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WO2012126275A1 - Composés dihydropyrazoles contenant le spiro - Google Patents

Composés dihydropyrazoles contenant le spiro Download PDF

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Publication number
WO2012126275A1
WO2012126275A1 PCT/CN2012/000327 CN2012000327W WO2012126275A1 WO 2012126275 A1 WO2012126275 A1 WO 2012126275A1 CN 2012000327 W CN2012000327 W CN 2012000327W WO 2012126275 A1 WO2012126275 A1 WO 2012126275A1
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group
alkyl
cycloalkyl
cyano
hydrogen atom
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Chinese (zh)
Inventor
张蕙
张艳
王金远
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KBP Biosciences Co Ltd
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KBP Biosciences Co Ltd
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Priority to CN201280011160.5A priority Critical patent/CN103492371B/zh
Publication of WO2012126275A1 publication Critical patent/WO2012126275A1/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
    • C07D401/14—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
    • 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
    • C07D401/04—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
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a dihydropyrazole compound containing a spiro ring, a pharmaceutically acceptable salt, an ester thereof, a solvate thereof or a prodrug or an isomer thereof, and a method for preparing the same, which comprises Pharmaceutical preparations of the compounds, pharmaceutically acceptable salts, esters, solvates thereof or prodrugs or isomers thereof, and the compounds, pharmaceutically acceptable salts, esters, solvates or prodrugs thereof.
  • kidney damage There are many causes of kidney damage, 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% to 40% of patients with type 2 diabetes have diabetic nephropathy, which has become the leading cause of end-stage renal disease (40%). There is currently no effective treatment for the treatment of kidney damage.
  • Aldosterone 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 promotes its receptor by binding to the mineralocorticoid receptor. The retention of sodium and the excretion of potassium play an important role in electrolyte balance and in altering the structure and function of endothelial cells, vascular smooth muscle cells, fibroblasts and adventitia of the arterial wall, and the matrix on the shield.
  • Drugs compete with the mineralocorticoid receptor to block the binding of aldosterone to the mineralocorticoid receptor to inhibit aldosterone-mediated toxicity and thereby reduce kidney damage.
  • the indications are for the treatment of hypertension, heart failure and kidney syndrome. Both of them are body compounds, which have poor selectivity to other steroid hormone receptors, are prone to cause hyperkalemia, and have large side effects; and 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, and their use in the treatment and/or prevention of drugs for kidney damage, hypertension or endocrine diseases.
  • the present invention provides:
  • Cy 1 is C 3-8 cycloalkyl, 5-10 membered heteroaryl or 6-14 aryl;
  • L is C(0), C(0)0, C(O), NHC(0), CH 2 C(0), NHC(0)NH, NHS(0), NHS(0) 2 , S( O) or S(0) 2 ;
  • X represents C, CH, O or N
  • Y 1 represents CH or N
  • Y 2 represents CH, CH 2 , N or NH
  • n 2 , n 3 and n 4 are each independently an integer of 0-4, and n 1 and n 4 cannot be 0 at the same time, n 2 and n 3 cannot be 0 at the same time;
  • R la is a hydrogen atom, a 13 ⁇ 4 atom, a cyano group, a nitro group, a hydroxyl group, an amino group, a carboxyl group, a methanesulfonyl group, a decyloxycarbonyl group;
  • R lb is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, an amino group, a nitro group, a decyl group, a sulfonic acid group, an amino decanoyl group, a d- 6 alkyl group, a C 1-6 alkoxy group, a C 3-8 ring.
  • alkyl C 2. 6 alkenyl group, C 5-8 cycloalkenyl, C 2-6 alkynyl, C 3-8 cycloalkoxy, d. 6 alkylamino, di (d_ 6 alkyl) amine , d.
  • the C 3-8 cycloalkyl group, the C 5-8 cycloalkenyl group, the phenyl group and the 3- to 8-membered heterocyclic group may be optionally 1 to 6 selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, an amino group, and d. Substituted with the same or different substituents in 6 alkyl or substituted d- 6 alkyl;
  • R 2b , R 3a and R 3b 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, .
  • C 5 8 cycloalkenyl, C 2-6 alkynyl or C 3 - 8 cycloalkyl group said d 6 alkyl, (3 ⁇ 4_ 8 cycloalkyl, C 2 6 alkenyl group, (5 _.
  • cycloalkenyl, C 2-6 alkynyl, d- 6 alkoxy and C 3-8 cycloalkoxy may be optionally 1 to 6 selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group. Substituted with the same or different substituents;
  • R 4 and R 5 are each independently hydrogen, C 1-6 alkyl or a 3-8 membered heterocyclic group, and R 4 and R 5 may form a C 3 .8 cycloalkyl group, C 5 _ with the X to which they are attached.
  • R 4a is a hydrogen atom, a nitro group, a cyano group, a pertin atom, a hydroxyl group, a carboxyl group, an amino group, a d. 6 alkyl group, a C 1-6 alkoxy group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 5-8 cycloalkyl alkenyl, C 2-6 alkynyl, or C 3 _ 8 cycloalkyl group, said d_ 6 alkyl, C 3 8 cycloalkyl, C 2 -.
  • the 8- cycloalkenyl group, the C 2 -6 alkynyl group, the d 6 alkoxy group, and the C 3 -8 cycloalkoxy group may be optionally 1 to 6 selected from a 13-tetralole atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group. Substituted by the same or different substituents;
  • R 5a is a hydrogen atom or (CH 2 ) P R 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)qR 7 , NHCOOR 7 , NHCONR 8 R 9 , S(0)qNR 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, d- 6 alkyl or C 3. 8 cycloalkyl, R 8 and R 9 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, the d_ 6 alkyl, C 3 _ 8 cycloalkyl, and 3-8 membered heterocyclyl may optionally be selected from 1-6 halogen atoms, cyano, pyrrolidinyl, OR 10, C (O) R 10 , C(O)OR 10 , OC(O)R 10 , C(0)NR n R 12 > NR U R 12 , NR n C(0)R 10 , S(O)qR 10 , SC ⁇ qNRUR 12 Or the same or different substituents in NRHs C qR 10 ; R 10 R 11 and R 12 each independently represent a hydrogen atom, d.
