WO2023066357A1 - Composés cycliques fusionnés, leur procédé de préparation et leur utilisation médicale - Google Patents

Composés cycliques fusionnés, leur procédé de préparation et leur utilisation médicale Download PDF

Info

Publication number
WO2023066357A1
WO2023066357A1 PCT/CN2022/126584 CN2022126584W WO2023066357A1 WO 2023066357 A1 WO2023066357 A1 WO 2023066357A1 CN 2022126584 W CN2022126584 W CN 2022126584W WO 2023066357 A1 WO2023066357 A1 WO 2023066357A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
general formula
cycloalkyl
heteroaryl
group
Prior art date
Application number
PCT/CN2022/126584
Other languages
English (en)
Chinese (zh)
Inventor
李心
董平
蒋宏健
贺峰
陶维康
Original Assignee
江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CN202280073122.6A priority Critical patent/CN118176187A/zh
Publication of WO2023066357A1 publication Critical patent/WO2023066357A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems

Definitions

  • the complement system is an important part of innate immunity, which plays an important role in resisting the invasion of foreign microorganisms, clearing aging damaged cells, and maintaining the homeostasis of the body.
  • Complement can be divided into classical pathway, lectin pathway and alternative pathway according to different activators, and these three pathways can converge in the terminal pathway.
  • the alternative pathway contributes 80% of the activity to the overall complement activation because of the positive feedback loop.
  • Complement factor D (Factor D) is an important component in this loop, which plays the role of initiating and amplifying the activation signal. After it binds to factor B bound to complement C3b, it undergoes a conformational change and cleaves factor B into Ba and Bb.
  • L 2 is selected from -(CR a2 R b2 ) r -, -(CR a2 R b2 ) r -O-, -O-(CR a2 R b2 ) r -, -NR c2 -, -O-, -(CR a2 R b2 ) r -NR c2 -, -NR c2 -(CR a2 R b2 ) r -, -C(O)-, -OC(O)-, -C(O)-O-, -S(O ) s -, -NR c2 -C(O)-, -C(O)-NR c2 -, -C(O)-NR c2 -, -C(O)-NR c2 -, -C(O)-NR c2 -, -C(O)-NR c2 -, -C(O)-
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 3 is the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano, -NR 5 R 6 , -C(O)NR 5 R 6 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -OR 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from deuterium atom, halogen, oxo, alkyl, deuterated alkanes One or more of radical, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR 8 R 9 , hydroxyl, hydroxyalkyl, cycl
  • cycloalkyl, heterocyclyl, aryl and heteroaryl wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from deuterium atom, halogen, oxo, alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, nitro, cyano, -NR R 9 , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • R a1 , R b1 , R a2 , R b2 , R a3 , R b3 , R a4 and R b4 are the same or different, and each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a hydroxyalkyl group, a deuterated Alkyl, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano, -NR 5 R 6 , -C(O)NR 5 R 6 , -C(O)R 7 , -C(O )OR 7 , -OC(O)R 7 , -OR 7 , cycloalkyl and heterocyclyl;
  • R u , R v and R w are the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano -NR 5 R 6 , -C(O)NR 5 R 6 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -OR 7 , cycloalkyl, Heterocyclic group, aryl group and heteroaryl group; wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from deuterium atom, halogen, oxo group, alkane radical, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, -NR 8 R 9 ,
  • R 3a , R u , R v , R w , R x , R y and R z are the same or different, and each independently selected from a deuterium atom, a hydrogen atom, a halogen, an alkyl group, a hydroxyalkyl group, a haloalkyl group, and an alkenyl group , alkynyl, haloalkoxy, nitro, cyano, -NR 5 R 6 , -C(O)NR 5 R 6 , -C(O)R 7 , -C(O)OR 7 , -OC(O )R 7 , -OR 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Deuterium atom, halogen, oxo, alkyl, deuterated alkyl, halo
  • R 2a is selected from hydrogen atom, deuterium atom, halogen, alkyl, hydroxyalkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano, -NR 5 R 6 , - C(O)NR 5 R 6 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -OR 7 , cycloalkyl, heterocyclyl, aryl, and heteroaryl base;
  • Each R 2b is the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, hydroxyalkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano -NR 5 R 6 , -C(O)NR 5 R 6 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -OR 7 , cycloalkyl, Heterocyclyl, aryl and heteroaryl;
  • V is a nitrogen atom or CR v ;
  • Y is a nitrogen atom or CR y ;
  • Z is a nitrogen atom or CRz ;
  • L 2 , L 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R a4 , R b4 , R a5 and R b5 are as defined in the general formula (I).
  • the compound represented by the general formula (I), general formula (I'), general formula (II), general formula (III) or general formula (IV) or its pharmaceutically acceptable A salt which is a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof:
  • Each R 2b is the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, hydroxyalkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano -NR 5 R 6 , -C(O)NR 5 R 6 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -OR 7 , cycloalkyl, Heterocyclyl, aryl and heteroaryl;
  • cycloalkyl, heterocyclyl, aryl and heteroaryl wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl Each independently is optionally selected from deuterium atom, halogen, oxo, alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, nitro, cyano, -NR 8 R 9 , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • V is a nitrogen atom or CR v ;
  • W is a nitrogen atom or CR w ;
  • X is a nitrogen atom or CR x ;
  • Y is a nitrogen atom or CR y ;
  • Z is a nitrogen atom or CRz ;
  • R 3a , R u , R v , R w , R x , R y and R z are the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, haloalkyl, alkenyl , alkynyl, haloalkoxy, nitro, cyano, -NR 5 R 6 , -C(O)NR 5 R 6 , -C(O)R 7 , -C(O)OR 7 , -OC(O )R 7 , -OR 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Deuterium atom, halogen, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, nitro,
  • n1 0, 1, 2 or 3;
  • L 2 , L 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R a4 , R b4 , R a5 and R b5 are as defined in the general formula (I).
  • the compound represented by general formula (I), general formula (I'), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof is general The compound shown in formula (V) or its pharmaceutically acceptable salt:
  • G is a nitrogen atom or CR 2a ;
  • Ring D is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 2a and R 2c are the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, hydroxyalkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro , cyano, -NR 5 R 6 , -C(O)NR 5 R 6 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -OR 7 , cycloalkane radical, heterocyclyl, aryl and heteroaryl;
  • Each R 2b is the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, hydroxyalkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, haloalkoxy, nitro, cyano -NR 5 R 6 , -C(O)NR 5 R 6 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -OR 7 , cycloalkyl, Heterocyclyl, aryl and heteroaryl;
  • cycloalkyl, heterocyclyl, aryl and heteroaryl wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl Each independently is optionally selected from deuterium atom, halogen, oxo, alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, nitro, cyano, -NR 8 R 9 , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;
  • U is a nitrogen atom or CR u ;
  • V is a nitrogen atom or CR v ;
  • W is a nitrogen atom or CR w ;
  • X is a nitrogen atom or CR x ;
  • Y is a nitrogen atom or CR y ;
  • Z is a nitrogen atom or CRz ;
  • R 3a , R u , R v , R w , R x , R y and R z are the same or different, and each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a hydroxyalkyl group, a haloalkyl group, and an alkenyl group , alkynyl, haloalkoxy, nitro, cyano, -NR 5 R 6 , -C(O)NR 5 R 6 , -C(O)R 7 , -C(O)OR 7 , -OC(O )R 7 , -OR 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally Deuterium atom, halogen, oxo, alkyl, deuterated alkyl, halo
  • n1 0, 1 or 2;
  • n2 is 0, 1 or 2;
  • L 2 , L 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a1 , R b1 , R a4 , R b4 , R a5 and R b5 are as defined in general formula (I) .
  • the compound represented by general formula (V) or a pharmaceutically acceptable salt thereof wherein: ring D is selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group and 5- or 6-membered heteroaryl or phenyl; preferably, ring D is 5-membered heteroaryl; more preferably, ring D is furyl.
  • the compound represented by general formula (V) or a pharmaceutically acceptable salt thereof wherein: for wherein G, R 2b , R 2c , n1 and n2 are as defined in general formula (V); preferably, for wherein G, R 2b , R 2c , n1 and n2 are as defined in general formula (V); more preferably, for wherein G, R 2b and n1 are as defined in general formula (V).
  • each R 2 is the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, C 1-6 alkyl and C 1-6 alkoxy ; Or two R 2 and the connected carbon atoms together form 5 to 10 yuan of heteroaryl; wherein said 5 to 10 yuan of heteroaryl is optionally selected from deuterium atom, halogen, C 1-6 alkyl , deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, nitro, cyano, amino and hydroxyl C 1-6 One or more substituents in the alkyl group are substituted.
