WO2012022120A1 - Dihydropyrazole compounds - Google Patents

Dihydropyrazole compounds Download PDF

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WO2012022120A1
WO2012022120A1 PCT/CN2011/001378 CN2011001378W WO2012022120A1 WO 2012022120 A1 WO2012022120 A1 WO 2012022120A1 CN 2011001378 W CN2011001378 W CN 2011001378W WO 2012022120 A1 WO2012022120 A1 WO 2012022120A1
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group
alkyl
cycloalkyl
halogen atom
independently selected
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PCT/CN2011/001378
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French (fr)
Chinese (zh)
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WO2012022120A8 (en
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张艳
陈俊宏
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山东轩竹医药科技有限公司
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Priority to CN201180031781.5A priority Critical patent/CN103052632B/en
Publication of WO2012022120A1 publication Critical patent/WO2012022120A1/en
Publication of WO2012022120A8 publication Critical patent/WO2012022120A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a dihydropyrazole compound, a pharmaceutically acceptable salt thereof or an isomer thereof, and a preparation method of the compound, the compound, the pharmaceutically acceptable salt thereof or the same Pharmaceutical preparations, and the use of these compounds, pharmaceutically acceptable salts thereof or isomers thereof for the preparation of a medicament for the treatment and/or prevention of kidney damage, cardiovascular diseases (such as hypertension) and/or endocrine diseases.
  • Background technique a dihydropyrazole compound, a pharmaceutically acceptable salt thereof or an isomer thereof, and a preparation method of the compound, the compound, the pharmaceutically acceptable salt thereof or the same.
  • kidney damage ⁇ Many, such as diabetes, high blood pressure and other common diseases can cause kidney damage. For example, 15% to 25% of type 1 diabetes and 30% - 40% of type 2 diabetes patients with diabetic nephropathy have become the leading cause of end-stage renal disease (40%). There is currently no effective treatment for the treatment of kidney damage.
  • Tyrone is a mineralocorticoid synthesized in the adrenal cortex. It is distributed in the kidney, colon, epithelial cells of the sweat gland, blood vessels, brain, heart muscle and other tissues. It binds to the mineralocorticoid receptor and activates its receptor. To promote sodium retention and potassium excretion, it plays an important role in electrolyte balance and changes in the structure and function of endothelial cells, vascular smooth muscle cells, fibroblasts and adventitial membranes and mediators on the arterial wall.
  • the drug binds to the mineralocorticoid receptor in a competitive manner, blocks the binding of aldosterone to the mineralocorticoid receptor, and inhibits aldosterone-mediated toxicity, thereby reducing kidney damage.
  • Spironolactone and Eplerenone which are used to treat high blood pressure, heart failure and kidney syndrome. Both are steroidal compounds, which have poor selectivity to other steroid hormone receptors, are prone to cause hyperkalemia, and have many side effects. Moreover, the structure is complicated and difficult to synthesize, and the physical and chemical properties are poor, which affects clinical application.
  • the object of the present invention is to provide novel non-steroidal compounds which are active and easy to synthesize and a process for their preparation.
  • Another object of the present invention is to provide novel alternatives to existing compounds for the prevention and/or treatment of kidney damage, cardiovascular diseases (such as hypertension) and/or endocrine diseases, and their preparation for the treatment and/or prevention of kidney damage , the use of drugs for cardiovascular diseases (such as high blood pressure) and / or endocrine diseases.
  • Cy 1 is a C 3-8 cycloalkyl group, a heteroaryl group or an aryl group;
  • Cy 2 is C 3-8 cycloalkyl, ( 5-8 cyclodecyl or 3-8 membered heterocyclic, said C 3-8 cycloalkyl, C 5-8 cyclyl and 3-8
  • the heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, a J. an alkyl group, a halogenated alkyl group, a phenyl group, a C 8 group; a cycloalkyl group and a 3-8 membered heterocyclic group;
  • L is C(0), C(0)0, C(0)NH, NHC(0), HC(0)NH, NHS(0), NHS(0) 2 , S(O) or S(0) 2 ;
  • X is N or CH
  • R la is a hydrogen atom, a halogen atom, a 1 ⁇ 2, a nitro group, a hydroxyl group, a carboxyl group, a methylsulfonyl group, a methoxycarbonyl group;
  • R lb is a halogen atom, «, hydroxy, carboxy, 1 ⁇ 2, nitro, fluorenyl, sulfonyl, «formyl, alkyl, alkene tt, C 3-8 cycloalkyl, C 2 _e alkenyl, (3 5-8 Cycloalkenyl, C 2-6 alkyne a C 3-8 cycloalkylalkylamino group, a di(C 1-6 alkyl)amino group, an alkyl fluorenyl group, an alkylcarbonyl group, an alkylaminoformyl group, an alkylamide group, an alkylsulfonyl group, C alkylaminosulfonyl, C alkylsulfonylamino, bis(C alkyl)aminoformyl, bis(C alkyl)aminosulfonyl, alkoxycarbonyl or alkylcarbonyloxy, Alkyl, C 3-8
  • R 2a is a hydrogen atom, an alkyl group, a C 3 -8 cycloalkyl group, a C 5 -8 cycloalkenyl group, a phenyl group or a 3-8 membered heterocyclic group, said C w alkyl group, C 3-8 cycloalkane
  • the base, C 5-8 cycloalkenyl, phenyl and 3-8 membered heterocyclyl can be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: halogen atom, cyanogen Base, hydroxyl, carboxyl, tt, alkyl and haloalkyl;
  • R 2b , R 3a , and R 3b are each independently a hydrogen atom, a nitro group, a halogen atom, an alkyl group, an alkoxy group, a C 3-8 cycloalkyl group, a C 2 -6 alkenyl group, a C 5-8 cycloalkenyl group.
  • C 2 -6 alkynyl or C 3-8 cycloalkoxy said alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, ( 5-8 cycloalkenyl, C 2-6 alkyne
  • the group, C 1-6 alkoxy group and C 3-8 cycloalkoxy group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: halogen atom, ⁇ 1 ⁇ 2 Hydroxyl, and «;
  • R 4 and R 5 and the X to which they are attached form a C 3-8 cycloalkyl group, a C 5-8 cycloalkenyl group, a phenyl group, a 3-8 membered heterocyclic group, a 5-10 membered fused ring group, 5-12 a spirocyclic group and a 6-10 membered bridged ring group, said C 3-8 cycloalkyl group, C 5-8 cycloalkenyl group, phenyl group, 3-8 membered heterocyclic group, 5-10 membered fused ring group a 5-12 membered spiro group and a 6-10 membered bridged ring group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 4a and 1 ⁇ ;
  • R 4a is a nitro group, a halogen atom, a hydroxyl group, a ', an alkyl group, an alkoxy group, a C 3-8 cycloalkyl group, a C 2 -6 alkenyl group, a C 5-8 cycloalkenyl group, a C 2-6 alkynyl group.
  • a C 3-8 cycloalkoxy group said alkyl group, C 3-8 cycloalkyl group, alkenyl group, C 5-8 cycloalkenyl group, alkynyl group, alkoxy group and C 3-8 cycloalkoxy group
  • substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group
  • R 5a is (CH 2 )pR 6 , wherein R 6 is OR 7 , C(0)R 7 , C(0)OR 7 , OC(0)R 7 , C(0)NR 8 R 9 , NR 8 C (0) R 7 , NR 8 R 9 , S(0) q R 7 , NHCOOR 7 , NHCONR 8 R 9 , S(0) q NR 8 R 9 , NR 8 S(0) q R 7 or C(0 NHS(0)qR 7 ;
  • R 7 , R 8 and R 9 are each independently a hydrogen atom, a C 1-6 alkyl group or a C 3-8 cycloalkyl group, and R 8 and R 9 may be used.
  • R 1G , R 11 and R 12 are each independently a hydrogen atom, an alkyl group, a C 3-8 cycloalkyl group or a phenyl group, and R 11 and R 12 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached,
  • the C w alkyl group, ( 3 -8 cycloalkyl group, phenyl group and 3-8 membered heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of : halogen atom, hydroxyl group and carboxyl group;
  • p is an integer from 0 to 6;
  • q is an integer of 0 to 2.
  • Cy 1 is a 3-8 membered heterocyclic group, ( 3-8 cycloalkyl or aryl;
  • Cy 2 is C 3 .8 cycloalkyl, C 5-8 cycloalkyl or 3-8 membered heterocyclic, said C 3-8 cycloalkyl, C 5-8 cyclodecyl and 3-8 member.
  • the heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, a C 1-6 alkyl group, a halogenated alkyl group, a phenyl group, C a 3-8 cycloalkyl group and a 3-8 membered heterocyclic group;
  • L is C(0), C(0)0, C(0)NH, NHC(0), S(O) or S(0) 2 ;
  • X is N or CH
  • R 1 is a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a decyl group, a sulfonic acid group, a formyl group, a -6 alkyl group, an alkoxy group, a C 3 -8 cycloalkyl group, a C 2 alkenyl group, a C 5-8 ring Alkenyl, C 2 _e alkynyl, C 3-8 cycloalkane, J- 6 , d- 6 alkylamino, bis(C 1-6 alkyl)amine, alkylthio, alkylcarbonyl, C alkyl Aminoformyl, alkylamido, alkylsulfonyl, alkylaminosulfonyl, alkylsulfonylamino, bis(C w alkyl)aminoformyl, bis(Cw alkyl)aminosulfonyl , alkoxycarbon
  • R 2a is a hydrogen atom, an alkyl group, a C 3-8 cycloalkyl group. a 5-8 cycloalkenyl group, a phenyl group or a 3-8 membered heterocyclic group, said alkyl group, C 3-8 cycloalkyl group, C 5-8 cycloalkenyl group, phenyl group and 3-8 membered heterocyclic group
  • it may be substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a 1 ⁇ 2, an alkyl group and a halogenated-6 alkyl group;
  • R 2b and R 3a are each independently a hydrogen atom, a nitro group, a halogen atom, an alkyl group, Alkoxy, C 3-8 cycloalkyl, C 2 -6 alkenyl, C 5-8 cycloalkenyl, C 2 -6 alkynyl or C 3-8 cycloalkoxy, said C 1-6 alkyl , C 3-8 cycloalkyl, C 2-6 alkenyl, C 5-8 cycloalkenyl, C 2 -6 alkynyl, alkoxy and C 8 cycloalkoxy may be optionally 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, and a ⁇ ;
  • R 4 and R 5 and the X to which they are attached form a C 3-8 cycloalkyl group, a C 5-8 cycloalkenyl group, a harmless group or a 3-8 membered heterocyclic group, said C 3-8 cycloalkyl group, ( 5 _ 8 cycloalkenyl, phenyl and 3-8 membered heterocyclyl may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 4a and R 5a ;
  • R 4a is nitro, L ⁇ , halogen atom, hydroxy, tt, alkyl, alkoxy, C 3-8 cycloalkyl, C 2-6 alkenyl, C 5 -8 cycloalkenyl, C 2- 6 alkynyl or C 3 -8 cycloalkoxy, said C 1-6 alkyl, C 3-8 cycloalkyl, C 2 alkenyl, C 5-8 cycloalkenyl, alkynyl, alkoxy And a C 3-8 cycloalkoxy group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group;
  • R 5a is (CH 2 )pR 6 , wherein R 6 is OR 7 , C(0)R 7 , C(0)OR 7 , OC(0)R 7 , C(0)NR 8 R 9 , NR 8 C (0) R 7 , NR 8 R 9 , S(0) q R 7 , NHCOOR 7 , NHCONR 8 R 9 , S(0) q NR 8 R 9 , NR 8 S(0)qR 7 or C(0) NHS(0)qR 7 ;
  • R 7 R 8 and R 9 are each independently a hydrogen atom, a C 1-6 alkyl group or a C 3-8 cycloalkyl group, and R 8 and R 9 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached,
  • the alkyl group, C 8 cycloalkyl group and 3-8 membered heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, Pyrrolidinyl, OR 1Q , C(0)R 10 , C(0)OR 10 , OC(0)R 1G , C(0)NR H R 12 , NR"R 12 , NR n C(0)R 10 , S(O)qR 10 , S(0) q NR u R 12 and NR n S(0)qR 10 ;
  • R 1G , R 11 and R 12 are each independently a hydrogen atom, an alkyl group, a C 3-8 cycloalkyl group or a phenyl group, and R 11 and R 12 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached,
  • the alkyl, C 3-8 cycloalkyl, strepyl and 3-8 membered heterocyclyl can be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: Atom, gas base, hydroxyl and carboxyl groups;
  • p is an integer from 0 to 6;
  • q is an integer from 0 to 2. According to an embodiment of the present invention, there is provided a compound of the formula (lb), a pharmaceutically acceptable salt thereof or an isomer thereof,
  • Cy 1 is a phenyl group, a pyridyl group or a pyrimidinyl group
  • Cy 2 is a C 3-8 cycloalkyl group or a 3-8 membered heterocyclic group, and the C 3-8 cycloalkyl group and the 3-8 membered heterocyclic group may be optionally 1, 2, 3, 4, 5 Or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, an alkyl group, a halogenated alkyl group, a phenyl group, a C 3-8 cycloalkyl group, and a 3-8 membered heterocyclic group;
  • L is C(O), C(0)0, C(0)NH, HC(O) or S(0) 2 ;
  • X is N or CH
  • R 1 is a halogen atom, a hydroxyl group, a sulfo group, a CM alkyl group, an alkane, a C 3-8 cycloalkyl group, a C 2 -6 alkenyl group, a C 2 _6 alkynyl group, a C 1-6 alkylamino group, a di(C) 1-6 alkyl)amino, alkylaminoformyl, alkylamido, alkylsulfonyl, alkylaminosulfonyl, alkylsulfonylamino, alkoxycarbonyl or -6 alkylcarbonyloxy
  • R 2a is a hydrogen atom, a C 3-8 cycloalkyl group, a C 5-8 cycloalkenyl group, a phenyl group or a 3-8 membered heterocyclic group, said C 3-8 cycloalkyl group, C 5-8 cycloolefin
  • the benzyl, strepyl and 3-8 membered heterocyclyl can be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, an amino group, C 1-6 alkyl and halogenated C alkyl;
  • R 2B, 1 each independently represent a hydrogen atom, tt, a halogen atom, C alkyl, C ⁇ e-alkoxy, C 3. 8 cycloalkyl or C 2-6 alkynyl group, according -alkyl, C 1 a -6 alkoxy group, a C 3-8 cycloalkyl group or a C 2-6 alkynyl group and may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, and an amino group;
  • R 4 and R 5 form a C 3-8 cycloalkyl group, a C 5-8 ring group or a 3-8 membered heterocyclic group with the X to which they are attached, said C 3-8 cycloalkyl group, C 5 -
  • the 8- cycloalkenyl and 3-8 membered heterocyclyl can be optionally substituted by 1, 2 or 3 substituents independently selected from R 4a and R 5a ;
  • 1 43 is a nitro group, a halogen atom, a hydroxyl group, a tt, an alkyl group, an alkane, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group or a C 2 -6 alkynyl group, said alkyl group, alkoxy group,
  • the C 3-8 cycloalkyl, alkenyl and alkynyl groups may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a «hydroxyl group, a carboxyl group and R 5A is (CH 2 )pR 6 , wherein R 6 is OR 7 , C(0)OR 7 , OC(0)R 7 , C(0)N 8 R 9 , N 8 C(0)R 7 , NR 8 R 9 , S(0)qR 7 , NHCONR 8 R 9 , S(0) q NR 8 R 9 , NR 8 S(0) q
  • R 7 , R 8 and R 9 are each independently a hydrogen atom, a d 6 alkyl group or a C 3 -8 cycloalkyl group, and R 8 and R 9 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached.
  • the C alkyl group, the C 8 cycloalkyl group and the 3-8 membered heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a pyrrolidine Base, OR 10 , C(0)OR 1Q , OC(0) R 1Q , C(0)NR N R 12 NR"R 12 , NR N C(0)R 10 , S(0) q R 10 , SC qN UR 12 and
  • R 1G , R 11 and R 12 are each independently a hydrogen atom, an alkyl group or a C 3 -8 cycloalkyl group, and R 11 and R 12 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, said alkane
  • the base, C 8 cycloalkyl and 3-8 membered heterocyclyl can be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: halogen atom, cyano group, hydroxyl group and gas group. ;
  • p is an integer from 0 to 4.
  • q is an integer from 0 to 2.
  • Cy 1 is a phenyl group or a pyridyl group
  • Cy 2 is a C 5 -6 cycloalkyl group or a 3-8 membered heterocyclic group, and the C 5 -6 cycloalkyl group and the 3-8 membered heterocyclic group may be optionally 1, 2, 3, 4, 5 or 6 Substituents independently selected from the group consisting of: halogen atom, cyano group, hydroxy group, carboxyl group, tt, C 1-6 alkyl group, haloalkyl group, phenyl group, C 3-8 cycloalkyl group and 5-7 membered heterocyclic ring base;
  • L is C(0), C(0)0, NHC(O) or C(0)NH
  • X is N or CH
  • R 1 is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, a sulfonic acid group, an alkyl group, a C 1-6 alkane L ⁇ , a C 3-8 cycloalkyl group, a C 2 -6 alkynyl group, a C alkylamino group.
  • the group, the alkylamino decanoyl group, the C"alkyl amide group, the alkylamino sulfonyl group, the C 1-6 alkylsulfonylamino group, the alkoxycarbonyl group and the alkylcarbonyloxy group may be optionally 1, 2.
  • substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, and tt, m is an integer of 1 to 3, wherein R 1 is the same or different;
  • R 2A is a hydrogen atom, a C 3-8 cyclodecyl group, a phenyl group, a C 5 —ecycloalkenyl group, or a 4-7 membered heterocyclic group, said C 3-8 cycloalkyl group, phenyl group, C 5 —6
  • the cycloalkenyl and 4-7 membered heterocyclyl can be optionally 1, 2, 3 or 4 independent Substituted by a substituent selected from the group consisting of: a halogen atom, a 1 ⁇ 2, a hydroxyl group, a carboxyl group, a 1 ⁇ 2, a C 1-6 alkyl group, and a halogenated alkyl group;
  • R 2b and R 3a are each independently a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkoxy group or a C 2 —e block group, and the alkyl group, the alkoxy group and the C 2 —6 alkynyl group may be optionally 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group;
  • R 4 and R 5 form a C 3 -8 cycloalkyl group or a 3-8 membered heterocyclic group with the X to which they are attached, and the C 3-8 cycloalkyl group and the 3-8 membered heterocyclic group may be optionally 1 or 2 substituents independently selected from R 4A and R 5A ;
  • halogen atom is, hydroxyl group, amino group, alkyl group, alkane! Or a C 3-8 cycloalkyl group, said C 1-6 group, alkoxy group and C 3-8 cycloalkyl group may be optionally 1, 2, 3 or 4 substituents independently selected from the group consisting of Substitution: halogen atom, hydroxyl group, carboxyl group and
  • R 5a is (C3 ⁇ 4)pR 6 , wherein R 6 is OR 7 , C(0)OR 7 , OC(0)R 7 , C(0)NR 8 R 9 , NR 8 C(0)R 7 , NR 8 R 9 or NHCONR 8 R 9 ;
  • R 7 , R 8 and R 9 are each independently a hydrogen atom, a C 1-6 alkyl group or a C 4-7 cycloalkyl group, and R 8 and R 9 may form a 4-7 membered heterocyclic group with the nitrogen to which they are attached.
  • the pit group, C 4 cycloalkyl group and 4-7 membered heterocyclic group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group, an OR 1Q , C(0)OR 1Q , OC(0)R 1Q , C(0)NR n R 12 , NR U R 12 , NR n C(0)R 10 and S(0) q R 1G ;
  • R 1G , R 11 and R 12 are each independently a hydrogen atom, a C alkyl group or a C 4-7 cycloalkyl group, and the alkyl group and the C 4-7 cycloalkyl group may be optionally 1, 2, 3, 4 , 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a «hydroxyl group and a carboxyl group;
  • p is an integer from 0 to 4.
  • q is an integer of 0 to 2.
  • Cy 1 is a phenyl group
  • Cy is a 3-8 membered heterocyclic group or a C 5 -6 cycloalkyl group, and the 3-8 membered heterocyclic group and the C 5 —e ring group may be optionally 1, 2, 3, 4, 5 or 6 Substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, a tt, a C 1-6 alkyl group, a halogenated C w alkyl group, a phenyl group, a C 4-6 cycloalkyl group, and 4-6 Metacyclic heterocyclic group;
  • L is C(0), C(0)NH, NHC(O) or C(0)0;
  • X is N or CH
  • R 1 is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, a sulfonic acid group, an alkyl group, a C 3-8 cycloalkyl group, a C 2 -6 alkynyl group, a C 1-6 alkylaminoformyl group, C 1 -6 alkylamide group, C 1-6 alkyl amine sulfonate
  • R 2a is a hydrogen atom, a strepto group, a cycloalkenyl group, a 5-6 membered heterocyclic group or a C 4 -6 cycloalkyl group, a stilbene group, a C 5 -6 cycloalkenyl group, a 5-6 membered heterocyclic group and C
  • the 4- 6 cycloalkyl group may be optionally substituted by 1, 2, 3 or 4 independently selected from the group consisting of: a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an alkyl group and a halogenated Ci_6 pit group;
  • R 2B and R 3A are each independently a hydrogen atom, a cyano group, a halogen atom or a CM alkyl group, and the CM alkyl group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group;
  • R 4 and R 5 form a C 4 _e cycloalkyl or 4-6 membered heterocyclyl group and X which they are attached, the C 4 _6 cycloalkyl, and 4-6 membered heterocyclyl can be optionally substituted with 1 or 2 substituents independently selected from R 4a and R 5a ;
  • 4 3 is a halogen atom, a hydroxyl group, an amino group, an alkyl group or an alkane, and the alkoxy group may be optionally 1, 2, 3 or Substituted by four substituents independently selected from the group consisting of: a halogen atom, tt, a hydroxyl group, a carboxyl group, and an amino group;
  • R 5a is (C3 ⁇ 4)pR 6 , wherein R 6 is OR 7 , C(0)OR 7 , OC(0)R 7 , R 8 C(0)R 7 , C(0)NR 7 R 8 or NR 8 R 9 ;
  • R 7 , R 8 and R 9 are each independently a hydrogen atom, a C 1-6 alkyl group or a C 4 - 7 cycloalkyl group, and the alkyl group and the C 4-7 cycloalkyl group may be optionally 1, 2. 3 or 4 substituents independently selected from the group consisting of: a halogen atom, OR 10 , C(O)OR 10 , OC(O)R 10 , CC NRUR 12 and NR"R 12 ;
  • R 1G , R 11 and R 12 are each independently a hydrogen atom or an alkyl group, and the alkyl group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group, Hydroxyl and carboxyl groups;
  • p is an integer from 0 to 3.
  • Cy 1 is a phenyl group
  • a substituent selected from the group consisting of: a halogen atom, tt, a hydroxyl group, a carboxyl group, a tt, a CM alkyl group, and a halogenated group ( ⁇ 4 alkyl group;
  • L is C(0), C(0)NH, NHC(O) or C(0)0;
  • X is N
  • R 1 is a halogen atom, a hydroxyl group, a carboxyl group, a C 3 cycloalkyl group, an ethyl group, an alkylamino decanoyl group, or an alkyl group, and the alkyl group may be optionally 1, 2, 3 or 4 independent Derived from the following substitutions: a halogen atom, «, a hydroxyl group, a ⁇ and an amino group, m is 1 or 2, wherein R 1 is the same or different;
  • R 2a is a hydrogen atom, a strepto group, a cycloalkenyl group, a 5-6 membered heterocyclic group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, said tricky group, a C 5 -6 ring group, a 5-6 membered hetero
  • the cyclo, cyclobutyl, cyclopentyl and cyclohexyl groups may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: halogen atom, cyano group, hydroxyl group, ', tt, C 1- 3- alkyl and halogenated C 1-3 alkyl;
  • the C M alkyl group wherein R 2b and R 3a are each independently a hydrogen atom, a cyano group, a halogen atom or a C 14 alkyl group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of : a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group;
  • R 4 and R 5 form a 4-6 membered heterocyclic group with the N to which they are attached, and the 4-6 membered heterocyclic group may be optionally substituted by d. 6 alkyl and/or R 5a ;
  • R 5a is (CH 2 )pR 6 , wherein R 6 is OR 7 , OC(0)R 7 , C(0)NR 7 R 8 or NR 8 R 9 ;
  • R 7 , R 8 and R 9 are each independently a hydrogen atom or a ( ⁇ 4 alkyl group, which may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: Halogen atom, to, OR 10 , C(0)OR 10 And NRUR 12 ;
  • R 1G , R 11 and R 12 are each independently a hydrogen atom or a CM alkyl group, and the d-4 alkyl group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group and a carboxyl group;
  • p 0 or 1.
  • substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a 1 ⁇ 2, a tt, a methyl group, an ethyl group and a trifluoromethyl group;
  • L is C(0), NH(CO) or C(0)NH
  • X is N
  • R 1 is a fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a cyclopropyl group, a hydroxyl group, an ethynyl group, a methylaminoformyl group or a hydroxymethyl group, and m is 1 Or 2, where R 1 is the same or different;
  • R 2a is cyclopentyl, phenyl, cyclopentenyl, pyrrolyl, piperidinyl, cyclobutyl, said cyclopentyl, phenyl, cyclopentenyl, pyrrolyl, piperidinyl, cyclobutyl
  • the group may be optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, ', an amino group, a C 1-3 alkyl group, and a halogenated C 1-3 alkyl group;
  • R 2b and R 3a are each independently a hydrogen atom, a halogen atom, a fluorenyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a methylol group or an aminomethyl group;
  • R 4 and R 5 and the N to which they are attached form a cyclohexyl group, a piperidinyl group, said cyclohexyl and piperidinyl group may be optionally substituted by an alkyl group and/or R 5a ;
  • R 5a is (CH 2 )pR 6 , wherein R 6 is OR 7 , OC(0)R 7 , C(0)NR 7 R 8 or NR 8 R 9 ;
  • R 7 , R 8 and R 9 are each independently a hydrogen atom or a d_ 3 pit group, and the alkyl group may be optionally substituted by 1, 2 or 3 independently selected from the group consisting of: a halogen atom, a hydroxyl group And NR"R 12 ;
  • R ", R 12 each independently represent a hydrogen atom, a methyl, ethyl or isopropyl
  • L is C(O) or NH(CO);
  • X is N or CH
  • R 1 is independently selected from the group consisting of a fluorine atom, a chlorine atom, a tt, a decyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a hydroxyl group, an ethyl group, and a methylamino decanoyl group, and m is 1 or 2, wherein m When 2, R 1 is the same or different;
  • R 2a is cyclopentyl, cyclopentenyl, cyclobutyl, phenyl, piperidinyl or pyrrolyl, said cyclopentyl, cyclopentenyl, cyclobutyl, phenyl, piperidinyl and pyrrole
  • the group may be optionally substituted by 1, 2 or 3 substituents independently selected from a halogen atom:
  • R 2b is a hydrogen atom
  • R 3a is a hydrogen atom, a methyl group or an ethyl group
  • R 4 and R 5 form a piperidinyl or cyclohexyl group with the X to which they are attached, and the cyclohexyl and piperidinyl groups may be optionally hydroxy, methyl, ethyl, tt, aminocarbonyl, decanoyloxy Ethyl decanoyl Substituting one or two substituents of a gas group, a gas group and an ethylene group.
  • L is C(O) or NHC(O);
  • X is N or CH
  • R 1 is independently selected from the group consisting of a chlorine atom, a cyano group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a hydroxyl group, an ethyl group group, and a methylaminoformyl group.
  • n 1 or 2, wherein when m is 2, R 1 is the same or different;
  • R 2a is cyclopentyl, cyclopentenyl, cyclobutyl, phenyl, piperidinyl or pyrrolyl; said cyclopentyl, cyclopentyl, cyclobutyl, phenyl, piperidinyl and pyrrole
  • the group may be optionally substituted by 1, 2 or 3 substituents independently selected from a halogen atom:
  • R 2b and R 3a are a hydrogen atom
  • R 4 and R 5 form a piperidinyl or cyclohexyl group with the X to which they are attached, and the cyclohexyl and piperidinyl groups may be optionally hydroxy, methyl, ethyl, tt, aminocarbonyl, decanoyloxy
  • One or two of the group, ethyl formyl group, methyl group and ethoxy group are taken as a <RTIgt;
  • X is N
  • R 1 is independently selected from the group consisting of a chlorine atom, a cyano group, and a methyl group.
  • n 2;
  • R 2a is cyclopentyl
  • R 2b and R 3a are a hydrogen atom
  • R 4 and R 5 form a 4-hydroxypiperidinyl group with the X to which they are attached.
  • the following compounds, pharmaceutically acceptable salts or isomers thereof are provided:
  • halogen atom as used in the present invention includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, preferably a fluorine atom and a chlorine atom.
  • alkyl group as used in the present invention means an alkane moiety having 1 to 6 carbon atoms and a straight or branched alkyl group derived by removing one hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, or Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 3-mercaptobutyl, 1,1-dimercaptopropyl, 1,2 - dimethylpropyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 2-decylpentyl, 3-decylpentyl, 4-methylm, 1,1-dimethyl Butyl, 1,2-dimethylbutyl, 1,3-dimercaptobutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,
  • C M alkyl group more preferably a C 1-3 alkyl group, and the term "( 14 alkyl group), "C 1-3 alkyl group” means a specific one of 1-4, 1 to 3 carbon atoms in the above examples.
  • C 2 -6 alkenyl group as used in the present invention means a linear or branched alkenyl group having 2 to 6 carbon atoms and having a double bond, such as an ethyl fluorenyl group, a 1-propenyl group, a 2-propenyl group, and a 1- Methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-mercapto-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2- Propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-decylbutenyl, 2-methyl Small butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1 - mercapto-3-butenyl, 2-mercapto-3-butenyl, 3-methyl-3-butbuten
  • 2-ethyl-3-butenyl 1,1,2-trimethyl-2-propenyl, 1-ethyl small methyl-2-propenyl, 1-ethyl-2-methyl- 1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1.3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, 2,4-pentyl Dienyl, 1,3-hexyldidecyl, 1,4-hexadienyl, 1,5-hexadienyl and 2,4-hexadienyl, and the like.
  • the double bond can be cis or trans.
  • C 2 _6 block group as used in the present invention means a straight or branched alkynyl group having a triple bond and having 2 to 6 carbon atoms, such as an ethynyl group, a 2-propynyl group, a 2-butynyl group, and 3 -butynyl, 1-mercapto-2-propynyl, 2-pentynyl,
  • 3-pentynyl 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butenyl, 2-methyl-3-butynyl, 1,1-di Methyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2 -Pentynyl, 4-decyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2 -mercapto-4-pentynyl, 3-mercapto-4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1 ,2-dimethyl-3-butynyl, 2,2-dimercapto-3-butynyl, 1-eth
  • alkoxy group as used in the present invention means a group in which the term “alkyl group” is bonded to other structures through an oxygen atom, such as methyl, ethyl tt, propyl tt, isopropyl, dibutyl, isobutyl, tert-butoxy, sec. Butoxy, pentyloxy, neopentyloxy, hexyloxy and the like.
  • alkylamino group of the present invention is a group in which the term "Cw alkyl group” is bonded to another structure through an amine group, such as a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group. , butylamino, isobutylamino, tert-butylamino, sec-butylamino, pentylamino, neopentylamino, hexylamino and the like.
  • the "bis(Cw alkyl)amino group” of the present invention is a group in which two identical or different "alkyl groups" are bonded to other structures through an amine group.
  • C 1-6 alkylthio group as used in the present invention means a group in which the term “alkyl group” is bonded to another structure through a sulfur atom, such as methylthio, ethylthio, propylthio, isopropylthio, butyl. Sulfur, isobutylthio, tert-butylthio, sec-butylthio, pentylthio, neopentylthio, hexylthio, and the like.
  • alkylcarbonyl as used in the present invention means that the term “CW alkyl” is bonded to other structures via a carbonyl group. a group such as methyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butyl 1, isobutylcarbonyl, tert-butylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, neopentylcarbonyl, hexyl Condensation and so on.
  • the "Cw alkylaminoformyl” of the present invention is a group in which the term “Cw pit group” is bonded to other structures via an aminoformyl group, such as methylaminodecanoyl, ethylaminoformyl, and propyl.
  • the "bis(Cw alkyl)aminoformyl group” of the present invention is a group in which two identical or different "Cw ⁇ " are bonded to other structures via an aminoformyl group.
  • the "d-6 alkoxycarbonyl group” of the present invention is a group in which the term "Cw alkoxy group” is bonded to another structure through a carbonyl group, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropyloxy group, Butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl and the like.
  • a carbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropyloxy group, Butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl,
  • alkylaminosulfonyl group of the present invention is a group in which the term “c ⁇ alkyl” is bonded to another structure through an aminosulfonyl group, such as a nonyl group, an ethylsulfonyl group, a propyl group, or a acyl group. Isopropylamino, acyl, butylaminosulfonyl, isobutylaminosulfonyl, tert-butylaminosulfonyl, sec-butylaminosulfonyl, sulfonyl, neopentylaminoacyl, hexylaminosulfonyl and the like.
  • the "di(C"alkyl)aminosulfonyl group of the present invention is a group in which two identical or different alkyl groups are bonded to other structures through an aminosulfonyl group.
  • Cw alkylcarbonyl is the group “alkyl”, respectively, which is attached to the other structure via an amide group, a sulfonyl group, a sulfonylamino group, or a carbonyloxy group.
  • C ⁇ cycloalkyl group as used in the present invention means an alkane moiety of 3 to 8 carbon atoms which is removed by a hydrogen atom-derived cyclic alkyl group such as a cyclopropyl group, a cyclobutyl group or a 1-fluorenylcyclobutyl group. , cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferred (: 4 _ 7 cycloalkyl, C 4 _e cycloalkyl and C 5 -6 cycloalkyl.
  • C 4-7 cycloalkyl is a specific example of 4 to 7, 4 to 6, and 5 to 6 carbon atoms in the above examples.
  • C 8 cycloalkoxy group as used in the present invention means a group in which the term “cycloalkyl group” is bonded to another structure through an oxygen atom, such as a cyclopropoxy group, a cyclobutoxy group, or a 1-fluorenyl ring. Oxyl, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.