  • R 11 and R 12 may form a 3-8 membered heterocyclic ring with the nitrogen to which they are attached
  • the d- 6 alkyl group, the C3-8 cycloalkyl group, the phenyl group and the 3-8 membered heterocyclic group may be optionally the same as 1 to 6 selected from a genio, a cyano group, a hydroxy group or a carboxy group. Or substituted with a different substituent;
  • p is an integer from 0 to 6;
  • q is an integer from 0-2.
  • Cy 1 is a 5-8 membered heteroaryl or 6-14 aryl
  • L is C(0), C(0)0, CH 2 C(0), NHC(0)NH, C(0)NH, NHC(0), NHS(0) 2 or S(0) 2 ;
  • X represents C, CH, O or N
  • Y 1 represents CH or N
  • Y 2 represents CH, CH 2 , N or NH
  • Nn ⁇ n 3 and n 4 are independently 0, 1, or 2, respectively, and n 1 and n 4 cannot be simultaneously
  • n 2 and n 3 cannot be 0 at the same time
  • R la is cyano, nitro, hydroxy, amino, carboxy, sulfonyl, methoxycarbonyl;
  • R lb is a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, a sulfonic acid group, a d. 6 alkyl group, an alkoxy group , C 2 _ 6 alkenyl, C 2. 6 alkynyl group, d. 6 alkylamino, di (d_ 6 alkyl) amino, d. 6 Yue alkylamino group, d_ 6 alkylamide group, D 6 alkylsulfonyl, d.
  • 6 alkyl amino sulfonyl group, a C 1-6 alkyl sulfonyl amide group, a ⁇ 6 alkoxycarbonyl group and a d 6 alkyl carbonyloxy group may optionally be 1 Substituted to 4 identical or different substituents selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group, m is 0, 1, 2 or 3, wherein when m is 2 or 3, the group represented by R lb Can be the same or different;
  • R 2a is a hydrogen atom, C 3 -. 8 cycloalkyl, C 5 8 cycloalkenyl, phenyl or 3-8-membered heterocyclic group,
  • the C 3-8 cycloalkyl group, C 5-8 cycloalkenyl group, phenyl group and 3-8 membered heterocyclic group may be optionally selected from 1 to 6 selected from a sulfonium atom, a cyano group, a hydroxy group, a carboxyl group and an amino group.
  • R 2b , R 3a and R 3b are each independently a hydrogen atom, a cyano group, a halogen atom, a d. 6 alkyl group, an alkoxy group, a C 3 -8 cycloalkyl group or a C 2 -6 alkynyl group, said d - 6 alkyl, d- 6 alkoxy,
  • C 3 - 8 cycloalkyl or C 2 6 alkynyl group and may optionally be selected from a 1-6 atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group in the same or different substituents;
  • R 4 and R 5 are each independently hydrogen, alkyl or a 3-8 membered heterocyclic group, and R 4 and R 5 may form a C 3 -8 cycloalkyl group, a C 5-8 cycloalkenyl group with the X to which they are attached.
  • a 3-8 membered heterocyclic group a 6-10 membered fused ring group, a 7-10 membered spirocyclic group or a 6-10 membered bridged ring group, said d- 6 alkyl group, C 3 -8 cycloalkyl group , C 5-8 cycloalkenyl 3-8 membered heterocyclic group, 6-10 membered fused ring group, 7-10 membered spiro ring group or
  • a 6-10 membered bridged ring group may be optionally substituted with 0-3 R 4a or;
  • R 4a is a hydrogen atom, a nitro group, a cyano group, a halogen atom, a hydroxyl group, an amino group, an alkyl group,
  • CL 6 alkoxy, C 3 -8 cycloalkyl, C 2 6 alkenyl or C 2 -. 6 alkynyl group, a C 1-6 alkyl group, C 1 -6 alkoxy, C 3 _ 8 a cycloalkyl group, a C 2-6 alkenyl group and a C 2-6 alkynyl group may be optionally substituted by 1 to 6 substituents selected from the same or different ones selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group;
  • R 5a is a hydrogen atom or (CH 2 ) P R 6 , wherein R 6 is OR 7 , C(0)OR 7 , OC(0)R 7 ,
  • R 7, R 8 and R 9 are each independently a hydrogen atom, d- 6 alkyl or C 3 - 8 cycloalkyl, R 8, and
  • R 9 may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, and the C 1-6 alkyl group, the C 3 -8 cycloalkyl group and the 3-8 membered heterocyclic group may be optionally 1 to 6 Selected from a halogen atom, a cyano group, a pyrrolidin group,
  • R 1Q , R 11 and R 12 are each independently a hydrogen atom, C 1- 6 alkyl or C 3.
  • R 11 and R 12 may form with the nitrogen to which they are attached a 3-8 membered heterocyclyl group, the C 1-6 alkyl, C 3-8 cycloalkyl and
  • the 3-8 membered heterocyclic group may be optionally substituted by 1 to 6 substituents selected from the same or different ones selected from a halogen atom, a cyano group, a hydroxyl group or a carboxyl group; p is 0, 1, 2, 3 or 4;
  • q 0, 1, or 2.