  • each R 2 is the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, C 1-6 alkyl and C 1-6 alkoxy ; Or two adjacent R 2 and the connected carbon atoms together form a 5-membered heteroaryl group; wherein the 5-membered heteroaryl group is optionally selected from deuterium atom, halogen, C 1-6 alkyl, Deuterated C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, nitro, cyano, amino and hydroxy C 1-6 alkane
  • One or more substituents in the group are substituted; preferably, each R 2 is the same or different, and each independently selected from hydrogen atom, deuterium atom
  • the general formula (I), general formula (I'), general formula (II), general formula (III), general formula (III-1) or general formula (III-2 ) or a pharmaceutically acceptable salt thereof wherein: n is 0, 1, 2 or 3; preferably 0 or 1.
  • each R 2b is the same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, C 1-6 alkyl and C 1-6 alkoxy; preferably selected from hydrogen atom, deuterium atom, halogen, methyl group and methoxy group; or two adjacent R 2b and the connected carbon atom together form a 5-membered heteroaryl group; wherein the 5-membered heteroaryl group is optionally selected from deuterium atom, halogen, C 1 -6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, nitro, cyano, amino and hydroxyl
  • One or more substituents in C 1-6 alkyl are substituted.
  • n1 is 0, 1 or 2, preferably 0 or 1.
  • each R 2c is the same or different, and each independently selected from a hydrogen atom, a deuterium atom, a halogen , C 1-6 alkyl and C 1-6 alkoxy; preferably a hydrogen atom.
  • the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof wherein: n2 is 0 or 1, preferably 0.
  • the general formula (I), general formula (I'), general formula (II), general formula (III), general formula (III-1), general formula (III-2 ), general formula (IV), general formula (V), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein: L 2 is -NR c2 - or -O-; and/or L 3 is -NR c3 - or -O-; R c2 and R c3 are as defined in general formula (I).
  • the general formula (I), general formula (I'), general formula (II), general formula (III), general formula (III-1), general formula (III-2 ), general formula (IV), general formula (V), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein: L 2 is -NR c2 - and L 3 is -O-; R c2 is as defined in general formula (I); or; L 2 is O; L 3 is -O-.
  • the general formula (I), general formula (I'), general formula (II), general formula (III), general formula (III-1), general formula (III-2 ), general formula (IV), general formula (V), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein: R c2 , R c3 , R c4 and R c5 are the same or different, and are each independently selected from a hydrogen atom, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic group; preferably, R c2 , R c3 , R c4 and R c5 are the same or different, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group and a 3- to 8-membered cycloalkyl group.
  • the general formula (I), general formula (I'), general formula (II), general formula (III), general formula (III-1), general formula (III-2 ), general formula (IV), general formula (V), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein: R c2 is selected from hydrogen atom, Methyl, ethyl and cyclopropyl; preferably, R c2 is selected from hydrogen atom, methyl and cyclopropyl.
  • the general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (V) a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: X is CR x ; Y is CR y ; Z is a nitrogen atom or CR z ; R x , R y and R z are as defined in general formula (I).
  • the general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (V) a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: X is CR x ; Y is CR y ; Z is a nitrogen atom or CR z ; R x , R y and R z are the same or different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl, hydroxy C 1-6 alkyl, halogenated C 1-6 alkyl, amino, nitro and Hydroxyl; preferably, R x , R y and R z are the same or different, and each independently selected from hydrogen atom, halogen and C 1-6 alkyl; more preferably, R x , R y and R z are the same or different , and are each independently a hydrogen atom or F.
  • the general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (V) a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: U, V and W are all CH; and/or X is CR x ; Y is CR y ; Z is a nitrogen atom or CR z ; R x , R y and R z are the same or different, and each independently selected from hydrogen atom, halogen and C 1-6 alkyl.
  • the general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (V) a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: R 3a is selected from hydrogen atom, halogen, C 1-6 alkyl, hydroxyl C 1- 6 alkyl, halogenated C 1-6 alkyl, amino, nitro and hydroxyl; preferably, R 3a is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 alkoxy; more preferably , R 3a is selected from hydrogen atom, halogen and C 1-6 alkyl.
  • the general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (V) a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: R 3a is selected from a hydrogen atom, F, Cl, methyl and methoxy.
  • R a4 and R b4 are the same or different, and each independently selected from a hydrogen atom, a C 1-6 alkyl group and a hydroxy C 1-6 alkyl group; preferably, R a4 and R b4 are the same or different, and are each independently a hydrogen atom or a hydroxy C 1- 6 alkyl groups; further preferably, R a4 and R b4 are the same or different, and each independently is a hydrogen atom or a hydroxymethyl group; more preferably, R a4 and R b4 are both hydrogen atoms.
  • R a5 and R b5 are the same or Different, and each independently selected from hydrogen atom, halogen, C 1-6 alkyl, hydroxy C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , halogenated C 1-6 alkoxy; or R a5 and R b5 together form an oxo group; preferably, R a5 and R b5 are both hydrogen atoms or R a5 and R b5 together form an oxo group; more preferably , R a5 and R b5 are hydrogen atoms.
  • the general formula (I), general formula (I'), general formula (II), general formula (III), general formula (III-1), general formula (III-2 ), the compound represented by general formula (V), general formula (IV-1) or general formula (IV-2) or its pharmaceutically acceptable salt wherein: R 4 is selected from hydrogen atom, halogen and C 1-6 Alkyl group; preferably, R 4 is a hydrogen atom or a C 1-6 alkyl group; more preferably, R 4 is a hydrogen atom.
  • each R 1 is the same or different, and each independently selected from hydrogen atom, halogen, C 1 -6 alkyl, hydroxy C 1-6 alkyl, halogenated C 1-6 alkyl, amino, nitro and hydroxyl; preferably, each R 1 is a hydrogen atom.
  • the general formula (I), general formula (I'), general formula (II), general formula (III), general formula (III-1), general formula (III-2 ), general formula (IV), general formula (V), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein: r and t are the same or different, and are each independently 1 or 2, preferably 1.
  • the compound represented by general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof wherein: Ring B is selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; L 2 is -NR c2 - or -O-; L 3 is -NR c3 - Or -O-; R c2 and R c3 are the same or different, and each independently selected from a hydrogen atom, C 1-6 alkyl and 3 to 8-membered cycloalkyl; R a1 and R b1 are hydrogen atoms; R a4 The same or different as R b4 , and each independently selected from a hydrogen atom, C 1-6 alkyl and hydroxy C 1-6 alkyl; R a5 and R b5 are the same or different, and each independently selected from a hydrogen atom
  • the compound represented by general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof wherein: Ring B is selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; L 2 is -NR c2 - or -O-; L 3 is -NR c3 - Or -O-; R c2 and R c3 are the same or different, and each independently selected from a hydrogen atom, C 1-6 alkyl and 3 to 8-membered cycloalkyl; R a1 and R b1 are hydrogen atoms; R a4 The same or different as R b4 , and each independently selected from a hydrogen atom, C 1-6 alkyl and hydroxy C 1-6 alkyl; R a5 and R b5 are the same or different, and each independently selected from a hydrogen atom
  • the compound represented by general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof wherein: Ring B is selected from Phenyl, pyridyl, benzofuryl and benzoxazolyl; L 2 is -NR c2 - or -O-; L 3 is -NR c3 - or -O-; R c2 and R c3 are the same or different, And each independently selected from a hydrogen atom, C 1-6 alkyl and 3 to 8-membered cycloalkyl; R a1 and R b1 are hydrogen atoms; R a4 and R b4 are the same or different, and each independently selected from hydrogen atom, C 1-6 alkyl and hydroxy C 1-6 alkyl; R a5 and R b5 are both hydrogen atoms; or R a5 and R b5 together form an oxo group; R 3a is selected from hydrogen atom,
