WO2023078463A1 - Composé azobenzène et son application - Google Patents

Composé azobenzène et son application Download PDF

Info

Publication number
WO2023078463A1
WO2023078463A1 PCT/CN2022/130697 CN2022130697W WO2023078463A1 WO 2023078463 A1 WO2023078463 A1 WO 2023078463A1 CN 2022130697 W CN2022130697 W CN 2022130697W WO 2023078463 A1 WO2023078463 A1 WO 2023078463A1
Authority
WO
WIPO (PCT)
Prior art keywords
membered
alkyl
halogenated
alkylamino
ring
Prior art date
Application number
PCT/CN2022/130697
Other languages
English (en)
Chinese (zh)
Inventor
戈伟智
张国利
李韶龙
罗云富
陈曙辉
Original Assignee
正大天晴药业集团股份有限公司
南京明德新药研发有限公司
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 正大天晴药业集团股份有限公司, 南京明德新药研发有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN202280073839.0A priority Critical patent/CN118201908A/zh
Publication of WO2023078463A1 publication Critical patent/WO2023078463A1/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Definitions

  • the present disclosure relates to the technical field of medicinal chemistry, in particular to an azabiphenyl compound and its application, in particular to a compound represented by formula (A) and a pharmaceutically acceptable salt thereof.
  • IgA nephropathy is one of the most common primary glomerulonephritis, accounting for about 25%-50% of primary glomerular diseases in my country. And the incidence of IgA nephropathy is higher in young and middle-aged people. About 40% of patients older than 20 years will develop end-stage renal disease.
  • Endothelin is a naturally occurring bicyclic peptide consisting of 21 amino acids existing in plasma. Endothelial cells are induced to synthesize and release endothelin-1 (ET) under various pathophysiological factors (aging, diabetes, insulin resistance, obesity, immune system activation, dyslipidemia, reactive oxygen species formation, nitric oxide deficiency, etc.) -1). There are two known receptors for endothelin, the endothelin A receptor (ETR-A) and the endothelin B receptor (ETR-B). Binding of endothelin to ETR-A on vascular smooth muscle cells causes vasoconstriction, cell proliferation, and extracellular matrix deposition.
  • Endothelin binds to ETR-B on endothelial cells, which can promote vasodilation, anti-cell proliferation and anti-fibrosis by mediating the production of nitric oxide.
  • Endothelin acting on the ETA receptors of kidney cells can produce different physiological effects, including vasoconstriction, endothelial cell injury, vessel wall thickening, tissue infiltration, inflammatory response, mesangial cell proliferation, podocyte injury, etc.
  • Excessive activation of renal ETA receptors can cause renal injury and renal fibrosis, leading to the occurrence and progression of chronic kidney disease, FSGS, and IgA nephropathy.
  • the present disclosure provides the compound described in formula (A) or a pharmaceutically acceptable salt thereof, which is selected from:
  • Z1 is selected from N or CR Z1 ;
  • Z2 is selected from N or CR Z2 ;
  • R Z1 or R Z2 are each independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1- 6 alkylamino, diC 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkane Baseamino, or halogenated two C 1-6 alkylamino;
  • X is selected from O or NH
  • Ring A is selected from the following groups optionally substituted by one or more R a : 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl;
  • Each R a is independently selected from halogen, -OH, oxo, -NH 2 , -CN, -C(O)R a1 , -C(O)NR a1 R a2 , -NR a1 C(O)R a2 , -NHC(O)NR a1 R a2 , -NR a1 C(O)OR a2 , -OC(O)R a1 , -C(O)OR a1 , -OC(O)OR a1 , -OC(O)OR a1 , -OC(O)NR a1 R a2 , -C 1-6 alkylene C(O)NR a1 R a2 , -C 1-6 alkylene NR a1 C(O)R a2 , -C 1-6 alkylene NHC(O) NR a1 R a2 , -C 1-6 alkylene NR a1
  • R a1 and R a2 are each independently selected from H or C 1-6 alkyl
  • R a3 are each independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, Two C 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino, or halogenated Substitute two C 1-6 alkylamino;
  • L is selected from a single bond, -O-, -S-, -NH-, -C(O)-, or the following groups optionally substituted by one or more RL : -CH 2 -, -N (C 1-6 alkyl)-, or -CH(C 1-6 alkyl)-;
  • R L are each independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di-C 1-6 alkyl Amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino, or halogenated two C 1-6 alkane Base amino;
  • Ring D is selected from the following groups optionally substituted by one or more R b : 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl Cyclic group, 6-10 membered aryl group, or 5-10 membered heteroaryl group;
  • R b are each independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, Two C 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino, or halogenated Substitute two C 1-6 alkylamino;
  • Y1 is selected from -O-, -S-, or -NH-;
  • Y 2 is selected from -O-, -S-, -NH-, -SO 2 -, -NHSO 2 -, -SO 2 NH-, -NHSO 2 NH-, -C(O)NH-, -NHC(O )-, -OC(O)NH-, -NHC(O)O-, or -NHC(O)NH-;
  • n is selected from 1, 2, 3, 4, 5, or 6;
  • Ring C is selected from 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heterocyclyl Aryl;
  • n is selected from 0, 1, 2, 3, or 4;
  • Each R 1 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, Two C 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino, or halogenated Substitute two C 1-6 alkylamino;
  • R 2 is selected from H, halogen, -OH, -NH 2 , -CN, or the following groups optionally substituted by one or more R 2a : C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylthio, C 1-6 alkylamino, two C 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-10 membered carbocyclyl , 5-10 membered heterocyclic group, 6-10 membered aryl group, or 5-10 membered heteroaryl group;
  • R 2a are each independently selected from oxo, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkane Baseamino, diC 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino , or halogenated two C 1-6 alkylamino;
  • R Z1 , R Z2 , X, R a , R a1 , R a2 , R a3 , R L , R b , R 1 , R 2 , R 2a , ring A, ring D or ring C are optionally replaced by one or more A substituent is substituted.
  • Z is selected from N.
  • Z 1 is selected from CR Z1 .
  • Z2 is selected from N.
  • Z 2 is selected from CR Z2 .
  • Z1 and Z2 are selected from N.
  • Z 1 is selected from CR 1 and Z 2 is selected from CR Z2 .
  • one of Z1 and Z2 is selected from N.
  • R Z1 or R Z2 are each independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkane Sulfuryl, C 1-4 alkylamino, diC 1-4 alkylamino, halogenated C 1-4 alkyl , halogenated C 1-4 alkoxy, halogenated C 1-4 alkylthio, halogen Substituted C 1-4 alkylamino, or halogenated two C 1-4 alkylamino .
  • R Z1 or R Z2 are each independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkane Baseamino, diC 1-4 alkylamino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy.
  • R Z1 or R Z2 are each independently selected from H, F, Cl, Br, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy group, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
  • R Z1 or R Z2 are each independently selected from H, F, Cl, Br, -OH, -NH 2 , -CN, methyl, methoxy, methylamino, dimethylamino, Trifluoromethyl, or trifluoromethoxy.
  • R Z1 or R Z2 are each independently selected from H.
  • X is selected from O.
  • X is selected from NH.
  • ring A is selected from the group consisting of 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl optionally substituted with one or more R a .
  • Ring A is selected from the group consisting of 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl optionally substituted with one or more R a .
  • Ring A is selected from the group consisting of cyclopropanyl , cyclobutanyl, cyclopentyl, cyclohexyl, cycloheptyl, Bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.3.0]octyl, spiro[3.3]heptyl , spiro[3.4]octyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, azepine Cycloheptyl, azabicyclo[3.1.0]hexyl, oxabicyclo[3.2.0]heptyl, azabicyclo[3.2.0]heptyl,
  • Ring A is selected from the group consisting of cyclopropanyl, spiro[3.3]heptyl, tetrahydrofuranyl, piperidinyl, or oxaspiro[3.3] optionally substituted with one or more R a ] Heptyl.
  • ring A is selected from the following groups optionally substituted with one or more R a :
  • each R a is independently selected from halogen, -OH, oxo, -NH 2 , -CN, -C(O)R a1 , -C(O)NR a1 R a2 , -NR a1 C (O)R a2 , -NHC(O)NR a1 R a2 , -NR a1 C(O)OR a2 , -OC(O)R a1 , -C(O)OR a1 , -OC(O)OR a1 , -OC(O)OR a1 , -OC(O)NR a1 R a2 , -C 1-4 alkylene C(O)NR a1 R a2 , -C 1-4 alkylene NR a1 C(O)R a2 , -C 1-4 alkylene Alkyl NHC(O)NR a1 R a2 , -C 1-4 alkylene NR
  • each R a is independently selected from halogen, -OH, oxo, -NH 2 , -CN, -C(O)R a1 , -C(O)NR a1 R a2 , -NR a1 C (O)R a2 , -OC(O)R a1 , -C(O)OR a1 , -C 1-4 alkylene C(O)NR a1 R a2 , -C 1-4 alkylene NR a1 C (O)R a2 , -C 1-4 alkylene OC(O)R a1 , -C 1-4 alkylene C(O)OR a1 , or optionally substituted by 1 or more R a3
  • each R a is independently selected from F, Cl, Br, -OH, oxo, -NH 2 , -CN, -C(O)R a1 , -C(O)NR a1 R a2 , -NR a1 C(O)R a2 , -OC(O)R a1 , -C(O)OR a1 , -C 1-2 alkylene C(O)NR a1 R a2 , -C 1-2 alkylene NR a1 C(O)R a2 , -C 1-2 alkylene OC(O)R a1 , -C 1-2 alkylene C(O)OR a1 , or optionally replaced by one or more R a3 is substituted by the following groups: methyl, ethyl, methoxy, ethoxy, methylamino, or dimethylamino.
  • each R a is independently selected from F, Cl, Br, -OH, oxo, -NH 2 , -CN, -C(O)NR a1 R a2 , -C(O)OR a1 , Or the following groups optionally substituted by 1 or more R a3 : methyl, ethyl, methoxy, ethoxy, methylamino, or dimethylamino.
  • R a1 , R a2 are each independently selected from H or C 1-4 alkyl.
  • R a1 , R a2 are each independently selected from H, methyl, or ethyl.
  • R a1 , R a2 are each independently selected from H or methyl.
  • each R a3 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1 -4 alkylamino, diC 1-4 alkylamino, halogenated C 1-4 alkyl , halogenated C 1-4 alkoxy, halogenated C 1-4 alkylthio, halogenated C 1-4 Alkylamino, or halogenated two C 1-4 alkylamino.
  • each R a3 is independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, DiC 1-4 alkylamino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy.
  • each R a3 is independently selected from H, F, Cl, Br, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, iso Propoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
  • each R a3 is independently selected from H, F, Cl, Br, -OH, -NH 2 , -CN, methoxy, or methylamino.
  • each R a is independently selected from F, Cl, Br, -OH, oxo, -NH 2 , -CN, -C(O)NR a1 R a2 , -C(O)OR a1 , Methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
  • each R a is independently selected from -C(O) NH2 , -C(O) NHCH3 , -COOH, -COOCH3 , methyl, or methoxy.
  • ring A is selected from the following groups optionally substituted with one or more R a : wherein each R a is independently selected from -C(O)NH 2 , -C(O)NHCH 3 , -COOH, -COOCH 3 , methyl, or methoxy.
  • Ring A is selected from the following groups:
  • L is selected from a single bond, -O-, -S-, -NH-, -C(O)-, or the following groups optionally substituted with one or more RL :- CH 2 -, -N(C 1-3 alkyl)-, or -CH(C 1-3 alkyl)-.
  • L is selected from a single bond, -O-, -S-, -NH-, -C(O)-, or the following groups optionally substituted with one or more RL :- CH2- , -N( CH3 )-, or -CH( CH3 )-.
  • L is selected from a single bond, -O-, -S-, -NH-, -C(O)-, -CH 2 -, -N(CH 3 )-, or -CH(CH 3 )-.
  • L is selected from single bonds.
  • each R L is independently selected from halogen, -OH, -NH 2 , -CN, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di C 1-4 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylthio, halogenated C 1-4 alkylamino, or halogenated DiC 1-4 alkylamino.
  • each R L is independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkyl Amino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy.
  • each R L is independently selected from H, F, Cl, Br, -OH, -NH2 , -CN, methoxy, methylamino, dimethylamino, trifluoromethyl, or Trifluoromethoxy.
  • the ring atoms of the ring D there is at least one N, O or S atom.
  • the ring atoms of the ring D there are at least 2 N atoms, at least 1 N atom and 1 S atom, or at least 2 O atoms.
  • the ring atoms of the ring D except for the C ring atoms, there are only 2 N atoms, only 1 N atom and 1 S atom, or only 2 O atoms.
  • Ring D is selected from the group consisting of 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered carbocyclyl optionally substituted with one or more R , 5-10 membered heterocyclic group, 6-10 membered aryl group, or 5-10 membered heteroaryl group.
  • Ring D is selected from the group consisting of 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, optionally substituted with one or more R b , or 5-10 membered heteroaryl.
  • ring D is selected from the following groups optionally substituted with one or more R b : Wherein ring B is selected from 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, and T1 is selected from C or N.
  • Ring B is selected from
  • Ring D is selected from the group consisting of benzo 5-6 membered cycloalkenyl , benzo 5-6 membered heterocyclyl, pyrido 5- 6-membered heterocyclic group, phenyl, naphthyl, or 9-10-membered heteroaryl group.
  • ring D is selected from the following groups optionally substituted with one or more R b : Phenyl, naphthyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, Quinolinyl, isoquinolinyl, or benzopyrimidinyl.
  • ring D is selected from the following groups optionally substituted with one or more R b : benzothiazolyl, or
  • ring D is selected from the following groups optionally substituted with one or more R b :
  • ring D is selected from
  • each R b is independently selected from halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1 -4 alkylamino, diC 1-4 alkylamino, halogenated C 1-4 alkyl , halogenated C 1-4 alkoxy, halogenated C 1-4 alkylthio, halogenated C 1-4 Alkylamino, or halogenated two C 1-4 alkylamino.
  • each R b is independently selected from halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy.
  • each R b is independently selected from F, Cl, Br, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy group, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
  • each Rb is independently selected from F, Cl, Br, -OH, -NH2 , -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
  • Y1 is selected from -O-.
  • Y 2 is selected from -O-, -S-, -NH-, -SO 2 -, -NHSO 2 -, -SO 2 NH-, -C(O)NH-, or -NHC( O)-.
  • Y2 is selected from -O-, -S-, or -NH-.
  • Y2 is selected from -O-.
  • Y1 is selected from -O-, and Y2 is selected from -O-.
  • m is selected from 1, 2, 3, or 4.
  • m is selected from 2, 3, or 4.
  • m is selected from 2.
  • the ring atoms of the ring C there is at least one N, O or S atom.
  • the ring atoms of the ring C there are 1, 2 or 3 N atoms, or 1 S atom.
  • the ring atoms of the ring C except for the C ring atoms, there are only N atoms or S atoms.
  • the ring atoms of the ring C there are only 1, 2 or 3 N atoms, or only 1 N atom and 1 S atom.
  • ring C is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, Or 5-10 membered heteroaryl.
  • ring C is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, Or 5-10 membered heteroaryl.
  • Ring C is selected from 6-10 membered aryl or 5-10 membered heteroaryl.
  • ring C is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyranyl Base, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, imidazo[1,2-b]pyridyl azinyl, pyrazolo[1,5-a]pyridyl, quinolinyl, isoquinolinyl, or benzopyrimidinyl.
  • ring C is selected from phenyl, naphthyl, thiazolyl, pyridyl, pyrimidinyl, triazinyl, or imidazo[1,2-b]pyridazinyl.
  • Ring C is selected from pyrimidinyl, pyridyl, thiazolyl, imidazopyridazinyl, and triazinyl.
  • Ring C is selected from
  • n is selected from 0, 1, or 2.
  • n is selected from 0 or 1.
  • each R 1 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1 -4 alkylamino, diC 1-4 alkylamino, halogenated C 1-4 alkyl , halogenated C 1-4 alkoxy, halogenated C 1-4 alkylthio, halogenated C 1-4 Alkylamino, or halogenated two C 1-4 alkylamino.
  • each R 1 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy.
  • each R1 is independently selected from F, Cl, Br, -OH, -NH2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy group, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
  • each R1 is independently selected from F, Cl, Br, -OH, -NH2 , -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
  • each R 1 is independently selected from F, Cl, Br, or trifluoromethoxy.
  • R 2 is selected from H, halogen, -OH, -NH 2 , -CN, or the following groups optionally substituted with one or more R 2a : C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, two C 1-4 alkylamino, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5 - 10-membered carbocyclic group, 5-10-membered heterocyclic group, 6-10-membered aryl group, or 5-10-membered heteroaryl group.
  • R 2 is selected from H, halogen, -OH, -NH 2 , -CN, or the following groups optionally substituted with one or more R 2a : C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, diC 1-4 alkylamino, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, benzene Base, or 5-6 membered heteroaryl.
  • R 2 is selected from H, halogen, -OH, -NH 2 , -CN, or the following groups optionally substituted with one or more R 2a : C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, two C 1-4 alkylamino, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heterocycloalkyl Aryl.
  • R 2 is selected from H, F, Cl, Br, -OH, -NH 2 , -CN, or the following groups optionally substituted with one or more R 2a : methyl, ethyl methoxy, ethoxy, methylamino, ethylamino, dimethylamino, cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane, azetidinyl, tetrahydrofuran group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.
  • R 2 is selected from H, F, Cl, Br, or the following groups optionally substituted with one or more R 2a : methyl or morpholinyl.
  • R is selected from H, methyl, or morpholinyl.
  • each R 2a is independently selected from oxo, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio , C 1-4 alkylamino, two C 1-4 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylthio, halogenated C 1-4 alkylamino, or halogenated diC 1-4 alkylamino.
  • each R 2a is independently selected from oxo, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino , diC 1-4 alkylamino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy.
  • each R 2a is independently selected from oxo, F, Cl, Br, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
  • each R 2a is independently selected from oxo, F, Cl, Br, -OH, -NH 2 , -CN, methyl, methoxy, methylamino, dimethylamino, trifluoro methyl, or trifluoromethoxy.
  • Z1 is selected from N;
  • Z 2 is selected from N;
  • X is selected from O or NH
  • Ring A is selected from the following groups optionally substituted by one or more R a : 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;
  • Each R a is independently selected from -C(O)NH 2 , -C(O)NHCH 3 , -COOH, -COOCH 3 , C 1-4 alkyl, or C 1-4 alkoxy;
  • L is selected from single bonds
  • R L are each independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, halogenated C 1 -4 alkyl, or halogenated C 1-4 alkoxy;
  • Ring D is selected from the following groups optionally substituted by one or more R b : benzo 5-6 membered cycloalkenyl, benzo 5-6 membered heterocyclyl, pyrido 5-6 membered heterocyclyl, Phenyl, naphthyl, or 9-10 membered heteroaryl;
  • R b are each independently selected from F, Cl, Br, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, Ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy;
  • Y1 is selected from -O-;
  • Y2 is selected from -O-;
  • n is selected from 1, 2, 3, or 4;
  • Ring C is selected from 6-10 membered aryl or 5-10 membered heteroaryl
  • n is selected from 0, 1, or 2;
  • Each R is independently selected from halogen, CN, C 1-3 alkyl and C 1-3 haloalkyl;
  • R 2 is selected from H, C 1-3 alkyl and C 5-6 heterocycloalkyl.
  • the 3-12 members are selected from 3-10 members, 3-6 members, 5-6 members, 5-8 members, or 5-10 members.
  • the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.
  • the heterocycloalkyl group contains 1 N atom.
  • the heterocycloalkyl group contains 1 O atom.
  • the heterocycloalkyl group contains 1 N atom and 1 O atom.
  • the heterocyclyl or heteroaryl contains 1 or 2 heteroatoms selected from N, O or S.
  • the heterocyclyl or heteroaryl contains 1 or 2 N atoms.
  • the heterocyclyl or heteroaryl contains 1 N atom and 1 O atom.
  • the heterocyclyl or heteroaryl contains 1 N atom and 1 S atom.
  • the heterocyclyl or heterocycloalkyl includes monocyclic, spiro, fused or bridged ring forms. In some embodiments, the heterocycloalkyl includes monocyclic or spirocyclic forms. In some embodiments, the heterocyclyl or heterocycloalkyl includes monocyclic or bridged ring forms.
  • the C 1-6 alkyl is selected from C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl.
  • the C 1-6 alkylene is selected from a C 1-4 alkylene, a C 1-3 alkylene, or a C 1-2 alkylene.
  • the halogen is selected from fluorine, chlorine, bromine, or iodine.
  • the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.
  • the "one or more” refers to an integer ranging from one to ten, for example, "one or more” is selected from 1, 2, 3, 4, 5, 6 , 7, 8, 9 or 10. In some embodiments, the “one or more” is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the “one or more” is selected from 1, 2, 3, 4, or 5. In some embodiments, the “one or more” is selected from 1, 2, 3, or 4. In some embodiments, the "one or more” is selected from 1, 2, or 3.
  • the present disclosure relates to a compound of formula (A-1), formula (A-2), formula (A-3) or formula (A-4) or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , Y 1 , Y 2 , X, m, n, L, ring A, ring D and ring C are as defined in formula (A) of the present disclosure.
  • the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.
  • the present disclosure provides the compound described in formula (II) or a pharmaceutically acceptable salt thereof, which is selected from:
  • T1 is selected from C and N;
  • Ring B is selected from 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
  • Structural units optionally substituted with one or more R b ;
  • R 1 , R 2 , R b , X, n, ring A and ring C are as defined in the above formula (A) of the present disclosure.
  • R 1 is selected from halogen, CN, C 1-3 alkyl and C 1-3 haloalkyl;
  • R 2 is selected from H, C 1-3 alkyl and C 5-6 heterocycloalkyl
  • X is selected from O and NH
  • T1 is selected from C and N;
  • Ring A is selected from C 3-10 cycloalkyl and 5-10 membered heterocycloalkyl, and the C 3-10 cycloalkyl and 5-10 membered heterocycloalkyl are optionally replaced by 1, 2 or 3 R a replace;
  • Ring B is selected from 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
  • Ring C is selected from 5-10 membered heteroaryl
  • R is selected from halogen, CN, C 1-3 alkyl, C 1-3 alkoxy and -C (O) R;
  • R is selected from -OH, C 1-3 alkoxy, -NH 2 and C 1-3 alkylamino;
  • n is selected from 1 and 2.
  • R 1 is selected from F, Cl, Br, CH 3 and CF 3 , and other variables are as in the present disclosure defined.
  • R 2 is selected from H, CH 3 and morpholinyl, and other variables are as defined in the present disclosure.
  • R a is selected from methyl and methoxy, and other variables are as defined in the present disclosure.
  • ring A is selected from cyclopropyl, bicyclo[1.1.1]pentyl, spiro[3.3] Heptyl, 2-oxospiro[3.3]heptyl, piperidinyl and tetrahydrofuryl, said cyclopropyl, bicyclo[1.1.1]pentyl, spiro[3.3]heptyl, piperidinyl and tetrahydrofuryl are optional Substituted by 1, 2 or 3 R a , other variables are as defined in the present disclosure.
  • ring A is selected from Other variables are as defined in this disclosure.
  • ring B is selected from Other variables are as defined in this disclosure.
  • ring C is selected from pyrimidyl, pyridyl, thiazolyl, imidazopyridazinyl and triazinyl, and other variables such as as defined in this disclosure.
  • ring C is selected from Other variables are as defined in this disclosure.
  • the present disclosure provides a compound described in formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:
  • R 1 is selected from halogen, CN, C 1-3 alkyl or C 1-3 haloalkyl;
  • X is selected from O or NH
  • T1 is selected from C or N;
  • Ring A is selected from C 3-10 cycloalkyl or 5-10 membered heterocycloalkyl, and the C 3-10 cycloalkyl and 5-10 membered heterocycloalkyl are optionally replaced by 1, 2 or 3 R a replace;
  • Ring B is selected from 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl;
  • Ring C is selected from 5-10 membered heteroaryl
  • R is selected from halogen, CN, C 1-3 alkyl or C 1-3 alkoxy;
  • hetero of said heterocycloalkyl, heterocycloalkenyl or heteroaryl contains 1, 2 or 3 heteroatoms independently selected from N, O, S or Se.
  • R 1 is selected from F, Cl, Br, CH 3 or CF 3 , and other variables are as defined in the present disclosure.
  • R a is selected from methyl or methoxy, and other variables are as defined in the present disclosure.
  • ring A is selected from cyclopropyl, bicyclo[1.1.1]pentyl, spiro[3.3]heptyl, 2- Oxyspiro[3.3]heptyl or tetrahydrofuranyl, said cyclopropyl, bicyclo[1.1.1]pentyl, spiro[3.3]heptyl or tetrahydrofuranyl optionally substituted by 1, 2 or 3 R , other variables as defined in this disclosure.
  • ring A is selected from Other variables are as defined in this disclosure.
  • ring B is selected from Other variables are as defined in this disclosure.
  • ring C is selected from pyrimidinyl, and other variables are as defined in the present disclosure.
  • the present disclosure also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof, the compound is selected from:
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the formula (I), formula (II), formula (A), formula (A-1), formula (A-2), formula (A-3) of the present disclosure ), or a compound of formula (A-4), or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present disclosure further include pharmaceutically acceptable excipients.
  • the present disclosure relates to a method for treating mammalian ETA receptor-related diseases, comprising administering a therapeutically effective amount of formula (I), formula (II), formula (A), A compound of formula (A-1), formula (A-2), formula (A-3), or formula (A-4), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure relates to formula (I), formula (II), formula (A), formula (A-1), formula (A-2), formula (A-3), or formula (A-4) Use of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein in the preparation of a medicament for treating ETA receptor-related diseases.
  • the present disclosure relates to formula (I), formula (II), formula (A), formula (A-1), formula (A-2), formula (A-3), or formula (A-4) Use of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein in the treatment of ETA receptor-related diseases.
  • the present disclosure relates to formula (I), formula (II), formula (A), formula (A-1), formula (A-2), formula (A-3) for the treatment of ETA receptor related diseases ), or a compound of formula (A-4), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the ETA receptor-related disease is selected from IgA nephropathy.
  • the present disclosure also provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a drug related to the treatment of IgA nephropathy.
  • the present disclosure also provides the following test method:
  • Test method 1 In vitro test of human ETA receptor antagonistic effect
  • Antagonism of compounds at endogenously expressed human ETA receptors in SK–N–MC cells was assessed by measuring their effects on human ETA receptor agonist-induced changes in cytoplasmic Ca2 + ion signaling using a fluorescent assay agent activity.
  • the functional activity of ETA receptor antagonistic effects was tested at Eurofins-Cerep SA according to current standard operating procedures.
  • DMEM Dulbecco's modified Eagle medium solution
  • HBSS Hank's balanced salt solution
  • Hepes Invitrogen
  • Fluo4 NW fluorescent probe Needle
  • Results are percent inhibition of control response to 1 nM endothelin-1;
  • the standard positive control is BQ-123, test several concentrations in each experiment, use Prism to analyze the data, generate a concentration-response curve, and calculate the IC 50 value of the compound.
  • Test method 2 In vitro test of human ETB receptor antagonistic effect
  • Antagonist activity of compounds on human ETB receptors expressed in transfected CHO cells was assessed by measuring their effect on human ETB receptor agonist-induced changes in cytoplasmic Ca2 + ion signaling using a fluorescent assay.
  • the functional activity of ETB receptor antagonistic effects was tested at Eurofins-Cerep SA according to current standard operating procedures.
  • Results are percent inhibition of the control response to 0.3 nM endothelin-1;
  • the standard positive control is BQ-788.
  • concentrations were tested in each experiment, and Prism was used to analyze the data to generate a concentration-response curve and calculate the IC 50 value of the compound.
  • This project uses 4 male SD rats, a group of 2 SD rats are administered intravenously, the dosage is 2mg/kg, and the administration concentration is 0.5mg/mL; another group of 2 SD rats is administered Oral administration, the dosage is 10mg/kg, and the administration concentration is 1mg/mL;
  • Plasma samples were stored in a -80°C freezer until analysis.
  • the collected samples are then subjected to LC-MS/MS analysis and data acquisition.
  • the collected analytical data was calculated with Phoenix WinNonlin 8.2.0 software to calculate relevant pharmacokinetic parameters.
  • mice in Group-1 and Group-2 were given an equal volume of solvent, once a day, with a volume of 1mL/100g, for 4 weeks; the rats in Group-3 were given Gastrointestinal 5mg/kg prednisone, once a day, intragastric volume of 1mL/100g, continuous administration for 4 weeks; Group-4 rats were intragastrically administered atrasentan, twice a day, intragastric volume of 1mL/100g 100g, administered continuously for 28 days; rats in Group-5, Group-6 and Group-7 were given the test compound by intragastric administration, once a day, with a volume of 1 mL/100g, administered continuously for 28 days. Group-4, 5, and 6, after the last administration and 24h urine protein collection, administered once more according to the corresponding dose, cross blood collection at 0, 0.5, 1, 4, 8, 24h after administration, each Plasma samples from three rats were collected at time points and stored at -80°C.
  • the compounds disclosed in the present disclosure all exhibit extremely high antagonism activity against human ETA receptors in vitro, have good drug efficacy in vivo, and the compounds disclosed in the present disclosure have good exposure and bioavailability, and can relieve renal injury in rats.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present disclosure, which is prepared from a compound with a specific substituent found in the present disclosure and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present disclosure contain basic and acidic functionalities and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
  • diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens.
  • Valence tautomers include interconversions through recombination of some of the bonding electrons.
  • Atropisomers which, unless otherwise stated, refer to optically active isomers resulting from hindered free rotation between single bonds.
  • Compounds of the present disclosure containing chiral axes can be isolated in racemic form. When the free rotation energy barrier of the single bond of the compound containing the chiral axis in the present disclosure is sufficiently high, its atropisomer can be separated in an optically pure form.
  • the compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All permutations of isotopic composition of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure.
  • ethyl is "optionally" substituted with halogen , meaning that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted (eg CH2CH2F ), polysubstituted (eg CHFCH2F , CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
  • substituteduent includes all substituents mentioned in the context of this text, such as the terms “alkyl”, “heteroalkyl”, “alkoxy”, “alkylamino”, “Dialkylamino”,”Alkylsulfonyl”,”Alkylthio”,"Alkenyl”,”Alkynyl”,”Cycloalkyl”,”Cycloalkenyl”,”Heterocyclyl”,”HeterocyclicAlkyl”,”aryl”,”heteroaryl”, etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of said "substituent” include hydroxyl, mercapto, halogen, amino, nitro group, nitroso group, cyano group, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, aldehyde group, imine group, alkyl group, halo-
  • the substituents are selected from hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide , carboxyl group, aldehyde group, imine group, C 1-12 alkyl group, halogenated-C 1-12 alkyl group, 3-12 membered cycloalkyl group, halogenated-3-12 membered cycloalkyl group, 3-12 Heterocycloalkyl, halo-3-12-membered heterocycloalkyl, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3-12-membered cycloalkenyl, halo-3-12 Cycloalkenyl, C 2-12 alkynyl, halo-C 2-12 alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkyny
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C mn herein, is that the moiety has an integer number of carbon atoms in the given range.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • variable e.g, R
  • R any variable
  • its definition is independent at each occurrence. So, for example, if a group is substituted by 2 R's, each R has independent options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
  • linking group listed does not specify its linking direction, its linking direction is arbitrary, for example, in A-L-Z, linking group L is -M-W-, which means that the structure can be A-M-W-Z or A-W-M-Z.
  • the substituent When a bond of a substituent cross-links two atoms in a ring, the substituent may be bonded to any atom on the ring.
  • the structural unit It means that it can be substituted at any position on cyclohexyl or cyclohexadiene.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxyl refers to a -OH group.
  • cyano refers to a -CN group.
  • mercapto refers to a -SH group.
  • amino refers to a -NH2 group.
  • nitro refers to a -NO2 group.
  • heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, sulfur, silicon and phosphorus. In one embodiment, the heteroatom is selected from N, O and S.
  • alkylene refers to a saturated linear or branched divalent hydrocarbon group of the general formula C n H 2n , usually having 1 to 20, 1 to 18, 1 to 16, 1 to 14, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
  • C 1-6 alkylene refers to an alkylene group containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 - or -CH 2 CH(CH 3 )-), Butylene (-CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 - or -CH 2 CH 2 CH(CH 3 )-), Pentylene , Hexylene, Heptylene, Octylene, Nonylene, Decylene, etc.
  • the alkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, Dialkylamino, Haloalkylamino, Halodialkylamino, Cycloalkyl, Cycloalkyloxy, Heterocyclyl, Heterocyclyloxy, Heterocycloalkyl, Heterocycloalkyloxy radical, heteroaryl, heteroaryloxy, aryl or aryloxy.
  • substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, Dialkylamino, Haloalkylamino, Halodialkylamino, Cycloalkyl, Cyclo
  • alkyl refers to a linear or branched saturated hydrocarbon group of the general formula C n H 2n+1 , usually having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
  • the alkyl group may be straight or branched and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
  • C 1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (such as methyl, ethyl, n - propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • 1 to 6 carbon atoms such as methyl, ethyl, n - propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.
  • C 1-3 alkyl refers to an alkyl group containing 1 to 3 carbon atoms, and the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups and the like; it may be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • the alkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxy Amino, Dialkylamino, Haloalkylamino, Halodialkylamino, Cycloalkyl, Cycloalkyloxy, Heterocyclyl, Heterocyclyloxy, Heterocycloalkyl, Heterocycloalkyloxy , heteroaryl, heteroaryloxy, aryl or aryloxy.
  • the alkyl portion (ie, alkyl group) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio has the same definition as above.
  • C 1-6 haloalkyl or "haloC 1-6 alkyl” denotes monohaloalkyl and polyhaloalkyl groups containing 1 to 6 carbon atoms.
  • C 1-6 haloalkyl or “haloC 1-6 alkyl” denotes monohaloalkyl and polyhaloalkyl groups containing 1 to 6 carbon atoms.
  • the "C 1-6 haloalkyl” or “haloC 1-6 alkyl” includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-5 , C 2- 4 , C 2-3 , C 6 , C 5 , C 4 , C 3 , C 2 , and C 1 haloalkyl, etc.
  • the C 1-3 haloalkyl includes C 1-2 , C 2-3 , C 3 , C 2 and C 1 haloalkyl and the like.
  • C 1-3 haloalkyl examples include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 3-bromopropyl and the like.
  • heteroalkyl refers to an alkyl group in which one or more carbon atoms (and hydrogen atoms attached thereto) are each independently replaced by the same or a different heteroatom group. Unless otherwise indicated, the heteroalkyl group contains 1, 2 or 3 heteroatom groups, non-limiting examples of which include O, S, N or NH, typically 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
  • C 1-6 heteroalkyl refers to a heteroalkyl group containing 1 to 6 carbon atoms and 1-3 heteroatom groups.
  • the heteroatom group can be placed anywhere on the heteroalkyl (eg, an internal or terminal position), including the position where the heteroalkyl is attached to the rest of the molecule. Typically, where more than one heteroatom group is present, the heteroatom groups are not adjacent to each other.
  • Exemplary heteroalkyl groups include, but are not limited to, alkoxy, alkoxyalkylene, alkylamino, alkylaminoalkylene, dialkylamino, dialkylaminoalkylene, and the like.
  • the heteroalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, Dialkylamino, Haloalkylamino, Halodialkylamino, Cycloalkyl, Cycloalkyloxy, Heterocyclyl, Heterocyclyloxy, Heterocycloalkyl, Heterocycloalkyloxy radical, heteroaryl, heteroaryloxy, aryl or aryloxy.
  • substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, Dialkylamino, Haloalkylamino, Halodialkylamino, Cycloalkyl, Cy
  • alkoxy refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. wherein the alkyl moiety is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, Dialkylamino, Haloalkylamino, Halodialkylamino, Cycloalkyl, Cycloalkyloxy, Heterocyclyl, Heterocyclyloxy, Heterocycloalkyl, Heterocycloalkyloxy radical, heteroaryl, heteroaryloxy, aryl or aryloxy.
  • alkylamino refers to an -NH-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. wherein the alkyl moiety is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, Dialkylamino, Haloalkylamino, Halodialkylamino, Cycloalkyl, Cycloalkyloxy, Heterocyclyl, Heterocyclyloxy, Heterocycloalkyl, Heterocycloalkyloxy radical, heteroaryl, heteroaryloxy, aryl or aryloxy.
  • dialkylamino refers to -N(alkyl) 2 , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms
  • diC 1-12 alkylamino refers to -N(C 1-12 alkyl) 2 , having 1 to 12 carbon atoms.
  • alkyl moiety is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, Dialkylamino, Haloalkylamino, Halodialkylamino, Cycloalkyl, Cycloalkyloxy, Heterocyclyl, Heterocyclyloxy, Heterocycloalkyl, Heterocycloalkyloxy radical, heteroaryl, heteroaryloxy, aryl or aryloxy.
  • substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, Dialkylamino, Haloalkylamino, Halodialkylamino, Cycloalkyl, Cyclo
  • alkylsulfonyl refers to a -SO2 -alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. wherein the alkyl moiety is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, Dialkylamino, Haloalkylamino, Halodialkylamino, Cycloalkyl, Cycloalkyloxy, Heterocyclyl, Heterocyclyloxy, Heterocycloalkyl, Heterocycloalkyloxy radical, heteroaryl, heteroaryloxy, aryl or aryloxy.
  • alkylthio refers to an -S-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. wherein the alkyl moiety is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, Dialkylamino, Haloalkylamino, Halodialkylamino, Cycloalkyl, Cycloalkyloxy, Heterocyclyl, Heterocyclyloxy, Heterocycloalkyl, Heterocycloalkyloxy radical, heteroaryl, heteroaryloxy, aryl or aryloxy.
  • alkenyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group with at least one double bond consisting of carbon atoms and hydrogen atoms, usually having 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms.
  • alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • the alkenyl is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, Dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl radical, heteroaryloxy, aryl or aryloxy.
  • substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, Dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl,
  • alkynyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having at least one triple bond consisting of carbon atoms and hydrogen atoms, usually having 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms.
  • alkynyl include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C- CH3 ), 2-propynyl (-CH2 - C ⁇ CH), 1,3-Butadiynyl (-C ⁇ CC ⁇ CH), etc.
  • the alkynyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, Dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl radical, heteroaryloxy, aryl or aryloxy.
  • substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, Dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl,
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3- to 12-membered ring, a 3- to 10-membered ring, a 3- to 8-membered ring, a 3- to 6-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2] Octyl, adamantyl, etc.
  • the cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkane Oxygen, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 2.
  • substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkane Oxygen, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(
  • -C(O)NH-alkyl -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl , -S(O) 2 -alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2 , cycloalkyl, cycloalkane alkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl radical, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
  • C 3-10 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 10 carbon atoms, which includes monocyclic, bicyclic and tricyclic systems, wherein bicyclic and tricyclic systems include Spiral, parallel and bridged rings.
  • the C 3-10 cycloalkyl group includes C 3-8 , C 3-6 , C 3-5 , C 4-10 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 etc.; it may be monovalent, divalent or multivalent.
  • C 3-10 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.
  • cycloalkenyl refers to a partially unsaturated non-aromatic carbocyclic ring having at least one double bond and which may exist as a monocyclic, bridged, fused or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3- to 10-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring.
  • Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.
  • the cycloalkenyl is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkane Oxygen, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 2.
  • substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkane Oxygen, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(
  • -C(O)NH-alkyl -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl , -S(O) 2 -alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2 , cycloalkyl, cycloalkane alkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl radical, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
  • carbocyclyl refers to a non-aromatic carbocyclic ring which is partially unsaturated and which may exist as a monocyclic, bridged, fused or spiro ring. Unless otherwise indicated, the carbocycle is typically 3 to 12, 3 to 10, 3 to 8, 4 to 8, 5 to 8, 5 to 6, 3 to 7, 3 to 6, or a 4 to 6 membered ring.
  • Non-limiting examples of carbocyclyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, benzocyclopentene benzocyclopentadienyl, benzocyclohexenyl, benzocyclohexadienyl, etc.
  • the carbocyclyl is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkane Oxygen, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 2.
  • -C(O)NH-alkyl -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl , -S(O) 2 -alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2 , cycloalkyl, cycloalkane alkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl radical, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
  • heterocyclyl refers to a non-aromatic ring which is partially unsaturated and which may exist as a monocyclic, bridged, fused or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3- to 12-membered, 3- to 12-membered, 3-10, 3-8, 4-8, 5-8, 5-6, 3-7, 3-6, or 4-6 rings.
  • heterocyclyl include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl , pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, etc.
  • the heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkane Oxygen, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 2.
  • -C(O)NH-alkyl -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl , -S(O) 2 -alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2 , cycloalkyl, cycloalkane alkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl radical, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
  • the term "5-6 membered heterocycloalkenyl" by itself or in combination with other terms respectively means a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond , whose 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, N and Se, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally is oxidized (ie NO and S(O) p , where p is 1 or 2).
  • bicyclic ring systems include spiro rings, fused rings and bridged rings, and any ring in this system is non-aromatic.
  • a heteroatom may occupy the attachment position of the heterocycloalkenyl to the rest of the molecule.
  • the 5-6 membered heterocycloalkenyl includes 5-membered and 6-membered heterocycloalkenyl and the like. Examples of 5-6 membered heterocycloalkenyl include, but are not limited to
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spiro ring.
  • the heterocycle is typically 3 to 12 rings containing 1 to 4 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from O, S, N, Se, P, Si and/or B. , 3 to 10, 4 to 8, 5 to 10, 5 to 8, 5 to 6, 3 to 7, or 4 to 6 rings, wherein the nitrogen atom is optionally quaternized, nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , where p is 1 or 2).
  • the heterocycloalkyl group includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro rings, fused rings and bridged rings. Additionally, in the heterocycloalkyl, a heteroatom may occupy the position at which the heterocycloalkyl is attached to the rest of the molecule.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thioethyl, cycloazaethyl
  • 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetyl, Cyclic, thiabutanyl
  • 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine , imidazolidinyl, tetrahydropyrazolyl
  • 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazin
  • the heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, Haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH 2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alk radical, -S(O) 2 -alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-alkyl, -S(O) 2 N(alkyl)
  • the term "5-10 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 3 to 10 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, N, and Se, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, merged and bridged rings.
  • the 5-10 membered heterocycloalkyl group includes 5-8 membered, 5-6 membered, 5-membered and 6-membered heterocycloalkyl groups and the like.
  • Examples of 5-10 membered heterocycloalkyl groups include, but are not limited to, 5-pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.
  • tetrahydrofuranyl including tetrahydrofuran-2-yl, etc.
  • tetrahydropyranyl piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, iso Thiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, and anthracenyl, and the like.
  • the aryl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxy ylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 2 , -C (O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S( O) 2 -alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-alkyl, -S(O) 2 N(alkyl) 2 , cyclo
  • heteroaryl refers to a monocyclic or fused polycyclic aromatic system containing at least one ring atom selected from N, O, S and Se, the remaining ring atoms being C, usually having 5 to 14 members, 5 to 12-membered, 5-10-membered, 5-8-membered, 5-7-membered or 5-6-membered rings, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • the heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 6 membered ring, or multiple fused rings comprising 5 to 14, especially 5 to 10 ring atoms.
  • Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolyl , tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, etc.
  • the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, Alkylamino, Dialkylamino, Haloalkylamino, Halodialkylamino, Carboxyl, -C(O)O-Alkyl, -OC(O)-Alkyl, -C(O)NH 2 , - C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S (O) 2 -Alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-Alkyl, -S(O) 2 N(Alkyl) 2 , Cy
  • the term "5-10 membered heteroaryl” means a cyclic group consisting of 5 to 10 ring atoms with a conjugated ⁇ -electron system, of which 1, 2, 3 or 4 ring atoms are Heteroatoms independently selected from O, S, N and Se, the rest being carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic ring system in which each ring is aromatic. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
  • the 5-10 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5-membered and 6-membered heteroaryl groups and the like.
  • Examples of the 5-10 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl
  • the term "5-6 membered heteroaryl” means a monocyclic group consisting of 5 to 6 ring atoms having a conjugated ⁇ -electron system, 1, 2, 3 or 4 of which are independently Heteroatoms selected from O, S, N and Se, the rest being carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
  • the 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl
  • the groups Y 1 and Y 2 in the present disclosure adopt a reading order from left to right, corresponding to the left group and the right group connected to Y 1 or Y 2 in the general formula shown.
  • the C atom in is a ring atom of ring A and is connected to the S atom outside ring A.
  • treating means administering a compound or formulation of the present disclosure to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with said disease, including preventing a disease or condition from occurring in a mammal, especially when such When the mammal is susceptible to the disease state, but has not been diagnosed as having the disease state.
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying Amounts of a compound of the disclosure for the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • the amount of a compound of the present disclosure that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art according to its own knowledge and this disclosure.
  • composition refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the pharmaceutical composition of the present disclosure can be prepared by combining the compound of the present disclosure with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • composition of the present disclosure can be produced by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, freeze-drying and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, gels, slurries, suspensions and the like for oral administration to patients.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating.
  • Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • the pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
  • the daily dosage is 0.01 to 200 mg/kg body weight.
  • the compound of the present disclosure can be prepared by various synthetic methods well known to those skilled in the art, including the following The specific embodiment, the embodiment formed by its combination with other chemical synthesis methods and equivalent replacements well known to those skilled in the art, the preferred embodiment includes but not limited to the examples of the present disclosure.
  • the compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art As an equivalent alternative, preferred embodiments include but are not limited to the examples of the present disclosure.
  • Y 1 and Y 2 can be O; R 1 , R 2 , X, m, n, L, ring A, ring D and ring C are as defined in formula (A) of the present disclosure.
  • the compound of formula (I) of the present disclosure can be prepared by those skilled in the art of organic synthesis through route 2,
  • R 1 , n, T 1 , ring A, ring B and ring C are as defined in formula (I) of the present disclosure.
  • Each of the products obtained from the reactions in the above schemes can be obtained by conventional separation techniques, including but not limited to filtration, distillation, crystallization, chromatographic separation, and the like.
  • Starting materials can be synthesized in-house or purchased from commercial establishments such as, but not limited to, Adrich or Sigma. These starting materials can be characterized using conventional means, such as physical constants and spectral data.
  • Compounds described in this disclosure may be obtained using synthetic methods as single isomers or as mixtures of isomers.
  • the structures of the compounds disclosed in the present disclosure can be confirmed by conventional methods known to those skilled in the art. If the disclosure involves the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • the cultured single crystal is collected with a Bruker D8venture diffractometer to collect diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • Solvents used in the present disclosure are commercially available.
  • Step 1 Synthesis of compound 001_2
  • cyclopropanesulfonamide (318.41 mg) was dissolved in dimethyl sulfoxide (15 mL), and potassium tert-butoxide (491.48 mg) was added thereto at 25 ° C, stirred for 30 minutes and then added to it 001_1 (500.00 mg) was added slowly, and stirred at room temperature for 15 hours after the addition was complete.
  • dilute with water 100 mL
  • adjust the pH to 6 with 2M dilute hydrochloric acid
  • extract with ethyl acetate 200 mL ⁇ 3
  • Step 1 Synthesis of Compound 002_1
  • Step 3 Synthesis of Compound 003_1
  • 001_3 (300.00mg), pyrazol[1,5-a]pyridin-6-inhalol borate (154.44mg) and potassium carbonate (367.82mg) were placed in a dry reaction
  • 1,4-dioxane (20mL) and water (2mL) to dissolve.
  • 1,1-bis(diphenylphosphine)ferrocenepalladium chloride 64.91 mg
  • Step 1 Synthesis of compound 004_1
  • potassium tert-butoxide 549.71 mg was added to ethylene glycol (8.00 mL), the reaction system was heated to 40 ° C and stirred for 30 minutes, and dissolved in ethylene glycol dimethyl ether (20 mL ) in 004_1 (800.00mg), the reaction system was heated to 110 ° C and stirred for 15 hours. After the reaction was completed, the reaction system was cooled to room temperature, diluted with water (30 mL), adjusted to pH 4 with 1 M dilute hydrochloric acid, extracted with ethyl acetate (100 mL ⁇ 3), and combined the organic phases.
  • Step 1 Synthesis of compound 005_1
  • 3,4-methylenedioxyphenylboronic acid pinacol ester (311.09mg), 004_2 (400.00mg) and potassium carbonate (470.89mg) were dissolved in 1,4-dioxane ring (20 mL) and water (2 mL), 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (83.10 mg) was added thereto, nitrogen was replaced three times, and the reaction was heated to 80°C and stirred for 15 hours.
  • Step 1 Synthesis of compound 006_2
  • 006_2 600.00 mg was dissolved in dimethyl sulfoxide (20 mL), and potassium tert-butoxide (1.34 g) was added thereto at 25 ° C. After stirring for one hour, slowly added 001_1 (904.37mg), stirred at 25°C for 11 hours after addition. After the reaction was completed, the reaction solution was poured into water (100 mL), adjusted to pH 5 with 1M dilute hydrochloric acid, extracted with ethyl acetate (50 mL ⁇ 3), and the organic phases were combined.
  • potassium tert-butoxide 250.56 mg was added to a mixed solvent of ethylene glycol (7.62 g) and ethylene glycol dimethyl ether (10 mL), and the reaction system was heated to 40° C. and stirred for 30 minutes.
  • 006_3 255.00 mg dissolved in ethylene glycol dimethyl ether (20 mL) was added thereto, and the reaction system was heated to 110° C. and stirred for 15 hours. After the reaction was completed, the reaction system was cooled to room temperature, diluted with water (100 mL), adjusted to pH 5 with 2M dilute hydrochloric acid, extracted with ethyl acetate (60 mL ⁇ 3), and the organic phases were combined.
  • Dissolve 002_1 500 mg in anhydrous N,N-dimethylformamide (3 mL) at room temperature and under a nitrogen atmosphere, cool the reaction system down to 0 °C under a nitrogen atmosphere, and add sodium hydride to it in batches (131.78mg, content 60%), the reaction system was stirred at 0°C for 0.5 hours, 2,5-dibromothiazole (480.22mg) was added thereto, and the reaction was heated to 20°C and stirred for 12 hours.
  • 2-chloro-5-bromopyrimidine 14 g was dissolved in tetrahydrofuran (210 mL), and potassium carbonate (47.01 g) was added. After the temperature of the reaction system was raised to 45°C, ethylene glycol (6.74 g) was added and stirred at 45°C for 12 hours.
  • reaction solution was poured into water (500mL) to quench, extracted with ethyl acetate (200mL ⁇ 3), the organic phase was washed with saturated brine (500mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure The solvent was removed to obtain compound 012_1, and the crude product was directly submitted to the next step.
  • 012_2 (5g) was dissolved in anhydrous toluene (75mL), and diethyl malonate (4.38g), tri-tert-butylphosphine (2.01g, 10 %-14% toluene solution) and potassium phosphate (15.84g), after nitrogen replacement three times, bis(dibenzylideneacetone)palladium (286.05mg) was added, and after nitrogen replacement again, the reaction system was heated to 70°C and stirred for 12 hours.
  • 012_4 (110 mg) was dissolved in phosphorus oxychloride (0.5 mL), and the reaction system was heated to 90° C. and stirred for 1 hour. After the reaction, cool the reaction system to room temperature and slowly pour it into water (5mL) to quench it, adjust the pH to 7-8 with ammonia water, extract with dichloromethane (5mL ⁇ 3), combine the organic phases, and add saturated saline (10mL ⁇ 2) Wash, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent.
  • 012_5 (92.7 mg) was dissolved in anhydrous toluene (3 mL), and 012_1 (67.91 mg) was added.
  • the reaction system was cooled to 0°C, potassium tert-butoxide (77.31 mg) was added and stirred at 0°C for 0.5 hours.
  • use 3M dilute hydrochloric acid to adjust the pH to 4 ⁇ 5 add water (10mL) to dilute, extract with ethyl acetate (15mL ⁇ 3), combine the organic phases, wash with saturated brine (10mL ⁇ 2), and dry over anhydrous sodium sulfate , filtered, and concentrated under reduced pressure to remove the solvent.
  • tert-butyl 4-sulfamoylpiperidine-1-carboxylate 0.5 g
  • 012_6 533.94 mg
  • dimethyl sulfoxide 10 mL
  • potassium carbonate 735.23mg
  • tetrabutylammonium fluoride 1M, 2.36mL
  • 012_7 (0.2 g) was dissolved in ethyl acetate hydrochloride (4M, 4 mL), and the reaction system was stirred at 25°C for 12 hours. After the reaction was completed, the reaction system was concentrated under reduced pressure to remove the solvent to obtain compound 012_8, and the crude product was directly sent to the next step.
  • reaction solution After the reaction is complete, slowly pour the reaction solution into ice water (20mL) to quench the reaction, adjust the pH to 2-3 with 2M dilute hydrochloric acid, add ethyl acetate (20mL ⁇ 3) for extraction, combine the organic phases, and wash with saturated saline (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent.
  • compound 014_5 (840 mg) was dissolved in dichloromethane (10 mL), and triethylamine (1.68 g, 2.31 mL) and 4-dimethylaminopyridine (141.81 mg) were added to the reaction system in sequence .
  • the reaction system was cooled down to 0° C. under a nitrogen atmosphere, and di-tert-butyl dicarbonate (3.05 mL) dissolved in dichloromethane (5 mL) was added dropwise thereto. After the dropwise addition, the reaction system was stirred at 20° C. for 12 hours. After the reaction was completed, the reaction system was directly concentrated under reduced pressure to remove the solvent.
  • tetrahydrofuran (3.5 mL) was put into a reaction flask, and the temperature was lowered to 0° C. under nitrogen protection, and sodium hydride (95.02 mg, content 60%) was added.
  • ethanethiol (196.82 mg) dropwise to the reaction system at 0°C under a nitrogen atmosphere, and stir at 0°C for 1 hour after the dropwise addition.
  • 014_6 (490 mg) dissolved in tetrahydrofuran (1.5 mL) was added dropwise to the reaction system at 0°C, and after the dropwise addition was completed, the temperature was raised to 20°C and stirred for 12 hours.
  • the reaction system was directly concentrated under reduced pressure to remove the solvent, and the resulting residue was diluted with water (10 mL), adjusted to pH 2-3 with 1M dilute hydrochloric acid, extracted with ethyl acetate (30 mL ⁇ 3), combined organic phases, and anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent to obtain compound 018_4, and the crude product is directly sent to the next step.
  • compound 018_5 (623mg) was dissolved in chlorobenzene (15mL), 2,2-dipyridine disulfide (737.00mg) was added, and placed under a metal halide lamp (500W ) for 2 hours.
  • the reaction system was directly concentrated under reduced pressure to remove the solvent, and the resulting residue was diluted with water (100 mL), adjusted to pH 6-7 with 3M dilute hydrochloric acid, stirred for 10 minutes, filtered, and the filter cake was collected, and vacuum-dried to remove the solvent , the compound 019_2 was obtained, and the crude product was directly submitted to the next step.
  • 019_2 (2 g) was dissolved in phosphorus oxychloride (16.50 g), and the reaction system was heated to 90° C. and stirred for 6 hours. After the reaction was completed, the reaction system was directly concentrated under reduced pressure, and the resulting residue was diluted with dichloromethane (20 mL), adjusted to pH 8-9 with saturated aqueous sodium bicarbonate solution, separated, and the organic phase was collected, and the aqueous phase was dichloromethane (20 mL ⁇ 2) extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent.
  • 019_3 800 mg
  • 012_1 593.68 mg
  • tetrahydrofuran 14 mL
  • the temperature of the reaction system was lowered to 0°C under a nitrogen atmosphere
  • sodium hydride 108.41 mg, content: 60%
  • the temperature was raised to 20°C and stirred for 12 hours.
  • 019_4 (560 mg) was dissolved in dimethyl sulfoxide (7 mL), and cyclopropanesulfonamide (139.04 mg), potassium carbonate (432.58 mg) and tetrabutyl Ammonium fluoride (1M solution in tetrahydrofuran, 2.09 mL) was heated to 100°C and stirred for 12 hours. After the reaction was completed, add water (20mL) to the reaction system to dilute, adjust the pH to 3-4 with 1M dilute hydrochloric acid, extract with ethyl acetate (20mL ⁇ 2), combine the organic phases, and wash with saturated brine (20mL).
  • 020_2 (1.4g) and 012_1 (974.83 mg) were dissolved in toluene (25mL), and the temperature was lowered to 0°C under the protection of nitrogen.
  • Potassium tert-butoxide (1.11 g) was added in batches to the reaction system, and stirred at 0° C. for 1 hour.
  • the reaction system was poured into water (10 mL) to quench the reaction, the pH value was adjusted to 3-4 with 2M dilute hydrochloric acid, extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, and saturated brine ( 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent.
  • Antagonism of compounds at endogenously expressed human ETA receptors in SK–N–MC cells was assessed by measuring their effects on human ETA receptor agonist-induced changes in cytoplasmic Ca2 + ion signaling using a fluorescent assay agent activity.
  • the functional activity of ETA receptor antagonistic effects was tested at Eurofins-Cerep SA according to current standard operating procedures.
  • SK-N-MC cells human endogenous (SK-N-MC cells)
  • DMEM Dulbecco's modified Eagle medium solution
  • FCSd 1% FCSd
  • HBSS Hank's balanced salt solution
  • Hepes Invitrogen
  • Fluo4NW fluorescent probe Needles
  • Results are percent inhibition of control response to 1 nM endothelin-1;
  • the standard positive control is BQ-123 (CAS accession number: 136553-81-6), test several concentrations in each experiment, use Prism to analyze the data, generate a concentration-response curve, and calculate the IC 50 value of the compound .
  • Antagonist activity of compounds on human ETB receptors expressed in transfected CHO cells was assessed by measuring their effect on human ETB receptor agonist-induced changes in cytoplasmic Ca2 + ion signaling using a fluorescent assay.
  • the functional activity of ETB receptor antagonistic effects was tested at Eurofins-Cerep SA according to current standard operating procedures.
  • Results are percent inhibition of the control response to 0.3 nM endothelin-1;
  • the standard positive control is BQ-788 sodium salt (CAS accession number: 156161-89-6), test several concentrations in each experiment, use Prism
  • the data are analyzed to generate a concentration-response curve and IC50 values for the compounds are calculated.
  • This project uses 4 male SD rats, which are weighed before administration, and the dosage is calculated according to the body weight, and then the rats are divided into two groups.
  • a group of 2 SD rats were administered intravenously, the dosage was 2 mg/kg, and the concentration was 0.5 mg/mL; another group of 2 SD rats were administered orally, and the dosage was 10 mg/kg.
  • Dosing concentration 1mg/mL;
  • Plasma samples were stored in a -80°C freezer until analysis.
  • mice 50 rats (SD rats, Changzhou Cavens Experimental Animal Co., Ltd.) were anesthetized with isoflurane gas. After general anesthesia, a unilateral nephrectomy was performed on the right side of the rats; the right kidney was removed, and then antibiotics were given by suturing; the rats in the control group (Group-1) had the same procedure as the model group but did not remove the kidney.
  • the rats in the model group were injected with 1 mg/kg anti-Thy1antibody into the tail vein, and the rats in the control group were injected with the same volume of normal saline through the tail vein. On the third day after the injection, the 24-hour urine of the rats was collected and tested.
  • the total protein content in urine The rats that failed to make the model were excluded, and grouped by simple random method according to the urine protein data, and the model rats were randomly divided into 6 groups, namely Group-2, Group-3, Group-4, Group -5, Group-6, Group-7 groups.
  • the rats in Group-1 and Group-2 groups were given an equal volume of solvent (5% DMSO + 20% PEG400 + 10% HS) once a day, with a volume of 1 mL/100g, Continuous administration for 4 weeks;
  • Group-3 rats were administered intragastrically with 5 mg/kg prednisone, once a day, with a intragastric volume of 1 mL/100g, for 4 consecutive weeks;
  • Group-4 rats were administered intragastrically with atraxane Tan (10mg/kg), once a day, intragastric volume of 1mL/100g, continuous administration for 4 weeks;
  • Group-5 rats were intragastrically administered the compound of the present disclosure (1mg/kg), once a day, intragastric administration The volume was 1mL/100g, administered continuously for 4 weeks;
  • Group-6 rats were given the compound of the disclosed embodiment (3mg/kg) by intragastric administration, once a day, and the volume of intragastric administration was 1mL/100g, administered continuously for 4 weeks;
  • the disclosed compound can reduce proteinuria content in rats, increase hematocrit, relieve renal injury in rats, inhibit proliferation of glomerular mesangial cells, increase of glomerular mesangial matrix and thickening of glomerular capsule wall Phenomenon.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La divulgation concerne un composé azobenzène et son application. La divulgation concerne spécifiquement un composé tel que représenté dans la formule (A) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2022/130697 2021-11-08 2022-11-08 Composé azobenzène et son application WO2023078463A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280073839.0A CN118201908A (zh) 2021-11-08 2022-11-08 氮杂联苯类化合物及其应用

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202111316594 2021-11-08
CN202111316594.3 2021-11-08
CN202210678010 2022-06-15
CN202210678010.5 2022-06-15
CN202211358693 2022-11-01
CN202211358693.2 2022-11-01

Publications (1)

Publication Number Publication Date
WO2023078463A1 true WO2023078463A1 (fr) 2023-05-11

Family

ID=86240701

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/130697 WO2023078463A1 (fr) 2021-11-08 2022-11-08 Composé azobenzène et son application

Country Status (3)

Country Link
CN (1) CN118201908A (fr)
TW (1) TWI833430B (fr)
WO (1) WO2023078463A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5292740A (en) * 1991-06-13 1994-03-08 Hoffmann-La Roche Inc. Sulfonamides
CN1095375A (zh) * 1992-12-10 1994-11-23 霍夫曼-拉罗奇有限公司 新的磺酰胺
CN1111242A (zh) * 1993-12-17 1995-11-08 田边制药株式会社 苯磺酰胺衍生物及其制备方法
WO2002008200A2 (fr) * 2000-07-21 2002-01-31 Actelion Pharmaceuticals Ltd Nouveaux sulfonamides arylethene

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5292740A (en) * 1991-06-13 1994-03-08 Hoffmann-La Roche Inc. Sulfonamides
CN1095375A (zh) * 1992-12-10 1994-11-23 霍夫曼-拉罗奇有限公司 新的磺酰胺
CN1111242A (zh) * 1993-12-17 1995-11-08 田边制药株式会社 苯磺酰胺衍生物及其制备方法
WO2002008200A2 (fr) * 2000-07-21 2002-01-31 Actelion Pharmaceuticals Ltd Nouveaux sulfonamides arylethene

Also Published As

Publication number Publication date
TW202327587A (zh) 2023-07-16
TWI833430B (zh) 2024-02-21
CN118201908A (zh) 2024-06-14

Similar Documents

Publication Publication Date Title
CN107698569B (zh) 作为jak抑制剂的联吡唑衍生物
JP2022532354A (ja) Ｎｌｒｐ３インフラマソーム阻害剤
WO2015165279A1 (fr) Composés polyfluorés agissant en tant qu'inhibiteurs de la tyrosine kinase de bruton
EP3640247B1 (fr) Inhibiteur de syk et procédé d'utilisation correspondant
WO2022100624A1 (fr) Composé à base de thiophène aminocarbonate oxy-substitué et son utilisation
WO2022100623A1 (fr) Composés thiophène hétérocycliques substitués par azote et leur utilisation
WO2019174577A1 (fr) Dérivés alcoxy de phtalazine isoxazole, procédé de préparation associé, composition pharmaceutique et utilisation correspondantes
CN104066431A (zh) 吡嗪激酶抑制剂
WO2020042995A1 (fr) Composé agoniste de protéine sting à activité élevée
WO2022194221A1 (fr) Composé de glutarimide substitué par un cycle fusionné à un furane
WO2023041055A1 (fr) Inhibiteur de kif18a
WO2019154294A1 (fr) Dérivé de pyrazolo[1,5-a][1,3,5]triazine-2-amine, son procédé de préparation et son utilisation médicale
WO2020168927A1 (fr) Composé cyclique condensé contenant de l'azote, son procédé de préparation et son utilisation
WO2022242767A1 (fr) Composé spiro et son utilisation
WO2023143424A1 (fr) Dérivé azacyclique et son application médicale
WO2022213980A1 (fr) Inhibiteur de tyk2 et son utilisation
CN103508931A (zh) 六氢并环戊二烯衍生物、其制备方法及其在医药上的应用
EP4267580A1 (fr) Dérivés de n-(pyridin-2-yl)-6,7,8,9-tétrahydro-5h-5,8-epiminocyclohepta[c]pyridine-10-carboxamide et composés similaires servant de modulateurs de gpr65 pour traiter le cancer
WO2021237121A1 (fr) Pyridines substituées
CA3153752A1 (fr) Formes cristallines a l'etat solide d'un modulateur selectif du canal potassique
WO2020259703A1 (fr) Composé de pyrazolopyrimidine, son procédé de préparation et ses applications
WO2023078463A1 (fr) Composé azobenzène et son application
WO2022222911A1 (fr) Composé pyrimidone et son utilisation
EP4126842A1 (fr) Inhibiteur de trka
WO2021114691A1 (fr) Composé à cycles condensés contenant de l'azote, son procédé de préparation et son utilisation

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: 22889484

Country of ref document: EP

Kind code of ref document: A1