  • L is C(0), C(0)0, CH 2 C(0) NHC(0)NH, C(0)NH or NHC(O);
  • X represents C, CH, O or N
  • Y 1 represents CH or N
  • Y 2 represents CH, CH 2 , N or NH
  • n 2 , n 3 and n 4 are each independently 0, 1 or 2, and n 1 and n 4 cannot be 0 at the same time, n 2 and n 3 cannot be 0 at the same time;
  • R la is cyano, nitro, hydroxy, amino, carboxy, sulfonyl, oxime oxycarbonyl
  • R lb is a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, a sulfonic acid group, a d 6 alkyl group, a d.
  • R 2a is a hydrogen atom, a cycloalkyl group, a phenyl group or a 4-7 membered heterocyclic group, and the cyclo 8 alkyl group, the phenyl group and the 4-7 membered heterocyclic group may be optionally selected from 1 to 4 Substituted with the same or different substituents in a aryl group, a cyano group, a hydroxy group, a carboxy group, an amino group, an alkyl group or a substituted d- 6 alkyl group;
  • R 2b, R 3a and R 3b are each independently a hydrogen atom, a cyano group, a halogen atom, d_ 6 alkyl group, an alkoxy group or a C 2 -.. 6 alkynyl group, the alkyl group d 6, d 6 alkoxy alkoxy and C 2.
  • 6 alkynyl group may be optionally substituted with 1 to 4 substituents selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group are the same or Substituted with the same substituent;
  • R 4 and R 5 are each independently hydrogen, d_ 6 alkyl, or 3-8 membered heterocyclyl group, R 4 and R 5 may form C 3. 8 cycloalkyl, or 3-8 membered heteroaryl to which they are attached, X a cycloalkyl group, the C 1-6 alkyl group, the C 3 -8 cycloalkyl group and the 3-8 membered heterocyclic group may be optionally substituted by 0-2 R 4a or R 5a ;
  • R 4a is a hydrogen atom, a cyano group, a halogen atom, a hydroxyl group, an amino group, a C 1-6 alkyl group, a d- 6 alkoxy group or a group.
  • 3.8 cycloalkyl, said d. 6 alkyl group, d. 6 alkoxy and C 3-8 cycloalkyl may be optionally substituted by 1 to 4 substituents selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, or Substituting the same or different substituents in the amino group;
  • R 5a is a hydrogen atom or (CH 2 ) P R 6 , wherein R 6 is OR 7 , C(0)OR 7 , OC(0)R 7 , C(0)NR 8 R 9 , S(0) q R 7 , NR 8 S(0) q R 7 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, d. 6 alkyl or (: 4 _ 7 cycloalkyl, and R 8 and R 9 may form a 4-7 membered heterocyclic group with the nitrogen to which they are attached.
  • the C 1-6 alkyl group, the C 4 _ 7 cycloalkyl group and the 4-7 membered heterocyclic group may be optionally 1 to 4 selected from a halogen atom, a cyano group, an OR 1Q , a C(0)OR 10 , OC(0)R 10 , C(0)NR n R 12 , NR n R 12 , NRHC CR 1 or S(0) q R 10 substituted with the same or different substituents;
  • R 1Q, R 11 and R 12 each independently represent a hydrogen atom, d_ 6 alkyl or (4 _ 7 cycloalkyl, said alkyl and d- 6 7 cycloalkyl group can be optionally selected from 1-6
  • p 0, 1, 2, 3 or 4;
  • q 0, 1, or 2.
  • Cy 1 is a phenyl group
  • L is C(0), CH 2 C(0), NHC(0), NHC(0)NH or C(0)0;
  • X stands for (, CH, 0 or N;
  • Y 1 represents CH or N
  • Y 2 represents CH, CH 2 , N or NH; Nnn 3 and n 4 are independently 0, 1, or 2, respectively, and n 1 and n 4 cannot be simultaneously
  • n 2 and n 3 cannot be 0 at the same time
  • R la is cyano, nitro, hydroxy, amino, carboxy, methylsulfonyl or methoxycarbonyl
  • R lb is a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, a sulfonic acid group, an alkyl group, an alkylamino group , d 6 alkylamido, d- 6 alkylaminosulfonyl, d. 6 alkylsulfonylamino, alkoxycarbonyl or d.
  • R 2a is a hydrogen atom or a C 4 6 cycloalkyl group, and the ⁇ 6 cycloalkyl group may be optionally selected from 1 to 4 selected from a genio atom, a cyano group, a hydroxyl group, a carboxyl group, an amino group, an alkyl group or a substituted d- Substituting the same or different substituents in the 6 alkyl group;
  • R 2b , R 3a and R 3b are each independently a hydrogen atom, a cyano group, a
  • R 4 and R 5 are each independently hydrogen, C 1-6 alkyl or 4-6 membered heterocyclic group, and R 4 and R 5 may form a C 6 cycloalkyl group or a 4-6 membered hetero atom with the X to which they are attached.
  • a cycloalkyl group, the d. 6 alkyl group, a C 4 cycloalkyl group and a 4-6 membered heterocyclic group may be optionally substituted by 0-2 R 4a or R 5a ;
  • R 4a is a hydrogen atom, a cyano group, a halogen atom, a hydroxyl group, an amino group, a C 1-6 alkyl group or a d. 6 alkoxy group, and the C 1-6 alkyl group and the C 1 -6 alkoxy group may be optionally selected. Substituted by 1 to 4 substituents selected from the same or different substituents of a gen atom, a cyano group, a hydroxy group, a carboxyl group or an amino group;
  • R 5a is a hydrogen atom or (CH 2 ) P R 6 , wherein R 6 is OR 7 , C(0)OR 7 , OC(0)R 7 , S(0)qR 7 , NR 8 S(0)qR 7 NR 8 C(0)R 7 or NR 8 R 9 ;
  • R 7 , R 8 and R 9 are each independently a hydrogen atom, a C 6 alkyl group or a ⁇ 7 cycloalkyl group, and the alkyl group and the C 7 cycloalkyl group may be optionally 1 to 4 selected from a halogen atom and a cyanogen group.
