WO2026032253A1 - Analogue de peptide cyclique, son procédé de préparation et son utilisation - Google Patents

Analogue de peptide cyclique, son procédé de préparation et son utilisation

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Publication number
WO2026032253A1
WO2026032253A1 PCT/CN2025/112664 CN2025112664W WO2026032253A1 WO 2026032253 A1 WO2026032253 A1 WO 2026032253A1 CN 2025112664 W CN2025112664 W CN 2025112664W WO 2026032253 A1 WO2026032253 A1 WO 2026032253A1
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Prior art keywords
alkylene
independently selected
alkyl
hydrogen
groups
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/112664
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English (en)
Chinese (zh)
Inventor
赵传武
王琛
王矿磊
杨汉煜
初燕燕
辛岭岭
郭文敏
柴晓玲
于云鹏
宋云龙
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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Application filed by CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd filed Critical CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Publication of WO2026032253A1 publication Critical patent/WO2026032253A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link

Definitions

  • This application relates to the field of pharmaceutical technology, specifically to a class of polypeptide derivatives, their preparation methods, and their pharmaceutical uses.
  • LDL-C low-density lipoprotein cholesterol
  • statins are the primary first-line drugs for lowering LDL-C; however, statins can be intolerable to some patients, or patients may not achieve the desired therapeutic effect at their tolerated doses.
  • Non-statin drugs such as the cholesterol inhibitor ezetimibe, combined with statins can further lower LDL-C by 15-20%.
  • Literature indicates that PCSK9 inhibitors combined with statins are even more effective in lowering LDL-C and can also overcome common statin side effects such as muscle pain.
  • PCSK9 may also regulate other proteins associated with LDLR family members, such as ApoER2 and VLDLR, as well as other cell surface proteins, such as CD36 and ACE2.
  • PCSK9 may play a key role in a variety of diseases, including cardiovascular disease, liver disease (such as non-alcoholic fatty liver disease NAFLD/NASH), infectious and autoimmune diseases, as well as neurocognitive impairment and cancer. Particularly in cardiovascular disease, PCSK9 increases disease risk by affecting cholesterol uptake. Furthermore, PCSK9 levels are significantly correlated with cholesterol, oxidized low-density lipoprotein (ox-LDL), and triglycerides.
  • ox-LDL oxidized low-density lipoprotein
  • this application provides a compound as shown in formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, having the following structure:
  • X1 , X2 , X3 , X4 , X5 , and X11 are each independently selected from hydrogen, deuterium, halogen, nitro, amino, hydroxyl, carboxyl, cyano, alkylsulfonyl, alkyl ester, alkylphosphonyl, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy , C2-6 alkenyl, C2-6 alkynyl , C3-6 cycloalkyl , and 3-12 membered heterocyclic groups.
  • the 3-6 cycloalkyl and 3-12 heterocyclic groups may optionally be substituted by one or more substituents selected from deuterium, halogen, nitro, hydroxyl, amino, hydroxyl, oxo, thio, carboxyl, cyano, alkylsulfonyl, alkyl ester, alkylphosphono, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, and 3-12 heterocyclic groups;
  • X7 and X9 are each independently selected from: [key, -[(CHR d ) p1 OC(O)] p2 -, -[(CHR d ) p1 O] p2 -, -[(CHR d ) p1 OC(O)O] p2 -, -[(CHR d ) p1 C(O)O] p2 -[(CHR d ) p O] p3 -, -[(CHR d ) p1 C(O)O] p2 -[(CHR d ) p1 OC(O)O] p3 -, -[(CHR d ) p1 OP(O)(OR e )O] p2 -, -[(CHR d ) p1 OP(O)(OR e )O] p2 -, -[(CHR d ) p
  • X 8 is independently selected from hydrogen, C1-6 alkyl, C3-6 carbocyclic, and 3-6 membered heterocyclic groups, wherein the C1-6 alkyl, C3-6 carbocyclic, and 3-6 membered heterocyclic groups are optionally substituted by one or more substituents selected from Rb ;
  • p1, p2, and p3 are each independently selected from 0, 1, 2, 3, 4, and 5;
  • R d is independently selected from hydrogen, halogen, amino, cyano, nitro, hydroxyl, mercapto, C1-6 alkyl, C3-6 cycloalkyl, wherein the C1-6 alkyl and C3-6 cycloalkyl are optionally substituted by one or more substituents selected from R f ;
  • Re is independently selected from hydrogen, C1-6 alkyl, benzyl, wherein the C1-6 alkyl and benzyl are optionally substituted by one or more substituents selected from Rg ;
  • Ra , Rb , Rc , Rf , and Rg are each independently selected from hydrogen, halogen, amino, cyano, nitro, hydroxyl, mercapto, C1-6 alkyl, and benzyl.
  • R1 and R2 are each independently selected from hydrogen, deuterium, -L1m1 - L2m2 - L3m3 - L4m4 - L5m5 - L6m6 - R3 , C1-6 alkyl , C1-6 alkoxy, C3-10 cycloalkyl , and 3-12 heterocyclic groups, wherein the C1-6 alkyl , C1-6 alkoxy, C3-10 cycloalkyl, and 3-12 heterocyclic groups are optionally substituted by one or more substituents selected from deuterium, halogen, hydroxyl, amino, hydroxyl, oxo, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, and 3-6 heterocyclic groups;
  • L1 , L2 , L3 , L4 , L5 , and L6 are each independently selected from: -O-, -N( R8 )-, -S-, -C(O)-, -C(O)O-, -N( R8 )C(O)-, -SO-, -SO2-, -SO2N ( R8 )-, -N( R8 )C(O)O-, -OC(O)O-, -N( R8 )C(O)N( R8 )-, -N(R8 ) S(O) 2N ( R8 )-, -S(O)( NR8 )-, -S(O)( NR8 )N( R8 )-, C1-6 alkylene, C2-8 alkenylene, C2-8 ynylene, C2-6 heteroalkylene, C 3-10 -membered cycloalkylene, 4-10-membered hetero
  • n1, m2, m3, m4, m5, and m6 are each independently selected from 0, 1, 2, and 3, and the sum of m1+m2+m3+m4+m5+m6 is less than 6;
  • Z1 is independently selected from oxo, halogen, amino, hydroxyl, nitro, cyano, -OR9, -C(O) R9 , -C(O) OR9 , -C(O)N( R9 ) 2 , -N( R9 ) 2 , -N( R9 )C(O) R9 , -N( R9 )C ( O) OR9 , -N( R9 )C(O)N( R9 ) 2 , -N( R9 )S(O) 2 ( R9 ), -NR9 , S(O) 2N ( R9 ) 2 , -NR9S (O) 2 , O( R9 ), -OC(O) R9 , -OC(O) OR9 , -OC(O)N( R9 ) 2 , -SR9 , -S(O) R9 -SF5 , -S(O)( NR9 )
  • R3 is independently selected from -NH2 , -N + H3 , -N + ( C1-3 alkyl) 3 , -NH-C(O)-L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 -R 4 , wherein R 4 is independently selected from -NH 2 , -N + H 3 , -N + (C 1-3 alkyl) 3 or n is independently selected from 1 and 2;
  • R 5 is independently selected from hydrogen, deuterium, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, and 3-12 membered heterocyclic groups;
  • R2 , R5 together with the carbon atom to which they are attached form a C3-6 cycloalkyl or C3-6 heterocyclic group optionally substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, C1-6 alkyl , C1-6 alkoxy;
  • X1 is H
  • X2 is halogen
  • X3 is H
  • X4 is methoxy
  • X5 is H
  • X6 is H
  • X7 and X8 are absent
  • R4 is hydrogen
  • ring A is... At that time, R1 or R2 is not:
  • ring A is
  • X1 , X2 , X3 , X4 , X5 , and X11 are each independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C2-6 alkenyl , C2-6 alkynyl , C3-6 cycloalkyl, and 3-6 membered heterocyclic groups.