  • the compound represented by general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof wherein: Ring B is selected from Phenyl, pyridyl, benzofuryl and benzoxazolyl; L 2 is -NR c2 - or -O-; L 3 is -NR c3 - or -O-; R c2 and R c3 are the same or different, And each independently selected from a hydrogen atom, C 1-6 alkyl and 3 to 8-membered cycloalkyl; R a1 and R b1 are hydrogen atoms; R a4 and R b4 are the same or different, and each independently selected from hydrogen atom, C 1-6 alkyl and hydroxy C 1-6 alkyl; R a5 and R b5 are both hydrogen atoms; or R a5 and R b5 together form an oxo group; R 3a is selected from hydrogen atom,
  • the compound represented by general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof wherein: ring B is selected from Phenyl, pyridyl, benzofuryl and benzoxazolyl; L 2 is -NR c2 - or -O-; L 3 is -O-; R c2 is selected from hydrogen atom, C 1-6 alkyl and 3 to 8-membered cycloalkyl; R a1 and R b1 are both hydrogen atoms; R a4 and R b4 are the same or different, and each independently is a hydrogen atom or a hydroxy C 1-6 alkyl group; R a5 and R b5 are both Hydrogen atom; or R a5 and R b5 form an oxo group together; R 3a is selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 alkoxy; each R 2 is the same
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a salt thereof,
  • R is C 1-6 alkyl
  • R' is a hydrogen atom or an amino protecting group, preferably a hydrogen atom or Boc;
  • Ring A, Ring B, Ring C, R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , L 5 , m, n and p are as defined in general formula (I) .
  • Another aspect of the present disclosure relates to compounds represented by general formula (I'A) or salts thereof,
  • R is C 1-6 alkyl
  • R' is a hydrogen atom or an amino protecting group, preferably a hydrogen atom or Boc;
  • Ring B, Ring C, U, V, W, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , R 4 , R a5 , R b5 , n and p are as in the general formula (I') defined.
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a salt thereof,
  • R is C 1-6 alkyl
  • R' is a hydrogen atom or an amino protecting group, preferably a hydrogen atom or Boc;
  • Ring B, U, V, W, X, Y, Z, R 2 , R 4 , R 3a , R a5 , R b5 , L 1 , L 2 , L 3 , L 4 and n are as in general formula (II) defined.
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a salt thereof,
  • R is C 1-6 alkyl
  • R' is a hydrogen atom or an amino protecting group, preferably a hydrogen atom or Boc;
  • Ring B U, V, W, X, Y, Z, R 2 , R 4 , R 3a , R a1 , R b1 , R a4 , R b4 , R a5 , R b5 , L 2 , L 3 and n such as defined in general formula (III).
  • Another aspect of the present disclosure relates to a compound represented by general formula (III-1A) or general formula (III-2A) or a salt thereof,
  • R is C 1-6 alkyl
  • R' is a hydrogen atom or an amino protecting group, preferably a hydrogen atom or Boc;
  • Another aspect of the present disclosure relates to a compound represented by general formula (IVA) or a salt thereof,
  • Another aspect of the present disclosure relates to a compound represented by general formula (IV-1A) or general formula (IV-2A) or a salt thereof,
  • R' is an amino protecting group
  • the compound represented by the general formula (IA) or its salt 1) first undergoes a deprotection reaction, and then undergoes an ester hydrolysis reaction; or 2) first undergoes an ester hydrolysis reaction, and then undergoes a deprotection reaction; Or 3) the deprotection reaction and the ester hydrolysis reaction occur simultaneously; obtain the compound shown in general formula (I) or its pharmaceutically acceptable salt;
  • the amino protecting group is preferably Boc;
  • Ring A, Ring B, Ring C, R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , L 5 , m, n and p are as defined in general formula (I) .
  • R' is an amino protecting group
  • the compound represented by the general formula (IIIA) or its salt 1) undergoes a deprotection reaction first, and then undergoes an ester hydrolysis reaction; or 2) first undergoes an ester hydrolysis reaction, and then undergoes a deprotection reaction; Or 3) the deprotection reaction and the ester hydrolysis reaction occur simultaneously; the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof is obtained;
  • the amino protecting group is preferably Boc;
  • R is C 1-6 alkyl
  • Another aspect of the present disclosure relates to a method for a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, comprising:
  • R' is a hydrogen atom or an amino protecting group
  • Ring B U, V, W, X, Y, Z, R 2 , R 4 , R 3a , R a1 , R b1 , R a4 , R b4 , R a5 , R b5 , L 2 , L 3 and n such as defined in general formula (III).
  • R' is a hydrogen atom
  • the compound represented by the general formula (III-2A) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof;
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:
  • R' is an amino protecting group
  • the compound represented by the general formula (IVA) or its salt 1) undergoes a deprotection reaction first, and then undergoes an ester hydrolysis reaction; or 2) first undergoes an ester hydrolysis reaction, and then undergoes a deprotection reaction; Or 3) the deprotection reaction and the ester hydrolysis reaction occur simultaneously; the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof is obtained;
  • the amino protecting group is preferably Boc;
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, comprising:
  • R' is a hydrogen atom or an amino protecting group
  • R' is a hydrogen atom
  • the compound represented by the general formula (IV-1A) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;
  • G, U, V, W, X, Y, Z, R 2b , R 3a , R a4 , R b4 , R a5 , R b5 , L 2 , L 3 and n1 are as defined in the general formula (IV).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, comprising:
  • R' is a hydrogen atom or an amino protecting group
  • R' is a hydrogen atom
  • the compound represented by the general formula (IV-2A) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;
  • R' is an amino protecting group
  • the compound represented by the general formula (IV-2A) or its salt 1) first undergoes a deprotection reaction, and then undergoes an ester hydrolysis reaction; or 2) first undergoes an ester hydrolysis reaction, and then undergoes a deprotection reaction reaction; or 3) deprotection reaction and ester hydrolysis reaction occur simultaneously; obtain the compound shown in general formula (IV-2) or its pharmaceutically acceptable salt;
  • the amino protecting group is preferably Boc;
  • R' is a hydrogen atom
  • the compound represented by the general formula (VA) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl
  • Ring D, G, U, V, W, X, Y, Z, R 2b , R 2c , R 3a , R 4 , R a1 , R b1 , R a4 , R b4 , R a5 , R b5 , L 2 , L 3 , n1 and n2 are as defined in the general formula (V).
  • the present disclosure further relates to general formula (I), general formula (I'), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV) , general formula (V), general formula (IV-1), general formula (IV-2) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation for treatment and / or prevention of paroxysmal nocturnal hemoglobinuria (PNH), reperfusion injury, multiple sclerosis, amyotrophic lateral sclerosis, autoimmune disease, ophthalmic disease, inflammatory disease, respiratory system disease, cardiovascular disease, Liver disease, kidney disease, abdominal aortic aneurysm, complications of hemodialysis, hemolytic anemia, cancer, and immune disorder diseases or diseases; wherein, the kidney disease is preferably selected from lupus nephritis, nephropathy glomerulopathy or hemolytic uremic syndrome; the ophthalmic disease is preferably dry age-related macular
  • the present disclosure also relates to a method for treating and/or preventing paroxysmal nocturnal hemoglobinuria (PNH), reperfusion injury, multiple sclerosis, amyotrophic lateral sclerosis, autoimmune diseases, ophthalmic diseases, inflammatory diseases,
  • a method for a disease or condition of respiratory system disease, cardiovascular disease, liver disease, kidney disease, abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, cancer and immune disorders comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), general formula (I'), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (V ), general formula (IV-1), general formula (IV-2) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it; wherein, the kidney disease is preferably selected from Lupus nephritis, glomerulopathy and hemolytic uremic syndrome; the
  • the present disclosure further relates to general formula (I), general formula (I'), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV) , a compound shown in general formula (V), general formula (IV-1), general formula (IV-2) or Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising it, which is used as a medicament.
  • the present disclosure also relates to general formula (I), general formula (I'), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV) , general formula (V), general formula (IV-1), general formula (IV-2) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for treating and and/or preventing a disease or condition mediated by complement factor D.