  • OR 1() C(0)OR 10 , OC(0)R 10 , CC NRUR 12 or NRHR 12 ;
  • R 1G , R 11 and R 12 are each independently a hydrogen atom or a d 6 alkyl group, and the alkyl group may be optionally substituted by 1 to 4 of the same or different ones selected from a halogen atom, a cyano group, a hydroxyl group or a carboxyl group.
  • Base substitution
  • p 0, 1, 2 or 3;
  • q 1 or 2.
  • L is C(0), NHC(O) or C(0)0;
  • X is N, O or CH
  • Y 2 is N or CH
  • Y 1 is ⁇
  • R LA is cyano, nitro, hydroxy, amino, carboxy, methylsulfonyl, methoxycarbonyl;
  • R LB is a hydrogen atom, a halogen atom, a cyano group, a carboxyl group or a C 1 -6 alkyl group, and the C 1-6 alkyl group may be optionally one to four selected from a genio atom, a cyano group, a hydroxyl group, a carboxyl group or Substituting the same or different substituents in the amino group, m is 1;
  • R 2A is a hydrogen atom, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, and the cyclobutyl group, the cyclopentyl group and the cyclohexyl group may be optionally 1 to 4 selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, Substituting the same or different substituents in the amino group, d. 3 alkyl or substituted d. 3 alkyl;
  • the alkyl group wherein R 2B , R 3A and R 3B are each independently a hydrogen atom, a cyano group, a sulfonium atom or an alkyl group may be optionally one to four selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group. Substituted by the same or different substituents;
  • R 4 and R 5 are each independently hydrogen, d- 4 alkyl, 4-6 membered heterocyclic group, and R 4 and R 5 may form a 4-6 membered heterocyclic group with the X to which they are attached, said CM
  • the alkyl group and the 4-6 membered heterocyclic group may be optionally substituted by R 5A ;
  • R 5A is a hydrogen atom, d. 4 alkyl or (CH 2 ) P R 6 , wherein R 6 is OR 7 , S(0) Q R 7 , NR 8 S(0)qR 7 or NR 8 R 9 ;
  • R 7 , R 8 and R 9 are each independently a hydrogen atom or a C 1-4 alkyl group, and the CM alkyl group may be optionally 1 to 4 selected from a halogen atom, a cyano group, OR 1Q , C(0). Substituting the same or different substituents in OR 1Q or NRUR 12 ;
  • R 1Q , R 11 and R 12 are each independently a hydrogen atom or a d 4 alkyl group, and the CM alkyl group may be optionally the same or different from 1 to 6 selected from a halogen atom, a cyano group, a hydroxyl group or a carboxyl group. Substituent substitution;
  • p is 0 or 1;
  • Cy 1 is a phenyl group
  • L is C(O) or NHC(O);
  • X is N, 0 or CH
  • Y 2 is N or CH
  • Y 1 is N
  • n 2 , n 3 and n 4 are each independently 0, 1 or 2, and n 1 and n 4 cannot be 0 at the same time, n 2 and n 3 cannot be 0 at the same time;
  • R la is a cyano group
  • R lb is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group or a hydroxy group, and m is 1;
  • R 2a is a cyclopentyl group, and the cyclopentyl group may be optionally 1 to 3 atomic atoms, a cyano group, a hydroxyl group, a carboxyl group, an amino group, a d- 3 alkyl group or a ? 3 ⁇ 4 generation. 1-3 alkyl substituted;
  • R 2b , R 3a and R 3b are each independently a hydrogen atom, a cyano group, a halogen atom, a fluorenyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a methylol group or an amino group;
  • R 4 and R 5 are each independently hydrogen, decyl, ethyl, tetrahydropyrrolidinyl or tetrahydrofuranyl, and R 4 and R 5 form a piperidinyl group, a morpholinyl group, a piperazinyl group with the X to which they are attached, Pyrrole Alkyl, 0 ⁇ or tetrahydropyrrolidinyl, tetrahydrofuranyl, the piperidinyl, morpholinyl,
  • R 5a is a hydrogen atom, a methyl group or (CH 2 ) P R 6 , wherein R 6 is OR 7 , S(0) q R 7 , NR 8 S(0) q R 7 or NR 8 R 9 ;
  • R 7 , R 8 and R 9 are each independently a hydrogen atom or an alkyl group, and the d 3 alkyl group may be optionally substituted by 1 to 3 halogen atoms, a cyano group, a hydroxyl group or NR"R 12 ;
  • R 11 R 12 are each independently a hydrogen atom, a methyl group, an ethyl group or an isopropyl group
  • Cy 1 , L, X, , ⁇ 2 , ⁇ 1 , ⁇ 2 , ⁇ 4 , R la , R lb , R 3a , R 3b , R 4 , R 5 , and m are as defined in claim 1, and the group represented by R 2a is as defined in any one of the above (1) to (6). But not hydrogen, R 2b is hydrogen.
  • a pharmaceutical composition comprising the compound according to any one of the above (1) to (7), a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug thereof or an isomer thereof.
  • ARB an
  • cardiovascular disease is hypertension, heart failure, myocardial infarction, angina pectoris, cardiac hypertrophy, myocarditis, cardiac vascular fibrosis, baroreceptor dysfunction, excessive body fluids or Arrhythmia.
  • a method of treating and/or preventing kidney damage, hypertension or endocrine diseases comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of any one of the above (1) to (8) a compound, a pharmaceutically acceptable salt, ester or solvate thereof or a prodrug or isomer thereof.