  • C 8 cycloalkenyl group as used in the present invention means a cyclic alkyl group derived by removing a hydrogen atom from an olefin moiety of 5 to 8 carbon atoms, a cyclopent-1-enyl group, a cyclopent-2-enyl group.
  • cyclopent-3-enyl cyclohex-1-yl, cyclohex-2-enyl, cyclohex-3-yl, cycloheptyl, alkenyl, cycloheptan-2-alyl, cycloheptane 3-alkenyl, cyclohept-4-enyl, cyclooctylalkenyl, cyclooctin-2-yl, cyclooct-3-enyl, cyclooct-4-yl, 2,4-cyclopentane Alkenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 2,4-cyclohexadienyl, 2,5-cyclohexanyl, 1,3- Cycloheptadienyl, 1,4-cycloheptadienyl, 2,4-cycloheptadienyl, 1,5-cyclooctadienyl and the
  • heteroaryl group means an aromatic group containing one or more hetero atoms as a ring atom in addition to a carbon atom.
  • the "hetero atom” is selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like.
  • heteroaryl may contain 5-20 ring atoms and contain one or more heteroatoms (referred to as 5-20 membered heteroaryl), preferably 5-10 ring atoms and contain one or more heteroatoms (referred to as 5-10 membered heteroaryl), examples of which include, but are not limited to, furan, -, pyrrole, imidazole, pyrazole, triazole, oxazole, isoxazole, oxazole, isothiazole, oxadiazole, tetra Azole, triazole, isophthalide, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, isobenzofuran, benzothiophene, anthracene, isoindole, quinoline, isoquinoline, Benzodiazine, pyridopyridine, acridine and the like.
  • the "aryl group” as used in the present invention means an aromatic group having only a carbon atom as a ring atom.
  • the aryl group may be a monocyclic, bicyclic or polycyclic aryl group, preferably a monocyclic aryl group. Specific examples include phenyl, naphthyl, anthryl and phenanthryl, and the like, preferably a phenyl group.
  • the "3-8 membered heterocyclic group” in the present invention means a 3-8 membered cyclic group having one or more hetero atoms as a ring atom, and the "hetero atom” means a nitrogen atom, an oxygen atom or a sulfur atom. Wait.
  • Heterocyclyl includes saturated or unsaturated heterocyclic groups.
  • saturated or unsaturated heterocyclic group examples include an oxiranyl group, a dioxanyl group, an anthracene group, an aziridine group, a 2H-azepine group, Diazacyclopropane, 3H-diazapropenyl, oxazepine, oxetanyl, 1,2-dioxetyl, heterocyclobutane, 1 , 2-dithiabutenyl, azetidinyl, 1,2-diazetanyl, azetidinyl, 1,2-diazabutenyl, Furanyl, tetrahydrofuranyl, thiol, 2,5-dihydrothio, tetrahydrothio, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, 1,3-dioxolyl, 1 ,3-dioxol-2-one, 1,2-dicyclopen
  • the "4-7 membered heterocyclic group”, "5-7 membered heterocyclic group” and “4-6 membered heterocyclic group” as used in the present invention mean 4-7 yuan and 5-7 yuan, respectively, in the above examples. Specific examples of a 4-6 membered saturated or unsaturated cyclic group.
  • the "5-10 membered fused ring group” as used in the present invention refers to a fused ring structure having 5 to 10 ring atoms formed by two or more ring structures sharing two adjacent atoms with each other. , including "5-10 yuan saturated and ring” and "5-10 yuan unsaturated ring", such as bicyclo [3.1.0] hexane, bicyclo [4.1.0] heptane, bicyclo [3.2.0] heptane Bicyclo[4.2.0]octane, octahydropentapentene, bicyclo[3.3.0]octadiene, 1,2,3,4-tetrahydropentacene, octahydroquinone, decahydronaphthalene, benzo Furanyl, isobenzofuranyl, dibenzofuranyl, benzo[b]thiophene, benzo[c]thienyl, fluorenyl, isodecyl,
  • the "5-12 membered spirocyclic group" as used in the present invention means a ring structure having 5 to 12 ring atoms formed by a class of at least two rings sharing one atom. Including "5 to 12 yuan saturated screw ring” and “5 to: 12 yuan unsaturated screw ring”.
  • the "6-10 membered bridged ring group” as used in the present invention means a ring structure having 6 to 10 ring atoms formed by any two rings sharing two atoms which are not directly connected. Including "6-10 yuan saturated bridge ring” and "6-10 yuan unsaturated bridge ring”.
  • the pharmaceutical preparation of the present invention containing the compound of the above formula (la) or (lb), a pharmaceutically acceptable salt thereof or an isomer thereof, includes one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, coating material or any type of formulation auxiliary.
  • materials useful as pharmaceutically acceptable carriers are sugars, but are not limited to lactose, glucose, and sucrose; starches such as, but not limited to, corn Starch and potato starch; cellulose and its derivatives, such as but not limited to, for example, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository Wax; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as, but not limited to, ethyl oleate and lauric acid Ethyl ester; agar; buffer such as,
  • the compounds of the present invention are formulated into any pharmaceutical preparation in a manner known in the art for administration to a patient in need of such treatment by oral, parenteral, rectal or pulmonary administration.
  • oral administration it can be prepared into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; or can be prepared into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. .
  • a suitable filler, a binder, a disintegrator, a lubricant or the like may be added.
  • injections can be prepared, including injection solutions, sterile powders for injection, and concentrated solutions for injection.
  • the injection When the injection is prepared, it can be produced by a conventional method in the prior art, and when the injection is formulated, an additional agent may be added, or a suitable additive may be added depending on the nature of the drug.
  • an additional agent When used for rectal administration, it can be made into a suppository or the like.
  • pulmonary administration When used for pulmonary administration, it can be made into an inhalant or a spray.
  • the invention also provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof or an isomer thereof for the preparation of a medicament for the treatment and/or prevention of kidney damage, cardiovascular diseases (such as hypertension) and/or endocrine diseases .
  • the present invention also provides a pharmaceutically acceptable salt of the compound of the formula (1) or (lb), which is a salt of a compound of the formula (la) or (lb) which is mixed with an acid or a base.
  • Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, carbonic acid Hydrogen salt, butyrate, camphorate, camphor sulfonate, carbonate, citrate, digluconate, glycerol phosphate, hemisulfate, heptanoate, caproic acid Salt, formate, fumarate, gluconate, glucuronate, glutenate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), Lactate, maleate, malate, malonate, sulfonate, nicotinate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, grass Acid salt, palmitate, palm acid salt, pect
  • the base addition salt can be used during the final isolation and purification of the compound by passing the carboxylic acid containing moiety with a suitable base such as, but not limited to, a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation. Or prepared in situ by reaction with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as, but not limited to, a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation.
  • a suitable base such as, but not limited to, a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation.
  • a suitable base such as, but not limited to, a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation.
  • a suitable base such as, but not limited to, a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation.
  • Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal based cations such as, but not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and non-toxic quaternary ammonium and amine cations, including ammonium, tetra Methylammonium, tetraethylammonium, decylamine, diamine, trimethylamine, triethylamine, diethylamine, ethylamine, and the like.
  • Other representative organic amines which can be used to form base addition salts include ethylenediamine, ethanolamine, diethanolamine, acridine, piperazine and the like.
  • the dihydropyrazole compounds of the present invention have two or more chiral centers.
  • the racemic is obtained by the synthesis, and the desired enantiomerically pure compound can be obtained by chiral resolution: chromatography can be carried out by a chiral stationary phase (such as high pressure liquid phase, supercritical fluid color).
  • Chiral fillers include, but are not limited to: Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.
  • the enantiomerically pure dihydropyrazole compound can be further derivatized like a racemic dihydropyrazole compound.
  • the present invention also provides a compound containing the same, a pharmaceutically acceptable salt thereof or an isomer thereof for the preparation and treatment of and/or prevention of kidney damage, cardiovascular diseases (including hypertension, heart failure, myocardial infarction, angina pectoris, cardiac hypertrophy) , myocarditis, cardiac vascular fibrosis, baroreceptor dysfunction, excessive body fluids and arrhythmias), and/or endocrine diseases (including primary/secondary aldosteronism, Addison's disease, Cushing)
  • cardiovascular diseases including hypertension, heart failure, myocardial infarction, angina pectoris, cardiac hypertrophy
  • myocarditis cardiac vascular fibrosis
  • baroreceptor dysfunction including excessive body fluids and arrhythmias
  • endocrine diseases including primary/secondary aldosteronism, Addison's disease, Cushing
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable salt thereof or an isomer thereof, and one or more other therapeutically active substances, the other therapeutically active substance being selected from the group consisting of vascular stress a ruthenium antagonist or a pharmaceutically acceptable salt thereof; an HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof; a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof; Dual inhibitor of intoxicating/neutral endopeptidase (ACE/NEP) or a pharmaceutically acceptable salt thereof; antidiabetic agent; diet pills; aldosterone receptor blocker; endothelin receptor blocker; CETP inhibition Na-K-ATPase membrane pump inhibitor; P-adrenergic receptor inhibitor or alpha-adrenergic receptor blocker; neutral endopeptidase ( ⁇ ) inhibitor and inotropic agent.
  • vascular stress a ruthenium antagonist or a pharmaceutically acceptable salt thereof
  • the compound of the present invention has excellent activity for lowering aldosterone and has an excellent effect for treating and/or preventing kidney damage and/or hypertension in various mammals including humans;
  • the compound of the invention has simple preparation process, good physical and chemical properties, stable shield capacity, and is easy to be industrially produced.
  • Test sample Part of the compounds 1, 2, 3 and 4 of the present invention, self-made, the chemical name, structural formula and preparation method are as described in the examples.
  • the compound of formula V (racemate), self-made, has the structural formula as described above.
  • DMSO dimethyl sulfoxide
  • Dual luciferase assay 1 pBind-NR (100 ng ⁇ L), 1 ⁇ pG51uc (100 ng ⁇ L), 2.5 D EM and 0.5 L Fugene were mixed and incubated for 15 minutes at room temperature to prepare a transfection solution. Prepare a cell suspension at 3xl0 5 cells/mL, add 100 ⁇ per well, and mix well with the above transfection solution. At 37. C. Incubate for 24 hours in a 5% CO 2 incubator.
  • the firefly sea kidney fluorescein pathway was determined by a dual fluorescein intoxication reporter assay system. This test measures the mineralocorticoid receptor IC 5G value of the test compound (test sample) (ie, blocks the salt skin) The concentration of the test compound required for 50% activation induced by the hormone receptor agonist is relative to the activation in the absence of the antagonist).
  • the compound 1, the compound 2, the compound 3 and the compound 4 of the present invention have a good antagonistic effect on the mineralocorticoid receptor, which is better than the positive control drug (the compound of the formula V); and the compound 2 is a mineralocorticoid. Receptor antagonism is best.
  • the raw material compounds used are commercially available, obtained from Shanghai Haiyan Yan Chemical; Shanghai Titan Chemical; Shanghai Darui, Beijing coupling technology Co., Ltd.; Zhengzhou Taiji Hongnuo Pharmaceutical Technology Co., Ltd.; Sichuan Guang ⁇ Bio; ⁇ (Shanghai) Chemical Technology; Alfa Aesar (China), Shanghai TCI, Beijing ⁇ ; Shanghai Bi De Pharmaceutical and other companies.
  • Ethyl 5-(1-(3-chlorophenyl)-5-cyclopentyl-4,5-dihydropyrazol-3-yl)pyridine-2-carboxylate 180 mg (0.43) in a 50 mL vial
  • the post-treatment system was neutralized to neutrality, the system was spun dry, water was added, and the pH was adjusted to 3, and the precipitate was filtered off with a small amount of methanol to give a product 50 mg, yield 29.4%.
  • Chiral column ChiralPak ⁇ -20 ⁇ , 250x30mmI.D.;
  • Chiral column ChiralPak AS- 10 ⁇ , 300 x 50mmI.D.;

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Abstract

Provided are a dihydropyrazole compound as represented by general formula (Ia), a pharmaceutically acceptable salt or isomer thereof, a preparation process thereof, a pharmaceutical preparation containing such compounds and the use thereof. The definitions of the various substituents in formula (Ia) are as described in the specification. The compounds can be used for treating and/or preventing renal injury, cardiovascular diseases, especially hypertension, and/or endocrine diseases.

Description

二氢吡唑类化合物 技术领域  Dihydropyrazoles Technical Field
本发明属于医药技术领域， 具体涉及二氢吡唑类化合物、 其药学上可接 受的盐或其异构体， 这些化合物的制备方法， 含有这些化合物、 其药学上可 接受的盐或其异构体的药物制剂， 以及这些化合物、 其药学上可接受的盐或 其异构体在制备治疗和 /或预防肾损伤、 心血管疾病 (如高血压)和 /或内分泌疾 病的药物中的应用。 背景技术  The invention belongs to the technical field of medicine, and particularly relates to a dihydropyrazole compound, a pharmaceutically acceptable salt thereof or an isomer thereof, and a preparation method of the compound, the compound, the pharmaceutically acceptable salt thereof or the same Pharmaceutical preparations, and the use of these compounds, pharmaceutically acceptable salts thereof or isomers thereof for the preparation of a medicament for the treatment and/or prevention of kidney damage, cardiovascular diseases (such as hypertension) and/or endocrine diseases. Background technique
原发性肾病、 继发性肾病如糖尿病肾病、 腎功能不全等肾损伤疾病， 临 床表现为大量蛋白尿， 若治疗不及时将会导致肾衰竭。 肾损伤的诱发原因 艮 多， 如糖尿病、 高血压等常见疾病均会导致肾损伤。 例如 15% ~ 25%的 I型 糖尿病及 30% - 40%的 II型糖尿病患者存在糖尿病肾病， 已成为终末期肾病 的首要病因 （占 40% )。 对肾损伤的治疗， 目前尚无有效治疗药物。  Primary nephropathy, secondary nephropathy such as diabetic nephropathy, renal insufficiency and other kidney damage diseases, clinical manifestations of large amounts of proteinuria, if not treated in time will lead to kidney failure. Causes of kidney damage 艮 Many, such as diabetes, high blood pressure and other common diseases can cause kidney damage. For example, 15% to 25% of type 1 diabetes and 30% - 40% of type 2 diabetes patients with diabetic nephropathy have become the leading cause of end-stage renal disease (40%). There is currently no effective treatment for the treatment of kidney damage.
酪固酮是一种在肾上腺皮质合成的盐皮质激素， 分布在肾、 结肠、 汗腺 的上皮细胞、 血管、 脑、 心肌等多个组织， 它通过与盐皮质激素受体结合， 活化其受体来促进钠的保留和钾的***， 对电解质平衡及改变动脉壁上的内 皮细胞、 血管平滑肌细胞、 纤维原细胞和动脉外膜和及介质上的基质的结构 和功能具有重要作用。  Tyrone is a mineralocorticoid synthesized in the adrenal cortex. It is distributed in the kidney, colon, epithelial cells of the sweat gland, blood vessels, brain, heart muscle and other tissues. It binds to the mineralocorticoid receptor and activates its receptor. To promote sodium retention and potassium excretion, it plays an important role in electrolyte balance and changes in the structure and function of endothelial cells, vascular smooth muscle cells, fibroblasts and adventitial membranes and mediators on the arterial wall.
醛固酮水平过高， 导致盐皮质激素受体被异常活化， 会导致电解质失衡 及肾血管损伤和纤维化， 造成腎损伤和高血压等。  Excessive levels of aldosterone cause abnormal activation of the mineralocorticoid receptor, which can lead to electrolyte imbalance and renal vascular damage and fibrosis, resulting in kidney damage and high blood pressure.
药物通过竟争性的与盐皮质激素受体结合， 阻断醛固酮与盐皮质激素受 体的结合， 来抑制醛固酮介导的毒害作用， 进而减少腎损伤。 目前上市的药 物有两个： 螺内酯（ Spironolactone )和依普利酮（ Eplerenone )， 适应症为治 疗高血压、 心力衰竭及腎脏综合症等。 二者均为甾体类化合物， 对其他类固 醇激素受体的选择性差， 容易造成高血钾症， 副作用较大； 而且结构复杂难 以合成， 理化性质差， 影响临床广泛应用。  The drug binds to the mineralocorticoid receptor in a competitive manner, blocks the binding of aldosterone to the mineralocorticoid receptor, and inhibits aldosterone-mediated toxicity, thereby reducing kidney damage. There are currently two drugs on the market: Spironolactone and Eplerenone, which are used to treat high blood pressure, heart failure and kidney syndrome. Both are steroidal compounds, which have poor selectivity to other steroid hormone receptors, are prone to cause hyperkalemia, and have many side effects. Moreover, the structure is complicated and difficult to synthesize, and the physical and chemical properties are poor, which affects clinical application.
专利 CN200780043333.0提到的非甾类化合物（如式 V所示）目前已进入 一期临床， 其临床前药效及安全性方面均好于上市药物， 在減少蛋白尿， 减 少肾损伤方面有效果。
Figure imgf000003_0001
式（ V ) The non-steroidal compound mentioned in the patent CN200780043333.0 (as shown in Formula V) has entered the first phase of clinical practice, and its preclinical efficacy and safety are better than the marketed drugs, in reducing proteinuria and reducing kidney damage. effect.
Figure imgf000003_0001
Formula (V)
但是， 体外细胞水平的活性测试显示其活性欠佳， 而且理化性质较差， 为提高临床治疗效果， 方便临床安全用药， 需要研发活性好， 易于合成， 理 化性质好的新非 类化合物。 发明内容  However, in vitro cell-level activity tests showed poor activity and poor physical and chemical properties. In order to improve clinical treatment and facilitate clinical safety, it is necessary to develop new non-organic compounds with good activity, easy synthesis, and good physicochemical properties. Summary of the invention
本发明目的在于提供新的活性好， 易于合成的非甾类化合物及其制备方 法。  SUMMARY OF THE INVENTION The object of the present invention is to provide novel non-steroidal compounds which are active and easy to synthesize and a process for their preparation.
本发明的另一目的在于提供新的替代现有预防和 /或治疗肾损伤、 心血管 疾病 (如高血压)和 /或内分泌疾病的化合物， 及其在制备用于治疗和 /或预防肾 损伤、 心血管疾病 (如高血压)和 /或内分泌疾病的药物中的应用。  Another object of the present invention is to provide novel alternatives to existing compounds for the prevention and/or treatment of kidney damage, cardiovascular diseases (such as hypertension) and/or endocrine diseases, and their preparation for the treatment and/or prevention of kidney damage , the use of drugs for cardiovascular diseases (such as high blood pressure) and / or endocrine diseases.
根据本发明的一种实施方案， 提供了通式（ l a )所示的化合物、 其药学 上可  According to one embodiment of the present invention, there is provided a compound of the formula (la) which is pharmaceutically acceptable
Figure imgf000003_0002
Figure imgf000003_0002
其中， Cy1为 C3-8环烷基、 杂芳基或芳基； Wherein Cy 1 is a C 3-8 cycloalkyl group, a heteroaryl group or an aryl group;
Cy2为 C3-8环烷基、（ 5-8环諦基或 3-8元杂环基， 所述的 C3-8环烷基、 C5-8 环婦基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取 代基取代： 卤素原子、 、 羟基、 、 J^. 烷基、 卤代 烷基、 苯基、 C 8环烷基和 3-8元杂环基； Cy 2 is C 3-8 cycloalkyl, ( 5-8 cyclodecyl or 3-8 membered heterocyclic, said C 3-8 cycloalkyl, C 5-8 cyclyl and 3-8 The heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, a J. an alkyl group, a halogenated alkyl group, a phenyl group, a C 8 group; a cycloalkyl group and a 3-8 membered heterocyclic group;
L为 C(0)、 C(0)0、 C(0)NH、 NHC(0)、 HC(0)NH、 NHS(0)、 NHS(0)2、 S(O)或 S(0)2; L is C(0), C(0)0, C(0)NH, NHC(0), HC(0)NH, NHS(0), NHS(0) 2 , S(O) or S(0) 2 ;
X为 N或 CH;  X is N or CH;
Rla为氢原子、 卤素原子、 ½、 硝基、 羟基、 、 羧基、 甲磺酰基、 甲氧羰基； R la is a hydrogen atom, a halogen atom, a 1⁄2, a nitro group, a hydroxyl group, a carboxyl group, a methylsulfonyl group, a methoxycarbonyl group;
Rlb为卤素原子、 «、 羟基、 羧基、 ½、 硝基、 巯基、 磺 、 « 甲酰基、 烷基、 烷 tt、 C3-8环烷基、 C2_e烯基、 （35-8环烯基、 C2-6炔 基、 C3-8环烷 烷基胺基、 二 (C1-6烷基)胺基、 烷石克基、 烷基 羰基、 烷基胺基甲酰基、 烷基酰胺基、 烷基磺酰基、 C 烷基胺 基磺酰基、 C 烷基磺酰胺基、 二 (C 烷基)胺基甲酰基、 二 (C 烷基)胺基磺 酰基、 烷氧羰基或 烷基羰氧基， 所迷的 烷基、 C3-8环烷基、 C2-6 烯基、 C5-8环烯基、 C2-6炔基、 烷氧基、 C3-8环烷氧基、 烷基胺基、 二R lb is a halogen atom, «, hydroxy, carboxy, 1⁄2, nitro, fluorenyl, sulfonyl, «formyl, alkyl, alkene tt, C 3-8 cycloalkyl, C 2 _e alkenyl, (3 5-8 Cycloalkenyl, C 2-6 alkyne a C 3-8 cycloalkylalkylamino group, a di(C 1-6 alkyl)amino group, an alkyl fluorenyl group, an alkylcarbonyl group, an alkylaminoformyl group, an alkylamide group, an alkylsulfonyl group, C alkylaminosulfonyl, C alkylsulfonylamino, bis(C alkyl)aminoformyl, bis(C alkyl)aminosulfonyl, alkoxycarbonyl or alkylcarbonyloxy, Alkyl, C 3-8 cycloalkyl, C 2 -6 alkenyl, C 5-8 cycloalkenyl, C 2 -6 alkynyl, alkoxy, C 3-8 cycloalkoxy, alkylamino Second
(C 烷基)胺基、 烷硫基、 C 烷基 ½、 C 烷基胺基甲酰基、 C 烷基 酰胺基、 C1-6烷基磺酰基、 烷基胺基磺酰基、 烷基横酰胺基、 二 (C^ 烷基)胺基甲酰基、 二 (Cw烷基)胺基磺酰基、 C1-6烷氧羰基和 烷基羰氧 基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 羟基、 «和 ^， n为 0〜4的整数， 其中 n为 2、 3或者 4时， Rlb 代表的基团可以相同或不同； (C alkyl)amino, alkylthio, C alkyl 1⁄2, C alkylaminoformyl, C alkylamido, C 1-6 alkylsulfonyl, alkylaminosulfonyl, alkyl Amido, bis(C^alkyl)aminoformyl, bis(Cw alkyl)aminosulfonyl, C1-6 alkoxycarbonyl and alkylcarbonyloxy can be optionally 1, 2, 3, 4 , 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, «and ^, n is an integer of 0 to 4, wherein when n is 2, 3 or 4, the group represented by R lb may be the same Or different
R2a为氢原子、 烷基、 C3_8环烷基、 C5-8环烯基、苯基或 3-8元杂环基， 所述的 Cw烷基、 C3-8环烷基、 C5-8环烯基、 苯基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基、 羧基、 tt、 烷基和卤代 烷基； R 2a is a hydrogen atom, an alkyl group, a C 3 -8 cycloalkyl group, a C 5 -8 cycloalkenyl group, a phenyl group or a 3-8 membered heterocyclic group, said C w alkyl group, C 3-8 cycloalkane The base, C 5-8 cycloalkenyl, phenyl and 3-8 membered heterocyclyl can be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: halogen atom, cyanogen Base, hydroxyl, carboxyl, tt, alkyl and haloalkyl;
R2b、 R3a、 R3b分别独立地为氢原子、 硝基、 、 卤素原子、 烷基、 烷氧基、 C3-8环烷基、 C2_6烯基、 C5-8环烯基、 C2_6炔基或 C3-8环烷氧基， 所述的 烷基、 C3-8环烷基、 C2-6烯基、 （ 5-8环烯基、 C2-6炔基、 C1-6烷氧基 和 C3-8环烷氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取 代： 卤素原子、 ■½、 羟基、 和«； R 2b , R 3a , and R 3b are each independently a hydrogen atom, a nitro group, a halogen atom, an alkyl group, an alkoxy group, a C 3-8 cycloalkyl group, a C 2 -6 alkenyl group, a C 5-8 cycloalkenyl group. , C 2 -6 alkynyl or C 3-8 cycloalkoxy, said alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, ( 5-8 cycloalkenyl, C 2-6 alkyne The group, C 1-6 alkoxy group and C 3-8 cycloalkoxy group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: halogen atom, ■1⁄2 Hydroxyl, and «;
R4和 R5与它们所连接的 X形成 C3-8环烷基、 C5-8环烯基、 苯基、 3-8元 杂环基、 5-10元稠环基、 5-12元螺环基和 6-10元桥环基，所述的 C3-8环烷基、 C5-8环烯基、 苯基、 3-8元杂环基、 5-10元稠环基、 5-12元螺环基和 6-10元 桥环基可任选被 1、 2、 3或 4个独立地选自 R4a和 1^的取代基取代； R 4 and R 5 and the X to which they are attached form a C 3-8 cycloalkyl group, a C 5-8 cycloalkenyl group, a phenyl group, a 3-8 membered heterocyclic group, a 5-10 membered fused ring group, 5-12 a spirocyclic group and a 6-10 membered bridged ring group, said C 3-8 cycloalkyl group, C 5-8 cycloalkenyl group, phenyl group, 3-8 membered heterocyclic group, 5-10 membered fused ring group a 5-12 membered spiro group and a 6-10 membered bridged ring group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 4a and 1^;
R4a为硝基、 、 卤素原子、 羟基、 ' 、 、 烷基、 烷氧 基、 C3-8环烷基、 C2_6烯基、 C5-8环烯基、 C2-6炔基或 C3-8环烷氧基， 所述的 烷基、 C3-8环烷基、 烯基、 C5-8环烯基、 炔基、 烷氧基和 C3-8 环烷氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤 素原子、 氰基、 羟基、 羧基和氨基； R 4a is a nitro group, a halogen atom, a hydroxyl group, a ', an alkyl group, an alkoxy group, a C 3-8 cycloalkyl group, a C 2 -6 alkenyl group, a C 5-8 cycloalkenyl group, a C 2-6 alkynyl group. Or a C 3-8 cycloalkoxy group, said alkyl group, C 3-8 cycloalkyl group, alkenyl group, C 5-8 cycloalkenyl group, alkynyl group, alkoxy group and C 3-8 cycloalkoxy group Optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group;
R5a为 (CH2)pR6,其中 R6为 OR7、 C(0)R7、 C(0)OR7、 OC(0)R7、 C(0)NR8R9、 NR8C(0)R7、 NR8R9、 S(0)qR7 , NHCOOR7、 NHCONR8R9、 S(0)qNR8R9、 NR8S(0)qR7或 C(0)NHS(0)qR7; R 5a is (CH 2 )pR 6 , wherein R 6 is OR 7 , C(0)R 7 , C(0)OR 7 , OC(0)R 7 , C(0)NR 8 R 9 , NR 8 C (0) R 7 , NR 8 R 9 , S(0) q R 7 , NHCOOR 7 , NHCONR 8 R 9 , S(0) q NR 8 R 9 , NR 8 S(0) q R 7 or C(0 NHS(0)qR 7 ;
R7、 R8和 R9分别独立地为氢原子， C1-6烷基或 C3-8环烷基， R8和 R9可 以与它们所连接的氮形成 3-8元杂环基， 所述 烷基、 C3-8环垸基和 3-8元 杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素 原子、 、吡咯烷基、 OR10, C(O)R10、 C(O)OR10 OC(O)R10、 C(0)NRnR12, R"R12、 NRHC(0)R10, S(O)qR10、 SCO^NRUR12和 NR^S O 10; R 7 , R 8 and R 9 are each independently a hydrogen atom, a C 1-6 alkyl group or a C 3-8 cycloalkyl group, and R 8 and R 9 may be used. Forming a 3-8 membered heterocyclic group with the nitrogen to which they are attached, said alkyl group, C 3-8 cyclodecyl group and 3-8 membered heterocyclic group optionally being 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: halogen atom, pyrrolidinyl group, OR 10 , C(O)R 10 , C(O)OR 10 OC(O)R 10 , C(0)NR n R 12 , R"R 12 , NR H C(0)R 10 , S(O) q R 10 , SCO^NRUR 12 and NR^SO 10 ;
R1G、 R11和 R12分别独立地为氢原子、 烷基、 C3-8环烷基或苯基， R11 和 R12可以与它们所连接的氮形成 3-8元杂环基，所述 Cw烷基、（ 3_8环烷基、 苯基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代 基取代： 卤素原子、 、 羟基和羧基； R 1G , R 11 and R 12 are each independently a hydrogen atom, an alkyl group, a C 3-8 cycloalkyl group or a phenyl group, and R 11 and R 12 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, The C w alkyl group, ( 3 -8 cycloalkyl group, phenyl group and 3-8 membered heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of : halogen atom, hydroxyl group and carboxyl group;
p为 0〜6的整数；  p is an integer from 0 to 6;
q为 0〜2的整数。  q is an integer of 0 to 2.