  • the present disclosure further relates to general formula (I), general formula (I'), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV) , general formula (V), general formula (IV-1), general formula (IV-2) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for treating and / or prevention of paroxysmal nocturnal hemoglobinuria (PNH), reperfusion injury, multiple sclerosis, amyotrophic lateral sclerosis, autoimmune disease, ophthalmic disease, inflammatory disease, respiratory system disease, cardiovascular disease, Diseases or conditions of liver disease, kidney disease, abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, cancer and immune disorders; said kidney disease is preferably selected from lupus nephritis, glomerulopathy and hemolytic uremic syndrome
  • the ophthalmic disease is preferably dry age-related macular degeneration; the glomerul
  • the disease or condition mediated by complement factor D is preferably selected from paroxysmal nocturnal hemoglobinuria (PNH), glomerulopathy, reperfusion injury, multiple sclerosis, amyotrophic lateral sclerosis, Autoimmune disease, ophthalmic disease, inflammatory disease, respiratory system disease, cardiovascular disease, kidney disease, liver disease, abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, cancer and immune disorders; wherein, the The kidney disease is preferably selected from lupus nephritis, glomerulopathy or hemolytic uremic syndrome; the ophthalmic disease is preferably dry age-related macular degeneration; the glomerulopathy is preferably C3 glomerulopathy or IgA kidney disease.
  • PNH paroxysmal nocturnal hemoglobinuria
  • glomerulopathy reperfusion injury
  • multiple sclerosis multiple sclerosis
  • amyotrophic lateral sclerosis Autoimmune disease
  • ophthalmic disease inflammatory disease,
  • the glomerulopathy described in the present disclosure is preferably selected from glomerulonephritis (including membranous proliferative glomerulonephritis (MPGN), immune complex membranous proliferative glomerulonephritis (IC-MPGN), C3 nephritis Glomerulonephritis (C3GN)), C3 glomerulopathy, IgA nephropathy (IgAnephropathy, IgAN), dense deposit disease (DDD), complement alternative pathway (AP) related nephropathy, in which membranous proliferative glomerulonephritis is preferably membranous Proliferative glomerulonephritis type II (MPGN II); hemolytic uremic syndrome is preferably atypical or typical hemolytic uremic syndrome; inflammatory disease is preferably arthritis or dermatomyositis (DM), wherein arthritis is preferably rheumatic Arthritis; respiratory disease is preferably chronic obstructive pulmonary disease
  • the active compound is preferably presented in unit dose form, or in such a form that the patient can self-administer it as a single dose.
  • a unit dosage form of a compound or composition of the present disclosure may be presented as a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder or liquid.
  • a suitable unit dosage may be from 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients wait.
  • auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients wait.
  • the compositions may contain from 0.1 to 99% by weight of active compound.
  • excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used.
  • fatty acids are also used in the preparation of injectables.
  • the disclosed compounds may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • the dosage of the drug to be administered depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the state of health of the patient, the behavior of the patient , patient's diet, administration time, administration method, rate of excretion, combination of drugs, severity of disease, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the compound or the content of the pharmaceutically acceptable saltkinds can be validated against traditional treatment regimens.
  • alkyl refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 (for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C 1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C 1-6 alkyl group).
  • Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkylene).
  • the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (ie, a C 1-12 alkylene group), more preferably an alkylene group having 1 to 6 carbon atoms (ie, a C 1-6 alkylene group).
  • Non-limiting examples include: -CH2- , -CH( CH3 )-, -C ( CH3 ) 2- , -CH2CH2-, -CH( CH2CH3 ) - , -CH2CH (CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, etc.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (ie C 2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (ie C 2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkynyl group).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents being preferably selected from the group consisting of D atom, alkoxy, halogen, haloalkyl, haloalkoxy, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic full carbocycle (ie monocyclic cycloalkyl) or polycyclic ring system (ie polycyclic cycloalkyl) having 3 to 20 (eg 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 3 to 20 membered cycloalkyl).
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e. a 3 to 12 membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e. a 3 to 8 membered cycloalkyl group). ), most preferably a cycloalkyl group having 3 to 6 ring atoms (ie a 3 to 6 membered cycloalkyl group).
  • Said monocyclic cycloalkyl non-limiting examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.
  • the polycyclic cycloalkyl includes: spirocycloalkyl, condensed cycloalkyl and bridged cycloalkyl.
  • spirocycloalkyl refers to a polycyclic ring system that shares one carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds in the ring, or may contain one or more rings selected from nitrogen, Oxygen and sulfur heteroatoms (the nitrogen may be optionally oxidized, i.e. form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • the spirocycloalkyl is preferably a spirocycloalkyl having 6 to 14 ring atoms (i.e.
  • spirocycloalkyl a 6 to 14 membered spirocycloalkyl, more preferably a spirocycloalkyl having 7 to 10 ring atoms (i.e. 7 to 10 member spirocycloalkyl).
  • the spirocycloalkyl group includes single spirocycloalkyl and polyspirocycloalkyl (such as double spirocycloalkyl, etc.), preferably single spirocycloalkyl or double spirocycloalkyl, more preferably 3-membered/4-membered, 3-membered Yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/ 6
  • connection point can be at any position
  • fused cycloalkyl refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl to a heterocyclic
  • cyclic groups, aryl groups or heteroaryl groups are condensed, wherein the point of attachment is on the monocyclic cycloalkyl group, which can contain one or more double bonds in the ring, and have 5 to 20 (for example, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered fused cycloalkyl).
  • the condensed cycloalkyl group is preferably a fused cycloalkyl group having 6 to 14 ring atoms (i.e. a 6 to 14 membered fused cycloalkyl group), more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e. 7 to 10 fused cycloalkyl).
  • the fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl , more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan , 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 y
  • connection point can be at any position
  • bridged cycloalkyl refers to an all-carbon polycyclic ring system which shares two carbon atoms not directly connected between the rings, which may contain one or more double bonds in the ring, and has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie, 5 to 20 membered bridged cycloalkyl).
  • the bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e. a 6 to 14 membered bridged cycloalkyl group), more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e.
  • the bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl .
  • Non-limiting examples include:
  • Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic heterocycle (i.e. monocyclic heterocyclyl) or polycyclic heterocyclic ring system (i.e. polycyclic heterocyclyl) containing at least one (eg 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e. form nitrogen oxides; the sulfur may optionally be oxo, i.e.
  • the heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e. a 3 to 12 membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e.
  • a 3 to 8 membered heterocyclic group ); more preferably a heterocyclyl group having 3 to 6 ring atoms (ie, a 3- to 6-membered heterocyclyl group); most preferably a heterocyclyl group having 5 or 6 ring atoms (ie, a 5- or 6-membered heterocyclyl group).
  • Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , Thiomorpholinyl and Homopiperazinyl, etc.
  • the polycyclic heterocyclic groups include spiro heterocyclic groups, condensed heterocyclic groups and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic ring system that shares one atom (called a spiro atom) between the rings, which may contain one or more double bonds in the ring, and at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • the condition is to contain at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered spiroheterocyclyl).
  • the spiroheterocyclyl is preferably a spiroheterocyclyl having 6 to 14 ring atoms (i.e.
