it continuously, and extract the upper liquid at 4 and 24 hours, and then filter it into HPLC. If the results are inconsistent at 4 hours and 24 hours, continue to take the measurement. Until the same.
将测定的供试品溶液的峰面积代入标准曲线方程， 计算出所测饱和平衡溶液的浓度 ( mg/ mL) ，即为溶解度。  The peak area of the measured test solution is substituted into the standard curve equation, and the concentration (mg/mL) of the measured saturated equilibrium solution is calculated as the solubility.
表 1、 溶解度测定实验结果  Table 1. Solubility test results
Figure imgf000120_0001
Figure imgf000120_0001
结论： 本发明化合物在 37°C/生理盐水中的溶解度明显优于对照化合物阿哌沙班。 测试例 2、 本发明化合物对凝血因子 Xa体外酶活性抑制作用  Conclusion: The solubility of the compound of the present invention in 37 ° C / physiological saline is significantly better than the control compound apixaban. Test Example 2. Inhibition of in vitro enzymatic activity of coagulation factor Xa by the compound of the present invention
以下方法可用来测定本发明化合物体外对人源凝血因子 Xa活性的抑制作用， 用抑制常数 Ki表示。  The following method can be used to determine the inhibitory effect of the compound of the present invention on the activity of human coagulation factor Xa in vitro, expressed by the inhibition constant Ki.
在含有 0.05 M Tris, 0.15 M NaCl, 0.1% PEG-8000的反应缓冲液 （pH=7.5) 中制备人源 凝血因子 Xa (Enzo life science) 工作液和显色底物 （sekisui, 货号： 222) 工作液。 测试化合 物加二甲亚砜 （DMSO ) 配制成 10 mM 的储备液， 再用含 1%DMS0 的反应缓冲液稀释成 0.1-1000 nM的工作液。 在 96孔板中加入 30 测试化合物工作液 （对照组加入 30 反应 缓冲液） 和 150 μ 凝血因子 Xa工作液， 凝血因子 Xa终浓度为 1 nM， 室温孵育 30分钟。 然 后加入显色底物工作液 120 μL, 终浓度为 0.2 mM, 启动反应。 用酶标仪 （Perkin Elmer, Envision) 在 405 nm处连续测定 30分钟， 每分钟测定一次。  Preparation of human coagulation factor Xa (Enzo life science) working solution and chromogenic substrate (sekisui, Cat. No. 222) in a reaction buffer (pH=7.5) containing 0.05 M Tris, 0.15 M NaCl, 0.1% PEG-8000. Working fluid. The test compound was added to dimethyl sulfoxide (DMSO) to make a 10 mM stock solution, which was then diluted to a 0.1-1000 nM working solution in a reaction buffer containing 1% DMS0. Add 30 test compound working solution (control group added 30 reaction buffer) and 150 μ clotting factor Xa working solution to 96-well plate. The final concentration of coagulation factor Xa is 1 nM, and incubate for 30 minutes at room temperature. Then, 120 μL of the chromogenic substrate working solution was added to a final concentration of 0.2 mM to initiate the reaction. The assay was performed continuously at 405 nm for 30 minutes using a microplate reader (Perkin Elmer, Envision) and measured every minute.
按以下公式计算测试化合物 Ki， 结果如表 2所示： Ki= IC50/(l+[S]/Km) The test compound Ki was calculated according to the following formula, and the results are shown in Table 2: Ki= IC 50 /(l+[S]/Km)
试中：  Try:
IC5Q_通过 SPSS16.0软件线性回归计算导致底物水解速率降低 50%的测试化合物浓度。IC 5Q _ The concentration of test compound which resulted in a 50% reduction in substrate hydrolysis rate was calculated by SPSS 16.0 software linear regression.
]_底物浓度  ]_Substrate concentration
Km—米氏常数， 0.35 mM  Km-Mie constant, 0.35 mM
表 2、 体外人源凝血因子 Xa抑制作用实验结果  Table 2. Experimental results of human coagulation factor Xa inhibition in vitro
Figure imgf000121_0001
结论： 本发明化合物具有一定的 FXa 抑制作用， 特别是实施例 2~3、 5、 9、 21-22,
Figure imgf000121_0001
Conclusion: The compounds of the present invention have certain FXa inhibitory effects, especially Examples 2~3, 5, 9, 21-22.
31-33的化合物在缓冲液中对人源 FXa抑制作用明显优于对照化合物阿哌沙班。 测试例 3、 体外对大鼠血浆凝血功能作用测定 The compound of 31-33 inhibited human FXa in buffer significantly better than the control compound apixaban. Test Example 3: Determination of plasma coagulation function in rats in vitro
(a)大鼠 （购自成都达硕生物科技有限公司， 许可证号： SOXK (川） 2008-24 ) 股动脉采 血， 用 3.8%枸橼酸钠抗凝， 抗凝剂与血的比例为 1 : 9， 2500 转 /分钟 4°C离心 （Beckman, Allegrax-30R) 10分钟， 上层即为富含血小板血浆， 取上层 15000转 /分钟 4°C离心 10分钟， 上层即为贫血小板血浆。 凝血酶原时间 （PT) ， 活化部分凝血活酶时间 （aPTT) 试剂配制和 测试参照试剂盒 （均购于北京赛科希德科技发展有限公司， 批号分别为 D1B058-1 , D2B061- 1 ) 说明书。 将不同浓度的本发明化合物及阿哌沙班与贫血小板血浆混合 （体积比例为 1 : 9) ， 化合物终浓度为 0-20μΜ， 全自动凝血仪 （北京赛科希德科技发展有限公司， SF-8000) 测试 PT、 aPTT。 Origin拟合二项式计算凝血时间延长一倍所需化合物浓度 EC2X， 结果如表 3 所示。 (a) Rat (purchased from Chengdu Dashuo Biotechnology Co., Ltd., license number: SOXK (chuan) 2008-24) Femoral artery blood collection, anticoagulation with 3.8% sodium citrate, the ratio of anticoagulant to blood is 1 : 9, 2500 rpm, 4°C centrifugation (Beckman, Allegrax-30R) for 10 minutes, the upper layer is platelet-rich plasma, and the upper layer is centrifuged at 15,000 rpm for 10 minutes at 4 ° C. The upper layer is platelet-poor plasma. Prothrombin time (PT), activated partial thromboplastin time (aPTT) reagent preparation and test reference kit (all purchased from Beijing Sectech Technology Development Co., Ltd., batch number D1B058-1, D2B061-1) . Different concentrations of the compound of the present invention and apixaban were mixed with platelet-poor plasma (volume ratio of 1:9), and the final concentration of the compound was 0-20 μΜ, fully automatic coagulation instrument (Beijing Sectech Technology Development Co., Ltd., SF -8000) Test PT, aPTT. The Origin fitting binomial calculates the compound concentration EC 2X required to double the clotting time. The results are shown in Table 3.