  • the 3-6 cycloalkyl and 3-6 membered heterocyclic groups are optionally substituted by one or more substituents selected from deuterium, halogen, nitro, hydroxyl, amino, hydroxyl, oxo, thio, carboxyl, cyano, sulfonyl, ester, phosphono, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C3-6 cycloalkyl, and 3-6 membered heterocyclic groups.
  • X1 is independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy.
  • X1 is independently selected from hydrogen, halogen, C1-3 alkyl, and more preferably, X1 is located at the meta position on the benzene ring.
  • X2 is independently selected from hydrogen, deuterium, and halogens; halogens are preferred; fluorine is more preferred.
  • X3 is independently selected from hydrogen, deuterium, and halogen; preferably hydrogen and halogen; more preferably hydrogen, fluorine, and chlorine.
  • X4 is independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, and C1-6 haloalkoxy.
  • X4 is independently selected from halogens, C1-6 alkoxy groups, C1-6 deuterated alkoxy groups, and C1-6 haloalkoxy groups (preferably C1-6 fluoroalkoxy groups).
  • X4 is independently selected from C1-6 alkoxy, C1-6 deuterated alkoxy, and C1-6 haloalkoxy (preferably C1-6 fluoroalkoxy).
  • X4 is independently selected from C1-3 alkoxy, C1-3 deuterated alkoxy, and C1-3 haloalkoxy (preferably C1-3 fluoroalkoxy).
  • X4 is independently selected from -OCH3 , -OCD3 , -OCF3 , -OCHF2 , and Cl.
  • X5 is independently selected from hydrogen, deuterium, and halogen; hydrogen is preferred.
  • X4 is independently selected from -OCH3 , -OCD3 , -OCF3 , -OCHF2 , and Cl, and X5 is hydrogen.
  • X4 is -OCH3 and X5 is hydrogen.
  • X 11 is independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, and 3-6 heterocyclic groups.
  • X11 is independently selected from hydrogen, halogen, C1-3 alkyl (e.g., methyl), and C3-4 cycloalkyl (e.g., cyclopropyl).
  • X 11 is independently selected from hydrogen, fluorine, chlorine, methyl, cyclopropyl; hydrogen is preferred.
  • X6 is independently selected from H, -C(O)-, -CH( Ra )OC(O)-,
  • the "*" terminal indicates connection to terminal O, and the "#” terminal indicates connection to terminal X7 ; when X6 is H, X7 and X8 do not exist.
  • X9 is a bond or -CH2OC (O)O-.
  • X8 is independently selected from hydrogen, C1-6 alkyl; preferably hydrogen, C1-4 alkyl.
  • X8 is independently selected from hydrogen, methyl, -C( CH3 ) 3 , and -CH( CH3 ) 2 .
  • X8 is methyl
  • X10 is independently selected from hydrogen, C1-4 alkyl; preferably hydrogen, methyl, -C( CH3 ) 3 , -CH( CH3 ) 2 .
  • X10 is hydrogen or -CH( CH3 ) 2 .
  • X6 is H, and X7 and X8 do not exist.
  • p1, p2, and p3 are each independently selected from 0, 1, and 2.
  • p1 is 1 or 2
  • p2 is 1
  • p3 is 0 or 1.
  • Ra is independently selected from hydrogen, C1-6 alkyl; preferably hydrogen, C1-2 alkyl; more preferably hydrogen, methyl.
  • R d is independently selected from hydrogen, C1-6 alkyl; preferably hydrogen, C1-3 alkyl; more preferably hydrogen.
  • It is hydrogen
  • R1 is independently selected from -L1m1 -L2m2 -L3m3 -L4m4 -L5m5 -L6m6 -R3 ;
  • L1 , L2 , L3 , L4 , L5 , and L6 are each independently selected from: -O-, -N( R8 )-, -C(O)-, -C(O)O-, -N( R8 )C(O)-, -C(O)N( R8 )-, C1-6 alkylene, C2-6 alkenylene, C2-6 ynynylene, C2-6 heteroalkylene, C3-6 cycloalkylene, 4-6 heterocyclic, phenyl, and 5-6 heteroaryl; wherein the C1-6 alkylene, C2-6 alkenylene, C2-6 ynynylene, C2-6 heteroalkylene, C3-6 cycloalkylene, 4-6 heterocyclic, phenyl, and 5-6 heteroaryl are optionally substituted by one to three substituents selected from Z1 ;
  • n1, m2, m3, m4, m5, and m6 are each independently selected from 0, 1, 2, and 3, and the sum of m1+m2+m3+m4+m5+m6 is less than 6;
  • Z1 is independently selected from halogen, amino, hydroxy, cyano, -OR9, -C(O) R9 , -C (O) OR9 , -C(O)N( R9 ) 2 , -N( R9 ) 2 , -N( R9 )C(O) R9 , -S(O) 2R9 , C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 heterocyclic, phenyl, 5-6 heteroaryl; or any two Z1s together with the atoms they are attached to form C3-6 cycloalkyl, C3-6 heterocyclic, phenyl, 5-6 heteroaryl.
  • R8 and R9 are each independently selected from hydrogen, deuterium, and C1-6 alkyl groups
  • R3 is independently selected from -NH2 , -N + H3 , -N + ( CH3 ) 3 , n is independently selected from 1 and 2.
  • R1 is independently selected from -C1-6 alkylene- R3 , -CH2NHC (O)-( C1-6 alkylene) mR3 , -CH2C (O)NH-( C1-6 alkylene) mR3 , -CH2NHC (O)-[( C1-6 alkylene) m -O-] 1-4- ( C1-6 alkylene) mR3 , -CH2NHC(O)-( C1-6 alkylene) m - C3-6 cycloalkylene-( C1-6 alkylene) m - R3 , -CH2NHC ( O)-( C1-6 alkylene)m-4-6 heterocyclic-( C1-6 alkylene) m - R3 , -CH2NHC (O) - (C1-6 alkylene ) m -phenyl-( C1-6 alkylene) m -R 3 ⁇ -CH 2 NHC(O)-(C 1-6 alkylene) m
  • R3 is independently selected from -NH2 , -N + H3 , -N + ( CH3 ) 3 , m is independently selected from 0 and 1, and n is independently selected from 1 and 2;
  • Z1 is independently selected from halogen, amino, hydroxy, cyano, -S(O)2R9 , C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 heterocyclic, phenyl, 5-6 heteroaryl; or any two Z1s together with the atoms they are attached to form C3-6 cycloalkyl, C3-6 heterocyclic, phenyl, 5-6 heteroaryl.
  • R9 is independently selected from hydrogen and C1-6 alkyl groups.
  • R1 is independently selected from -C1-6 alkylene- R3 , -CH2NHC (O)-( C1-6 alkylene) mR3 , -CH2C (O)NH-( C1-6 alkylene) mR3 , -CH2NHC (O)-[( C1-3 alkylene) m - O- ] 1-2- ( C1-3 alkylene) mR3 , -CH2NHC( O)-(C1-3 alkylene)m-C3-6 cycloalkylene-(C1-3 alkylene )m - R3 , -CH2NHC ( O)-( C1-3 alkylene)m-4-6 heterocyclic-( C1-3 alkylene) m - R3 , -CH2NHC (O) - (C1-3 alkylene ) m -phenyl-( C1-3 alkylene) m -R 3 ⁇ -CH 2 NHC(O)-(C 1-3 alkylene) m
  • R3 is independently selected from -NH2 , -N + H3 , -N + ( CH3 ) 3 , m is independently selected from 0 and 1, and n is independently selected from 1 and 2;
  • halogen groups e.g., fluorine, chlorine, bromine
  • amino hydroxyl
  • cyano cyano
  • -S(O )2R9 e.g., methyl, ethyl
  • phenyl, 5-6 heteroaryl e.g., pyridyl
  • any two Z 1s together with the atoms they are attached to form C 3-6 cycloalkyl e.g., cyclopropane, cyclobutane, cyclopentane, cyclohexane
  • 4-6 heterocyclic e.g., phenyl, 5-6 heteroaryl (e.g., pyridyl); ".” indicates a linking site, phenyl, and 5-6 membered heteroaryl groups;
  • R9 is independently selected from hydrogen and C1-3 alkyl groups (e.g., methyl, ethyl).