  • the spiroheterocyclyl includes single spiroheterocyclyl and polyspiroheterocyclyl (such as double spiroheterocyclyl, etc.), preferably single spiroheterocyclyl or double spiroheterocyclyl, more preferably 3-membered/4-membered, 3-membered Yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/ 6 yuan,
  • fused heterocyclyl refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds, and which contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • sulfoxides or sulfones but not Including -O-O-, -O-S- or -S-S-), which is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group with a cycloalkyl, aryl or heteroaryl
  • the fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (ie, a 6 to 14 membered fused heterocyclic group), more preferably a condensed heterocyclic group having 7 to 10 ring atoms (ie, 7 to 10 membered fused heterocyclyl).
  • the fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic fused heterocyclic groups or tricyclic fused heterocyclic groups, more preferably 3 Yuan/4 Yuan, 3 Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/ 5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan Or a 7-membered/6-membered bicyclic condensed heterocyclic group.
  • bridged heterocyclyl refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, and may contain one or more double bonds in the ring, and at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • the bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e. a 6 to 14 membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e. 7 to 10 bridged heterocyclyl).
  • bicyclic bridged heterocyclic group and polycyclic bridged heterocyclic group such as tricyclic bridged heterocyclic group, tetracyclic bridged heterocyclic group, etc.
  • bicyclic bridged heterocyclic group or tricyclic bridged heterocyclic group base preferably bicyclic bridged heterocyclic group or tricyclic bridged heterocyclic group base.
  • Non-limiting examples include:
  • the heterocyclyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.
  • aryl refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl) or a polycyclic aromatic ring system (i.e., a polycyclic aryl) having a conjugated ⁇ -electron system, which has 6 to 14 (e.g., 6 , 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (ie 6 to 14 membered aryl).
  • the aryl group is preferably an aryl group having 6 to 10 ring atoms (ie, a 6 to 10 membered aryl group).
  • the monocyclic aryl group such as phenyl.
  • Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracenyl, phenanthrenyl and the like.
  • the polycyclic aryl also includes the condensing of phenyl with one or more of heterocyclic or cycloalkyl, or the fused of naphthyl with one or more of heterocyclic or cycloalkyl, wherein the connection point On phenyl or naphthyl, and in this case, the number of ring atoms continues to mean the number of ring atoms in a polycyclic aromatic ring system, non-limiting examples include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy one or Multiple.
  • the heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e. a 5 to 10 membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e. a 5 or 6 membered heteroaryl group).
  • Non-limiting examples of the monocyclic heteroaryl include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (such as etc.), pyrazinyl, pyridazinyl, etc.
  • the polycyclic heteroaryl non-limiting examples include: indolyl, indazolyl, quinolinyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene group, quinazoline group, benzothiazolyl group, carbazolyl group, etc.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aryls, wherein the point of attachment is on the aromatic ring, and in this case the number of ring atoms continues to represent the polycyclic heteroaryl The number of ring atoms in the system.
  • the polycyclic heteroaryl also includes monocyclic heteroaryl fused with one or more of cycloalkyl or heterocyclic, wherein the point of attachment is on the monocyclic heteroaryl ring, and in this case, the ring
  • the number of atoms continues to indicate the number of ring atoms in the polycyclic heteroaryl ring system.
  • Non-limiting examples include:
  • Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • amino-protecting group refers to an easily detachable group introduced on an amino group in order to keep the amino group unchanged when other parts of the molecule are reacted.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl (Fmoc), allyl Oxycarbonyl (Alloc), Trimethylsilylethoxycarbonyl (Teoc), Methoxycarbonyl, Ethoxycarbonyl, Phthalyl (Pht), p-Toluenesulfonyl (Tos), Trifluoroacetyl (Tfa), Trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.
  • hydroxyl protecting group refers to an easy-to-remove group introduced on the hydroxyl group, which is used to block or protect the hydroxyl group and react on other functional groups of the compound.
  • Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Diphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), methyl Acyl, acetyl, benzoyl, p-nitrobenzoyl, etc.
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • deuteroalkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxyl refers to -OH.
  • mercapto refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.
  • stereoisomer refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in compounds of the present disclosure may be present with additional asymmetric atoms.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer.
  • An isomer of a certain compound in the present disclosure can be prepared by asymmetric synthesis or chiral auxiliary agents, or, when the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxyl), with appropriate optical Reactive acids or bases form diastereomeric salts, which are then resolved by conventional methods well known in the art to yield the pure isomers. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or both Two configurations.
  • tautomer or tautomeric form
  • tautomer refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. It includes all possible tautomers, ie present as single isomers or as mixtures of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like. An example of lactam-lactim equilibrium is shown below:
  • isotopic derivatives refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass.
  • isotopes that may be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, etc., such as 2 H (deuterium, D), respectively, 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N , 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I, and 131 I, etc., preferably deuterium.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All permutations of isotopic composition of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure.
  • Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein the replacement of deuterium may be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.
  • this position is understood to mean that the abundance of deuterium is at least 1000 times greater than the natural abundance (which is 0.015%) (i.e., at least 15% deuterium doped enter).
  • the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (ie, at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).
  • C 1-6 alkyl optionally substituted by halogen or cyano includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen or cyano.
  • Substituted or “substituted” means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. Possible or impossible substitutions can be determined (by experiment or theory) by those skilled in the art without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond such as an alkene.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have proper biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect.
  • the determination of the therapeutically effective dose varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate therapeutically effective dose in individual cases can be determined by those skilled in the art according to routine tests.
  • the term "pharmaceutically acceptable” means those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction or Other problems or complications that have a reasonable benefit/risk ratio and are valid for the intended use.
  • the preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R' is a hydrogen atom or an amino protecting group
  • R' is a hydrogen atom
  • the compound represented by the general formula (IA) or its salt undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;
  • R' is an amino protecting group
  • the compound represented by the general formula (IA) or its salt 1) first undergoes a deprotection reaction under acidic conditions, and then undergoes an ester hydrolysis reaction under basic conditions; or 2) first reacts with an alkali Under acidic conditions, ester hydrolysis reaction occurs, and then deprotection reaction occurs under acidic conditions; or 3) deprotection reaction and ester hydrolysis reaction occur simultaneously; obtain the compound or pharmaceutically acceptable salt thereof shown in general formula (I); preferably Specifically, the compound represented by the general formula (IA) or its salt first undergoes a deprotection reaction under acidic conditions; then undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable Salt;
  • the amino protecting group is preferably Boc;
  • R is C 1-6 alkyl