  • angiotensin II antagonist Agent ARB
  • a calcium channel blocker CB
  • an angiotensin converting enzyme ACE
  • ANEP Double inhibitor of endopeptidase
  • ACENEP dual inhibitor of angiotensin converting enzyme/neutral endopeptidase
  • renin inhibitor diuretic, furosemide, chlorine Thiazide, biguanide, oc-glucosidase inhibitor, dipeptidyl peptidase (VI) inhibitor, 11 beta-hydroxysteroid dehydrogenase inhibitor, endothelin receptor blocker, cholesterol ester transferase (CETP) ) inhibitor
  • HMG-Co-A also Pro-enzyme
  • the present invention or a pharmaceutically acceptable salt, ester or solvate thereof
  • the present invention further preferably comprises the following compounds or pharmaceutically acceptable salts, esters or solvates thereof or prodrugs or isomers thereof:
  • alkyl refers to a straight or branched alkyl group derived from alkane having from 1 to 6 carbon atoms removed by a hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, or Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 1 ,1-dimethylpropyl, 1,2 - dimethylpropyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1-di Methyl butyl, 1,
  • CM alkyl Preferably d- 4 alkyl group, more preferably an alkyl group, the term "CM alkyl", “Cw of alkyl” refers to the specific examples 1 to 4, 1 to 3 carbon atoms contained 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 containing a double bond, such as a vinyl group, a 1-propenyl group, a 2-propenyl group, and 1 - Methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-fluorenyl-2- Propenyl, 2-mercapto-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
  • the double bond can optionally be cis and trans.
  • C 2 -6 alkynyl group as used in the present invention means a straight or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a 2-propynyl group, a 2-butynyl group, or the like.
  • the " ⁇ 6 alkoxy group” of the present invention means a group in which the term "C alkyl group” is bonded to another structure through an oxygen atom, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group.
  • Base isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy and the like.
  • the "( ⁇ -6 alkylamino group)" of the present invention is a group in which the term “alkyl group” is bonded to another structure through an amine group, such as methylamino group, ethylamino group, propylamino group, and isopropyl group.
  • "Di(Cw alkyl)amino” is a group of two identical or different "d. 6 alkyl” groups attached to the other structure via an amine group.
  • alkylthio as used in the present invention means a group in which the term “alkyl” is bonded to another structure through a sulfur atom, such as thiol, ethylthio, propylthio, isopropylthio, butylthio, iso Butylthio, tert-butylthio, sec-butylthio, pentylthio, neopentylthio, hexylthio, and the like.
  • the "( ⁇ -6 alkylcarbonyl)" means a group in which the term "CW alkyl group" is bonded to another structure through a carbonyl group, such as a mercaptocarbonyl group, an ethylcarbonyl group, a propylcarbonyl group, an isopropylcarbonyl group, Butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, neopentylcarbonyl, hexylcarbonyl and the like.
  • a carbonyl group such as a mercaptocarbonyl group, an ethylcarbonyl group, a propylcarbonyl group, an isopropylcarbonyl group, Butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, n
  • the "d. 6 alkylaminoformyl” described in the winter invention is a group in which the term “d- 6 alkyl” is bonded to other structures via a carbamoyl group, such as methylamino decanoyl, ethylamino hydrazine.
  • the "bis(d- 6 alkyl)carbamoyl group" of the present invention is a group in which two identical or different "d- 6 alkyl groups" are bonded to other structures via an aminoformyl group.
  • the "C 6 alkoxycarbonyl group” of the present invention is a group in which the term “d- 6 alkoxy group” is bonded to another structure through a carbonyl group, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropyloxycarbonyl 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 isopropyloxycarbonyl group, Butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, neopenty
  • alkylaminosulfonyl group of the present invention is a group in which the term “.6 alkyl group” is bonded to another structure through an aminosulfonyl group, such as methylaminosulfonyl group, ethylaminosulfonyl group, propylamino group.
  • d- 6 alkyl amido group "d.6 alkylsulfonyl group”, “Cw alkylsulfonylamino group”, "d- 6 alkylcarbonyloxy group” of the present invention are respectively the term "d- 6 alkyl group”.
  • C 8 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-methylcyclobutyl group.
  • Base cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • Preference is given to C 4 _ 7 cycloalkyl, C 4 6 cycloalkyl and C 5 - 6 cycloalkyl.
  • ⁇ 7 cycloalkyl "C cycloalkyl” are specific examples of the above examples containing 4 to 7, 4 to 6 carbon atoms.
  • the "C 3 .8 cycloalkoxy group” as used in the present invention means a group in which the term “ ⁇ 8 cycloalkyl group” is bonded to another structure through an oxygen atom, such as a cyclopropoxy group, a cyclobutoxy group, or a 1- Indenylcyclobutoxy, 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 cyclohexan-1-yl, cyclohex-2-enyl, cyclohex-3-yl, cycloheptan-1-enyl, cyclohept-2-enyl, ring Hept-3-enyl, cyclohept-4-enyl, cyclooct-1-enyl, cyclooct-2-enyl, cyclooct-3-enyl, cyclooctyl-4-enyl, 2,4 -cyclopentadienyl, 1,3-cyclohexadienyl, 1 ,4-cyclohexadienyl, 2,4-cyclohexadienyl, 2,5-cyclohexadienyl, 1 ,3 - cycloheptadienyl, 1, 4-cycloheptadienyl, 2,4-cycloheptadienyl, 1,5-cycloocta
  • heteroaryl of the present invention includes one or more ring atoms in addition to carbon atoms.
  • a hetero atom including but not limited to an oxygen atom, a nitrogen atom, and a sulfur atom.
  • the heteroaryl group may be bonded through a carbon or a hetero atom. It includes a 5-8 membered monocyclic heteroaryl group and a 8-14 membered fused heterocyclic aryl group.
  • 5-8 membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, furyl, thiophene Base, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-.
  • 5-10 membered heteroaryl refers to a specific example of a ring atom number of 5 to 10 in the above “heteroaryl group”.
  • the term “5-6 membered heteroaryl group” means a ring atom of the above “heteroaryl group”. The specific examples are 5-6.
  • the "aryl group” of the present invention may be a single ring or 2 or 3 fused rings, preferably a monocyclic aryl group, and specific examples include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group and the like, and a phenyl group is preferable.
  • the "6-14 membered aryl group” as used in the present invention means a monovalent moiety obtained by removing a hydrogen atom from a cyclic aromatic compound having a ring atom of 6 to 14 members.
  • the "6-14 membered aryl group” has a ring atom all of which is a carbon atom, and includes a 6-8 membered monocyclic carbonaryl group and an 8-14 membered fused ring carbonaryl group.
  • the 6-8 membered monocyclic carboaryl group means an all unsaturated aryl group such as a phenyl group, a cyclooctyltetraenyl group or the like.
  • 8- 14-membered fused ring carboaryl refers to a cyclic group in which two or more ring structures share two adjacent carbon atoms, and at least one ring is an all-unsaturated aromatic ring. Including 8-14 members of all unsaturated fused ring carbon aryl groups, such as naphthyl, anthracenyl and phenanthryl, etc., and also include 8-14 membered partially saturated fused ring carbon aryl groups, such as benzo 3-8 saturated single rings.
  • a cycloalkyl, benzo 3-8 member partially saturated monocyclic cycloalkyl group specific examples are 2,3-dihydroindenyl, fluorenyl, 1,2,3,4-tetrahydronaphthyl, 1,4- Dihydronaphthyl and the like.
  • the "3-8 membered heterocyclic group” in the present invention means a 3-8 membered cyclic group containing one or more hetero atoms, and the "hetero atom” means a nitrogen atom, an oxygen atom, a sulfur atom or the like.
  • the "heterocyclic group” includes a saturated or unsaturated monoheterocyclic group and a saturated or unsaturated fused heterocyclic group.
  • saturated or unsaturated monoheterocyclic group examples include: an oxiranyl group, a dioxanyl group, a thietyl group, an aziridine group, a 2/-azacyclopropane group.
  • diaziridine 3 /-diazapropenyl, oxazepine, oxetanyl, 1,2-dioxetyl, thietane 1,2-dithiabutenyl, azetidinyl, 1,2-diazetanyl, azetidinyl, 1,2-diazacyclobutene , furyl, tetrahydrofuranyl, thienyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, 1,3-dioxolyl, 1 ,3-dioxol-2-one, 1,2-dithiolane, 1,3-dithiolanyl, imidazolyl, 4,5-dihydroimidazolyl , imidazolidinyl, pyrazolyl, 4,5-dihydrihydr
  • the "5-10 membered fused ring group” as used in the present invention means a fused ring structure having 5 to 10 carbon atoms formed by two or more ring structures sharing two adjacent atoms with each other. . Including "5-10 yuan saturated fused ring” and “5-10 yuan unsaturated fused ring”.
  • the "6-10 membered fused ring group” of the present invention means a 6-10 membered fused ring structure in the above examples.
  • the "5-12 membered spirocyclic group” of the present invention means a structure having 5 to 12 carbon atoms formed by a class of at least two rings sharing one atom. Including "5-12 yuan saturated spiral ring” and "5-12 yuan unsaturated screw ring”.
  • a 5-12-membered saturated spirocyclic group means that all of the rings of the spirocyclic group are saturated cyclic groups, and specific examples include, but are not limited to:
  • the cyclic group structure replaces a group formed by any substitutable hydrogen atom.
  • the 5-12 membered partially saturated spiro group refers to a cyclic group in which at least one ring of the spiro group is unsaturated, and specific examples include but are not limited thereto.
  • the cyclic group structure replaces a group formed by any substitutable hydrogen atom.
  • a 7- to 10-membered spiro group is preferred, including "7-10 membered saturated spiro group" and "7-10 member unsaturated spiro group”.
  • the "7- to 10-membered spirocyclic group" of the present invention means a 7- to 10-membered spiro ring structure in the above examples.
  • the "6-10 membered bridged ring group” as used in the present invention means a structure containing 6 to 10 carbon atoms formed by any two rings which are not directly connected to each other. Including “6-10 yuan saturated bridge ring” and “6-10 yuan unsaturated bridge ring”.
  • 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-aza-helium ring [5.3.0] decane, bicyclo [2.2.1] hept-5-ene, bicyclo [3.2.1] Oct-6-ene, bicyclo (4.3.0) indol-5-ene, dicyclopentadiene, and the like.
  • integer of 0-4" in the present invention means 0, 1, 2, 3, 4; the "integer of 0-6” means 0, 1, 2, 3, 4, 5, 6; "Integer of 0-2" means 0, 1, and 2.
  • Raw material 1 (1.3-2 equivalents) is dissolved in a polar aprotic solvent (eg dimethylacetamide), feed 2 (1 equivalent) is added, and finally 3 equivalents of tertiary amine (including not limited to diisopropylethyl) Amine), at 90. C-120. After the reaction of C for 3-6 hours, the reaction is terminated, cooled, poured into water, extracted, and the organic phase is dried, dried, and purified by preparative liquid chromatography to give the compound of formula (I).
  • a polar aprotic solvent eg dimethylacetamide
  • feed 2 (1 equivalent
  • 3 equivalents of tertiary amine including not limited to diisopropylethyl) Amine
  • composition of the present invention containing the compound of the above formula (I), a pharmaceutically acceptable salt, ester or solvate thereof or a prodrug or isomer thereof may comprise 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, carboxy hydrazine Cellulose sodium, 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 ethyl laurate; agar; buffers such as,
  • the present invention also provides a compound of the present invention, a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug thereof or an isomer thereof, in the preparation of a medicament for treating and/or preventing kidney damage, cardiovascular disease or endocrine disease Applications.