  • R1 is independently selected from -C1-6 alkylene- R3 , -CH2NHC (O)-( C1-6 alkylene) mR3 , -CH2NHC (O)-[( C1-6 alkylene)m -O- ] 1-4- ( C1-6 alkylene) mR3 , -CH2NHC(O)-( C1-6 alkylene) m - C3-6 cycloalkylene- (C1-6 alkylene ) m -R3, -CH2NHC(O)-( C1-6 alkylene) m - 4-6 -membered heterocyclic-( C1-6 alkylene) m - R3, -CH2NHC ( O)-( C1-6 alkylene) m-phenyl-(C1-6 alkylene)m - R3 , -CH2NHC(O)-( C1-6 alkylene) m - R3 , and -CH2NHC (O)-( C1-6 alkylene)-(
  • Z1 is independently selected from halogen, amino, hydroxy, cyano, -S(O)2R9 , C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 heterocyclic, phenyl, 5-6 heteroaryl; or any two Z1s together with the atoms they are attached to form C3-6 cycloalkyl, C3-6 heterocyclic, phenyl, 5-6 heteroaryl.
  • R8 and R9 are each independently selected from hydrogen and C1-6 alkyl groups.
  • R1 is independently selected from -CH2NHC (O)-( C1-6 alkylene ) mR3 , -CH2NHC (O)-( C1-6 alkylene) m - C3-6 cycloalkylene-( C1-6 alkylene) m - R3 , -CH2NHC(O)-( C1-6 alkylene) m - 4-6 heterocyclic-( C1-6 alkylene) m - R3 , -CH2NHC(O)-( C1-6 alkylene) m -5-6 heteroaryl-( C1-6 alkylene) m - R3 , -CH2NHC(O )-(C1-6 alkylene ) m -O-( C1-6 alkylene) m - C3-6 cycloalkylene-( C1-6 alkylene) m - R3 , -CH2NHC (O) N (C 1-3 alkyl)-(C 1-6 alkylene) m -R3 ,
  • Z1 is independently selected from halogen, amino, hydroxy, cyano, -S(O) 2R9 , C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, 4-6 heterocyclic, phenyl, 5-6 heteroaryl; or any two Z1s together with the atoms they are attached to form a C3-6 cycloalkyl or C3-6 heterocyclic group;
  • R9 are each independently selected from hydrogen or C1-6 alkyl groups.
  • Z1 is independently selected from halogen, amino, hydroxy, cyano, -S(O) 2R9 , C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, phenyl, 5-6 heteroaryl; or any two Z1s together with the atoms they are attached to form a C3-6 cycloalkyl or C3-6 heterocyclic group;
  • R9 is selected from hydrogen or C1-6 alkyl.
  • Z1 is independently selected from -S(O) 2R9 , C1-6 alkyl , C1-6 alkoxy, C2-6 alkenyl, phenyl, or 5-6 heteroaryl; R9 is selected from hydrogen or C1-6 alkyl.
  • R1 is selected from -CH2NHC (O)-( CH2 ) m7 - R3 and -CH2NHS (O) 2- ( CH2 ) m8 - R3 , where m7 and m8 are each independently 4, 5, 6, or 7, wherein one or two adjacent -( CH2 )- are optionally replaced by any of the following substituents: C3-6 cycloalkyl, C3-6 heterocyclic, phenyl, 5-6 membered heteroaryl, -C(O)NH-, or -N( CH3 )- (more preferably).
  • R3 is independently selected from -N + H3 , -N + ( CH3 ) 3 , n is independently selected from 1 or 2; -( CH2 ) m7- and -( CH2 ) m8- are optionally substituted by 1 or 2 substituents selected from Z1 , Z1 being independently selected from -S( O)2R9 , C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, phenyl or 5-6 heteroaryl; R9 is selected from hydrogen or C1-6 alkyl.
  • R1 is selected from -CH2NHC (O)-( CH2 ) m7 - R3 , where m7 is 4, 5, 6, or 7, and one or two adjacent -( CH2 )- are optionally replaced by any of the following segments: -C(O)NH- or -N( CH3 )-; optionally, further, another -( CH2 )- is replaced by -O-; R3 is independently selected from -N + H3 , -N + ( CH3 ) 3 , n is independently selected from 1 or 2; the -( CH2 ) m7- is optionally substituted by 1 or 2 substituents selected from Z1 , Z1 being independently selected from -S(O) 2R9 , C1-6 alkyl , C1-6 alkoxy, C2-6 alkenyl, phenyl or 5-6 heteroaryl; R9 is selected from hydrogen or C1-6 alkyl.
  • R1 is selected from -CH2NHS (O) 2- ( CH2 ) m8 - R3 , where m8 is 4, 5, or 6; R3 is independently selected from -N + H3 , -N + ( CH3 ) 3 , n is selected independently from 1 or 2.
  • R1 is independently selected from the following groups:
  • R1 described above contains A- .
  • A- is independently selected from Cl- , CH3COO- , HCOO- , C10H19O2- , C9H18O2- , and CF3COO- .
  • A- is Cl- or CF3COO- .
  • A- is Cl- .
  • R1 is independently selected from the following groups:
  • R3 is independently selected from -NH2 , -N + H3 , -N + ( CH3 ) 3 , -NH-C(O)-L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 -R 4 , where R 4 is independently selected from -NH 2 , -N + H 3 , -N + (CH 3 ) 3 or n is independently selected from 1 and 2; preferably, R3 is -NH2 , -N + H3 , -N + ( CH3 ) 3 , n is 1 or 2.
  • -L1m1 -L2m2 -L3m3 -L4m4 -L5m5 -L6m6 - are independently selected from: -CH2NHC (O)-( C1-6 alkylene ) m- , -CH2C ( O ) NH-( C1-6 alkylene) m-, -CH2NHC(O ) -( C1-6 alkylene) m- ( R6 ) m- ( C1-6 alkylene) m- , -CH2NHC(O)-[( C1-6 alkylene) m -O-] 1-4- ( C1-6 alkylene) m- (R6) m- ( C1-6 alkylene) m- , -CH2NHC ( O ) N ( R8 )- (C1-6 alkylene ) m- , -CH2NHC (O)- ( C1-6 alkylene) m- ( R6 ) ) m -[-CH2NHC
  • Z1 is independently selected from halogen groups (e.g., fluorine, chlorine, bromine), amino, hydroxyl, cyano, -OR9 , -C(O) R9 , -C(O) OR9 , -C(O)N( R9 ) 2 , -N( R9 ) 2 , -N( R9 )C(O ) R9 , -S(O) 2R9 , C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 heterocyclic, phenyl, 5-6 heteroaryl; or any two Z1s together with the atoms they are attached to form C3-6 cycloalkyl, C3-6 heterocyclic, phenyl, 5-6 heteroaryl.
  • halogen groups e.g., fluorine, chlorine, bromine
  • R8 and R9 are each independently selected from hydrogen, deuterium, and C1-6 alkyl; preferably, R8 and R9 are each independently selected from hydrogen, deuterium, methyl, and ethyl.
  • n is independently selected from 0, 1, 2, 3; preferably, m is independently selected from 0, 1.