根据本发明的一种实施方案， 提供了通式（ l b )所示的化合物、 其药学 上可  According to an embodiment of the present invention, there is provided a compound of the formula (1b) which is pharmaceutically acceptable
Figure imgf000005_0001
Figure imgf000005_0001
其中， Cy1为 3-8元杂环基、 （ 3-8环烷基或芳基； Wherein Cy 1 is a 3-8 membered heterocyclic group, ( 3-8 cycloalkyl or aryl;
Cy2为 C3.8环烷基、 C5-8环締基或 3-8元杂环基， 所述的 C3-8环烷基、 C5-8 环諦基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取 代基取代： 卤素原子、 、 羟基、 、 C1-6烷基、 卤代 烷基、 苯基、 C3-8环烷基和 3-8元杂环基； Cy 2 is C 3 .8 cycloalkyl, C 5-8 cycloalkyl or 3-8 membered heterocyclic, said C 3-8 cycloalkyl, C 5-8 cyclodecyl and 3-8 member. The heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, a C 1-6 alkyl group, a halogenated alkyl group, a phenyl group, C a 3-8 cycloalkyl group and a 3-8 membered heterocyclic group;
L为 C(0)、 C(0)0、 C(0)NH、 NHC(0)、 S(O)或 S(0)2; L is C(0), C(0)0, C(0)NH, NHC(0), S(O) or S(0) 2 ;
X为 N或 CH;  X is N or CH;
R1为卤素原子、 、 羟基、 羧基、 、 硝基、 巯基、 磺酸基、 甲酰基、 _6烷基、 烷氧基、 C3-8环烷基、 C2 烯基、 C5-8环烯基、 C2_e炔 基、 C3-8环烷^ J^、 d— 6烷基胺基、 二 (C1-6烷基)胺基、 烷硫基、 烷基 羰基、 C 烷基胺基甲酰基、 烷基酰胺基、 烷基磺酰基、 烷基胺 基磺酰基、 烷基磺酰胺基、 二 (Cw烷基)胺基甲酰基、 二 (Cw烷基)胺基磺 酰基、 烷氧羰基或 烷基羰氧基， 所述的 C1-6烷基、 （¾-8环烷基、 C2-6 烯基、 C5-8环烯基、 C2_6炔基、 C1-6烷氧基、 C3-8环烷氧基、 烷基胺基、 二 (C1-6烷基)胺基、 C 烷硫基、 C 烷基 tt、 C1-6烷基胺基甲酰基、 C 烷基 酰胺基、 C 烷基磺酰基、 C 烷基胺基磺酰基、 C 烷基磺酰胺基、 二 (c1-6 烷基)胺基甲酰基、 二 (Cw烷基)胺基礒酰基、 C1-6烷氧羰基和 烷基羰氧 基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 ^、 羟基、 ^^和 m为 0〜5的整数， 其中 R1相同或不同； R 1 is a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a decyl group, a sulfonic acid group, a formyl group, a -6 alkyl group, an alkoxy group, a C 3 -8 cycloalkyl group, a C 2 alkenyl group, a C 5-8 ring Alkenyl, C 2 _e alkynyl, C 3-8 cycloalkane, J- 6 , d- 6 alkylamino, bis(C 1-6 alkyl)amine, alkylthio, alkylcarbonyl, C alkyl Aminoformyl, alkylamido, alkylsulfonyl, alkylaminosulfonyl, alkylsulfonylamino, bis(C w alkyl)aminoformyl, bis(Cw alkyl)aminosulfonyl , alkoxycarbonyl or alkylcarbonyloxy, said C 1-6 alkyl, (3⁄4 -8 cycloalkyl, C 2-6 alkenyl, C 5-8 cycloalkenyl, C 2 -6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkoxy, alkylamino, bis(C 1-6 alkyl)amine, C alkylthio, C alkyl tt, C 1-6 alkyl Aminoformyl, C alkylamido, C alkylsulfonyl, C alkylaminosulfonyl, C alkylsulfonylamino, bis(c 1-6 alkyl)aminoformyl, bis(Cw alkane) Aminocarbonyl, C 1-6 alkoxycarbonyl and alkyl carbonyl The group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, ^, a hydroxyl group, ^^ and m being an integer of 0 to 5, wherein R 1 is the same or different;
R2a为氢原子、 烷基、 C3-8环烷基、。5-8环烯基、 苯基或 3-8元杂环基， 所述的 烷基、 C3-8环烷基、 C5-8环烯基、 苯基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基、 ½、 、 烷基和卤代 _6烷基； R 2a is a hydrogen atom, an alkyl group, a C 3-8 cycloalkyl group. a 5-8 cycloalkenyl group, a phenyl group or a 3-8 membered heterocyclic group, said alkyl group, C 3-8 cycloalkyl group, C 5-8 cycloalkenyl group, phenyl group and 3-8 membered heterocyclic group Optionally, it may be substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a 1⁄2, an alkyl group and a halogenated-6 alkyl group;
R2b、 R3a分别独立地为氢原子、 硝基、 、 卤素原子、 烷基、
Figure imgf000006_0001
烷氧基、 C3-8环烷基、 C2_6烯基、 C5-8环烯基、 C2_6炔基或 C3-8环烷氧基， 所 述的 C1-6烷基、 C3-8环烷基、 C2-6烯基、 C5-8环烯基、 C2_6炔基、 烷氧基和 C 8环烷氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基、 和 ^； R 2b and R 3a are each independently a hydrogen atom, a nitro group, a halogen atom, an alkyl group,
Figure imgf000006_0001
Alkoxy, C 3-8 cycloalkyl, C 2 -6 alkenyl, C 5-8 cycloalkenyl, C 2 -6 alkynyl or C 3-8 cycloalkoxy, said C 1-6 alkyl , C 3-8 cycloalkyl, C 2-6 alkenyl, C 5-8 cycloalkenyl, C 2 -6 alkynyl, alkoxy and C 8 cycloalkoxy may be optionally 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, and a ^;
R4和 R5与它们所连接的 X形成 C3-8环烷基、 C5-8环烯基、 笨基或 3-8元 杂环基， 所述的 C3-8环烷基、 （ 5_8环烯基、 苯基和 3-8元杂环基可任选被 1、 2、 3或 4个独立地选自 R4a和 R5a的取代基取代； R 4 and R 5 and the X to which they are attached form a C 3-8 cycloalkyl group, a C 5-8 cycloalkenyl group, a stupid group or a 3-8 membered heterocyclic group, said C 3-8 cycloalkyl group, ( 5 _ 8 cycloalkenyl, phenyl and 3-8 membered heterocyclyl may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 4a and R 5a ;
R4a为硝基、 L^、 卤素原子、 羟基、 、 tt, 烷基、 烷氧 基、 C3-8环烷基、 C2-6烯基、 C5-8环烯基、 C2-6炔基或 C3_8环烷氧基， 所述的 C1-6烷基、 C3-8环烷基、 C2 烯基、 C5-8环烯基、 炔基、 烷氧基和 C3-8 环烷氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤 素原子、 氰基、 羟基、 羧基和氨基； R 4a is nitro, L ^ , halogen atom, hydroxy, tt, alkyl, alkoxy, C 3-8 cycloalkyl, C 2-6 alkenyl, C 5 -8 cycloalkenyl, C 2- 6 alkynyl or C 3 -8 cycloalkoxy, said C 1-6 alkyl, C 3-8 cycloalkyl, C 2 alkenyl, C 5-8 cycloalkenyl, alkynyl, alkoxy And a C 3-8 cycloalkoxy group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group;
R5a为 (CH2)pR6,其中 R6为 OR7、 C(0)R7、 C(0)OR7、 OC(0)R7、 C(0)NR8R9、 NR8C(0)R7、 NR8R9、 S(0)qR7、 NHCOOR7、 NHCONR8R9、 S(0)qNR8R9 , NR8S(0)qR7或 C(0)NHS(0)qR7; R 5a is (CH 2 )pR 6 , wherein R 6 is OR 7 , C(0)R 7 , C(0)OR 7 , OC(0)R 7 , C(0)NR 8 R 9 , NR 8 C (0) R 7 , NR 8 R 9 , S(0) q R 7 , NHCOOR 7 , NHCONR 8 R 9 , S(0) q NR 8 R 9 , NR 8 S(0)qR 7 or C(0) NHS(0)qR 7 ;
R7 R8和 R9分别独立地为氢原子， C1-6烷基或 C3-8环烷基， R8和 R9可 以与它们所连接的氮形成 3-8元杂环基， 所述 烷基、 C 8环烷基和 3-8元 杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素 原子、氰基、吡咯烷基、 OR1Q、 C(0)R10, C(0)OR10, OC(0)R1G、 C(0)NRHR12, NR"R12、 NRnC(0)R10, S(O)qR10、 S(0)qNRuR12和 NRnS(0)qR10; R 7 R 8 and R 9 are each independently a hydrogen atom, a C 1-6 alkyl group or a C 3-8 cycloalkyl group, and R 8 and R 9 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, The alkyl group, C 8 cycloalkyl group and 3-8 membered heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, Pyrrolidinyl, OR 1Q , C(0)R 10 , C(0)OR 10 , OC(0)R 1G , C(0)NR H R 12 , NR"R 12 , NR n C(0)R 10 , S(O)qR 10 , S(0) q NR u R 12 and NR n S(0)qR 10 ;
R1G、 R11和 R12分别独立地为氢原子、 烷基、 C3-8环烷基或苯基， R11 和 R12可以与它们所连接的氮形成 3-8元杂环基，所述 烷基、 C3-8环烷基、 笨基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代 基取代： 卤素原子、 氣基、 羟基和羧基； R 1G , R 11 and R 12 are each independently a hydrogen atom, an alkyl group, a C 3-8 cycloalkyl group or a phenyl group, and R 11 and R 12 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, The alkyl, C 3-8 cycloalkyl, strepyl and 3-8 membered heterocyclyl can be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: Atom, gas base, hydroxyl and carboxyl groups;
p为 0〜6的整数；  p is an integer from 0 to 6;
q为 0~2的整数。 根据本发明的一种实施方案， 提供了式（lb )的化合物， 其药学上可接 受的盐或其异构体， q is an integer from 0 to 2. According to an embodiment of the present invention, there is provided a compound of the formula (lb), a pharmaceutically acceptable salt thereof or an isomer thereof,
其中， Cy1为苯基、 吡啶基或嘧啶基； Wherein Cy 1 is a phenyl group, a pyridyl group or a pyrimidinyl group;
Cy2为 C3-8环烷基或 3-8元杂环基， 所述的 C3-8环烷基和 3-8元杂环基可 任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 氰 基、 羟基、 羧基、 、 烷基、 卤代 烷基、 笨基、 C3-8环烷基和 3-8 元杂环基； Cy 2 is a C 3-8 cycloalkyl group or a 3-8 membered heterocyclic group, and the C 3-8 cycloalkyl group and the 3-8 membered heterocyclic group may be optionally 1, 2, 3, 4, 5 Or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, an alkyl group, a halogenated alkyl group, a phenyl group, a C 3-8 cycloalkyl group, and a 3-8 membered heterocyclic group;
L为 C(O), C(0)0， C(0)NH、 HC(O)或 S(0)2; L is C(O), C(0)0, C(0)NH, HC(O) or S(0) 2 ;
X为 N或 CH;  X is N or CH;
R1为卤素原子、 、 羟基、 、磺 、 CM烷基、 烷 、 C3-8 环烷基、 C2_6烯基、 C2_6炔基、 C1-6烷基胺基、 二 (C1-6烷基)胺基、 烷基胺 基甲酰基、 烷基酰胺基、 烷基磺酰基、 烷基胺基磺酰基、 烷 基磺酰胺基、 烷氧羰基或 _6烷基羰氧基，所述的 烷基、 烷氧基、 ( 3-8环烷基、 C2_6烯基、 C2_6炔基、 C1-6烷基胺基、 二 (C^烷基)胺基、 C1-6烷 基胺基甲酰基、 C 烷基酰胺基、 C 烷基磺酰基、 C 烷基胺基磺酰基、 C1-6 烷基横酰胺基、 烷氧羰基和 C1-6烷基羰氧基可任选被 1、 2、 3或 4个独立 地选自以下的取代基取代： 卤素原子、 、 羟基、 羧基和氨基， m为 0〜3 的整数， 其中 R1相同或不同； R 1 is a halogen atom, a hydroxyl group, a sulfo group, a CM alkyl group, an alkane, a C 3-8 cycloalkyl group, a C 2 -6 alkenyl group, a C 2 _6 alkynyl group, a C 1-6 alkylamino group, a di(C) 1-6 alkyl)amino, alkylaminoformyl, alkylamido, alkylsulfonyl, alkylaminosulfonyl, alkylsulfonylamino, alkoxycarbonyl or -6 alkylcarbonyloxy The alkyl group, alkoxy group, ( 3-8 cycloalkyl group, C 2 _6 alkenyl group, C 2 _6 alkynyl group, C 1-6 alkylamino group, bis(C^alkyl)amino group, C 1-6 alkylaminocarbonyl, C alkyl amide, C alkyl sulfonyl, C alkyl amino sulfonyl, C 1-6 alkyl amide amide, alkoxycarbonyl and C 1-6 alkane The carbonyloxy group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, a carboxyl group and an amino group, m being an integer of 0 to 3, wherein R 1 is the same or different ;
R2a为氢原子、 C3-8环烷基、 C5-8环烯基、 苯基或 3-8元杂环基， 所述的 C3-8环烷基、 C5-8环烯基、 笨基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6 个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基、 羧基、 氨基、 C1-6 烷基和卤代 C 烷基； R 2a is a hydrogen atom, a C 3-8 cycloalkyl group, a C 5-8 cycloalkenyl group, a phenyl group or a 3-8 membered heterocyclic group, said C 3-8 cycloalkyl group, C 5-8 cycloolefin The benzyl, strepyl and 3-8 membered heterocyclyl can be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, an amino group, C 1-6 alkyl and halogenated C alkyl;
R2B、 1 分别独立地为氢原子、 tt、 卤素原子、 C 烷基、 C^e烷氧基、 C3.8环烷基或 C2-6炔基， 所述的 烷基、 C1-6烷氧基、 C3-8环烷基或 C2-6炔 基和可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原 子、 氰基、 羟基、 羧基和氨基； R 2B, 1 each independently represent a hydrogen atom, tt, a halogen atom, C alkyl, C ^ e-alkoxy, C 3. 8 cycloalkyl or C 2-6 alkynyl group, according -alkyl, C 1 a -6 alkoxy group, a C 3-8 cycloalkyl group or a C 2-6 alkynyl group and may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, and an amino group;
R4和 R5与它们所连接的 X形成 C3-8环烷基、 C5-8环婦基或 3-8元杂环基， 所述的 C3-8环烷基、 C5-8环烯基和 3-8元杂环基可任选被 1、 2或 3个独立地 选自 R4a和 R5a的取代基取代； R 4 and R 5 form a C 3-8 cycloalkyl group, a C 5-8 ring group or a 3-8 membered heterocyclic group with the X to which they are attached, said C 3-8 cycloalkyl group, C 5 - The 8- cycloalkenyl and 3-8 membered heterocyclyl can be optionally substituted by 1, 2 or 3 substituents independently selected from R 4a and R 5a ;
1 43为硝基、 、 卤素原子、 羟基、 tt、 烷基、 烷 、 C3-8 环烷基、 C2-6烯基或 C2_6炔基， 所述的 烷基、 烷氧基、 C3-8环烷基、 烯基和 炔基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基 取代： 卤素原子、 «、 羟基、 羧基和 R5A为（CH2)pR6, 其中 R6为 OR7、 C(0)OR7、 OC(0)R7、 C(0)N 8R9、 N 8C(0)R7、 NR8R9、 S(0)qR7、 NHCONR8R9、 S(0)qNR8R9、 NR8S(0)qR7或 C(0)NHS(0)QR7; 1 43 is a nitro group, a halogen atom, a hydroxyl group, a tt, an alkyl group, an alkane, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group or a C 2 -6 alkynyl group, said alkyl group, alkoxy group, The C 3-8 cycloalkyl, alkenyl and alkynyl groups may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a «hydroxyl group, a carboxyl group and R 5A is (CH 2 )pR 6 , wherein R 6 is OR 7 , C(0)OR 7 , OC(0)R 7 , C(0)N 8 R 9 , N 8 C(0)R 7 , NR 8 R 9 , S(0)qR 7 , NHCONR 8 R 9 , S(0) q NR 8 R 9 , NR 8 S(0) q R 7 or C(0)NHS(0) Q R 7 ;
R7、 R8和 R9分别独立地为氢原子、 d_6烷基或 C3_8环烷基， R8和 R9可 以与它们所连接的氮形成 3-8元杂环基， 所迷 C 烷基、 C 8环烷基和 3-8元 杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素 原子、 、吡咯烷基、 OR10, C(0)OR1Q、 OC(0) R1Q、 C(0)NRNR12 NR"R12、 NRNC(0)R10, S(0)qR10, S C qN UR12和
Figure imgf000008_0001
R 7 , R 8 and R 9 are each independently a hydrogen atom, a d 6 alkyl group or a C 3 -8 cycloalkyl group, and R 8 and R 9 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached. The C alkyl group, the C 8 cycloalkyl group and the 3-8 membered heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a pyrrolidine Base, OR 10 , C(0)OR 1Q , OC(0) R 1Q , C(0)NR N R 12 NR"R 12 , NR N C(0)R 10 , S(0) q R 10 , SC qN UR 12 and
Figure imgf000008_0001
R1G、 R11和 R12分别独立地为氢原子、 烷基或 C3-8环烷基， R11和 R12 可以与它们所连接的氮形成 3-8元杂环基， 所述 烷基、 C 8环烷基和 3-8 元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤 素原子、 氰基、 羟基和氣基； R 1G , R 11 and R 12 are each independently a hydrogen atom, an alkyl group or a C 3 -8 cycloalkyl group, and R 11 and R 12 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, said alkane The base, C 8 cycloalkyl and 3-8 membered heterocyclyl can be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: halogen atom, cyano group, hydroxyl group and gas group. ;
p为 0〜4的整数；  p is an integer from 0 to 4;
q为 0~2的整数。  q is an integer from 0 to 2.
根据本发明的一种实施方案， 提供了式（lb )的化合物， 其药学上可接 受的盐或其异构体，  According to one embodiment of the present invention, there is provided a compound of the formula (lb), a pharmaceutically acceptable salt thereof or an isomer thereof,
其中， Cy1为苯基或吡啶基； Wherein Cy 1 is a phenyl group or a pyridyl group;
Cy2为 C5_6环烷基或 3-8元杂环基， 所述的 C5_6环烷基和 3-8元杂环基可 任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 氰 基、 羟基、 羧基、 tt、 C1-6烷基、 卤代 烷基、 苯基、 C3-8环烷基和 5-7 元杂环基； Cy 2 is a C 5 -6 cycloalkyl group or a 3-8 membered heterocyclic group, and the C 5 -6 cycloalkyl group and the 3-8 membered heterocyclic group may be optionally 1, 2, 3, 4, 5 or 6 Substituents independently selected from the group consisting of: halogen atom, cyano group, hydroxy group, carboxyl group, tt, C 1-6 alkyl group, haloalkyl group, phenyl group, C 3-8 cycloalkyl group and 5-7 membered heterocyclic ring base;
L为 C(0)、 C(0)0、 NHC(O)或 C(0)NH;  L is C(0), C(0)0, NHC(O) or C(0)NH;
X为 N或 CH;  X is N or CH;
R1为氢原子、 卤素原子、 氰基、 羟基、 羧基、 磺酸基、 烷基、 C1-6 烷 L^、 C3-8环烷基、 C2_6炔基、 C 烷基胺基、 二 ( _6烷基)胺基、 烷基 胺基甲酰基、 烷基酰胺基、 C1-6烷基胺基磺酰基、 C1-6烷基磺酰胺基、 C1-6 烷氧羰基或 烷基羰氧基， 所述的 烷基、 C3-8环烷基、 C2_6炔基、 C1-6 烷氧基、 烷基胺基、 二 (C1-6烷基)胺基、 烷基胺基曱酰基、 C"烷基酰 胺基、 烷基胺基磺酰基、 C1-6烷基磺酰胺基、 烷氧羰基和 烷基羰 氧基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰 基、 羟基、 羧基和 tt, m为 1~3的整数， 其中 R1相同或不同； R 1 is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, a sulfonic acid group, an alkyl group, a C 1-6 alkane L^, a C 3-8 cycloalkyl group, a C 2 -6 alkynyl group, a C alkylamino group. , bis( -6 alkyl)amino, alkylaminoformyl, alkylamido, C 1-6 alkylaminosulfonyl, C 1-6 alkylsulfonylamino, C 1-6 alkoxycarbonyl Or alkylcarbonyloxy, said alkyl, C 3-8 cycloalkyl, C 2 -6 alkynyl, C 1-6 alkoxy, alkylamino, bis(C 1-6 alkyl)amine The group, the alkylamino decanoyl group, the C"alkyl amide group, the alkylamino sulfonyl group, the C 1-6 alkylsulfonylamino group, the alkoxycarbonyl group and the alkylcarbonyloxy group may be optionally 1, 2. 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, and tt, m is an integer of 1 to 3, wherein R 1 is the same or different;
R2A为氢原子、 C3-8环垸基、 苯基、 C5_e环烯基、 或 4-7元杂环基， 所述的 C3-8环烷基、 苯基、 C5_6环烯基和 4-7元杂环基可任选被 1、 2、 3或 4个独立 地选自以下的取代基取代： 卤素原子、 ½、 羟基、 羧基、 ½、 C1-6烷基和 鹵代 烷基； R 2A is a hydrogen atom, a C 3-8 cyclodecyl group, a phenyl group, a C 5 —ecycloalkenyl group, or a 4-7 membered heterocyclic group, said C 3-8 cycloalkyl group, phenyl group, C 5 —6 The cycloalkenyl and 4-7 membered heterocyclyl can be optionally 1, 2, 3 or 4 independent Substituted by a substituent selected from the group consisting of: a halogen atom, a 1⁄2, a hydroxyl group, a carboxyl group, a 1⁄2, a C 1-6 alkyl group, and a halogenated alkyl group;
R2b、 R3a分别独立地为氢原子、 氰基、 卤素原子、 烷基、 烷氧基 或 C2_e块基， 所述的 烷基、 烷氧基和 C2_6炔基可任选被 1、 2、 3或 4 个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基、 羧基和氨基；R 2b and R 3a are each independently a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkoxy group or a C 2 —e block group, and the alkyl group, the alkoxy group and the C 2 —6 alkynyl group may be optionally 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group;
R4和 R5与它们所连接的 X形成 C3-8环烷基或 3-8元杂环基， 所述的 C3-8 环烷基和 3-8元杂环基可任选被 1或 2个独立地选自 R4A和 R5A的取代基取代；R 4 and R 5 form a C 3 -8 cycloalkyl group or a 3-8 membered heterocyclic group with the X to which they are attached, and the C 3-8 cycloalkyl group and the 3-8 membered heterocyclic group may be optionally 1 or 2 substituents independently selected from R 4A and R 5A ;
1 43为 、 卤素原子、 羟基、 氨基、 烷基、 烷！^或 C3-8环烷 基， 所述的 C1-6 基、 烷氧基和 C3-8环烷基可任选被 1、 2、 3或 4个独立 地选自以下的取代基取代： 卤素原子、 、 羟基、 羧基和 1 43 is, halogen atom, hydroxyl group, amino group, alkyl group, alkane! Or a C 3-8 cycloalkyl group, said C 1-6 group, alkoxy group and C 3-8 cycloalkyl group may be optionally 1, 2, 3 or 4 substituents independently selected from the group consisting of Substitution: halogen atom, hydroxyl group, carboxyl group and
R5a为 (C¾)pR6, 其中 R6为 OR7、 C(0)OR7、 OC(0)R7、 C(0)NR8R9、 NR8C(0)R7、 NR8R9或 NHCONR8R9; R 5a is (C3⁄4)pR 6 , wherein R 6 is OR 7 , C(0)OR 7 , OC(0)R 7 , C(0)NR 8 R 9 , NR 8 C(0)R 7 , NR 8 R 9 or NHCONR 8 R 9 ;
R7、 R8和 R9分别独立地为氢原子、 C1-6烷基或 C4-7环烷基， R8和 R9可 以与它们所连接的氮形成 4-7元杂环基， 所述 坑基、 C4 环烷基和 4-7元 杂环基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰基、 OR1Q、 C(0)OR1Q、 OC(0)R1Q、 C(0)NRnR12 , NRUR12、 NRnC(0)R10 和 S(0)qR1G; R 7 , R 8 and R 9 are each independently a hydrogen atom, a C 1-6 alkyl group or a C 4-7 cycloalkyl group, and R 8 and R 9 may form a 4-7 membered heterocyclic group with the nitrogen to which they are attached. The pit group, C 4 cycloalkyl group and 4-7 membered heterocyclic group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group, an OR 1Q , C(0)OR 1Q , OC(0)R 1Q , C(0)NR n R 12 , NR U R 12 , NR n C(0)R 10 and S(0) q R 1G ;
R1G、 R11和 R12分别独立地为氢原子、 C 烷基或 C4-7环烷基， 所述 烷基和 C4-7环烷基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基 取代： 鹵素原子、 «、 羟基和羧基； R 1G , R 11 and R 12 are each independently a hydrogen atom, a C alkyl group or a C 4-7 cycloalkyl group, and the alkyl group and the C 4-7 cycloalkyl group may be optionally 1, 2, 3, 4 , 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a «hydroxyl group and a carboxyl group;
p为 0〜4的整数；  p is an integer from 0 to 4;
q为 0〜2的整数。  q is an integer of 0 to 2.
根据本发明的一种实施方案， 提供了式 Ub ) 的化合物， 其药学上可接 受的盐或其异构体，  According to one embodiment of the invention, there is provided a compound of formula Ub), a pharmaceutically acceptable salt thereof or an isomer thereof,
其中， Cy1为苯基； Wherein Cy 1 is a phenyl group;
Cy 为 3-8元杂环基或 C5_6环烷基， 所述的 3-8元杂环基和 C5_e环坑基可 任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 氰 基、 羟基、 羧基、 tt、 C1-6烷基、 卤代 Cw烷基、 苯基、 C4-6环烷基和 4-6 元杂环基； Cy is a 3-8 membered heterocyclic group or a C 5 -6 cycloalkyl group, and the 3-8 membered heterocyclic group and the C 5 —e ring group may be optionally 1, 2, 3, 4, 5 or 6 Substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, a tt, a C 1-6 alkyl group, a halogenated C w alkyl group, a phenyl group, a C 4-6 cycloalkyl group, and 4-6 Metacyclic heterocyclic group;
L为 C(0)、 C(0)NH、 NHC(O)或 C(0)0;  L is C(0), C(0)NH, NHC(O) or C(0)0;
X为 N或 CH;  X is N or CH;
R1为氢原子、 卤素原子、 氰基、 羟基、 羧基、 磺酸基、 烷基、 C3-8 环烷基、 C2_6炔基、 C1-6烷基胺基甲酰基、 C1-6烷基酰胺基、 C1-6烷基胺基磺 酰基、 C 烷基磺酰胺基、 烷氧羰基或 d-6烷基羰氧基，所述的 烷基、R 1 is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, a sulfonic acid group, an alkyl group, a C 3-8 cycloalkyl group, a C 2 -6 alkynyl group, a C 1-6 alkylaminoformyl group, C 1 -6 alkylamide group, C 1-6 alkyl amine sulfonate An acyl group, a C alkylsulfonylamino group, an alkoxycarbonyl group or a d-6 alkylcarbonyloxy group, said alkyl group,
( 3-8环烷基、 C2_6炔基、 烷基胺基曱酰基、 d_6烷基酰胺基、 烷基胺基 磺酰基、 烷基磺酰胺基、 烷氧羰基和 烷基羰氧基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基、 羧基和氨 基， m为 1~2的整数， 其中 R1相同或不同； ( 3-8 cycloalkyl, C 2 -6 alkynyl, alkylamino decanoyl, d_6 alkylamido, alkylaminosulfonyl, alkylsulfonylamino, alkoxycarbonyl and alkylcarbonyloxy Optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group, m being an integer from 1 to 2, wherein R 1 is the same or different;
R2a为氢原子、 笨基、 环烯基、 5-6元杂环基或 C4_6环烷基， 所迷的笨 基、 C5_6环烯基、 5-6元杂环基和 C4_6环烷基可任选被 1、 2、 3或 4个独立地 选自以下的取^ ^取代： 卤素原子、 、 羟基、 羧基、 氨基、 烷基和卤 代 Ci_6坑基； R 2a is a hydrogen atom, a strepto group, a cycloalkenyl group, a 5-6 membered heterocyclic group or a C 4 -6 cycloalkyl group, a stilbene group, a C 5 -6 cycloalkenyl group, a 5-6 membered heterocyclic group and C The 4- 6 cycloalkyl group may be optionally substituted by 1, 2, 3 or 4 independently selected from the group consisting of: a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an alkyl group and a halogenated Ci_6 pit group;
R2B、 R3A分别独立地为氢原子、 氰基、 卤素原子或 CM烷基， 所迷的 CM 烷基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰 基、 羟基、 羧基和氨基； R 2B and R 3A are each independently a hydrogen atom, a cyano group, a halogen atom or a CM alkyl group, and the CM alkyl group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group;
R4和 R5与它们所连接的 X形成 C4_e环烷基或 4-6元杂环基， 所述的 C4_6 环烷基和 4-6元杂环基可任选被 1或 2个独立地选自 R4a和 R5a的取代基取代； 43为 、 卤素原子、羟基、氨基、 烷基或 烷 所述的 烷基和 烷氧基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 tt、 羟基、 羧基和氨基； R 4 and R 5 form a C 4 _e cycloalkyl or 4-6 membered heterocyclyl group and X which they are attached, the C 4 _6 cycloalkyl, and 4-6 membered heterocyclyl can be optionally substituted with 1 or 2 substituents independently selected from R 4a and R 5a ; 4 3 is a halogen atom, a hydroxyl group, an amino group, an alkyl group or an alkane, and the alkoxy group may be optionally 1, 2, 3 or Substituted by four substituents independently selected from the group consisting of: a halogen atom, tt, a hydroxyl group, a carboxyl group, and an amino group;
R5a为（C¾)pR6， 其中 R6为 OR7、 C(0)OR7、 OC(0)R7、 R8C(0)R7、 C(0)NR7R8或 NR8R9; R 5a is (C3⁄4)pR 6 , wherein R 6 is OR 7 , C(0)OR 7 , OC(0)R 7 , R 8 C(0)R 7 , C(0)NR 7 R 8 or NR 8 R 9 ;
R7、 R8和 R9分别独立地为氢原子、 C1-6烷基或 C4-7环烷基， 所述 烷 基和 C4-7环烷基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤 素原子、 、 OR10, C(O)OR10、 OC(O)R10、 C C NRUR12和 NR"R12; R 7 , R 8 and R 9 are each independently a hydrogen atom, a C 1-6 alkyl group or a C 4 - 7 cycloalkyl group, and the alkyl group and the C 4-7 cycloalkyl group may be optionally 1, 2. 3 or 4 substituents independently selected from the group consisting of: a halogen atom, OR 10 , C(O)OR 10 , OC(O)R 10 , CC NRUR 12 and NR"R 12 ;
R1G、 R11和 R12分别独立地为氢原子或 烷基， 所述 烷基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基和羧 基； R 1G , R 11 and R 12 are each independently a hydrogen atom or an alkyl group, and the alkyl group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group, Hydroxyl and carboxyl groups;
p为 0~3的整数。  p is an integer from 0 to 3.
根据本发明的一种实施方案， 提供了式（lb ) 的化合物， 其药学上可接 受的盐或其异构体，  According to one embodiment of the invention, there is provided a compound of formula (lb), a pharmaceutically acceptable salt thereof or an isomer thereof,
其中， Cy1为苯基；
Figure imgf000010_0001
Wherein Cy 1 is a phenyl group;
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000011_0001
地选自以下的取代基取代： 卤素原子、 tt、 羟基、 羧基、 tt、 CM烷基和 卤代（^4烷基； Substituted by a substituent selected from the group consisting of: a halogen atom, tt, a hydroxyl group, a carboxyl group, a tt, a CM alkyl group, and a halogenated group (^ 4 alkyl group;
L为 C(0)、 C(0)NH、 NHC(O)或 C(0)0;  L is C(0), C(0)NH, NHC(O) or C(0)0;
X为 N;  X is N;
R1为卤素原子、 、 羟基、 羧基、 C3环烷基、 乙块基、 烷基胺基 曱酰基、 或 烷基， 所述的 烷基可任选被 1、 2、 3或 4个独立地选自 以下的取 取代： 卤素原子、 «、 羟基、 ^^和氨基， m为 1或 2, 其 中 R1相同或不同; R 1 is a halogen atom, a hydroxyl group, a carboxyl group, a C 3 cycloalkyl group, an ethyl group, an alkylamino decanoyl group, or an alkyl group, and the alkyl group may be optionally 1, 2, 3 or 4 independent Derived from the following substitutions: a halogen atom, «, a hydroxyl group, a ^^ and an amino group, m is 1 or 2, wherein R 1 is the same or different;
R2a为氢原子、 笨基、 环烯基、 5-6元杂环基、 环丁基、 环戊基或环己 基， 所述的笨基、 C5_6环婦基、 5-6元杂环基、 环丁基、 环戊基和环己基可任 选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基、 ' 、 tt、 C1-3烷基和卤代 C1-3烷基； R 2a is a hydrogen atom, a strepto group, a cycloalkenyl group, a 5-6 membered heterocyclic group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, said stupid group, a C 5 -6 ring group, a 5-6 membered hetero The cyclo, cyclobutyl, cyclopentyl and cyclohexyl groups may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: halogen atom, cyano group, hydroxyl group, ', tt, C 1- 3- alkyl and halogenated C 1-3 alkyl;
R2b、 R3a分别独立地为氢原子、 氰基、 卤素原子或 C14烷基所述的 CM 烷基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰 基、 羟基、 羧基和氨基； The C M alkyl group wherein R 2b and R 3a are each independently a hydrogen atom, a cyano group, a halogen atom or a C 14 alkyl group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of : a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group;
R4和 R5与它们所连接的 N形成 4-6元杂环基， 所述的 4-6元杂环基可任 选被 d.6烷基和 /或 R5a取代； R 4 and R 5 form a 4-6 membered heterocyclic group with the N to which they are attached, and the 4-6 membered heterocyclic group may be optionally substituted by d. 6 alkyl and/or R 5a ;
R5a为 (CH2)pR6, 其中 R6为 OR7、 OC(0)R7、 C(0)NR7R8或 NR8R9; R 5a is (CH 2 )pR 6 , wherein R 6 is OR 7 , OC(0)R 7 , C(0)NR 7 R 8 or NR 8 R 9 ;
R7、 R8和 R9分别独立地为氢原子或(^4烷基，所述(^_4烷基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 to、 OR10, C(0)OR10 和 NRUR12; R 7 , R 8 and R 9 are each independently a hydrogen atom or a (^ 4 alkyl group, which may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: Halogen atom, to, OR 10 , C(0)OR 10 And NRUR 12 ;
R1G、 R11和 R12分别独立地为氢原子或 CM烷基， 所述 d_4烷基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟 基和羧基； R 1G , R 11 and R 12 are each independently a hydrogen atom or a CM alkyl group, and the d-4 alkyl group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group and a carboxyl group;
p为 0或 1。  p is 0 or 1.
根据本发明的一种实施方案， 提供了式（lb )的化合物， 其药学上可接 受的盐或其异构体， According to one embodiment of the present invention, there is provided a compound of the formula (lb), a pharmaceutically acceptable salt thereof or an isomer thereof,
1为苯基;  1 is a phenyl group;
Figure imgf000012_0001
Figure imgf000012_0001
可任选被 1、 2或 3个独立地选自以下的取代基取代： 卤素原子、氰基、羟基、 ½、 tt、 甲基、 乙基和三氟曱基； Optionally, it may be substituted by 1, 2 or 3 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a 1⁄2, a tt, a methyl group, an ethyl group and a trifluoromethyl group;
L为 C(0)、 NH(CO)或 C(0)NH;  L is C(0), NH(CO) or C(0)NH;
X为 N;  X is N;
R1为氟原子、 氯原子、 氰基、 甲基、 乙基、 异丙基、 三氟甲基、 环丙基、 羟基、 乙炔基、 甲基胺基甲酰基或羟甲基， m为 1或 2, 其中 R1相同或不同；R 1 is a fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a cyclopropyl group, a hydroxyl group, an ethynyl group, a methylaminoformyl group or a hydroxymethyl group, and m is 1 Or 2, where R 1 is the same or different;
R2a为环戊基、 苯基、 环戊烯基、 吡咯基、 哌啶基、 环丁基， 所述的环戊 基、 苯基、 环戊烯基、 吡咯基、 哌啶基、 环丁基可任选被 1、 2或 3个独立地 选自以下的取代基取代： 卤素原子、 氰基、 羟基、 ' 、 氨基、 C1-3烷基和卤 代 C1-3烷基； R 2a is cyclopentyl, phenyl, cyclopentenyl, pyrrolyl, piperidinyl, cyclobutyl, said cyclopentyl, phenyl, cyclopentenyl, pyrrolyl, piperidinyl, cyclobutyl The group may be optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, ', an amino group, a C 1-3 alkyl group, and a halogenated C 1-3 alkyl group;
R2b、 R3a分别独立地为氢原子、 、 卤素原子、 曱基、 乙基、 异丙基、 三氟甲基、 羟甲基或氨甲基； R 2b and R 3a are each independently a hydrogen atom, a halogen atom, a fluorenyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a methylol group or an aminomethyl group;
R4和 R5与它们所连接的 N形成环己基、 哌啶基， 所述的环己基和哌啶 基可任选被 烷基和 /或 R5a取代； R5a为 (CH2)pR6， 其中 R6为 OR7、 OC(0)R7、 C(0)NR7R8或 NR8R9; R 4 and R 5 and the N to which they are attached form a cyclohexyl group, a piperidinyl group, said cyclohexyl and piperidinyl group may be optionally substituted by an alkyl group and/or R 5a ; R 5a is (CH 2 )pR 6 , wherein R 6 is OR 7 , OC(0)R 7 , C(0)NR 7 R 8 or NR 8 R 9 ;
R7、 R8和 R9分别独立地为氢原子或 d_3坑基，所述 烷基可任选被 1、 2或 3个独立地选自以下的取^ ^取代： 卤素原子、 、 羟基和 NR"R12; R 7 , R 8 and R 9 are each independently a hydrogen atom or a d_ 3 pit group, and the alkyl group may be optionally substituted by 1, 2 or 3 independently selected from the group consisting of: a halogen atom, a hydroxyl group And NR"R 12 ;
R"、 R12分别独立地为氢原子、 甲基、 乙基或异丙基； R ", R 12 each independently represent a hydrogen atom, a methyl, ethyl or isopropyl;
p为 0。  p is 0.