  • cardiovascular diseases include, but are not limited to, hypertension, heart failure, myocardial infarction, angina pectoris, heart uterus, myocarditis, cardiac vascular fibrosis, baroreceptor dysfunction, excessive body fluids or arrhythmia; endocrine diseases including but not Limited to primary/secondary aldosteronism, Addison's disease, Cushing's syndrome or Bart's syndrome.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable salt thereof, an ester or a prodrug thereof, or an isomer thereof, and optionally one or more pharmaceutically acceptable carriers.
  • compositions of the present invention may also contain one or more additional therapeutically active substances including, but not limited to, angiotensin II antagonists (ARBs) or a pharmaceutically acceptable salt thereof, a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof, an angiotensin converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof, or a neutral endopeptidase (ANEP) dual inhibitor, angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) dual inhibitor or pharmaceutically acceptable salt thereof, renin inhibitor, diuretic, furosemide, chlorothiazide, Biguanide, ⁇ -glucosidase inhibitor, dipeptidyl peptidase (VI) inhibitor, 11 p-hydroxysteroid dehydrogenase inhibitor, endothelin receptor blocker, cholesterol ester transferase (CETP) inhibitor , HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, Na-K-ATPa
  • the invention also provides a method of treating and/or preventing 'injury, hypertension or endocrine disease, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, Esters or solvates or their prodrugs or isomers, wherein one or more other therapeutically active substances may also be administered in combination, examples of other active therapeutic agents are listed above.
  • the compounds of the present invention can be formulated into any pharmaceutical preparation by methods known in the art, and administered to patients in need of such treatment in the form of 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 disintegrant, a lubricant or the like may be added.
  • parenteral administration it can be prepared as an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection.
  • the injection When the injection is prepared, it can be produced by a conventional method in the prior art of pharmacy.
  • the additive When the injection is formulated, the additive may be added, or a suitable additive may be added depending on the nature of the drug.
  • the injection When used for rectal administration, it can be made into a suppository or the like.
  • pulmonary administration it can be formulated as an inhalant or a spray.
  • the amount of administration and frequency of administration of the compounds of the present invention can be adjusted according to the judgment of the clinician or the pharmacist, for example, by factors such as age, health and size of the patient, and the severity of the condition to be treated.
  • the total daily dose of the compounds of the invention will range from about 0.1 to about 2000 mg per day, although variations may occur, depending on the purpose of the treatment, the patient, and the route of administration.
  • the dosage is from about 1 to about 200 mg/ Days, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 10 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 100 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 500 to about 2000 mg/day, administered in a single dose or in two to four divided doses.
  • a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof is used in combination with other therapeutically active substances, they are administered simultaneously, separately or sequentially to form a single administration.
  • a pharmaceutical composition in a manner.
  • the amount of the other therapeutically active substance to be used in combination may be based on the amount used clinically, and may be appropriately selected depending on the subject to be administered, the route of administration, the disease, the combination, and the like.
  • the form of administration of the other therapeutic active agent shield is not particularly limited as long as the compound of the present invention and other therapeutically active substance are combined at the time of administration.
  • the compound of the formula (I) of the present invention can be prepared into a pharmaceutically acceptable salt by a known method, and the salt is a salt obtained by mixing a compound of the formula (I) 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, camphorsulfonate, carbonate, citrate, digluconate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, citrate, Fumarate, gluconate, glucuronate, glutamate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, Malate, malonate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, palmitate, fruit Gluconate
  • 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 Not limited to lithium, sodium, potassium, calcium, magnesium and aluminum salts, etc., as well as non-toxic quaternary ammonium and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, decylamine, diamine, tridecylamine, three Ethylamine, diethylamine, ethylamine, and the like.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.
  • Steps of any of the above compounds of the invention include all epimeric, diastereomeric and tautomeric forms.
  • a key is represented by a wedge, this indicates that the key will come out of the paper in three dimensions, and when a key is shaded, this indicates that the key will return to the paper in three dimensions.
  • the present invention claims a "stereoisomer" of a compound of the formula (I) which contains one or more asymmetric centers and thus acts as a racemate and a racemic mixture, a single enantiomeric A conformation, a mixture of diastereomers and a single diastereomer.
  • the compounds of the invention have asymmetric centers, each of which will independently produce two optical isomers, and the scope of the invention includes all possible optical isomers and mixtures of diastereomers and pure or partially Pure compound.
  • the invention includes all stereoisomeric forms of these compounds.
  • the spirocyclic dihydropyrazole compound of the present invention has more than one chiral center.
  • the synthesized is a racemate, and the desired enantiomerically pure compound can be obtained by chiral resolution: by chromatography with a chiral stationary phase (such as high pressure liquid phase preparation, supercritical fluid chromatography).
  • Chiral fillers include, but are not limited to, Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.
  • the enantiomerically pure dihydropyrazole compound containing a spiro ring can be further derivatized like a racemic dihydropyrazole compound containing a spiro ring.
  • the compound of the present invention has the following advantages:
  • the compound of the present invention a pharmaceutically acceptable salt thereof or an isomer thereof has a good antagonistic effect on an aldosterone receptor (i.e., a mineralocorticoid receptor) for treating and/or preventing various mammals (including humans).
  • an aldosterone receptor i.e., a mineralocorticoid receptor
  • the compounds of the invention have low toxicity and side effects; (3)
  • the compound of the invention has simple preparation process, good physical and chemical properties, stable quality and easy large-scale industrial production.