  • -L1m1 -L2m2 -L3m3 -L4m4 -L5m5 -L6m6 - are independently selected from: -CH2NHC (O)-( C1-6 alkylene) m- , -CH2C ( O ) NH-( C1-6 alkylene) m-, -CH2NHC ( O ) -( C1-3 alkylene) m- ( R6 ) m- ( C1-3 alkylene) m- , -CH2NHC (O)-[( C1-3 alkylene) m -O-] 1-2- ( C1-3 alkylene) m- (R6) m- ( C1-3 alkylene) m- , -CH2NHC (O) N ( R8 )- (C1-3 alkylene ) m- , -CH2NHC (O)- (C1-3 alkylene ) m- ( R6 ) ) m -[-O
  • Z1 is independently selected from halogen groups (e.g., fluorine, chlorine, bromine), amino, hydroxyl, cyano, -C(O) R9 , -C(O) OR9 , -C(O)N( R9 ) 2 , -N( R9 ) 2 , -N( R9 )C(O) R9 , -S (O) 2R9 , C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 4-6 heterocyclic, phenyl, 5-6 heteroaryl; or any two Z1s together with the atoms they are attached to form C3-6 cycloalkyl, C3-6 heterocyclic, phenyl, 5-6 heteroaryl.
  • halogen groups e.g., fluorine, chlorine, bromine
  • R8 and R9 are each independently selected from hydrogen, deuterium, and C1-3 alkyl; preferably, R8 and R9 are each independently selected from hydrogen, deuterium, methyl, and ethyl.
  • n is independently selected from 0 and 1.
  • -L 1 m1 -L 2 m2 -L 3 m3 -L 4 m4 -L 5 m5 -L 6 m6 - are independently selected from: -CH 2 NHC(O)-(C 1-6 alkylene) m -, -CH 2 NHC(O)-(C 1-6 alkylene) m -(R 6 ) m -(C 1-6 alkylene) m -, -CH 2 NHC(O)-[(C 1-6 alkylene) m -O-] 1-4 -(C 1-6 alkylene) m -(R 6 ) m -(C 1-6 alkylene) m -, -CH 2 NHC(O)N(R 8 )-(C 1-6 alkylene) m -, -CH 2 NHC(O)-(C 1-6 alkylene) m -(R 6 ) m -[-O-(C 1-6 alkyl
  • Z1 is independently selected from halogen, amino, hydroxy, cyano, -OR9, -C(O) R9 , -C (O) OR9 , -C(O)N( R9 ) 2 , -N( R9 ) 2 , -N( R9 )C(O) R9 , -S(O) 2R9 , C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 heterocyclic, phenyl, 5-6 heteroaryl; or any two Z1s together with the atoms they are attached to form C3-6 cycloalkyl, C3-6 heterocyclic, phenyl, 5-6 heteroaryl.
  • R8 and R9 are each independently selected from hydrogen, deuterium, and C1-6 alkyl groups; m is independently selected from 0, 1, 2, and 3.
  • -L1m1 -L2m2 -L3m3 -L4m4 -L5m5 -L6m6 - are independently selected from the following groups :
  • R6 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, imidazolyl, and pyrazolyl.
  • R6 is independently selected
  • Z1 is independently selected from halogen groups (e.g., fluorine, chlorine, bromine), amino groups, hydroxyl groups, cyano groups, -C(O) C1-3 alkyl groups, -C(O) OC1-3 alkyl groups, -C(O) NH2 , -C(O)N( C1-3 alkyl) 2 , -N( C1-3 alkyl) 2 , -NHC(O) C1-3 alkyl groups, -S(O) 2C1-3 alkyl groups, C1-3 alkyl groups, C1-3 alkoxy groups, C2-4 alkenyl groups, C2-4 alkynyl groups, C3-6 cycloalkyl groups, 4-6 heterocyclic groups, phenyl groups, and 5-6 heteroaryl groups; or any two Z1 groups together with the atoms they are attached to form C3-6 cycloalkyl groups, 4-6 heterocyclic groups, phenyl groups, and 5-6 heteroaryl groups.
  • halogen groups e.g
  • halogen groups e.g., fluorine, chlorine, bromine
  • A- is independently selected from Cl-, CH3COO-, HCOO-, C10H19O2- , C9H18O2- , and CF3COO- . In some embodiments , A- is Cl- or CF3COO- . In some embodiments, A- is Cl- .
  • R2 is independently selected from C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, and 3-6 heterocyclic groups, wherein the C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, and 3-6 heterocyclic groups are optionally substituted by one or more substituents selected from halogens.
  • R2 is independently selected from C1-2 alkyl or C3-4 cycloalkyl.
  • R2 is independently selected from methyl or cyclopropyl.
  • R5 is independently selected from hydrogen.
  • R2 , R5 together with the carbon atoms they are attached to form C3-6 cycloalkyl or C3-6 heterocyclic groups.
  • R2 , R5 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; preferably cyclopropyl.
  • the carbon atoms bonded to R2 and R5 have an S configuration.
  • X1 is hydrogen
  • X2 is a halogen (e.g., fluorine)
  • X3 is hydrogen
  • X4 is a C1-3 alkoxy (e.g., -OCH3 ) or C1-3 haloalkoxy (e.g., C1-3 fluoroalkoxy, e.g., -OCF3 )
  • X5 is hydrogen
  • ring A is...
  • X 11 is hydrogen or halogen (e.g., fluorine).
  • X1 is hydrogen
  • X2 is fluorine
  • X3 is hydrogen
  • X4 is -OCH3 or -OCF3
  • X5 is hydrogen
  • ring A is...
  • X 11 is hydrogen or fluorine.
  • X1 is hydrogen
  • X2 is fluorine
  • X3 is hydrogen
  • X4 is -OCH3
  • X5 is hydrogen
  • ring A is...
  • R1 is -CH2NHC (O) -C1-6 alkylene- R3 or -CH2NHS (O) 2 - C1-6 alkylene- R3
  • R3 is independently selected from -N + H3 , -N + ( CH3 ) 3
  • n is independently selected from 1 or 2
  • the C1-6 alkylene group is optionally substituted by 1, 2 or 3 substituents selected from Z1 ; any two Z1 groups together with the atoms they are attached to form a C3-6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl) or a C3-6 heterocyclic group.
  • R1 is -CH2NHC (O)-( CH2 ) m7 - R3 or -CH2NHS (O) 2- ( CH2 ) m8 - R3 , where m7 and m8 are each independently 4, 5, 6 or 7, wherein one or two adjacent -( CH2 )- are optionally replaced by any of the following substituents: C3-6 cycloalkyl (preferably) C3-6 heterocyclic group (preferred) R3 is independently selected from -N + H3 , -N + ( CH3 ) 3 , n is selected independently from 1 or 2.
  • R1 is
  • R1 is
  • R2 is a C1-6 alkyl (preferably C1-4 alkyl, more preferably C1-2 alkyl) or C3-6 cycloalkyl (preferably C3-4 cycloalkyl), R5 is hydrogen, X6 is hydrogen, and X7 and X8 are absent.
  • R2 is methyl or cyclopropyl
  • R5 is hydrogen
  • X6 is hydrogen
  • X7 and X8 are absent.
  • R2 is methyl
  • R5 is hydrogen
  • X6 is hydrogen
  • X7 and X8 are absent.
  • X1 is hydrogen
  • X2 is fluorine
  • X3 is hydrogen
  • X4 is -OCH3 or -OCF3
  • X5 is hydrogen
  • ring A is... "**" indicates a connection to the methylene end
  • "##" indicates a connection to the ethylidene end
  • R2 is methyl or cyclopropyl
  • R5 is hydrogen
  • X6 is hydrogen
  • X7 and X8 are not present.