  • Ring A, Ring B, Ring C, R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , L 5 , m, n and p are as defined in general formula (I) .
  • the preparation method of the compound represented by general formula (I') or its pharmaceutically acceptable salt of the present disclosure comprises the following steps:
  • R' is a hydrogen atom or an amino protecting group
  • R' is a hydrogen atom
  • the compound represented by the general formula (I'A) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof;
  • R' is an amino protecting group
  • the compound or salt thereof represented by general formula (I'A) 1) deprotects first under acidic conditions, and then undergoes ester hydrolysis under basic conditions; or 2) first An ester hydrolysis reaction occurs under alkaline conditions, and then a deprotection reaction occurs under acidic conditions; or 3) a deprotection reaction and an ester hydrolysis reaction occur simultaneously; a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof is obtained ;
  • the compound or salt thereof shown in the general formula (I'A) first undergoes a deprotection reaction under acidic conditions; then undergoes an ester hydrolysis reaction under basic conditions to obtain the compound shown in the general formula (I') or Its pharmaceutically acceptable salt;
  • the amino protecting group is preferably Boc;
  • R is C 1-6 alkyl
  • Ring B, Ring C, U, V, W, L 1 , L 2 , L 3 , L 4 , R 2 , R 3 , R 4 , R a5 , R b5 , n and p are as in the general formula (I') defined.
  • the preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R' is a hydrogen atom or an amino protecting group
  • R' is a hydrogen atom
  • the compound represented by the general formula (IIA) or its salt undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;
  • R' is an amino protecting group
  • the compound represented by general formula (IIA) or its salt 1) undergoes a deprotection reaction under acidic conditions first, and then undergoes an ester hydrolysis reaction under basic conditions; or 2) first reacts with a base Under acidic conditions, ester hydrolysis reaction occurs, and then deprotection reaction occurs under acidic conditions; or 3) deprotection reaction and ester hydrolysis reaction occur simultaneously; obtain the compound or its pharmaceutically acceptable salt shown in general formula (II); preferably Preferably, the compound shown in general formula (IIA) or its salt first undergoes a deprotection reaction under acidic conditions; then undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound shown in general formula (II) or its pharmaceutically acceptable Salt;
  • the amino protecting group is preferably Boc;
  • R is C 1-6 alkyl
  • Ring B, U, V, W, X, Y, Z, R 2 , R 4 , R 3a , R a5 , R b5 , L 1 , L 2 , L 3 , L 4 and n are as in general formula (II) defined.
  • the preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R' is a hydrogen atom or an amino protecting group
  • R' is a hydrogen atom
  • the compound represented by the general formula (IIIA) or its salt undergoes an ester hydrolysis reaction under basic conditions to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
  • R' is an amino protecting group
  • the compound represented by general formula (IIIA) or its salt 1) undergoes a deprotection reaction under acidic conditions, and then undergoes an ester hydrolysis reaction under basic conditions; or 2) first reacts with a base Under acidic conditions, an ester hydrolysis reaction occurs, and then a deprotection reaction occurs under acidic conditions; or 3) a deprotection reaction and an ester hydrolysis reaction occur simultaneously; obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof; preferably Specifically, the compound represented by the general formula (IIIA) or its salt first undergoes a deprotection reaction under acidic conditions; then undergoes an ester hydrolysis reaction under basic conditions to obtain the compound represented by the general formula (III) or its pharmaceutically acceptable Salt;
  • the amino protecting group is preferably Boc;
  • R is C 1-6 alkyl
  • Ring B U, V, W, X, Y, Z, R 2 , R 4 , R 3a , R a1 , R b1 , R a4 , R b4 , R a5 , R b5 , L 2 , L 3 and n such as defined in general formula (III).
  • the preparation method of the compound represented by the general formula (III-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R' is a hydrogen atom or an amino protecting group
  • R' is a hydrogen atom
  • the compound represented by the general formula (III-1A) or its salt undergoes an ester hydrolysis reaction under basic conditions to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof ;
  • R' is an amino protecting group
  • the compound or salt thereof represented by general formula (III-1A) 1) deprotects first under acidic conditions, and then undergoes ester hydrolysis under basic conditions; or 2) first An ester hydrolysis reaction occurs under alkaline conditions, and then a deprotection reaction occurs under acidic conditions; or 3) the deprotection reaction and the ester hydrolysis reaction occur simultaneously; the compound shown in the general formula (III-1) or its pharmaceutically acceptable
  • the compound or its salt shown in general formula (III-1A) first undergoes deprotection reaction under acidic conditions; then undergoes ester hydrolysis reaction under basic conditions to obtain the compound shown in general formula (III-1) or a pharmaceutically acceptable salt thereof;
  • the amino protecting group is preferably Boc;
  • R is C 1-6 alkyl
  • Ring B U, V, W, X, Y, Z, R 2 , R 4 , R 3a , R a1 , R b1 , R a4 , R b4 , R a5 , R b5 , L 2 , L 3 and n such as defined in general formula (III).
  • the preparation method of the compound represented by the general formula (III-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R' is a hydrogen atom or an amino protecting group
  • R' is a hydrogen atom
  • the compound represented by the general formula (III-2A) or its salt undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof ;
  • R' is an amino protecting group
  • the compound represented by the general formula (III-2A) or its salt 1) first undergoes a deprotection reaction under acidic conditions, and then undergoes an ester hydrolysis reaction under basic conditions; or 2) first An ester hydrolysis reaction occurs under alkaline conditions, and then a deprotection reaction occurs under acidic conditions; or 3) the deprotection reaction and the ester hydrolysis reaction occur simultaneously; the compound shown in general formula (III-2) or its pharmaceutically acceptable salt; preferably, the compound or its salt shown in the general formula (III-2A) first undergoes a deprotection reaction under acidic conditions; then undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound shown in the general formula (III-2)
  • the compound or its pharmaceutically acceptable salt is preferably Boc;
  • R is C 1-6 alkyl
  • Ring B U, V, W, X, Y, Z, R 2 , R 4 , R 3a , R a1 , R b1 , R a4 , R b4 , R a5 , R b5 , L 2 , L 3 and n such as defined in general formula (III).
  • the preparation method of the compound represented by the general formula (IV) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R' is a hydrogen atom or an amino protecting group
  • R' is a hydrogen atom
  • the compound represented by the general formula (IVA) or its salt undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;
  • R' is an amino protecting group
  • the compound represented by the general formula (IVA) or its salt 1) first undergoes a deprotection reaction under acidic conditions, and then undergoes an ester hydrolysis reaction under basic conditions; or 2) first reacts with a base Under acidic conditions, an ester hydrolysis reaction occurs, and then a deprotection reaction occurs under acidic conditions; or 3) a deprotection reaction and an ester hydrolysis reaction occur simultaneously; obtain a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof; preferably
  • the compound shown in general formula (IVA) or its salt first undergoes a deprotection reaction under acidic conditions; then undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound shown in general formula (IV) or its pharmaceutically acceptable Salt;
  • the amino protecting group is preferably Boc;
  • R is C 1-6 alkyl
  • R' is a hydrogen atom or Boc
  • G, U, V, W, X, Y, Z, R 2b , R 3a , R a4 , R b4 , R a5 , R b5 , L 2 , L 3 and n1 are as defined in the general formula (IV).
  • the preparation method of the compound represented by the general formula (IV-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R' is a hydrogen atom or an amino protecting group
  • R' is a hydrogen atom
  • the compound represented by the general formula (IV-1A) or its salt undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof ;
  • R' is an amino protecting group
  • the compound represented by the general formula (IV-1A) or its salt 1) first undergoes a deprotection reaction under acidic conditions, and then undergoes an ester hydrolysis reaction under basic conditions; or 2) first An ester hydrolysis reaction occurs under alkaline conditions, and then a deprotection reaction occurs under acidic conditions; or 3) a deprotection reaction and an ester hydrolysis reaction occur simultaneously; a compound represented by general formula (IV-1) or its pharmaceutically acceptable
