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WO2019205983A1 - Composé oxa-spiro, son procédé de préparation et ses utilisations - Google Patents

Composé oxa-spiro, son procédé de préparation et ses utilisations Download PDF

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Publication number
WO2019205983A1
WO2019205983A1 PCT/CN2019/082841 CN2019082841W WO2019205983A1 WO 2019205983 A1 WO2019205983 A1 WO 2019205983A1 CN 2019082841 W CN2019082841 W CN 2019082841W WO 2019205983 A1 WO2019205983 A1 WO 2019205983A1
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Prior art keywords
group
alkyl
ring
formula
halogen
Prior art date
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PCT/CN2019/082841
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English (en)
Chinese (zh)
Inventor
田强
张毅涛
宋智泉
宋立强
蔡家强
王利春
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Priority to CN201980016139.6A priority Critical patent/CN111836807A/zh
Publication of WO2019205983A1 publication Critical patent/WO2019205983A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present application relates to the field of medicine, and in particular to an oxaspirocyclic compound, a process for its preparation and its use in activating opioid receptor activity.
  • Opioid receptors are an important class of G protein coupled receptors (GPCRs), widely distributed in the central and peripheral nervous systems, mainly in three subtypes of ⁇ , ⁇ and ⁇ , and are opioids. And the target of analgesic effects of endogenous opioid peptides.
  • GPCRs G protein coupled receptors
  • Traditional opioid receptor agonists, such as morphine and its derivatives, are primarily active against the mu receptor and are most effective in the treatment of chronic arthritis, inflammatory neuralgia, postoperative pain, and moderate to severe pain caused by various cancers. Drug. These traditional drugs have side effects such as respiratory depression, gastrointestinal side effects, drug addiction, confusion, and tolerance problems, which are closely related to the function of ⁇ -arrestin.
  • the present inventors have discovered a class of oxaspirocyclic compounds which selectively act on the G protein pathway to activate opioid receptors, and the present application is based on the above findings.
  • the present application provides a compound of formula (I), a solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof,
  • R 1 is selected from the group consisting of hydroxyl, cyano, halogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR a , -NR b R c , -SR a , CO 2 R a and -C(O)NR b R c ; alternatively, R 1 forms a ring with ring A;
  • R 2 is selected from the group consisting of hydroxy, cyano, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, -OR a , -NR b R c , -SR a , -CO 2 R a and -C(O)NR b R c ;
  • R 3 is selected from hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or, R 2 and R 3 to form a ring;
  • R a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected Substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, alkyl and haloalkyl;
  • R b and R c are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl and sulfonyl; wherein said alkyl, cycloalkyl, heterocycloalkane
  • the aryl group, the aryl group, the heteroaryl group, the acyl group, the sulfonyl group are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, alkyl and haloalkyl;
  • V is selected from C and N;
  • R d , R e and R f are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl and heterocycloalkyl; or R d and R e are bonded to a carbon atom to which they are attached;
  • n 1 is selected from 1, 2, 3 and 4;
  • Ring A is selected from the group consisting of an aromatic ring, a heteroaryl ring, an aliphatic carbocyclic ring, and an aliphatic heterocyclic ring;
  • n and n are independently selected from 0, 1, 2, 3, 4 and 5;
  • x and y are independently selected from 1, 2, 3 and 4;
  • q is selected from 0, 1, and 2.
  • R 1 is selected from hydroxy, cyano, halo, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -OR a, -NR b R c , -SR a, - CO 2 R a and -C(O)NR b R c ; alternatively, R 1 forms a ring with ring A.
  • R 1 is heterocycloalkyl
  • R 2 is selected from hydroxy, cyano, halo, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -OR a, -NR b R c , -SR a, - CO 2 R a and -C(O)NR b R c .
  • R 2 is selected from the group consisting of hydrogen and alkenyl.
  • the compound has the structure shown in formula (II),
  • R 1 is selected from the group consisting of hydroxyl, cyano, halogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR a , -NR b R c , -SR a , CO 2 R a and -C(O)NR b R c ; alternatively, R 1 forms a ring with ring A;
  • R 2 is selected from the group consisting of hydroxy, cyano, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, -OR a , -NR b R c , -SR a , -CO 2 R a and -C(O)NR b R c ;
  • R 3 is selected from hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or, R 2 and R 3 to form a ring;
  • R a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected Substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, alkyl and haloalkyl;
  • R b and R c are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl and sulfonyl; wherein said alkyl, cycloalkyl, heterocycloalkane
  • the aryl group, the aryl group, the heteroaryl group, the acyl group, the sulfonyl group are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, alkyl and haloalkyl;
  • R d , R e and R f are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl and alkoxy; or R d and R e are bonded to a carbon atom to which they are attached;
  • n 1 is selected from 1, 2, 3 and 4;
  • Ring A is selected from the group consisting of an aromatic ring, a heteroaryl ring, an aliphatic carbocyclic ring, and an aliphatic heterocyclic ring;
  • n and n are independently selected from 0, 1, 2, 3, 4 and 5;
  • x and y are independently selected from 1, 2, 3 and 4;
  • q is selected from 0, 1, and 2.
  • R 1 is selected from the group consisting of hydroxyl, cyano, halogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -OR a , -NR b R c , -SR a , -CO 2 R a and -C (O)NR b R c ; alternatively, R 1 forms a ring with ring A;
  • R 2 is selected from the group consisting of hydroxyl, cyano, halogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, -OR a , -NR b R c , -SR a , -CO 2 R a and -C (O)NR b R c ;
  • R 3 is selected from hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or, R 2 and R 3 to form a ring;
  • R a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected Substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, alkyl and haloalkyl;
  • R b and R c are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl and sulfonyl; wherein said alkyl, cycloalkyl, heterocycloalkane
  • the aryl group, the aryl group, the heteroaryl group, the acyl group, the sulfonyl group are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, alkyl and haloalkyl;
  • W and U are independently selected from -(CR d R e ) m1 -, -(CR d R e ) m1 -O- and -(CR d R e ) m1 -NR f -;
  • R d , R e and R f are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl and alkoxy; or R d and R e are bonded to a carbon atom to which they are attached;
  • n 1 is selected from 1, 2, 3 and 4;
  • Ring A is selected from the group consisting of an aromatic ring, a heteroaryl ring, an aliphatic carbocyclic ring, and an aliphatic heterocyclic ring;
  • n and n are independently selected from 0, 1, 2, 3, 4 and 5;
  • x and y are independently selected from 1, 2, 3 and 4.
  • the compound has the structure shown in formula (III),
  • the compound has the structure of formula (III-1) or formula (III-2),
  • R d and R e are each independently selected from hydrogen, hydroxy, halogen, C 1-6 alkyl , C 1-6 alkoxy, C 3-8 cycloalkyl, and 4-8 membered heterocycloalkyl; or, R d and R e are attached to the carbon atoms 3-7 membered aliphatic heterocyclic;
  • m 1 is selected from From 1 and 2;
  • q is selected from 0, 1 and 2;
  • x is selected from 1, 2 and 3.
  • R d and R e are independently selected from hydrogen, hydroxy, halogen, C 1-4 alkyl, C 1- 4 alkoxy, C 3-6 cycloalkyl, and 3-6 membered heterocycloalkyl;
  • m 1 is 1 or 2;
  • x is selected from 1, 2 and 3.
  • R d and R e are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-4 alkyl and C 1- 4 alkoxy;
  • m 1 is 1 or 2;
  • x is 1 or 2.
  • each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR d R e ) m1 -O-;
  • R d and R e are independently Is selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 4-8 membered heterocycloalkyl; or
  • R d and R e are linked to The carbon atom forms a 3-7 membered alicyclic ring;
  • m 1 is 1 or 2; and
  • x is 1, 2 or 3.
  • each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR d R e ) m1 -O-;
  • R d and R e are independently Is selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy; or R d and R e form a 3-7 membered heterocyclic ring with the attached carbon atom;
  • m 1 is 1 or 2;
  • x is 1, 2 or 3.
  • W in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is linked to the 4-position in the formula; R d and R e are independently selected from the group consisting of hydrogen, hydroxyl, halogen, C 1-6 alkyl and C 1 -6 alkoxy; m 1 is 1 or 2; x is 1, 2 or 3.
  • W in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is attached to the 4-position in the formula; R d and R e are independently selected from the group consisting of hydrogen, hydroxyl, halogen, C 1-4 alkyl and C 1 -4 alkoxy; m 1 is 1 or 2; x is 1 or 2.
  • W in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from Wherein, the 1 position is connected to the 3 position in the formula, and the 2 position is connected to the 4 position in the formula; x is 1 or 2.
  • R d , R e and R f are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 4-8 membered heterocycloalkyl; or, R d And R e form a 3-7 membered heterocyclic ring with the attached carbon atom;
  • m 1 is 1 or 2;
  • q is 0, 1 or 2; and
  • x is 1, 2 or 3.
  • R d , R e and R f are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl, and C 1-6 alkoxy; or, R d and R e form a 3-7 membered heterocyclic ring with the attached carbon atom;
  • m 1 is 1 or 2;
  • q is 0, 1 or 2;
  • x is 1, 2 or 3.
  • W in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is linked to the 4-position in the formula; R d , R e and R f are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl And C 1-6 alkoxy; m 1 is 1 or 2; q is 0, 1 or 2; x is 1, 2 or 3.
  • W in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from Wherein, the 1-position is bonded to the 3-position in the formula, and the 2-position is linked to the 4-position in the formula; R d , R e and R f are independently selected from hydrogen, hydroxy, halogen, C 1-4 alkyl And C 1-4 alkoxy; m 1 is 1 or 2; q is 0, 1 or 2; x is 1 or 2.
  • W in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is linked to the 4-position in the formula; R d , R e and R f are independently selected from the group consisting of hydrogen, hydroxyl, fluorine, chlorine, methyl and B. Base; m 1 is 1 or 2; q is 0, 1 or 2; x is 1 or 2.
  • W in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from Wherein the 1 position is connected to the 3 position in the formula, and the 2 position is connected to the 4 position in the formula; x is 1 or 2.
  • each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR d R e ) m1 - and -(CR d R e ) m1 -O-;
  • R d and R e are each independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 4-8 membered heterocycloalkane Or;
  • R d and R e are a 3-7 membered heterocyclic ring with a carbon atom to be bonded;
  • m 1 is selected from 1, 2, 3 and 4;
  • q is selected from 0, 1 and 2;
  • y is selected from 1, 2 And 3.
  • each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR d R e ) m1 - and -(CR d R e ) m1 -O-;
  • R d and R e are each independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocycloalkane Or;
  • R d and R e are a 3-6 membered alicyclic ring with a carbon atom to be bonded;
  • m 1 is selected from 1 and 2;
  • y is selected from 1, 2 and 3.
  • each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR d R e ) m1 -; R d and R e are independently selected From hydrogen, hydroxy, halogen, C 1-4 alkyl and C 1-4 alkoxy; m 1 is 1 or 2; y is selected from 1 or 2.
  • various types I, Formula II, Formula III, Formula III-1 and III-2 in the formula U is independently selected from -CH 2 - and -CH 2 CH 2 -; y is 1.
  • each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR d R e )m 1 -O-; R d and R e Independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 4-8 membered heterocycloalkyl; m 1 is 1, 2 or 3 ;y is 1, 2 or 3.
  • each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from -(CR d R e )m 1 -O-; R d and R e Independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy; m 1 is 1, 2 or 3; y is 1, 2 or 3.
  • each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is attached to the 5-position in the formula; R d and R e are independently selected from the group consisting of hydrogen, hydroxyl, halogen, C 1-6 alkyl and C 1 -6 alkoxy; m 1 is 1 or 2; y is 1, 2 or 3.
  • each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of Wherein, the 1-position is linked to the 3-position in the formula, and the 2-position is attached to the 5-position in the formula; R d and R e are independently selected from the group consisting of hydrogen, hydroxyl, halogen, C 1-4 alkyl and C 1 -4 alkoxy; m 1 is 1 or 2; y is 1 or 2.
  • each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of Wherein, the 1 position is connected to the 3 position in the formula, and the 2 position is connected to the 5 position in the formula; y is 1 or 2.
  • W and U in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 are each independently selected from -(CR d R e ) m1 -;
  • R d and R e is independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 4-8 membered heterocycloalkyl;
  • m 1 is 1 or 2 ;
  • x and y are independently selected from 1, 2 and 3.
  • W and U in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 are each independently selected from -(CR d R e ) m1 -; wherein, R d and R e are independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy; m 1 is 1 or 2; and x and y are independently selected from 1, 2 and 3.
  • W and U in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 are each independently selected from -(CR d R e ) m1 -; R d and R e is independently selected from the group consisting of hydrogen, hydroxy, halogen, C 1-4 alkyl and C 1-4 alkoxy; m 1 is 1 or 2; and x and y are independently 1 or 2.
  • W and U in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 are each independently selected from -CH 2 - and -CH 2 CH 2 -; x And y are independently 1 or 2.
  • R 1 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, halogen, C 1-6 alkyl, halo. C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OR a , -NR b R c , -SR a , -CO 2 R a and -C(O)NR b R c ; or R 1 forms a ring with ring A, said ring is ring A and a 5-6 membered heterocyclic ring or ring A 5-6 yuan heteroaryl ring;
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally selected from one or more selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, carboxy, C 1-6 alkyl and halo C 1-6 alkyl;
  • R b and R c are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, a C 1-6 alkanoyl group and a C 1-6 alkylsulfonyl group; wherein the C 1-6 alkyl group, the C 3-8 cycloalkyl group, the 3-8 membered heterocycloalkyl group, and the C 6-10 aryl group;
  • the base, 5-10 membered heteroaryl, C 1-6 alkanoyl and C 1-6 alkylsulfonyl are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano a carboxyl group, a C 1-6 alkyl group and a halogenated C 1-6 alkyl group;
  • n is selected from the group consisting of 0, 1, 2, 3, 4 and 5.
  • R 1 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, halogen, C 1-6 alkyl, halo. C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OR a , -NR b R c , -SR a , -CO 2 R a And -C(O)NR b R c ; or R 1 forms a ring with ring A, said cyclo ring is ring A and 5-6 membered alicyclic ring or ring A and 5-6 membered heteroaryl ring;
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally selected from one or more selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, carboxy, C 1-6 alkyl and halo C 1-6 alkyl;
  • R b and R c are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, a C 1-6 alkanoyl group and a C 1-6 alkylsulfonyl group; wherein the C 1-6 alkyl group, the C 3-8 cycloalkyl group, the 3-8 membered heterocycloalkyl group, and the C 6-10 aryl group;
  • the base, 5-10 membered heteroaryl, C 1-6 alkanoyl and C 1-6 alkylsulfonyl are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano a carboxyl group, a C 1-6 alkyl group and a halogenated C 1-6 alkyl group;
  • n is selected from the group consisting of 0, 1, 2, 3, 4 and 5.
  • R 1 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, halogen, C 1-6 alkyl, and Or a ; or, R 1 forms a ring with ring A, and the ring is ring A and a 5-6 membered heterocyclic ring;
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally selected from one or more selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, carboxy, C 1-6 alkyl and halo C 1-6 alkyl;
  • n is selected from 0, 1, 2, 3 and 4.
  • R 1 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxy, cyano, halogen, C 1-4 alkyl, and Or a ; or, R 1 forms a ring with ring A, and the ring is ring A and a 5-6 membered heterocyclic ring;
  • R a is selected from the group consisting of hydrogen, C 1-4 alkyl and 5-6 membered heterocycloalkyl; wherein said C 1-4 alkyl group and 5-6 membered heterocycloalkyl group are optionally one or more Substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, C 1-4 alkyl and halo C 1-4 alkyl;
  • n 1 or 2.
  • R 1 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, fluoro, chloro, bromo, iodo, methyl , ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , tert-butoxy, isobutoxy and tetrahydrofuranyloxy; or, R 1 forms a ring with ring A, and the ring is ring A and 1,4-dioxane;
  • n 1 or 2.
  • R 1 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, fluoro, chloro, methyl, ethyl, a methoxy group, an ethoxy group, a n-propoxy group, and a tetrahydrofuranyloxy group; or, R 1 forms a ring with a ring A, and the ring is a ring A and a 1,4-dioxane ring;
  • n 1 or 2.
  • R 1 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of cyano, fluoro, methoxy, and tetrahydrofuranyloxy; , R 1 forms a ring with ring A, and the ring is ring A and 1,4-dioxane;
  • n 1 or 2.
  • R 1 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from cyano, halo, and —OR a ; or, R 1 and A forms a cis ring, and the cyclized ring is a ring A and a 5-6 membered heterocyclic ring;
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally selected from one or more selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, carboxy, C 1-6 alkyl and halo C 1-6 alkyl;
  • n is selected from 0, 1, 2, 3 and 4;
  • R 1 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from cyano, halo, and —OR a ; or, R 1 and A forms a cis ring, and the cyclized ring is a ring A and a 5-6 membered heterocyclic ring;
  • R a is selected from the group consisting of hydrogen, C 1-4 alkyl and 5-6 membered heterocycloalkyl; wherein said C 1-4 alkyl group and 5-6 membered heterocycloalkyl group are optionally one or more Substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, C 1-4 alkyl and halo C 1-4 alkyl;
  • n 1 or 2.
  • R 1 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of cyano, fluoro, chloro, bromo, iodo, methoxy, Ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy and tetrahydrofuranyloxy; or, R 1 forms a ring with ring A, and the ring is Ring A and 1,4-dioxane;
  • n 1 or 2.
  • R 1 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from cyano, halo, and 3-6 membered heterocycloalkyl;
  • n 0, 1, or 2.
  • R 1 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of cyano, halo, and 5-6 membered heterocycloalkyl;
  • n 0, 1, or 2.
  • R 1 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of cyano, fluoro, and morpholinyl;
  • m 0 or 1.
  • R 2 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, halogen, C 1-6 alkyl, halo.
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally selected from one or more selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, carboxy, C 1-6 alkyl and halo C 1-6 alkyl;
  • R b and R c are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, a C 1-6 alkanoyl group, a C 1-6 alkylsulfonyl group; wherein the C 1-6 alkyl group, the C 3-8 cycloalkyl group, the 3-8 membered heterocycloalkyl group, the C 6-10 aryl group;
  • the base, 5-10 membered heteroaryl, C 1-6 alkanoyl and C 1-6 alkylsulfonyl are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano a carboxyl group, a C 1-6 alkyl group and a halogenated C 1-6 alkyl group;
  • n is selected from the group consisting of 0, 1, 2, 3, 4 and 5.
  • R 2 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, halogen, C 1-6 alkyl, halo. C 1-6 alkyl, C 1-6 hydroxyalkyl, -C 1-4 alkyl-OC 1-4 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -10 aryl, 5-10 membered heteroaryl, -OR a , -NR b R c , -SR a , -CO 2 R a and -C(O)NR b R c ;
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally selected from one or more selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, carboxy, C 1-6 alkyl and halo C 1-6 alkyl;
  • R b and R c are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, a C 1-6 alkanoyl group, a C 1-6 alkylsulfonyl group; wherein the C 1-6 alkyl group, the C 3-8 cycloalkyl group, the 3-8 membered heterocycloalkyl group, the C 6-10 aryl group;
  • the base, 5-10 membered heteroaryl, C 1-6 alkanoyl and C 1-6 alkylsulfonyl are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano a carboxyl group, a C 1-6 alkyl group and a halogenated C 1-6 alkyl group;
  • n is selected from the group consisting of 0, 1, 2, 3, 4 and 5.
  • R 2 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxy, cyano, halogen, C 1-4 alkyl, halo. C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, -C 1-4 alkyl-OC 1-4 alkyl, -OR a and -CO 2 R a ;
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally selected from one or more selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, carboxy, C 1-6 alkyl and halo C 1-6 alkyl;
  • n is selected from 0, 1, 2, 3 and 4.
  • R 2 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxy, cyano, halogen, C 1-4 alkyl, halo. C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, -C 1-3 alkyl-OC 1-3 alkyl, -OR a and -CO 2 R a ;
  • R a is selected from the group consisting of hydrogen, C 1-4 alkyl and 5-6 membered heterocycloalkyl; wherein said C 1-4 alkyl group and 5-6 membered heterocycloalkyl group are optionally one or more Substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, C 1-4 alkyl and halo C 1-4 alkyl;
  • n 1 or 2.
  • R 2 of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, fluoro, chloro, bromo, iodo, methyl ,ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, hydroxymethyl , 1-hydroxyethyl, 2-hydroxyethyl, -CH 2 OCH 3 , cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy , isobutoxy, tetrahydrofuranyloxy and -C(O)OCH 3 ;
  • n 1 or 2.
  • R 2 of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, fluoro, chloro, methyl, ethyl, N-propyl, isopropyl, fluoromethyl, difluoromethyl, hydroxymethyl, hydroxyethyl, -CH 2 OCH 3 , cyclopropyl, methoxy, ethoxy, tetrahydrofuranyloxy and C(O)OCH 3 ;
  • n 1 or 2.
  • R 2 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, halogen, C 1-6 alkyl, halo. C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OR a , -NR b R c , -SR a , -CO 2 R a And -C(O)NR b R c ;
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally selected from one or more selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, carboxy, C 1-6 alkyl and halo C 1-6 alkyl;
  • R b and R c are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, a C 1-6 alkanoyl group, a C 1-6 alkylsulfonyl group; wherein the C 1-6 alkyl group, the C 3-8 cycloalkyl group, the 3-8 membered heterocycloalkyl group, the C 6-10 aryl group;
  • the base, 5-10 membered heteroaryl, C 1-6 alkanoyl and C 1-6 alkylsulfonyl are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano a carboxyl group, a C 1-6 alkyl group and a halogenated C 1-6 alkyl group;
  • n is selected from the group consisting of 0, 1, 2, 3, 4 and 5.
  • various types I, Formula II, Formula III, Formula III-1 and III-2 in the formula R 2 is independently selected from hydroxy, cyano, halo and -OR a;
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally selected from one or more selected from the group consisting of Substituent substitution: halogen, hydroxy, amino, cyano, carboxy, C 1-6 alkyl and halo C 1-6 alkyl;
  • n is selected from 0, 1, 2, 3 and 4.
  • various types I, Formula II, Formula III, Formula III-1 and III-2 in the formula R 2 is independently selected from hydroxy, cyano, halo and -OR a;
  • R a is selected from the group consisting of hydrogen, C 1-4 alkyl and 5-6 membered heterocycloalkyl; wherein said C 1-4 alkyl group and 5-6 membered heterocycloalkyl group are optionally one or more Substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, cyano, carboxy, C 1-4 alkyl and halo C 1-4 alkyl;
  • n 1 or 2.
  • R 2 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, cyano, fluoro, chloro, bromo, iodo, methoxy Base, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy and tetrahydrofuranyloxy;
  • n 1 or 2.
  • R 2 of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is selected from the group consisting of hydroxyl, methoxy, and tetrahydrofuranyloxy;
  • n 1 or 2.
  • Formula I and / or Formula II and / or III and / or Formula III-1 and and / or the formula III-2 R 2 is independently selected from C 2-6 alkenyl, Halogenated C 2-6 alkenyl, C 2-6 alkynyl or halo C 2-6 alkynyl.
  • Formula I and / or Formula II and / or III and / or Formula III-1 and / or Formula III-2 in R 2 is independently selected from C 2-4 alkenyl group, Halogenated C 2-4 alkenyl, C 2-4 alkynyl or halo C 2-4 alkynyl.
  • Formula I and / or Formula II and / or III and / or Formula III-1 and / or Formula III-2 in R 2 is independently selected from vinyl, propenyl, fluoro Vinyl, 1,1-difluorovinyl, 2-methylpropenyl, ethynyl, propynyl, fluoroethynyl.
  • R 2 of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, C 1-6 alkyl, C 1-6 hydroxyalkane And C 2-6 alkenyl;
  • n 0, 1, or 2.
  • R 2 of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 are independently selected from the group consisting of hydroxyl, C 1-4 alkyl, C 1-4 hydroxyalkyl And C 2-4 alkenyl;
  • n 0, 1, or 2.
  • R 2 of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydroxyl, methyl, hydroxymethyl, and vinyl;
  • n 0 or 1.
  • Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of C 6-10 aromatic rings, 5-10 membered heteroaryl rings, C 3-8 aliphatic carbocyclic ring and 3-8 membered aliphatic heterocyclic ring.
  • Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of a C 6-10 aromatic ring and a 5-10 membered heteroaryl ring.
  • Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of a benzene ring and a 5-6 membered heteroaryl ring.
  • Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, Imidazole ring, thiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, 1,2,4-1H-triazole ring and pyrazole ring.
  • Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, Imidazole ring, thiazole ring, pyridine ring, pyrimidine ring, pyrazine ring and pyridazine ring.
  • Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of a benzene ring and a thiophene ring.
  • Ring A of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently a phenyl ring.
  • R 3 of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyl, halo C 1 -6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl.
  • R 3 of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydrogen, hydroxy, C 1-6 alkyl, and halo C 1 -6 alkyl.
  • R 3 of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydrogen and C 1-4 alkyl.
  • R 3 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl. , n-butyl, isobutyl and tert-butyl.
  • R 3 of each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, and isopropyl. .
  • R 3 in each of Formula I, Formula II, Formula III, Formula III-1, and Formula III-2 is hydrogen.
  • the compound is selected from the group consisting of
  • the compound is selected from the group consisting of
  • the compound is selected from the group consisting of
  • the pharmaceutically acceptable salt of the compound is a trifluoroacetate, formate.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, as hereinbefore described; It also contains one or more pharmaceutical excipients.
  • the pharmaceutical composition can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, and muscular. Internal, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or input, or by means of an explant reservoir. Among them, oral administration, intraperitoneal or intravenous administration is preferred.
  • the compounds of the present application can be formulated into any orally acceptable formulation including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsule formulation generally comprises lactose and dried cornstarch.
  • Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension. If desired, some sweeteners, fragrances or colorants may also be added to the above oral formulations.
  • the compounds of the present application may be formulated into different topical preparations according to different affected faces or organs.
  • the form is as follows:
  • the compound of the present application When applied topically to the eye, the compound of the present application can be formulated into a micronized suspension or solution in a form of isotonic, sterile saline at a pH which may or may not be added with a preservative such as benzyl chloride. Alkoxide.
  • the compound can also be formulated in the form of a cream such as a Vaseline cream.
  • the compounds of the present invention can be formulated into a suitable ointment, lotion or cream preparation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers which may be used in ointment preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents or creams which may be used include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present application can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions.
  • a sterile injectable preparation including sterile aqueous or oily suspension or sterile injection solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the application provides a compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition as hereinbefore described, for use in the preparation of an activated opioid Use in drugs that are active for substance receptors (eg, mu-opioid receptors).
  • substance receptors eg, mu-opioid receptors
  • the application provides a compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition thereof, as described above, for use in activating opioids Sample receptor (eg, ⁇ -opioid receptor) activity.
  • Sample receptor eg, ⁇ -opioid receptor
  • the application provides a method of activating an opioid receptor (eg, mu-opioid receptor) activity in a subject, comprising administering to the subject an effective amount of a compound as hereinbefore described, A solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination of the foregoing, or a pharmaceutical composition.
  • an opioid receptor eg, mu-opioid receptor
  • the application provides a compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition as hereinbefore described in the preparation of an analgesic drug the use of.
  • the application provides a compound, solvate, stereoisomer, crystalline form, pharmaceutically acceptable salt or ester thereof, or any combination thereof, or a pharmaceutical composition thereof, as described above, for analgesia .
  • the application provides a method of analgesia comprising administering to a subject in need thereof an effective amount of a compound, solvate, stereoisomer, crystalline form thereof, pharmaceutically acceptable, as hereinbefore described a salt or ester, or any combination of the above, or a step of a pharmaceutical composition.
  • the application provides a method of preparing a compound as hereinbefore described, comprising the steps of:
  • R 1 , R 2 , R 3 , W, U, V, A, m, n, x, y are as described above;
  • the compound of formula I is obtained by reductive amination of a compound of formula I-A and a compound of formula I-B.
  • the reductive amination reaction can be carried out with reference to experimental conditions generally employed in the art.
  • an acid and/or a reducing agent is added to the reductive amination reaction.
  • the acid is selected from the group consisting of AcOH and TFA.
  • the reducing agent is selected from the group consisting of NaBH 4 , NaCNBH 3 , and NaBH(OAc) 3 .
  • the method of preparing the compound comprises the steps of:
  • R 1 , R 2 , R 3 , W, U, A, m, n, x, y are as described above;
  • the compound of formula II is obtained by reductive amination of a compound of formula IA and a compound of formula II-B.
  • the reductive amination reaction can be carried out with reference to experimental conditions generally employed in the art.
  • an acid and/or a reducing agent is added to the reductive amination reaction.
  • the acid is selected from the group consisting of AcOH and TFA.
  • the reducing agent is selected from the group consisting of NaBH 4 , NaCNBH 3 , and NaBH(OAc) 3 .
  • solvate means a substance formed by combining a compound of the present application with a pharmaceutically acceptable solvent.
  • Pharmaceutically acceptable solvents include water, ethanol, acetic acid, and the like.
  • Solvates include stoichiometric amounts of solvates and non-stoichiometric amounts of solvates, preferably hydrates.
  • stereoisomer includes conformational isomers and configurational isomers, wherein the configurational isomers primarily include cis and trans isomers and optical isomers.
  • the compounds described herein may exist in stereoisomeric forms and thus encompass all possible stereoisomeric forms, as well as any combination or any mixture thereof. For example, a single enantiomer, a single diastereomer or a mixture of the above.
  • the compounds described herein contain an olefinic double bond, it includes the cis isomer and the trans isomer, as well as any combination thereof, unless otherwise specified.
  • the molecules, atoms or ions of some natural or artificial compounds can be repeatedly arranged in a regular cycle in space, and the arrangement has a periodicity of three-dimensional space, which is repeated at a certain distance.
  • the compound may exist in two or more crystalline states, and the molecules having the same structure are crystallized into different solid forms, which are called polymorphs or polymorphs.
  • crystal form When referring to a particular crystalline form, it is often referred to as "crystal form", the term "crystalline form" as used in this application.
  • salts refers to a salt of a compound of the present application that is pharmaceutically acceptable and has pharmacological activity of the parent compound.
  • Such salts include: acid addition salts with inorganic acids or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; organic acids such as acetic acid, propionic acid, Caproic acid, cyclopentanoic acid, glycolic acid, pyruvic acid, trifluoroacetic acid, formic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid , mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,
  • the term "pharmaceutically acceptable ester” refers to an ester which is formed by esterification of an alcohol when a compound of the present application is present; when the compound of the present application has a hydroxyl group, it is organic An ester formed by an esterification reaction of an acid, an inorganic acid, an organic acid salt or the like. The ester can be hydrolyzed to form the corresponding acid or alcohol in the presence of an acid or a base.
  • cycloalkyl means a saturated cyclic hydrocarbon group which may be a monocyclic or polycyclic fused system and which may be fused to an aromatic ring.
  • examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • heterocycloalkyl refers to a monocyclic or bicyclic saturated or partially saturated ring, optionally substituted with at least one and up to four heteroatoms independently selected from N, O or S.
  • a group such as a 3-8 membered heterocycloalkyl group, a 3-6 membered heterocycloalkyl group, a 4-6 membered heterocycloalkyl group or a 5-6 membered heterocycloalkyl group.
  • Examples of such groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl or piperazinyl, and the like.
  • aryl refers to a monocyclic or bicyclic aromatic group containing at least one aromatic ring, preferably a C6-10 aryl group, ie 6, 7, 8, 9 or 10 carbon atoms.
  • Aryl examples of the aromatic group in the present application include a phenyl group, a naphthyl group, a 1,2,3,4-tetrahydronaphthyl group, an anthracenyl group and the like.
  • heteroaryl refers to a monocyclic or bicyclic aromatic ring group, optionally substituted with at least one heteroatom independently selected from N, O or S, preferably 5-10 members.
  • Examples of such groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, Isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, triazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, fluorenyl, iso Mercapto, pyridazinyl, pyrazinyl, quinolyl and the like.
  • alkyl refers to a straight or branched chain saturated hydrocarbon group.
  • C1-6 alkyl means a straight or branched alkyl group having from 1 to 6, ie 1, 2, 3, 4, 5 or 6 carbon atoms, typically methyl, ethyl, positive Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl, pentyl and hexyl.
  • C 1-4 alkyl means a straight or branched alkyl group having 1, 2, 3 or 4 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, and Butyl, isobutyl, sec-butyl and tert-butyl groups.
  • halogen refers to fluoro, chloro, bromo and iodo.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as previously described.
  • a halogenated C 1-6 alkyl group a halogenated C 1-4 alkyl group or the like.
  • Specific examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl, chloroethyl, and the like.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, as described above.
  • C1-6 hydroxyalkyl C1-4 hydroxyalkyl.
  • Specific examples include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl.
  • alkoxy refers to a group having an alkyl-O- structure, wherein the alkyl group is as previously described.
  • Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • acyl refers to a group having an alkyl-C(O)- structure, wherein the alkyl group is as previously described.
  • alkyl group is as previously described.
  • a C 1-6 alkanoyl group a C 1-4 alkanoyl group, and the like.
  • Specific examples include, but are not limited to, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, t-butanoyl, and the like.
  • sulfonyl refers to a group having the structure of an alkyl-S(O) 2- structure, wherein the alkyl group is as previously described. For example, a C 1-6 alkylsulfonyl group, a C 1-4 alkylsulfonyl group or the like.
  • Specific examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, and tert-butyl Sulfonyl and the like.
  • aromatic ring refers to a monocyclic or polycyclic ring system comprising at least one aromatic ring.
  • a C 6-10 aromatic ring that is, an aromatic ring of 6, 7, 8, 9 or 10 carbon atoms.
  • aromatic ring in the present application include a benzene ring, a naphthalene ring, a 1,2,3,4-tetrahydronaphthalene ring, an anthracene ring, and the like.
  • heteromatic ring refers to an aromatic monocyclic or polycyclic ring system containing from 5 to 14 ring atoms, wherein one to four ring atoms are independently O, N or S, and the remaining rings
  • the atom is a carbon atom.
  • pyrrole ring furan ring, thiophene ring, imidazole ring, pyrazole ring, triazole ring, tetrazole ring, oxazole ring, isoxazole ring, oxadiazole ring, thiazole ring, isothiazole Ring, thiadiazole ring, pyridine ring, pyrimidine ring, triazine ring, benzimidazole ring, benzoxazole ring, benzothiazole ring, benzofuran ring, benzothiophene ring, anthracene ring, isoindole Ring, pyridazine ring, pyrazine ring, quinoline ring, and the like.
  • aliphatic carbocycle refers to a saturated or partially saturated non-aromatic hydrocarbon ring which may be a monocyclic or polycyclic fused system.
  • a C 3-8 aliphatic carbocyclic ring a C 3-6 aliphatic carbocyclic ring, a C 3-5 aliphatic carbocyclic ring or the like.
  • Specific examples include, but are not limited to, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring.
  • aliphatic heterocycle refers to a saturated or partially saturated non-aromatic monocyclic ring, optionally substituted with at least one and up to four heteroatoms independently selected from N, O or S. Multi-ring. For example, a 3-8-membered aliphatic heterocyclic ring, a 3-6-membered aliphatic heterocyclic ring, and a 3-5-membered aliphatic heterocyclic ring.
  • a pyrrolidine ring a tetrahydrofuran ring, a dihydrofuran ring, a tetrahydrothiophene ring, a piperidine ring, a morpholine ring or a piperazine ring, and the like.
  • the group When a group is described as "optionally substituted with one or more substituents selected from the group consisting of", the group may be unsubstituted or (2) substituted. If a carbon on a group is described as being optionally substituted with one or more substituents selected from the group consisting of one or more hydrogens on the carbon (to the extent of any hydrogen present), alone and / Alternatively, they may be replaced by an optional substituent that is independently selected. If a nitrogen on a group is described as being optionally substituted with one or more of the following substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Optional substituent substitution.
  • the invention also includes pharmaceutically acceptable isotopic compounds of the compounds which are structurally identical to the compounds of the invention, except that one or more atoms are of the same atomic number but differ in atomic mass or mass number from atoms which are dominant in nature. Atomic substitution of mass or mass number.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H); isotopes of carbon (e.g., 11 C, 13 C, and 14 C); isotopes of chlorine (e.g.
  • isotope of fluorine eg 18 F
  • isotopes of iodine eg 123 I and 125 I
  • isotopes of nitrogen eg 13 N and 15 N
  • isotopes of oxygen eg 15 O, 17 O and 18 O
  • isotope of phosphorus eg, 32 P
  • isotope of sulfur eg, 35 S.
  • pharmaceutical excipient refers to the excipients and additives used in the manufacture of pharmaceuticals and formulation formulations, which means that in addition to the active ingredients, a reasonable assessment has been made in terms of safety. And a substance contained in a pharmaceutical preparation.
  • pharmaceutical excipients also have important functions such as solubilization, solubilization, and controlled release, which are important components that may affect the quality, safety and effectiveness of drugs. According to its source, it can be divided into natural materials, semi-synthetic materials and total synthetic materials.
  • solvent propellant
  • solubilizer cosolvent
  • emulsifier colorant
  • binder disintegrant
  • filler filler
  • lubricant wetting agent
  • osmotic pressure regulator stabilizer
  • Glidants flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH adjusters, buffers, plasticizers, surface active agents Agent, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, filter aid, release retardant, etc.
  • solvent propellant
  • solubilizer cosolvent
  • emulsifier colorant
  • binder disintegrant
  • filler filler
  • lubricant wetting agent
  • osmotic pressure regulator stabilizer
  • Glidants osmotic pressure regulator
  • flavoring agents preservatives
  • suspending agents coating materials
  • fragrances anti
  • the term "subject" refers to an animal, particularly a mammal, preferably a human.
  • the term "effective amount" refers to an amount sufficient to achieve, or at least partially achieve, a desired effect.
  • a prophylactically effective amount refers to an amount sufficient to prevent, arrest, or delay the onset of a disease
  • a therapeutically effective amount refers to an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. Determination of such an effective amount is well within the capabilities of those skilled in the art.
  • the amount effective for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the general condition of the patient such as age, weight and sex, the mode of administration of the drug, and other treatments administered simultaneously. and many more.
  • the nuclear magnetic resonance ( 1 H NMR) measuring instrument used a Bruker 400 MHz nuclear magnetic resonance apparatus; the solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), and hexa- dimethyl sulfoxide (DMSO-d 6). ); the internal standard substance is tetramethylsilane (TMS). All ⁇ values are expressed in ppm.
  • MS mass spectrometer
  • ESI Agilent 6120B
  • the compounds in the examples were purified using preparative liquid phase (Prep-HPLC), and the methods for preparing liquid phase purification included methods A, B and C.
  • Step 2 N-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3-dihydro-1H-indole-2 -Amine synthesis
  • Step 1 Synthesis of (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde
  • Step 2 (R)-N-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3-dihydro-1H - ⁇ -2-Amine synthesis
  • Step 1 N-(2-((R)-9-(pyridin-2-yl-6-oxaspiro[4.5]decane-9-yl)ethyl)-5-morpholine-2,3- Synthesis of dihydro-1H-indol-2-amine
  • Step 1 (S)-N-(2-((R)-9-(pyridin-2-yl-6-oxaspiro[4.5]decane-9-yl)ethyl-1,2,3, Synthesis of 4-tetrahydronaphthalen-2-amine
  • Step 2 (R)-(2-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-2,3-di Synthesis of hydrogen-1H-indol-2-yl)methanol
  • Step 1 (R)-N-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-6,7,8,9- Synthesis of tetrahydro-5H-benzo[7]cyclopentene-7-amine
  • Step 1 (R)-2-Methyl-nitro-(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3 -Synthesis of dihydro-1H-indol-2-amine
  • Step 3 Synthesis of tert-butyl-N-(2(hydroxymethyl)indol-2-yl)carbamate
  • Step 4 Synthesis of tert-butyl-N-(2-formylhydrazin-2-yl)carbamate
  • Step 5 Synthesis of tert-butyl N-(2-vinylindol-2-yl)carbamate
  • Methyltriphenylphosphonium iodide (556 mg, 1.38 mmol) was dissolved in THF (10 mL), the solution was dark yellow, and n-BuLi (2.5 M n-hexane solution) (1.38 mmol, 0.55 mL) was added under ice bath. After reacting at this temperature for 30 minutes, the solution turned pale yellow, and tert-butyl-N-(2-formylhydrazin-2-yl)carbamate (45 mg, 0.17 mmol) in THF (5 mL) Solution. The reaction was slowly raised to room temperature for 2 hours. The reaction was detected by LC-MS to the end point. After the mixture was diluted with water (20 mL), EtOAc (EtOAc m.
  • Step 7 (R)-N-(2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2-vinyl-2,3 -Synthesis of dihydro-1H-indol-2-amine
  • Step 1 Synthesis of tert-butyl (6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)carbamate
  • Step 2 Synthesis of tert-butyl (6-hydroxy-5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)carbamate
  • Step 4 N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-5,6-dihydro-4H -Synthesis of cyclopenta[b]thiophene-5-amine
  • Step 1 (R)-N-(2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3-dihydro-1H -non-2-amine (hydrochloride)
  • This assay was to test the agonistic effects of compounds on the ⁇ opioid receptor ( ⁇ OR) G protein signaling pathway.
  • Activation of the ⁇ protein G signal pathway regulates intracellular cAMP levels, and changes in intracellular cAMP levels by homogeneous time-resolved fluorescence (HTRF) reflect the agonistic activity of the compound.
  • the maximal effect E max (100% of the maximum effect of 1 ⁇ M full agonist DAMGO (H-Tyr-D-Ala-Gly-N-MePhe-Gly-OH)) based on the compound causing changes in cAMP levels and half of the maximum effect
  • the compound concentration EC 50 was used to evaluate the in vitro activity of the compounds.
  • Serial dilutions of the test compound samples were prepared on 384-well LDV plates, and the sample dilution sequence was transferred to the experimental plate (Corning-3824) using an Echo machine, transferring 30 nL per well, and transferring 30 nL positive control DAMGO (HPE) and negative. Control DMSO (ZPE) to the corresponding wells. Then, 5 ⁇ L of stimulation buffer (STB) and 5 ⁇ L of hMOR/CHO cell suspension (10000 cells/well) were sequentially added to each well of the experimental plate, and the final concentrations of the compounds of IBMX and NKH477 in the 10 ⁇ L system were 100 ⁇ M and 1.5 ⁇ M, respectively. The plate was incubated for 40 min in a 37 ° C incubator. The cAMP levels were then tested according to the cAMP Dynamic 2 kit instructions.
  • STB stimulation buffer
  • hMOR/CHO cell suspension 10000 cells/well
  • the levels of the agonistic ⁇ OR G protein signaling pathway of the tested compounds were determined by the above assay, and the measured EC 50 and E max results are shown in Table 1 (100% with a maximum effect of 1 ⁇ M full agonist DAMGO).
  • Embodiment 11 57.5 79.4 Example twelve 15.3 73.6 Example thirteen 21.4 63.4 Example fifteen 22.5 100.8 Example sixteen 23.0 70.3 Example seventeen 1.0 65.8 Example 18 1.3 63.9
  • This assay was to test the activity of the ⁇ opioid receptor ( ⁇ OR) to recruit ⁇ inhibitory protein 2 after activation by the compounds of the present application.
  • the mu opioid receptor ( ⁇ OR) was detected by enzyme fragment complementation (EFC) to recruit ⁇ inhibitory protein 2 after activation by the compound.
  • EFC enzyme fragment complementation
  • the agonist binds to the ⁇ opioid receptor ( ⁇ OR) overexpressing the ⁇ -gal fragment and recruits the ⁇ -inhibitor-coupled ⁇ -gal complementary fragment to form a fully catalytically active enzyme, which catalyzes the substrate to produce chemiluminescence.
  • the maximum effect Emax maximum effect of 1 ⁇ M full agonist DAMGO is 100%) based on the level of ⁇ -arrestin 2 recruitment by the compound.
  • test compound samples were prepared on 384-well LDV plates, and the sample dilution sequence was transferred to a test plate (PerkinElmer) using an Echo machine, transferring 60 nL per well while transferring 60 nL positive control DAMGO (HPE) and negative control DMSO ( ZPE) to the corresponding hole.
  • 20 ⁇ L of U2OS/OPRM1 cell suspension (7500 cells/well) was added to each well of the assay plate, centrifuged at 300 rpm for 30 s, and incubated at room temperature for 2 hours.
  • 6 ⁇ L of PathHunter detection reagent was added to each well of the assay plate according to the PathHunter test kit instructions, and allowed to stand on Envision after standing at room temperature for 60 minutes.
  • Test compound activated ⁇ OR recruitment ⁇ 2 inhibitory protein level E max.
  • N/A means no agonistic activity.
  • Example 18 was administered by single injection of awake unbound C57 mice to evaluate its effect on the respiratory system of awake unbound C57 mice.
  • the compounds of the present application selectively agonize the ⁇ opioid receptor ( ⁇ OR) G protein signaling pathway.

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Abstract

L'invention concerne un composé oxa-spiro, son procédé de préparation et ses utilisations. En particulier, l'invention concerne un composé représenté par la formule (I), un solvate, un stéréo-isomère, une forme cristalline, et un sel ou un ester pharmaceutiquement acceptable de celui-ci, ou toute combinaison de ceux-ci, ainsi qu'un procédé de préparation et des utilisations associés dans l'activation de l'activité d'un récepteur opioïde et la préparation de médicaments analgésiques.
PCT/CN2019/082841 2018-04-28 2019-04-16 Composé oxa-spiro, son procédé de préparation et ses utilisations Ceased WO2019205983A1 (fr)

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WO2022143715A1 (fr) * 2020-12-29 2022-07-07 上海海雁医药科技有限公司 Dérivé de pyrrolopyrazole à substitution oxaspiro, intermédiaire de celui-ci, et procédé de préparation associé
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AU2021207143B2 (en) * 2020-01-17 2023-12-14 Shanghai Haiyan Pharmaceutical Technology Co., Ltd. Optically pure oxaspiro-substituted pyrrolopyrazole derivative, preparation method therefor and pharmaceutical use thereof
JP2023510618A (ja) * 2020-01-17 2023-03-14 上海海雁医薬科技有限公司 光学的に純粋なオキサスピロ置換ピロロピラゾール誘導体、その調製方法及び医学的使用
CN113214264A (zh) * 2020-01-21 2021-08-06 上海海雁医药科技有限公司 二氢吡咯并五元杂芳基取代的氧杂螺环衍生物、其制法与医药上的用途
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JP7751645B2 (ja) 2020-12-29 2025-10-08 上海海雁医薬科技有限公司 オキシスピロ環置換ピロロピラゾール誘導体及びその中間体並びにその調製方法
JP2024501554A (ja) * 2020-12-29 2024-01-12 上海海雁医薬科技有限公司 オキシスピロ環置換ピロロピラゾール誘導体及びその中間体並びにその調製方法
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WO2022143715A1 (fr) * 2020-12-29 2022-07-07 上海海雁医药科技有限公司 Dérivé de pyrrolopyrazole à substitution oxaspiro, intermédiaire de celui-ci, et procédé de préparation associé
CN117529481A (zh) * 2021-07-13 2024-02-06 上海海雁医药科技有限公司 Mor受体激动剂的药学上可接受的盐、其多晶型物及其用途
RU2846322C2 (ru) * 2021-07-13 2025-09-04 Шанхай Хайян Фармасьютикал Текнолоджи Ко., Лтд. Фармацевтически приемлемая соль агониста mor-рецептора, ее полиморф и их применение
JP2024524719A (ja) * 2021-07-13 2024-07-05 上海海雁医薬科技有限公司 Ｍｏｒ受容体アゴニストの薬学的に許容できる塩、その多形体及びその使用
JP7707406B2 (ja) 2021-07-13 2025-07-14 上海海雁医薬科技有限公司 Ｍｏｒ受容体アゴニストの薬学的に許容できる塩、その多形体及びその使用
WO2023011422A1 (fr) * 2021-08-02 2023-02-09 上海枢境生物科技有限公司 Dérivé d'oxaspiro, son procédé de préparation et son utilisation
CN117751126A (zh) * 2021-08-02 2024-03-22 上海枢境生物科技有限公司 氧杂螺环类衍生物、制备方法及其用途
WO2023138603A1 (fr) * 2022-01-19 2023-07-27 天地恒一制药股份有限公司 Agoniste du récepteur opioïde, son procédé de préparation et son utilisation
CN117126146A (zh) * 2022-05-25 2023-11-28 天地恒一制药股份有限公司 阿片受体激动剂及其制备方法和用途

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