  • X1 is hydrogen
  • X2 is fluorine
  • X3 is hydrogen
  • X4 is -OCH3
  • X5 is hydrogen
  • ring A is... "**" indicates a connection to the methylene end
  • "##" indicates a connection to the ethylidene end
  • R2 is methyl
  • R5 is hydrogen
  • X6 is hydrogen
  • X7 and X8 are absent
  • R1 is -CH2NHC (O)-( C5-6 alkylene) R3 , -CH2NHC (O) -C3-6 cycloalkylene-( C4-5 alkylene) -R3
  • R3 is -N + ( CH3 ) 3 .
  • n is 1; (preferably R1 is -CH2NHC (O)-( CH2 ) 5 - R3 , -CH2NHC (O)-cyclopropyl-( CH2 ) 4 - R3 , R3 is -N + ( CH3 ) 3 , n is 1; more preferably R1 is ).
  • R1 or R3 when R1 or R3 contains a cation, it necessarily also contains A- .
  • A- is a pharmaceutically acceptable anion.
  • R3 when R3 contains -N + H3 , -N + ( CH3 ) 3 , or...
  • n is 1 or 2
  • R3 is -N + H3A- , -N + ( CH3 ) 3A- , or A - , where n is 1 or 2.
  • the compound provided in this application or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:
  • A- is a pharmaceutically acceptable anion
  • A- is independently selected from Cl- , CH3COO- , HCOO- , C10H19O2- , C9H18O2- , CF3COO- ; preferably Cl- , CF3COO- .
  • the compound provided in this application or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:
  • This application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described herein, its stereoisomer, or a pharmaceutically acceptable salt thereof.
  • composition described in this application comprises the compound described in this application or its stereoisomer or its pharmaceutically acceptable salt, and pharmaceutically acceptable excipients.
  • the administration of the compound of this application, its stereoisomer, or its pharmaceutically acceptable salt can be carried out in pure form or as a suitable pharmaceutical composition by any acceptable route of administration for providing a drug of similar use.
  • the pharmaceutical composition of this application can be prepared by combining the compound of this application with a suitable pharmaceutically acceptable excipient.
  • the pharmaceutical composition of this application can be formulated into solid, semi-solid, liquid, or gaseous formulations.
  • the above-mentioned pharmaceutical compositions can be prepared using excipients conventional in the field of pharmaceutical preparations by conventional preparation methods.
  • This application also provides, in another aspect, the use of the compound described herein or its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of this application, in the preparation of a medicament for antagonizing the activity of PCSK9 in a subject.
  • this application provides a method for antagonizing the activity of PCSK9 in a subject, comprising administering to the subject a therapeutically effective amount of the PCSK9-specific antagonist of this application (i.e., the compound described in this application or its stereoisomer or its pharmaceutically acceptable salt or the pharmaceutical composition of this application).
  • a therapeutically effective amount of the PCSK9-specific antagonist of this application i.e., the compound described in this application or its stereoisomer or its pharmaceutically acceptable salt or the pharmaceutical composition of this application.
  • this application provides a compound of this application or its stereoisomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for antagonizing the activity of PCSK9 in a subject.
  • this application provides the use of the compound described herein or its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of this application, in antagonizing the activity of PCSK9 in a subject.
  • the methods for antagonizing PCSK9 function are used as defined herein for the treatment of PCSK9-associated diseases, conditions, or symptoms, or alternatively for providing therapy in diseases, conditions, or symptoms in which the effects of a PCSK9 antagonist may be beneficial.
  • treatment method refers to a process of action that results in a change in at least one symptom of a disease state that may be preventative or therapeutic in nature.
  • This application also provides, in another aspect, the use of the compound described herein or its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of this application, in the preparation of a medicament for treating symptoms associated with PCSK9 activity.
  • this application provides a method for treating symptoms associated with PCSK9 activity, comprising administering to a subject a therapeutically effective amount of the compound described in this application or its stereoisomer or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of this application.
  • this application provides the compounds described in this application or their stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions of this application for the treatment of symptoms associated with PCSK9 activity.
  • this application provides the use of the compound described herein or its stereoisomer or its pharmaceutically acceptable salt or the pharmaceutical composition of this application in the treatment of symptoms associated with PCSK9 activity.
  • the condition associated with PCSK9 activity is a cardiovascular disease related to dyslipidemia, preferably atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular diseases and cardiovascular metabolic conditions.
  • this application relates to a treatment method for a condition associated with PCSK9 activity, or a treatment method for a condition resulting from PCSK9 activity, or a treatment method for a condition where PCSK9 function is contraindicated for a particular individual.
  • the method comprises administering to the individual a therapeutically effective amount of a PCSK9 antagonist compound of formula I or a pharmaceutically acceptable salt thereof.
  • the condition is a cardiovascular disease related to dyslipidemia, preferably atherosclerosis, hypercholesterolemia, coronary artery disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular diseases and cardiovascular metabolic conditions.
  • the treatment methods according to this application include administering to an individual a therapeutically (or preventively) effective amount of the PCSK9-specific antagonist of this application.
  • therapeutically effective or “preventively effective” refer to the amount used, meaning the amount necessary at the intended dose for the desired duration of duration to achieve the desired therapeutic and/or preventive effect.
  • the desired effect may, for example, be the relief, reduction, decrease, or cessation of at least one symptom associated with the treated condition.
  • the PCSK9 antagonist compound of this application is preferably administered in the form of a pharmaceutical composition as described in this application.
  • This application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in this application or its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of this application, and another, two or more compounds having the same or similar indications.
  • C mn refers to the number of carbon atoms in the given range.
  • C 1-6 means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms.
  • any variable e.g., R ⁇ sub> d ⁇ /sub>
  • its definition is independent in each case. Therefore, for example, if a group, a site, or an atom is substituted by two R ⁇ sub> d ⁇ /sub>, each R ⁇ sub> d ⁇ /sub> has an independent option.
  • multiple refers to 2 to 10, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 2, 3, 4, 5, 6, 7, 8; more preferably 2, 3, 4, 5, 6; and even more preferably 2 or 3.
  • L1 is selected from -N( R8 )C(O)- or -SO2N ( R8 )-, it means that L1 is selected from -N( R8 )C(O)-, -C(O)N( R8 )-, -SO2N ( R8 )-, or -N( R8 ) SO2- .
  • alkyl refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C1-10 alkyl), more preferably containing 1-8 carbon atoms ( C1-8 alkyl), more preferably containing 1-6 carbon atoms (i.e., C1-6 alkyl), or containing 1-4 carbon atoms (i.e., C1-4 alkyl), or containing 1-3 carbon atoms (i.e., C1-3 alkyl).
  • C1-6 alkyl means that the group is alkyl and the number of carbon atoms on the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.
  • alkylene refers to a divalent alkyl group as defined above, a straight-chain or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C1-10 alkylene), more preferably containing 1-8 carbon atoms ( C1-8 alkylene), more preferably containing 1-6 carbon atoms (i.e., C1-6 alkylene), or containing 1-4 carbon atoms (i.e., C1-4 alkylene), or containing 1-3 carbon atoms (i.e., C1-3 alkylene).
  • C1-6 alkylene means that the group is alkylene and the number of carbon atoms on the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methylene, ethylene, n-propylene, n-pentylene, n-hexylene, etc.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon atoms and hydrogen atoms, having at least one double bond.
  • An alkenyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2-10 alkenyl), more preferably 2-8 carbon atoms ( C2-8 alkenyl), and even more preferably 2-6 carbon atoms (i.e., C2-6 alkenyl), 2-5 carbon atoms (i.e., C2-5 alkenyl), 2-4 carbon atoms (i.e., C2-4 alkenyl), 2-3 carbon atoms (i.e., C2-3 alkenyl), or 2 carbon atoms (i.e., C2 alkenyl).
  • C2-6 alkenyl means that the group is alkenyl and the number of carbon atoms on the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5, or 6).
  • alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon atoms and hydrogen atoms, having at least one triple bond.
  • the alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2-10 alkynyl), more preferably 2-8 carbon atoms ( C2-8 alkynyl), and even more preferably 2-6 carbon atoms (i.e., C2-6 alkynyl), 2-5 carbon atoms (i.e., C2-5 alkynyl), 2-4 carbon atoms (i.e., C2-4 alkynyl), 2-3 carbon atoms (i.e., C2-3 alkynyl), or 2 carbon atoms (i.e., C2 alkynyl).
  • C2-6 alkynyl means that the group is alkynyl and the number of carbon atoms on the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5, or 6).
  • alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.
  • alkoxy refers to an -O-alkyl group, which is defined as above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6 , i.e., C1-6 alkoxy) or 1-3 carbon atoms (i.e., C1-3 alkoxy).
  • Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.
  • alkenyl refers to the divalent groups formed by removing two hydrogen atoms from the corresponding molecule.
  • heteroalkylene refers to an alkylene residue in which one or more carbon atoms (and associated hydrogen atoms) are replaced by a heteroatom. Examples include “oxaalkylene,””thioalkylene,” and “aziralkylene.”
  • the heteroatom is preferably O, N, or S, and the number of heteroatoms is preferably one, two, or three.
  • oxaalkylene refers to an alkylene residue in which one or more carbon atoms (and associated hydrogen atoms) are replaced by oxygen, such as “alkoxy” or "alkoxyalkyl.”
  • C3 oxaalkylene includes -OC1-3 alkoxy, -CH2OCH2CH3 , -CH2CH2OCH3 , etc. Examples include methoxy, ethoxy, propoxy , methoxypropyl , etc.
  • oxaalkyl means as understood in the art [see Nomenclature and Index of Chemical Substances for Chemical Extraction, published by the American Chemical Society, 196, but not limited to 127(a)], that is, a compound in which oxygen is bonded to its adjacent atoms via a single bond (forming an ether bond); it does not refer to the double oxygen bond found in the carbonyl group.
  • thiazide alkylene is similar to "oxazide alkylene".
  • azaalkylene refers to an alkylene containing the atomic group "NH", for example , C3 azaalkylene includes -NHCH2CH2CH3 , -CH2NHCH2CH3 , -CH2CH2NHCH3 , etc.
  • halogen refers to F, Cl, Br, and I.
  • halogenated alkyl refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms , are replaced by a halogen.
  • Representative examples of halogenated alkyl groups include CCl3, CF3, CHF2, CH2F , CHCl2 , CH2Cl , CH2Br , CH2I , CH2CF3 , CF2CF3 , etc.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., C3-12 cycloalkyl), more preferably containing 3-10 carbon atoms ( C3-10 cycloalkyl), and even more preferably 3-8 carbon atoms ( C3-8 cycloalkyl), 3-6 carbon atoms ( C3-6 cycloalkyl), or 5-6 carbon atoms ( C5-6 cycloalkyl).
  • C3-12 cycloalkyl preferably containing 3-12 carbon atoms (i.e., C3-12 cycloalkyl), more preferably containing 3-10 carbon atoms ( C3-10 cycloalkyl), and even more preferably 3-8 carbon atoms ( C3-8 cycloalkyl), 3-6 carbon atoms ( C3-6 cycloalkyl), or 5-6 carbon atoms ( C5-6 cycloalkyl).
  • Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc.
  • the term “carbocyclic group” refers to a non-aromatic cyclic hydrocarbon group (" C3-14 carbocyclic group”) having 3 to 14 ring carbon atoms and without heteroatoms in the non-aromatic ring system.
  • the carbocyclic group has 3 to 8 ring carbon atoms (" C3-8 carbocyclic group”), or 3 to 6 ring carbon atoms (" C3-6 carbocyclic group”), or 5 to 8 ring carbon atoms (" C5-8 carbocyclic group”).
  • the carbocyclic group has 5 to 6 ring carbon atoms (" C5-6 carbocyclic group”).
  • Exemplary C3-6 carbon cycloyl groups include, but are not limited to, cyclopropyl ( C3 ), cyclopropenyl ( C3 ), cyclobutyl (C4), cyclobutenyl ( C4 ), cyclopentyl ( C5 ), cyclopentenyl ( C5 ), cyclohexyl ( C6 ), cyclohexenyl ( C6 ), cyclohexadienyl ( C6 ), etc.
  • Exemplary C5-8 carbon cycloyl groups include, but are not limited to , the aforementioned C3-6 carbon cycloyl groups, as well as cycloheptyl ( C7 ), cycloheptenyl ( C7 ), cycloheptadienyl ( C7 ), cyclohepttrienyl ( C7 ), cyclooctyl ( C8 ), cyclooctenyl ( C8 ), bicyclo[2.2.1]heptyl ( C7 ), bicyclo[2.2.2]octyl ( C8 ), etc.
  • the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or a fused (fused-ring), bridged (bridged-ring), or spiro-fused (spirocyclic) ring system, such as a bicyclic system (“bicyclic carbocyclic”), and may be saturated or partially unsaturated.
  • “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the attachment point is on the carbocyclic ring, and in such cases, the number of carbons in the carbocyclic ring system is the number of carbons in the fused carbocyclic system.
  • each example of the carbocyclic group is independently optionally substituted, for example, unsubstituted (an “unsubstituted carbocyclic”) or substituted with one or more substituents (an “substituted carbocyclic”).
  • the carbocyclic group is an unsubstituted C5-8 carbocyclic group.
  • the carbocyclic group is a substituted C5-8 carbocyclic group.
  • heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic substituent having a ring carbon atom and 1 to 4 ring heteroatoms, comprising 3 to 20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., forming an oxo group).
  • it comprises 3 to 10 ring atoms (3-10 membered heterocyclic group), more preferably 3 to 8 ring atoms (3-8 membered heterocyclic group), or 3 to 6 ring atoms (3-6 membered heterocyclic group), or 4 to 6 ring atoms (4-6 membered heterocyclic group), 5 to 8 ring atoms (5-8 membered heterocyclic group), or 5 to 6 ring atoms (5-6 membered heterocyclic group).
  • the heteroatoms are preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3).
  • Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc.
  • Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.
  • a “heterocyclic group” can be a monocyclic (“monocyclic heterocyclic group”) or a fused (“fused heterocyclic group” or “heterofused-ring group”), bridged (“heterobridged ring group” or “bridged ring heterocyclic group”) or spiro-fused (“heterospirocyclic group” or “spirocyclic heterocyclic group”) ring system, such as a bicyclic system (“bicyclic heterocyclic group”), and can be saturated or partially unsaturated.
  • a bicyclic heterocyclic system can include one or more heteroatoms in one or two rings.
  • Heterocyclic group also includes a ring system in which the heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the attachment point is on the carbocyclic or heterocyclic ring; or “heterocyclic group” also includes a ring system in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, or a ring system in which a cycloalkyl ring as defined above is fused with one or more heteroaryl groups, wherein the attachment point is on the heterocyclic or cycloalkyl ring, and in such cases, the number of members in the heterocyclic ring system is the number of atoms in the fused ring system.
  • each example of a heterocyclic group is independently optionally substituted, for example, unsubstituted (an "unsubstituted heterocyclic group") or substituted with one or more substituents (a "substituted heterocyclic group”).
  • exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirropropyl, oxiranyl, and thiorenyl.
  • Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azahexacyclobutane, oxacyclobutane, and thiohexacyclobutane.
  • Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazine, morpholinyl, dithiocyclohexyl, and dioxazinanyl.
  • Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazacyclohexyl, oxadiazine, thiadiazine, oxathiazine, and dioxazinanyl.
  • Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxadiazine, and thioheptanyl.
  • Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxadiazine, and thioheptanyl.
  • Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc.
  • Exemplary 6-membered heterocyclic groups fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.
  • heterocyclic alkyl refers to a monocyclic, saturated “heterocyclic group” or “heterocycle” as defined above, with the same definition of ring atoms, i.e., containing 3 to 20 ring atoms ("3-20-membered heterocyclic alkyl"), and the number of heteroatoms is 1 to 4 (1, 2, 3 or 4), preferably 1 to 3 (1, 2 or 3), wherein each heteroatom is independently selected from N, O or S.
  • One or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and one or more carbocyclic atoms may optionally be oxidized (i.e., forming an oxo group).
  • heterocyclic group or “heterocyclic” section above has given some exemplary examples of “heterocyclic alkyl”, and also includes, but is not limited to, azirropropyl, oxacyclopropyl, thiocyclopropyl, azirrobutyl, oxacyclobutyl, thiocyclobutyl, tetrahydrofuranyl, oxacyclohexyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiohexyl, oxazolyl, dioxyl, dithiohexyl, thiazolyl, pyrroliyl, pyrazolyl, imidazolinidine, etc.
  • aryl refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, preferably 6-10 carbon atoms.
  • aryl may be used interchangeably with the term “aromatic cycloyl”. Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, or pyrene.
  • heteroaryl or “heteroary cycloyl” refers to an aromatic monocyclic or polycyclic system containing a 5-14 member structure, or preferably a 5-10 member structure, or preferably a 5-8 member structure, more preferably a 5-6 member structure, wherein one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms is preferably one, two or three.
  • heteroaryl groups include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, and benzo[] Pyrazinyl, benzimidazolyl, benziphthalazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a
  • salts of the compounds of this application can be formed by methods known to those skilled in the art, such as by reacting the compounds of this application with a certain amount (e.g., a certain equivalent) of an acid or base in a medium such as a salt precipitation medium or an aqueous medium, followed by lyophilization.
  • the compounds of this application contain a three-coordinate nitrogen atom, such as a primary, secondary, or tertiary amine moiety, wherein, as is known, the lone pair of electrons present on the nitrogen atom can be protonated with a suitable acid or alkylated with a suitable reagent (e.g., an alkyl bromide) under appropriate reaction conditions to provide a four-coordinate charged nitrogen stabilized by an anion (e.g., a halide ion or a conjugate base) produced in the process. Therefore, the compounds of this application can be prepared in the form of a free base or isolated as a quaternary complex or a salt complex.
  • a suitable reagent e.g., an alkyl bromide
  • salts of the compounds of this application are included within the scope of the compounds of this application as described herein, whether they are salts formed with inorganic and/or organic acids, base salts formed with inorganic and/or organic bases, salts formed including zwitterionic salts (e.g., where the compound contains a basic moiety, such as, but not limited to, a nitrogen atom, such as an amine, pyridine, or imidazole; and an acidic moiety, such as, but not limited to, both carboxylic acids), or quaternary ammonium complexes.
  • a basic moiety such as, but not limited to, a nitrogen atom, such as an amine, pyridine, or imidazole
  • an acidic moiety such as, but not limited to, both carboxylic acids
  • the structural representation of the compounds in this application also includes all other forms of such compounds discussed above, regardless of whether they are in the form of a free base, a salt, a zwitterion, or a quaternary ammonium.
  • one aspect of this application is to provide the compounds in the form of pharmaceutically acceptable salts, zwitterion complexes, or quaternary ammonium complexes.
  • Those skilled in the art will recognize examples of compounds in this application that can form such complexes, including instances where the tetracoordinate nitrogen can be quaternized or protonated and the charged nitrogen form is stabilized by an associated anion.
  • pharmaceutically acceptable salt refers to a salt (including quaternary ammonium complexes and internal salts such as zwitterion complexes) that has effects similar to or greater than those of the free base form of the compound and is not biologically or otherwise undesirable (e.g., neither toxic nor otherwise harmful to its recipient).
  • Examples of pharmaceutically acceptable acid salts include, but are not limited to, acetates (including trifluoroacetate), adipates, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, diglucuronates, dodecyl sulfates, ethanesulfonates, fumarates, glucohepate, glycerophosphates, hemisulfates, heptarates, hexanoates, hydrochlorides, hydrobromide, hydroiodates, 2-hydroxyethanesulfonate, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, o
  • the compounds in this application also include their “isotope derivatives".
  • isotope derivative refers to compounds in this application that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive.
  • isotopes for labeling are: hydrogen isotopes, 2H and 3H ; carbon isotopes: 13C and 14C ; chlorine isotopes: 35Cl and 37Cl ; fluorine isotope: 18F ; iodine isotopes: 123I and 125I ; nitrogen isotopes: 13N and 15N ; oxygen isotopes: 15O , 17O , and 18O ; and sulfur isotope 35S .
  • isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 3H and 13C , in particular, are more widely used due to their ease of labeling and detection.
  • Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.
  • the compounds in this application also include their “solvates” or “solvents”.
  • solvate and “solvent” refer to the physical association of the compound with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. Solvent molecules in a solvate may exist in a regular and/or disordered arrangement. Solvates may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate” encompasses both solution phases and separable solvates.
  • Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • hydrate refers to a substance in which water molecules are bonded to cations or anions in a compound by coordinate or covalent bonds, or in which water ions do not directly bond to cations or anions but exist in a specific proportion at defined positions in a solid crystal lattice.
  • stereoisomer refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups.
  • Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis/trans) isomers, and trans-restricted isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
  • the term “geometric isomer (cis/trans) isomer” may contain an E or Z configuration of a carbon-carbon or carbon-nitrogen double bond, wherein the term “E” represents a higher-order substituent on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and the term “Z” represents a higher-order substituent on the same side of the carbon-carbon or carbon-nitrogen double bond (determined using the Cahn-Ingold Prelog priority rule).
  • the compounds of this application may also exist in the form of a mixture of “E” and “Z” isomers.
  • the compounds in this application also include their “prodrugs.”
  • the term “prodrug” refers to a drug that is converted into a parent drug in vivo.
  • Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are generally related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include metabolism that is too rapid or poor bioavailability, which may itself be related to physicochemical properties. For example, they can be bioavailable orally, whereas the parent drug cannot.
  • Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug.
  • prodrug can be any compound of this application that is administered as an ester (“prodrug”) to facilitate transmembrane transport, where water solubility is detrimental to migration but beneficial once inside the cell, and is subsequently metabolized and hydrolyzed into a carboxylic acid, i.e., the active entity.
  • prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to exhibit the active moiety.
  • treatment covers any treatment of a patient’s disease, symptom, and condition, including: (a) suppressing the symptoms of the disease, symptom, and condition, i.e., preventing its development; or (b) alleviating the symptoms of the disease, symptom, and condition, i.e., causing the disease or symptoms to subside; or (c) improving or eliminating the disease, symptom, and condition or one or more symptoms associated with said disease.
  • the therapeutically effective dose described in this application refers to a pharmaceutically recognized effective dosage, that is, an amount of active compound sufficient to significantly improve the condition without causing serious side effects.
  • the compound in this application is a highly selective and highly active PCSK9 inhibitor with oral absorption characteristics
  • the compound of this application can significantly improve the LDL uptake capacity of HepG2 cells
  • the compounds of this application may be used to treat cardiovascular diseases related to dyslipidemia
  • the compound of this application has excellent oral administration properties
  • the compound in this application has no significant inhibitory effect on hERG channels and has a low risk of cardiotoxicity;
  • Figure 1 shows the mass spectrum of the compound obtained in Example 1-1.
  • Figure 2 shows the mass spectrum of the compound obtained in Example 2-1.
  • Figure 3 shows the mass spectrum of the compound obtained in Example 3-1.
