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WO2014169845A2 - 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones, procédé de préparation et d'utilisation desdites substances - Google Patents

4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones, procédé de préparation et d'utilisation desdites substances Download PDF

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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
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group
fluorenyl
oxo
phenyl
heterocyclic ring
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PCT/CN2014/075683
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English (en)
Chinese (zh)
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WO2014169845A3 (fr
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
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四川海思科制药有限公司
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Priority to CN201480003262.1A priority Critical patent/CN105026392B/zh
Publication of WO2014169845A2 publication Critical patent/WO2014169845A2/fr
Publication of WO2014169845A3 publication Critical patent/WO2014169845A3/fr

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    • 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%).

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Abstract

La présente invention concerne des 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones, telles que représentées dans la formule (I), et un procédé de préparation et d'utilisation desdites substances. La définition de chaque substituant dans le composé de formule (I) est la même que la définition figurant dans la description.
PCT/CN2014/075683 2013-04-19 2014-04-18 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones, procédé de préparation et d'utilisation desdites substances WO2014169845A2 (fr)

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CN110143914A (zh) * 2019-06-21 2019-08-20 常州恒邦药业有限公司 一种阿哌沙班中间体的制备方法
CN110143914B (zh) * 2019-06-21 2022-03-29 常州恒邦药业有限公司 一种阿哌沙班中间体的制备方法
WO2022247920A1 (fr) 2021-05-27 2022-12-01 江苏恒瑞医药股份有限公司 Composé quinolinamine, son procédé de préparation et son utilisation dans des produits pharmaceutiques

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