表 3、 本发明化合物对大鼠血浆的抗凝血作用 （以 PT EC2X和 aPTT EC2x表示） Table 3. Anticoagulant effects of the compounds of the invention on rat plasma (expressed as PT EC 2X and aPTT EC 2x )
Figure imgf000122_0002
Figure imgf000122_0002
结论： 本发明化合物体外对大鼠血浆有明显的抗凝血作用， 优于对照化合物阿哌沙班。 (b) 20名 25-35周岁健康志愿者， 手肘静脉穿刺采血 20 mL于 3.8%枸橼酸钠抗凝管中， 抗凝剂与血的比例为 1： 9， 2500 转 /分钟 4°C离心 (Beckman, Allegrax-30R) 10分钟， 取上 层富含血小板血浆 15000转 /分钟 4°C离心 10分钟， 收集上层贫血小板血浆用于凝血酶原时间 ( PT ) 和活化部分凝血活酶时间 （aPTT ) 检测。 试剂配制和测试参照试剂盒 （均购于 Instrumentation laboratory公司， 批号分别为 N0821168和 N0820966) 说明书。 将不同浓度的 本发明化合物及阿哌沙班与贫血小板血浆混合 （体积比例为 1 : 9 ) ， 化合物终浓度为 0- 20μΜ， 全自动凝血仪 (Instrumentation laboratory, ACL ELITE) 测试 PT、 aPTT。 Origin拟合 二项式计算凝血时间延长一倍所需化合物浓度 EC2X， 结果如表 4所示。 Conclusion: The compound of the present invention has obvious anticoagulant effect on rat plasma in vitro, which is superior to the control compound apixaban. (b) 20 healthy volunteers aged 25-35 years old, 20 mL of blood was collected from the elbow vein in a 3.8% sodium citrate anticoagulation tube. The ratio of anticoagulant to blood was 1: 9, 2500 rpm 4°. C centrifugation (Beckman, Allegrax-30R) for 10 minutes, taking the upper platelet-rich plasma 15000 rpm for 10 minutes at 4 ° C, collecting the upper platelet-poor plasma for prothrombin time ( PT ) and activated partial thromboplastin time (aPTT) detection. Reagent preparation and test reference kits (all purchased from Instrumentation Laboratory, batch number N0821168 and N0820966, respectively) instructions. Different concentrations of the compound of the present invention and apixaban were mixed with platelet-poor plasma (volume ratio of 1:9), and the final concentration of the compound was 0-20 μΜ, and PT and aPTT were tested by an automatic instrumentation instrument (ACL ELITE). The Origin fitting binomial calculates the compound concentration EC 2X required to double the clotting time. The results are shown in Table 4.
表 4、 本发明化合物对人血浆的抗凝血作用 （以 PT
Figure imgf000122_0001
EC2x表示） Table 4. Anticoagulant effects of the compounds of the invention on human plasma (with PT
Figure imgf000122_0001
EC 2x )
Figure imgf000122_0003
3 1.3 6.0
Figure imgf000122_0003
3 1.3 6.0
5 0.67 2.8 5 0.67 2.8
8 1.4 4.68 1.4 4.6
9 2.3 5.79 2.3 5.7
10 1.0 3.310 1.0 3.3
12 2.2 7.712 2.2 7.7
15 (化合物 1-2) 6.8 8.1 15 (Compound 1-2) 6.8 8.1
21 0.9 3.5 21 0.9 3.5
22 3.9 14.422 3.9 14.4
28 3.3 11.828 3.3 11.8
29 3.0 11.129 3.0 11.1
31 1.4 5.231 1.4 5.2
32 1.0 3.332 1.0 3.3
33 0.9 2.6 结论： 本发明化合物体外对人血浆有明显的抗凝血作用， 特别是实施例 2、 8、 21、 31-33的化合物明显优于对照化合物阿哌沙班。 测试例 4、 药代动力学评价 33 0.9 2.6 Conclusion: The compounds of the present invention have significant anticoagulant effects on human plasma in vitro, and in particular, the compounds of Examples 2, 8, 21, 31-33 are significantly superior to the control compound apixaban. Test Example 4, Pharmacokinetic Evaluation
雄性 SD 大鼠 （购自上海斯莱克实验动物有限责任公司， 许可证号： SCXK ( SH ) 2007000546318 ) 180-220g, 禁食给水过夜， 3 只大鼠口服灌胃 5 mg/kg, 3 只大鼠静脉注射 0.5 mg/kg。 口服给药组， 在给药前和在给药后 15、 30和 45分钟以及 1、 2、 4、 8、 12和 24 小时采血； 静脉给药组， 在给药前和在给药后 5、 15和 30分钟以及 1、 2、 4、 8、 12和 24小 时采血。 血液样品 3500 转 /分钟 4°C离心 10分钟， 收集血浆， 于 -40°C保存。 取各时间点大 鼠血浆 20 L， 加入含内标的乙腈溶液 200 混合后， 涡旋混合 5分钟， 3700转 /分钟离心 15分钟， 取上清液 80 μ L与 80 μ L水混合， 取混和液 10 μ L进行 LC-MS/MS (安捷伦科技有 限公司， ΑΡΙ4000) 分析。 主要药代动力学参数用 WinNonlin 6.3软件非房室模型分析， 结果 如表 5、 6所示。 表 5 本发明化合物口服生物利用度实验结果  Male SD rats (purchased from Shanghai Slack Laboratory Animals Co., Ltd., license number: SCXK (SH) 2007000546318) 180-220g, fasting water supply overnight, 3 rats orally administered 5 mg/kg, 3 large Rats were given an intravenous injection of 0.5 mg/kg. In the oral administration group, blood was collected before administration and at 15, 30, and 45 minutes after administration, and at 1, 2, 4, 8, 12, and 24 hours; intravenous administration group, before administration and after administration 5 Blood was collected at 15 and 30 minutes and 1, 2, 4, 8, 12 and 24 hours. Blood samples were centrifuged at 3500 rpm for 10 minutes at 4 ° C. Plasma was collected and stored at -40 °C. Take 20 L of rat plasma at each time point, add 200 times of acetonitrile solution containing internal standard, vortex for 5 minutes, centrifuge at 3700 rpm for 15 minutes, mix 80 μL of the supernatant with 80 μL of water, and mix. 10 μL of the solution was analyzed by LC-MS/MS (Agilent Technologies, Inc., ΑΡΙ4000). The main pharmacokinetic parameters were analyzed using WinNonlin 6.3 software non-compartmental model. The results are shown in Tables 5 and 6. Table 5 Results of oral bioavailability test of the compound of the present invention
Figure imgf000123_0001
9 口服 29.3
Figure imgf000123_0001
9 oral 29.3
10 口服 19.910 oral 19.9
24 口服 26.224 oral 26.2