  • Figure 4 shows the mass spectrum of the compound obtained in Example 4-1.
  • Figure 5 shows the mass spectrum of the compound obtained in Example 7-1.
  • the structures of the compounds in this application were determined by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS) and/or high-performance liquid chromatography (HPLC).
  • NMR nuclear magnetic resonance
  • LC-MS liquid chromatography-mass spectrometry
  • HPLC high-performance liquid chromatography
  • Step 1 Preparation of 6-(tert-butoxy)-N,N,N-trimethyl-6-oxohex-1-ammonium bromide
  • the preparation method is the same as that of intermediate Int 2, except that the raw material trimethylamine in step 1 is replaced with 1-methylpyrrolidine.
  • Intermediate Int 3 (2.5g), LC-MS: (M) + : 200.15.
  • the preparation method is the same as that of intermediate Int 2, except that the raw material tert-butyl 6-bromohexanoate in step 1 is replaced with intermediate Int 4 to obtain intermediate Int 5 (2.0 g).
  • the starting material (R)-2-((benzyloxycarbonyl)amino)-3-(tert-butoxycarbonylamino)propionic acid (11 g) was dissolved in DMF (150 mL), and potassium carbonate (8.8 g) was added with stirring. The temperature was controlled at 0 °C, and iodomethane (4.8 g) was slowly added dropwise. After the addition was complete, the temperature was raised to 20 °C and the reaction was carried out for 2 h. The reaction was confirmed to be complete by LC-MS.
  • the preparation method is the same as that of intermediate 25, except that the raw material (((9H-fluorene-9-yl)methoxy)carbonyl)-L-alanine in step 3 is replaced with the raw material (((9H-fluorene-9-yl)methoxy)carbonyl)-L-cyclopropylglycine, to obtain intermediate 40 (150 mg), LC-MS: (M+H) + : 524.23.
  • the preparation method is the same as that of intermediate 21, except that the raw material p-Boc-4-methoxy-L-phenylalanine is replaced with Boc-4-trifluoromethoxy-L-phenylalanine to obtain intermediate 44 (160 mg), LC-MS: (M+H) + : 740.30.
  • intermediate 46-3 (0.4 g) was dissolved in 10 mL of DCM, SOCl2 (0.34 g) was added to the reaction system, and finally DMF (1 drop) was added. After reacting for 4 hours, intermediate 46 (crude product) was obtained and used directly in the next synthesis without purification.
  • the preparation method was the same as in Examples 1-1, except that intermediate 39 was replaced with intermediate 43 to obtain the target compound of the example (15.1 mg), LC-MS: (M) + : 1594.7.
  • HepG2 cells were cultured in MEM medium containing 10% FBS at 37°C and 5% CO2. 100 ⁇ L of cells were added to 20,000 cells/well in a 96-well poly-D-lysine-coated culture plate. The cell culture plates were incubated overnight at 37°C and 5% CO2 .
  • HepG2 cells were starved using FBS-free MEM medium. Cell plates were cultured overnight at 37°C and 5% CO2 .
  • the excitation wavelength is 480 nm and the emission wavelength is 530 nm.
  • the experimental results show that the compounds of this application can significantly improve the LDL uptake capacity of HepG2 cells.
  • the experimental results of exemplary compounds are shown in the table below.
  • A represents EC 50 ⁇ 200 nM
  • B represents 200 nM ⁇ EC 50 ⁇ 300 nM
  • C represents EC 50 ⁇ 300 nM.
  • PCSK9 (Acro) protein is immobilized onto the SA chip via biotin-SA tag capture, and the channel is closed after immobilization.
  • the final binding and dissociation curves were obtained by subtracting the reference channel and buffer blank control from the experimental channel signal values.
  • the affinity data were obtained by fitting the curves using the 1:1 binding mode kinetics method.
  • the experimental results show that the compounds of this application have high affinity for PCSK9 protein (all less than 1 nM, preferably KD value less than 500 pM, more preferably KD value less than 20 pM).
  • the experimental results of exemplary compounds are shown below.
  • A represents K ⁇ sub> D ⁇ /sub> ⁇ 20 pM
  • B represents 20 pM ⁇ K ⁇ sub> D ⁇ /sub> ⁇ 500 pM.
  • the structure of the reference compound is as follows:
  • mice Male ICR mice were administered the compound by gavage at 10 mg/kg (in combination with 400 mg/kg sodium decanoate) or intravenously at 1 mg/kg.
  • gavage group 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h; intravenous group: 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h
  • 100 ⁇ L of blood was collected from the mouse orbital sinus and placed in EDTA-K2 anticoagulant tubes.
  • the plasma samples were obtained by centrifugation at 3000g for 10 min within 2 h.
  • Electrophysiological detection was performed using a fully automated patch clamp QPatch 48X (Sophion) device.
  • the quality control process included aspirating cell suspension from the centrifuge's cell container and positioning the cells onto the chip wells using a pressure controller to establish a high-resistance seal and form a whole-cell recording mode. Once a stable control current baseline was obtained, the test substance was aspirated from the MTP-96 plate according to the concentration gradient and applied to the cells. The current detected in the compound-free extracellular fluid for each cell served as its control group, and two cells were independently tested repeatedly. All Qpatch electrophysiological experiments were performed at 24°C.
  • Compound treatment The compound was diluted in dilution gradients of 0.3, 1, 3, 10, and 30 ⁇ M.
  • IC 50 value was calculated using GraphPad Prism software.
  • mice Male B6-hPCSK9-CDS transgenic C57 mice, after reaching the barrier system and acclimatizing for 2-10 days, were fed Western Diets. After a period of feeding, blood was collected from the orbital sinus into EP tubes, incubated at room temperature for 30 minutes, and then centrifuged at 8000 rpm for 10 minutes to collect serum samples. Serum LDL-C levels were measured using an automated blood biochemistry analyzer. Mice were randomly assigned to groups based on their LDL-C levels and administered the drug orally. The serum LDL-C level was the key indicator monitored during the experiment. The rate of change in LDL-C was calculated using the following formula.
  • LDL-C change rate [(LDL-C after administration) - (LDL-C on the day of administration)] / (LDL-C on the day of administration) ⁇ 100%

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Abstract

L'invention concerne un composé représenté par la formule (I) ou un stéréoisomère de celui-ci ou un sel pharmaceutiquement acceptable de celui-ci. Le composé présente une activité de traitement des maladies cardiovasculaires liées à la dyslipidémie, et antagonise de manière significative la PCSK9 chez un sujet.
PCT/CN2025/112664 2024-08-06 2025-08-05 Analogue de peptide cyclique, son procédé de préparation et son utilisation Pending WO2026032253A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112313243A (zh) * 2018-06-21 2021-02-02 默沙东公司 Pcsk9拮抗剂化合物
US20210069288A1 (en) * 2019-08-30 2021-03-11 Merck Sharp & Dohme Corp. Pcsk9 antagonist compounds
WO2024040125A1 (fr) * 2022-08-17 2024-02-22 Merck Sharp & Dohme Llc Formes cristallines d'un inhibiteur de pcsk9, compositions et utilisations
CN118159281A (zh) * 2021-08-19 2024-06-07 默沙东有限责任公司 治疗pcsk9活性相关病况的化合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112313243A (zh) * 2018-06-21 2021-02-02 默沙东公司 Pcsk9拮抗剂化合物
US20210069288A1 (en) * 2019-08-30 2021-03-11 Merck Sharp & Dohme Corp. Pcsk9 antagonist compounds
CN118159281A (zh) * 2021-08-19 2024-06-07 默沙东有限责任公司 治疗pcsk9活性相关病况的化合物
WO2024040125A1 (fr) * 2022-08-17 2024-02-22 Merck Sharp & Dohme Llc Formes cristallines d'un inhibiteur de pcsk9, compositions et utilisations

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