  • the compound or its salt shown in general formula (IV-1A) first undergoes deprotection reaction under acidic conditions; then undergoes ester hydrolysis reaction under basic conditions to obtain the compound shown in general formula (IV-1) or a pharmaceutically acceptable salt thereof;
  • the amino protecting group is preferably Boc;
  • R is C 1-6 alkyl
  • G, U, V, W, X, Y, Z, R 2b , R 3a , R a4 , R b4 , R a5 , R b5 , L 2 , L 3 and n1 are as defined in the general formula (IV).
  • the preparation method of the compound represented by the general formula (IV-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R' is a hydrogen atom or an amino protecting group
  • R' is a hydrogen atom
  • the compound represented by the general formula (IV-2A) or its salt undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof ;
  • R' is an amino protecting group
  • the compound represented by the general formula (IV-2A) or its salt 1) first undergoes a deprotection reaction under acidic conditions, and then undergoes an ester hydrolysis reaction under basic conditions; or 2) first An ester hydrolysis reaction occurs under alkaline conditions, and then a deprotection reaction occurs under acidic conditions; or 3) a deprotection reaction and an ester hydrolysis reaction occur simultaneously; the compound shown in general formula (IV-2) or its pharmaceutically acceptable salt; preferably, the compound or its salt shown in the general formula (IV-2A) first undergoes a deprotection reaction under acidic conditions; then undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound shown in the general formula (IV-2) or a pharmaceutically acceptable salt thereof;
  • the amino protecting group is preferably Boc;
  • R is C 1-6 alkyl
  • G, U, V, W, X, Y, Z, R 2b , R 3a , R a4 , R b4 , R a5 , R b5 , L 2 , L 3 and n1 are as defined in the general formula (IV).
  • the preparation method of the compound represented by the general formula (V) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R' is a hydrogen atom or an amino protecting group
  • R' is a hydrogen atom
  • the compound represented by the general formula (VA) or its salt undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof;
  • R' is an amino protecting group
  • the compound represented by the general formula (VA) or its salt 1) undergoes a deprotection reaction under acidic conditions, and then undergoes an ester hydrolysis reaction under basic conditions; or 2) first reacts with a base Under acidic conditions, ester hydrolysis reaction occurs, and then deprotection reaction occurs under acidic conditions; or 3) deprotection reaction and ester hydrolysis reaction occur simultaneously; obtain the compound or pharmaceutically acceptable salt thereof shown in general formula (V); preferably Specifically, the compound represented by the general formula (VA) or its salt first undergoes a deprotection reaction under acidic conditions; then undergoes an ester hydrolysis reaction under alkaline conditions to obtain the compound represented by the general formula (V) or its pharmaceutically acceptable Salt;
  • the amino protecting group is preferably Boc;
  • R is C 1-6 alkyl
  • Ring D, G, U, V, W, X, Y, Z, R 2b , R 2c , R 3a , R 4 , R a1 , R b1 , R a4 , R b4 , R a5 , R b5 , L 2 , L 3 , n1 and n2 are as defined in the general formula (V).
  • the reagents that provide basic conditions include organic bases and inorganic bases
  • the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropyl Lithium amide, potassium acetate, sodium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide
  • the inorganic base includes but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide , lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably lithium hydroxide monohydrate or lithium hydroxide.
  • reagents that provide acidic conditions include but are not limited to hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, hydrochloric acid in 1,4-dioxane solution, Sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me 3 SiCl and TMSOTf, preferably hydrogen chloride in 1,4-dioxane or hydrochloric acid in 1,4-dioxane.
  • the above synthesis scheme is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-Hexane, Dimethyl Sulfoxide, 1,4-Dioxane, Water, N,N-Dimethylformamide, N,N-Dimethylacetamide and mixtures thereof.
  • the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-Hexane, Dimethyl Sulfoxide, 1,4-Dioxane
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined with Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model : waters ACQuity Qda Detector/waters SQ Detector) and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui chemical companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developer used for reaction, the eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography comprise: A: n-hexane/ethyl acetate system, B: dichloromethane/methanol, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acetic acid can also be added Adjust with alkaline or acidic reagents.
  • TLC thin-layer chromatography
  • Example 1-P1 and Example 1-P2 are Example 1-P1 and Example 1-P2
  • Embodiment 3-P1 and Embodiment 3-P2 are identical to Embodiment 3-P1 and Embodiment 3-P2
  • Chiral HPLC analysis retention time 4.867 minutes, purity: 99% (chromatographic column: CHIRALPAK IG 150*4.6mm, 5 ⁇ m; mobile phase: n-hexane and ethanol+0.1% diethanolamine, flow rate: 1.0mL/min).
  • Chiral HPLC analysis retention time 7.860 minutes, purity: 99% (chromatographic column: CHIRALPAK IG150*4.6mm, 5 ⁇ m; mobile phase: n-hexane and ethanol+0.1% diethanolamine, flow rate: 1.0mL/min).
  • the crude compound 6c (1.8g, 7.52mmol) was dissolved in 1,4-dioxane, copper acetate (4.09g, 22.5mmol) and pyridine (2.37g, 29.9mmol) were added, and the reaction was stirred for 15 minutes. Boronic acid (1.35g, 22.5mmol), replaced with nitrogen, heated to 100°C and stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 6d (1 g, yield: 52%).
  • the crude compound 7b-P1 or 7b-P2 (100mg, 0.21mmol) was dissolved in methanol (2mL), tetrahydrofuran (2mL) and water (2mL), and lithium hydroxide monohydrate (46mg, 1.1mmol) was added, and the reaction was stirred for 14 hours , the reaction solution was filtered, and the residue was purified by high-performance liquid chromatography after the filtrate was concentrated under reduced pressure (instrument model: Gilson 281, chromatographic column: X-Bridge, Prep 30 ⁇ 150mm; 5 ⁇ m; C18 Mobile phase: water (10mM bicarbonate ammonium) and acetonitrile, gradient ratio: acetonitrile 50%-60%, flow rate: 30mL/min) to obtain the title compound 7-P1 or 7-P2 (50mg, yield: 53%).
  • Dissolve compound 11d (35 mg, 68.58 ⁇ mol) in ethyl acetate (5 mL), add 4M hydrochloric acid in 1,4-dioxane solution (3 mL), stir and react for 3 hours, pour the reaction solution into water, and extract with ethyl acetate (5 mL ⁇ 2), the organic phases were combined, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 11e (30 mg), which was directly used in the next reaction without purification.
  • Dissolve compound 12b (500mg, 1.96mmol) in anhydrous tetrahydrofuran (30mL), add 1M tetrahydrofuran solution of methylmagnesium bromide (351mg, 2.94mmol) dropwise at -70°C, keep stirring at the temperature for 2 hours, and add Quenched with aqueous ammonium chloride, extracted with ethyl acetate (10 mL ⁇ 2), combined the organic phases, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 12c (500 mg, yield: 94%).
  • the crude compound 12h (30 mg, 62.71 ⁇ mol) was dissolved in anhydrous dichloromethane (5 mL), and triphenylphosphine (18 mg, 68.62 ⁇ mol), bis(4-chlorobenzyl) azodicarboxylate (25 mg, 68.08 ⁇ mol) was stirred for 14 hours.
  • the reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 12i (20 mg, yield: 69%).
  • the crude compound 12k (15 mg, 29.72 ⁇ mol) was dissolved in methanol (3 mL), added lithium hydroxide monohydrate (25 mg, 595.75 ⁇ mol), stirred for 14 hours, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was prepared by HPLC Chromatographic purification (instrument model: Gilson 281 chromatographic column: X-Bridge, Prep 30 ⁇ 150mm; 5 ⁇ m; C18 mobile phase: water (10mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55%-60%, flow rate: 30 mL/min) to obtain the title compound 12 (5 mg, yield: 35%).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention concerne des composés cycliques fusionnés, leurs procédés de préparation et leurs utilisations médicales. Plus précisément, la présente invention concerne le composé cyclique fusionné représenté par la formule générale (I), un procédé de préparation de celui-ci, une composition pharmaceutique comprenant le composé, l'utilisation de celui-ci en tant qu'agent thérapeutique, en particulier en tant qu'inhibiteur du facteur D du complément, et son utilisation dans la préparation fe médicaments pour le traitement et/ou la prévention de maladies ou de troubles médiés par le facteur D du complément
PCT/CN2022/126584 2021-10-21 2022-10-21 Composés cycliques fusionnés, leur procédé de préparation et leur utilisation médicale WO2023066357A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280073122.6A CN118176187A (zh) 2021-10-21 2022-10-21 稠合环类化合物、其制备方法及其在医药上的应用