29 口服 28.0 结论： 本发明化合物的生物利用度明显优于对照化合物阿哌沙班。 表 6本发明化合物 Tmax实验结果 29 Oral 28.0 Conclusion: The bioavailability of the compounds of the invention is significantly better than the control compound apixaban. Table 6 Tmax experimental results of the compound of the present invention
实施例编号 给药方式 达峰时间 Tmax (h) 阿哌沙班 口服 2.00  Example No. Method of administration Peak time Tmax (h) Apixaban Oral 2.00
1 口服 0.42  1 oral 0.42
2 口服 1.33 2 Oral 1.33
3 口服 1.003 oral 1.00
8 口服 0.678 oral 0.67
9 口服 0.429 oral 0.42
10 口服 1.1710 oral 1.17
21 口服 0.2521 oral 0.25
22 口服 1.0022 Oral 1.00
24 口服 0.25 结论： 本发明化合物的起效时间明显快于对照化合物阿哌沙班。 24 Oral 0.25 Conclusion: The onset time of the compounds of the invention was significantly faster than the control compound apixaban.
测试例 5: 兔动静脉旁路血栓模型测定抗血栓作用  Test Example 5: Determination of antithrombotic effects in a rabbit arteriovenous bypass thrombus model
雄性 2 月龄 （1.9-2.4kg) 新西兰白兔 （上海市松江区车墩实验动物良种场） ， 根据体重 随机分为溶媒对照组， 阿哌沙班组， 本发明化合物组。 溶媒和各化合物均采用注射泵静脉推 注的给药方式， 给药体积为 3ml/kg。  Male 2 months old (1.9-2.4 kg) New Zealand white rabbits (Shanghai Pinjiang experimental animal breeding field) were randomly divided into vehicle control group, apixaban group, and compound group of the present invention according to body weight. The vehicle and each compound were administered by intravenous injection of a syringe pump at a dose of 3 ml/kg.
新西兰白兔用戊巴比妥钠 (60 mg/kg, i.v)麻醉后， 将留置导管插入到右侧颈动脉和左侧颈 静脉。 动脉与静脉导管用内含丝线的 8 cm长的硅化聚乙烯管短路连接。 给药 20min后， 打开 动静脉分流管， 持续分流 40min。 完成后将含血栓的聚乙烯管与导管分开， 取出聚乙烯管中 覆盖丝线的血栓， 测定血栓重量， 以血栓形成抑制率的形式表示， 结果如表 7所示。  After the New Zealand white rabbit was anesthetized with sodium pentobarbital (60 mg/kg, i.v.), the indwelling catheter was inserted into the right carotid artery and the left jugular vein. The arterial and venous catheters were short-circuited with an 8 cm long siliconized polyethylene tube containing wires. After 20 minutes of administration, the arteriovenous shunt was opened and the shunt was continued for 40 min. After completion, the thrombus-containing polyethylene tube was separated from the catheter, and the thrombus covering the silk thread in the polyethylene tube was taken out, and the weight of the thrombus was measured and expressed in the form of thrombus inhibition rate. The results are shown in Table 7.
表 7 本发明化合物对兔动静脉血栓的抗血栓形成作用  Table 7 Antithrombotic effects of the compounds of the invention on rabbit arteriovenous thrombosis
Figure imgf000124_0001
化合物 9 10. 7 40. 1 76. 0 86. 3 注： 表示未测
Figure imgf000124_0001
Compound 9 10. 7 40. 1 76. 0 86. 3 Note: Indicates not tested
结果表明： 化合物 9 显著抑制兔动静脉血栓模型的血栓生成， 并呈剂量依赖关系。 化合 物 9的抗血栓形成作用明显优于同剂量阿哌沙班。  The results showed that Compound 9 significantly inhibited thrombus formation in a rabbit model of arteriovenous thrombosis in a dose-dependent manner. The antithrombotic effect of Compound 9 was significantly better than the same dose of apixaban.
测试例 6: 大鼠尾出血模型测定出血时间  Test Example 6: Rat tail bleeding model determines bleeding time
雄性 10周龄（300-350g) Sprague-Dawley大鼠 （成都达硕生物科技有限公司） ， 根据体 重随机分为溶媒对照组， 阿哌沙班组， HSK-1 108组和 HSK-3144组。 溶媒和各化合物均采用 口服给药方式， 给药体积为 10ml/kg。  Male Sprague-Dawley rats (Chengdu Dashuo Biotechnology Co., Ltd.) at 10 weeks of age (300-350 g) were randomly divided into vehicle control group, apixaban group, HSK-1 108 group and HSK-3144 group according to body weight. The vehicle and each compound were administered orally in a dosage of 10 ml/kg.
各组 Sprague-Dawley大鼠用水合氯醛 (300 mg/kg, i.p)麻醉后， 于受试化合物口服后药峰 时间 （溶媒组于给药后 30min) ， 用手术刀片迅速切断距离大鼠尾部顶端 4mm处， 并立即浸 入 37°C林格氏液中， 观察大鼠尾部出血情况 30min。 尾部出血停止后 30s 内不再出血为出血 停止， 记录出血开始至出血停止的时间。 最大观察时间为 30min (更长的出血时间赋值为 30min) 。 实验结果以出血时间延长倍数表示并以阿哌沙班作为对比药物， 结果如表 8所示。  Each group of Sprague-Dawley rats was anesthetized with chloral hydrate (300 mg/kg, ip), and the test compound was orally administered at the peak time (30 minutes after drug administration). The surgical blade was used to quickly cut off the tail of the rat. At the top 4 mm, and immediately immersed in 37 ° C Ringer's solution, the tail bleeding of the rats was observed for 30 min. No bleeding occurred within 30 s after the end of bleeding stopped. Stop bleeding, recording the time from the start of bleeding to the stop of bleeding. The maximum observation time is 30 minutes (the longer bleeding time is assigned to 30 minutes). The results of the experiment were expressed as a multiple of the bleeding time and apixaban was used as a comparative drug. The results are shown in Table 8.
表 8 本发明化合物对大鼠尾出血时间的影响  Table 8 Effect of the compound of the present invention on tail bleeding time in rats
Figure imgf000125_0001
Figure imgf000125_0001
注： 表示未测。  Note: Indicates not tested.
结果表明： 化合物 9在剂量 20mg/kg下使出血时间延长 3-4倍， 与阿哌沙班 2mg/kg剂量相 当。 因此， 与阿哌沙班相比， 化合物 9更能降低出血风险， 更安全。  The results showed that Compound 9 prolonged the bleeding time by 3-4 times at a dose of 20 mg/kg, which was equivalent to the apixaban 2 mg/kg dose. Therefore, Compound 9 is more safe and safer than apixaban.