根据本发明的一种实施方案， 提供了式（lb )的化合物， 其药学上可接 受的盐或其异构体， According to one embodiment of the present invention, there is provided a compound of the formula (lb), a pharmaceutically acceptable salt thereof or an isomer thereof,
1为苯基;  1 is a phenyl group;
Figure imgf000013_0001
Figure imgf000013_0001
甲基和乙基； Methyl and ethyl;
L为 C(O)或 NH(CO);  L is C(O) or NH(CO);
X为 N或 CH;  X is N or CH;
R1独立地选自氟原子、 氯原子、 tt、 曱基、 乙基、 异丙基、 环丙基、 羟基、 乙块基、 和甲基胺基曱酰基， m为 1或 2, 其中 m为 2时， R1相同或 不同； R 1 is independently selected from the group consisting of a fluorine atom, a chlorine atom, a tt, a decyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a hydroxyl group, an ethyl group, and a methylamino decanoyl group, and m is 1 or 2, wherein m When 2, R 1 is the same or different;
R2a为环戊基、 环戊烯基、 环丁基、 苯基、 哌啶基或吡咯基， 所述的环戊 基、 环戊烯基、 环丁基、 苯基、 哌啶基和吡咯基可任选被 1、 2或 3个独立地 选自卤素原子的取代基取代： R 2a is cyclopentyl, cyclopentenyl, cyclobutyl, phenyl, piperidinyl or pyrrolyl, said cyclopentyl, cyclopentenyl, cyclobutyl, phenyl, piperidinyl and pyrrole The group may be optionally substituted by 1, 2 or 3 substituents independently selected from a halogen atom:
R2b为氢原子； R3a为氢原子、 甲基或乙基； R 2b is a hydrogen atom; R 3a is a hydrogen atom, a methyl group or an ethyl group;
R4和 R5与它们所连接的 X形成哌啶基或环己基， 所述的环己基和哌啶 基可任选被羟基、 甲基、 乙基、 tt、 氨基羰基、 曱基甲酰氧基、 乙基曱酰 氣基、 甲氣基和乙氣基中的一或两个取代基取代。 R 4 and R 5 form a piperidinyl or cyclohexyl group with the X to which they are attached, and the cyclohexyl and piperidinyl groups may be optionally hydroxy, methyl, ethyl, tt, aminocarbonyl, decanoyloxy Ethyl decanoyl Substituting one or two substituents of a gas group, a gas group and an ethylene group.
根据本发明的一种实施方案， 提供了式（lb ) 的化合物， 其药学上可接 受的盐或其异构体， According to one embodiment of the invention, there is provided a compound of formula (lb), a pharmaceutically acceptable salt thereof or an isomer thereof,
1为苯基;  1 is a phenyl group;
Figure imgf000014_0001
Figure imgf000014_0001
L为 C(O)或 NHC(O);  L is C(O) or NHC(O);
X为 N或 CH;  X is N or CH;
R1彼此独立地选自氯原子、 氰基、 甲基、 乙基、 异丙基、 环丙基、 羟基、 乙块基、 和甲基胺基甲酰基， R 1 is independently selected from the group consisting of a chlorine atom, a cyano group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a hydroxyl group, an ethyl group group, and a methylaminoformyl group.
m为 1或 2， 其中 m为 2时 R1相同或不同； m is 1 or 2, wherein when m is 2, R 1 is the same or different;
R2a为环戊基、 环戊烯基、 环丁基、 苯基、 哌啶基或吡咯基； 所述的环戊 基、 环戊婦基、 环丁基、 苯基、 哌啶基和吡咯基可任选被 1、 2或 3个独立地 选自卤素原子的取代基取代： R 2a is cyclopentyl, cyclopentenyl, cyclobutyl, phenyl, piperidinyl or pyrrolyl; said cyclopentyl, cyclopentyl, cyclobutyl, phenyl, piperidinyl and pyrrole The group may be optionally substituted by 1, 2 or 3 substituents independently selected from a halogen atom:
R2b和 R3a为氢原子； R 2b and R 3a are a hydrogen atom;
R4和 R5与它们所连接的 X形成哌啶基或环己基， 所述的环己基和哌啶 基可任选被羟基、 甲基、 乙基、 tt、 氨基羰基、 曱基甲酰氧基、 乙基甲酰 基、 甲 基和乙氧基中的一或两个取^ &取代。 R 4 and R 5 form a piperidinyl or cyclohexyl group with the X to which they are attached, and the cyclohexyl and piperidinyl groups may be optionally hydroxy, methyl, ethyl, tt, aminocarbonyl, decanoyloxy One or two of the group, ethyl formyl group, methyl group and ethoxy group are taken as a <RTIgt;
根据本发明的一种实施方案， 提供了式（lb )的化合物， 其药学上可接 受的盐或其异构体， According to one embodiment of the present invention, there is provided a compound of the formula (lb), a pharmaceutically acceptable salt thereof or an isomer thereof,
1为苯基；
Figure imgf000014_0002
1 is a phenyl group;
Figure imgf000014_0002
L为 C(O);  L is C(O);
X为 N;  X is N;
R1彼此独立地选自氯原子、 氰基、 甲基， R 1 is independently selected from the group consisting of a chlorine atom, a cyano group, and a methyl group.
m为 2;  m is 2;
R2a为环戊基 R 2a is cyclopentyl
R2b和 R3a为氢原子； R 2b and R 3a are a hydrogen atom;
R4和 R5与它们所连接的 X形成 4-羟基哌啶基。 根据本发明的一种实施方案， 提供了以下化合物， 其药学上可接受的盐 或其异构体：R 4 and R 5 form a 4-hydroxypiperidinyl group with the X to which they are attached. According to one embodiment of the invention, the following compounds, pharmaceutically acceptable salts or isomers thereof are provided:
Figure imgf000015_0001
Figure imgf000015_0001
Figure imgf000016_0001
具体实施方式
Figure imgf000016_0001
Detailed ways
本发明所述的 "卤素原子"包括氟原子、 氯原子、 溴原子、 碘原子， 优选 氟原子和氯原子。  The "halogen atom" as used in the present invention includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, preferably a fluorine atom and a chlorine atom.
本发明所述" 烷基"指含有 1-6个碳原子的烷烃部分去除一个氢原子衍 生的直链或支链的烷基， 如甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 仲丁基、 叔丁基、 正戊基、 异戊基、 2-甲基丁基、 3-曱基丁基、 1,1-二曱基丙 基、 1,2-二甲基丙基、 新戊基、 1-乙基丙基、 正己基、 异己基、 2-曱基戊基、 3-曱基戊基、 4-甲基 m、 1，1-二甲基丁基、 1,2-二甲基丁基、 1,3-二曱基丁基、 2，2-二甲基丁基、 2,3-二甲基丁基、 3,3-二甲基丁基、 1-乙基丁基、 2-乙基丁基、 1,1,2-三甲基丙基、 1,2,2-三甲基丙基、 1-乙基 -1-甲基丙基和 1-乙基 -2-甲基丙基。 优选 CM烷基， 更优选 C1-3烷基， 术语" ( 14烷基"、 "C1-3烷基"指上述实例中的 含有 1-4个、 1~3个碳原子的具体实例。 The "alkyl group" as used in the present invention means an alkane moiety having 1 to 6 carbon atoms and a straight or branched alkyl group derived by removing one hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, or Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 3-mercaptobutyl, 1,1-dimercaptopropyl, 1,2 - dimethylpropyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 2-decylpentyl, 3-decylpentyl, 4-methylm, 1,1-dimethyl Butyl, 1,2-dimethylbutyl, 1,3-dimercaptobutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethyl Butyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methyl Propyl and 1-ethyl-2-methylpropyl. Preferred is a C M alkyl group, more preferably a C 1-3 alkyl group, and the term "( 14 alkyl group), "C 1-3 alkyl group" means a specific one of 1-4, 1 to 3 carbon atoms in the above examples. Example.
本发明所述" C2_6烯基"指含有双键的碳原子数为 2~6 的直链或支链的烯 基， 如乙浠基、 1-丙烯基、 2-丙烯基、 1-甲基乙烯基、 1-丁烯基、 2-丁烯基、 3-丁烯基、 1-曱基 -1-丙烯基、 2-甲基 -1-丙烯基、 1-甲基 -2-丙烯基、 2-甲基 -2- 丙烯基、 1-戊烯基、 2-戊烯基、 3-戊烯基、 4-戊烯基、 1-曱基小丁烯基、 2-甲 基小丁烯基、 3-甲基 -1-丁烯基、 1-甲基 -2-丁婦基、 2-甲基 -2-丁烯基、 3-甲基 -2-丁烯基、 1-曱基 -3-丁烯基、 2-曱基 -3-丁烯基、 3-甲基 -3-丁烯基、 1,1-二曱 基 -2-丙婦基、 1,2-二甲基 -1-丙烯基、 1,2-二甲基 -2-丙烯基、 1-乙基 -1-丙烯基、 1-乙基 -2-丙婦基、 1-己烯基、 2-己烯基、 3-己婦基、 4-己烯基、 5-己烯基、 1- 甲基小戊烯基、 2-曱基小戊烯基、 3-甲基小戊烯基、 4-甲基小戊婦基、 1-甲基 -2-戊烯基、 2-甲基 -2-戊烯基、 3-甲基 -2-戊烯基、 4-甲基 -2-戊烯基、 1-甲基 -3- 戊烯基、 2-甲基 -3-戊烯基、 3-甲基 -3-戊烯基、 4-甲基 -3-戊烯基、 1-甲基 -4-戊烯 基、 2-甲基 -4-戊烯基、 3-甲基 -4-戊烯基、 4-甲基 -4-戊烯基、 1,1-二甲基 -2-丁浠 基、 1,1-二曱基 -3-丁婦基、 1,2-二曱基 -1-丁烯基、 1，2-二甲基 -2-丁烯基、 1,2-二 曱基 -3-丁婦基、 1,3-二甲基小丁烯基、 1,3-二曱基 -2-丁烯基、 1,3-二曱基 -2-丁 烯基、 2,2-二甲基 -3-丁烯基、 2,3-二甲基小丁烯基、 2,3-二甲基 -2-丁烯基、 2,3- 二曱基 -3-丁烯基、 3,3-二曱基 -1-丁婦基、 3,3-二曱基 -2-丁烯基、 1-乙基 -1-丁烯 基、 1-乙基 -2-丁烯基、 1-乙基 -3-丁烯基、 2-乙基小丁烯基、 2-乙基 -2-丁浠基、The "C 2 -6 alkenyl group" as used in the present invention means a linear or branched alkenyl group having 2 to 6 carbon atoms and having a double bond, such as an ethyl fluorenyl group, a 1-propenyl group, a 2-propenyl group, and a 1- Methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-mercapto-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2- Propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-decylbutenyl, 2-methyl Small butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1 - mercapto-3-butenyl, 2-mercapto-3-butenyl, 3-methyl-3-butenyl, 1,1-dimercapto-2-propanyl, 1,2- Dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2 -hexenyl, 3-hexyl, 4-hexenyl, 5-hexenyl, 1- Methyl pentenyl, 2-mercapto-pentenyl, 3-methyl pentenyl, 4-methyl-pivalanyl, 1-methyl-2-pentenyl, 2-methyl- 2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4 -pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-didecyl-3-butanyl, 1,2-di 1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimercapto-3-butanyl, 1,3-dimethylbutenyl, 1, 3-dimercapto-2-butenyl, 1,3-dimercapto-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethylbutene , 2,3-dimethyl-2-butenyl, 2,3-dimercapto-3-butenyl, 3,3-dimercapto-1-butanyl, 3,3-diindole 2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyls-butenyl, 2-ethyl-2-butenyl,
2-乙基 -3-丁浠基、 1,1,2-三曱基 -2-丙烯基、 1-乙基小甲基 -2-丙浠基、 1-乙基 -2- 甲基 -1-丙烯基、 1-乙基 -2-甲基 -2-丙烯基、 1.3-丁二烯基、 1,3-戊二烯基、 1,4- 戊二烯基、 2,4-戊二烯基、 1,3-己二諦基、 1，4-己二烯基、 1,5-己二烯基和 2,4- 己二烯基等。 双键可为顺式或反式。 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl small methyl-2-propenyl, 1-ethyl-2-methyl- 1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1.3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, 2,4-pentyl Dienyl, 1,3-hexyldidecyl, 1,4-hexadienyl, 1,5-hexadienyl and 2,4-hexadienyl, and the like. The double bond can be cis or trans.
本发明所述" C2_6块基"是指含有三键的碳原子数为 2〜6 的直链或支链炔 基， 如乙炔基、 2-丙炔基、 2-丁炔基、 3-丁炔基、 1-曱基 -2-丙炔基、 2-戊炔基、The "C 2 _6 block group" as used in the present invention means a straight or branched alkynyl group having a triple bond and having 2 to 6 carbon atoms, such as an ethynyl group, a 2-propynyl group, a 2-butynyl group, and 3 -butynyl, 1-mercapto-2-propynyl, 2-pentynyl,
3-戊炔基、 4-戊炔基、 1-甲基 -2-丁炔基、 1-甲基 -3-丁块基、 2-甲基 -3-丁炔基、 1,1-二甲基 -2-丙炔基、 1-乙基 -2-丙炔基、 2-己炔基、 3-己炔基、 4-己炔基、 5- 己炔基、 1-甲基 -2-戊炔基、 4-曱基 -2-戊炔基、 1-甲基 -3-戊炔基、 2-甲基 -3-戊炔 基、 1-甲基 -4-戊炔基、 2-曱基 -4-戊炔基、 3-曱基 -4-戊炔基、 1,1-二甲基 -2-丁炔 基、 1,1-二甲基 -3-丁炔基、 1,2-二甲基 -3-丁炔基、 2,2-二曱基 -3-丁炔基、 1-乙基 -2-丁炔基、 1-乙基 -3-丁炔基、 2-乙基 -3-丁炔基和 1-乙基小甲基 -2-丙炔基等。 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butenyl, 2-methyl-3-butynyl, 1,1-di Methyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2 -Pentynyl, 4-decyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2 -mercapto-4-pentynyl, 3-mercapto-4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1 ,2-dimethyl-3-butynyl, 2,2-dimercapto-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2 Ethyl-3-butynyl and 1-ethyl small methyl-2-propynyl.
本发明所述" 烷氧基 "指术语" 烷基"通过氧原子与其他结构相连接 的基团， 如甲 、 乙 tt、 丙 tt、 异丙 、 丁 、 异丁 、 叔丁氧 基、 仲丁氧基、 戊氧基、 新戊氧基、 己氧基等。  The "alkoxy group" as used in the present invention means a group in which the term "alkyl group" is bonded to other structures through an oxygen atom, such as methyl, ethyl tt, propyl tt, isopropyl, dibutyl, isobutyl, tert-butoxy, sec. Butoxy, pentyloxy, neopentyloxy, hexyloxy and the like.
本发明所述" 烷基胺基"为术语 "Cw烷基"通过胺基与其他结构相连接 的基团， 如甲基胺基、 乙基胺基、 丙基胺基、 异丙基胺基、 丁基胺基、 异丁基 胺基、 叔丁基胺基、 仲丁基胺基、 戊氣基胺基、 新戊基胺基、 己氡基胺基等。 本发明所述"二 (Cw烷基)胺基"为两个相同或不同的" 烷基"通过胺基与其他 结构相连接的基团。  The "alkylamino group" of the present invention is a group in which the term "Cw alkyl group" is bonded to another structure through an amine group, such as a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group. , butylamino, isobutylamino, tert-butylamino, sec-butylamino, pentylamino, neopentylamino, hexylamino and the like. The "bis(Cw alkyl)amino group" of the present invention is a group in which two identical or different "alkyl groups" are bonded to other structures through an amine group.
本发明所述" C1-6烷硫基 "指术语" 烷基"通过硫原子与其他结构相连接 的基团， 如甲硫基、 乙硫基、 丙硫基、 异丙硫基、 丁硫基、 异丁硫基、 叔丁硫 基、 仲丁硫基、 戊硫基、 新戊硫基、 己硫基等。 The "C 1-6 alkylthio group" as used in the present invention means a group in which the term "alkyl group" is bonded to another structure through a sulfur atom, such as methylthio, ethylthio, propylthio, isopropylthio, butyl. Sulfur, isobutylthio, tert-butylthio, sec-butylthio, pentylthio, neopentylthio, hexylthio, and the like.
本发明所述" 烷基羰基"指术语 "CW烷基"通过羰基与其他结构相连接 的基团， 如甲基 、 乙基羰基、 丙基羰基、 异丙基羰基、 丁基 ½、 异丁基 羰基、 叔丁基羰基、 仲丁基羰基、 戊基羰基、 新戊基羰基、 己基凝基等。 The term "alkylcarbonyl" as used in the present invention means that the term "CW alkyl" is bonded to other structures via a carbonyl group. a group such as methyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butyl 1, isobutylcarbonyl, tert-butylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, neopentylcarbonyl, hexyl Condensation and so on.
本发明所述 "Cw烷基胺基甲酰基"为术语 "Cw坑基"通过胺基甲酰基与其 他结构相连接的基团，如甲基胺基曱酰基、 乙基胺基甲酰基、丙基胺基曱酰基、 异丙基胺基甲酰基、丁基胺基甲跣基、异丁基胺基甲酰基、叔丁基胺基曱酰基、 仲丁基胺基曱酰基、 胺基甲酰基、新戊基胺基曱酰基、己基胺基甲酰基等。 本发明所述"二 (Cw烷基)胺基甲酰基"为两个相同或不同的" Cw^"通过胺基 甲酰基与其他结构相连接的基团。  The "Cw alkylaminoformyl" of the present invention is a group in which the term "Cw pit group" is bonded to other structures via an aminoformyl group, such as methylaminodecanoyl, ethylaminoformyl, and propyl. Aminocarbonyl decanoyl, isopropylaminocarbamoyl, butylaminomethylguanidinyl, isobutylaminoformyl, tert-butylaminodecanoyl, sec-butylaminodecanoyl, carbamoyl , neopentylaminodecanoyl, hexylaminoformyl and the like. The "bis(Cw alkyl)aminoformyl group" of the present invention is a group in which two identical or different "Cw^" are bonded to other structures via an aminoformyl group.
本发明所述" d-6烷氧羰基"为术语 "Cw烷氧基 "通过羰基与其他结构相连 接的基团， 如甲氧羰基、 乙氧羰基、 丙氧羰基、 异丙氧叛基、 丁氧羰基、 异丁 氧羰基、 叔丁氧羰基、 仲丁氧羰基、 戊氧羰基、 新戊氧羰基、 己氧羰基等。  The "d-6 alkoxycarbonyl group" of the present invention is a group in which the term "Cw alkoxy group" is bonded to another structure through a carbonyl group, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropyloxy group, Butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl and the like.
本发明所述" 烷基胺基磺酰基"为术语 "c^烷基"通过胺基磺酰基与其 他结构相连接的基团，如曱基 酰基、乙基 磺酰基、丙基 ^碌酰基、 异丙基氨基横酰基、丁基氨基磺酰基、异丁基氨基磺酰基、叔丁基氨基磺酰基、 仲丁基氨基磺酰基、 磺酰基、新戊基氨基蹟酰基、己基氨基磺酰基等。 本发明所述"二 (C"烷基)胺基磺酰基"为两个相同或不同的 烷基"通过胺基 磺酰基与其他结构相连接的基团。  The "alkylaminosulfonyl group" of the present invention is a group in which the term "c^alkyl" is bonded to another structure through an aminosulfonyl group, such as a nonyl group, an ethylsulfonyl group, a propyl group, or a acyl group. Isopropylamino, acyl, butylaminosulfonyl, isobutylaminosulfonyl, tert-butylaminosulfonyl, sec-butylaminosulfonyl, sulfonyl, neopentylaminoacyl, hexylaminosulfonyl and the like. The "di(C"alkyl)aminosulfonyl group of the present invention is a group in which two identical or different alkyl groups are bonded to other structures through an aminosulfonyl group.
本发明所述" Ci_6烷基酰胺基"、 " _6烷基磺酰基"、 "Cw烷基磺酰胺基"、 The "Ci-6 alkyl amido group", "-6 alkylsulfonyl group", "Cw alkylsulfonylamino group",
"Cw烷基羰 分别为术语" 烷基"通过酰胺基、 磺酰基、 磺酰胺基、 羰 氧基与其他结构相连接的基团。 "Cw alkylcarbonyl is the group "alkyl", respectively, which is attached to the other structure via an amide group, a sulfonyl group, a sulfonylamino group, or a carbonyloxy group.
本发明所述的 "C^环烷基 "是指 3~8个碳原子的烷烃部分去除一个氢原子 衍生的环状烷基， 如环丙基、 环丁基、 1-曱基环丁基、 环戊基、 环己基、 环庚 基、环辛基等。优选（：4_7环烷基、 C4_e环烷基和 C5_6环烷基。术语" C4-7环烷基，，、 "C4_6环烷基"、 "C5_6环烷基 "分别为上述实例中含有 4〜7个、 4~6个、 5~6个碳 原子的具体实例。 The "C^cycloalkyl group" as used in the present invention means an alkane moiety of 3 to 8 carbon atoms which is removed by a hydrogen atom-derived cyclic alkyl group such as a cyclopropyl group, a cyclobutyl group or a 1-fluorenylcyclobutyl group. , cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferred (: 4 _ 7 cycloalkyl, C 4 _e cycloalkyl and C 5 -6 cycloalkyl. The term "C 4-7 cycloalkyl,", "C 4 -6 cycloalkyl", "C 5 _6 ring The alkyl group is a specific example of 4 to 7, 4 to 6, and 5 to 6 carbon atoms in the above examples.
本发明所述的 "C 8环烷氧基"是指术语" 环烷基"通过氧原子与其他结 构相连接的基团， 如环丙氧基、 环丁氧基、 1-曱基环丁氧基、 环戊氧基、 环己 氧基、 环庚氧基、 环辛氧基等。 The "C 8 cycloalkoxy group" as used in the present invention means a group in which the term "cycloalkyl group" is bonded to another structure through an oxygen atom, such as a cyclopropoxy group, a cyclobutoxy group, or a 1-fluorenyl ring. Oxyl, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.
本发明所述的 "C^8环烯基 "是指 5~8个碳原子的烯烃部分去除一个氢原子 衍生的环状烷基， 环戊 -1-烯基、 环戊 -2-烯基、 环戊 -3-烯基、 环己 -1-婦基、 环 己 -2-烯基、 环己 -3-婦基、 环庚小烯基、 环庚 -2-烯基、 环庚 -3-烯基、 环庚 -4- 烯基、 环辛小烯基、 环辛 -2-婦基、 环辛 -3-烯基、 环辛 -4-婦基、 2,4-环戊二烯 基、 1,3-环己二烯基、 1,4-环己二烯基、 2,4-环己二烯基、 2，5-环己二婦基、 1,3- 环庚二烯基、 1,4-环庚二烯基、 2,4-环庚二烯基和 1,5-环辛二烯基等。 所述的 "杂芳基"是指除碳原子外还含有一个或多个杂原子作为环原子的 芳族基团。 所述"杂原子"选自氮原子、 氧原子、 硫原子等。 该"杂芳基 "可以 含有 5-20个环原子且含有一个或多个杂原子 （称为 5-20元杂芳基）， 优选含 有 5-10个环原子且含有一个或多个杂原子（称为 5-10元杂芳基）， 其实例包 括但不仅限于呋喃、 -分、 吡咯、 咪唑、 吡唑、 ***、 噁唑、 异噁唑、 唑、 异噻唑、 噁二唑、 四唑、 噁***、 异吖漆、 吡啶、 哒嗪、 嘧啶、 吡嗪、 三嗪、 苯并呋喃、 异苯并呋喃、 苯并噻吩、 吲哚、 异吲哚、 喹啉、 异喹啉、 苯并二 嗪、 吡啶并吡啶、 吖啶等。 The "C 8 cycloalkenyl group" as used in the present invention means a cyclic alkyl group derived by removing a hydrogen atom from an olefin moiety of 5 to 8 carbon atoms, a cyclopent-1-enyl group, a cyclopent-2-enyl group. , cyclopent-3-enyl, cyclohex-1-yl, cyclohex-2-enyl, cyclohex-3-yl, cycloheptyl, alkenyl, cycloheptan-2-alyl, cycloheptane 3-alkenyl, cyclohept-4-enyl, cyclooctylalkenyl, cyclooctin-2-yl, cyclooct-3-enyl, cyclooct-4-yl, 2,4-cyclopentane Alkenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 2,4-cyclohexadienyl, 2,5-cyclohexanyl, 1,3- Cycloheptadienyl, 1,4-cycloheptadienyl, 2,4-cycloheptadienyl, 1,5-cyclooctadienyl and the like. The "heteroaryl group" means an aromatic group containing one or more hetero atoms as a ring atom in addition to a carbon atom. The "hetero atom" is selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like. The "heteroaryl" may contain 5-20 ring atoms and contain one or more heteroatoms (referred to as 5-20 membered heteroaryl), preferably 5-10 ring atoms and contain one or more heteroatoms (referred to as 5-10 membered heteroaryl), examples of which include, but are not limited to, furan, -, pyrrole, imidazole, pyrazole, triazole, oxazole, isoxazole, oxazole, isothiazole, oxadiazole, tetra Azole, triazole, isophthalide, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, isobenzofuran, benzothiophene, anthracene, isoindole, quinoline, isoquinoline, Benzodiazine, pyridopyridine, acridine and the like.
本发明所述的 "芳基 "是指仅仅以碳原子作为环原子的芳族基团。 所述芳 基可以是单环、 双环或多环芳基， 优选单环芳基。 具体实例包括苯基、 萘基、 蒽基和菲基等， 优选苯基。  The "aryl group" as used in the present invention means an aromatic group having only a carbon atom as a ring atom. The aryl group may be a monocyclic, bicyclic or polycyclic aryl group, preferably a monocyclic aryl group. Specific examples include phenyl, naphthyl, anthryl and phenanthryl, and the like, preferably a phenyl group.
本发明所述" 3-8元杂环基"是指含有一至多个杂原子作为环原子的 3-8元 环状基团， 所述"杂原子"是指氮原子、 氧原子、 硫原子等。 "杂环基"包括饱 和或不饱和的杂环基。 所述"饱和或不饱和的杂环基，，的实例有： 环氧乙烷基、 二氧杂环丙烷基、 υ杂环丙烷基、 氮杂环丙烷基、 2H-氮杂环丙烷基、 二氮杂 环丙烷基、 3H-二氮杂环丙烯基、 氧氮杂环丙烷基、 氧杂环丁烷基、 1,2-二氧杂 环丁烷基、 充杂环丁烷基、 1,2-二硫杂环丁烯基、 氮杂环丁烷基、 1,2-二氮杂环 丁烷基、 氮杂环丁二婦基、 1,2-二氮杂环丁烯基、 呋喃基、 四氢呋喃基、 噻分 基、 2,5-二氢噻分基、 四氢噻 基、 吡咯基、 二氢吡咯基、 吡咯烷基、 1,3-二氧 杂环戊烷基、 1,3-二氧杂环戊烯 -2-酮基、 1,2-二疏杂环戊烯基、 1,3-二硫杂环戊 烷基、 咪唑基、 4，5-二氢咪唑基、 咪唑烷基、 ρ比唑基、 4,5-二氢吡唑基、 吡唑烷 基、 噁唑基、 4,5-二氢噁峻基、 异噁唑基、 4，5-二氢异噁唑基、 2，3-二氢异噁唑 基、 1,2,3-噁二唑基、 1,2,5-噁二唑基、 噻唑基、 4，5-二氢噻唑基、 异噻唾基、 1,2,3-噻二唑基、 1,2,4-噻二唑基、 1,3,4-噻二唾基、 1,2,3-***基、 1,2，4-***基、 四峻基、 2H-吡喃基、 2H-吡喃 -2-酮基、 3,4-二氢 -2H-吡喃基、 4H-吡喃基、 四 氢吡喃基、 4H-吡喃 -4-酮基、 吡啶基、 2-吡啶酮基、 4-吡啶酮基、 哌啶基、 1,4- 二氧杂环己二烯基、 1,4-二硫杂环己二烯基、 1,4-氧硫杂环己二烯基、 1,4-二氧 杂环己烷基、 1，3-二氧杂环己烷基、 1，3-氧硫杂环己烷基、 2H-1,2-噁嗪基、 4 -1,2- 噁嗪基、 6 /-1，2-噁嗪基、 2H-1,3-噁嗪基、 4H-1,3-噁嗪基、 6H-1,3-噁嗪基、 2ff-l,4- 噁嗪基、 4H-1,4-噁嗪基、 5,6-二氢 -4H-1,3-噁嗪基、 吗啉基、 2H-1,3-噻嗪基、 4H-1,3-噻嗪基、5,6-二氢 -4H-1 ,3-噻嗪基、6H-1,3-噻嗪基、2H-1,4-噻嗪基、4H-1,4- 噻咯基、哒嗪基、嘧 、吡嗪基、哌11秦基、 1,2,3-三嗪基、 1,2,4-三嗪基、 1,3,5- 三嗪基、 1,2,4，5-四嗪基、 氧杂环庚三烯基、 A杂环庚三烯基、 1，4-二氧杂环辛 三烯基、氮杂环庚三烯基、 1,2-二氮杂环庚三烯基、 1,3-二氮杂环庚三烯基、 1,4- 二氮杂环庚三烯基、 氮杂环辛四烯基、 1,4-二氢 -1,4-二氮杂环辛三烯基等。 The "3-8 membered heterocyclic group" in the present invention means a 3-8 membered cyclic group having one or more hetero atoms as a ring atom, and the "hetero atom" means a nitrogen atom, an oxygen atom or a sulfur atom. Wait. "Heterocyclyl" includes saturated or unsaturated heterocyclic groups. Examples of the "saturated or unsaturated heterocyclic group," are an oxiranyl group, a dioxanyl group, an anthracene group, an aziridine group, a 2H-azepine group, Diazacyclopropane, 3H-diazapropenyl, oxazepine, oxetanyl, 1,2-dioxetyl, heterocyclobutane, 1 , 2-dithiabutenyl, azetidinyl, 1,2-diazetanyl, azetidinyl, 1,2-diazabutenyl, Furanyl, tetrahydrofuranyl, thiol, 2,5-dihydrothio, tetrahydrothio, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, 1,3-dioxolyl, 1 ,3-dioxol-2-one, 1,2-dicyclopentenyl, 1,3-dithiolanyl, imidazolyl, 4,5-dihydroimidazolyl , imidazolidinyl, ρ-pyrazolyl, 4,5-dihydropyrazolyl, pyrazolidinyl, oxazolyl, 4,5-dihydrocyanyl, isoxazolyl, 4,5-dihydro Isoxazolyl, 2,3-dihydroisoxazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, thiazolyl, 4,5-dihydrothiazide , isothiathiol, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolidin, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrasyl, 2H-pyranyl, 2H-pyran-2-one, 3,4-dihydro-2H-pyranyl, 4H-pyranyl, tetra Hydropyranyl, 4H-pyran-4-one, pyridyl, 2-pyridinone, 4-pyridinone, piperidinyl, 1,4-dioxadienyl, 1,4 -dithiahexadienyl, 1,4-oxethiohexadienyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3 -oxathiane, 2H-1,2-oxazinyl, 4 -1,2-oxazinyl, 6 /-1,2-oxazinyl, 2H-1,3-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 2ff-l,4-oxazinyl, 4H-1,4-oxazinyl, 5,6-dihydro-4H-1 , 3-oxazinyl, morpholinyl, 2H-1,3-thiazinyl, 4H-1,3-thiazinyl, 5,6-dihydro-4H-1, 3-thiazinyl, 6H- 1,3-thiazin-yl, 2H-1,4- thiazine-yl, 4H-1,4- thiazol pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazine 11 Qin yl, 1,2,3- Azinyl, 1,2,4-triazinyl, 1,3,5- Triazinyl, 1,2,4,5-tetrazinyl, oxepanethylene, A heterocycloheptalienyl, 1,4-dioxoldinyl, azacyclo Alkenyl, 1,2-diazaheptatrienyl, 1,3-diazaheptatrienyl, 1,4-diazaheptatrienyl, azacyclotetradecenyl, 1,4-Dihydro-1,4-diazacyclooctanetrienyl and the like.
本发明所述的 "4-7元杂环基"、 "5-7元杂环基"、 "4-6元杂环基，，分别是指 上述实例中 4-7元、 5-7元、 4-6元饱和或不饱和的环状基团的具体实例。  The "4-7 membered heterocyclic group", "5-7 membered heterocyclic group" and "4-6 membered heterocyclic group" as used in the present invention mean 4-7 yuan and 5-7 yuan, respectively, in the above examples. Specific examples of a 4-6 membered saturated or unsaturated cyclic group.
本发明所迷" 5-10 元稠环基"是指一类由两个或两个以上环状结构彼此 共用两个相邻的原子连接起来形成的含有 5-10 个环原子的稠环结构， 包括 "5-10元饱和并环"及" 5-10元不饱和并环"， 如双环 [3.1.0]己烷、 双环 [4.1.0]庚 烷、双环 [3.2.0]庚烷、双环 [4.2.0]辛烷、八氢癸五烯、双环 [3.3.0]辛二烯、 1,2,3,4- 四氢癸五烯、 八氢 茚、 十氢萘、 苯并呋喃基、 异苯并呋喃基、 二苯并呋 喃基、 苯并 [b]噻分基、 苯并 [c]噻吩基、 吲哚基、 异吲哚基、 苯并噁唑基、 苯 并噻唑基、 苯并咪唑基、 吲唑基、 苯并***基、 2H-色原烯基、 2H-色原烯 -2- 酮基、 4H-色烯基、 4H-色烯 -4-酮基、 色满基、 喹啉基、 异喹啉基、 2-喹啉酮 基、 4-喹啉酮基、 1-异喹啉酮基、 4H-1,3-苯并噁嗪基、 酞嗪基、 噌啉基、 2,3- 二氮杂萘、 喹唑啉基、 3,4-二氢喹唑啉基、 嘌呤基、 1,8-萘啶基、 1,7-萘啶基、 1,6-萘啶基、 1,5-萘啶基、 2,7-萘啶基、 2,6-萘啶基、 蝶啶基、 喹喔啉基、 1,2- 二氢喹喔啉基、 吟嗪基、 四氢咪唑并 [4,5-c]吡啶基、 3-氧代 -1,3-二氢异苯并呋 喃基、 4,6-二氢 呋喃并 咪唑基、 3α,4,6,6α-四氢 呋喃并 [3,4-ί ]咪 峻基、 4,6-二氢 噻吩并 [3,4- 咪唑基、 4,6-二氢 吡咯并 [3 ,4- 咪唑基、 4,5,6,7-四氢 -1H-苯并 [ 咪唑基、 1H-吡唑并 [3,4-b]吡^^等。  The "5-10 membered fused ring group" as used in the present invention refers to a fused ring structure having 5 to 10 ring atoms formed by two or more ring structures sharing two adjacent atoms with each other. , including "5-10 yuan saturated and ring" and "5-10 yuan unsaturated ring", such as bicyclo [3.1.0] hexane, bicyclo [4.1.0] heptane, bicyclo [3.2.0] heptane Bicyclo[4.2.0]octane, octahydropentapentene, bicyclo[3.3.0]octadiene, 1,2,3,4-tetrahydropentacene, octahydroquinone, decahydronaphthalene, benzo Furanyl, isobenzofuranyl, dibenzofuranyl, benzo[b]thiophene, benzo[c]thienyl, fluorenyl, isodecyl, benzoxazolyl, benzothiazole Base, benzimidazolyl, oxazolyl, benzotriazolyl, 2H-chromogenyl, alkenyl 2H-chromogen-2-one, 4H-chromenyl, 4H-chromen-4-one , chromanyl, quinolyl, isoquinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, 4H-1,3-benzoxazinyl, pyridazine , porphyrin, 2,3-naphthyridine, quinazolinyl, 3,4-dihydroquinazolinyl, fluorenyl, 1,8-naphthyridinyl, 1,7 -naphthyridinyl, 1,6-naphthyridinyl, 1,5-naphthyridinyl, 2,7-naphthyridinyl, 2,6-naphthyridinyl, pteridinyl, quinoxalinyl, 1,2- Dihydroquinoxalinyl, pyridazinyl, tetrahydroimidazo[4,5-c]pyridinyl, 3-oxo-1,3-dihydroisobenzofuranyl, 4,6-dihydrofuran Imidazolyl, 3α,4,6,6α-tetrahydrofuro[3,4-ί]mithiol, 4,6-dihydrothieno[3,4-imidazolyl, 4,6-dihydropyrrolo[3 , 4-imidazolyl, 4,5,6,7-tetrahydro-1H-benzo[imidazolyl, 1H-pyrazolo[3,4-b]pyrazine, and the like.
本发明所述" 5-12 元螺环基"是指一类至少有两个环共享一个原子形成 的含有 5-12个环原子的环结构。 包括" 5〜12元饱和螺环"及" 5〜： 12元不饱和螺 环"。 如螺 [2.4]庚烷、 螺 [2.5]辛烷、 螺 [3.4]辛烷、 螺 [3.5]壬烷、 螺 [4.4]壬烷、 螺 [4.4]壬 -2-烯、 螺 [4.5]癸烷等。  The "5-12 membered spirocyclic group" as used in the present invention means a ring structure having 5 to 12 ring atoms formed by a class of at least two rings sharing one atom. Including "5 to 12 yuan saturated screw ring" and "5 to: 12 yuan unsaturated screw ring". Such as spiro[2.4]heptane, spiro[2.5]octane, spiro[3.4]octane, spiro[3.5]decane, spiro[4.4]decane, spiro[4.4]non-2-ene, spiro[4.5] Decane and so on.
本发明所述" 6-10 元桥环基"是指任意两个环共用两不直接相连的原子 形成的含有 6-10个环原子的环结构。 包括" 6-10元饱和桥环"及" 6-10元不饱 和桥环"。 如双环 [2.1.1]己烷、 双环 [2.2.1]庚烷、 双环 [3.2.0]庚烷、 双环 [2.2.2] 辛烷、 双环 [3.2.1]辛烷、 双环 [3.3.0]辛烷、 双环 [3.3.1]壬烷、 双环 (4.3.0)壬烷、 4-氮杂双环 [5.3.0]癸烷、 双环 [2.2.1]庚 -5-烯、 双环 [3.2.1]辛 -6-烯、 双环 (4.3.0) 壬 -5-烯、 双环戊二烯等。  The "6-10 membered bridged ring group" as used in the present invention means a ring structure having 6 to 10 ring atoms formed by any two rings sharing two atoms which are not directly connected. Including "6-10 yuan saturated bridge ring" and "6-10 yuan unsaturated bridge ring". Such as bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [3.2.0] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.1] octane, bicyclo [3.3. 0] octane, bicyclo[3.3.1]decane, bicyclo (4.3.0) decane, 4-azabicyclo[5.3.0]nonane, bicyclo[2.2.1]hept-5-ene, bicyclo [ 3.2.1] Oct-6-ene, bicyclo (4.3.0) 壬-5-ene, dicyclopentadiene, and the like.
本发明上述化合物可以采用下述流程中描述的方法和 /或本领域普通技 术人员已知的其它技术来合成， 但不仅限于以下方法。  The above compounds of the present invention can be synthesized by the methods described in the following schemes and/or other techniques known to those of ordinary skill in the art, but are not limited to the following methods.
反应方程式：
Figure imgf000021_0001
反应步骤： Reaction equation:
Figure imgf000021_0001
Reaction steps:
步骤 1 中间体 1的制备  Step 1 Preparation of intermediate 1
干燥的反应瓶中，将乙醇钠 （2当量)加入曱苯中，加入原料 1 (约 1当量)， 再加原料 2 (约 1-3当量)， 加毕， 加热 80。C-110。C， 氮气保护下避光反应过 夜。 后处理将反应体系倒入冰水中， 加冰乙酸中和， 萃取， 干燥有机相， 旋 干， 柱层析， 得中间体 1。  In a dry reaction flask, sodium ethoxide (2 equivalents) is added to the benzene, and the raw material 1 (about 1 equivalent) is added, and the raw material 2 (about 1-3 equivalents) is added, and the mixture is heated and heated. C-110. C, protected from light overnight under nitrogen protection. Post-treatment The reaction system is poured into ice water, neutralized with glacial acetic acid, extracted, and the organic phase is dried, dried, and subjected to column chromatography to give Intermediate 1.
步骤 2 中间体 2的制备  Step 2 Preparation of intermediate 2
在干燥单口瓶中，加入 POCl3， 0。C下加中间体 1 ,加毕升温至 90。C-115 。C反应， TLC监测反应完毕， 旋去 POCl3， 加少量曱苯再次旋干， 剩余物倒 入;水水中， 乙酸乙酯萃取得到粗品， 柱层析， 得中间体 2。 In a dry single-mouth bottle, POCl 3 , 0 was added. Intermediate 1 was added under C, and the temperature was raised to 90. C-115. C reaction, TLC monitoring reaction is completed, POCl 3 is vortexed, a small amount of benzene is added and the residue is poured again, and the residue is poured into water; ethyl acetate is extracted in water to obtain a crude product, and column chromatography is carried out to obtain intermediate 2.
步骤 3 式（ l a )化合物的制备  Step 3 Preparation of the compound of formula (la)
将中间体 2 (约 1当量)溶于大极性非质子性溶剂 （例如 NJV-二曱基乙酰 胺）， 原料 3 (约 1-3当量)， 最后加入约 3-5当量叔胺 (包括不限于二异丙基 乙基胺）， 加毕室温反应半小时， 在升温 90。C-120。C反应过夜。 后处理体系 冷却后倒入水中， 萃取， 干燥有机相， 旋干。 柱层析得到式（ l b )化合物。  Intermediate 2 (about 1 equivalent) is dissolved in a macropolar aprotic solvent (eg NJV-dimercaptoacetamide), starting material 3 (about 1-3 equivalents), and finally about 3-5 equivalents of tertiary amine (including Not limited to diisopropylethylamine), the reaction was carried out at room temperature for half an hour, and the temperature was raised by 90. C-120. C reacted overnight. After-treatment system, after cooling, pour into water, extract, dry the organic phase, and spin dry. Column chromatography gave the compound of formula (lb).
反应方程式中， Cy】、 Cy2、 L、 X、 Rla、 Rlb、 R2a、 R2b、 R3a、 R3b、 R4、 R5和 n如前文对于式 (la)所定义。 In the reaction equation, Cy], Cy 2 , L, X, R la , R lb , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 and n are as defined above for the formula (la).
本发明的含有上述通式 (la)或 (lb)化合物、 其药学上可接受的盐或其异构 体的药物制剂， 包括一种或多种药用载体。  The pharmaceutical preparation of the present invention containing the compound of the above formula (la) or (lb), a pharmaceutically acceptable salt thereof or an isomer thereof, includes one or more pharmaceutically acceptable carriers.
本文所用术语 "药用载体"是指无毒、 惰性的固体、 半固体或液体的填充 剂、 稀释剂、 包嚢材料或任何类型的制剂用助剂。 可用作药用载体的物质的 一些实例是糖类， 但不限于乳糖、 葡萄糖和蔗糖； 淀粉， 例如但不限于玉米 淀粉和马铃薯淀粉； 纤维素及其衍生物， 例如但不限于如羧曱基纤维素钠、 乙基纤维素和乙酸纤维素； 粉末化西黄蓍胶； 麦芽； 明胶； 滑石； 可可油和 栓剂蜡； 油， 例如但不限于如花生油、 棉子油、 红花油、 芝麻油、 橄榄油、 玉米油和大豆油； 二醇类如丙二醇； 酯， 例如但不限于如油酸乙酯和月桂酸 乙酯； 琼脂； 緩沖剂， 例如但不限于如氢氧化镁和氢氧化铝； 海藻酸； 无热 原水、 等渗生理盐水； 林格氏溶液； 乙醇和磷酸盐緩冲液， 根据配制者的判 断， 其它无毒的相容润滑物， 例如但不限于如月桂基硫酸钠和硬脂酸镁以及 着色剂、 释放剂、 包衣剂、 甜味剂、 芳香剂和香料、 防腐剂和抗氧化剂也可 存在于所述药物制剂中。 The term "pharmaceutically acceptable carrier" as used herein means a non-toxic, inert solid, semi-solid or liquid filler, diluent, coating material or any type of formulation auxiliary. Some examples of materials useful as pharmaceutically acceptable carriers are sugars, but are not limited to lactose, glucose, and sucrose; starches such as, but not limited to, corn Starch and potato starch; cellulose and its derivatives, such as but not limited to, for example, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository Wax; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as, but not limited to, ethyl oleate and lauric acid Ethyl ester; agar; buffer such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water, isotonic saline; Ringer's solution; ethanol and phosphate buffer, according to the formulator Judging, other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, fragrances and fragrances, preservatives and antioxidants It may also be present in the pharmaceutical preparation.
本发明化合物用本领域已知的方式配制成任一药物制剂， 以口服、 肠胃 外、 直肠或经肺给药等方式施用于需要这种治疗的患者。 用于口服给药时， 可制成常规的固体制剂， 如片剂、 胶嚢剂、 丸剂、 颗粒剂等； 也可制成口服 液体制剂， 如口服溶液剂、 口服混悬剂、 糖浆剂等。 制成口服制剂时， 可以 加入适宜的填充剂、 粘合剂、 崩解剂、 润滑剂等。 用于肠胃外给药时， 可制 成注射剂， 包括注射液、 注射用无菌粉末与注射用浓溶液。 制成注射剂时， 可釆用现有制药领域中的常规方法生产， 配制注射剂时， 可以不加入附加剂， 也可根据药物的性质加入适宜的附加剂。 用于直肠给药时， 可制成栓剂等。 用于经肺给药时， 可制成吸入剂或喷雾剂等。  The compounds of the present invention are formulated into any pharmaceutical preparation in a manner known in the art for administration to a patient in need of such treatment by oral, parenteral, rectal or pulmonary administration. For oral administration, it can be prepared into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; or can be prepared into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. . When the oral preparation is prepared, a suitable filler, a binder, a disintegrator, a lubricant or the like may be added. For parenteral administration, injections can be prepared, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When the injection is prepared, it can be produced by a conventional method in the prior art, and when the injection is formulated, an additional agent may be added, or a suitable additive may be added depending on the nature of the drug. When used for rectal administration, it can be made into a suppository or the like. When used for pulmonary administration, it can be made into an inhalant or a spray.
本发明还提供了本发明化合物、 其药学上可接受的盐或其异构体的在制 备治疗和 /或预防肾损伤、 心血管疾病 (如高血压)和 /或内分泌疾病的药物中的 应用。  The invention also provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof or an isomer thereof for the preparation of a medicament for the treatment and/or prevention of kidney damage, cardiovascular diseases (such as hypertension) and/or endocrine diseases .
同时， 本发明还提供了通式 (la)或 (lb)所示化合物药学上可接受的盐， 是 指式 (la)或 (lb)所示化合物与酸或碱混合制成的盐。  Meanwhile, the present invention also provides a pharmaceutically acceptable salt of the compound of the formula (1) or (lb), which is a salt of a compound of the formula (la) or (lb) which is mixed with an acid or a base.
适宜的酸加成盐是由形成无毒盐的酸形成。 具有代表性的酸加成盐包括 但不限于乙酸盐、 己二酸盐、 藻酸盐、 柠檬酸盐、 天冬氨酸盐、 苯曱酸盐、 苯磺酸盐、 硫酸氢盐、 碳酸氢盐、 丁酸盐、 樟脑酸盐、 樟脑磺酸盐、 碳酸盐、 柠檬酸盐、二葡糖酸盐 (digluconate)、甘油磷酸盐、 半硫酸盐 (hemisulfate)、 庚 酸盐、 己酸盐、 甲酸盐、 富马酸盐、 葡萄糖酸盐、 葡萄糖醛酸盐、 谷羲酸盐、 盐酸盐、 氢溴酸盐、 氢碘酸盐、 2-羟基乙磺酸盐 (isethionate)、 乳酸盐、 马来 酸盐、苹果酸盐、丙二酸盐、曱磺酸盐、烟酸盐、2-萘磺酸盐、烟酸盐 (nicotinate)、 硝酸盐、 乳清酸盐、 草酸盐、 棕榈酸盐、 朴酸盐、 果胶酸盐 (pectinate)、 过硫 酸盐、 3-苯基丙酸盐、 苦味酸盐 (picrate)、 三甲基乙酸盐 (pivalate)、 丙酸盐、 蔗糖盐、 硬脂酸盐、 琥珀酸盐、 硫酸盐、 酒石酸盐、 硫氰酸盐、 磷酸盐、 磷 酸氢盐、 磷酸二氢盐、 对甲苯磺酸盐、 三氟乙酸盐及十一酸盐。 Suitable acid addition salts are formed from acids which form non-toxic salts. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, carbonic acid Hydrogen salt, butyrate, camphorate, camphor sulfonate, carbonate, citrate, digluconate, glycerol phosphate, hemisulfate, heptanoate, caproic acid Salt, formate, fumarate, gluconate, glucuronate, glutenate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), Lactate, maleate, malate, malonate, sulfonate, nicotinate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, grass Acid salt, palmitate, palm acid salt, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionic acid Salt, sucrose salt, stearate, succinate, sulfate, tartrate, thiocyanate, phosphate, phosphorus Acid hydrogen salt, dihydrogen phosphate, p-toluenesulfonate, trifluoroacetate and eleven acid salt.
碱加成盐可在化合物的最后分离和纯化过程中， 通过使含有羧酸的部分 与适当的碱 (如但不限于药用可接受的金属阳离子的氢氧化物、碳酸盐或碳酸 氢盐)或者与氨或有机伯胺、 仲胺或叔胺反应原位制备。 药用可接受的盐包括 但不限于基于碱金属或碱土金属的阳离子， 如但不限于锂、 钠、 钾、 钙、 镁 和铝盐等， 以及非毒性季氨和胺阳离子， 包括铵、 四甲基铵、 四乙基铵、 曱 胺、 二曱胺、 三甲胺、 三乙胺、 二乙胺、 乙胺等。 其它可用于形成碱加成盐 的代表性有机胺包括乙二胺、 乙醇胺、 二乙醇胺、 哝啶、 哌嗪等。  The base addition salt can be used during the final isolation and purification of the compound by passing the carboxylic acid containing moiety with a suitable base such as, but not limited to, a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation. Or prepared in situ by reaction with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal based cations such as, but not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and non-toxic quaternary ammonium and amine cations, including ammonium, tetra Methylammonium, tetraethylammonium, decylamine, diamine, trimethylamine, triethylamine, diethylamine, ethylamine, and the like. Other representative organic amines which can be used to form base addition salts include ethylenediamine, ethanolamine, diethanolamine, acridine, piperazine and the like.
Figure imgf000023_0001
Figure imgf000023_0001
Cy2、 L、 X、 Rla、 Rlb、 R3a、 R3b、 R4、 R5和 n如前文对式 ( la )所定义的。Cy 2 , L, X, R la , R lb , R 3a , R 3b , R 4 , R 5 and n are as defined above for the formula ( la ).
)所示的化合物或其药学上可接受的盐，  a compound or a pharmaceutically acceptable salt thereof,
Figure imgf000023_0002
Figure imgf000023_0002
其中， Cy Cy2、 L、 X、 R1, R2a、 R2b、 R3a、 R4、 R5和 m如前文对式（ lb ) 所定义的。 Wherein Cy Cy 2 , L, X, R 1 , R 2a , R 2b , R 3a , R 4 , R 5 and m are as defined above for formula ( lb ).
本发明的二氢吡唑类化合物有两个或者更多个手性中心。 合成得到的是 消旋体， 所需要的对映体純的化合物可以通过手性拆分的方法得到： 可以通 过具有手性固定相的色谱法（像高压制备液相、 超临界流体色 ）。 手性填料 包括但不限于： Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H。 对映体纯的二氢吡唑类化合物可以像消旋的二氢吡唑类化合物一样进一步衍 生化。  The dihydropyrazole compounds of the present invention have two or more chiral centers. The racemic is obtained by the synthesis, and the desired enantiomerically pure compound can be obtained by chiral resolution: chromatography can be carried out by a chiral stationary phase (such as high pressure liquid phase, supercritical fluid color). Chiral fillers include, but are not limited to: Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H. The enantiomerically pure dihydropyrazole compound can be further derivatized like a racemic dihydropyrazole compound.
本发明还提供了含有本发明化合物、 其药学上可接受的盐或其异构体在 制备治疗和 /或预防腎损伤、 心血管疾病（包括高血压、 心力衰竭、 心肌梗塞、 心绞痛、 心脏肥大、 心肌炎、 心脏血管纤维化、 压力感受器官能障碍、 过多 的体液和心律不齐)， 和 /或内分泌疾病 （包括原发 /继发性醛甾酮增多症、 阿 狄森氏病、 库兴氏综合症和巴特式综合症） 的药物中的应用。 本发明还提供了一种药物组合物， 其包含本发明化合物、 其药学上可接 受的盐或其异构体和一种或多种其它治疗活性物质， 所述其它治疗活性物质 选自血管紧张素 Π拮抗剂或其药学上可接受的盐； HMG-Co-A还原酶抑制剂 或其药学上可接受的盐； 钙通道阻滞剂 （CCB )或其药学上可接受的盐； 血 管紧张素转化醉 /中性内肽酶（ ACE/NEP )双重抑制剂或其药学上可接受的盐； 抗糖尿病药；减肥药；醛固酮受体阻滞剂； 内皮素受体阻滞剂； CETP抑制剂； Na-K-ATP酶膜泵抑制剂； P -肾上腺素能受体抑制剂或 α -肾上腺素能受体阻 断剂； 中性内肽酶（ΝΕΡ )抑制剂和变力剂。 The present invention also provides a compound containing the same, a pharmaceutically acceptable salt thereof or an isomer thereof for the preparation and treatment of and/or prevention of kidney damage, cardiovascular diseases (including hypertension, heart failure, myocardial infarction, angina pectoris, cardiac hypertrophy) , myocarditis, cardiac vascular fibrosis, baroreceptor dysfunction, excessive body fluids and arrhythmias), and/or endocrine diseases (including primary/secondary aldosteronism, Addison's disease, Cushing) The application of drugs in the syndrome and Barth Syndrome. The invention also provides a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable salt thereof or an isomer thereof, and one or more other therapeutically active substances, the other therapeutically active substance being selected from the group consisting of vascular stress a ruthenium antagonist or a pharmaceutically acceptable salt thereof; an HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof; a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof; Dual inhibitor of intoxicating/neutral endopeptidase (ACE/NEP) or a pharmaceutically acceptable salt thereof; antidiabetic agent; diet pills; aldosterone receptor blocker; endothelin receptor blocker; CETP inhibition Na-K-ATPase membrane pump inhibitor; P-adrenergic receptor inhibitor or alpha-adrenergic receptor blocker; neutral endopeptidase (ΝΕΡ) inhibitor and inotropic agent.
本发明化合物与最接近的现有技术相比， 具有以下优点：  The compounds of the invention have the following advantages over the closest prior art:
( 1 )本发明化合物具有优良的降低醛固酮活性， 对用于治疗和 /或预防 各种哺乳动物（包括人类） 肾损伤和 /或高血压有优良效果；  (1) The compound of the present invention has excellent activity for lowering aldosterone and has an excellent effect for treating and/or preventing kidney damage and/or hypertension in various mammals including humans;
( 2 )本发明化合物毒性和副作用较低；  (2) the compounds of the invention have low toxicity and side effects;
( 3 )本发明化合物制备工艺简单， 理化性质好， 盾量稳定， 易于进行大 莫工业生产。  (3) The compound of the invention has simple preparation process, good physical and chemical properties, stable shield capacity, and is easy to be industrially produced.
以下通过体外药理实验进一步阐述本发明化合物有益效果， 但不应将此 理解为本发明化合物仅具有下列有益效果。  The beneficial effects of the compounds of the present invention are further illustrated by in vitro pharmacological experiments, but it should not be construed that the compounds of the present invention have only the following beneficial effects.
实验例 本发明化合物的体外药理活性  Experimental Example In vitro pharmacological activity of the compounds of the present invention
供试品： 本发明部分化合物 1、 2、 3和 4， 自制， 其化学名称、 结构式 及制备方法如实施例所述。  Test sample: Part of the compounds 1, 2, 3 and 4 of the present invention, self-made, the chemical name, structural formula and preparation method are as described in the examples.
式 V化合物 (消旋体)， 自制， 其结构式如前文所述。  The compound of formula V (racemate), self-made, has the structural formula as described above.
核受体试验 ( Nuclear receptor assay )  Nuclear receptor assay
实验方法：  experimental method:
准确称取供试品化合物 1、 2、 3、 4和式 V化合物， 加入 DMSO (二甲基亚 砜）溶解，充分混匀， 配成 1000 μΜ。然后用 DMSO将上述母液逐级稀释至 200 μΜ、 40 μΜ、 8 μΜ、 1.6 μΜ、 0.3 μΜ、 0·06μΜ、 0.01 μΜ、 0 μΜ。  Accurately weigh the test compound 1, 2, 3, 4 and the compound of formula V, add DMSO (dimethyl sulfoxide) to dissolve, mix well, and prepare 1000 μΜ. The above mother liquor was then diluted with DMSO to 200 μΜ, 40 μΜ, 8 μΜ, 1.6 μΜ, 0.3 μΜ, 0·06 μΜ, 0.01 μΜ, 0 μΜ.
双荧光素酶检测：取 1 pBind-NR (100 ng^L)、 1 μΐ pG51uc (100 ng^L)、 2.5 D EM和 0.5 L Fugene混匀， 室温下孵育 15分钟， 制备成转染液。 按 照 3xl05 cells/mL制备细胞混悬液， 每孔加 100 μί, 与上述转染液混匀。 于 37 。C、 5%C02培养箱中孵育 24小时。 Dual luciferase assay: 1 pBind-NR (100 ng^L), 1 μΐ pG51uc (100 ng^L), 2.5 D EM and 0.5 L Fugene were mixed and incubated for 15 minutes at room temperature to prepare a transfection solution. Prepare a cell suspension at 3xl0 5 cells/mL, add 100 μί per well, and mix well with the above transfection solution. At 37. C. Incubate for 24 hours in a 5% CO 2 incubator.
取 1 上述各浓度供试品加入各培养孔中， 30分钟后加入 1 激动剂（溶 于 10%DMSO的 Aldosterone ), 于 37 °C、 5%C02培养箱中孵育 24小时。 1 test mixture of each of the above concentrations was added to each well, and after 30 minutes, 1 agonist (Aldosterone in 10% DMSO) was added, and incubated at 37 ° C in a 5% CO 2 incubator for 24 hours.
萤火虫海腎荧光素 言号通路通过双荧光素醉报告基因测试***测定。 此试验测量待测化合物（供试品）的盐皮质激素受体 IC5G值 (即阻断盐皮 质激素受体激动剂所诱导的活化 50%所需要的待测化合物的浓度， 相对于拮 抗剂不存在下的活化)。 The firefly sea kidney fluorescein pathway was determined by a dual fluorescein intoxication reporter assay system. This test measures the mineralocorticoid receptor IC 5G value of the test compound (test sample) (ie, blocks the salt skin) The concentration of the test compound required for 50% activation induced by the hormone receptor agonist is relative to the activation in the absence of the antagonist).
上述实验是委托上海睿智化学研究有限公司进行的。  The above experiment was commissioned by Shanghai Ruizhi Chemical Research Co., Ltd.
实验结果和结论：  Experimental results and conclusions:
表 1 本发明化合物对盐皮盾激素受体（MR )的拮抗作用  Table 1 Antagonistic effects of the compounds of the present invention on the salt-skin shield hormone receptor (MR)
样品 IC50(nM) Sample IC 50 (nM)
化合物 1 23.9  Compound 1 23.9
化合物 2 3.98  Compound 2 3.98
化合物 3 38.2  Compound 3 38.2
化合物 4 21.5  Compound 4 21.5
化合物 10 19.4  Compound 10 19.4
式 V化合物 45  Formula V compound 45
由表 1可见， 本发明化合物 1、 化合物 2、 化合物 3和化合物 4对盐皮质激素 受体均具有较好的拮抗作用， 好于阳性对照药 （式 V化合物） ； 且化合物 2 对盐皮质激素受体的拮抗作用最好。 以下通过实施例形式的具体实施方式， 对本发明的上述内容作进一步的 详细说明。 但不应将此理解为本发明上述主题的范围仅限于以下实施例。  As can be seen from Table 1, the compound 1, the compound 2, the compound 3 and the compound 4 of the present invention have a good antagonistic effect on the mineralocorticoid receptor, which is better than the positive control drug (the compound of the formula V); and the compound 2 is a mineralocorticoid. Receptor antagonism is best. The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples.
在实施例中， 所使用的原料化合物是市售可得的， 获自上海景颜化工； 上海泰坦化学； 上海达瑞，； 北京偶合科技有限公司； 郑州泰基鸿诺药物科技 有限公司； 四川广瀚生物； 韶远（上海）化学科技； 阿法埃莎（中国）， 上海 TCI, 北京百灵威； 上海毕得医药等公司。  In the examples, the raw material compounds used are commercially available, obtained from Shanghai Haiyan Yan Chemical; Shanghai Titan Chemical; Shanghai Darui, Beijing coupling technology Co., Ltd.; Zhengzhou Taiji Hongnuo Pharmaceutical Technology Co., Ltd.; Sichuan Guang瀚Bio; 韶远 (Shanghai) Chemical Technology; Alfa Aesar (China), Shanghai TCI, Beijing 百灵威; Shanghai Bi De Pharmaceutical and other companies.
缩写含义：  Abbreviation meaning:
POCI3 碑跣三氯 ( phosphoryl trichloride )  POCI3 inferior phosphoryl trichloride
DIEA 二异丙基乙胺  DIEA diisopropylethylamine
Boc 叔丁氧痰基  Boc tert-butoxycarbonyl
Boc20 二碳酸二叔丁酯 Boc 2 0 di-tert-butyl dicarbonate
HATU 2-(7-偶氮苯并三氮唑) - WW-四甲基脲六氟磷酸酯  HATU 2-(7-azobenzotriazole) - WW-tetramethylurea hexafluorophosphate
DMF N、N-二甲基甲酰胺  DMF N, N-dimethylformamide
TFA 三氟乙酸  TFA trifluoroacetic acid
DMA Ν,Ν-二甲基乙酰胺  DMA Ν, Ν-dimethylacetamide
实施例 1 2-氯 -4-Γ5-环戊基 -3-Γ4- -羟基哌啶 -1-羰基)哌嗪 -1-基 4,5-二氢 吡唑小基 1苯甲腈（化合物 1 ) 的制备 Example 1 2-Chloro-4-indolyl 5-cyclopentyl-3-indole-4-hydroxylidine-1-carbonyl) piperazin-1-yl 4,5-dihydropyrazole small 1 benzonitrile (compound) Preparation of 1)
Figure imgf000026_0001
Figure imgf000026_0001
( )-3-环戊基丙烯酸乙酯的制备  Preparation of ( )-3-ethyl cyclopentyl acrylate
室温下， 将环戊基曱醛 4.91 g (50 mmol)溶于 200 mL二氯甲烷中， 分批 加入乙氧曱酰基亚曱基三苯基膦 26.13 g (75 mmol), 室温反应过夜。 减压旋 去溶剂， 加入少量粗硅胶， 旋干， 柱层析（石油醚:乙酸乙酯 =15:1 )得无色油 状物 7.38 g， 收率： 87.7%。4.91 g (50 mmol) of cyclopentylfurfural was dissolved in 200 mL of dichloromethane at room temperature, and 26.13 g (75 mmol) of ethoxydecanodecyltriphenylphosphine was added portionwise and allowed to react at room temperature overnight. The solvent was evaporated under reduced pressure. EtOAc (EtOAc m.).
(5-环戊基 -3-氧代吡唑啉 -1-基)苯曱腈的制备  Preparation of (5-cyclopentyl-3-oxopyrazolin-1-yl)benzonitrile
Figure imgf000026_0002
Figure imgf000026_0002
在干燥的 500 mL单口瓶中加入无水乙醇 100 mL, 将金属钠 1.15 g (50.0 mmol)分批加入， 钠全溶后加入甲苯 100 mL, 再加入 2-氯 -4-肼基笨曱腈盐酸 盐 5 g (24.50 mmol), 再加 (£)-3-环戊基丙烯酸乙酯 4.65 g (27.8 mmol), 加毕， 氮气保护下避光反应过夜。 后处理将反应体系倒入水水中， 加冰乙酸中和至 pH=7, 乙酸乙酯萃取两遍， 无水 Na2S04干燥， 旋干得粗品 3.0 g。 粗品柱层 析略微纯化， 得到粗品 2.6 g。Add 100 mL of absolute ethanol to a dry 500 mL single-mouth bottle, add 1.75 g (50.0 mmol) of sodium metal in portions, add 100 mL of toluene after total sodium dissolution, and add 2-chloro-4-indolyl albino nitrile. 5 g of hydrochloride (24.50 mmol), followed by (£)-ethyl 4-cyclopentyl acrylate 4.65 g (27.8 mmol), and the reaction was allowed to stand overnight under nitrogen. After the reaction, the reaction system was poured into water, neutralized with glacial acetic acid to pH = 7, extracted twice with ethyl acetate, dried over anhydrous Na 2 SO 4 and then evaporated to dryness. The crude column chromatography was slightly purified to give 2.6 g of crude material.
3-氯 -5-环戊基 -4,5-二氢 -1H-吡唑小基)苯甲腈的制备  Preparation of 3-chloro-5-cyclopentyl-4,5-dihydro-1H-pyrazole small)benzonitrile
Figure imgf000026_0003
Figure imgf000026_0003
在 50ml干燥单口瓶中，加入 P0C13 26 mL, 0。C下加 2-氯 -4-(5-环戊基 -3- 氧代吡唑啉 -1-基)苯甲腈粗品 2.6 g,加毕升温至 90。C反应 3小时， TLC监测 反应完毕， 旋去 P0C13， 加少量曱苯再次旋干， 剩余物倒入 50 mL的冰水中， 乙酸乙酯萃取得到粗品 3.12 g, 柱层析得到浅黄色固体 1.88 g。 2-氯 -4-[5-环戊基 -3-[4-(4-羟基哌啶小羰基)哌嗪小基] -4,5-二氢 -1H- 吡 -1-基]苯甲腈的制备 In a 50 ml dry single-mouth bottle, P0C1 3 26 mL, 0 was added. 2.6 g of crude 2-chloro-4-(5-cyclopentyl-3-oxopyrazolin-1-yl)benzonitrile was added under C, and the temperature was raised to 90. After reacting for 3 hours, the reaction was completed by TLC. P0C1 3 was spun off, and a small amount of hydrazine was added to dryness again. The residue was poured into 50 mL of ice water and extracted with ethyl acetate to give a crude product 3.12 g. g. 2-Chloro-4-[5-cyclopentyl-3-[4-(4-hydroxypiperidines small carbonyl) piperazine small group] -4,5-dihydro-1H-pyrid-1-yl]benzene Preparation of nitrile
Figure imgf000027_0001
Figure imgf000027_0001
在 50 mL单口瓶中加入 NN-二甲基乙酰胺 12.5 mL, 2-氯 -4-(3-氯 -5-环戊 基 -4,5-二氢 吡唑 -1-基)苯甲腈 625 mg (2.03 mmol), 4-(4-羟基哌啶 -1-基羰 基)哌 盐酸盐 660 mg (2.64 mmol), 最后加 DIEA 1.05 mL (6.10 mmol), 加毕 室温反应 0.5小时， 在升温 100。( 反应过夜。 后处理体系冷却后倒入水中， 乙酸乙酯萃取两遍，水洗，无水 Na2S04干燥，旋干。柱层析得到纯品 180 mg, 收率 18.3%。 Add NN-dimethylacetamide 12.5 mL, 2-chloro-4-(3-chloro-5-cyclopentyl-4,5-dihydropyrazol-1-yl)benzonitrile to a 50 mL vial 625 mg (2.03 mmol), 4-(4-hydroxypiperidin-1-ylcarbonyl)piperidine hydrochloride 660 mg (2.64 mmol), and finally DIEA 1.05 mL (6.10 mmol). Increase the temperature by 100. (Reaction overnight. The post-treatment system was cooled, poured into water, extracted with ethyl acetate twice, washed with water, dried over anhydrous Na 2 SO 4 and then evaporated to dryness.
分子式： C25H33C1N602 理论分子量： 485.02 质谱（M+H )实测分 子量： 485 Molecular formula: C 25 H 33 C1N 6 0 2 theoretical molecular weight: 485.02 mass spectrometry (M+H) measured molecular weight: 485
1H- MR(i¾-DMSO, 400 MHz): δ 7.47 (IH, d), 6.93 (IH, d), 6.74 (IH, dd), 4.78-4.65 (IH, br s), 4.63-4.50 (IH, m), 3.67-3.57 (1H， m)， 3.50-3.42 (2H, m), 3.45-3.25 (2H, br s), 3.22-3.10 (5H, m), 2.93-2.75 (3H， m), 2.38-2.25 (IH, m), 1.77-1.65 (3H, m), 1.65-1.02 (10H, m).  1H-MR (i3⁄4-DMSO, 400 MHz): δ 7.47 (IH, d), 6.93 (IH, d), 6.74 (IH, dd), 4.78-4.65 (IH, br s), 4.63-4.50 (IH, m), 3.67-3.57 (1H, m), 3.50-3.42 (2H, m), 3.45-3.25 (2H, br s), 3.22-3.10 (5H, m), 2.93-2.75 (3H, m), 2.38 -2.25 (IH, m), 1.77-1.65 (3H, m), 1.65-1.02 (10H, m).
实施例 2 2-氯 -4-「5-环戊基 -3-『3-(4-羟基哌啶小羰基)吖丁啶 -1-基 1-4,5-二 氢  Example 2 2-Chloro-4-"5-cyclopentyl-3-"3-(4-hydroxypiperidines small carbonyl)azetidin-1-yl 1-4,5-dihydrogen
(1) 1- (叔丁氧羰基)吖丁啶 -3-羧酸的制备 (1) Preparation of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid
BocN^ ^COOH  BocN^ ^COOH
干燥的反应瓶中加入 Boc20 25.535 g (117 mmol), 70 mL甲醇， 搅拌过 程中滴加吖丁啶 -3-羧酸 10.11 g (100 mmol)和三乙胺 27.8 mL (200 mmol) 的 105 mL甲醇溶液，加毕， 室温搅拌过夜。后处理将体系旋干，加入 100 mL水， 用 1 mol/L的 NaOH调节 pH至 9, 用二氯曱烷萃取两次， 弃去有 机相， 水层用盐酸调 pH至 2, 用二氯甲烷萃取三次， 干燥旋干得到白色 固体 16.25 g, 收率 80.8%。 Boc 2 0 25.535 g (117 mmol), 70 mL of methanol was added to the dried reaction flask, while azetidine-3-carboxylic acid 10.11 g (100 mmol) and triethylamine 27.8 mL (200 mmol) were added dropwise during stirring. 105 mL of methanol solution, added, and stirred at room temperature overnight. After the treatment, the system was spun dry, added with 100 mL of water, adjusted to pH 9 with 1 mol/L NaOH, extracted twice with dichloromethane, discarded The organic layer was adjusted to pH 2 with hydrochloric acid, extracted three times with dichloromethane, and dried and dried to give a white solid, 16.25 g, yield 80.8%.
-1-羰基)吖丁啶 -1-羧酸叔丁酯的制备
Figure imgf000028_0001
Preparation of tert-butyl -1-carbonyl)azetidine-1-carboxylic acid
Figure imgf000028_0001
干燥的反应瓶中加入 1- (叔丁氧羰基)吖丁啶 -3-羧酸 9.25 g (46.0 mmol), 4-羟基哝啶 5.13 g (50.7 mmol), 加入 N,N-二曱基甲酰胺 100 mL, 二氯甲烷 100 mL, 二异丙基乙基胺 8.8 mL (50.5 mmol), 最后加 HATU 17.5 g (46.1 mmol), 加毕， 室温反应过夜。 后处理体系旋蒸， 加水共沸带走大部分 DMF, 剩余物用二氯甲烷萃取， 水洗， 有机相干燥， 旋干。 粗品柱层析（石油醚： 乙酯 = 1 :1— _1:2 )洗脱， 得到含量为 87%的产物 3 g, 用乙酸乙酯溶解， 碳酸 氢钠洗涤有机相干燥， 旋干， 得到较纯产物 1.75 g， 收率 13.4%。  Add 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid 9.25 g (46.0 mmol), 4-hydroxyacridine 5.13 g (50.7 mmol) to a dry reaction flask, and add N,N-diindenyl The amide 100 mL, dichloromethane 100 mL, diisopropylethylamine 8.8 mL (50.5 mmol), and finally HATU 17.5 g (46.1 mmol), added, and allowed to react at room temperature overnight. The post-treatment system is steamed, azeotropically removed with most of the DMF, the residue is extracted with dichloromethane, washed with water, dried with organic phase, and dried. The crude column chromatography (petroleum ether: ethyl ester = 1 :1 - 1:1:2) eluted to give 3 g of product (yield: 87%), which was dissolved in ethyl acetate, washed with sodium bicarbonate and dried. The purer product was 1.75 g, and the yield was 13.4%.
基)吖丁啶三氟乙酸盐的制备
Figure imgf000028_0002
Preparation of azetidine trifluoroacetate
Figure imgf000028_0002
干燥的反应瓶中加入二氯甲烷 43 mL, 3-(4-羟基哌啶小羰基)吖丁啶 -1- 羧酸叔丁酯 1.75 g (6.15 mmol), 滴加 TFA 8 mL, 室温下反应 2小时， 反应结 束体系旋干得到粗品 2 g。  In a dry reaction flask, add 43 mL of dichloromethane, 1.75 g (6.15 mmol) of 3-(4-hydroxypiperidines small carbonyl)azetidine-1-carboxylic acid tert-butyl ester, add TFA 8 mL, and react at room temperature. After 2 hours, the reaction was completed and the system was dried to give a crude material (2 g).
(4) 2-氯 -4-[5-环戊基 -3-[3-(4-羟基哌啶 -1-羰基)吖丁啶小基] -4,5-二氢  (4) 2-Chloro-4-[5-cyclopentyl-3-[3-(4-hydroxypiperidin-1-carbonyl)azetidine small group]-4,5-dihydro
Figure imgf000028_0003
Figure imgf000028_0003
干燥的反应瓶中加入氢化钙干燥的 DMA 15 mL, 2-氯 -4-(3-氯 -5-环戊基 -4,5-二氢 吡唑 -1-基)苯甲腈（制备方法见实施例 1 (3) )802 mg (2.60 mmol), 3-(4-羟基哌啶 -1-基談基)吖丁啶三氟乙酸盐粗品 1.15 g, DffiA 2.6 mL, 加毕， 氮气保护下 100。C避光反应 3小时， 后处理体系冷却后倒入水中， 乙酸乙酯 萃取三次，水洗， 干燥旋干。制备液相 C18柱， 流动相（乙腈:水 =0% - 60% ), 得到淡黄色固体 215 mg， 收率 18.1%。  Calcium hydride dried DMA 15 mL, 2-chloro-4-(3-chloro-5-cyclopentyl-4,5-dihydropyrazol-1-yl)benzonitrile was added to the dried reaction flask. See Example 1 (3) ) 802 mg (2.60 mmol), 3-(4-hydroxypiperidin-1-yl)azetidine trifluoroacetate crude 1.15 g, DffiA 2.6 mL, added, nitrogen Protected under 100. C was protected from light for 3 hours, and the after-treatment system was cooled, poured into water, extracted with ethyl acetate three times, washed with water, dried and dried. A liquid phase C18 column was prepared, and the mobile phase (acetonitrile: water = 0% - 60%) afforded pale yellow solid 215 mg, yield 18.1%.
分子式： C24H3GC1N502 理论分子量： 455.98 质语（M+H )实测分 子量： 456 Molecular formula: C 2 4H 3G C1N 5 0 2 theoretical molecular weight: 455.98 slang (M+H) measured molecular weight: 456
1H-NMR(^-DMSO, 400 MHz): δ 7.47 (1Η, d), 6.89 (1H, d), 6.72 (1H, dd), 4.79 (1H， d), 4.63-4.49 (1H, m)， 4.21-3.98 (4H, m), 3.95-3.76 (2H, m), 3.75-3.63 (IH, m), 3.13-2.98 (3H, m), 2.58 (IH, d), 2.36-2.19 (IH, m), 1.77-1.04 (12H, m). 实施例 3 2-氯 -4-Γ5-环戊基 -3-Γ6-(4-羟基哌啶 -1-羰基)吡啶 -3-基 1-4,5-二氢 1H-NMR (^-DMSO, 400 MHz): δ 7.47 (1Η, d), 6.89 (1H, d), 6.72 (1H, dd), 4.79 (1H, d), 4.63-4.49 (1H, m), 4.21-3.98 (4H, m), 3.95-3.76 (2H, m), 3.75-3.63 (IH, m), 3.13-2.98 (3H, m), 2.58 (IH, d), 2.36-2.19 (IH, m), 1.77-1.04 (12H, m). Example 3 2-Chloro-4-indole 5 -cyclopentyl-3-indole-6-(4-hydroxypiperidin-1-carbonyl)pyridin-3-yl 1-4,5-dihydro
Figure imgf000029_0001
Figure imgf000029_0001
(1) 5-((1Ε,2Ε)-1-(2-(3-氯 -4-氰基苯基)亚联氨基) -3-环戊基烯丙基)吡啶 -2-  (1) 5-((1Ε,2Ε)-1-(2-(3-Chloro-4-cyanophenyl)imino)-3-cyclopentylallyl)pyridine-2-
Figure imgf000029_0002
Figure imgf000029_0002
在干燥的 100 mL单口瓶中加入无水乙醇 30 mL ,加入 2-氯 -4-肼基苯腈 盐酸盐 2.03 g (9.95 mmol),再加入 (£)-5-(3-环戊基丙烯酰基)吡啶 -2-甲酸甲酯 2.0 g (7.32 mmol), 室温下搅拌反应 36 h。 后处理体系抽滤， 滤饼用冷的无水 乙醇洗一次， 干燥， 得到粗品 1.8 g。  Add 30 mL of absolute ethanol to a dry 100 mL single-mouth bottle, add 2-chloro-4-mercaptobenzonitrile hydrochloride 2.03 g (9.95 mmol), and add (£)-5-(3-cyclopentyl) Methyl acryl)pyridine-2-carboxylate 2.0 g (7.32 mmol), and the reaction was stirred at room temperature for 36 h. The post-treatment system was suction filtered, and the filter cake was washed once with cold anhydrous ethanol and dried to give a crude material, 1.8 g.
(2) 5-(1-(3-氯 -4-氰基苯基) -5-环戊基 ~4,5-二氢 -1H-吡唑 -3-基)吡啶 -2-曱 酸  (2) 5-(1-(3-Chloro-4-cyanophenyl)-5-cyclopentyl ~4,5-dihydro-1H-pyrazole-3-yl)pyridine-2-indole
Figure imgf000029_0003
Figure imgf000029_0003
将 5-((1£,2£ 1-(2-(3-氯 -4-氰基苯基)亚联氨基) -3-环戊基烯丙基)吡啶 -2- 甲酸乙酯粗品 1.8 g加到 20 mL浓盐酸中， 80。C反应两小时停止反应。 后处 理体系加 40 mL水， 乙酸乙酯萃取四次， 干燥， 旋干， 得到粗品 800 mg。 制 备液相制备得到产物 180 mg, 收率 10.0%。 5-((1£, 2£ 1-(2-(3-chloro-4-cyanophenyl)imino)-3-cyclopentylallyl)pyridine-2-carboxylic acid ethyl ester crude 1.8 g was added to 20 mL of concentrated hydrochloric acid, and the reaction was stopped at 80 ° C for two hours. The post-treatment system was added with 40 mL of water, extracted with ethyl acetate four times, dried, and dried to give a crude product of 800 mg. Prepared in the liquid phase to obtain the product 180 mg, the yield was 10.0%.
(3) 5-(1-(3-氯 -4-氰基苯基) -5-环戊基 -4,5-二氢 吡唑 -3-基)吡啶 -2-曱 酸  (3) 5-(1-(3-Chloro-4-cyanophenyl)-5-cyclopentyl-4,5-dihydropyrazole-3-yl)pyridine-2-indole
Figure imgf000030_0001
Figure imgf000030_0001
在 50 mL单口瓶中将 5-(1-(3-氯 苯基) -5-环戊基 -4,5-二氢 吡唑 -3-基)吡啶 -2-甲酸乙酯 180 mg (0.43 mmol),加到 2 mL THF中，再加入曱醇 2 mL, 加毕， 滴加 10% NaOH 0.2 mL, 后室温反应 1小时。 后处理体系中和到 中性， 体系旋干， 加水， 再调 pH至 3 , 抽滤析出物， 用少量甲醇洗涤得到产 物 50 mg, 收率 29.4%。  Ethyl 5-(1-(3-chlorophenyl)-5-cyclopentyl-4,5-dihydropyrazol-3-yl)pyridine-2-carboxylate 180 mg (0.43) in a 50 mL vial Add to 2 mL of THF, add 2 mL of sterol, add, add 10 mL of NaOH 0.2 mL, and react at room temperature for 1 hour. The post-treatment system was neutralized to neutrality, the system was spun dry, water was added, and the pH was adjusted to 3, and the precipitate was filtered off with a small amount of methanol to give a product 50 mg, yield 29.4%.
(4) 2-氯 -4-(5-环戊基 -3-(6-(4-羟基哌啶 -1-羰基)吡啶 -3-基) -4,5-二氢 吡 -1-基)苯曱腈的制备  (4) 2-Chloro-4-(5-cyclopentyl-3-(6-(4-hydroxypiperidin-1-carbonyl)pyridin-3-yl)-4,5-dihydropyridin-1-yl Preparation of benzoquinone
Figure imgf000030_0002
Figure imgf000030_0002
干燥的反应瓶中， 分别加入 5-(1-(3-氯 -4-氰基苯基) -5-环戊基 -4,5-二氢 -1H-吡唑 -3-基)吡啶 -2-甲酸 100 mg ( 0.253 mmol ), 4-羟基哌啶 27 mg ( 0.267 mmol ), DMF 5 mL, CH2C12 5 mL, DIEA 0.052 mL ( 0.3 mmol ), 最后力口入 HATU 97 mg ( 0.255 mmol ), 室温过夜反应。 后处理将溶剂旋干， 中低压液 相制备色讲分离， 得到纯品黄色固体 40 mg, 收率 33.1%。 In a dry reaction flask, 5-(1-(3-chloro-4-cyanophenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)pyridine- 2-carboxylic acid 100 mg (0.253 mmol), 4-hydroxypiperidine 27 mg (0.267 mmol), DMF 5 mL, CH 2 C1 2 5 mL, DIEA 0.052 mL (0.3 mmol), and finally HATU 97 mg (0.255) Mmmol), reacted overnight at room temperature. The solvent was spin-dried by post-treatment, and the medium and low-pressure liquid phase preparation was separated to obtain a pure yellow solid 40 mg, yield: 33.1%.
分子式： C26H28C1N502 理论分子量： 477.19 Molecular formula: C 26 H 28 C1N 5 0 2 theoretical molecular weight: 477.19
^-NMR^-DMSO, 400 MHz): δ 8.96 (1Η, d), 8.30 (1H, dd), 7.73 (1H, d), 7.63 (1H, d), 7.44 (1H, d), 7.21 (1H, dd), 4.96-4.89 (1H, m), 4.80 (1H, d), 4.08-3.96 (1H, m), 3.78-3.69 (1H, m), 3.60-3.41 (2H, m), 3.27-3.11 (3H, m), 1.85-1.18 (12H, m), 1.08-0.93 (1H, m )。  ^-NMR^-DMSO, 400 MHz): δ 8.96 (1Η, d), 8.30 (1H, dd), 7.73 (1H, d), 7.63 (1H, d), 7.44 (1H, d), 7.21 (1H , dd), 4.96-4.89 (1H, m), 4.80 (1H, d), 4.08-3.96 (1H, m), 3.78-3.69 (1H, m), 3.60-3.41 (2H, m), 3.27-3.11 (3H, m), 1.85-1.18 (12H, m), 1.08-0.93 (1H, m).
实施例 4 2-氯 -4-Γ5-环戊基 -3-『4-(4-羟基哌啶 -1-羰基)哌啶 -1-基 1-4,5-二氢 吡唑 -1-基 1苯曱腈（化合物 4 )的制备
Figure imgf000031_0001
Example 4 2-Chloro-4-indolyl 5-cyclopentyl-3-"4-(4-hydroxypiperidin-1-carbonyl)piperidin-1-yl 1-4,5-dihydropyrazole-1- Preparation of base 1 benzoquinone (compound 4)
Figure imgf000031_0001
1-叔丁基 4-甲基哌啶 -1,4-二羧酸酯的制备  Preparation of 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate
.0  .0
BocN i  BocN i
0  0
干燥的反应瓶中， 将哌啶 -4-羧酸甲酯 7.15 g (50 mmol)和三乙胺 14 mL (100 mmol)加入到 60 mL甲醇溶液中 ,滴加溶于 30 mL甲醇的 Boc20 13.8 mL (60 mmol), 过夜反应。 后处理将溶剂旋干， 加入约 50 mL水， 用乙酸乙酯萃 取三次， 干燥， 旋蒸， 得到无色液体 11.81 g, 收率 97.2%。 In a dry reaction flask, add 1.15 g (50 mmol) of methyl piperidine-4-carboxylate and 14 mL (100 mmol) of triethylamine to 60 mL of methanol solution, and add Boc 2 dissolved in 30 mL of methanol. 0 13.8 mL (60 mmol), overnight reaction. After the solvent was evaporated, the mixture was evaporated to dryness.
(2) 1- (叔丁氧羰基)哌啶 -4-羧酸的制备
Figure imgf000031_0002
(2) Preparation of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid
Figure imgf000031_0002
干燥的反应瓶中， 将 1-叔丁基 4-甲基哌啶 -1,4-二羧酸酯 11.81 g加入到 150 mL甲醇中， 滴加 10% NaOH溶液 50 mL, 室温下过夜反应。 后处理将溶 剂旋干， 加水、 二氯甲烷萃取两次， 倒掉二氯甲烷相， 用盐酸调节水相至 pH 为 2~3, 用二氯甲烷萃取 4次， 干燥， 旋蒸， 得到白色固体 11.13 g。  In a dry reaction flask, 11.81 g of 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate was added to 150 mL of methanol, and 50 mL of a 10% NaOH solution was added dropwise thereto, and the mixture was reacted at room temperature overnight. After the treatment, the solvent was spun dry, extracted with water and dichloromethane twice, and the dichloromethane phase was evaporated. The aqueous phase was adjusted to pH 2 to 3 with hydrochloric acid, extracted 4 times with dichloromethane, dried and then evaporated to give white. Solid 11.13 g.
哌啶- 1 -羰基)哌啶- 1 -羧酸叔丁酯的制备
Figure imgf000031_0003
Preparation of piperidine-1 -carbonyl)piperidine-1-carboxylic acid tert-butyl ester
Figure imgf000031_0003
干燥的反应瓶中， 分别加入 1- (叔丁氧羰基)哌啶 -4-羧酸 11.13 g (48.5 mmol), 4-羟基哌啶 5.4 g (53.4mmol)， DMF 100 mL,二氯曱烷 100 mL, DIEA 9 mL (51.8 mmol), 最后加入 HATU 18.41 g (48.5 mmol), 室温下过夜反应。 后处理将溶剂旋干， 柱层析纯化（石油醚： 乙酸乙酯 =1 :1—1:1.5 )， 得到白色 固体， 用饱和碳酸氢钠溶液洗涤得到纯品白色固体 8 g, 收率 52.8%。  In a dry reaction flask, add 11.13 g (48.5 mmol) of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid, 5.4 g (53.4 mmol) of 4-hydroxypiperidine, DMF 100 mL, dichloromethane. 100 mL, DIEA 9 mL (51.8 mmol), finally HATU 18.41 g (48.5 mmol) was added and allowed to react overnight at room temperature. After work-up, the solvent was evaporated to dryness and purified eluted eluted eluted eluted eluted eluted %.
-1-基羰基)哌啶三氟乙酸盐的制备
Figure imgf000031_0004
Preparation of -1-ylcarbonyl)piperidine trifluoroacetate
Figure imgf000031_0004
干燥的反应瓶中， 将 4-(4-羟基哌啶 -1-羰基)哌啶 -1-羧酸叔丁酯 0.6 g (1.9 mmol)加入到 10 mL二氯甲烷中， 水浴中滴加 TFA 5 mL, 滴加完毕移至室温 反应 后处理将溶剂旋干， 得粗品 1.53 g, 重结晶得产品 482 mg， 收 率： 76.9%。 In a dry reaction flask, 0.6 g (1.9 mmol) of 4-(4-hydroxypiperidin-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester was added to 10 mL of dichloromethane, and TFA was added dropwise in a water bath. 5 mL, transfer to room temperature after the addition After the reaction, the solvent was dried to give 1.53 g of crude material, which was crystallized to give product 482 mg, yield: 76.9%.
(5) 2-氯 -4-[5-环戊基 -3-[4-(4-羟基哌啶小羰基)哌啶 -1-基] -4,5-二氢 吡 -1-基]笨甲腈的制备  (5) 2-Chloro-4-[5-cyclopentyl-3-[4-(4-hydroxypiperidinylcarbonyl)piperidin-1-yl]-4,5-dihydropyridin-1-yl] Preparation of benzoic nitrile
Figure imgf000032_0001
Figure imgf000032_0001
干燥的反应瓶中加入氢化钙干燥的 N,N-二曱基乙酰胺 5 mL， 2-氯 -4-(3- 氯 -5-环戊基 -4,5-二氢 -1H-吡唑 -1-基)苯曱腈（制备方法见实施例 1 (3) ) 150 mg (0.487 mmol), 4-(4-羟基哌啶 -1-基羰基)哌啶三氟乙酸盐 323 mg (0.99 mmol), DIEA 0.5 mL, 加毕， 氮气保护下避光 100 °C反应过夜， 后处理体系冷却后 倒入水中， 乙酸乙酯萃取三次， 水洗， 干燥旋干。 制备液相 C18柱制备得到 淡黄色产物 60 mg, 收率 25.5%。  Calcium hydride dried N,N-dimercaptoacetamide 5 mL, 2-chloro-4-(3-chloro-5-cyclopentyl-4,5-dihydro-1H-pyrazole) -1-yl)benzonitrile (for the preparation method, see Example 1 (3)) 150 mg (0.487 mmol), 4-(4-hydroxypiperidin-1-ylcarbonyl)piperidine trifluoroacetate 323 mg ( 0.99 mmol), DIEA 0.5 mL, added, reacted under nitrogen atmosphere at 100 ° C overnight, the post-treatment system was cooled, poured into water, extracted with ethyl acetate three times, washed with water, dried and dried. Preparation of a liquid phase C18 column gave a pale yellow product of 60 mg, yield 25.5%.
分子式： C26H34C1N502 理论分子量： 484.03 质谱（M+H )实测分 子量： 484.2 Molecular formula: C 26 H 34 C1N 5 0 2 theoretical molecular weight: 484.03 mass spectrometry (M+H) measured molecular weight: 484.2
'H- MRC^-DMSO, 400 MHz): δ 7.45 (IH, d), 6.90 (1H, d), 6.73 (1H, d), 4.75 (IH, d), 4.60-4.48 (1H， m), 3.96-3.64 (5H,m), 3.28-3.08 (2H, m)， 3.02-2.75 (5H, m), 2.54 (3H, m), 2.38-2.25(lH, m), 1.82-1.04 (13H, m).  'H- MRC^-DMSO, 400 MHz): δ 7.45 (IH, d), 6.90 (1H, d), 6.73 (1H, d), 4.75 (IH, d), 4.60-4.48 (1H, m), 3.96-3.64 (5H,m), 3.28-3.08 (2H, m), 3.02-2.75 (5H, m), 2.54 (3H, m), 2.38-2.25(lH, m), 1.82-1.04 (13H, m ).
实施例 5 2-氯 -4-『5-环戊基 -3-「2-(4-羟基哌啶 -1-狻基)吡咯烷 -1-基 4,5-二 氢 -1H-吡唑 -1-基 1苯曱腈（化合物 5 ) 的制备  Example 5 2-Chloro-4-"5-cyclopentyl-3-"2-(4-hydroxypiperidin-1-indenyl)pyrrolidin-1-yl 4,5-dihydro-1H-pyrazole Preparation of -1-yl 1benzonitrile (Compound 5)
Figure imgf000032_0002
Figure imgf000032_0002
- (叔丁氧羰基)吡咯烷 -2-羧酸的制备
Figure imgf000032_0003
- Preparation of (tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid
Figure imgf000032_0003
干燥的反应瓶中 , 将 L-脯氨酸 7.475 g (65 mmol)和三乙胺 18.2 mL (130 mmol)加入到 100 mL甲醇中， 滴加溶于 30 mL甲醇的 Boc20 18 mL (78.4 mmol), 室温下过夜反应。 后处理将溶剂旋干， 加入约 50 mL水， 用 1 mol/L 的 NaOH水溶液调节体系至 pH为 8~9,用二氯甲烷萃取两次，分液分去二氯 甲烷相， 水相用盐酸调节至 pH为 2, 用二氯曱烷萃取 4次， 干燥， 旋蒸， 得 到白色固体 12.7 g， 收率 90.9%。 In a dry reaction flask, L-valine 7.475 g (65 mmol) and triethylamine 18.2 mL (130) Methyl) was added to 100 mL of methanol, and Boc 2 0 18 mL (78.4 mmol) dissolved in 30 mL of methanol was added dropwise and allowed to react at room temperature overnight. After the treatment, the solvent was spin-dried, about 50 mL of water was added, the system was adjusted to pH 8-9 with 1 mol/L NaOH aqueous solution, extracted twice with dichloromethane, and the dichloromethane phase was separated, and the aqueous phase was separated. Hydrochloric acid was adjusted to pH 2, extracted 4 times with dichloromethane, dried and then evaporated to give a white solid (12.7 g).
基哌啶- 1 -tt)吡咯烷 -1 -羧酸叔丁酯的制备
Figure imgf000033_0001
Preparation of tert-butyl pyridin-1 -carboxylate
Figure imgf000033_0001
干燥的反应瓶中， 分别加入 1- (叔丁氧羰基)吡咯烷 -2-羧酸 12.6 g (58.5 mmol), 4-羟基哌啶 6.63 g (65.5 mmol), DMF 100 mL,二氯甲烷 100 mL, DIEA 11.1 mL (63.7 mmol), 最后加入 HATU 22.4 g (59 mmol), 室温下过夜反应。后 处理将溶剂旋干， 柱层析纯化（石油醚： 乙酸乙酯 =1:1 -1 :1.5 )， 得到白色固 体， 用 1 mol/L NaOH溶液洗涤得到纯品白色固体 10.5 g， 收率 60.1%。 In a dry reaction flask, add 1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid 12.6 g (58.5 mmol), 4-hydroxypiperidine 6.63 g (65.5 mmol), DMF 100 mL, dichloromethane 100 mL, DIEA 11.1 mL (63.7 mmol), finally added HATU 22.4 g (59 mmol), and react overnight at room temperature. After work-up, the solvent was evaporated to dryness and purified by column chromatography (ethyl ether: ethyl acetate = 1:1 -1 : 1.5 ) to give a white solid, which was washed with 1 mol/L NaOH to give a white solid 10.5 g. 60.1%.
- 1 -基羰基)吡咯烷三氟乙酸盐的制备
Figure imgf000033_0002
Preparation of 1- 1 -carbonylcarbonylpyrrolidine trifluoroacetate
Figure imgf000033_0002
干燥的反应瓶中， 将 2-(4-羟基哌啶 -1-羰基)吡咯烷 -1-羧酸叔丁酯 0.3 g (1 mmol)加入到 5 mL二氯曱烷中， 水浴中滴加 TFA 2.5 mL, 滴加完毕移至室温 反应 4小时。 后处理将溶剂旋干， 得粗品 0.8 g, 重结晶得产品 0.27 g, 收率： 86.0%。  In a dry reaction flask, 0.3 g (1 mmol) of 2-(4-hydroxypiperidin-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester was added to 5 mL of dichloromethane, and added dropwise in a water bath. TFA 2.5 mL, after the addition was completed, the reaction was allowed to proceed to room temperature for 4 hours. The solvent was spin-dried to give a crude product of 0.8 g, which was recrystallized to give the product 0.27 g, yield: 86.0%.
(4) 2-氯 -4-[5-环戊基 -3-[2-(4-羟基哌啶 -1-羰基)吡咯烷 -1-基] -4,5-二氢 制备  (4) 2-Chloro-4-[5-cyclopentyl-3-[2-(4-hydroxypiperidin-1-carbonyl)pyrrolidin-1-yl]-4,5-dihydropropion
Figure imgf000033_0003
Figure imgf000033_0003
千燥的反应瓶中加入氢化钙干燥的 N,N-二甲基乙酰胺 4.5 mL, 2-氯 -4-(3- 氯 -5-环戊基 -4,5-二氢 吡唑 -1-基)苯甲腈（制备方法见实施例 1 (3) ) 236 mg (0.77 mmol), 2-(4-羟基哌啶 -1-基羰基)吡咯烷三氟乙酸盐 572 mg (1.83 mmol), DIEA 0.77 mL, 加毕， 氮气保护下避光 100。C反应过夜， 后处理体系冷却后 倒入水中， 乙酸乙酯萃取三次， 水洗， 干燥旋干。 制备液相 C18柱制备得到 淡黄色产物 90 mg, 收率 25.0%。 分子式： C25H32C1N502 理论分子量： 470.01 质谱（M+H )实测分 子量： 470.2 Calcium hydride dried N,N-dimethylacetamide 4.5 mL, 2-chloro-4-(3-chloro-5-cyclopentyl-4,5-dihydropyrazole-1) -yl)benzonitrile (for preparation, see Example 1 (3)) 236 mg (0.77 mmol), 2-(4-hydroxypiperidin-1-ylcarbonyl)pyrrolidinium trifluoroacetate 572 mg (1.83 mmol) ), DIEA 0.77 mL, added, protected from light 100 under nitrogen. C was reacted overnight, the after-treatment system was cooled, poured into water, extracted with ethyl acetate three times, washed with water, dried and dried. Preparation of a liquid phase C18 column gave a pale yellow product, 90 mg, yield 25.0%. Molecular formula: C 25 H 32 C1N 5 0 2 theoretical molecular weight: 470.01 mass spectrometry (M+H) measured molecular weight: 470.2
^-NMR^-DMSO, 400 MHz): δ 7.43 (IH, d), 6.87 (1H, s), 6.80-6.48 (1H, m), 4.95-4.71 (2H, m)， 4.60-4.40 (IH, m), 4.10-3.62 (3H， m)， 3.58-3.37 (2H, m), 3.25-3.10 (IH, m), 2.96-2.65 (2H, m), 2.37-2.16 (2H, m), 1.95-1.10 (15H, m).  ^-NMR^-DMSO, 400 MHz): δ 7.43 (IH, d), 6.87 (1H, s), 6.80-6.48 (1H, m), 4.95-4.71 (2H, m), 4.60-4.40 (IH, m), 4.10-3.62 (3H, m), 3.58-3.37 (2H, m), 3.25-3.10 (IH, m), 2.96-2.65 (2H, m), 2.37-2.16 (2H, m), 1.95- 1.10 (15H, m).
实施例 6 4-『5-环戊基 -3-『3-(4-羟基哌啶 -1-羰基)吖丁啶 -1-基 4,5-二氢  Example 6 4-"5-Cyclopentyl-3-"3-(4-hydroxypiperidin-1-carbonyl)azetidin-1-yl 4,5-dihydrogen
Figure imgf000034_0001
Figure imgf000034_0001
基苯甲腈盐酸盐的制备
Figure imgf000034_0002
Preparation of phenylbenzonitrile hydrochloride
Figure imgf000034_0002
在干燥的 100 mL单口瓶中加入无水乙醇 30 mL， 4-氟 -2-甲基苯曱腈 8.16 g (60.4 mmol), 水合肼 5.84 mL (99 mmol), 加毕回流反应 48小时。 后处理加 水稀释，抽滤固体，水洗，干燥得白色固体。将得到的固体溶于 160 mL***， 通氯化氢气体， 抽滤固体， ***洗涤， 真空干燥得到固体 7.2 g, 收率 64.9%。  In a dry 100 mL single-mouth bottle, 30 mL of absolute ethanol, 8.16 g (60.4 mmol) of 4-fluoro-2-methylbenzonitrile, and 5.84 mL (99 mmol) of hydrazine hydrate were added, and reflux reaction was carried out for 48 hours. After work-up and dilution with water, the solid was suction filtered, washed with water and dried to give a white solid. The obtained solid was dissolved in 160 mL of diethyl ether, filtered, filtered, evaporated, evaporated, evaporated
戊基 -3-氧代吡唑啉- 1 -基) -2-甲基苯曱腈的制备  Preparation of pentyl-3-oxopyrazolin-1-yl)-2-methylbenzonitrile
Figure imgf000034_0003
Figure imgf000034_0003
在干燥的 100 mL单口瓶中加入无水乙醇 12 mL,将金属钠 207mg (9 mmol) 分批加入，钠全溶后取出 1/3的乙醇钠溶液备用， 剩余 2/3的乙醇钠中加入甲 苯 12 mL， 再加入 4-肼基 -2-曱基苯甲腈盐酸盐 552 mg (3 mmol), 再加 ( )-3- 环戊基丙烯酸乙酯（制备方法见实施例 1 (1) ) 500 mg (3 mmol), 加毕， 氮气 保护下避光 90°C反应 1小时， 补加备用的乙醇钠， 再加入 ( )-3-环戊基丙烯 酸乙酯 1 g (5.9 mmol)后， 氮气保护下避光 90°C反应过夜。 后处理将反应体 系倒入冰水中， 乙酸乙酯萃取两次， 无水 Na2S04干燥， 旋干得粗品 900 mg。 粗品柱层析略微纯化， 得到粗品 500 mg。 5-环戊基 -4，5-二氢 吡唑 -1-基) -2-甲基苯甲腈的制备 Add 12 mL of absolute ethanol to a dry 100 mL single-mouth bottle, and add 207 mg (9 mmol) of sodium metal in portions. After sodium is completely dissolved, remove 1/3 of sodium ethoxide solution for use, and add 2/3 of the remaining sodium ethoxide. Toluene 12 mL, then add 4-mercapto-2-mercaptobenzonitrile hydrochloride 552 mg (3 mmol), followed by ( )-3-cyclopentyl acrylate (see Method 1 for preparation) )) 500 mg (3 mmol), add, under nitrogen protection, avoid reaction at 90 ° C for 1 hour, add spare sodium ethoxide, then add ( ) ethyl 3-cyclopentyl acrylate 1 g (5.9 mmol) Thereafter, the reaction was allowed to stand overnight at 90 ° C under nitrogen atmosphere. The workup of the reaction system was poured into ice-water, extracted with ethyl acetate twice and dried over anhydrous Na 2 S0 4, spin done crude 900 mg. The crude column chromatography was slightly purified to give a crude material (500 mg). Preparation of 5-cyclopentyl-4,5-dihydropyrazol-1-yl)-2-methylbenzonitrile
Figure imgf000035_0001
Figure imgf000035_0001
在 25 mL千燥单口瓶中，加入 POCl3 8 mL, 0。C下加 4-(5-环戊基 -3-氧代 吡唾啉 -1-基) -2-甲基苯甲腈粗品 500 mg, 再加入 NN-二甲基苯胺 0.1 mL, 加 毕升温至 100。C反应 3小时， TLC监测反应完毕， 旋去 POCl3 , 加少量甲苯 再次旋干， 剩余物倒入 50 mL的;水水中， 乙酸乙酯萃取得到粗品后柱层析得 到浅黄色固体 300 mg。 In a 25 mL dry single-mouth bottle, add POCl 3 8 mL, 0. Add C-diethyl 5-(5-cyclopentyl-3-oxopyridin-1-yl)-2-methylbenzonitrile to 500 mg, then add NN-dimethylaniline 0.1 mL. To 100. After reacting for 3 hours, the reaction was completed by TLC. The POCl 3 was spun off, and a small amount of toluene was added to spin dry again. The residue was poured into 50 mL of water and extracted with ethyl acetate to give a crude product.
(4) 4-[5-环戊基 -3-[3-(4-羟基哌啶 -1-羰基)吖丁啶小基] -4,5-二氢 吡 唑 -  (4) 4-[5-Cyclopentyl-3-[3-(4-hydroxypiperidin-1-carbonyl)azetidine small group]-4,5-dihydropyrazole -
Figure imgf000035_0002
Figure imgf000035_0002
干燥的反应瓶中加入氢化钙干燥的 N.N-二甲基乙酰胺 5 mL, 4-(3-氯 -5- 环戊基 -4,5-二氢 吡唑 -1-基) -2-甲基苯甲腈 100 mg (0.35 mmol), 3-(4-羟基 哌啶 -1-基羰基)吖丁啶三氟乙酸盐（制备方法见实施例 2 (3) )263 mg, DIEA 0.8 mL,加毕，氮气保护下避光 100。C反应 4小时，后处理体系冷却后倒入水中 , 乙酸乙酯萃取三遍， 水洗， 干燥旋干。 制备液相 C18柱制备得到淡黄色产物 30 mg, 收率 19.8%。  Calcium hydride dried NN-dimethylacetamide 5 mL, 4-(3-chloro-5-cyclopentyl-4,5-dihydropyrazol-1-yl)-2-methyl Benzobenzonitrile 100 mg (0.35 mmol), 3-(4-hydroxypiperidin-1-ylcarbonyl)azetidine trifluoroacetate (for preparation, see Example 2 (3)) 263 mg, DIEA 0.8 mL , plus, under the protection of nitrogen, protected from light 100. After reacting for 4 hours, the work-up system was cooled, poured into water, extracted with ethyl acetate three times, washed with water, dried and dried. Preparation of a liquid phase C18 column gave a pale yellow product 30 mg, yield 19.8%.
分子式： C25H33N502 理论分子量： 435.56 质谱（M+H )实测分子 量： 436.2 Molecular formula: C 25 H 33 N 5 0 2 theoretical molecular weight: 435.56 mass spectrometry (M+H) measured molecular weight: 436.2
1H-NMR(i¾-DMSO, 400 MHz): δ 7.34 (1Η, d), 6.72 (1H, s), 6.64 (1H, dd), 4.76 (1H, d), 4.50-4.40 (1H， m), 4.18-3.94 (4H, m), 3.92-3.63 (3H, m), 3.54-3.40 (1H, m), 3.13-2.98 (3H, m), 2.36-2.19 (4H, m), 1.78-1.04 (12H, m).  1H-NMR (i3⁄4-DMSO, 400 MHz): δ 7.34 (1Η, d), 6.72 (1H, s), 6.64 (1H, dd), 4.76 (1H, d), 4.50-4.40 (1H, m), 4.18-3.94 (4H, m), 3.92-3.63 (3H, m), 3.54-3.40 (1H, m), 3.13-2.98 (3H, m), 2.36-2.19 (4H, m), 1.78-1.04 (12H , m).
实施例 6 2-氯 -4-「5CSV环戊基 -3-「3-(4-羟基哌啶 -1-羰基）吖丁啶 -1- 基 1-4,5-二氢 吡唑 -1-基 1苯曱腈（化合物 7 )和 2-氯 -4-「5^>-环戊基 -3-「3-(4- 羟基哌啶 -1-羰基)吖丁啶 -1-基 1-4,5-二氢 吡唑 -1-基 1苯曱腈（化合物 8 ) 的 制备  Example 6 2-Chloro-4-"5CSV cyclopentyl-3-"3-(4-hydroxypiperidin-1-carbonyl)azetidin-1-yl 1-4,5-dihydropyrazole-1 -yl 1benzonitrile (Compound 7) and 2-chloro-4-"5^>-cyclopentyl-3-"3-(4-hydroxypiperidin-1-carbonyl)azetidin-1-yl 1 Preparation of -4,5-dihydropyrazol-1-yl 1benzonitrile (Compound 8)
2-氯 -4-[5CS 环戊基 -3-[3-(4-羟基哌啶 -1-羰基)吖丁啶小基] -4,5-二氢 吡唑 -1-基]苯甲腈和 2-氯 -4-[5fK)-环戊基 -3-[3-(4-羟基哌啶小羰基)吖丁啶 -1- 基] -4,5-二氢 吡唑 -1-基]苯曱腈的制备是通过对外消旋化合物（化合物 2 ) 利用超临界流体色谱法进行手性拆分得到的。 2-Chloro-4-[5CS cyclopentyl-3-[3-(4-hydroxypiperidin-1-carbonyl)azetidine small group]-4,5-dihydropyrazol-1-yl]benzene Nitrile and 2-chloro-4-[5fK)-cyclopentyl-3-[3-(4-hydroxypiperidinylcarbonyl)azetidin-1-yl]-4,5-dihydropyrazole-1- Benzoquinone is prepared by racemic compound (compound 2) Chiral resolution by supercritical fluid chromatography.
具体的拆分条件：  Specific split conditions:
手性柱： ChiralPak Αϋ-20μ, 250x30mmI.D.;  Chiral column: ChiralPak Αϋ-20μ, 250x30mmI.D.;
流动相： 45%异丙醇 /55%超临界二氧化碳， 流速： 80 mL /min;  Mobile phase: 45% isopropanol / 55% supercritical carbon dioxide, flow rate: 80 mL / min;
保留时间 = 3.23 min, t2 = 6.45min„ Retention time = 3.23 min, t 2 = 6.45 min „
实施例 7 2-氯 -4-「5CS 环戊基 -3-「4-(4-羟基哌啶 -1-羰基)哌啶 -1-基 1-4,5- 二氢 吡唑 -1-基 1苯甲腈（化合物 9 )和 2-氯 -4-「5 ?)-环戊基 -3-「4-(4-羟基哌 啶小狻基)哌啶 -1-基 14,5-二氢 吡唑 -1-基 1苯甲腈（化合物 10 )的制备  Example 7 2-Chloro-4-"5CS cyclopentyl-3-"4-(4-hydroxypiperidin-1-carbonyl)piperidin-1-yl 1-4,5-dihydropyrazole-1- Base 1 benzonitrile (Compound 9) and 2-chloro-4-"5?)-cyclopentyl-3-"4-(4-hydroxypiperidinyl)-piperidin-1-yl 14,5- Preparation of dihydropyrazol-1-yl 1benzonitrile (Compound 10)
2-氯 -4-[50¾-环戊基 -3-[4-(4-羟基哌啶 -1-羰基)哌啶 -1-基] -4,5-二氢 吡 唑 -1-基]苯甲腈（化合物 11 )和 2-氯 -4-[5( ?)-环戊基 -3-[4-(4-羟基哌啶 -1-羰基) 哌啶 -1-基] -4,5-二氢 吡唑 -1-基]苯甲腈的制备是通过对外消旋化合物（化 合物 4 )利用超临界流体色谱法进行手性拆分得到的。  2-Chloro-4-[503⁄4-cyclopentyl-3-[4-(4-hydroxypiperidin-1-carbonyl)piperidin-1-yl]-4,5-dihydropyrazol-1-yl] Benzonitrile (Compound 11) and 2-chloro-4-[5(?)-cyclopentyl-3-[4-(4-hydroxypiperidin-1-carbonyl)piperidin-1-yl]-4, The preparation of 5-dihydropyrazol-1-yl]benzonitrile was carried out by chiral resolution of the racemic compound (Compound 4) by supercritical fluid chromatography.
具体的拆分条件：  Specific split conditions:
手性柱： ChiralPak AS- 10μ, 300 x50mmI.D.;  Chiral column: ChiralPak AS- 10μ, 300 x 50mmI.D.;
流动相： 八相= (：02, 8相= 511^1101:( 0^2: 1， 流速： 170 mL /min); 保留时间 t} = 2.47 min, t2 = 3.55min。 Mobile phase: Eight phase = (: 0 2 , 8 phase = 511^1101: (0^2: 1, flow rate: 170 mL / min); retention time t } = 2.47 min, t 2 = 3.55 min.
参照上述方法， 还制备了如下化合物：  Referring to the above method, the following compounds were also prepared:
Figure imgf000036_0001
9£
Figure imgf000036_0001
9 £
Figure imgf000037_0001
.Cl00/ll0ZN3/X3d ΟΖΐ而 ΖΐΟΖ OAV Li
Figure imgf000037_0001
.Cl00/ll0ZN3/X3d ΟΖΐ而ΖΐΟΖ OAV Li
Figure imgf000038_0001
.CT00/ll0ZN3/X3d 0ΖΪ而 OAV 8e
Figure imgf000038_0001
.CT00/ll0ZN3/X3d 0ΖΪ and OAV 8e
Figure imgf000039_0001
.CT00/ll0ZN3/X3d 0ΖΪ而 OAV
Figure imgf000039_0001
.CT00/ll0ZN3/X3d 0ΖΪ and OAV

Claims

权 利 要 求 、 其药学上可接受的盐或其异构体,  Claims, pharmaceutically acceptable salts thereof or isomers thereof,
Figure imgf000040_0001
Figure imgf000040_0001
其中， Cy1为 C3-8环烷基、 杂芳基或芳基； Wherein Cy 1 is a C 3-8 cycloalkyl group, a heteroaryl group or an aryl group;
Cy2为 C3-8环烷基、 C5-8环烯基或 3-8元杂环基， 所述的 C3-8环烷基、 C5-8 环婦基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取 代基取代： 卤素原子、 氰基、 羟基、 、 ·½、 C1-6烷基、 卤代 C1-6烷基、 苯基、 （ 3.8环烷基和 3-8元杂环基； Cy 2 is a C 3-8 cycloalkyl group, a C 5-8 cycloalkenyl group or a 3-8 membered heterocyclic group, said C 3-8 cycloalkyl group, C 5-8 ring group and 3-8 members. The heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a 1⁄2, a C 1-6 alkyl group, a halogenated group. C 1-6 alkyl, phenyl, (38 cycloalkyl, and 3-8 membered heterocyclyl.;
L为 C(0)、 C(0)0、 C(0)NH、 NHC(0)、 NHC(0)NH、 NHS(0)、 HS(0)2、 s(o)或 s(o)2; L is C(0), C(0)0, C(0)NH, NHC(0), NHC(0)NH, NHS(0), HS(0) 2 , s(o) or s(o) 2 ;
X为 N或 CH;  X is N or CH;
Rla为氢原子、 卤素原子、 、 硝基、 羟基、 、 羧基、 甲磺酰基、 甲氧羰基； R la is a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a carboxyl group, a methanesulfonyl group or a methoxycarbonyl group;
Rlb为鹵素原子、 tt、 羟基、 羧基、 ^ 硝基、 巯基、 磺«、 氨基 甲酰基、 C1-6烷基、 （ 1-6烷^^、 C3-8环烷基、 C2_6烯基、 （ 5-8环烯基、 C2-6炔 基、 C3-8环烷 、 C1-6烷基胺基、 二 (C1-6烷基)胺基、 C1-6烷硫基、 烷基 羰基、 烷基胺基甲酰基、 烷基酰胺基、 烷基磺酰基、 c1-6烷基胺 基磺酰基、 C 烷基磧酰胺基、 二 (C 烷基)胺基曱酰基、 二 (C 烷基)胺基磺 酰基、 烷氧羰基或 C1-6烷基羰氧基， 所述的 烷基、 c3-8环烷基、 c2-6 烯基、 C5-8环烯基、 C2_6炔基、 C1-6烷氧基、 C3-8环烷氧基、 烷基胺基、 二 (C 烷基)胺基、 C 烷硫基、 C 烷基羰基、 C 烷基胺基甲酰基、 C 烷基 酰胺基、 烷基磺酰基、 C1-6烷基胺基磺酰基、 烷基磺酰胺基、 二 (Cw 烷基)胺基甲酰基、 二 (Cw烷基)胺基磺酰基、 C1-6烷氧羰基和 _6烷基羰氧 基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 、 羟基、 ½和 ^, n为 0〜4的整数， 其中 n为 2、 3或者 4时， Rlb 代表的基团可以相同或不同； R lb is a halogen atom, tt, a hydroxyl group, a carboxyl group, a nitro group, a fluorenyl group, a sulfonyl group, a carbamoyl group, a C 1-6 alkyl group, ( 1-6 alkane^^, a C 3-8 cycloalkyl group, a C 2 group ) _6 alkenyl, ( 5-8 cycloalkenyl, C 2-6 alkynyl, C 3-8 cycloalkane, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1- 6 alkylthio, alkylcarbonyl, alkylaminoformyl, alkylamido, alkylsulfonyl, c1-6 alkylaminosulfonyl, C alkylnonanoyl, di(C alkyl) An amino decanoyl group, a di(C alkyl)aminosulfonyl group, an alkoxycarbonyl group or a C 1-6 alkylcarbonyloxy group, said alkyl group, c 3-8 cycloalkyl group, c 2-6 alkenyl group , C 5-8 cycloalkenyl, C 2 -6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkoxy, alkylamino, bis(C alkyl)amine, C alkylthio , C alkylcarbonyl, C alkylaminoformyl, C alkylamido, alkylsulfonyl, C 1-6 alkylaminosulfonyl, alkylsulfonylamino, bis(Cw alkyl)amine Formyl, bis(Cw alkyl)aminosulfonyl, C1-6 alkoxycarbonyl and -6 alkylcarbonyloxy can be optionally 1, 2, 3, 4, 5 or 6 independently selected from Take Substituent substitution: halogen atom, hydroxyl group, 1⁄2 and ^, n is an integer of 0 to 4, wherein when n is 2, 3 or 4, the groups represented by R lb may be the same or different;
R2a为氢原子、 C1-6烷基、 C3-8环烷基、 C5-8环烯基、 苯基或 3-8元杂环基， 所述的 烷基、 C3-8环烷基、 C5-8环烯基、 苯基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 鹵素原子、 氰基、 羟基、 、 tt、 烷基和卤代 烷基； R 2a is a hydrogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 5-8 cycloalkenyl group, a phenyl group or a 3-8 membered heterocyclic group, said alkyl group, C 3-8 A cycloalkyl group, a C 5-8 cycloalkenyl group, a phenyl group and a 3-8 membered heterocyclic group may optionally be 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a tt group, an alkyl group and a halogenated alkyl group;
R2b、 R3a、 R3b分别独立地为氢原子、 硝基、 氰基、 卤素原子、 C1-6烷基、 烷氧基、 C3-8环烷基、 C2-6烯基、 C5-8环烯基、 C2-6块基或 C3-8环烷氧基， 所述的 烷基、 C3-8环烷基、 C2_6烯基、 C5-8环烯基、 C2_6炔基、 C1-6烷氧基 和 C3-8环烷氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取 代： 卤素原子、 、 羟基、 «和«； R 2b , R 3a , and R 3b are each independently a hydrogen atom, a nitro group, a cyano group, a halogen atom, a C 1-6 alkyl group, an alkoxy group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 5-8 cycloalkyl alkenyl, C 2 -6 block group or C 3-8 cycloalkoxy group, the alkyl group, C 3-8 cycloalkyl, C 2 _6 alkenyl group, a C 5-8 cycloalkyl alkenyl The base, C 2 -6 alkynyl, C 1-6 alkoxy and C 3-8 cycloalkoxy may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from: Halogen atom, hydroxyl group, «and«;
R4和 R5与它们所连接的 X形成 C3-8环烷基、 C5-8环烯基、 苯基、 3-8元 杂环基、 5-10元稠环基、 5-12元螺环基和 6-10元桥环基，所述的 C3-8环坑基、 C5-8环烯基、 苯基、 3-8元杂环基、 5-10元稠环基、 5-12元螺环基和 6-10元 桥环基可任选被 1、 2、 3或 4个独立地选自 R4a和 R5 々取代基取代； R 4 and R 5 and the X to which they are attached form a C 3-8 cycloalkyl group, a C 5-8 cycloalkenyl group, a phenyl group, a 3-8 membered heterocyclic group, a 5-10 membered fused ring group, 5-12 a spirocyclic group and a 6-10 membered bridged ring group, said C 3-8 ring pit group, C 5-8 cycloalkenyl group, phenyl group, 3-8 membered heterocyclic group, 5-10 membered fused ring group 5-12 member spiro group and 6-10 member bridged ring group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 4a and R 5 ;;
R4a为硝基、 、 卤素原子、 羟基、 ½、 烷基、 烷氧 基、 C3-8环烷基、 C2_e烯基、 C5-8环烯基、 C2 块基或 C3-8环烷氧基， 所述的 烷基、 （ 3-8环烷基、 烯基、 C5-8环烯基、 C2_e炔基、 烷氧基和 C3-8 环烷氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤 素原子、 氰基、 羟基、 羧基和氨基； R 4a is nitro, a halogen atom, a hydroxyl group, a 1⁄2, an alkyl group, an alkoxy group, a C 3-8 cycloalkyl group, a C 2 —e alkenyl group, a C 5-8 cycloalkenyl group, a C 2 block group or a C 3 group ; -8 cycloalkoxy, said alkyl, ( 3-8 cycloalkyl, alkenyl, C 5-8 cycloalkenyl, C 2 -e alkynyl, alkoxy and C 3-8 cycloalkoxy Optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group;
！^为^!^)^6,其中 R6为 OR7、C(0)R7、C(0)OR7、OC(0)R7、C(0)NR8R9、 NR8C(0)R7、 N 8R9、 S(0)qR7、 NHCOOR7、 NHCONR8R9、 S(0)q R8R9 , R8S(0)qR7或 C(0) HS(0)qR7; ! ^ is ^!^)^ 6 , where R 6 is OR 7 , C(0)R 7 , C(0)OR 7 , OC(0)R 7 , C(0)NR 8 R 9 , NR 8 C( 0) R 7 , N 8 R 9 , S(0) q R 7 , NHCOOR 7 , NHCONR 8 R 9 , S(0) q R 8 R 9 , R 8 S(0) q R 7 or C(0) HS(0)qR 7 ;
R7、 R8和 R9分别独立地为氢原子， C1-6烷基或 C3-8环烷基， R8和 R9可 以与它们所连接的氮形成 3-8元杂环基， 所述 C1-6烷基、 C3-8环烷基和 3-8元 杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素 原子、 ·½、吡咯烷基、 OR10、 C(O)R10、 C(O)OR10、 OC(O)R10、 C(0)NRuR12、 NR"R12、 NRnC(0)R10, S(O)qR10、 S C^N ^R12和 NRUS C qR10; R 7 , R 8 and R 9 are each independently a hydrogen atom, a C 1-6 alkyl group or a C 3-8 cycloalkyl group, and R 8 and R 9 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached. The C 1-6 alkyl group, the C 3-8 cycloalkyl group, and the 3-8 membered heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of : halogen atom, ·1⁄2, pyrrolidinyl group, OR 10 , C(O)R 10 , C(O)OR 10 , OC(O)R 10 , C(0)NR u R 12 , NR"R 12 , NR n C(0)R 10 , S(O) q R 10 , SC^N ^R 12 and NRUS C qR 10 ;
R1G、 R11和 R12分别独立地为氢原子、 C 烷基、 C3-8环烷基或苯基， R11 和 R12可以与它们所连接的氮形成 3-8元杂环基，所述 C1-6烷基、 C3-8环烷基、 苯基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代 基取代： 卤素原子、 ^&、 羟基和羧基； R 1G , R 11 and R 12 are each independently a hydrogen atom, a C alkyl group, a C 3-8 cycloalkyl group or a phenyl group, and R 11 and R 12 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached. The C 1-6 alkyl group, the C 3-8 cycloalkyl group, the phenyl group and the 3-8 membered heterocyclic group may be optionally 1, 2, 3, 4, 5 or 6 independently selected from the following Substituent substitution: halogen atom, ^&, hydroxyl group and carboxyl group;
p为 0~6的整数；  p is an integer from 0 to 6;
q为 0~2的整数。 、 其药学上可接受的盐或其异构体, q is an integer from 0 to 2. a pharmaceutically acceptable salt thereof or an isomer thereof,
Figure imgf000042_0001
Figure imgf000042_0001
其中， Cy1为 3-8元杂环基、 C3-8环烷基或芳基； Wherein Cy 1 is a 3-8 membered heterocyclic group, a C 3-8 cycloalkyl group or an aryl group;
Cy2为 C3-8环烷基、 C5-8环烯基或 3-8元杂环基， 所述的 C3-8环烷基、 C5-8 环締基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取 代基取代： 卤素原子、 、 羟基、 、 、 烷基、 卤代 烷基、 苯基、 C 8环烷基和 3-8元杂环基； Cy 2 is a C 3-8 cycloalkyl group, a C 5-8 cycloalkenyl group or a 3-8 membered heterocyclic group, said C 3-8 cycloalkyl group, C 5 - 8 ring-constituting group and 3-8 members. The heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, an alkyl group, a halogenated alkyl group, a phenyl group, a C 8 naphthenic group. And a 3-8 membered heterocyclic group;
L为 C(0)、 C(0)0、 C(0)NH、 NHC(0)、 S(O)或 S(0)2; L is C(0), C(0)0, C(0)NH, NHC(0), S(O) or S(0) 2 ;
X为 N或 CH;  X is N or CH;
R1为卤素原子、 、 羟基、 ½、 硝基、 巯基、 磺^^ 甲酰基、 烷基、 烷 ½、 C3-8环烷基、 烯基、 C5-8环烯基、 C2-6炔 基、 C3-8环烷 、 烷基胺基、 二 (Cw烷基)胺基、 烷硫基、 烷基 羰基、 烷基胺基甲酰基、 烷基酰胺基、 烷基磺酰基、 C1-6烷基胺 基横酰基、 C 烷基磺酰胺基、 二 烷基)胺基甲酰基、 二 (C 烷基)胺基磺 酰基、 烷氧羰基或 烷基羰氧基， 所述的 C1-6烷基、 C3_8环烷基、 C2-6 烯基、 C5-8环烯基、 C2_6炔基、 烷氧基、 C3-8环烷氧基、 烷基胺基、 二 烷基)胺基、 C 烷硫基、 C1-6烷基羰基、 烷基胺基甲酰基、 C 烷基 酰胺基、 烷基磺酰基、 Cw烷基胺基磺酰基、 烷基横酰胺基、 二 (Cw 烷基)胺基曱酰基、 二 (Q_6烷基)胺基磺酰基、 Ci.6烷氧羰基和 C1-6烷基羰氧 基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 鹵素原子、 ·½、 羟基、 和 ^, m为 0〜5的整数， 其中 R1相同或不同； R 1 is a halogen atom, a hydroxyl group, a 1⁄2, a nitro group, a decyl group, a sulfonyl group, an alkyl group, an alkane group, a C 3-8 cycloalkyl group, an alkenyl group, a C 5-8 cycloalkenyl group, a C 2 - 6 alkynyl, C 3-8 cycloalkane, alkylamino group, bis(Cw alkyl)amino group, alkylthio group, alkylcarbonyl group, alkylaminoformyl group, alkylamido group, alkylsulfonyl group, a C 1-6 alkylamino acid acyl group, a C alkyl sulfonyl amide group, a dialkyl) carbamoyl group, a di(C alkyl)amino sulfonyl group, an alkoxycarbonyl group or an alkylcarbonyloxy group, C 1-6 alkyl, C 3 -8 cycloalkyl, C 2 6 alkenyl, C 5-8 cycloalkenyl, C 2 -6 alkynyl, alkoxy, C 3-8 cycloalkoxy, Alkylamino, dialkyl)amino, C alkylthio, C 1-6 alkylcarbonyl, alkylaminoformyl, C alkylamido, alkylsulfonyl, C w alkylamine sulfonate An acyl group, an alkyl amide group, a bis(Cw alkyl)amino decanoyl group, a bis(Q-6 alkyl)aminosulfonyl group, a Ci.6 alkoxycarbonyl group and a C 1-6 alkylcarbonyloxy group may optionally be 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a 1⁄2, a hydroxyl group, and a ^, m is an integer from 0 to 5, wherein R 1 is the same or different;
R2a为氢原子、 烷基、（ 3-8环烷基、 C5-8环烯基、 苯基或 3-8元杂环基， 所述的 d_6烷基、 C3-8环烷基、 （5-8环烯基、 苯基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基、 、 tt、 烷基和卤代 C1-6烷基； R 2a is a hydrogen atom, an alkyl group, ( 3-8 cycloalkyl, C 5-8 cycloalkenyl, phenyl or a 3-8 membered heterocyclic group, said d-6 alkyl group, C 3-8 cycloalkyl group ( 5-8 cycloalkenyl, phenyl and 3-8 membered heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: halogen atom, cyano group , hydroxy, tt, alkyl and halo C 1-6 alkyl;
R2b、 1 分别独立地为氢原子、 硝基、 氰基、 卤素原子、 烷基、 C1-6 烷氧基、 C3-8环烷基、 C2-6烯基、 C5-8环烯基、 C2_6块基或 C3-8环烷氧基， 所 述的 C1-6烷基、 C3-8环烷基、 C2-6烯基、 C5-8环浠基、 C2_6炔基、 烷氧基和 C3-8环烷氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基、 和氨基； R4和 R5与它们所连接的 X形成 C3-8环烷基、 （ 5-8环烯基、 苯基或 3-8元 杂环基， 所述的 C3-8环烷基、 C5-8环烯基、 苯基和 3-8元杂环基可任选被 1、 2、 3或 4个独立地选自 R4a和 R5a的取代基取代； R 2b and 1 are each independently a hydrogen atom, a nitro group, a cyano group, a halogen atom, an alkyl group, a C 1-6 alkoxy group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 5-8 group. cycloalkenyl, C 2 _ 6 block basis or C 3 - 8 cycloalkyl group, the C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 5-8 cycloalkyl The fluorenyl group, the C 2 -6 alkynyl group, the alkoxy group and the C 3-8 cycloalkoxy group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: halogen atom, a cyano group, a hydroxyl group, and an amino group; R 4 and R 5 and the X to which they are attached form a C 3-8 cycloalkyl group, a ( 5-8 cycloalkenyl group, a phenyl group or a 3-8 membered heterocyclic group, said C 3 -8 cycloalkyl group, C 5-8 cycloalkenyl, phenyl and 3-8 membered heterocyclyl can be optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 4a and R 5a ;
1 43为硝基、 、 卤素原子、 羟基、 、 tt、 烷基、 烷氧 基、 C3-8环烷基、 C2_6烯基、 C5-8环烯基、 C2_6炔基或 C3-8环烷氧基， 所述的 烷基、 C3-8环烷基、 C2 烯基、 C5-8环烯基、 炔基、 烷氧基和 C3-8 环烷氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤 素原子、 氰基、 羟基、 羧基和氨基； 1 43 is a nitro group, a halogen atom, a hydroxyl group, a tt, an alkyl group, an alkoxy group, a C 3-8 cycloalkyl group, a C 2 —6 alkenyl group, a C 5-8 cycloalkenyl group, a C 2 —6 alkynyl group or C 3-8 cycloalkoxy, said alkyl, C 3-8 cycloalkyl, C 2 alkenyl, C 5-8 cycloalkenyl, alkynyl, alkoxy and C 3-8 cycloalkoxy The group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group;
R5a为 (CH2)pR6,其中 R6为 OR7、 C(0)R7、 C(0)OR7、 OC(0)R7、 C(0)NR8R9、 NR8C(0)R7、 NR8R9、 S(0)qR7、 NHCOOR7、 NHCONR8R9、 S(0)qNR8R9、 NR8S(0)qR7或 C(0)NHS(0)qR7; R 5a is (CH 2 )pR 6 , wherein R 6 is OR 7 , C(0)R 7 , C(0)OR 7 , OC(0)R 7 , C(0)NR 8 R 9 , NR 8 C (0) R 7 , NR 8 R 9 , S(0) q R 7 , NHCOOR 7 , NHCONR 8 R 9 , S(0) q NR 8 R 9 , NR 8 S(0) q R 7 or C(0 NHS(0)qR 7 ;
R7、 R8和 R9分别独立地为氢原子， C1-6烷基或 C3-8环烷基， R8和 R9可 以与它们所连接的氮形成 3-8元杂环基， 所述 烷基、 C3-8环烷基和 3-8元 杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素 原子、氰基、吡咯烷基、 OR10, C(0)R1G、 C(0)OR1Q、 OC(0)R1G、 C(0)NRuR12、 "R12、 NRnC(0)R10, S(0)qR10. S(0)q uR12和 NRUs R10; R 7 , R 8 and R 9 are each independently a hydrogen atom, a C 1-6 alkyl group or a C 3-8 cycloalkyl group, and R 8 and R 9 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached. The alkyl group, C 3-8 cycloalkyl group and 3-8 membered heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: halogen atom, Cyano, pyrrolidinyl, OR 10 , C(0)R 1G , C(0)OR 1Q , OC(0)R 1G , C(0)NR u R 12 , "R 12 , NR n C(0) R 10 , S(0) q R 10 . S(0) q u R 12 and NRUs R 10 ;
R1G、 R11和 R12分别独立地为氢原子、 烷基、 C3-8环烷基或苯基， R11 和 R12可以与它们所连接的氮形成 3-8元杂环基，所述 Cw烷基、 C3-8环烷基、 苯基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代 基取代： 卤素原子、 、 羟基和羧基； R 1G , R 11 and R 12 are each independently a hydrogen atom, an alkyl group, a C 3-8 cycloalkyl group or a phenyl group, and R 11 and R 12 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, The C w alkyl group, the C 3-8 cycloalkyl group, the phenyl group and the 3-8 membered heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of : halogen atom, hydroxyl group and carboxyl group;
p为 0~6的整数；  p is an integer from 0 to 6;
q为 0〜2的整数。  q is an integer of 0 to 2.
3、 如权利要求 2所述的化合物、 其药学上可接受的盐或其异构体， 其中， Cy1为苯基、 吡吱基或嘧啶基； The compound according to claim 2, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein Cy 1 is a phenyl group, a pyridyl group or a pyrimidinyl group;
Cy2为 C^8环烷基或 3-8元杂环基， 所述的 C3-8环烷基和 3-8元杂环基可 任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 氰 基、 羟基、 羧基、 ½、 C1-6烷基、 卤代 d-6烷基、 笨基、 C3-8环烷基和 3-8 元杂环基； Cy 2 is C 8 8 -cycloalkyl or 3-8 membered heterocyclic, and the C 3-8 cycloalkyl and 3-8 membered heterocyclic group may be optionally 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, a 1⁄2, a C 1-6 alkyl group, a halogenated d- 6 alkyl group, a stupid group, a C 3-8 cycloalkyl group, and a 3-8 membered heterocyclic group;
L为 C(O), C(0)0, C(0)NH、 NHC(O)或 S(0)2; L is C(O), C(0)0, C(0)NH, NHC(O) or S(0) 2 ;
X为 N或 CH;  X is N or CH;
R1为卤素原子、 «、 羟基、 ½、磺 、 C1-6烷基、 C1-6烷 tt、 C3-8 环烷基、 C2_6烯基、 C2_e炔基、 C1-6烷基胺基、 二 (C1-6烷基)胺基、 烷基胺 基甲酰基、 C 烷基酰胺基、 烷基磺酰基、 烷基胺基磺酰基、 烷 基磺酰胺基、 烷氧羰基或 C 烷基羰氣基，所述的 CW烷基、 烷氧基、 C3-8环烷基、 C2_6烯基、 C2_6炔基、 C1-6烷基胺基、 二 (C^烷基)胺基、 C1-6烷 基胺基甲酰基、 C 烷基酰胺基、 C 烷基磺酰基、 C 烷基胺基磺酰基、 Ci-6 烷基横酰胺基、 C1-6烷氧羰基和 烷基羰氧基可任选被 1、 2、 3或 4个独立 地选自以下的取代基取代： 卤素原子、 、 羟基、 羧基和氨基， m为 0~3 的整数， 其中 R1相同或不同； R 1 is a halogen atom, «, hydroxy, 1⁄2, sulfonyl, C 1-6 alkyl, C 1-6 alkane tt, C 3-8 cycloalkyl, C 2 -6 alkenyl, C 2 _e alkynyl, C 1 -6 alkylamino group, di(C 1-6 alkyl)amino group, alkylamine Carboxyyl, C alkylamido, alkylsulfonyl, alkylaminosulfonyl, alkylsulfonylamino, alkoxycarbonyl or C alkylcarbonyl, said C W alkyl, alkoxy , C 3-8 cycloalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C 1-6 alkylamino, bis(C^alkyl)amino, C 1-6 alkylaminoformyl , C alkyl amide group, C alkyl sulfonyl group, C alkyl amino sulfonyl group, Ci -6 alkyl amide group, C 1-6 alkoxycarbonyl group and alkyl carbonyloxy group may optionally be 1, 2 , 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, a carboxyl group, and an amino group, m is an integer of 0 to 3, wherein R 1 is the same or different;
R2a为氢原子、 C3-8环烷基、 C5-8环烯基、 苯基或 3-8元杂环基， 所述的 C3-8环烷基、 C5-8环烯基、 苯基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6 个独立地选自以下的取代基取代： 卤素原子、 、 羟基、 羧基、 氨基、 C1-6 烷基和鹵代 C 烷基； R 2a is a hydrogen atom, a C 3-8 cycloalkyl group, a C 5-8 cycloalkenyl group, a phenyl group or a 3-8 membered heterocyclic group, said C 3-8 cycloalkyl group, C 5-8 cycloolefin The phenyl group and the 3-8 membered heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, a carboxyl group, an amino group, a C 1 group ; -6 alkyl and halogenated C alkyl;
R2b、 1 3£1分别独立地为氢原子、 、 卤素原子、 烷基、 烷氧基、R 2b and 1 3 £1 are each independently a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group,
C 8环烷基或 C2-e炔基， 所述的 烷基、 烷氧基、 C3-8环烷基或 C2_6炔 基和可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原 子、 氰基、 羟基、 羧基和氨基； C 8 cycloalkyl or C 2 -e alkynyl, said alkyl, alkoxy, C 3-8 cycloalkyl or C 2 -6 alkynyl and optionally 1, 2, 3, 4, 5 Or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, and an amino group;
R4和 R5与它们所连接的 X形成 C3_8环烷基、 C5-8环烯基或 3-8元杂环基， 所述的 C3-8环烷基、 C5-8环烯基和 3-8元杂环基可任选被 1、 2或 3个独立地 选自 R4a和 R5a的取代基取代； R 4 and R 5 form a C 3 _ 8 cycloalkyl group which they are attached and X, C 5- 8 cycloalkenyl or a 3-8 membered heterocyclic group, the C 3-8 cycloalkyl group, C 5- The 8- cycloalkenyl and 3-8 membered heterocyclyl can be optionally substituted by 1, 2 or 3 substituents independently selected from R 4a and R 5a ;
为硝基、 、 卤素原子、 羟基、 、 C 烷基、 烷 、 C3-8 环烷基、 C2_e烯基或 C2_e炔基， 所述的 C 烷基、 _6烷氧基、 C3-8环烷基、 C2_6烯基和 C2_6炔基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基 取代： 卤素原子、 、 羟基、 羧基和 Is a nitro group, a halogen atom, a hydroxyl group, a C alkyl group, an alkane, a C 3-8 cycloalkyl group, a C 2 —e alkenyl group or a C 2 —e alkynyl group, said C alkyl group, _6 alkoxy group, C The 3-8 cycloalkyl, C 2 -6 alkenyl and C 2 -6 alkynyl may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, Carboxyl and
R5a为（CH2)pR6， 其中 R6为 OR7、 C(0)OR7、 OC(0)R7、 C(0)N 8R9、 NR8C(0)R7、 NR8R9、 S(0)qR7、 NHCON V, S(0)qNR8R9, NR8S(0)qR7或 C(0)NHS(0)qR7; R 5a is (CH 2 )pR 6 , wherein R 6 is OR 7 , C(0)OR 7 , OC(0)R 7 , C(0)N 8 R 9 , NR 8 C(0)R 7 , NR 8 R 9 , S(0) q R 7 , NHCON V, S(0) q NR 8 R 9 , NR 8 S(0) q R 7 or C(0)NHS(0) q R 7 ;
R7、 R8和 R9分别独立地为氢原子、 烷基或 C3-8环烷基， R8和 R9可 以与它们所连接的氮形成 3-8元杂环基， 所述 C1-6烷基、 C3-8环烷基和 3-8元 杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素 原子、 tt、吡咯烷基、 OR10, C(O)OR10、 OC(O) R10, C(0)NRnR12, NRnR12、 NRnC(O)R10> S(0)qR10, S ^qNRUR12和
Figure imgf000044_0001
R 7 , R 8 and R 9 are each independently a hydrogen atom, an alkyl group or a C 3-8 cycloalkyl group, and R 8 and R 9 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, said C The 1-6 alkyl group, the C 3-8 cycloalkyl group and the 3-8 membered heterocyclic group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: halogen atom, Tt, pyrrolidinyl, OR 10 , C(O)OR 10 , OC(O) R 10 , C(0)NR n R 12 , NR n R 12 , NR n C(O)R 10 > S(0) qR 10 , S ^qNRUR 12 and
Figure imgf000044_0001
R1Q、 R11和 R12分别独立地为氢原子、 烷基或 C3-8环烷基， R11和 R12 可以与它们所连接的氮形成 3-8元杂环基， 所述 烷基、 C^8环烷基和 3-8 元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤 素原子、 氰基、 羟基和羧基； R 1Q , R 11 and R 12 are each independently a hydrogen atom, an alkyl group or a C 3-8 cycloalkyl group, and R 11 and R 12 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, said alkane The base, C 8 8 cycloalkyl and 3-8 membered heterocyclyl can be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: Atom, cyano, hydroxy and carboxy;
p为 0~4的整数；  p is an integer from 0 to 4;
q为 0〜2的整数。  q is an integer of 0 to 2.
4、 如权利要求 2所述的化合物、 其药学上可接受的盐或其异构体， 其中， Cy1为笨基或吡啶基； The compound according to claim 2, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein Cy 1 is a strepyl or pyridyl group;
Cy2为 C5_e环烷基或 3-8元杂环基， 所述的 C5_6环烷基和 3-8元杂环基可 任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 氰 基、 羟基、 羧基、 tt、 C 烷基、 卤代 _6烷基、 苯基、 C3-8环烷基和 5-7 元杂环基； Cy 2 is a C 5 —e cycloalkyl group or a 3-8 membered heterocyclic group, and the C 5 —6 cycloalkyl group and the 3-8 membered heterocyclic group may be optionally 1, 2, 3, 4, 5 or 6 Substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, a tt, a C alkyl group, a halogenated-6 alkyl group, a phenyl group, a C 3-8 cycloalkyl group, and a 5-7 membered hetero Ring base
L为 C(0)、 C(0)0、 NHC(O)或 C(0)NH;  L is C(0), C(0)0, NHC(O) or C(0)NH;
X为 N或 CH;  X is N or CH;
R1为氢原子、 卤素原子、 氰基、 羟基、 羧基、 磺酸基、 烷基、 烷 、 （ 3-8环烷基、 C2_e炔基、 C1-6烷基胺基、 二 (Cw烷基)胺基、 d.6烷基 胺基甲酰基、 烷基酰胺基、 烷基胺基磺酰基、 烷基磺酰胺基、 C1-6 烷氧羰基或 烷基羰氧基， 所述的 烷基、 C3-8环烷基、 C2_6炔基、 C1-6 烷 tt、 C1-6烷基胺基、 二 (Cw烷基)胺基、 C1-6烷基胺基甲酰基、 烷基酰 胺基、 C 烷基胺基磺酰基、 烷基磺酰胺基、 C 烷氧羰基和 C 烷基羰 氧基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰 基、 羟基、 羧基和氨基， m为 1~3的整数， 其中 R1相同或不同； R 1 is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, a sulfonic acid group, an alkyl group, an alkane, a ( 3-8 cycloalkyl group, a C 2 _e alkynyl group, a C 1-6 alkylamino group, a Cw alkyl)amino, d. 6 alkylaminoformyl, alkylamido, alkylaminosulfonyl, alkylsulfonylamino, C1-6 alkoxycarbonyl or alkylcarbonyloxy, Alkyl, C 3-8 cycloalkyl, C 2 -6 alkynyl, C 1-6 alk tt, C 1-6 alkylamino, bis(Cw alkyl)amine, C 1-6 alkyl Aminoformyl, alkylamido, C alkylaminosulfonyl, alkylsulfonylamino, C alkoxycarbonyl and Calkylcarbonyloxy can be optionally selected 1, 2, 3 or 4 independently Substituted from the following substituents: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, and an amino group, m is an integer of 1 to 3, wherein R 1 is the same or different;
R2a为氢原子、 C3-8环烷基、 苯基、 C^6环烯基、 或 4-7元杂环基， 所述的 C3-8环烷基、 苯基、 C5_6环烯基和 4-7元杂环基可任选被 1、 2、 3或 4个独立 地选自以下的取代基取代： 卤素原子、 、 羟基、 羧基、 tt、 d_6烷基和 鹵代 烷基； R 2a is a hydrogen atom, a C 3-8 cycloalkyl group, a phenyl group, a C 6 cycloalkenyl group, or a 4-7 membered heterocyclic group, said C 3-8 cycloalkyl group, phenyl group, C 5 _6 The cycloalkenyl group and the 4-7 membered heterocyclic group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, a carboxyl group, a tt, a d-6 alkyl group and a halogenated alkyl group;
R2b、 R3a分别独立地为氢原子、 ·½、 卤素原子、 烷基、 C 烷！^ 或 C2_6炔基， 所迷的 烷基、 Cw烷氧基和 C2_e块基可任选被 1、 2、 3或 4 个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基、 羧基和氨基；R 2b and R 3a are each independently a hydrogen atom, a halogen atom, an alkyl group, or a C alkane! ^ or C 2 -6 alkynyl, the alkyl, C w alkoxy and C 2 -e block may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from: halogen atom, a cyano group, a hydroxyl group, a carboxyl group, and an amino group;
R4和 R5与它们所连接的 X形成 C3-8环烷基或 3-8元杂环基， 所述的 C3_8 环烷基和 3-8元杂环基可任选被 1或 2个独立地选自 R4a和 R5a的取代基取代；R 4 and R 5 form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclic group with the X to which they are attached, and the C 3 -8 cycloalkyl group and the 3-8 membered heterocyclic group may be optionally 1 or 2 substituents independently selected from R 4a and R 5a ;
1 43为"½、 卤素原子、 羟基、 氨基、 烷基、 烷 «~或 C3-8环烷 基， 所述的 C 烷基、 烷氧基和 C3-8环烷基可任选被 1、 2、 3或 4个独立 地选自以下的取代基取代： 卤素原子、 tt、 羟基、 羧基和氨基； 1 43 is "1⁄2, a halogen atom, a hydroxyl group, an amino group, an alkyl group, an alkane «~ or a C 3-8 cycloalkyl group, and the C alkyl group, the alkoxy group and the C 3-8 cycloalkyl group may be optionally 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, tt, a hydroxyl group, a carboxyl group and an amino group;
R5a为 (CH2)pR6, 其中 R6为 OR7、 C(0)OR7、 OC(0)R7、 C(0)NR8R9、 NR8C(0)R7、 NR8R9或 NHCONR8R9; R 5a is (CH 2 )pR 6 , wherein R 6 is OR 7 , C(0)OR 7 , OC(0)R 7 , C(0)NR 8 R 9 , NR 8 C(0)R 7 , NR 8 R 9 or NHCONR 8 R 9 ;
R7、 R8和 R9分别独立地为氢原子、 C1-6烷基或 C4-7环烷基， R8和 R9可 以与它们所连接的氮形成 4-7元杂环基， 所述 烷基、 C4j环烷基和 4-7元 杂环基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰基、 OR1Q、 C(0)OR1Q、 OC(0)R1Q、 C(0)NR"R12、 N NR12 , NR'^^R10 和 S(0)QR10; R 7 , R 8 and R 9 are each independently a hydrogen atom, a C 1-6 alkyl group or a C 4-7 cycloalkyl group, and R 8 and R 9 may form a 4-7 membered heterocyclic group with the nitrogen to which they are attached. The alkyl group, C 4 j cycloalkyl group and 4-7 membered heterocyclic group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: halogen atom, cyano group, OR 1Q , C(0)OR 1Q , OC(0)R 1Q , C(0)NR"R 12 , N N R 12 , NR'^^R 10 and S(0) Q R 10 ;
R1Q、 R1 1和 R12分别独立地为氢原子、 烷基或 C4-7环烷基， 所述 C1-6 烷基和 Ομ7环烷基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基 取代： 卤素原子、 、 羟基和羧基； R 1Q , R 1 1 and R 12 are each independently a hydrogen atom, an alkyl group or a C 4-7 cycloalkyl group, and the C 1-6 alkyl group and the Ομ 7 cycloalkyl group may be optionally 1, 2, 3 , 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group and a carboxyl group;
ρ为 0~4的整数；  ρ is an integer from 0 to 4;
q为 0~2的整数。  q is an integer from 0 to 2.
5、 如权利要求 2所述的化合物、 其药学上可接受的盐或其异构体， 其中， Cy1为苯基； The compound according to claim 2, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein Cy 1 is a phenyl group;
Cy2为 3-8元杂环基或 C5_6环烷基， 所述的 3-8元杂环基和 环烷基可 任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 氰 基、 羟基、 羧基、 tt、 C^e烷基、 卤代 烷基、 苯基、 C4_6环烷基和 4-6 元杂环基； Cy 2 is a 3-8 membered heterocyclic group or a C 5 -6 cycloalkyl group, and the 3-8 membered heterocyclic group and cycloalkyl group may be optionally 1, 2, 3, 4, 5 or 6 independently Substituted with a substituent selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, a tt, a C alkyl group, a halogenated alkyl group, a phenyl group, a C 4 -6 cycloalkyl group, and a 4-6 membered heterocyclic group;
L为 C(0)、 C(0)NH、 NHC(O)或 C(0)0;  L is C(0), C(0)NH, NHC(O) or C(0)0;
X为 N或 CH;  X is N or CH;
R1为氢原子、 卤素原子、 氰基、 羟基、 羧基、 磺酸基、 烷基、 C 8 环烷基、 C2_6块基、 烷基胺基曱酰基、 烷基酰胺基、 烷基胺基磺 酰基、 C 烷基磺酰胺基、 C 烷氧羰基或 C 烷基羰氧基，所述的 C 烷基、 C3-8环烷基、 C2_e炔基、 烷基胺基甲酰基、 烷基酰胺基、 C1-6烷基胺基 磺酰基、 烷基磺酰胺基、 烷氧羰基和 烷基羰氧基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基、 羧基和氨 基， m为 1~2的整数， 其中 R1相同或不同； R 1 is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, a sulfonic acid group, an alkyl group, a C 8 cycloalkyl group, a C 2 -6 block group, an alkylamino decanoyl group, an alkylamide group, an alkylamine a sulfamoyl group, a C alkylsulfonylamino group, a C alkoxycarbonyl group or a C alkylcarbonyloxy group, said C alkyl group, C 3-8 cycloalkyl group, C 2 _e alkynyl group, alkylamino formyl group The alkylamide group, the C 1-6 alkylaminosulfonyl group, the alkylsulfonylamino group, the alkoxycarbonyl group and the alkylcarbonyloxy group may be optionally 1, 2, 3 or 4 independently selected from the following Substituent substitution: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group, m is an integer of 1 to 2, wherein R 1 is the same or different;
R2A为氢原子、 苯基、 C5_6环浠基、 5-6元杂环基或 环烷基， 所述的苯 基、 C5_6环烯基、 5-6元杂环基和 Cue环烷基可任选被 1、 2、 3或 4个独立地 选自以下的取代基取代： 卤素原子、 氰基、 羟基、 、 氨基、 烷基和卤 代 Ci_6坑基； R 2A is a hydrogen atom, a phenyl group, a C 5 -6 cyclodecyl group, a 5-6 membered heterocyclic group or a cycloalkyl group, said phenyl group, C 5 -6 cycloalkenyl group, 5-6 membered heterocyclic group and Cue The cycloalkyl group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, an amino group, an alkyl group and a halogenated Ci_6 pit group;
R2B、 R3A分别独立地为氢原子、 氰基、 卤素原子或 CM烷基， 所述的 CM 烷基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰 基、 羟基、 羧基和氨基； R 2B and R 3A are each independently a hydrogen atom, a cyano group, a halogen atom or a CM alkyl group, and the CM alkyl group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: Halogen atom, cyanogen Base, hydroxyl, carboxyl and amino groups;
R4和 R5与它们所连接的 X形成 C4_6环烷基或 4-6元杂环基， 所述的 C4 环烷基和 4-6元杂环基可任选被 1或 2个独立地选自 R4A和 R5A的取代基取代；R 4 and R 5 form a C 4 -6 cycloalkyl group or a 4-6 membered heterocyclic group with the X to which they are attached, and the C 4 cycloalkyl group and the 4-6 membered heterocyclic group may be optionally 1 or 2 Substituent substitutions independently selected from R 4A and R 5A ;
11½为 、 卤素原子、 羟基、 、 烷基或 烷 所述的 烷基和 烷氧基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基、 和氨基； 11 ½ to, a halogen atom, a hydroxyl, alkyl or alkoxy said alkyl and alkoxy groups may be optionally substituted with 1, 2, 3 or 4 substituents independently selected from the following substituents: a halogen atom, a cyano group , hydroxyl, and amino groups;
R5A为（CH2)p 6， 其中 R6为 OR7、 C(0)OR7、 OC(0)R7、 NR8C(0)R7、 C(0) R7R8或 NR8R9; R 5A is (CH 2 )p 6 , wherein R 6 is OR 7 , C(0)OR 7 , OC(0)R 7 , NR 8 C(0)R 7 , C(0) R 7 R 8 or NR 8 R 9 ;
R7、 R8和 R9分别独立地为氢原子、 C1-6烷基或 C4-7环烷基， 所述 烷 基和 C4-7环烷基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 鹵 素原子、 、 OR10, C(O)OR10、 OC(O)R10、 C NRUR12和 NRUR12; R 7 , R 8 and R 9 are each independently a hydrogen atom, a C 1-6 alkyl group or a C 4 - 7 cycloalkyl group, and the alkyl group and the C 4-7 cycloalkyl group may be optionally 1, 2. 3 or 4 substituents independently selected from the group consisting of: a halogen atom, OR 10 , C(O)OR 10 , OC(O)R 10 , C NRUR 12 and NRUR 12 ;
R1Q、 R11和 R12分别独立地为氢原子或 CM烷基， 所述 烷基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基和羧 基； R 1Q , R 11 and R 12 are each independently a hydrogen atom or a CM alkyl group, and the alkyl group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group , hydroxyl and carboxyl groups;
p为 0~3的整数。  p is an integer from 0 to 3.
6、 如权利要求 2所述的化合物、 其药学上可接受的盐或其异构体,6. A compound according to claim 2, a pharmaceutically acceptable salt thereof or an isomer thereof,
1为笨基;  1 is stupid;
Figure imgf000047_0001
地选自以下的取代基取代： 卤素原子、 、 羟基、 羧基、 CM烷基和 卤代 CM烷基；
Figure imgf000047_0001
Substituted with a substituent selected from the group consisting of: a halogen atom, a hydroxyl group, a carboxyl group, a C M alkyl group, and a halogenated CM alkyl group;
L为 C(0)、 C(0)NH、 NHC(O)或 C(0)0;  L is C(0), C(0)NH, NHC(O) or C(0)0;
X为 N;  X is N;
R1为卤素原子、 、 羟基、 羧基、 C3环烷基、 乙炔基、 C 烷基胺基 甲酰基、 或 烷基， 所述的 C 烷基可任选被 1、 2、 3或 4个独立地选自 以下的取^ ^取代： 卤素原子、 、 羟基、 和氨基， m为 1或 2， 其 中 R1相同或不同; R 1 is a halogen atom, a hydroxyl group, a carboxyl group, a C 3 cycloalkyl group, an ethynyl group, a C alkylaminoformyl group, or an alkyl group, and the C alkyl group may be optionally 1, 2, 3 or 4 Independently selected from the group consisting of: a halogen atom, a hydroxyl group, and an amino group, m is 1 or 2, wherein R 1 is the same or different;
R2a为氢原子、 苯基、 C 环烯基、 5-6元杂环基、 环丁基、 环戊基或环己 基， 所述的苯基、 环婦基、 5-6元杂环基、 环丁基、 环戊基和环己基可任 选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基、 、 _3烷基和卤代 C1-3烷基； R 2a is a hydrogen atom, a phenyl group, a C cycloalkenyl group, a 5-6 membered heterocyclic group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, said phenyl group, a cyclopentyl group, a 5-6 membered heterocyclic group. The cyclobutyl, cyclopentyl and cyclohexyl groups may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a -3- alkyl group and a halogenated C. 1-3 alkyl;
R2b、 R3a分别独立地为氢原子、 氰基、 卤素原子或 CM烷基所述的 CM 烷基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 氰 基、 羟基、 羧基和氨基； The CM alkyl group wherein R 2b and R 3a are each independently a hydrogen atom, a cyano group, a halogen atom or a C M alkyl group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a carboxyl group and an amino group;
R4和 R5与它们所连接的 N形成 4-6元杂环基， 所述的 4-6元杂环基可任 选被 烷基和 /或 R5a取代； R 4 and R 5 form a 4-6 membered heterocyclic group with the N to which they are attached, and the 4-6 membered heterocyclic group may be optionally substituted by an alkyl group and/or R 5a ;
R5a为 (CH2)pR6， 其中 R6为 OR7、 OC(0)R7、 C(0)NR7R8或 N 8R9; R 5a is (CH 2 )pR 6 , wherein R 6 is OR 7 , OC(0)R 7 , C(0)NR 7 R 8 or N 8 R 9 ;
R7、 R8和 R9分别独立地为氢原子或 烷基，所述 CM烷基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代： 卤素原子、 、 OR10. C(0)OR10 和 RUR12; R 7 , R 8 and R 9 are each independently a hydrogen atom or an alkyl group, and the CM alkyl group may be optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: halogen atom, OR 10 . C(0)OR 10 and RUR 12 ;
R1Q、 R11和 R12分别独立地为氢原子或 CM烷基， 所述 CM烷基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟 基和羧基； R 1Q , R 11 and R 12 are each independently a hydrogen atom or a CM alkyl group, and the CM alkyl group may be optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group and a carboxyl group;
p为 0或 1。  p is 0 or 1.
7、 如权利要求 2所述的化合物、 其药学上可接受的盐或其异构体，7. A compound according to claim 2, a pharmaceutically acceptable salt thereof or an isomer thereof,
1为苯基;  1 is a phenyl group;
Figure imgf000048_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000049_0001
可任选被 1、 2或 3个独立地选自以下的取代基取代： 卤素原子、氰基、羟基、 、 、 甲基、 乙基和三氟甲基； Optionally, it may be substituted by 1, 2 or 3 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, a methyl group, an ethyl group, and a trifluoromethyl group;
L为 C(0)、 NH(CO)或 C(0)NH;  L is C(0), NH(CO) or C(0)NH;
X为 N;  X is N;
R1为氟原子、 氯原子、 氰基、 甲基、 乙基、 异丙基、 三氟曱基、 环丙基、 羟基、 乙炔基、 甲基胺基甲酰基或羟甲基， m为 1或 2， 其中 R1相同或不同；R 1 is a fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a cyclopropyl group, a hydroxyl group, an ethynyl group, a methylaminoformyl group or a hydroxymethyl group, and m is 1 Or 2, where R 1 is the same or different;
R2a为环戊基、 苯基、 环戊烯基、 吡咯基、 哌啶基、 环丁基， 所述的环戊 基、 苯基、 环戊烯基、 吡咯基、 哌啶基、 环丁基可任选被 1、 2或 3个独立地 选自以下的取代基取代： 卤素原子、 氰基、 羟基、 、 氨基、 （^_3烷基和卤 代 C1-3烷基； R 2a is cyclopentyl, phenyl, cyclopentenyl, pyrrolyl, piperidinyl, cyclobutyl, said cyclopentyl, phenyl, cyclopentenyl, pyrrolyl, piperidinyl, cyclobutyl The base may be optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of: a halogen atom, a cyano group, a hydroxyl group, an amino group, a (^ -3 alkyl group, and a halogenated C1-3 alkyl group;
R2b、 R3a分别独立地为氢原子、 、 卤素原子、 甲基、 乙基、 异丙基、 三氟甲基、 羟甲基或氨甲基； R 2b and R 3a are each independently a hydrogen atom, a halogen atom, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a methylol group or an aminomethyl group;
R4和 R5与它们所连接的 N形成环己基、 哌啶基， 所述的环己基和哌啶 基可任选被 烷基和 /或 R5a取代； R 4 and R 5 and the N to which they are attached form a cyclohexyl group, a piperidinyl group, said cyclohexyl and piperidinyl group may be optionally substituted by an alkyl group and/or R 5a ;
R5a为 (CH2)pR6, 其中 R6为 OR7、 OC(0)R7、 C(0) 7R8或 NR8R9; R 5a is (CH 2 )pR 6 , wherein R 6 is OR 7 , OC(0)R 7 , C(0) 7 R 8 or NR 8 R 9 ;
R7、 R8和 R9分别独立地为氢原子或(^3烷基，所述 Cw烷基可任选被 1、 2或 3个独立地选自以下的取代基取代： 卤素原子、 氰基、 羟基和 NR"R12; R 7, R 8 and R 9 are each independently a hydrogen atom or (3 ^ alkyl, the alkyl may be optionally substituted with C w 1, 2 or 3 substituents independently selected from the following substituents: a halogen atom, Cyano, hydroxyl and NR"R 12 ;
R11 R12分别独立地为氢原子、 甲基、 乙基或异丙基； R 11 R 12 are each independently a hydrogen atom, a methyl group, an ethyl group or an isopropyl group;
p为 0。  p is 0.
8、 如权利要求 2所述的化合物、 其药学上可接受的盐或其异构体，The compound according to claim 2, a pharmaceutically acceptable salt thereof or an isomer thereof,
1为苯基;  1 is a phenyl group;
Figure imgf000049_0002
Figure imgf000049_0002
Figure imgf000050_0001
Figure imgf000050_0001
甲基和乙基； Methyl and ethyl;
L为 C(O)或 NH(CO);  L is C(O) or NH(CO);
X为 N或 CH;  X is N or CH;
R1独立地选自氟原子、 氯原子、 氰基、 甲基、 乙基、 异丙基、 环丙基、 羟基、 乙炔基、 和曱基胺基曱酰基， m为 1或 2, 其中 m为 2时， R1相同或 不同； R 1 is independently selected from the group consisting of a fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a hydroxyl group, an ethynyl group, and a decylamino decanoyl group, and m is 1 or 2, wherein m When 2, R 1 is the same or different;
R2a为环戊基、 环戊烯基、 环丁基、 苯基、 哌啶基或吡咯基， 所述的环戊 基、 环戊烯基、 环丁基、 苯基、 哌啶基和吡咯基可任选被 1、 2或 3个独立地 选自卤素原子的取代基取代： R 2a is cyclopentyl, cyclopentenyl, cyclobutyl, phenyl, piperidinyl or pyrrolyl, said cyclopentyl, cyclopentenyl, cyclobutyl, phenyl, piperidinyl and pyrrole The group may be optionally substituted by 1, 2 or 3 substituents independently selected from a halogen atom:
R2b为氢原子； R3a为氢原子、 甲基或乙基； R 2b is a hydrogen atom; R 3a is a hydrogen atom, a methyl group or an ethyl group;
R4和 R5与它们所连接的 X形成哌啶基或环己基， 所述的环己基和哌啶 基可任选被羟基、 甲基、 乙基、 tt、 氨基羰基、 曱基甲酰氧基、 乙基甲酰 氧基、 曱氧基和乙氧基中的一或两个取代基取代。 R 4 and R 5 form a piperidinyl or cyclohexyl group with the X to which they are attached, and the cyclohexyl and piperidinyl groups may be optionally hydroxy, methyl, ethyl, tt, aminocarbonyl, decanoyloxy Substituted by one or two substituents of the group, ethyl formyloxy group, decyloxy group and ethoxy group.
9、 如权利要求 2所述的化合物、 其药学上可接受的盐或其异构体，9. A compound according to claim 2, a pharmaceutically acceptable salt thereof or an isomer thereof,
1为苯基;  1 is a phenyl group;
Figure imgf000050_0002
Figure imgf000050_0002
L为 C(O)或 NHC(O);  L is C(O) or NHC(O);
X为 N或 CH;  X is N or CH;
R1彼此独立地选自氯原子、 氰基、 甲基、 乙基、 异丙基、 环丙基、 羟基、 乙炔基、 和曱基胺基甲酰基， m为 1或 2， 其中 m为 2时 R1相同或不同； R 1 is independently selected from the group consisting of a chlorine atom, a cyano group, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a hydroxyl group, an ethynyl group, and a decylaminoformyl group. m is 1 or 2, wherein when m is 2, R 1 is the same or different;
R2a为环戊基、 环戊烯基、 环丁基、 苯基、 哌啶基或吡咯基； 所述的环戊 基、 环戊浠基、 环丁基、 苯基、 哌啶基和吡咯基可任选被 1、 2或 3个独立地 选自卤素原子的取 取代： R 2a is cyclopentyl, cyclopentenyl, cyclobutyl, phenyl, piperidinyl or pyrrolyl; said cyclopentyl, cyclopentanyl, cyclobutyl, phenyl, piperidinyl and pyrrole The group may be optionally substituted by 1, 2 or 3 independently selected from a halogen atom:
R2b和 R3a为氢原子； R 2b and R 3a are a hydrogen atom;
R4和 R5与它们所连接的 X形成哌啶基或环己基， 所述的环己基和哌啶 基可任选被羟基、 曱基、 乙基、 、 氨基羰基、 曱基甲酰氧基、 乙基甲酰 氣基、 甲氧基和乙氧基中的一或两个取 基取代。 R 4 and R 5 form a piperidinyl or cyclohexyl group with the X to which they are attached, and the cyclohexyl and piperidinyl groups may be optionally hydroxy, decyl, ethyl, aminocarbonyl, decylcarbonyloxy One or two of the ethyl formyl group, the methoxy group and the ethoxy group are substituted.
10、 如权利要求 2所述的化合物、 其药学上可接受的盐或其异构体， 其中， Cy1为苯基； The compound according to claim 2, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein Cy 1 is a phenyl group;
C
Figure imgf000051_0001
C
Figure imgf000051_0001
L为 C(O);  L is C(O);
X为 N;  X is N;
R1彼此独立地选自氯原子、 ^、 甲基， R 1 is independently selected from the group consisting of a chlorine atom, a ^, a methyl group,
m为 2;  m is 2;
1^为环戊基  1^ is cyclopentyl
R2b和 R3a为氢原子； R 2b and R 3a are a hydrogen atom;
R4和 R5与它们所连接的 X形成 4-羟基哌啶基。 R 4 and R 5 form a 4-hydroxypiperidinyl group with the X to which they are attached.
药学上可接受的  Pharmacologically acceptable
Figure imgf000051_0002
Figure imgf000051_0002
Figure imgf000052_0001
Figure imgf000052_0001
12、 通式（ Ila )所示的化合物或其药学上可接受的盐,  12. A compound of the formula (Ila) or a pharmaceutically acceptable salt thereof,
Figure imgf000052_0002
Figure imgf000052_0002
其中， R2b为氢， R2a如权利要求 1所述， 但不能为氢， Cy Cy2, L X、 Rla、 Rlb、 R3a、 R3b、 R4、 R5和 n如权利要求 1所述。 Wherein R 2b is hydrogen, R 2a is as defined in claim 1, but is not hydrogen, Cy Cy 2 , LX, R la , R lb , R 3a , R 3b , R 4 , R 5 and n are as claimed in claim 1 Said.
物或其药学上可接受的盐，  Or a pharmaceutically acceptable salt thereof,
Figure imgf000052_0003
Figure imgf000052_0003
其中， Cy Cy2、 L、 X、 R1, R2a、 R2b、 R3a、 R4、 R5和 m如权利要求 2 所述。 Wherein Cy Cy 2 , L, X, R 1 , R 2a , R 2b , R 3a , R 4 , R 5 and m are as defined in claim 2.
14、含有权利要求 1〜13任一项所述的化合物、其药学上可接受的盐或其 异构体的药物制剂， 其特征在于包括一种或多种药用载体。  A pharmaceutical preparation comprising a compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof or an isomer thereof, characterized by comprising one or more pharmaceutically acceptable carriers.
15、含有权利要求 1〜13任一项所述的化合物、其药学上可接受的盐或其 异构体在制备治疗和 /或预防肾损伤和 /或心血管疾病包括高血压、 心力衰竭、 心肌梗塞、 心绞痛、 心脏肥大、 心肌炎、 心脏血管纤维化、 压力感受器官能 障碍、 过多的体液和心律不齐， 或内分泌疾病， 包括原发 /继发性醛 酮增多 症、 阿狄森氏病、 库兴氏综合症和巴特式综合症的药物中的应用。  15. A compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof or an isomer thereof for the treatment and/or prevention of kidney damage and/or cardiovascular diseases including hypertension, heart failure, Myocardial infarction, angina pectoris, cardiac hypertrophy, myocarditis, cardiac vascular fibrosis, baroreceptor dysfunction, excessive fluid and arrhythmia, or endocrine disorders, including primary/secondary aldosteronism, Addison's disease , the application of Cushing's syndrome and Bart's syndrome drugs.
16、 药物组合物， 其特征在于包含权利要求 1-13任一项所述的化合物、 其药学上可接受的盐或其异构体和一种或多种治疗活性物质， 所述治疗活性 物质选自血管紧张素 II拮抗剂或其药学上可接受的盐； HMG-Co-A还原酶抑 制剂或其药学上可接受的盐； 钙通道阻滞剂（CCB )或其药学上可接受的盐； 血管紧张素转化酶 /中性内肽酶（ACE/NEP )双重抑制剂或其药学上可接受的 盐； 抗糖尿病药； 减肥药； 醛固酮受体阻滞剂； 内皮素受体阻滞剂； CETP 抑制剂； Na-K-ATP酶膜泵抑制剂； β -肾上腺素能受体抑制剂或 α -肾上腺素 能受体阻断剂； 中性内肽酶（ΝΕΡ )抑制剂和变力剂。 16. A pharmaceutical composition, characterized by comprising a compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof or an isomer thereof, and one or more therapeutically active substances, said therapeutically active substance Angiotensin II antagonist or a pharmaceutically acceptable salt thereof; HMG-Co-A reductase inhibitor a preparation or a pharmaceutically acceptable salt thereof; a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof; an angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) dual inhibitor or a pharmaceutical thereof Acceptable salts; antidiabetic agents; diet pills; aldosterone receptor blockers; endothelin receptor blockers; CETP inhibitors; Na-K-ATPase membrane pump inhibitors; beta-adrenergic receptors Agent or alpha-adrenergic receptor blocker; neutral endopeptidase (ΝΕΡ) inhibitor and inotropic agent.
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WO2017064121A1 (en) 2015-10-13 2017-04-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of choroidal neovascularisation
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