  • the beneficial effects of the compounds of the present invention are further illustrated by in vitro pharmacological experiments, but it should not be understood that the compounds of the present invention have only the following beneficial effects.
  • Test sample Part of the compound of the present invention (see Table 1), self-made, and its chemical name, structural formula and preparation method are as described in the examples.
  • test compound see Table 1
  • DMSO dimethyl methacrylatediol
  • the mother liquor was then diluted with DMSO to 200 ⁇ , 40 ⁇ , 8 ⁇ , 1.6 ⁇ , 0.3 ⁇ , 0 ⁇ 06 ⁇ , ⁇ . ⁇ , 0 ⁇ .
  • Double luciferase assay pBind-N (100 ng ⁇ L), l ⁇ L pG51uc (100 ng/ul), 2.5 ⁇ DMEM and 0.5 L Fugene were mixed and incubated for 15 min at room temperature to prepare a transfection solution.
  • a cell suspension was prepared according to 3xl0 5 cells/mL, and 100 L per well was added, and mixed with the above transfection solution. Incubate for 24 hours at 37 ° C in a 5% CO 2 incubator.
  • This test measures the mineralocorticoid receptor IC 5 Q value (ie, the resistance) of the test compound (test sample).
  • the compounds of the present invention have a good antagonistic effect on the salt Shield Hormone receptor.
  • 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 Guangsheng Bio, Suiyuan (Shanghai) Chemical Technology, Alfa Aesar (China), Shanghai TCI, Beijing Belling, Shanghai Bi De Pharmaceutical and other companies.
  • 6-(4-hydroxypiperidin-1-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 0.400 g (1.23 mmol) dissolved in To 2.5 mL of dichloromethane, 1.9 mL of trifluoroacetic acid was added, and the mixture was stirred for two hours in a water bath. After the completion of the reaction, the solvent was evaporated to give a pale white solid, 0.408 g, yield 17.6%.
  • tert-butyl 2,7-diazaspiro[3.5]decane-2-carboxylate (1.13 g, 5.0 mmol)
  • triphosgene (1.70 g, 6.0 mmol)
  • DIEA 3.46 mL, 20 mmol
  • add 30 mL of 1,2-dichloroethane stir in water bath for 5 min, transfer to room temperature for 1 h, add 4-hydroxypiperidine (2.023 g, 20 mmol), react for 15 h
  • LC - MS monitors the disappearance of the raw materials and stops the reaction.
  • the reaction solution was added with water, extracted with dichloromethane, and the organic extracts were combined.
  • the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated.
  • the yield was 49.8%.
  • the reaction mixture was evaporated to drynesshhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh The separation column was purified to obtain 730 mg of a pale yellow viscous liquid with a yield of 96.0%.
  • H- should be R(i-DMSO, 400 MHz): ⁇ 7.44 (IH, d), 7.12 (IH, d), 6.89 (IH, d), 6.71 (IH, d), 4.59-4.48 (IH, m ), 4.22-4.11 (IH, m), 3.70-3.57 (IH d), 3.32-3.24 (3H, m), 3.22-3.06 (3H, m), 3.05-2.95 (IH, m), 2.93 (3H, Br s), 2.85-2.68 (2H, m), 2.34-2.21 (1H, m), 2.04-1.88 (4H, m), 1.87-1.76 (2H : m), 1.75-1.36 (10H, m), 1.32 -1.18 (4H, m), 1.13-1.02 (IH, m).
  • the configuration of the compound of the present invention can also be estimated by referring to the prior art.
  • the compounds described in the Journal of Medicinal Chemistry (2010), 53(16), 5979-6002 are consistent with the targets of the compounds of the present invention, and the configuration and compounds of the compounds for analyzing the single chiral centers are also described.

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Abstract

L'invention concerne des composés de la formule (I), des sels, esters, ou solvates, ou des promédicaments ou isomères de ceux-ci, pharmaceutiquement acceptables. Dans cette formule, Cy1, L, X, Y1, Y2, n1, n2, n3, n4, R1a, R1b, R3a, R3b, R4, R5 et m sont tels que définis dans la description.
PCT/CN2012/000327 2011-03-18 2012-03-16 Composés dihydropyrazoles contenant le spiro Ceased WO2012126275A1 (fr)

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WO2015096035A1 (fr) * 2013-12-24 2015-07-02 Merck Sharp & Dohme Corp. Inhibiteurs du canal potassique médullaire externe rénal
US20240308985A1 (en) * 2021-12-29 2024-09-19 Psy Therapeutics, Inc. Inhibiting monoacylglycerol lipase (magl)

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CN112194656B (zh) * 2020-10-23 2022-12-02 青岛农业大学 一类含苯并噁唑酮的吡唑啉衍生物及其制备与杀菌用途

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WO2008067874A1 (fr) * 2006-10-26 2008-06-12 Bayer Schering Pharma Aktiengesellschaft Dipyridyl-dihydropyrazolones substituées et leur utilisation
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WO2010130796A1 (fr) * 2009-05-15 2010-11-18 Novartis Ag Arylpyridine en tant qu'inhibiteurs de l'aldostérone synthase

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WO2015096035A1 (fr) * 2013-12-24 2015-07-02 Merck Sharp & Dohme Corp. Inhibiteurs du canal potassique médullaire externe rénal
US9839629B2 (en) 2013-12-24 2017-12-12 Merck Sharp & Dohme Corp. Inhibitors of the renal outer medullary potassium channel
US20240308985A1 (en) * 2021-12-29 2024-09-19 Psy Therapeutics, Inc. Inhibiting monoacylglycerol lipase (magl)
US12286421B2 (en) * 2021-12-29 2025-04-29 Psy Therapeutics, Inc. Inhibiting monoacylglycerol lipase (MAGL)

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