Claims

权利要求书 Claim
1、 一种通式 （I) 所示的化合物， 或者其立体异构体、 氮氧化合物、 水合物、 溶剂化 物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中： A compound of the formula (I), or a stereoisomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
Figure imgf000126_0001
Figure imgf000126_0001
A选自 C6— 14芳基或 5至 14元杂芳基， 所述芳基或杂芳基任选进一步被 0至 5个 R7取 代； A is selected from C 6 -14 aryl or 5- to 14-membered heteroaryl, which is optionally further substituted with 0 to 5 R 7 ;
B选自 3至 10元杂环， 所述的杂环含有 1至 4个选自 N、 0或 S的杂原子， 所述杂环 任选进一步被 0至 3个取代基所取代， 所述取代基选自 R7a或者 (=0); B is selected from a 3- to 10-membered heterocyclic ring containing 1 to 4 hetero atoms selected from N, 0 or S, and the heterocyclic ring is optionally further substituted with 0 to 3 substituents, The substituent is selected from R 7a or (=0);
X选自 0或者 S(=0)p; X is selected from 0 or S(=0) p;
R R2、 R3和 R4各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸 基、 d— 4垸氧基、 d— 4垸氧基垸基、 -(CH2)nNR8R8a、 -(CH2)nC(=0)NR8R8a、 -OC(=0)NR8R8a、 -OC(=0)OR8、 -OC(=0)R8、 -C(=0)OR8、 -N(R8b)C(=0)NR8R8a、 -N(R8)C(=0)OR8a、 -N(R8)C(=0)R8a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 C3— 1()碳环、 3 至 10 元杂环、 -0-(CH2)n-C3— 1Q碳环或者 -0-(CH2)n-(3至 10元杂环)， 所述的杂环含有 1至 4个选 自 N、 0或 S的杂原子， 所述的垸基、 垸氧基、 碳环或杂环各自独立任选进一步被 0至 4 个选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 4垸基、 d— 4垸氧基或 -NR7R7a的 取代基所取代； RR 2 , R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4 methoxy, d- 4 oxo Base group, -(CH 2 ) n NR 8 R 8a , -(CH 2 ) n C(=0)NR 8 R 8a , -OC(=0)NR 8 R 8a , -OC(=0)OR 8 , -OC(=0)R 8 , -C(=0)OR 8 , -N(R 8b )C(=0)NR 8 R 8a , -N(R 8 )C(=0)OR 8a , - N(R 8 )C(=0)R 8a , —(CH 2 ) n S(=0) p R 8 , —(CH 2 ) n -alkenyl-R 8 , —(CH 2 ) n -alkynyl -R 8 , C 3 - 1 () carbocyclic ring, 3 to 10 membered heterocyclic ring, -0-(CH 2 ) n -C 3 - 1Q carbocyclic ring or -0-(CH 2 ) n - (3 to 10 yuan) Heterocyclic ring), the heterocyclic ring contains 1 to 4 hetero atoms selected from N, 0 or S, and the fluorenyl group, the decyloxy group, the carbocyclic ring or the heterocyclic ring are each independently optionally further 0 to 4 Substituted with a substituent selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4- decyloxy or -NR 7 R 7a ;
作为选择， R1和 R2可以形成 (=0); Alternatively, R 1 and R 2 may form (=0);
作为选择， R3和 R4可以形成 (=0); Alternatively, R 3 and R 4 may form (=0);
作为选择， R R2、 R3、 R4中任意两个基团可与它们相连的原子一起形成一个 3至 6 元环， 包含螺环或并环， 所述 3至 6元环含有 0至 3个选自 N、 0或者 S的杂原子， 并且 形成的 3至 6元环可以任选进一步被 0至 4个 R7a取代； Alternatively, any two of RR 2 , R 3 , and R 4 may form a 3 to 6 membered ring together with the atoms to which they are attached, including a spiro or a bicyclic ring, and the 3 to 6 membered ring contains 0 to 3 a hetero atom selected from N, 0 or S, and the formed 3 to 6 membered ring may be optionally further substituted with 0 to 4 R 7a ;
R5各自独立地选自 H、 F、 Cl、 Br、 I、 三氟甲基、 d_4垸基、 d_4垸氧基、 羟基、 巯 基、 氨基、 氰基、 -(CR7R7a)n-C(=0)-NR7R7a或者 -(CR7R7a)nNR7R7a; R 5 is each independently selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, d 4 fluorenyl, d 4 methoxy, hydroxy, decyl, amino, cyano, -(CR 7 R 7a ) n -C(=0)-NR 7 R 7a or -(CR 7 R 7a ) n NR 7 R 7a ;
R6选自 -C(=0)NR7R7a、 氰基、 三氟甲基、 -(CH2)nS(=0)pR8、 -C(R7R7a)R8、 -C(R7R7a)OR8、R 6 is selected from -C(=0)NR 7 R 7a , cyano, trifluoromethyl, -(CH 2 ) n S(=0) p R 8 , -C(R 7 R 7a )R 8 , C(R 7 R 7a )OR 8 ,
C3— 1Q碳环或者 3至 10元杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述碳 环或杂环各自独立任选进一步被 0至 4个 R8取代； R7和 1 各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 C14垸基、 C14垸氧基、 -C(=0)-Ci_s垸基、 -C(=0)OR8、 -N(R8)C(=0)R8a、 -(CR8R8a)n R8R8a、 -(CH2)nC(=0) R8R8a、 -(CH2)nS(=0)pR8、 -(CH2)n-烯基 -R8、 -(CH2)n-炔基 -R8、 -(CH2)n-C3— 1()碳环、 -C(=0)-(3 至 10 元杂环)、 -(CH2)n-(3至 10元杂环)、 -0-(CH2)n-C3_1()碳环或者 -0-(CH2)n-(3至 10元杂环)， 所 述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述垸基、 垸氧基、 碳环或者杂环任选进 一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺 基、 甲基炔基、 氨基、 -C(=0)-(3 至 10元杂环)、 -C(=0)0-d.4垸基、 羟基取代的 3垸 基、 -C^C -d— 3垸基、 C3—1Q碳环或 3至 10元杂环的取代基所取代； a C 3 —1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, each independently optionally further being 0 to 4 R 8 substitution; R 7 and 1 are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, C 14 fluorenyl, C 14 decyloxy, -C(=0)-Ci_s decyl, -C (=0)OR 8 , -N(R 8 )C(=0)R 8a , -(CR 8 R 8a )n R 8 R 8a , -(CH 2 ) n C(=0) R 8 R 8a , -(CH 2 ) n S(=0) p R 8 , -(CH 2 ) n -alkenyl-R 8 , -(CH 2 ) n -alkynyl-R 8 , -(CH 2 ) n -C 3 — 1 () carbocyclic ring, —C(=0)—(3 to 10 membered heterocyclic ring), —(CH 2 ) n —(3 to 10 membered heterocyclic ring), —0-(CH 2 ) n —C 3 a 1() carbocyclic ring or a-0-(CH 2 ) n - (3 to 10 membered heterocyclic ring), the heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, the fluorenyl group, The methoxy, carbocyclic or heterocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 -mercapto, d- 4- methoxy, hydroxy, decyl, cyano, amide , methyl alkynyl, amino, -C(=0)-(3 to 10 membered heterocyclic), -C(=0)0-d.4 fluorenyl, hydroxy substituted 3 fluorenyl, -C^C Substituted with a substituent of a -d- 3 fluorenyl group, a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring;
作为选择， R7和 1 可以形成 (=0); Alternatively, R 7 and 1 can be formed (=0);
作为选择， R7和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 所 述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个 选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -C(=0)-(3至 10元杂环)、 (=ο)ο- 4垸基、 羟基取代的 d— 3垸基或 -C^C -d— 3垸 基的取代基所取代； Alternatively, R 7 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, Methyl alkynyl, amino, -C(=0)-(3 to 10-membered heterocyclic), (=ο)ο- 4 fluorenyl, hydroxy-substituted d- 3 fluorenyl or -C^C-d- 3 Substituted by a substituent of a fluorenyl group;
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3— 1()碳 环或 3至 10元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者 碳环任选进一步被 0至 4个选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -C(=0)-3至 10元杂环、 -C^C O-d— 4垸基、 羟基取代的 3垸基或 -Cl^C -d— 3垸基的取代基所取代； Alternatively, when two R 7a are attached to the same atom, they may form a C 3 - 1 () carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 a hetero atom selected from N, 0 or S, optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 fluorenyloxy , hydroxy, decyl, cyano, amido, methyl alkynyl, amino, -C(=0)-3 to 10-membered heterocyclic ring, -C^C Od- 4 fluorenyl, hydroxy-substituted 3 fluorenyl or Substituted by a substituent of a Cl^C-d- 3 fluorenyl group;
R8、 ！^ 和 R8b各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d_4垸 基、 d_4垸氧基、 C3_1Q碳环或 3至 10元杂环； R 8 , ! ^ and R 8b are each independently selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d 4 fluorenyl, d 4 methoxy, C 3 _ 1Q carbon ring or 3 to 10 Heterocycle
作为选择， R8和 1 可与它们相连的原子一起形成 C3— 1Q碳环或 3至 10元的杂环， 所 述杂环含有 1至 3个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 4个 选自 H、 F、 Cl、 Br、 I、 d— 4垸基、 d— 4垸氧基、 羟基、 巯基、 氰基、 酰胺基、 甲基炔基、 氨基、 -C(=0)-(3至 10元杂环)、 (=0)0- 4垸基、 羟基取代的 3垸基或 -C^C -d— 3垸 基的取代基所取代； Alternatively, R 8 and 1 may form a C 3 - 1Q carbocyclic ring or a 3 to 10 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S, The heterocyclic ring or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, d- 4 fluorenyl, d- 4 methoxy, hydroxy, decyl, cyano, amide, methyl alkynyl group, an amino group, -C (= 0) - ( 3 to 10-membered heterocyclyl), (= 0) 0-4 embankment group, a hydroxy-substituted alkyl with 3 or -C ^ C -d- 3-yl embankment Substituted by a substituent;
m选自 0、 1、 2或者 3 ;  m is selected from 0, 1, 2 or 3;
n选自 0、 1、 2、 3或者 4;  n is selected from 0, 1, 2, 3 or 4;
p选自 0、 1或者 2;  p is selected from 0, 1 or 2;
条件是该化合物不为： 1-(2,3-二氢苯并呋喃 -5-基；) -7-氧代 -6-[4-(2-氧代哌啶 -1-基;)苯基] - Provided that the compound is not: 1-(2,3-dihydrobenzofuran-5-yl;)-7-oxo-6-[4-(2-oxopiperidin-1-yl;)benzene Base] -
4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酰胺或 1-(2,3-二氢苯并呋喃 -5-基) -7-氧代 -6-[4-(2-氧 代哌啶 -1-基)苯基] -4,5,6,7-四氢 -1H-吡唑并 [3,4-c]吡啶 -3-甲酸乙酯。 2、 根据权利要求 1 所述的化合物， 或者其立体异构体、 氮氧化合物、 水合物、 溶剂 化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中： 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide or 1-(2,3-dihydrobenzofuran-5-yl)-7- Oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3 - ethyl formate. 2. A compound according to claim 1 or a stereoisomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
X选自 0或 S;  X is selected from 0 or S;
A选自取代的或未取代的苯基， 当被取代时， 选择被 1至 5个 R7取代； A is selected from substituted or unsubstituted phenyl groups, and when substituted, is selected to be substituted with 1 to 5 R 7 ;
B 一：  B one:
Figure imgf000128_0001
Figure imgf000128_0001
当被取代时， 任选进一步被 1至 3个取代基所取代， 所述取代基选自 R7a或者 (=0); When substituted, optionally further substituted with from 1 to 3 substituents selected from R 7a or (=0);
R1, R2、 R3和 R4各自独立选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 甲基、 乙基、 丙基、 R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, propyl,
2-丙基、 正丁基、 异丁基、 甲氧基、 乙氧基、 丙氧基、 丁氧基、 环丙氧基、 氨基甲酰基、 N-乙基氨基甲基、 烯丙基、 甲基炔基、 环丙基、 环丁基、 环戊基、 -OC(=0) NH(CH3)、 -OC(=0)OCH3或 -NH(C=0)NH(CH3); 2-propyl, n-butyl, isobutyl, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, carbamoyl, N-ethylaminomethyl, allyl, Methyl alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, -OC(=0)NH(CH 3 ), -OC(=0)OCH 3 or -NH(C=0)NH(CH 3 ) ;
作为选择， R1和 R2可以形成 (=0); Alternatively, R 1 and R 2 may form (=0);
作为选择， R3和 R4可以形成 (=0); Alternatively, R 3 and R 4 may form (=0);
作为选择， 其中 R R2、 R3、 R4中任意两个基团可以形成环丙基、 环丁基、 环戊基、 环己基、 吡啶基、 呋喃基、 噻吩基、 吡咯基、 N-垸基吡咯基、 哌啶基、 吗啉基、 硫代吗啉 基、 四氢呋喃基或四氢吡咯基； Alternatively, any two of RR 2 , R 3 , and R 4 may form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyridyl group, a furyl group, a thienyl group, a pyrrolyl group, and an N-fluorene group. Pyryl pyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl or tetrahydropyrrolyl;
R5选自 H、 F、 Cl、 Br、 I、 三氟甲基、 羟基、 巯基、 氰基、 氨基、 甲基、 乙基、 丙 基、 异丙基、 正丁基、 异丁基、 叔丁基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基、 丁氧基、 叔丁氧基、 氨基甲酰基或者氨基亚甲基； R 5 is selected from the group consisting of H, F, Cl, Br, I, trifluoromethyl, hydroxy, decyl, cyano, amino, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert Butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, carbamoyl or aminomethylene;
R6选自 -C(=0)NR7R7a、 氰基、 三氟甲基、 -(CH2)nS(=0)2R8、 -C(R7R7a)R8、 -C(R7R7a)OR8、R 6 is selected from -C(=0)NR 7 R 7a , cyano, trifluoromethyl, -(CH 2 ) n S(=0) 2 R 8 , -C(R 7 R 7a )R 8 , C(R 7 R 7a )OR 8 ,
C3— 4碳环或者 3至 4元杂环， 所述碳环或杂环各自独立任选进一步被 0至 4个 R8取代， 所 述杂环含有 1至 3个选自 N、 0或 S的杂原子； a C 3 — 4 carbocyclic ring or a 3 to 4 membered heterocyclic ring, each of which is optionally independently further substituted by 0 to 4 R 8 , the heterocyclic ring having 1 to 3 selected from N, 0 or a hetero atom of S;
R7和 1 各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 羟甲基、 三 氟甲基、 甲基、 乙基、 丙基、 异丙基、 异丁基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基、 甲 氧基羰基、 乙氧基羰基、 乙酰基、 氨基甲酰基、 烯丙基、 甲基炔基、 环丙基、 环丙基亚甲 基、 环丁基、 环戊基、 环己基、 吡啶基、 吡咯基、 哌啶基、 四氢呋喃基或四氢吡咯基； 作为选择， R7和 1 可以形成 (=0); 作为选择， R7和 1 可与它们相连的原子一起形成 C3— 5碳环或 3至 5元的杂环， 所述 杂环含有 1至 3个选自 N、 0或 S的杂原子； R 7 and 1 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, hydroxymethyl, trifluoromethyl, methyl, ethyl, propyl, isopropyl, Isobutyl, methoxy, ethoxy, propoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, carbamoyl, allyl, methylalkynyl, cyclopropyl , cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrrolyl, piperidinyl, tetrahydrofuranyl or tetrahydropyrrolyl; alternatively, R 7 and 1 can form (=0) ; Alternatively, R 7 and 1 may form a C 3 - 5 carbocyclic ring or a 3 to 5 membered heterocyclic ring together with the atoms to which they are attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, 0 or S;
作为选择， 当两个 R7a连接在同一个原子上时， 可与它们相连的原子一起形成 C3— 5碳 环或 3至 5元的杂环， 所述杂环含有 1至 3个选自 N、 0或 S的杂原子； Alternatively, when two R 7a are bonded to the same atom, they may form a C 3 - 5 carbocyclic ring or a 3 to 5 membered heterocyclic ring together with the atoms to which they are attached, the heterocyclic ring having 1 to 3 selected from the group consisting of a hetero atom of N, 0 or S;
R8选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 甲基、 乙基、 异丙基、 甲氧 基、 乙氧基、 异丙氧基、 环丙基、 环丁基、 氧杂环丙基、 氧杂环丁基或氮杂环丁基； m选自 0、 1或者 2; R 8 is selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, Cyclobutyl, oxetanyl, oxetanyl or azetidinyl; m is selected from 0, 1 or 2;
n选自 0、 1或者 2;  n is selected from 0, 1 or 2;
p选自 0、 1或者 2。  p is selected from 0, 1 or 2.
3、 根据权利要求 2 所述的化合物， 或者其立体异构体、 氮氧化合物、 水合物、 溶剂 化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中： 3. A compound according to claim 2, or a stereoisomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
X为 0;  X is 0;
A为苯基， 其中苯基任选进一步被 0至 4个 F取代；  A is a phenyl group, wherein the phenyl group is optionally further substituted with 0 to 4 F;
B选自 一：  B is selected from one:
Figure imgf000129_0001
或
Figure imgf000129_0001
or
R1 , R2、 R3和 R4各自独立的选 β Η、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 甲 基、 乙基、 环丙基、 甲氧基或乙氧基； R 1 , R 2 , R 3 and R 4 are each independently selected from β F, F, Cl, Br, I, hydroxy, decyl, cyano, amino, methyl, ethyl, cyclopropyl, methoxy or B. Oxylate
作为选择， R1和 R2可以形成 (=0); Alternatively, R 1 and R 2 may form (=0);
作为选择， R3和 R4可以形成 (=0); Alternatively, R 3 and R 4 may form (=0);
作为选择， 其中 R R2、 R3、 R4中任意两个基团可以形成环丙基、 环丁基、 环戊基、 环己基、 吡啶基、 呋喃基、 噻吩基、 吡咯基、 N-垸基吡咯基、 哌啶基、 吗啉基、 硫代吗啉 基、 四氢呋喃基或四氢吡咯基； Alternatively, any two of RR 2 , R 3 , and R 4 may form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a pyridyl group, a furyl group, a thienyl group, a pyrrolyl group, and an N-fluorene group. Pyryl pyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl or tetrahydropyrrolyl;
R5各自独立的选自 H、 F、 Cl、 三氟甲基、 羟基、 氨基、 甲基、 乙基、 丙基、 异丙 基、 甲氧基、 乙氧基、 丙氧基或者异丙氧基； R 5 is independently selected from H, F, Cl, trifluoromethyl, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy base;
R6选自氨基甲酰基、 2-异丙醇基、 1 -环丙醇基、 氰基、 三氟甲基、 1 -氟乙基、 乙氧基 甲酰基、 1-氟甲基、 1 ,1-二氟甲基、 1-羟基乙基或 1-羟基甲基； R 6 is selected from the group consisting of carbamoyl, 2-isopropanol, 1-cyclopropanol, cyano, trifluoromethyl, 1-fluoroethyl, ethoxycarbonyl, 1-fluoromethyl, 1 . 1-difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl;
m选自 0、 1或者 2;  m is selected from 0, 1 or 2;
p选自 0、 1或者 2。 p is selected from 0, 1 or 2.
4、 根据权利要求 3 所述的化合物， 或者其立体异构体、 氮氧化合物、 水合物、 溶剂 化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中： 4. A compound according to claim 3, or a stereoisomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
X为 0;  X is 0;
A为苯基， 其中苯基任选进一步被 0至 4个 F取代；  A is a phenyl group, wherein the phenyl group is optionally further substituted with 0 to 4 F;
B选自如下结构之一：  B is selected from one of the following structures:
Figure imgf000130_0001
Figure imgf000130_0001
R1 , R2、 R3和 R4各自独立的选自 H、 甲基或乙基； R 1 , R 2 , R 3 and R 4 are each independently selected from H, methyl or ethyl;
作为选择， R1和 R2可以形成 (=0); Alternatively, R 1 and R 2 may form (=0);
作为选择， R3和 R4可以形成 (=0); Alternatively, R 3 and R 4 may form (=0);
作为选择， 其中 R R2、 R3、 R4中任意两个基团可以形成环丙基; Alternatively, wherein any two of RR 2 , R 3 , and R 4 may form a cyclopropyl group;
R5各自独立的选 g H、 F、 Cl、 三氟甲基、 羟基、 甲基或者乙基； R 5 is independently selected from the group consisting of g H, F, Cl, trifluoromethyl, hydroxy, methyl or ethyl;
R6选自氨基甲酰基、 2-异丙醇基、 1 -环丙醇基、 氰基、 1 -氟乙基、 乙氧基 甲酰基、 1-氟甲基、 1 ,1-二氟甲基、 1-羟基乙基或 1-羟基甲基 R 6 is selected from the group consisting of carbamoyl, 2-isopropanol, 1-cyclopropanol, cyano, 1-fluoroethyl, ethoxycarbonyl, 1-fluoromethyl, 1 ,1-difluoro Base, 1-hydroxyethyl or 1-hydroxymethyl
5、 根据权利要求 1 所述的化合物， 或者其立体异构体、 氮氧化合物、 水合物、 溶剂 5. The compound according to claim 1, or a stereoisomer thereof, an oxynitride, a hydrate, a solvent
Ac 化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中：  Ac a compound, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
X为 0;  X is 0;
Α为苯基， 其中苯基任选进一步被 0至 4个 F取代；  Α is phenyl, wherein the phenyl group is optionally further substituted by 0 to 4 F;
B 一：  B one:
Figure imgf000130_0002
Figure imgf000130_0002
R1 , R2、 R3和 R4各自独立的选自 H或甲基； R 1 , R 2 , R 3 and R 4 are each independently selected from H or methyl;
R5各自独立的选 g H、 F、 CI或者甲基； R 5 is independently selected from g H, F, CI or methyl;
R6选自氨基甲酰基、 2-异丙醇基、 1 -环丙醇基、 氰基、 三氟甲基、 1 -氟乙基、 乙氧基 甲酰基、 1-氟甲基、 1 ,1-二氟甲基、 1-羟基乙基或 1-羟基甲基。 R 6 is selected from the group consisting of carbamoyl, 2-isopropanol, 1-cyclopropanol, cyano, trifluoromethyl, 1-fluoroethyl, ethoxycarbonyl, 1-fluoromethyl, 1 . 1-Difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl.
6、 根据权利要求 5 所述的化合物， 或者其立体异构体 氮氧化合物、 水合物、 溶剂 化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中: 6. A compound according to claim 5, or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
R5选自 H或 F; R6为氨基甲酰基。 R 5 is selected from H or F ; and R 6 is a carbamoyl group.
7、 根据权利要求 5 所述的化合物， 或者其立体异构体 氮氧化合物、 水合物、 溶剂 化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中: 7. A compound according to claim 5, or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein:
X为 0;  X is 0;
A为苯基， 其中苯基可以进一步被 1个 F取代；  A is a phenyl group, wherein the phenyl group may be further substituted by one F;
B选 之一：  One of the B choices:
Figure imgf000131_0001
Figure imgf000131_0001
R1 , R2、 R3和 R4各自独立的选自 H; R 1 , R 2 , R 3 and R 4 are each independently selected from H ;
R5各自独立的选自 H或者 F; R 5 is independently selected from H or F;
R6为氨基甲酰基； R 6 is a carbamoyl group;
m为 1。  m is 1.
8、 根据权利要求 5 所述的化合物， 或者其立体异构体、 氮氧化合物、 水合物、 溶剂 化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中： 8. A compound according to claim 5, or a stereoisomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
X为 0;  X is 0;
A 其中苯基可以进一步被 1个 F取代；
Figure imgf000131_0002
A wherein the phenyl group may be further substituted by 1 F;
Figure imgf000131_0002
R1 , R2各自独立的选自 H或者甲基 R 1 and R 2 are each independently selected from H or methyl
R3、 R4各自独立的选自 H; R 3 and R 4 are each independently selected from H;
R5各自独立的选自 H或者 F; R 5 is independently selected from H or F;
R6选自氨基甲酰基或者三氟甲基； R 6 is selected from carbamoyl or trifluoromethyl;
m为 1。  m is 1.
9、 根据权利要求 5 所述的化合物， 或者其立体异构体、 氮氧化合物、 水合物、 溶剂 化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中： 9. A compound according to claim 5, or a stereoisomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
X为 0;  X is 0;
A为苯基， 其中苯基可以进一步被 1个 F取代； B选自如下结构之一:
Figure imgf000132_0001
A is a phenyl group, wherein the phenyl group may be further substituted with 1 F; B is selected from one of the following structures:
Figure imgf000132_0001
R1 , R2各自独立的选自 Η或者甲基； R 1 and R 2 are each independently selected from hydrazine or methyl;
R3、 R4各自独立的选自 H; R 3 and R 4 are each independently selected from H ;
R5各自独立的选自 H或者 F; R 5 is independently selected from H or F ;
R6选自氨基甲酰基或者三氟甲基； R 6 is selected from carbamoyl or trifluoromethyl;
m为 1。  m is 1.
10、 根据权利要求 5所述的化合物， 或者其立体异构体、 氮氧化合物、 水合物、 溶剂 化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中： 10. A compound according to claim 5, or a stereoisomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
X为 0;  X is 0;
A为苯基， 其中苯基可以进一步被 1个 F取代；
Figure imgf000132_0002
或 〜Ν' A is a phenyl group, wherein the phenyl group may be further substituted with 1 F;
Figure imgf000132_0002
Or ~Ν'
Β选自如下结构之一：  Β is selected from one of the following structures:
R1 , R2、 R3、 R4各自独立的选自 H; R 1 , R 2 , R 3 , R 4 are each independently selected from H;
R5各自独立的选自 H或者 F; R 5 is independently selected from H or F ;
R6为氨基甲酰基； R 6 is a carbamoyl group;
m为 1。  m is 1.
1 1、 根据权利要求 1 或者 5 所述的化合物， 或者其立体异构体、 氮氧化合物、 水合 物、 溶剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中化合物选自如下结构 之一： A compound according to claim 1 or 5, or a stereoisomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, wherein the compound is selected Since one of the following structures:
Figure imgf000132_0003
Figure imgf000132_0003
Figure imgf000133_0001
Figure imgf000133_0001
12、 根据权利要求 11 所述的化合物， 或者其立体异构体、 氮氧化合物、 水合物、 溶 剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中化合物选自如下结构之一：  The compound according to claim 11, or a stereoisomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from the following structures One:
Figure imgf000133_0002
Figure imgf000133_0002
13、 根据权利要求 1~12 中任一项所述的化合物， 或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中所述的盐选自盐 酸盐、 氢溴酸盐、 硫酸盐、 硝酸盐、 磷酸盐、 乙酸盐、 马来酸盐、 琥珀酸盐、 扁桃酸盐、 富马酸盐、 丙二酸盐、 苹果酸盐、 2-羟基丙酸盐、 草酸盐、 羟乙酸盐、 水杨酸盐、 葡萄糖 醛酸盐、 半乳糖醛酸盐、 枸橼酸盐、 酒石酸盐、 门冬氨酸盐、 谷氨酸盐、 苯甲酸盐、 肉桂 酸盐、 对甲苯磺酸盐、 苯磺酸盐、 甲磺酸盐、 乙磺酸盐、 三氟甲磺酸盐或它们的组合。 The compound according to any one of claims 1 to 12, or a stereoisomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, Wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonic acid Salt, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronide, galacturonate, citrate, tartrate, aspartate Salt, glutamate, benzoate, cinnamon An acid salt, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, triflate or a combination thereof.
14、 根据权利要求 1~12 中任一项所述的化合物， 或者其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 其中共晶形成物包括 脯氨酸、 苯丙氨酸、 焦谷氨酸。 The compound according to any one of claims 1 to 12, or a stereoisomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, The eutectic formations include proline, phenylalanine, and pyroglutamic acid.
15、 一种药物组合物， 所述药物组合物含有治疗有效剂量的根据权利要求 1~12 中任 一项所述的化合物或其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上 可以接受的盐、 共晶或前药， 以及药学上可接受的载体或者赋形剂。 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 12, or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolism A product, a pharmaceutically acceptable salt, a eutectic or prodrug, and a pharmaceutically acceptable carrier or excipient.
16、 权利要求 1~12 中任一项所述的化合物或其立体异构体、 氮氧化合物、 水合物、 溶剂化物、 代谢产物、 药学上可以接受的盐、 共晶或前药， 在制备治疗血栓栓塞疾病的药 物中的用途。 The compound according to any one of claims 1 to 12, or a stereoisomer thereof, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, in the preparation Use in medicines for the treatment of thromboembolic disorders.
17、 根据权利要求 16 所述的用途， 其中所述的血栓栓塞疾病选自静脉血栓形成、 深 部静脉血栓形成、 血栓性静脉炎、 脑动脉血栓形成、 动脉栓塞、 冠状动脉血栓形成、 肺栓 塞、 肾栓塞， 脑栓塞， 动脉粥样硬化、 急性冠状综合征、 不稳定心绞痛、 急性冠状动脉综 合征、 心肌梗塞、 动脉硬化症、 局部缺血瘁死、 暂时性的缺血、 外用阻塞性动脉疾病、 中 风或者脑血管疾病。 17. The use according to claim 16, wherein said thromboembolic disease is selected from the group consisting of venous thrombosis, deep vein thrombosis, thrombophlebitis, cerebral arterial thrombosis, arterial embolism, coronary thrombosis, pulmonary embolism, Renal embolism, cerebral embolism, atherosclerosis, acute coronary syndrome, unstable angina pectoris, acute coronary syndrome, myocardial infarction, atherosclerosis, sudden ischemic death, transient ischemia, external obstructive arterial disease , stroke or cerebrovascular disease.
18、 含有权利要求 1~14 中任一项所述的化合物或其药学上可以接受的盐的药物试 剂， 其中所述药物试剂包括： 治疗上有效剂量的第一种治疗剂和第二种治疗剂， 其中所述 第一治疗剂是权利要求 1~14 中的任一个权利要求中的所述化合物或其药学上可以接受的 盐形式， 所述第二治疗剂是选自第二种 Xa 因子抑制剂、 抗凝剂、 抗血小板剂、 凝血酶抑 制剂、 溶血栓剂以及纤维蛋白溶解剂中的至少一种试剂。 A pharmaceutical agent comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical agent comprises: a therapeutically effective amount of a first therapeutic agent and a second treatment The first therapeutic agent is a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, the second therapeutic agent being selected from the second factor Xa At least one of an inhibitor, an anticoagulant, an antiplatelet agent, a thrombin inhibitor, a thrombolytic agent, and a fibrinolytic agent.
19、 根据权利要求 18 所述的药物试剂， 其中所述第二种治疗剂是选自华法林、 阿司 匹林、 氯吡格雷、 未分级肝素、 低分子量肝索、 合成的五糖、 水蛙素、 阿加由班、 阿可匹 林、 布洛芬、 甲氧奈丙酸、 苏灵大、 吲哚美辛、 甲灭酸、 屈噁昔康、 双氯芬酸、 苯磺唑 酮、 吡罗昔康、 噻氯匹定、 氯吡格雷、 替罗非班、 埃替菲巴肽、 阿昔单抗美加拉群、 二硫 酸水蛭素、 组织纤溶酶原激活剂、 修饰的组织型纤溶酶原激活剂、 复合纤溶酶链激酶、 尿 激酶和链激酶中的至少一种试剂。 19. The pharmaceutical agent according to claim 18, wherein the second therapeutic agent is selected from the group consisting of warfarin, aspirin, clopidogrel, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, spirulina , Agaban, acomipine, ibuprofen, methoxypropionate, sulindac, indomethacin, mefenamic acid, dexamethasone, diclofenac, benzoxazolone, piroxicam, thiazide Chloropidine, clopidogrel, tirofiban, eptifibatide, abciximab mecarragine, hirudin disulfate, tissue plasminogen activator, modified tissue plasminogen activator At least one agent of a combination of plasmin, urokinase, and streptokinase.
PCT/CN2014/075683 2013-04-19 2014-04-18 4,5-dihydro-pyrazolo [3, 4-c] pyrid-2-ones, preparation method and application thereof WO2014169845A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201480003262.1A CN105026392B (en) 2013-04-19 2014-04-18 4,5-dihydro-pyrazolo [3, 4-c] pyrid-2-ones, preparation method and application thereof

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN201310138026.8 2013-04-19
CN201310138026 2013-04-19
CN201310372920 2013-08-23
CN201310372920.1 2013-08-23
CN201310428690.6A CN104109165A (en) 2013-04-19 2013-09-18 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-one derivatives, and preparation method and application thereof
CN201310428690.6 2013-09-18

Publications (2)

Publication Number Publication Date
WO2014169845A2 true WO2014169845A2 (en) 2014-10-23
WO2014169845A3 WO2014169845A3 (en) 2014-12-11

Family

ID=51706170

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/075683 WO2014169845A2 (en) 2013-04-19 2014-04-18 4,5-dihydro-pyrazolo [3, 4-c] pyrid-2-ones, preparation method and application thereof

Country Status (2)

Country Link
CN (2) CN104109165A (en)
WO (1) WO2014169845A2 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110143914A (en) * 2019-06-21 2019-08-20 常州恒邦药业有限公司 A kind of preparation method of Eliquis intermediate
US11312711B2 (en) 2016-03-17 2022-04-26 Hoffmann-La Roche Inc. Morpholine derivative
WO2022247920A1 (en) 2021-05-27 2022-12-01 江苏恒瑞医药股份有限公司 Quinolinamine compound, preparation method therefor and application thereof in pharmaceuticals

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3064497A1 (en) * 2015-07-20 2016-09-07 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Dimer impurities of apixaban and method to remove them
CN107474030B (en) * 2016-06-08 2021-03-30 首都医科大学 Warfarin-aspirin conjugates, their synthesis, antithrombotic activity and uses
CN109232596B (en) * 2018-09-05 2020-03-17 大连九信精细化工有限公司 Synthetic method of dibenzofuran carbazole

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE280171T1 (en) * 1998-12-23 2004-11-15 Bristol Myers Squibb Pharma Co NITROGEN-CONTAINING HETEROBICYCLES AS FACTOR XA INHIBITORS
ATE373655T1 (en) * 2000-06-23 2007-10-15 Bristol Myers Squibb Pharma Co 1-(HETEROARYL-PHENYL)-CONDENSED PYRAZOLE DERIVATIVES AS FACTOR XA INHIBITORS
CN1578660B (en) * 2001-09-21 2010-11-24 百时美施贵宝公司 Lactam-containing compounds and derivatives thereof as factor xa inhibitors
TW200303201A (en) * 2001-12-10 2003-09-01 Bristol Myers Squibb Co Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
CN101065379B (en) * 2004-09-28 2011-05-11 布里斯托尔-迈尔斯斯奎布公司 Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
DE102006025315A1 (en) * 2006-05-31 2007-12-06 Bayer Healthcare Ag Tetrahydro-pyrrolopyridine, tetrahydro-pyrazolopyridine, tetrahydro-imidazopyridine and tetrahydro-triazolopyridine derivatives and their use

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11312711B2 (en) 2016-03-17 2022-04-26 Hoffmann-La Roche Inc. Morpholine derivative
CN110143914A (en) * 2019-06-21 2019-08-20 常州恒邦药业有限公司 A kind of preparation method of Eliquis intermediate
CN110143914B (en) * 2019-06-21 2022-03-29 常州恒邦药业有限公司 Preparation method of apixaban intermediate
WO2022247920A1 (en) 2021-05-27 2022-12-01 江苏恒瑞医药股份有限公司 Quinolinamine compound, preparation method therefor and application thereof in pharmaceuticals

Also Published As

Publication number Publication date
CN104109165A (en) 2014-10-22
CN105026392B (en) 2017-05-10
CN105026392A (en) 2015-11-04
WO2014169845A3 (en) 2014-12-11

Similar Documents

Publication Publication Date Title
JP7575952B2 (en) 15-PGDH inhibitors
WO2014169845A2 (en) 4,5-dihydro-pyrazolo [3, 4-c] pyrid-2-ones, preparation method and application thereof
JP2004517860A (en) Aza- and polyaza-naphthalenylcarboxamides useful as HIV integrase inhibitors
JP2004513134A (en) Aza- and polyaza-naphthalenyl ketones useful as HIV integrase inhibitors
WO2015120777A1 (en) Pyridone or pyrimidone derivative, preparation method therefor and application thereof
TW200804372A (en) Two cyclic cinnamide compound
JP2004510819A (en) Aza- and polyaza-naphthalenylcarboxamides useful as HIV integrase inhibitors
KR102171710B1 (en) Novel substituted pyrido-piperazinone derivatives as gamma secretase modulators
TWI826509B (en) Heteroaromatic compounds as vanin inhibitors
TWI835840B (en) INHIBITORS OF αVβ6 INTEGRIN
EA033827B1 (en) Benzimidazole derivatives as antihistamine agents
WO2010050525A1 (en) Compound having tafia inhibitory activity
CN104395312B (en) The Spirocyclic derivatives of 4,5-dihydro-pyrazolo [3,4-c] pyridin-2-ones, its preparation method and application
WO2015051713A1 (en) 4,5-dihydro-pyrazolo[3,4-c]pyridin-2-one spiro derivative, preparation method and use thereof
JP5597202B2 (en) 3- (biaryloxy) propionic acid derivatives
JP5726321B2 (en) Oxazolo [5,4-B] pyridin-5-yl compounds and their use in cancer treatment
CN112778273B (en) Cyclic ketopyridone compounds and preparation method and application thereof
WO2024023266A1 (en) Novel compounds
CN113135929B (en) Furopyridone amide compound, preparation method and application thereof
AU2022222458A9 (en) Factor xiia inhibitors
CN113135930B (en) Furopyridone imidazole compound, preparation method and application thereof
CN112778277B (en) Cyclic ketone pyridone biaryl compound, preparation method and application thereof
TWI857918B (en) INHIBITORS OF αvβ6 INTEGRIN
WO2024084217A1 (en) 3a,4,5,6-tetrahydro-1 h-pyrazolo[3,4-c]pyridin-7(7ah)-one derivatives as factor xiia inhibitors
CN116829547A (en) Factor XIIa inhibitors

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201480003262.1

Country of ref document: CN

122 Ep: pct application non-entry in european phase

Ref document number: 14786038

Country of ref document: EP

Kind code of ref document: A2