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202111224923.1 2021-10-21
CN202111224923 2021-10-21
CN202210064744.4 2022-01-20
CN202210064744 2022-01-20
CN202210236899 2022-03-11
CN202210236899.1 2022-03-11

Publications (1)

Publication Number Publication Date
WO2023066357A1 true WO2023066357A1 (fr) 2023-04-27

Family

ID=86057936

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/126584 WO2023066357A1 (fr) 2021-10-21 2022-10-21 Composés cycliques fusionnés, leur procédé de préparation et leur utilisation médicale

Country Status (3)

Country Link
CN (1) CN118176187A (fr)
TW (1) TW202330489A (fr)
WO (1) WO2023066357A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019195720A1 (fr) * 2018-04-06 2019-10-10 Biocryst Pharmaceuticals, Inc. Benzofurane, benzopyrrole, benzothiophène substitués et inhibiteurs du complément structurellement apparentés
WO2021021909A1 (fr) * 2019-07-31 2021-02-04 Biocryst Pharmaceuticals, Inc. Schémas posologiques pour inhibiteurs oraux du facteur d du complément
WO2021072198A1 (fr) * 2019-10-09 2021-04-15 Biocryst Pharmaceuticals, Inc. Inhibiteurs oraux du facteur d du complément
WO2021072156A1 (fr) * 2019-10-09 2021-04-15 Biocryst Pharmaceuticals, Inc. Inhibiteurs de facteur d du complément oral

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019195720A1 (fr) * 2018-04-06 2019-10-10 Biocryst Pharmaceuticals, Inc. Benzofurane, benzopyrrole, benzothiophène substitués et inhibiteurs du complément structurellement apparentés
WO2021021909A1 (fr) * 2019-07-31 2021-02-04 Biocryst Pharmaceuticals, Inc. Schémas posologiques pour inhibiteurs oraux du facteur d du complément
WO2021072198A1 (fr) * 2019-10-09 2021-04-15 Biocryst Pharmaceuticals, Inc. Inhibiteurs oraux du facteur d du complément
WO2021072156A1 (fr) * 2019-10-09 2021-04-15 Biocryst Pharmaceuticals, Inc. Inhibiteurs de facteur d du complément oral

Also Published As

Publication number Publication date
CN118176187A (zh) 2024-06-11
TW202330489A (zh) 2023-08-01

Similar Documents

Publication Publication Date Title
US10385060B2 (en) Piperidine derivative and preparation method and pharmaceutical use thereof
WO2020135771A1 (fr) Intermédiaire de composé hétérocyclique, son procédé de préparation et son utilisation
EP4097099B1 (fr) Agonistes hétérocycliques de glp-1
JP5735986B2 (ja) 新規抗マラリア剤
CN112679495A (zh) 雌激素受体调节剂
WO2020011246A1 (fr) Composé contenant un cycle benzénique, son procédé de préparation et son utilisation
WO2016169421A1 (fr) Dérivé imidazo isoindole, méthode de préparation correspondante et utilisation médicale correspondante
CN109641897B (zh) Bcl-2选择性抑制剂及其制备和用途
KR20190123812A (ko) 6원 헤테로환 유도체 및 그를 함유하는 의약 조성물
WO2021093795A1 (fr) Inhibiteur de rock, son procédé de préparation et son utilisation
WO2021208918A1 (fr) Composés tricycliques servant d'inhibiteurs d'egfr
WO2020192652A1 (fr) Procédé de préparation de composés amides et son utilisation dans le domaine médical
US10889569B2 (en) Condensed ring group azacyclobutyl triazole derivative, preparation method therefor and use thereof in medicine
TW202028210A (zh) 用於治療與apj受體活性相關的病狀的化合物及組成物
WO2022166860A1 (fr) Inhibiteur de pim kinase
CN108863850B (zh) 联芳基类化合物及其制备方法和用途
WO2023016484A1 (fr) Dérivé de sulfonamide, son procédé de préparation et son utilisation médicale
WO2019062657A1 (fr) Dérivé hétérocylique d'azote, son procédé de préparation et son utilisation pharmaceutique
WO2020011220A1 (fr) Dérivé hétéroaryle, son procédé de préparation et son utilisation médicale
JP3537446B2 (ja) 三環性ベンゾアゼピン化合物
WO2022257960A1 (fr) Composé bicyclique pour traiter des maladies médiées par le récepteur ep2 et ep4
WO2020094156A1 (fr) Dérivé de pyridine-2(1h)-cétone substitué par un dihétérocycle, son procédé de préparation et son utilisation pharmaceutique
WO2022258040A1 (fr) Composé hétérocyclique pour inhibiteur de tead
WO2023280254A1 (fr) Inhibiteur de tead
WO2023066357A1 (fr) Composés cycliques fusionnés, leur procédé de préparation et leur utilisation médicale

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22882962

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE