WO2012022120A1 - Composé dihydro-pyrazole - Google Patents

Composé dihydro-pyrazole 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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WO2012022120A8 (fr
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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/zh
Publication of WO2012022120A1 publication Critical patent/WO2012022120A1/fr
Publication of WO2012022120A8 publication Critical patent/WO2012022120A8/fr

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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

Fait l'objet de cette invention un composé dihydro-pyrazole de formule (1a), son sel pharmaceutiquement acceptable et son isomère, son procédé de préparation, ses préparations pharmaceutiques et ses applications. Les substituants de formule (1a) sont tels que définis dans le descriptif. Application : traitement et/ou prévention de lésions rénales, de maladies cardiovasculaires, notamment l'hypertension et/ou les maladies endocriniennes.
PCT/CN2011/001378 2010-08-18 2011-08-18 Composé dihydro-pyrazole WO2012022120A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017064121A1 (fr) 2015-10-13 2017-04-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de la néovascularisation choroïdienne
WO2018019843A1 (fr) 2016-07-26 2018-02-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonistes du récepteur des minéralocorticoïdes pour le traitement de l'arthrose
WO2021180818A1 (fr) 2020-03-11 2021-09-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés permettant de déterminer si un sujet a ou risque d'avoir une choriorétinopathie séreuse centrale
WO2023031277A1 (fr) 2021-08-31 2023-03-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes de traitement de la rosacée oculaire

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008049538A1 (fr) * 2006-10-26 2008-05-02 Bayer Schering Pharma Aktiengesellschaft Dihydropyrazolones substituées et leur utilisation comme inhibiteurs de l'hif-prolyl-4-hydroxylase
WO2008067874A1 (fr) * 2006-10-26 2008-06-12 Bayer Schering Pharma Aktiengesellschaft Dipyridyl-dihydropyrazolones substituées et leur utilisation
WO2009129945A1 (fr) * 2008-04-23 2009-10-29 Bayer Schering Pharma Aktiengesellschaft Dihydropyrazolones substituées utilisées comme inhibiteurs de la hif-prolyl-4-hydroxylase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008049538A1 (fr) * 2006-10-26 2008-05-02 Bayer Schering Pharma Aktiengesellschaft Dihydropyrazolones substituées et leur utilisation comme inhibiteurs de l'hif-prolyl-4-hydroxylase
WO2008067874A1 (fr) * 2006-10-26 2008-06-12 Bayer Schering Pharma Aktiengesellschaft Dipyridyl-dihydropyrazolones substituées et leur utilisation
WO2009129945A1 (fr) * 2008-04-23 2009-10-29 Bayer Schering Pharma Aktiengesellschaft Dihydropyrazolones substituées utilisées comme inhibiteurs de la hif-prolyl-4-hydroxylase

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017064121A1 (fr) 2015-10-13 2017-04-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de la néovascularisation choroïdienne
WO2018019843A1 (fr) 2016-07-26 2018-02-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonistes du récepteur des minéralocorticoïdes pour le traitement de l'arthrose
WO2021180818A1 (fr) 2020-03-11 2021-09-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés permettant de déterminer si un sujet a ou risque d'avoir une choriorétinopathie séreuse centrale
WO2023031277A1 (fr) 2021-08-31 2023-03-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes de traitement de la rosacée oculaire

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CN103052632B (zh) 2014-03-19
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