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WO2023078463A1 - Azobenzene compound and application thereof - Google Patents

Azobenzene compound and application thereof Download PDF

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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
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Prior art keywords
membered
alkyl
halogenated
alkylamino
ring
Prior art date
Application number
PCT/CN2022/130697
Other languages
French (fr)
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
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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/en
Publication of WO2023078463A1 publication Critical patent/WO2023078463A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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.

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Abstract

An azobenzene compound and an application thereof. Specifically disclosed are a compound as shown in formula (A) and a pharmaceutically acceptable salt thereof.

Description

氮杂联苯类化合物及其应用Azabiphenyl compounds and their applications
相关申请的引用References to related applications
本申请要求于2021年11月08日向中国国家知识产权局提交的第202111316594.3号中国发明专利申请、于2022年06月15日向中国国家知识产权局提交的第202210678010.5号中国发明专利申请、以及于2022年11月01日向中国国家知识产权局提交的第202211358693.2号中国发明专利申请的优先权和权益，所述申请公开的全部内容通过引用整体并入本文中。This application requires the Chinese Invention Patent Application No. 202111316594.3 submitted to the State Intellectual Property Office of China on November 8, 2021, the Chinese Invention Patent Application No. 202210678010.5 submitted to the State Intellectual Property Office of China on June 15, 2022, and the Chinese Invention Patent Application No. Priority and rights to the Chinese Invention Patent Application No. 202211358693.2 filed with the State Intellectual Property Office of China on November 01, 2020, the entire disclosure of said application is incorporated herein by reference in its entirety.
技术领域technical field
本公开涉及医药化学技术领域，特别是涉及一种氮杂联苯类化合物及其应用，具体涉及式(A)所示化合物及其药学上可接受的盐。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.
背景技术Background technique
IgA肾病(IgA Nephropathy)是最常见的原发性肾小球肾炎之一，在我国约占原发性肾小球疾病的25％-50％。并且IgA肾病在中青年人中发病率更高。在大于20岁的患者中，约有40％的患者会发展为终末期肾病。IgA nephropathy (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.
内皮素(endothelin，ET)是存在于血浆中的天然存在的由21个氨基酸组成的双环肽。在各种病生理因素(衰老，糖尿病、胰岛素抵抗、肥胖、免疫系统激活、血脂异常、活性氧形成、一氧化氮缺乏等)条件下，均会诱导内皮细胞合成并释放内皮素-1(ET-1)。内皮素有两种已知的受体，即内皮素A受体(ETR-A)和内皮B素受体(ETR-B)。内皮素与血管平滑肌细胞上的ETR-A结合会引起血管收缩，细胞增殖和细胞外基质沉积。内皮素与内皮细胞上的ETR-B结合，可通过介导一氧化氮的产生，促进血管舒张，抗细胞增殖和抗纤维化。内皮素作用于肾脏细胞的ETA受体可以产生不同的生理效应，包括血管收缩，内皮细胞损伤，血管壁增厚，组织浸润，炎症反应，系膜细胞增殖，足细胞损伤等。肾脏ETA受体被过度激活会造成肾损伤及肾纤维化，导致慢性肾病，FSGS，IgA肾病的发生与进展。Endothelin (ET) 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.
发明内容Contents of the invention
本公开提供式(A)所述化合物或其药学上可接受的盐，其选自：The present disclosure provides the compound described in formula (A) or a pharmaceutically acceptable salt thereof, which is selected from:
Figure PCTCN2022130697-appb-000001
Figure PCTCN2022130697-appb-000001
其中，in,
Z 1选自N或CR Z1； Z1 is selected from N or CR Z1 ;
Z 2选自N或CR Z2； Z2 is selected from N or CR Z2 ;
R Z1或R Z2各自独立地选自H、卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、或卤代二C 1-6烷基氨基； 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选自O或NH；X is selected from O or NH;
环A选自任选地被一个或多个R a取代的以下基团：3-12元环烷基或3-12元杂环烷基； 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;
R a各自独立地选自卤素、-OH、氧代、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-NHC(O)NR a1R a2、-NR a1C(O)OR a2、-OC(O)R a1、-C(O)OR a1、-OC(O)OR a1、-OC(O)NR a1R a2、-C 1-6亚烷基C(O)NR a1R a2、-C 1-6亚烷基NR a1C(O)R a2、-C 1-6亚烷基NHC(O)NR a1R a2、-C 1-6亚烷基NR a1C(O)OR a2、-C 1-6亚 烷基OC(O)R a1、-C 1-6亚烷基C(O)OR a1、-C 1-6亚烷基OC(O)NR a1R a2、或任选地被1个或多个R a3取代的如下基团：C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、3-12元环烷基、3-12元杂环烷基、5-10元杂环基、6-10元芳基、或5-10元杂芳基； 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)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 C(O)OR a2 , -C 1-6 alkylene OC(O)R a1 , -C 1-6 alkylene C(O)OR a1 , -C 1-6 alkylene OC(O)NR a1 R a2 , or the following groups optionally substituted by one or more R a3 : C 1-6 alkyl, C 1-6 alkoxy Base, C 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl ;
R a1、R a2各自独立地选自H或C 1-6烷基； R a1 and R a2 are each independently selected from H or C 1-6 alkyl;
R a3各自独立地选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、或卤代二C 1-6烷基氨基； 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选自单键、-O-、-S-、-NH-、-C(O)-、或是任选地被一个或多个R L取代的以下基团：-CH 2-、-N(C 1-6烷基)-、或-CH(C 1-6烷基)-； 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各自独立地选自卤素、-OH、-NH 2、-CN、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、或卤代二C 1-6烷基氨基； 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;
环D选自任选地被一个或多个R b取代的以下基团：3-12元环烷基、3-12元杂环烷基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基； 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各自独立地选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、或卤代二C 1-6烷基氨基； 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;
Y 1选自-O-、-S-、或-NH-； Y1 is selected from -O-, -S-, or -NH-;
Y 2选自-O-、-S-、-NH-、-SO 2-、-NHSO 2-、-SO 2NH-、-NHSO 2NH-、-C(O)NH-、-NHC(O)-、-OC(O)NH-、-NHC(O)O-、或-NHC(O)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-;
m选自1、2、3、4、5、或6；m is selected from 1, 2, 3, 4, 5, or 6;
环C选自3-12元环烷基、3-12元杂环烷基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基；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选自0、1、2、3、或4；n is selected from 0, 1, 2, 3, or 4;
R 1各自独立地选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、或卤代二C 1-6烷基氨基； 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选自H、卤素、-OH、-NH 2、-CN、或是任选地被一个或多个R 2a取代的以下基团：C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、3-12元环烷基、3-12元杂环烷基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基； 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各自独立地选自氧代、卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、或卤代二C 1-6烷基氨基； 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、环A、环D或环C任选地被一个或多个取代基取代。 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.
在一些实施方案中，Z 1选自N。 In some embodiments, Z is selected from N.
在一些实施方案中，Z 1选自CR Z1。 In some embodiments, Z 1 is selected from CR Z1 .
在一些实施方案中，Z 2选自N。 In some embodiments, Z2 is selected from N.
在一些实施方案中，Z 2选自CR Z2。 In some embodiments, Z 2 is selected from CR Z2 .
在一些实施方案中，Z 1和Z 2选自N。 In some embodiments, Z1 and Z2 are selected from N.
在一些实施方案中，Z 1选自CR 1，且Z 2选自CR Z2。 In some embodiments, Z 1 is selected from CR 1 and Z 2 is selected from CR Z2 .
在一些实施方案中，Z 1和Z 2之一选自N。 In some embodiments, one of Z1 and Z2 is selected from N.
在一些实施方案中，R Z1或R Z2各自独立地选自H、卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤代C 1-4烷硫基、卤代C 1- 4烷基氨基、或卤代二C 1-4烷基氨基。 In some embodiments, 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 .
在一些实施方案中，R Z1或R Z2各自独立地选自H、卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、 C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1-4烷基、或卤代C 1-4烷氧基。 In some embodiments, 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.
在一些实施方案中，R Z1或R Z2各自独立地选自H、F、Cl、Br、-OH、-NH 2、-CN、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、甲基氨基、乙基氨基、二甲基氨基、三氟甲基、或三氟甲氧基。 In some embodiments, 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.
在一些实施方案中，R Z1或R Z2各自独立地选自H、F、Cl、Br、-OH、-NH 2、-CN、甲基、甲氧基、甲基氨基、二甲基氨基、三氟甲基、或三氟甲氧基。 In some embodiments, 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.
在一些实施方案中，R Z1或R Z2各自独立地选自H。 In some embodiments, R Z1 or R Z2 are each independently selected from H.
在一些实施方案中，X选自O。In some embodiments, X is selected from O.
在一些实施方案中，X选自NH。In some embodiments, X is selected from NH.
在一些实施方案中，环A选自任选地被一个或多个R a取代的以下基团：3-10元环烷基或3-10元杂环烷基。 In some embodiments, 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 .
在一些实施方案中，环A选自任选地被一个或多个R a取代的以下基团：3-8元环烷基或3-8元杂环烷基。 In some embodiments, 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 .
在一些实施方案中，环A选自任选地被一个或多个R a取代的以下基团：环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、双环[1.1.1]戊基、双环[3.1.0]己基、双环[3.2.0]庚基、双环[2.2.2]辛基、双环[3.3.0]辛基、螺[3.3]庚基、螺[3.4]辛基、氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、氧杂环庚烷基、氮杂环庚烷基、氮杂双环[3.1.0]己基、氧杂双环[3.2.0]庚基、氮杂双环[3.2.0]庚基、氧杂双环[2.2.2]辛基、氮杂双环[2.2.2]辛基、氧杂双环[3.3.0]辛基、氮杂双环[3.3.0]辛基、氧杂螺[3.3]庚基、氮杂螺[3.3]庚基、氧杂螺[3.4]辛基、或氮杂螺[3.4]辛基。 In some embodiments, 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, oxabicyclo[2.2.2]octyl, azabicyclo[3.2.0]heptyl Bicyclo[2.2.2]octyl, oxabicyclo[3.3.0]octyl, azabicyclo[3.3.0]octyl, oxaspiro[3.3]heptyl, azaspiro[3.3]heptyl, oxygen heterospiro[3.4]octyl, or azaspiro[3.4]octyl.
在一些实施方案中，环A选自任选地被一个或多个R a取代的以下基团：环丙烷基、螺[3.3]庚基、四氢呋喃基、哌啶基、或氧杂螺[3.3]庚基。 In some embodiments, 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.
在一些实施方案中，环A选自任选地被一个或多个R a取代的以下基团：
Figure PCTCN2022130697-appb-000002
Figure PCTCN2022130697-appb-000003
In some embodiments, ring A is selected from the following groups optionally substituted with one or more R a :
Figure PCTCN2022130697-appb-000002
Figure PCTCN2022130697-appb-000003
在一些实施方案中，R a各自独立地选自卤素、-OH、氧代、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-NHC(O)NR a1R a2、-NR a1C(O)OR a2、-OC(O)R a1、-C(O)OR a1、-OC(O)OR a1、-OC(O)NR a1R a2、-C 1-4亚烷基C(O)NR a1R a2、-C 1-4亚烷基NR a1C(O)R a2、-C 1-4亚烷基NHC(O)NR a1R a2、-C 1-4亚烷基NR a1C(O)OR a2、-C 1-4亚烷基OC(O)R a1、-C 1-4亚烷基C(O)OR a1、-C 1-4亚烷基OC(O)NR a1R a2、或任选地被1个或多个R a3取代的如下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、3-6元环烷基、3-6元杂环烷基、5-6元杂环基、苯基、或5-6元杂芳基。 In some embodiments, 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)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 a1 C(O)OR a2 , -C 1-4 alkylene OC(O)R a1 , -C 1-4 alkylene C(O)OR a1 , -C 1-4 alkylene OC(O)NR a1 R a2 , or the following groups optionally substituted by one or more R a3 : C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heterocyclyl Aryl.
在一些实施方案中，R a各自独立地选自卤素、-OH、氧代、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-OC(O)R a1、-C(O)OR a1、-C 1-4亚烷基C(O)NR a1R a2、-C 1-4亚烷基NR a1C(O)R a2、-C 1-4亚烷基OC(O)R a1、-C 1-4亚烷基C(O)OR a1、或任选地被1个或多个R a3取代的如下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、3-6元环烷基、3-6元杂环烷基、5-6元杂环基、苯基、或5-6元杂芳基。 In some embodiments, 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 The following groups: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heterocycle Base, phenyl, or 5-6 membered heteroaryl.
在一些实施方案中，R a各自独立地选自F、Cl、Br、-OH、氧代、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-OC(O)R a1、-C(O)OR a1、-C 1-2亚烷基C(O)NR a1R a2、-C 1-2亚烷基NR a1C(O)R a2、-C 1-2亚烷基OC(O)R a1、-C 1-2亚烷基C(O)OR a1、或任选地被1个或多个R a3取代的如下基团：甲基、乙基、甲氧基、乙氧基、甲基氨基、或二甲基氨基。 In some embodiments, 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.
在一些实施方案中，R a各自独立地选自F、Cl、Br、-OH、氧代、-NH 2、-CN、-C(O)NR a1R a2、-C(O)OR a1、或任选地被1个或多个R a3取代的如下基团：甲基、乙基、甲氧基、乙氧基、甲基氨基、或二甲基氨基。 In some embodiments, 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.
在一些实施方案中，R a1、R a2各自独立地选自H或C 1-4烷基。 In some embodiments, R a1 , R a2 are each independently selected from H or C 1-4 alkyl.
在一些实施方案中，R a1、R a2各自独立地选自H、甲基、或乙基。 In some embodiments, R a1 , R a2 are each independently selected from H, methyl, or ethyl.
在一些实施方案中，R a1、R a2各自独立地选自H或甲基。 In some embodiments, R a1 , R a2 are each independently selected from H or methyl.
在一些实施方案中，R a3各自独立地选自卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、 C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤代C 1-4烷硫基、卤代C 1-4烷基氨基、或卤代二C 1-4烷基氨基。 In some embodiments, 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.
在一些实施方案中，R a3各自独立地选自H、卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1-4烷基、或卤代C 1-4烷氧基。 In some embodiments, 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.
在一些实施方案中，R a3各自独立地选自H、F、Cl、Br、-OH、-NH 2、-CN、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、甲基氨基、乙基氨基、二甲基氨基、三氟甲基、或三氟甲氧基。 In some embodiments, 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.
在一些实施方案中，R a3各自独立地选自H、F、Cl、Br、-OH、-NH 2、-CN、甲氧基、或甲基氨基。 In some embodiments, each R a3 is independently selected from H, F, Cl, Br, -OH, -NH 2 , -CN, methoxy, or methylamino.
在一些实施方案中，R a各自独立地选自F、Cl、Br、-OH、氧代、-NH 2、-CN、-C(O)NR a1R a2、-C(O)OR a1、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、甲基氨基、乙基氨基、二甲基氨基、三氟甲基、或三氟甲氧基。 In some embodiments, 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.
在一些实施方案中，R a各自独立地选自-C(O)NH 2、-C(O)NHCH 3、-COOH、-COOCH 3、甲基、或甲氧基。 In some embodiments, each R a is independently selected from -C(O) NH2 , -C(O) NHCH3 , -COOH, -COOCH3 , methyl, or methoxy.
在一些实施方案中，环A选自任选地被一个或多个R a取代的以下基团：
Figure PCTCN2022130697-appb-000004
Figure PCTCN2022130697-appb-000005
其中R a各自独立地选自-C(O)NH 2、-C(O)NHCH 3、-COOH、-COOCH 3、甲基、或甲氧基。 In some embodiments, ring A is selected from the following groups optionally substituted with one or more R a :
Figure PCTCN2022130697-appb-000004
Figure PCTCN2022130697-appb-000005
wherein each R a is independently selected from -C(O)NH 2 , -C(O)NHCH 3 , -COOH, -COOCH 3 , methyl, or methoxy.
在一些实施方案中，环A选自以下基团：
Figure PCTCN2022130697-appb-000006
Figure PCTCN2022130697-appb-000007
In some embodiments, Ring A is selected from the following groups:
Figure PCTCN2022130697-appb-000006
Figure PCTCN2022130697-appb-000007
在一些实施方案中，L选自单键、-O-、-S-、-NH-、-C(O)-、或是任选地被一个或多个R L取代的以下基团：-CH 2-、-N(C 1-3烷基)-、或-CH(C 1-3烷基)-。 In some embodiments, 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)-.
在一些实施方案中，L选自单键、-O-、-S-、-NH-、-C(O)-、或是任选地被一个或多个R L取代的以下基团：-CH 2-、-N(CH 3)-、或-CH(CH 3)-。 In some embodiments, 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 )-.
在一些实施方案中，L选自单键、-O-、-S-、-NH-、-C(O)-、-CH 2-、-N(CH 3)-、或-CH(CH 3)-。 In some embodiments, L is selected from a single bond, -O-, -S-, -NH-, -C(O)-, -CH 2 -, -N(CH 3 )-, or -CH(CH 3 )-.
在一些实施方案中，L选自单键。In some embodiments, L is selected from single bonds.
在一些实施方案中，R L各自独立地选自卤素、-OH、-NH 2、-CN、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤代C 1-4烷硫基、卤代C 1-4烷基氨基、或卤代二C 1-4烷基氨基。 In some embodiments, 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.
在一些实施方案中，R L各自独立地选自H、卤素、-OH、-NH 2、-CN、C 1-4烷氧基、C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1-4烷基、或卤代C 1-4烷氧基。 In some embodiments, 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.
在一些实施方案中，R L各自独立地选自H、F、Cl、Br、-OH、-NH 2、-CN、甲氧基、甲基氨基、二甲基氨基、三氟甲基、或三氟甲氧基。 In some embodiments, each R L is independently selected from H, F, Cl, Br, -OH, -NH2 , -CN, methoxy, methylamino, dimethylamino, trifluoromethyl, or Trifluoromethoxy.
在一些实施方案中，所述环D的环原子中，至少含有1个N、O或S原子。In some embodiments, among the ring atoms of the ring D, there is at least one N, O or S atom.
在一些实施方案中，所述环D的环原子中，至少含有2个N原子、至少含有1个N原子和1个S原子、或至少含有2个O原子。In some embodiments, among 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.
在一些实施方案中，所述环D的环原子中，除C环原子外，只含有2个N原子、只含有1个N原子和1个S原子、或只含有2个O原子。In some embodiments, among 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.
在一些实施方案中，环D选自任选地被一个或多个R b取代的以下基团：3-10元环烷基、3-10元杂环烷基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基。 In some embodiments, 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.
在一些实施方案中，环D选自任选地被一个或多个R b取代的以下基团：5-10元碳环基、5-10元杂环 基、6-10元芳基、或5-10元杂芳基。 In some embodiments, 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.
在一些实施方案中，环D选自任选地被一个或多个R b取代的以下基团：
Figure PCTCN2022130697-appb-000008
其中环B选自5-6元杂环烯基、或5-6元杂芳基，T 1选自C、或N。 In some embodiments, ring D is selected from the following groups optionally substituted with one or more R b :
Figure PCTCN2022130697-appb-000008
Wherein ring B is selected from 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, and T1 is selected from C or N.
在一些实施方案中，环B选自
Figure PCTCN2022130697-appb-000009
In some embodiments, Ring B is selected from
Figure PCTCN2022130697-appb-000009
在一些实施方案中，环D选自任选地被一个或多个R b取代的以下基团：苯并5-6元环烯基、苯并5-6元杂环基、吡啶并5-6元杂环基、苯基、萘基、或9-10元杂芳基。 In some embodiments, 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.
在一些实施方案中，环D选自任选地被一个或多个R b取代的如下基团：
Figure PCTCN2022130697-appb-000010
苯基、萘基、吲哚基、苯并吡唑基、苯并咪唑基、苯并噻唑基、
Figure PCTCN2022130697-appb-000011
喹啉基、异喹啉基、或苯并嘧啶基。 In some embodiments, ring D is selected from the following groups optionally substituted with one or more R b :
Figure PCTCN2022130697-appb-000010
Phenyl, naphthyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl,
Figure PCTCN2022130697-appb-000011
Quinolinyl, isoquinolinyl, or benzopyrimidinyl.
在一些实施方案中，环D选自任选地被一个或多个R b取代的如下基团：
Figure PCTCN2022130697-appb-000012
苯并噻唑基、或
Figure PCTCN2022130697-appb-000013
In some embodiments, ring D is selected from the following groups optionally substituted with one or more R b :
Figure PCTCN2022130697-appb-000012
benzothiazolyl, or
Figure PCTCN2022130697-appb-000013
在一些实施方案中，环D选自任选地被一个或多个R b取代的如下基团：
Figure PCTCN2022130697-appb-000014
In some embodiments, ring D is selected from the following groups optionally substituted with one or more R b :
Figure PCTCN2022130697-appb-000014
在一些实施方案中，环D选自
Figure PCTCN2022130697-appb-000015
In some embodiments, ring D is selected from
Figure PCTCN2022130697-appb-000015
在一些实施方案中，R b各自独立地选自卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤代C 1-4烷硫基、卤代C 1-4烷基氨基、或卤代二C 1-4烷基氨基。 In some embodiments, 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.
在一些实施方案中，R b各自独立地选自卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1-4烷基、或卤代C 1-4烷氧基。 In some embodiments, 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.
在一些实施方案中，R b各自独立地选自F、Cl、Br、-OH、-NH 2、-CN、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、甲基氨基、乙基氨基、二甲基氨基、三氟甲基、或三氟甲氧基。 In some embodiments, 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.
在一些实施方案中，R b各自独立地选自F、Cl、Br、-OH、-NH 2、-CN、甲基、甲氧基、甲基氨基、二甲基氨基、三氟甲基、或三氟甲氧基。 In some embodiments, each Rb is independently selected from F, Cl, Br, -OH, -NH2 , -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
在一些实施方案中，Y 1选自-O-。 In some embodiments, Y1 is selected from -O-.
在一些实施方案中，Y 2选自-O-、-S-、-NH-、-SO 2-、-NHSO 2-、-SO 2NH-、-C(O)NH-、或-NHC(O)-。 In some embodiments, Y 2 is selected from -O-, -S-, -NH-, -SO 2 -, -NHSO 2 -, -SO 2 NH-, -C(O)NH-, or -NHC( O)-.
在一些实施方案中，Y 2选自-O-、-S-、或-NH-。 In some embodiments, Y2 is selected from -O-, -S-, or -NH-.
在一些实施方案中，Y 2选自-O-。 In some embodiments, Y2 is selected from -O-.
在一些实施方案中，Y 1选自-O-，且Y 2选自-O-。 In some embodiments, Y1 is selected from -O-, and Y2 is selected from -O-.
在一些实施方案中，m选自1、2、3、或4。In some embodiments, m is selected from 1, 2, 3, or 4.
在一些实施方案中，m选自2、3、或4。In some embodiments, m is selected from 2, 3, or 4.
在一些实施方案中，m选自2。In some embodiments, m is selected from 2.
在一些实施方案中，所述环C的环原子中，至少含有1个N、O或S原子。In some embodiments, among the ring atoms of the ring C, there is at least one N, O or S atom.
在一些实施方案中，所述环C的环原子中，含有1、2或3个N原子、或1个S原子。In some embodiments, among the ring atoms of the ring C, there are 1, 2 or 3 N atoms, or 1 S atom.
在一些实施方案中，所述环C的环原子中，除C环原子外，只含有N原子或S原子。In some embodiments, among the ring atoms of the ring C, except for the C ring atoms, there are only N atoms or S atoms.
在一些实施方案中，所述环C的环原子中，除C环原子外，只含有1、2或3个N原子、或只含有1个N原子和1个S原子。In some embodiments, among the ring atoms of the ring C, except the C ring atoms, there are only 1, 2 or 3 N atoms, or only 1 N atom and 1 S atom.
在一些实施方案中，环C选自3-10元环烷基、3-10元杂环烷基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基。In some embodiments, 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.
在一些实施方案中，环C选自3-8元环烷基、3-8元杂环烷基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基。In some embodiments, 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.
在一些实施方案中，环C选自6-10元芳基或5-10元杂芳基。In some embodiments, Ring C is selected from 6-10 membered aryl or 5-10 membered heteroaryl.
在一些实施方案中，环C选自苯基、萘基、吡咯基、吡唑基、咪唑基、呋喃基、噁唑基、异噁唑基、噻吩基、噻唑基、异噻唑基、吡喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吲哚基、苯并吡唑基、苯并咪唑基、苯并噻唑基、咪唑并[1,2-b]哒嗪基、吡唑并[1,5-a]吡啶基、喹啉基、异喹啉基、或苯并嘧啶基。In some embodiments, 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.
在一些实施方案中，环C选自苯基、萘基、噻唑基、吡啶基、嘧啶基、三嗪基、或咪唑并[1,2-b]哒嗪基。In some embodiments, ring C is selected from phenyl, naphthyl, thiazolyl, pyridyl, pyrimidinyl, triazinyl, or imidazo[1,2-b]pyridazinyl.
在一些实施方案中，环C选自嘧啶基、吡啶基、噻唑基、咪唑并哒嗪基和三嗪基。In some embodiments, Ring C is selected from pyrimidinyl, pyridyl, thiazolyl, imidazopyridazinyl, and triazinyl.
在一些实施方案中，环C选自
Figure PCTCN2022130697-appb-000016
In some embodiments, Ring C is selected from
Figure PCTCN2022130697-appb-000016
在一些实施方案中，n选自0、1、或2。In some embodiments, n is selected from 0, 1, or 2.
在一些实施方案中，n选自0或1。In some embodiments, n is selected from 0 or 1.
在一些实施方案中，R 1各自独立地选自卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤代C 1-4烷硫基、卤代C 1-4烷基氨基、或卤代二C 1-4烷基氨基。 In some embodiments, 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.
在一些实施方案中，R 1各自独立地选自卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1-4烷基、或卤代C 1-4烷氧基。 In some embodiments, 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.
在一些实施方案中，R 1各自独立地选自F、Cl、Br、-OH、-NH 2、-CN、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、甲基氨基、乙基氨基、二甲基氨基、三氟甲基、或三氟甲氧基。 In some embodiments, 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.
在一些实施方案中，R 1各自独立地选自F、Cl、Br、-OH、-NH 2、-CN、甲基、甲氧基、甲基氨基、二甲基氨基、三氟甲基、或三氟甲氧基。 In some embodiments, each R1 is independently selected from F, Cl, Br, -OH, -NH2 , -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
在一些实施方案中，R 1各自独立地选自F、Cl、Br、或三氟甲氧基。 In some embodiments, each R 1 is independently selected from F, Cl, Br, or trifluoromethoxy.
在一些实施方案中，R 2选自H、卤素、-OH、-NH 2、-CN、或是任选地被一个或多个R 2a取代的以下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷基氨基、二C 1-4烷基氨基、3-10元环烷基、3-10元杂环烷 基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基。 In some embodiments, 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.
在一些实施方案中，R 2选自H、卤素、-OH、-NH 2、-CN、或是任选地被一个或多个R 2a取代的以下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷基氨基、二C 1-4烷基氨基、3-8元环烷基、3-8元杂环烷基、苯基、或5-6元杂芳基。 In some embodiments, 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.
在一些实施方案中，R 2选自H、卤素、-OH、-NH 2、-CN、或是任选地被一个或多个R 2a取代的以下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二C 1-4烷基氨基、3-6元环烷基、3-6元杂环烷基、苯基、或5-6元杂芳基。 In some embodiments, 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.
在一些实施方案中，R 2选自H、F、Cl、Br、-OH、-NH 2、-CN、或是任选地被一个或多个R 2a取代的以下基团：甲基、乙基、甲氧基、乙氧基、甲基氨基、乙基氨基、二甲基氨基、环丙烷基、环丁烷基、环戊烷基、环己烷基、氮杂环丁烷基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、苯基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、或吡嗪基。 In some embodiments, 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.
在一些实施方案中，R 2选自H、F、Cl、Br、或是任选地被一个或多个R 2a取代的以下基团：甲基或吗啉基。 In some embodiments, R 2 is selected from H, F, Cl, Br, or the following groups optionally substituted with one or more R 2a : methyl or morpholinyl.
在一些实施方案中，R 2选自H、甲基、或吗啉基。 In some embodiments, R is selected from H, methyl, or morpholinyl.
在一些实施方案中，R 2a各自独立地选自氧代、卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤代C 1-4烷硫基、卤代C 1-4烷基氨基、或卤代二C 1-4烷基氨基。 In some embodiments, 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.
在一些实施方案中，R 2a各自独立地选自氧代、卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1-4烷基、或卤代C 1-4烷氧基。 In some embodiments, 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.
在一些实施方案中，R 2a各自独立地选自氧代、F、Cl、Br、-OH、-NH 2、-CN、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、甲基氨基、乙基氨基、二甲基氨基、三氟甲基、或三氟甲氧基。 In some embodiments, 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.
在一些实施方案中，R 2a各自独立地选自氧代、F、Cl、Br、-OH、-NH 2、-CN、甲基、甲氧基、甲基氨基、二甲基氨基、三氟甲基、或三氟甲氧基。 In some embodiments, each R 2a is independently selected from oxo, F, Cl, Br, -OH, -NH 2 , -CN, methyl, methoxy, methylamino, dimethylamino, trifluoro methyl, or trifluoromethoxy.
在一些实施方案中，所述式(A)所述化合物或其药学上可接受的盐，其中，In some embodiments, the compound of formula (A) or a pharmaceutically acceptable salt thereof, wherein,
Z 1选自N； Z1 is selected from N;
Z 2选自N； Z 2 is selected from N;
X选自O或NH；X is selected from O or NH;
环A选自任选地被一个或多个R a取代的以下基团：3-8元环烷基或3-8元杂环烷基； 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;
R a各自独立地选自-C(O)NH 2、-C(O)NHCH 3、-COOH、-COOCH 3、C 1-4烷基、或C 1-4烷氧基； 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选自单键；L is selected from single bonds;
R L各自独立地选自H、卤素、-OH、-NH 2、-CN、C 1-4烷氧基、C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1-4烷基、或卤代C 1-4烷氧基； 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;
环D选自任选地被一个或多个R b取代的以下基团：苯并5-6元环烯基、苯并5-6元杂环基、吡啶并5-6元杂环基、苯基、萘基、或9-10元杂芳基； 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各自独立地选自F、Cl、Br、-OH、-NH 2、-CN、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、甲基氨基、乙基氨基、二甲基氨基、三氟甲基、或三氟甲氧基； 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;
Y 1选自-O-； Y1 is selected from -O-;
Y 2选自-O-； Y2 is selected from -O-;
m选自1、2、3、或4；m is selected from 1, 2, 3, or 4;
环C选自6-10元芳基或5-10元杂芳基；Ring C is selected from 6-10 membered aryl or 5-10 membered heteroaryl;
n选自0、1、或2；n is selected from 0, 1, or 2;
R 1各自独立地选自卤素、CN、C 1-3烷基和C 1-3卤代烷基； Each R is independently selected from halogen, CN, C 1-3 alkyl and C 1-3 haloalkyl;
R 2选自H、C 1-3烷基和C 5-6杂环烷基。 R 2 is selected from H, C 1-3 alkyl and C 5-6 heterocycloalkyl.
在一些实施方案中，所述3-12元选自3-10元、3-6元、5-6元、5-8元、或5-10元。In some embodiments, the 3-12 members are selected from 3-10 members, 3-6 members, 5-6 members, 5-8 members, or 5-10 members.
在一些实施方案中，所述杂环烷基含有1个或2个选自N或O的杂原子。In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.
在一些实施方案中，所述杂环烷基含有1个N原子。In some embodiments, the heterocycloalkyl group contains 1 N atom.
在一些实施方案中，所述杂环烷基含有1个O原子。In some embodiments, the heterocycloalkyl group contains 1 O atom.
在一些实施方案中，所述杂环烷基含有1个N原子和1个O原子。In some embodiments, the heterocycloalkyl group contains 1 N atom and 1 O atom.
在一些实施方案中，所述杂环基或杂芳基含有1个或2个选自N、O或S的杂原子。In some embodiments, the heterocyclyl or heteroaryl contains 1 or 2 heteroatoms selected from N, O or S.
在一些实施方案中，所述杂环基或杂芳基含有1个或2个N原子。In some embodiments, the heterocyclyl or heteroaryl contains 1 or 2 N atoms.
在一些实施方案中，所述杂环基或杂芳基含有1个N原子和1个O原子。In some embodiments, the heterocyclyl or heteroaryl contains 1 N atom and 1 O atom.
在一些实施方案中，所述杂环基或杂芳基含有1个N原子和1个S原子。In some embodiments, the heterocyclyl or heteroaryl contains 1 N atom and 1 S atom.
在一些实施方案中，所述杂环基或杂环烷基包括单环、螺环、并环或桥环的形式。在一些实施方案中，所述杂环烷基包括单环或螺环的形式。在一些实施方案中，所述杂环基或杂环烷基包括单环或桥环的形式。In some embodiments, 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.
在一些实施方案中，所述C 1-6烷基选自C 1-4烷基、C 1-3烷基、或C 1-2烷基。 In some embodiments, the C 1-6 alkyl is selected from C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl.
在一些实施方案中，所述C 1-6亚烷基选自C 1-4亚烷基、C 1-3亚烷基、或C 1-2亚烷基。 In some embodiments, the C 1-6 alkylene is selected from a C 1-4 alkylene, a C 1-3 alkylene, or a C 1-2 alkylene.
在一些实施方案中，所述卤素选自氟、氯、溴、或碘。In some embodiments, the halogen is selected from fluorine, chlorine, bromine, or iodine.
在一些实施方案中，所述卤代选自氟代、氯代、或溴代。在一些实施方案中，所述卤代选自氟代或氯代。在一些实施方案中，所述卤代选自氟代。In some embodiments, 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.
在一些实施方案中，所述“一个或多个”是指一个至十个以内的整数，例如“一个或多个”选自1个、2个、3个、4个、5个、6个、7个、8个、9个或10个。在一些实施方案中，所述“一个或多个”选自1个、2个、3个、4个、5个、或6个。在一些实施方案中，所述“一个或多个”选自1个、2个、3个、4个、或5个。在一些实施方案中，所述“一个或多个”选自1个、2个、3个、或4个。在一些实施方案中，所述“一个或多个”选自1个、2个、或3个。In some embodiments, 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.
本公开涉及式(A-1)、式(A-2)、式(A-3)或式(A-4)化合物或其药学上可接受的盐，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,
Figure PCTCN2022130697-appb-000017
Figure PCTCN2022130697-appb-000017
其中，R 1、R 2、Y 1、Y 2、X、m、n、L、环A、环D和环C如本公开式(A)所定义。 Wherein, 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.
在一些实施方案中，本公开包含上述定义的变量及其实施方案，以及它们的任意组合。In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.
本公开提供式(II)所述化合物或其药学上可接受的盐，其选自：The present disclosure provides the compound described in formula (II) or a pharmaceutically acceptable salt thereof, which is selected from:
Figure PCTCN2022130697-appb-000018
Figure PCTCN2022130697-appb-000018
其中，in,
T 1选自C和N； T1 is selected from C and N;
环B选自5-6元杂环烯基和5-6元杂芳基；Ring B is selected from 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
结构单元
Figure PCTCN2022130697-appb-000019
任选地被一个或多个R b取代； Structural units
Figure PCTCN2022130697-appb-000019
optionally substituted with one or more R b ;
R 1、R 2、R b、X、n、环A和环C如本公开上述式(A)中所定义。 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.
在一些实施方案中，所述式(II)化合物或其药学上可接受的盐，其中，In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein,
R 1选自卤素、CN、C 1-3烷基和C 1-3卤代烷基； R 1 is selected from halogen, CN, C 1-3 alkyl and C 1-3 haloalkyl;
R 2选自H、C 1-3烷基和C 5-6杂环烷基； R 2 is selected from H, C 1-3 alkyl and C 5-6 heterocycloalkyl;
X选自O和NH；X is selected from O and NH;
T 1选自C和N； T1 is selected from C and N;
环A选自C 3-10环烷基和5-10元杂环烷基，所述C 3-10环烷基和5-10元杂环烷基任选被1、2或3个R a取代； 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;
环B选自5-6元杂环烯基和5-6元杂芳基；Ring B is selected from 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
环C选自5-10元杂芳基；Ring C is selected from 5-10 membered heteroaryl;
R a选自卤素、CN、C 1-3烷基、C 1-3烷氧基和-C(O)R； R is selected from halogen, CN, C 1-3 alkyl, C 1-3 alkoxy and -C (O) R;
R选自-OH、C 1-3烷氧基、-NH 2和C 1-3烷氨基； R is selected from -OH, C 1-3 alkoxy, -NH 2 and C 1-3 alkylamino;
n选自1和2。n is selected from 1 and 2.
本公开的一些方案中，所述式(A)或式(II)化合物或其药学上可接受的盐中，R 1选自F、Cl、Br、CH 3和CF 3，其他变量如本公开所定义。 In some schemes of the present disclosure, in the compound of formula (A) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is selected from F, Cl, Br, CH 3 and CF 3 , and other variables are as in the present disclosure defined.
本公开的一些方案中，所述式(A)或式(II)化合物或其药学上可接受的盐中，R 2选自H、CH 3和吗啉基，其他变量如本公开所定义。 In some aspects of the present disclosure, in the compound of formula (A) or formula (II) or a pharmaceutically acceptable salt thereof, R 2 is selected from H, CH 3 and morpholinyl, and other variables are as defined in the present disclosure.
本公开的一些方案中，所述式式(A)或(II)化合物或其药学上可接受的盐中，R a选自甲基和甲氧基，其他变量如本公开所定义。 In some aspects of the present disclosure, in the compound of formula (A) or (II) or a pharmaceutically acceptable salt thereof, R a is selected from methyl and methoxy, and other variables are as defined in the present disclosure.
本公开的一些方案中，所述式(A)或式(II)化合物或其药学上可接受的盐中，环A选自环丙基、双环[1.1.1]戊基、螺[3.3]庚基、2-氧螺[3.3]庚基、哌啶基和四氢呋喃基，所述环丙基、双环[1.1.1]戊基、螺[3.3]庚基、哌啶基和四氢呋喃基任选被1、2或3个R a取代，其他变量如本公开所定义。 In some schemes of the present disclosure, in the compound of formula (A) or formula (II) or a pharmaceutically acceptable salt thereof, 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.
本公开的一些方案中，所述式(II)化合物或其药学上可接受的盐中，环A选自
Figure PCTCN2022130697-appb-000020
Figure PCTCN2022130697-appb-000021
其他变量如本公开所定义。 In some schemes of the present disclosure, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, ring A is selected from
Figure PCTCN2022130697-appb-000020
Figure PCTCN2022130697-appb-000021
Other variables are as defined in this disclosure.
本公开的一些方案中，所述式(II)化合物或其药学上可接受的盐中，环B选自
Figure PCTCN2022130697-appb-000022
Figure PCTCN2022130697-appb-000023
其他变量如本公开所定义。 In some schemes of the present disclosure, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, ring B is selected from
Figure PCTCN2022130697-appb-000022
Figure PCTCN2022130697-appb-000023
Other variables are as defined in this disclosure.
本公开的一些方案中，所述式(II)化合物或其药学上可接受的盐中，环C选自嘧啶基、吡啶基、噻唑基、咪唑并哒嗪基和三嗪基，其他变量如本公开所定义。In some schemes of the present disclosure, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, ring C is selected from pyrimidyl, pyridyl, thiazolyl, imidazopyridazinyl and triazinyl, and other variables such as as defined in this disclosure.
本公开的一些方案中，所述式(II)化合物或其药学上可接受的盐中，环C选自
Figure PCTCN2022130697-appb-000024
Figure PCTCN2022130697-appb-000025
其他变量如本公开所定义。 In some schemes of the present disclosure, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, ring C is selected from
Figure PCTCN2022130697-appb-000024
Figure PCTCN2022130697-appb-000025
Other variables are as defined in this disclosure.
本公开提供式(I)所述化合物或其药学上可接受的盐，其选自：The present disclosure provides a compound described in formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:
Figure PCTCN2022130697-appb-000026
Figure PCTCN2022130697-appb-000026
其中，in,
R 1选自卤素、CN、C 1-3烷基或C 1-3卤代烷基； R 1 is selected from halogen, CN, C 1-3 alkyl or C 1-3 haloalkyl;
X选自O或NH；X is selected from O or NH;
T 1选自C或N； T1 is selected from C or N;
环A选自C 3-10环烷基或5-10元杂环烷基，所述C 3-10环烷基和5-10元杂环烷基任选被1、2或3个R a取代； 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;
环B选自5-6元杂环烯基或5-6元杂芳基；Ring B is selected from 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl;
环C选自5-10元杂芳基；Ring C is selected from 5-10 membered heteroaryl;
R a选自卤素、CN、C 1-3烷基或C 1-3烷氧基； R is selected from halogen, CN, C 1-3 alkyl or C 1-3 alkoxy;
所述杂环烷基、杂环烯基或杂芳基之“杂”包含1、2或3个独立选自N、O、S或Se的杂原子。The "hetero" of said heterocycloalkyl, heterocycloalkenyl or heteroaryl contains 1, 2 or 3 heteroatoms independently selected from N, O, S or Se.
本公开的一些方案中，所述式(I)化合物或其药学上可接受的盐中，R 1选自F、Cl、Br、CH 3或CF 3，其他变量如本公开所定义。 In some aspects of the present disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 is selected from F, Cl, Br, CH 3 or CF 3 , and other variables are as defined in the present disclosure.
本公开的一些方案中，所述式(I)化合物或其药学上可接受的盐中，R a选自甲基或甲氧基，其他变量如本公开所定义。 In some aspects of the present disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, R a is selected from methyl or methoxy, and other variables are as defined in the present disclosure.
本公开的一些方案中，所述式(I)化合物或其药学上可接受的盐中，环A选自环丙基、双环[1.1.1]戊基、螺[3.3]庚基、2-氧螺[3.3]庚基或四氢呋喃基，所述环丙基、双环[1.1.1]戊基、螺[3.3]庚基或四氢呋喃基任选被1、2或3个R a取代，其他变量如本公开所定义。 In some schemes of the present disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, 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.
本公开的一些方案中，所述式(I)化合物或其药学上可接受的盐中，环A选自
Figure PCTCN2022130697-appb-000027
其他变量如本公开所定义。 In some schemes of the present disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring A is selected from
Figure PCTCN2022130697-appb-000027
Other variables are as defined in this disclosure.
本公开的一些方案中，所述式(I)化合物或其药学上可接受的盐中，环B选自
Figure PCTCN2022130697-appb-000028
Figure PCTCN2022130697-appb-000029
其他变量如本公开所定义。 In some schemes of the present disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring B is selected from
Figure PCTCN2022130697-appb-000028
Figure PCTCN2022130697-appb-000029
Other variables are as defined in this disclosure.
本公开的一些方案中，所述式(I)化合物或其药学上可接受的盐中，环C选自嘧啶基，其他变量如本公开所定义。In some aspects of the present disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring C is selected from pyrimidinyl, and other variables are as defined in the present disclosure.
本公开还有一些方案是由上述各变量任意组合而来。There are also some schemes in the present disclosure that are formed by any combination of the above-mentioned variables.
本公开还提供了下式所示化合物或其药学上可接受的盐，所述化合物选自：The present disclosure also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof, the compound is selected from:
Figure PCTCN2022130697-appb-000030
Figure PCTCN2022130697-appb-000030
Figure PCTCN2022130697-appb-000031
Figure PCTCN2022130697-appb-000031
另一方面，本公开涉及药物组合物，其包含本公开的式(I)、式(II)、式(A)、式(A-1)、式(A-2)、式(A-3)、或式(A-4)化合物、或其药学上可接受的盐。在一些实施方案中，本公开的药物组合物还包括药学上可接受的辅料。In another aspect, the present disclosure relates to 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. In some embodiments, the pharmaceutical compositions of the present disclosure further include pharmaceutically acceptable excipients.
另一方面，本公开涉及治疗哺乳动物ETA受体相关疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式(I)、式(II)、式(A)、式(A-1)、式(A-2)、式(A-3)、或式(A-4)化合物、或其药学上可接受的盐、或本公开的药物组合物。In another aspect, 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.
另一方面，本公开涉及式(I)、式(II)、式(A)、式(A-1)、式(A-2)、式(A-3)、或式(A-4)化合物、或其药学上可接受的盐、或本公开的药物组合物在制备治疗ETA受体相关疾病的药物中的用途。In another aspect, 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.
另一方面，本公开涉及式(I)、式(II)、式(A)、式(A-1)、式(A-2)、式(A-3)、或式(A-4)化合物、或其药学上可接受的盐、或本公开的药物组合物在治疗ETA受体相关疾病中的用途。In another aspect, 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.
另一方面，本公开涉及用于治疗ETA受体相关疾病的式(I)、式(II)、式(A)、式(A-1)、式(A-2)、式(A-3)、或式(A-4)化合物、或其药学上可接受的盐、或本公开的药物组合物。On the other hand, 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.
在本公开的一些实施方案中，所述ETA受体相关疾病选自IgA肾病。In some embodiments of the present disclosure, the ETA receptor-related disease is selected from IgA nephropathy.
本公开还提供了上述的化合物或其药学上可接受的盐在制备治疗IgA肾病相关的药物中的应用。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.
本公开还提供了如下的测试方法：The present disclosure also provides the following test method:
测试方法1：人体ETA受体拮抗效应的体外测试Test method 1: In vitro test of human ETA receptor antagonistic effect
实验目的：Purpose:
通过使用荧光检测方法测定化合物对人ET A受体激动剂诱导的胞质Ca 2+离子信号变化的作用来评估化合物在SK–N–MC细胞中内源表达的人ET A受体上的拮抗剂活性。ET A受体拮抗效应的功能活性在Eurofins-Cerep SA根据现行的标准操作程序进行测试。 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.
实验方案：Experimental program:
1.将细胞悬浮于用1％FCSd补充的Dulbecco's改良的Eagle培养基溶液(DMEM,Invitrogen)中，然后以5×10 4个细胞/孔的密度分布在384板中(100μL/孔)； 1. Cells were suspended in Dulbecco's modified Eagle medium solution (DMEM, Invitrogen) supplemented with 1% FCSd, and then distributed in 384 plates at a density of 5× 10 cells/well (100 μL/well);
2.将在20mM 4-(2-羟乙基)哌嗪-1-乙磺酸(Hepes,Invitrogen)(pH7.4)补充的Hank's平衡盐溶液(HBSS,Invitrogen)中羧苯磺胺与荧光探针(Fluo4 NW,Invitrogen)混合，再加入到每个孔中，然后在37℃下与细胞平衡60分钟，再在22℃下与细胞平衡15分钟；2. In the Hank's balanced salt solution (HBSS, Invitrogen) supplemented in 20mM 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (Hepes, Invitrogen) (pH7.4), carbenzylsulfonamide and fluorescent probe Needle (Fluo4 NW, Invitrogen) was mixed and added to each well, then equilibrated with cells at 37°C for 60 minutes, and then at 22°C for 15 minutes;
3.将测定板置于微板读数器(CellLux，PerkinElmer)中，加入测试化合物与阳性对照的适当浓度的DMSO溶液或HBSS缓冲液，5分钟后再加入1nM内皮素–1或HBSS缓冲液(基底对照)，然后测量与游离细胞溶质的Ca 2+离子浓度成比例的荧光强度变化值； 3. Place the assay plate in a microplate reader (CellLux, PerkinElmer), add the DMSO solution or HBSS buffer solution of the appropriate concentration of the test compound and the positive control, and then add 1nM endothelin-1 or HBSS buffer solution ( base control), and then measure the fluorescence intensity change value proportional to the Ca 2+ ion concentration of the free cytosol;
4.结果是对1nM内皮素–1的对照响应的百分比抑制；4. Results are percent inhibition of control response to 1 nM endothelin-1;
5.标准阳性对照是BQ–123，在每个实验中测试几个浓度，使用Prism分析数据，产生一个浓度–响应的曲线，计算化合物的IC 50值。 5. 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.
测试方法2：人体ETB受体拮抗效应的体外测试Test method 2: In vitro test of human ETB receptor antagonistic effect
实验目的：Purpose:
通过使用荧光检测方法测定化合物对人ET B受体激动剂诱导的胞质Ca 2+离子信号变化的作用来评估化合物在转染的CHO细胞中表达人的ET B受体上的拮抗剂活性。ET B受体拮抗效应的功能活性在Eurofins-Cerep SA根据现行的标准操作程序进行测试。 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.
实验方案：Experimental program:
1.将细胞悬浮在DMEM缓冲液(Invitrogen)中，然后以3×10 4细胞/孔的密度分布在384板中(100μL/孔)； 1. Suspend the cells in DMEM buffer (Invitrogen), and then distribute them in 384 plates at a density of 3×10 4 cells/well (100 μL/well);
2.将在20mM Hepes(Invitrogen)(pH7.4)补充的HBSS缓冲液(Invitrogen)中羧苯磺胺与荧光探针(Fluo4 Direct,Invitrogen)混合，再加入到每个孔中，然后在37℃下与细胞平衡60分钟，再在22℃下与细胞平衡15分钟；2. In the HBSS buffer (Invitrogen) supplemented with 20mM Hepes (Invitrogen) (pH7.4), carbenzylsulfonamide was mixed with the fluorescent probe (Fluo4 Direct, Invitrogen), then added to each well, and then incubated at 37°C Equilibrate with the cells for 60 minutes at 22°C for 15 minutes;
3.将测定板置于微板读数器(CellLux，PerkinElmer)中，加入测试化合物与阳性对照的适当浓度的DMSO溶液或HBSS缓冲液，5分钟后再加入0.3nM内皮素–1或HBSS缓冲液(基底对照)，然后测量与游离细胞溶质的Ca 2+离子浓度成比例的荧光强度变化值； 3. Place the assay plate in a microplate reader (CellLux, PerkinElmer), add the appropriate concentration of the test compound and positive control in DMSO solution or HBSS buffer, and then add 0.3nM endothelin-1 or HBSS buffer after 5 minutes (basal control), then measure the fluorescence intensity change value proportional to the Ca 2+ ion concentration of the free cytosol;
4.结果是对0.3nM内皮素–1的对照响应的百分比抑制；4. Results are percent inhibition of the control response to 0.3 nM endothelin-1;
5.标准阳性对照是BQ–788，在每个实验中测试几个浓度，使用Prism分析数据，产生一个浓度–响应的曲线，计算化合物的IC 50值。 5. The standard positive control is BQ-788. Several 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.
测试方法3：大鼠的药代动力学测试Test Method 3: Pharmacokinetic Test in Rats
实验目的：测定化合物在SD大鼠中的药代动力学参数。Experimental purpose: To determine the pharmacokinetic parameters of the compound in SD rats.
实验方法：experimental method:
1.该项目使用4只雄性SD大鼠，一组2只SD大鼠进行静脉注射给药，给药剂量为2mg/kg，给药浓度0.5mg/mL；另外一组2只SD大鼠进行口服给药，给药剂量为10mg/kg，给药浓度1mg/mL；1. 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;
2.收集给药后0.083(仅静脉组)、0.25、0.5、1、2、4、6、8、24h的血浆样品。2. Collect plasma samples at 0.083 (only in the intravenous group), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.
3.血液样本采集后置于冰上，并于1小时之内离心分离血浆(离心条件：6000g，3分钟，2-8℃)。血浆样本在分析前存放时则放于-80℃冰箱内。3. Place the blood sample on ice after collection, and centrifuge the plasma within 1 hour (centrifugation conditions: 6000g, 3 minutes, 2-8°C). Plasma samples were stored in a -80°C freezer until analysis.
4.然后对收集的样品进行LC-MS/MS分析并采集数据。采集的分析数据用Phoenix WinNonlin 8.2.0软件计算相关药代动力学参数。4. 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.
测试方法4：体内药效研究Test Method 4: In Vivo Drug Efficacy Study
试验目的：探索受试药物对Thy1肾炎治疗作用Purpose of the test: To explore the therapeutic effect of the tested drug on Thy1 nephritis
实验方案：Experimental program:
1.取50只大鼠采用异氟烷气体麻醉。全身麻醉过后，在大鼠右侧行单侧肾脏切除术；切除右侧肾脏，之后缝合给予抗生素；对照组大鼠操作步骤同模型组但是不切除肾脏。单侧肾脏切除术后一周，模型组大鼠尾静脉注射1mg/kg anti-Thy1 antibody，对照组大鼠尾静脉注射等体积生理盐水，注射后第三天，收集大鼠24h尿液，检测尿液中尿总蛋白含量；剔除造模未成功大鼠，并根据尿蛋白数据使用简单随机法分组，将造模大鼠随机分成6组，分别为Group-2、Group-3、Group-4、Group-5、Group-6、Group-7组。1. Take 50 rats and anesthetize them with isoflurane gas. After general anesthesia, unilateral nephrectomy was performed on the right side of the rats; the right kidney was removed, and antibiotics were given after suturing; the rats in the control group were operated in the same steps as the model group but the kidney was not removed. One week after unilateral nephrectomy, the rats in the model group were injected with 1 mg/kg anti-Thy1 antibody 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 for urine concentration. The urine total protein content in the liquid; 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.
2.抗体注射后第四天，Group-1、Group-2组大鼠灌胃等体积溶媒，一日一次，灌胃体积为1mL/100g，连续给药4周；Group-3组大鼠灌胃5mg/kg强的松，一日一次，灌胃体积为1mL/100g，连续给药4周；Group-4组大鼠灌胃阿曲生坦，一日两次，灌胃体积为1mL/100g，连续给药28天；Group-5、Group-6和Group-7组大鼠灌胃测试化合物，一日一次，灌胃体积为1mL/100g，连续给药28天。Group-4、5、6组，于末次给药结束并24h尿蛋白采集完成后，再按照相应剂量给药一次，于给药后0、0.5、1、4、8、24h交叉采血，每个时间点收集三只大鼠的血浆样品，-80℃保存。2. On the fourth day after antibody injection, the rats 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.
3.抗体注射后第三天、给药第7天、给药第28天分别收集大鼠24h尿液，检测24h尿蛋白含量；尿液收集完毕后，取各组大鼠血液样本检测红细胞压积。3. On the third day after antibody injection, on the seventh day of administration, and on the 28th day of administration, 24-hour urine was collected from rats, and the 24-hour urine protein content was detected; after the urine was collected, blood samples were taken from rats in each group to detect red blood cell pressure product.
4.取血结束后CO 2法安乐死大鼠，取肾脏组织，PAS染色观察肾脏组织的病变程度。 4. After the blood collection, the rats were euthanized by CO 2 method, and the kidney tissue was taken, and the lesion degree of the kidney tissue was observed by PAS staining.
技术效果technical effect
本公开的化合物都展现出对人ET A受体的体外拮抗极高活性，具有良好的体内药效，且本公开化合物具有较好的暴露量和生物利用度，并能够缓解大鼠肾损伤。 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.
定义和说明Definition and Description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" as used herein 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.
术语“药学上可接受的盐”是指本公开化合物的盐，由本公开发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本公开的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本公开的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。本公开的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "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. When compounds of the present disclosure contain relatively acidic functionalities, 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. When compounds of the present disclosure contain relatively basic functionalities, 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.
本公开的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, 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.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。The word "comprise" or "comprise" and its English variants such as comprises or comprising should be interpreted in an open and non-exclusive sense, ie "including but not limited to".
除非另有说明，术语“异构体”意在包括几何异构体、顺反异构体、立体异构体、对映异构体、旋光异构体、非对映异构体和互变异构体。Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereoisomers and interconversions isomer.
本公开的化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。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.
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2022130697-appb-000032
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。 Unless otherwise stated, when there is a double bond structure in the compound, such as carbon-carbon double bond, carbon-nitrogen double bond and nitrogen-nitrogen double bond, and each atom on the double bond is connected with two different substituents (including nitrogen atom In the double bond of the nitrogen atom, a lone pair of electrons on the nitrogen atom is regarded as a substituent connected to it), if there is a wavy line between the atom on the double bond and its substituent in the compound
Figure PCTCN2022130697-appb-000032
Linked means the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise stated, the terms "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.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means dextrorotation, "(-)" means levorotation, and "(±)" means racemization.
除非另有说明，用楔形实线键
Figure PCTCN2022130697-appb-000033
和楔形虚线键
Figure PCTCN2022130697-appb-000034
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022130697-appb-000035
和直形虚线键
Figure PCTCN2022130697-appb-000036
表示立体中心的相对构型，用波浪线
Figure PCTCN2022130697-appb-000037
表示楔形实线键
Figure PCTCN2022130697-appb-000038
或楔形虚线键
Figure PCTCN2022130697-appb-000039
或用波浪线
Figure PCTCN2022130697-appb-000040
表示直形实线键
Figure PCTCN2022130697-appb-000041
或直形虚线键
Figure PCTCN2022130697-appb-000042
Unless otherwise noted, keys with wedge-shaped solid lines
Figure PCTCN2022130697-appb-000033
and dotted wedge keys
Figure PCTCN2022130697-appb-000034
Indicates the absolute configuration of a stereocenter, with a straight solid-line bond
Figure PCTCN2022130697-appb-000035
and straight dashed keys
Figure PCTCN2022130697-appb-000036
Indicates the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2022130697-appb-000037
Indicates wedge-shaped solid-line bond
Figure PCTCN2022130697-appb-000038
or dotted wedge key
Figure PCTCN2022130697-appb-000039
or with tilde
Figure PCTCN2022130697-appb-000040
Indicates a straight solid line key
Figure PCTCN2022130697-appb-000041
or straight dotted key
Figure PCTCN2022130697-appb-000042
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise stated, 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%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise stated, 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% .
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本公开某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。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. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), 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).
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。The compounds and intermediates of the present disclosure may also exist in different tautomeric forms and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic 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.
本公开化合物可以具有一个或多个阻转异构体，除非另有说明，所述阻转异构体是指由于单键之间的自由旋转受阻而产生的光活性异构体。本公开的含有手性轴的化合物可以以外消旋形式被分离出来。当本公开含有手性轴化合物的单键自由旋转的能垒足够高时，其阻转异构体可以以光活性纯的形式被分离出来。Compounds of the present disclosure may have one or more 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.
本公开的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。 The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For another example, 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. Compared with non-deuterated drugs, 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.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。 The term "optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur . For example, 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.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "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. When a substituent is oxygen (ie =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "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.
本文所述的“取代基”包括本文上下文中所提及的所有取代基，例如下文提及的术语“烷基”、“杂烷基”、“烷氧基”、“烷基氨基”、“二烷基氨基”、“烷基磺酰基”、“烷硫基”、“烯基”、“炔基”、“环烷基”、“环烯基”、“杂环基”、“杂环烷基”、“芳基”、“杂芳基”等，及相应的非限制性或示例性基团，其中所述“取代基”一些非限制性实例包括羟基、巯基、卤素、氨基、硝基、亚硝基、氰基、叠氮基团、亚砜基团、砜基团、磺酰胺基团、羧基、醛基、亚胺基团、烷基、卤代-烷基、环烷基、卤代-环烷基、杂环烷基、卤代-杂环烷基、烯基、卤代-烯基、环烯基、卤代-环烯基、炔基、卤代-炔基、环炔基、卤代-环炔基、杂烷基、卤代-杂烷基、 烷氧基、烷硫基、芳基、芳基氧基、芳基硫基、芳基亚烷基、芳基烷氧基、芳基烷硫基、杂芳基、杂芳基氧基、杂芳基硫基、杂芳基亚烷基、杂芳基烷氧基、杂芳基烷硫基、杂环基、杂环基氧基、杂环基硫基、杂环基亚烷基、杂环基烷氧基、杂环基烷硫基、酰基、酰氧基、氨基甲酸酯基团、酰胺基、脲基、环氧基团、酯基团和氧代等，所述取代基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH 2、-C(O)NH-烷基、-C(O)N(烷基) 2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O) 2-烷基、-S(O) 2NH 2、-S(O) 2NH-烷基、-S(O) 2N(烷基) 2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。 The "substituent" described herein 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-alkyl group, cycloalkyl group , halo-cycloalkyl, heterocycloalkyl, halo-heterocycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, Cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkylene, aryl arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkylene, heteroarylalkoxy, heteroarylalkylthio, heterocyclic radical, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate, amido , ureido, epoxy, ester, and oxo, etc., said substituents are optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano radical, 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 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, hetero Cycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
在本文的部分实施方案中，所述取代基选自羟基、巯基、卤素、氨基、硝基、亚硝基、氰基、叠氮基团、亚砜基团、砜基团、磺酰胺基团、羧基、醛基、亚胺基团、C 1-12烷基、卤代-C 1-12烷基、3-12元环烷基、卤代-3-12元环烷基、3-12元杂环烷基、卤代-3-12元杂环烷基、C 2-12烯基、卤代-C 2-12烯基、3-12元环烯基、卤代-3-12元环烯基、C 2-12炔基、卤代-C 2-12炔基、8-12元环炔基、卤代-8-12元环炔基、C 1-12杂烷基、卤代-C 1-12杂烷基、C 1-12烷氧基、C 1-12烷硫基、6-10元芳基、6-10元芳基氧基、6-10元芳基硫基、6-10元芳基C 1-12亚烷基、6-10元芳基C 1-12烷氧基、6-10元芳基C 1-12烷硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、5-10元杂芳基亚烷基、5-10元杂芳基烷氧基、5-10元杂芳基烷硫基、3-12元杂环基、3-12元杂环基氧基、3-12元杂环基硫基、3-12元杂环基C 1-12亚烷基、3-12元杂环基C 1-12烷氧基、3-12元杂环基C 1-12烷硫基、C 1-12酰基、C 1-12酰氧基、氨基甲酸酯基团、C 1-12酰胺基、脲基、环氧基团、C 2- 12酯基团和氧代，所述取代基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 1-12烷氧基、卤代C 1-12烷氧基、C 1-12烷基氨基、二C 1-12烷基氨基、卤代C 1-12烷基氨基、卤代二C 1-12烷基氨基、羧基、-C(O)O-C 1-12烷基、-OC(O)-C 1-12烷基、-C(O)NH 2、-C(O)NH-C 1-12烷基、-C(O)N(C 1-12烷基) 2、-NHC(O)-C 1-12烷基、-C(O)-C 1-12烷基、-S(O)-C 1-12烷基、-S(O) 2-C 1-12烷基、-S(O) 2NH 2、-S(O) 2NH-C 1-12烷基、-S(O) 2N(C 1-12烷基) 2、3-12元环烷基、3-12元环烷基C 1-12亚烷基、3-12元环烷基氧基、3-12元杂环基、3-12元杂环基C 1-12亚烷基、3-12元杂环基氧基、3-12元杂环烷基、3-12元杂环烷基C 1-12亚烷基、3-12元杂环烷基氧基、5-10元杂芳基、5-10元杂芳基C 1-12亚烷基、5-10元杂芳基氧基、6-10元芳基、6-10元芳基C 1-12亚烷基或6-10元芳基氧基。 In some embodiments herein, 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 cycloalkynyl, C 1-12 heteroalkyl, halo -C 1-12 heteroalkyl, C 1-12 alkoxy, C 1-12 alkylthio, 6-10 aryl, 6-10 aryloxy, 6-10 arylthio, 6-10 aryl C 1-12 alkylene, 6-10 aryl C 1-12 alkoxy, 6-10 aryl C 1-12 alkylthio, 5-10 heteroaryl, 5-10-membered heteroaryloxy, 5-10-membered heteroarylthio, 5-10-membered heteroarylalkylene, 5-10-membered heteroarylalkoxy, 5-10-membered heteroarylalkane Sulfuryl, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered Heterocyclic C 1-12 alkoxy, 3-12 membered heterocyclic C 1-12 alkylthio, C 1-12 acyl, C 1-12 acyloxy, carbamate group, C 1- 12 amide groups, ureido groups, epoxy groups, C 2-12 ester groups and oxo, said substituents are optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxyl, amino, Nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, C 1- 12 alkylamino, two C 1-12 alkylamino, halogenated C 1-12 alkylamino, halogenated two C 1-12 alkylamino, carboxyl, -C(O)OC 1-12 alkyl, - OC(O)-C 1-12 alkyl, -C(O)NH 2 , -C(O)NH-C 1-12 alkyl, -C(O)N(C 1-12 alkyl) 2 , -NHC(O)-C 1-12 alkyl, -C(O)-C 1-12 alkyl, -S(O)-C 1-12 alkyl, -S(O) 2 -C 1-12 Alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-C 1-12 alkyl, -S(O) 2 N(C 1-12 alkyl) 2 , 3-12 membered cycloalkane Base, 3-12 membered cycloalkyl C 1-12 alkylene, 3-12 membered cycloalkyloxy, 3-12 heterocyclic group, 3-12 membered heterocyclic C 1-12 alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl C 1-12 alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered Heteroaryl, 5-10 membered heteroaryl C 1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 aryl, 6-10 aryl C 1-12 alkylene or 6-10 membered aryloxy group.
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
本文中的C m-n，是该部分具有给定范围中的整数个碳原子。例如“C 1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。 C mn , herein, is that the moiety has an integer number of carbon atoms in the given range. For example "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.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. So, for example, if a group is substituted by 2 R's, each R has independent options.
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为共价键。 When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
当其中一个变量选自共价键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表共价键时表示该结构实际上是A-Z。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，比如A-L-Z中，连接基团L为-M-W-，此时表示该结构可以为A-M-W-Z或者A-W-M-Z。When one of the variables is selected from a covalent bond, it means that the two groups connected are directly connected. For example, when L in A-L-Z represents a covalent bond, it means that the structure is actually A-Z. When the 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.
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元
Figure PCTCN2022130697-appb-000043
表示其可在环己基或者环己二烯上的任意一个位置发生取代。 When a bond of a substituent cross-links two atoms in a ring, the substituent may be bonded to any atom on the ring. For example, the structural unit
Figure PCTCN2022130697-appb-000043
It means that it can be substituted at any position on cyclohexyl or cyclohexadiene.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
术语“羟基”指-OH基团。The term "hydroxyl" refers to a -OH group.
术语“氰基”指-CN基团。The term "cyano" refers to a -CN group.
术语“巯基”指-SH基团。The term "mercapto" refers to a -SH group.
术语“氨基”指-NH 2基团。 The term "amino" refers to a -NH2 group.
术语“硝基”指-NO 2基团。 The term "nitro" refers to a -NO2 group.
术语“杂原子”包括除碳或氢外的任何元素的原子。优选的杂原子是硼、氮、氧、硫、硅和磷。在一个实施方案中，杂原子选自N、O和S。The term "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.
术语“亚烷基”是指通式为C nH 2n的饱和直链或支链二价烃基，通常具有1至20个、1至18个、1至16个、1至14个、1至12个、1至10个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。例如，术语“C 1-6亚烷基”指含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、亚乙基(-CH 2CH 2-)、亚丙基(-CH 2CH 2CH 2-或-CH 2CH(CH 3)-)、亚丁基(-CH 2CH 2CH 2CH 2-、-CH 2CH(CH 3)CH 2-或-CH 2CH 2CH(CH 3)-)、亚戊基、亚己基、亚庚基、亚辛基、亚壬基、亚癸基等。所述亚烷基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。 The term "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. For example, the term "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.
术语“烷基”是指通式为C nH 2n+1的直链或支链饱和烃基，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。该烷基可以是直链或支链的，通常具有1至12个、1至8个、1至6个、1至4个或1至3个碳原子。例如，术语“C 1- 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。术语“C 1-3烷基”指含有1至3个碳原子的烷基，所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。所述烷基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。 The term "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. For example, the term "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.). The term "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. Similarly, the alkyl portion (ie, alkyl group) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio has the same definition as above.
除非另有规定，术语“C 1-6卤代烷基”或“卤代C 1-6烷基”表示包含1至6个碳原子的单卤代烷基和多卤代烷基。 Unless otherwise specified, the term "C 1-6 haloalkyl" or "haloC 1-6 alkyl" denotes monohaloalkyl and polyhaloalkyl groups containing 1 to 6 carbon atoms.
除非另有规定，术语“C 1-6卤代烷基”或“卤代C 1-6烷基”表示包含1至6个碳原子的单卤代烷基和多卤代烷基。所述“C 1-6卤代烷基”或“卤代C 1-6烷基”包括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、和C 1卤代烷基等。所述C 1-3卤代烷基包括C 1-2、C 2-3、C 3、C 2和C 1卤代烷基等。C 1-3卤代烷基的实例包括但不限于三氟甲基、三氯甲基、2,2,2-三氟乙基、五氟乙基、五氯乙基、3-溴丙基等。 Unless otherwise specified, the term "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. Examples of C 1-3 haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 3-bromopropyl and the like.
术语“杂烷基”指其中一个或多个碳原子(以及与其相连的氢原子)各自独立地被相同或不同杂原子基团置换的烷基。除非另有指示，所述杂烷基包含1个、2个或3个杂原子基团，所述杂原子基团非限制性实例包括O、S、N或NH，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。例如，术语“C 1- 6杂烷基”指含有1至6个碳原子以及1-3个杂原子基团的杂烷基。所述杂原子基团可以被置于杂烷基的任意位置(例如，内部或末端位置)，包括将杂烷基连接于分子其余部分的位置。通常，在存在超过一个杂原子基团的情况下，所述杂原子基团彼此不相邻。示例性杂烷基包括但不限于烷氧基、烷氧基亚烷基、烷基氨基、烷基氨基亚烷基、二烷基氨基、二烷基氨基亚烷基等。所述杂烷基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。 The term "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. For example , the term "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.
术语“烷氧基”指-O-烷基，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。其中，烷基部分任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。The term "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.
术语“烷基氨基”指-NH-烷基，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。其中，烷基部分任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、 氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。The term "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.
术语“二烷基氨基”指-N(烷基) 2，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子，例如，二C 1-12烷基氨基是指-N(C 1-12烷基) 2，具有1至12个碳原子。其中，烷基部分任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。 The term "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, For example, diC 1-12 alkylamino refers to -N(C 1-12 alkyl) 2 , having 1 to 12 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.
术语“烷基磺酰基”指-SO 2-烷基，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。其中，烷基部分任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。 The term "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.
术语“烷硫基”指-S-烷基，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。其中，烷基部分任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。The term "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.
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基，通常具有2至12个、2至8个、2至6个、2至4个或2至3个碳原子。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。所述烯基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。The term "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. Non-limiting examples of 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.
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基，通常具有2至12个、2至8个、2至6个、2至4个或2至3个碳原子。炔基的非限制性实例包括但不限于乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH 3)、2-丙炔基(-CH 2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。所述炔基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。 The term "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. Non-limiting examples of 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.
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至12元环、3至10元环、3至8元环、3至6元环、5至8元环或5至6元环。环烷基非限制性实例包括但不限于环丙烷基、环丁烷基、环戊烷基、环己烷基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。所述环烷基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH 2、-C(O)NH-烷基、-C(O)N(烷基) 2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O) 2-烷基、-S(O) 2NH 2、-S(O) 2NH-烷基、-S(O) 2N(烷基) 2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。 The term "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. -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.
除非另有规定，“C 3-10环烷基”表示由3至10个碳原子组成的饱和环状碳氢基团，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。所述C 3-10环烷基包括C 3-8、C 3-6、C 3-5、C 4-10、C 4-8、C 4-6、C 4-5、C 5-8或C 5-6等；其可以是一价、二价或者多价。C 3-10环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷等。 Unless otherwise specified, "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. Examples of C 3-10 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.
术语“环烯基”是指部分不饱和的具有至少一个双键的并且可以以呈单环、桥环、并环或螺环存在的非芳族碳环。除非另有指示，该碳环通常为3至10元环、4至8元环、5至8元环或5至6元环。环烯基的 非限制性实例包括但不限于环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基、环庚二烯基等。所述环烯基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH 2、-C(O)NH-烷基、-C(O)N(烷基) 2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O) 2-烷基、-S(O) 2NH 2、-S(O) 2NH-烷基、-S(O) 2N(烷基) 2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。 The term "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. -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.
术语“碳环基”是指部分不饱和的并且可以以单环、桥环、并环或螺环存在的非芳族碳环。除非另有指示，该碳环通常为3至12元、3至10元、3至8元、4至8元、5至8元、5至6元、3至7元、3至6元、或4至6元环。碳环基的非限制性实例包括但不限于环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基、环庚二烯基、苯并环戊烯基、苯并环戊二烯基、苯并环己烯基、苯并环己二烯基等。所述碳环基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH 2、-C(O)NH-烷基、-C(O)N(烷基) 2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O) 2-烷基、-S(O) 2NH 2、-S(O) 2NH-烷基、-S(O) 2N(烷基) 2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。 The term "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.
术语“杂环基”是指部分不饱和的并且可以以单环、桥环、并环或螺环存在的非芳族环。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧、氮、磷、硅和/或硼的杂原子(优选1或2个杂原子)的3至12元、3至10元、3至8元、4至8元、5至8元、5至6元、3至7元、3至6元、或4至6元环。杂环基的非限制性实例包括但不限于环氧乙烷基、四氢呋喃基、二氢呋喃基、吡咯烷基、N-甲基吡咯烷基、二氢吡咯基、哌啶基、哌嗪基、吡唑烷基、4H-吡喃基、吗啉基、硫代吗啉基、四氢噻吩基等。所述杂环基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH 2、-C(O)NH-烷基、-C(O)N(烷基) 2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O) 2-烷基、-S(O) 2NH 2、-S(O) 2NH-烷基、-S(O) 2N(烷基) 2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。 The term "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. Non-limiting examples of 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.
除非另有规定，术语“5-6元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由5至6个环原子组成的部分不饱和的环状基团，其1、2、3或4个环原子为独立选自O、S、N和Se的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环，此体系的任意环都是非芳香性的。此外，就该“5-6元杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。所述5-6元杂环烯基包括5元和6元杂环烯基等。5-6元杂环烯基的实例包括但不限于
Figure PCTCN2022130697-appb-000044
Figure PCTCN2022130697-appb-000045
Unless otherwise specified, 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). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro rings, fused rings and bridged rings, and any ring in this system is non-aromatic. In addition, with respect to the "5-6 membered heterocycloalkenyl", 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
Figure PCTCN2022130697-appb-000044
Figure PCTCN2022130697-appb-000045
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至4个独立地选自O、S、N、Se、P、Si和/或B的杂原子(优选1或2个杂原子)的3至12元、3至10元、4至8元、5至10元、5至8元、5至6元、3至7元或4至6元环，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。所述杂环烷基包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，所述杂环烷基中，杂原子可以占据杂环烷 基与分子其余部分的连接位置。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。所述杂环烷基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH 2、-C(O)NH-烷基、-C(O)N(烷基) 2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O) 2-烷基、-S(O) 2NH 2、-S(O) 2NH-烷基、-S(O) 2N(烷基) 2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。 The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, 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. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thioethyl, cycloazaethyl, and non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetyl, Cyclic, thiabutanyl, and 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine , imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, Examples of 4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, 7-membered heterocycloalkyl include But not limited to azepanyl, oxepanyl, thiepanyl. 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) 2 , cycloalkyl, cyclo Alkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, hetero Aryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
除非另有规定，术语“5-10元杂环烷基”本身或者与其他术语联合分别表示由3至10个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S、N和Se的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“5-10元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5-10元杂环烷基包括5-8元、5-6元、5元和6元杂环烷基等。5-10元杂环烷基的实例包括但不限于5吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。 Unless otherwise specified, 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. In addition, as for the "5-10 membered heterocycloalkyl group", a heteroatom may occupy the attachment position of the heterocycloalkyl group to the rest of the molecule. 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.
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、和蒽基等。所述芳基任选地被一个或多个选自以下的取代基取代：羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH 2、-C(O)NH-烷基、-C(O)N(烷基) 2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O) 2-烷基、-S(O) 2NH 2、-S(O) 2NH-烷基、-S(O) 2N(烷基) 2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。 The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. For example, 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 , cycloalkyl, cycloalkylene , Cycloalkyloxy, Heterocyclyl, Heterocyclylalkylene, Heterocyclyloxy, Heterocycloalkyl, Heterocycloalkylene, Heterocycloalkyloxy, Heteroaryl, Heteroaryl alkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
术语“杂芳基”是指单环或稠合多环的芳香体系，其中含有至少一个选自N、O、S和Se的环原子，其余环原子为C，通常具有5至14元、5至12元、5至10元、5至8元、5至7元或5至6元环，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。所述杂芳基可通过杂原子或碳原子连接到分子的其余部分。优选的杂芳基具有单个4至8元环，尤其是5至6元环，或包含5至14个，尤其是5至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。所述杂芳基任选地被一个或多个选自以下的取代基取代：羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH 2、-C(O)NH-烷基、-C(O)N(烷基) 2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O) 2-烷基、-S(O) 2NH 2、-S(O) 2NH-烷基、-S(O) 2N(烷基) 2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。 The term "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 , Cycloalkyl, Cycloalkylalkylene radical, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, hetero Arylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.
除非另有规定，术语“5-10元杂芳基”是表示由5至10个环原子组成的具有共轭π电子体系的环状基团，其1、2、3或4个环原子为独立选自O、S、N和Se的杂原子，其余为碳原子。其可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-10元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5- 10元杂芳基包括5-8元、5-7元、5-6元、5元和6元杂芳基等。所述5-10元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。 Unless otherwise specified, the term "5-10 membered heteroaryl" means a cyclic group consisting of 5 to 10 ring atoms with a conjugated π-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 , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2 -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.) , purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolinyl (including 3-quinolinyl and 6-quinolinyl, etc.) .
除非另有规定，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S、N和Se的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。 Unless otherwise specified, the term "5-6 membered heteroaryl" means a monocyclic group consisting of 5 to 6 ring atoms having a conjugated π-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 , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2 -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidyl (including 2-pyrimidyl and 4-pyrimidyl, etc.).
本公开中的基团Y 1与Y 2采用从左至右的阅读顺序，对应的与所示通式中Y 1或Y 2连接的左侧基团及右侧基团连接。 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.
本公开中的基团
Figure PCTCN2022130697-appb-000046
包括但不限于
Figure PCTCN2022130697-appb-000047
groups in this disclosure
Figure PCTCN2022130697-appb-000046
including but not limited to
Figure PCTCN2022130697-appb-000047
应当理解，结构片段
Figure PCTCN2022130697-appb-000048
中的C原子为环A的环原子，且与环A外的S原子连接。 It should be understood that the structural fragment
Figure PCTCN2022130697-appb-000048
The C atom in is a ring atom of ring A and is connected to the S atom outside ring A.
术语“治疗”意为将本公开所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：The term "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:
(i)抑制疾病或疾病状态，即遏制其发展；(i) inhibiting a disease or disease state, i.e. arresting its development;
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(ii) amelioration of a disease or disease state, even if the disease or disease state regresses.
术语“预防”意为将本公开所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，包括预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。The term "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.
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本公开化合物的用量。构成“治疗有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically 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.
术语“药物组合物”是指一种或多种本公开的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本公开的化合物。The term "pharmaceutical 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.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "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.
本公开的药物组合物可通过将本公开的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。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.
给予本公开化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。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.
本公开的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。The pharmaceutical 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.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本公开的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in oral form. For oral administration, 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.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。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.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
本公开式(I)化合物的所有施用方法中，每天给药的剂量为0.01到200mg/kg体重，本公开的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本公开的实施例。In all methods of administration of the compound of formula (I) in the present disclosure, 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.
本公开的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本公开的实施例。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.
本公开式(A)化合物的部分化合物可由有机合成领域技术人员通过路线1来制备，Some compounds of the compound of formula (A) of the present disclosure can be prepared by those skilled in the field of organic synthesis through route 1,
路线1Route 1
Figure PCTCN2022130697-appb-000049
Figure PCTCN2022130697-appb-000049
其中，Y 1和Y 2可为O；R 1、R 2、X、m、n、L、环A、环D和环C如本公开式(A)所定义。 Wherein, 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.
本公开式(I)化合物可由有机合成领域技术人员通过路线2来制备，The compound of formula (I) of the present disclosure can be prepared by those skilled in the art of organic synthesis through route 2,
路线2route 2
Figure PCTCN2022130697-appb-000050
Figure PCTCN2022130697-appb-000050
其中，R 1、n、T 1、环A、环B和环C如本公开式(I)所定义。 Wherein, R 1 , n, T 1 , ring A, ring B and ring C are as defined in formula (I) of the present disclosure.
上述路线中反应所得的每一个产物可以通过传统分离技术来得到，这种传统技术包括但不限于过滤、蒸馏、结晶、色谱分离等。起始原料可以通过自己合成或从商业机构(例如，但不限于Adrich或Sigma)购买获得。这些原料可以使用常规手段进行表征，比如物理常数和光谱数据。本公开所描述的化合物可以使用合成方法得到单一的异构体或者是异构体的混合物。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.
本公开的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本公开涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022130697-appb-000051
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。 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 CuKα radiation, and the scanning method is:
Figure PCTCN2022130697-appb-000051
After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
本公开所使用的溶剂可经市售获得。Solvents used in the present disclosure are commercially available.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022130697-appb-000052
软件命名，市售化合物采用供应商目录名称。 Compounds are named according to the conventional naming principles in this field or using
Figure PCTCN2022130697-appb-000052
The software is named, and the commercially available compounds adopt the supplier catalog name.
具体实施方式Detailed ways
下面通过实施例对本公开进行详细描述，但并不意味着对本公开任何不利限制。本文已经详细地描述了本公开，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本公开精神和范围的情况下针对本公开具体实施方式进行各种变化和改进将是显而易见的。The present disclosure will be described in detail through examples below, but it does not imply any adverse limitation on the present disclosure. The present disclosure has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure. will be obvious.
实施例1Example 1
Figure PCTCN2022130697-appb-000053
Figure PCTCN2022130697-appb-000053
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000054
Figure PCTCN2022130697-appb-000054
步骤1：化合物001_2的合成Step 1: Synthesis of compound 001_2
室温和氮气的保护下，将环丙烷磺酰胺(318.41mg)溶解于二甲基亚砜(15mL)中，在25℃下向其中加入叔丁醇钾(491.48mg)，搅拌30分钟后向其中缓慢加入001_1(500.00mg)，加完后在室温搅拌15小时。反应结束，加水(100mL)稀释，使用2M的稀盐酸调节pH到6，乙酸乙酯(200mL×3)萃取，合并有机相。有机相经饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：二氯甲烷/甲醇＝100/1–30/1，体积比)，得到化合物001_2。 1H NMR(400MHz,CDCl 3)δ:8.60(s,1H),7.84(s,1H),3.46–3.17(m,1H),1.53–1.44(m,2H),1.21–1.14(m,2H) At room temperature and under the protection of nitrogen, 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. After the reaction was completed, dilute with water (100 mL), adjust the pH to 6 with 2M dilute hydrochloric acid, extract with ethyl acetate (200 mL×3), and combine the organic phases. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: dichloromethane/methanol=100/1-30/1, volume ratio) to obtain compound 001_2. 1 H NMR (400MHz, CDCl 3 ) δ: 8.60(s,1H), 7.84(s,1H), 3.46–3.17(m,1H), 1.53–1.44(m,2H), 1.21–1.14(m,2H )
步骤2：化合物001_3的合成Step 2: Synthesis of compound 001_3
室温和氮气保护下，将叔丁醇钾(2.30g)加入到乙二醇(42.58g)中，反应体系升温至40℃搅拌三十分钟，向其中加入溶解于乙二醇二甲醚(20mL)中的001_2(3.2g)，将反应体系升温到110℃搅拌18小时。反应结束，反应体系降温到室温，加水(100mL)稀释，使用2M的稀盐酸调节pH到6，乙酸乙酯(200mL×3)萃取，合并有机相。有机相经饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–0/1，体积比)，得到化合物001_3。 1H NMR(400MHz,CDCl 3)δ:8.42(s,1H),7.61(s,1H),4.64–4.55(m,2H),4.06–3.96(m,2H),3.42–3.25(m,1H),1.54–1.38(m,2H),1.19–1.08(m,2H) Under the protection of room temperature and nitrogen, potassium tert-butoxide (2.30g) was added to ethylene glycol (42.58g), the reaction system was heated to 40°C and stirred for 30 minutes, and dissolved in ethylene glycol dimethyl ether (20mL ) in 001_2 (3.2g), the reaction system was heated to 110 ° C and stirred for 18 hours. After the reaction was completed, the reaction system was cooled to room temperature, diluted with water (100 mL), adjusted to pH 6 with 2M dilute hydrochloric acid, extracted with ethyl acetate (200 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=10/1-0/1, volume ratio) to obtain compound 001_3. 1 H NMR (400MHz, CDCl 3 ) δ: 8.42(s,1H), 7.61(s,1H), 4.64–4.55(m,2H), 4.06–3.96(m,2H), 3.42–3.25(m,1H ),1.54–1.38(m,2H),1.19–1.08(m,2H)
步骤3：化合物001_4的合成Step 3: Synthesis of Compound 001_4
在室温和氮气保护氛围下，将001_3(200.00mg)、5–苯并噻唑嚬哪醇硼酸酯(154.44mg)和碳酸钾(245.21mg)放于干燥反应瓶中，加入1,4–二氧六环(20mL)和水(1mL)溶解。在25℃下加入1,1–双(二苯基膦)二茂铁氯化钯(43.27mg)后升温到80℃搅拌13小时。反应结束，加水(100mL)稀释，使用2M的稀盐酸调节pH到6，乙酸乙酯(200mL×3)萃取，合并有机相。有机相经饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–0/1，体积比)，得到化合物001_4。 1H NMR(400MHz,CDCl 3)δ:9.08(s,1H),8.58(s,1H),8.10(d,J＝7.6Hz,2H),7.39(d,J＝9.6Hz,1H),7.08(s,1H),4.51(d,J＝4.2Hz,2H),3.84(d,J＝4.7Hz,2H),3.38(s,1H),2.04(s,1H),1.37(s,2H),1.11(d,J＝7.2Hz,2H) At room temperature and under a nitrogen atmosphere, put 001_3 (200.00mg), 5-benzothiazolinalcohol borate (154.44mg) and potassium carbonate (245.21mg) in a dry reaction flask, add 1,4-di Hexane (20 mL) and water (1 mL) were dissolved. After adding 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (43.27 mg) at 25°C, the mixture was heated up to 80°C and stirred for 13 hours. After the reaction was completed, dilute with water (100 mL), adjust the pH to 6 with 2M dilute hydrochloric acid, extract with ethyl acetate (200 mL×3), and combine the organic phases. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=10/1-0/1, volume ratio) to obtain compound 001_4. 1 H NMR (400MHz, CDCl 3 ) δ: 9.08(s, 1H), 8.58(s, 1H), 8.10(d, J=7.6Hz, 2H), 7.39(d, J=9.6Hz, 1H), 7.08 (s,1H),4.51(d,J=4.2Hz,2H),3.84(d,J=4.7Hz,2H),3.38(s,1H),2.04(s,1H),1.37(s,2H) ,1.11(d,J=7.2Hz,2H)
步骤4：化合物001的合成Step 4: Synthesis of compound 001
在室温和氮气保护氛围下，将氢化钠(122.40mg,含量60％)溶解于无水四氢呋喃(20mL)中，25℃下加入溶解于无水四氢呋喃(2mL)和N,N–二甲基甲酰胺(2mL)混合溶剂的001_4(150.00mg)，之后加入溶解于无水四氢呋喃(2mL)的5–溴–2–氯嘧啶(147.86mg)，反应体系升温到70℃搅拌2小时。反应完毕后，将反应体系降温到室温，加入饱和氯化铵溶液(100mL)淬灭反应，使用2M的稀盐酸调节pH到4，乙酸乙酯(20mL×3)萃取，合并有机相。有机相经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得残余物经分散于甲醇(1mL)中，在室温下搅拌1小时，过滤，收集固体，干燥得到化合物001。MS-ESI m/z:549.0,551.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:9.06(s,1H),8.56(s,1H),8.42(s,2H),8.10(t,J＝ 6.0Hz,2H),7.44(d,J＝8.4Hz,1H),7.02(s,1H),4.81(t,J＝4.0Hz,2H),4.68(t,J＝4.4Hz,2H),3.39(d,J＝4.5Hz,1H),1.36(s,2H),1.10(d,J＝7.0Hz,2H). Sodium hydride (122.40mg, content 60%) was dissolved in anhydrous tetrahydrofuran (20mL) at room temperature under a nitrogen atmosphere, and dissolved in anhydrous tetrahydrofuran (2mL) and N,N-dimethylformaldehyde were added at 25°C 001_4 (150.00 mg) in a mixed solvent of amide (2 mL), and then 5-bromo-2-chloropyrimidine (147.86 mg) dissolved in anhydrous tetrahydrofuran (2 mL) was added, and the reaction system was heated to 70° C. and stirred for 2 hours. After the reaction was completed, the reaction system was cooled to room temperature, and saturated ammonium chloride solution (100 mL) was added to quench the reaction. The pH was adjusted to 4 with 2M dilute hydrochloric acid, extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was dispersed in methanol (1 mL), stirred at room temperature for 1 hour, filtered, and the solid was collected and dried to obtain compound 001. MS-ESI m/z: 549.0, 551.0[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ: 9.06(s,1H), 8.56(s,1H), 8.42(s,2H), 8.10 (t,J=6.0Hz,2H),7.44(d,J=8.4Hz,1H),7.02(s,1H),4.81(t,J=4.0Hz,2H),4.68(t,J=4.4Hz ,2H),3.39(d,J=4.5Hz,1H),1.36(s,2H),1.10(d,J=7.0Hz,2H).
实施例2Example 2
Figure PCTCN2022130697-appb-000055
Figure PCTCN2022130697-appb-000055
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000056
Figure PCTCN2022130697-appb-000056
步骤1：化合物002_1的合成Step 1: Synthesis of Compound 002_1
在室温和氮气保护氛围下，将3,4–亚甲二氧基苯硼酸频哪醇酯(7.26g)、001_3(3.3g)和氢氧化钾(1.64g)溶解于无水乙醇(100mL)和水(10mL)中，向其中加入1,1-双(二苯基膦)二茂铁氯化钯(357.01mg)，置换氮气三次，反应升温至85℃搅拌12小时。反应结束，降至室温，减压浓缩除去溶剂，加水(30mL)稀释，过滤，收集滤液，滤液用3M稀盐酸溶液调pH到3–4，乙酸乙酯(50mL×3)萃取，合并有机相，依次加入饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–1/1，体积比)，得到化合物002_1。 1H NMR(400MHz,CDCl 3)δ:8.51(s,1H),7.11–6.97(m,1H),6.93(d,J＝8.3Hz,1H),6.80–6.74(m,2H),6.05(s,2H),4.53–4.45(m,2H),3.89–3.81(m,2H),3.53–3.24(m,1H),1.44–1.34(m,2H),1.15–1.06(m,2H). At room temperature and under a nitrogen atmosphere, 3,4-methylenedioxyphenylboronic acid pinacol ester (7.26g), 001_3 (3.3g) and potassium hydroxide (1.64g) were dissolved in absolute ethanol (100mL) and water (10 mL), 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (357.01 mg) was added thereto, nitrogen was replaced three times, and the reaction temperature was raised to 85° C. and stirred for 12 hours. After the reaction is completed, cool down to room temperature, concentrate under reduced pressure to remove the solvent, add water (30mL) to dilute, filter, collect the filtrate, adjust the pH of the filtrate to 3–4 with 3M dilute hydrochloric acid solution, extract with ethyl acetate (50mL×3), and combine the organic phases , followed by adding saturated brine (50 mL×2) for washing, drying over anhydrous sodium sulfate, filtering, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-1/1, volume ratio) to obtain compound 002_1. 1 H NMR (400MHz, CDCl 3 ) δ: 8.51(s, 1H), 7.11–6.97(m, 1H), 6.93(d, J=8.3Hz, 1H), 6.80–6.74(m, 2H), 6.05( s,2H),4.53–4.45(m,2H),3.89–3.81(m,2H),3.53–3.24(m,1H),1.44–1.34(m,2H),1.15–1.06(m,2H).
步骤2：化合物002的合成Step 2: Synthesis of compound 002
在室温和氮气保护氛围下，将氢化钠(109.60mg,含量60％)溶解于无水四氢呋喃(20mL)中，25℃下加入溶解于无水四氢呋喃(2mL)和N,N–二甲基甲酰胺(2mL)混合溶剂的002_1(130.00mg)。之后加入溶解于无水四氢呋喃(2mL)的5–溴–2–氯嘧啶(132.56mg)，反应体系升温到70℃搅拌2小时。反应完毕后，将反应体系降温到室温，加入饱和氯化铵溶液(10mL)淬灭反应，使用2M的稀盐酸调节pH到4，乙酸乙酯(40mL×3)萃取，合并有机相。有机相经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得残余物经制备HPLC分离(流动相：乙腈/水；中性：NH 4HCO 3)分离纯化得到化合物002.MS-ESI m/z:536.1,538.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ:8.50(s,3H),6.98(s,1H),6.86(d,J＝8.5Hz,1H),6.76–6.69(m,2H),6.03(s,2H),4.77–4.71(m,2H),4.68–4.63(m,2H),3.47–3.26(m,1H),1.43–1.34(m,2H),1.15–1.05(m,2H). Sodium hydride (109.60mg, content 60%) was dissolved in anhydrous tetrahydrofuran (20mL) at room temperature and under a nitrogen atmosphere, and dissolved in anhydrous tetrahydrofuran (2mL) and N,N-dimethylformaldehyde were added at 25°C 002_1 (130.00mg) of the mixed solvent of amides (2mL). Then, 5-bromo-2-chloropyrimidine (132.56 mg) dissolved in anhydrous tetrahydrofuran (2 mL) was added, and the reaction system was heated to 70° C. and stirred for 2 hours. After the reaction was completed, the reaction system was cooled to room temperature, and saturated ammonium chloride solution (10 mL) was added to quench the reaction. The pH was adjusted to 4 with 2M dilute hydrochloric acid, extracted with ethyl acetate (40 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was separated and purified by preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4 HCO 3 ) to obtain compound 002. MS-ESI m/z: 536.1,538.1[M+H] + . 1 H NMR ( 400MHz, CDCl 3 )δ: 8.50(s,3H),6.98(s,1H),6.86(d,J＝8.5Hz,1H),6.76–6.69(m,2H),6.03(s,2H),4.77 –4.71(m,2H),4.68–4.63(m,2H),3.47–3.26(m,1H),1.43–1.34(m,2H),1.15–1.05(m,2H).
实施例3Example 3
Figure PCTCN2022130697-appb-000057
Figure PCTCN2022130697-appb-000057
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000058
Figure PCTCN2022130697-appb-000058
步骤3：化合物003_1的合成Step 3: Synthesis of Compound 003_1
在室温和氮气保护氛围下，将001_3(300.00mg)、吡唑[1,5-a]并吡啶-6-嚬哪醇硼酸酯(154.44mg)和碳酸钾(367.82mg)放于干燥反应瓶中，加入1,4–二氧六环(20mL)和水(2mL)溶解。在25℃下加入1,1–双(二苯基膦)二茂铁氯化钯(64.91mg)后升温到80℃搅拌13小时。反应结束，加水(100mL)稀释，使用2M的稀盐酸调节pH到6，乙酸乙酯(200mL×3)萃取，合并有机相。有机相经饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–0/1，体积比)，得到化合物003_1。 1H NMR(400MHz,CDCl 3)δ:8.58(s,1H),8.42(s,1H),7.97(d,J＝2.4Hz,1H),7.65(d,J＝9.2Hz,1H),7.00(d,J＝9.2Hz,2H),6.57(s,1H),4.52(t,J＝2.4Hz,2H),3.86(s,2H),2.65(s,1H),1.40(t,J＝7.4Hz,4H). At room temperature and under a nitrogen atmosphere, 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 In the bottle, add 1,4-dioxane (20mL) and water (2mL) to dissolve. After adding 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (64.91 mg) at 25°C, the mixture was heated up to 80°C and stirred for 13 hours. After the reaction was completed, dilute with water (100 mL), adjust the pH to 6 with 2M dilute hydrochloric acid, extract with ethyl acetate (200 mL×3), and combine the organic phases. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=10/1-0/1, volume ratio) to obtain compound 003_1. 1 H NMR (400MHz, CDCl 3 ) δ: 8.58(s, 1H), 8.42(s, 1H), 7.97(d, J=2.4Hz, 1H), 7.65(d, J=9.2Hz, 1H), 7.00 (d,J=9.2Hz,2H),6.57(s,1H),4.52(t,J=2.4Hz,2H),3.86(s,2H),2.65(s,1H),1.40(t,J= 7.4Hz, 4H).
步骤4：化合物003的合成Step 4: Synthesis of Compound 003
在室温和氮气保护氛围下，将氢化钠(122.40mg,含量60％)溶解于无水四氢呋喃(20mL)中，25℃下加入溶解于无水四氢呋喃(2mL)和N,N–二甲基甲酰胺(2mL)混合溶剂的003_1(150.00mg)。之后加入溶解于无水四氢呋喃(2mL)的5–溴–2–氯嘧啶(147.86mg)，反应体系升温到70℃搅拌2小时。反应完毕后，将反应体系降温到室温，加入饱和氯化铵溶液(100mL)淬灭反应，使用2M的稀盐酸调节pH到4，乙酸乙酯(20mL×3)萃取，合并有机相。有机相依次经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得残余物经制备HPLC分离(流动相：乙腈/水；中性：NH 4HCO 3)分离纯化得到化合物003。MS-ESI m/z:532.0,534.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:8.54(s,1H),8.41(d,J＝2.2Hz,3H),7.90(d,J＝2.2Hz,1H),7.51(d,J＝9.2Hz,1H),6.96(d,J＝9.0Hz,1H),6.50(d,J＝2.2Hz,1H),4.73-4.75(m,2H),4.62-4.64(m,2H),3.36(s,1H),1.34-1.36(m,2H),1.08-1.10(m,2H). Sodium hydride (122.40mg, content 60%) was dissolved in anhydrous tetrahydrofuran (20mL) at room temperature under a nitrogen atmosphere, and dissolved in anhydrous tetrahydrofuran (2mL) and N,N-dimethylformaldehyde were added at 25°C 003_1 (150.00mg) of the mixed solvent of amides (2mL). Then, 5-bromo-2-chloropyrimidine (147.86 mg) dissolved in anhydrous tetrahydrofuran (2 mL) was added, and the reaction system was heated to 70° C. and stirred for 2 hours. After the reaction was completed, the reaction system was cooled to room temperature, and saturated ammonium chloride solution (100 mL) was added to quench the reaction. The pH was adjusted to 4 with 2M dilute hydrochloric acid, extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phase was successively washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was separated and purified by preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4 HCO 3 ) to obtain compound 003. MS-ESI m/z: 532.0, 534.0[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ: 8.54(s, 1H), 8.41(d, J=2.2Hz, 3H), 7.90(d ,J=2.2Hz,1H),7.51(d,J=9.2Hz,1H),6.96(d,J=9.0Hz,1H),6.50(d,J=2.2Hz,1H),4.73-4.75(m ,2H),4.62-4.64(m,2H),3.36(s,1H),1.34-1.36(m,2H),1.08-1.10(m,2H).
实施例4Example 4
Figure PCTCN2022130697-appb-000059
Figure PCTCN2022130697-appb-000059
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000060
Figure PCTCN2022130697-appb-000060
步骤1：化合物004_1的合成Step 1: Synthesis of compound 004_1
室温和氮气的保护下，将1–甲基环丙烷磺酰胺(1.00g)溶解于二甲基亚砜(20mL)中，在25℃下向其中加入叔丁醇钾(1.66g)，搅拌30分钟后，向其中缓慢加入001_1(2.02g)，加完后在25℃下搅拌15小时。反应结束，加水(60mL)稀释，使用1M的稀盐酸调节pH到4，乙酸乙酯(30mL×3)萃取，合并有机相。有机相经饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–1/1，体积比)，得到化合物004_1。 1H NMR(400MHz,CDCl 3)δ:8.58(s,1H),7.64(s,1H),1.96-1.81(m,2H),1.58(s,3H),1.04-0.95(m,2H). At room temperature and under the protection of nitrogen, 1-methylcyclopropanesulfonamide (1.00g) was dissolved in dimethyl sulfoxide (20mL), and potassium tert-butoxide (1.66g) was added thereto at 25°C, and stirred for 30 Minutes later, 001_1 (2.02 g) was slowly added thereto, and stirred at 25° C. for 15 hours after the addition was complete. After the reaction was completed, dilute with water (60 mL), adjust the pH to 4 with 1M dilute hydrochloric acid, extract with ethyl acetate (30 mL×3), and combine the organic phases. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=10/1-1/1, volume ratio) to obtain compound 004_1. 1 H NMR (400MHz, CDCl 3 ) δ: 8.58(s,1H), 7.64(s,1H), 1.96-1.81(m,2H), 1.58(s,3H), 1.04-0.95(m,2H).
步骤2：化合物004_2的合成Step 2: Synthesis of compound 004_2
室温和氮气保护下，将叔丁醇钾(549.71mg)加入到乙二醇(8.00mL)中，反应体系升温至40℃搅拌三十分钟，向其中加入溶解于乙二醇二甲醚(20mL)中的004_1(800.00mg)，将反应体系升温到110℃搅拌15小时。反应结束，反应体系降温到室温，加水(30mL)稀释，使用1M的稀盐酸调节pH到4，乙酸乙酯(100mL×3)萃取，合并有机相。有机相经饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：二氯甲烷/甲醇＝20/1，体积比)，得到化合物004_2。 1H NMR(400MHz,CDCl 3)δ:8.41(s,1H),7.48(s,1H),4.68-4.40(m,2H),4.11-3.86(m,2H),2.44(t,J＝6.0Hz,1H),1.96-1.78(m,2H),1.60(s,3H),1.14-0.60(m,2H). At room temperature and under the protection of nitrogen, 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. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: dichloromethane/methanol=20/1, volume ratio) to obtain compound 004_2. 1 H NMR (400MHz, CDCl 3 ) δ: 8.41(s, 1H), 7.48(s, 1H), 4.68-4.40(m, 2H), 4.11-3.86(m, 2H), 2.44(t, J=6.0 Hz,1H),1.96-1.78(m,2H),1.60(s,3H),1.14-0.60(m,2H).
步骤3：化合物004_3的合成Step 3: Synthesis of Compound 004_3
在室温和氮气保护氛围下，将004_2(400.00mg)、5–苯并噻唑嚬哪醇硼酸酯(357.25mg)和1,1–双(二苯基膦)二茂铁氯化钯(83.41mg)放于干燥反应瓶中，加入1,4–二氧六环(20mL)和水(1mL)溶解。在25℃下加入碳酸钾(472.68mg)后升温到80℃搅拌13小时。反应结束，减压浓缩除去大部分溶剂，加水(30mL)稀释，使用1M的稀盐酸调节pH到5，乙酸乙酯(30mL×3)萃取，合并有机相。有机相经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/2–0/1，体积比)，得到化合物004_3。MS-ESI m/z:407.0[M+H] +. At room temperature and under a nitrogen atmosphere, 004_2 (400.00 mg), 5-benzothiazolinalcohol borate (357.25 mg) and 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (83.41 mg) in a dry reaction vial, add 1,4-dioxane (20mL) and water (1mL) to dissolve. After adding potassium carbonate (472.68 mg) at 25°C, the mixture was heated up to 80°C and stirred for 13 hours. After the reaction was completed, most of the solvent was removed by concentration under reduced pressure, diluted with water (30 mL), adjusted to pH 5 with 1M dilute hydrochloric acid, extracted with ethyl acetate (30 mL×3), and combined the organic phases. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/2-0/1, volume ratio) to obtain compound 004_3. MS-ESI m/z:407.0[M+H] + .
步骤4：化合物004的合成Step 4: Synthesis of Compound 004
在室温和氮气保护氛围下，将氢化钠(141.70mg,含量60％)溶解于无水四氢呋喃(20mL)中。25℃下加入溶解于无水N,N–二甲基甲酰胺(2mL)的004_3(180.00mg)。之后加入溶解于无水四氢呋喃(1mL)的5–溴–2–氯嘧啶(171.31mg)，反应体系升温到70℃搅拌2小时。反应完毕后，将反应体系降温到室温，加入饱和氯化铵溶液(20mL)淬灭反应，使用1M的稀盐酸调节pH到4，乙酸乙酯(20mL×3)萃取，合并有机相。有机相经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得残余物分散于甲醇(10mL)中，在室温下搅拌1小时，过滤，收集固体，干燥得到化合物004.MS-ESI m/z:562.9,564.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ:9.08(s,1H),8.54(s,1H),8.43(s,2H),8.09-7.99(m,2H),7.36(d,J＝8.6Hz,1H),6.86(s,1H),4.79-4.68(m,2H),4.66-4.57(m,2H),1.87(s,2H),1.52(s,3H),0.95(s,2H). Sodium hydride (141.70 mg, content 60%) was dissolved in anhydrous tetrahydrofuran (20 mL) at room temperature under a nitrogen atmosphere. 004_3 (180.00 mg) dissolved in anhydrous N,N-dimethylformamide (2 mL) was added at 25°C. Then, 5-bromo-2-chloropyrimidine (171.31 mg) dissolved in anhydrous tetrahydrofuran (1 mL) was added, and the reaction system was heated to 70° C. and stirred for 2 hours. After the reaction was completed, the reaction system was cooled to room temperature, and saturated ammonium chloride solution (20 mL) was added to quench the reaction. The pH was adjusted to 4 with 1M dilute hydrochloric acid, extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was dispersed in methanol (10 mL), stirred at room temperature for 1 hour, filtered, and the solid was collected and dried to obtain compound 004. MS-ESI m/z: 562.9,564.9[M+H] + . 1 H NMR (400MHz , CDCl 3 )δ: 9.08(s, 1H), 8.54(s, 1H), 8.43(s, 2H), 8.09-7.99(m, 2H), 7.36(d, J=8.6Hz, 1H), 6.86( s,1H),4.79-4.68(m,2H),4.66-4.57(m,2H),1.87(s,2H),1.52(s,3H),0.95(s,2H).
实施例5Example 5
Figure PCTCN2022130697-appb-000061
Figure PCTCN2022130697-appb-000061
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000062
Figure PCTCN2022130697-appb-000062
步骤1：化合物005_1的合成Step 1: Synthesis of compound 005_1
在室温和氮气保护氛围下，将3,4–亚甲二氧基苯硼酸频哪醇酯(311.09mg)、004_2(400.00mg)和碳酸钾(470.89mg)溶解于1,4–二氧六环(20mL)和水(2mL)，向其中加入1,1–双(二苯基膦)二茂铁氯化钯(83.10mg)，置换氮气三次，反应升温至80℃搅拌15小时。反应结束，降至室温，减压浓缩除去溶剂，加水(30mL)稀释，用1M稀盐酸溶液调pH到3–4，乙酸乙酯(30mL×3)萃取，合并有机相，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/2–0/1，体积比)，得到化合物005_1。MS–ESI m/z:394.0[M+H] +. At room temperature and under a nitrogen atmosphere, 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. After the reaction is completed, cool down to room temperature, concentrate under reduced pressure to remove the solvent, add water (30mL) to dilute, adjust the pH to 3–4 with 1M dilute hydrochloric acid solution, extract with ethyl acetate (30mL×3), combine the organic phases, and dilute with saturated saline (20mL ), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/2-0/1, volume ratio) to obtain compound 005_1. MS–ESI m/z:394.0[M+H] + .
步骤2：化合物005的合成Step 2: Synthesis of Compound 005
在室温和氮气保护氛围下，将氢化钠(194.86mg,含量60％)溶解于无水四氢呋喃(20mL)中，25℃下加入溶解于无水N,N–二甲基甲酰胺(2mL)的005_1(400.00mg)。之后加入溶解于无水四氢呋喃(2mL)的5–溴–2–氯嘧啶(235.57mg)，反应体系升温到70℃搅拌2小时。反应完毕后，将反应体系降温到室温，加入饱和氯化铵溶液(10mL)淬灭反应，使用2M的稀盐酸调节pH到4，乙酸乙酯(20mL×3)萃取，合并有机相。有机相经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得残余物经制备HPLC分离(流动相：乙腈/水；中性：NH 4HCO 3)分离纯化得到化合物005.MS-ESI m/z:549.9,551.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ:8.55-8.09(m,3H),6.87-6.67(m,4H),6.03(s,2H),4.75-4.69(m,2H),4.68-4.62(m,2H),1.85(s,2H),1.51(s,3H),0.93(s,2H). Sodium hydride (194.86mg, content 60%) was dissolved in anhydrous tetrahydrofuran (20mL) at room temperature under a nitrogen atmosphere, and dissolved in anhydrous N,N-dimethylformamide (2mL) was added at 25°C. 005_1 (400.00 mg). Then, 5-bromo-2-chloropyrimidine (235.57 mg) dissolved in anhydrous tetrahydrofuran (2 mL) was added, and the reaction system was heated to 70° C. and stirred for 2 hours. After the reaction was completed, the reaction system was cooled to room temperature, and saturated ammonium chloride solution (10 mL) was added to quench the reaction. The pH was adjusted to 4 with 2M dilute hydrochloric acid, extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was separated and purified by preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4 HCO 3 ) to obtain compound 005. MS-ESI m/z: 549.9,551.9[M+H] + . 1 H NMR ( 400MHz, CDCl 3 )δ:8.55-8.09(m,3H),6.87-6.67(m,4H),6.03(s,2H),4.75-4.69(m,2H),4.68-4.62(m,2H), 1.85(s,2H),1.51(s,3H),0.93(s,2H).
实施例6Example 6
Figure PCTCN2022130697-appb-000063
Figure PCTCN2022130697-appb-000063
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000064
Figure PCTCN2022130697-appb-000064
步骤1：化合物006_2的合成Step 1: Synthesis of compound 006_2
在室温和氮气保护下，将化合物006_1(800.00mg)溶解于无水四氢呋喃(20mL)中，加入氨水(8.76g,浓度：28％)，反应体系在25℃搅拌12小时。反应完毕，将反应液减压浓缩除去溶剂，残余物加水(50mL)稀释，用1M稀盐酸溶液调pH到5–6，乙酸乙酯(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂得到化合物006_2，粗品直接投下一步。Compound 006_1 (800.00mg) was dissolved in anhydrous tetrahydrofuran (20mL) at room temperature under nitrogen protection, ammonia water (8.76g, concentration: 28%) was added, and the reaction system was stirred at 25°C for 12 hours. After the reaction is complete, the reaction liquid is concentrated under reduced pressure to remove the solvent, the residue is diluted with water (50 mL), the pH is adjusted to 5–6 with 1M dilute hydrochloric acid solution, extracted with ethyl acetate (30 mL×3), the organic phases are combined, anhydrous sodium sulfate After drying and filtering, the filtrate was concentrated under reduced pressure to remove the solvent to obtain compound 006_2, and the crude product was directly sent to the next step.
步骤2：化合物006_3的合成Step 2: Synthesis of Compound 006_3
室温和氮气的保护下，将006_2(600.00mg)溶解于二甲基亚砜(20mL)中，在25℃下向其中加入叔丁醇钾(1.34g)，搅拌一小时后，向其中缓慢加入001_1(904.37mg)，加料完毕后在25℃下搅拌11小时。反应结束，将反应液倒入水(100mL)中，使用1M的稀盐酸调节pH到5，乙酸乙酯(50mL×3)萃取，合并有机相。有机相经饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–1/2，体积比)，得到化合物006_3。 1H NMR(400MHz,DMSO_d 6)δ:8.58(s,1H),4.53(s,1H),4.11(dd,J＝4.6,9.8Hz,1H),3.95(t,J＝9.0Hz,1H),3.90–3.82(m,1H),3.74–3.68(m,2H),2.38–2.18(m,2H). Under the protection of room temperature and nitrogen, 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. The organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=10/1-1/2, volume ratio) to obtain compound 006_3. 1 H NMR (400MHz,DMSO_d 6 )δ:8.58(s,1H),4.53(s,1H),4.11(dd,J=4.6,9.8Hz,1H),3.95(t,J=9.0Hz,1H) ,3.90–3.82(m,1H),3.74–3.68(m,2H),2.38–2.18(m,2H).
步骤3：化合物006_4的合成Step 3: Synthesis of compound 006_4
室温和氮气保护下，将叔丁醇钾(250.56mg)加入到乙二醇(7.62g)和乙二醇二甲醚(10mL)的混合溶剂中，反应体系升温至40℃搅拌三十分钟。向其中加入溶解于乙二醇二甲醚(20mL)中的006_3(255.00mg)，将反应体系升温到110℃搅拌15小时。反应结束，反应体系降温到室温，加水(100mL)稀释，使用2M的稀盐酸调节pH到5，乙酸乙酯(60mL×3)萃取，合并有机相。有机相经饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝3/1–1/4，体积比)，得到化合物006_4。 1H NMR(400MHz,CDCl 3)δ:8.33(s,1H),7.49(s,1H),4.75(s,1H),4.53(t,J＝4.6Hz,2H),4.22(dd,J＝5.4,10.2Hz,1H),4.09–3.97(m,2H),3.93(t,J＝4.4Hz,2H),3.86–3.77(m,1H),2.52–2.38(m,1H),2.33–2.21(m,2H). At room temperature and under the protection of nitrogen, 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. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=3/1-1/4, volume ratio) to obtain compound 006_4. 1 H NMR (400MHz, CDCl 3 ) δ: 8.33(s, 1H), 7.49(s, 1H), 4.75(s, 1H), 4.53(t, J=4.6Hz, 2H), 4.22(dd, J= 5.4,10.2Hz,1H),4.09–3.97(m,2H),3.93(t,J＝4.4Hz,2H),3.86–3.77(m,1H),2.52–2.38(m,1H),2.33–2.21 (m,2H).
步骤4：化合物006_5的合成Step 4: Synthesis of compound 006_5
在室温和氮气保护氛围下，将3,4–亚甲二氧基苯硼酸频哪醇酯(192.02mg)和006_4(190.00mg)溶解于1,4–二氧六环(20mL)和水(2mL)。向其中加入碳酸钾(213.96mg)并在25℃下搅拌分钟，然后加入1,1–双(二苯基膦)二茂铁氯化钯(113.27mg)，置换氮气三次，反应升温至80℃搅拌12小时。反应结束，降至室温，减压浓缩除去溶剂，加水(30mL)稀释，用1M稀盐酸溶液调pH到3～4，乙酸乙酯(30mL×3)萃取，合并有机相，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝5/1–1/3，体积比)，得到化合物006_5。 1H NMR(400MHz,CDCl 3)δ:8.42(s,1H),6.87(d,J＝8.0Hz,2H),6.72–6.63(m,2H),6.00(s,2H),4.43(t,J＝4.6Hz,2H),4.14(dd,J＝5.8,9.8Hz,1H),4.09–3.99(m,2H),3.95–3.86(m,1H),3.83–3.81(m,1H),3.80(t,J＝4.4Hz,2H),2.44–2.33 (m,1H),2.31–2.20(m,1H). At room temperature and under a nitrogen atmosphere, 3,4-methylenedioxyphenylboronic acid pinacol ester (192.02 mg) and 006_4 (190.00 mg) were dissolved in 1,4-dioxane (20 mL) and water ( 2mL). Potassium carbonate (213.96mg) was added thereto and stirred at 25°C for 1 minute, then 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (113.27mg) was added, nitrogen was replaced three times, and the reaction was heated to 80°C Stir for 12 hours. After the reaction is completed, cool down to room temperature, concentrate under reduced pressure to remove the solvent, add water (30mL) to dilute, adjust the pH to 3-4 with 1M dilute hydrochloric acid solution, extract with ethyl acetate (30mL×3), combine the organic phases, and dilute with saturated saline (20mL ), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=5/1-1/3, volume ratio) to obtain compound 006_5. 1 H NMR (400MHz, CDCl 3 ) δ: 8.42(s, 1H), 6.87(d, J=8.0Hz, 2H), 6.72–6.63(m, 2H), 6.00(s, 2H), 4.43(t, J＝4.6Hz, 2H), 4.14(dd, J＝5.8, 9.8Hz, 1H), 4.09–3.99(m, 2H), 3.95–3.86(m, 1H), 3.83–3.81(m, 1H), 3.80 (t,J=4.4Hz,2H),2.44–2.33(m,1H),2.31–2.20(m,1H).
步骤5：化合物006的合成Step 5: Synthesis of Compound 006
在室温和氮气保护氛围下，将氢化钠(103.17mg，含量60％)溶解于无水四氢呋喃(20mL)中，25℃下加入溶解于无水N,N–二甲基甲酰胺(2mL)的006_5(132.00mg)。之后加入溶解于无水四氢呋喃(1mL)的5–溴–2–氯嘧啶(124.73mg)，反应体系升温到70℃搅拌2小时。反应完毕后，将反应体系降温到室温，加入饱和氯化铵溶液(30mL)淬灭反应，使用1M的稀盐酸调节pH到5，乙酸乙酯(20mL×3)萃取，合并有机相。有机相经饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得残余物经制备HPLC分离(流动相：乙腈/水；中性：NH 4HCO 3)分离纯化得到化合物006.MS-ESI m/z:566.1,568.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ:8.42(s,2H),8.40(s,1H),6.80(d,J＝8.4Hz,1H),6.67–6.60(m,2H),5.96(s,2H),4.80(s,1H),4.66(t,J＝4.6Hz,2H),4.57(t,J＝4.6Hz,2H),4.16–4.09(m,1H),4.07–3.99(m,1H),3.95–3.87(m,1H),3.85–3.75(m,1H),2.42–2.33(m,1H),2.29–2.20(m,1H). Sodium hydride (103.17mg, content 60%) was dissolved in anhydrous tetrahydrofuran (20mL) at room temperature under a nitrogen atmosphere, and dissolved in anhydrous N,N-dimethylformamide (2mL) was added at 25°C. 006_5 (132.00 mg). Then, 5-bromo-2-chloropyrimidine (124.73 mg) dissolved in anhydrous tetrahydrofuran (1 mL) was added, and the reaction system was heated to 70° C. and stirred for 2 hours. After the reaction was completed, the reaction system was cooled to room temperature, and saturated ammonium chloride solution (30 mL) was added to quench the reaction. The pH was adjusted to 5 with 1 M dilute hydrochloric acid, extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was separated and purified by preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4 HCO 3 ) to obtain compound 006. MS-ESI m/z: 566.1,568.1[M+H] + . 1 H NMR ( 400MHz, CDCl 3 )δ: 8.42(s, 2H), 8.40(s, 1H), 6.80(d, J=8.4Hz, 1H), 6.67–6.60(m, 2H), 5.96(s, 2H), 4.80 (s,1H),4.66(t,J=4.6Hz,2H),4.57(t,J=4.6Hz,2H),4.16–4.09(m,1H),4.07–3.99(m,1H),3.95– 3.87(m,1H),3.85–3.75(m,1H),2.42–2.33(m,1H),2.29–2.20(m,1H).
实施例7Example 7
Figure PCTCN2022130697-appb-000065
Figure PCTCN2022130697-appb-000065
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000066
Figure PCTCN2022130697-appb-000066
步骤1：化合物007的合成Step 1: Synthesis of compound 007
在室温和氮气保护氛围下，将002_1(200mg)溶解于无水四氢呋喃(3mL)中，加入碳酸铯(721.40mg)，25℃加入2,5–二氯嘧啶(102.10mg)，反应体系升温到75℃搅拌12小时。反应完毕后，将反应体系降温到室温，加入水(10mL)稀释，使用3M的稀盐酸调节pH到3～4，乙酸乙酯(15mL×3)萃取，合并有机相。有机相经饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得残余物经制备HPLC分离(流动相：乙腈/水；中性：NH 4HCO 3)分离纯化得到化合物007.MS-ESI m/z:492.1[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.90(s,1H),8.66(s,2H),8.50(s,1H),6.90(d,J＝8.0Hz,1H),6.77–6.62(m,2H),6.03(s,2H),4.69–4.63(m,2H),4.62–4.58(m,2H),3.33–3.31(m,1H),1.09–0.97(m,4H). At room temperature and under a nitrogen atmosphere, 002_1 (200 mg) was dissolved in anhydrous tetrahydrofuran (3 mL), cesium carbonate (721.40 mg) was added, 2,5-dichloropyrimidine (102.10 mg) was added at 25 ° C, and the reaction system was heated to Stir at 75°C for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, diluted with water (10 mL), adjusted to pH 3-4 with 3M dilute hydrochloric acid, extracted with ethyl acetate (15 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was separated and purified by preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4 HCO 3 ) to obtain compound 007. MS-ESI m/z: 492.1[M+H] + . 1 H NMR (400MHz, DMSO_d 6 )δ: 9.90(s, 1H), 8.66(s, 2H), 8.50(s, 1H), 6.90(d, J=8.0Hz, 1H), 6.77–6.62(m, 2H), 6.03(s ,2H),4.69–4.63(m,2H),4.62–4.58(m,2H),3.33–3.31(m,1H),1.09–0.97(m,4H).
实施例8Example 8
Figure PCTCN2022130697-appb-000067
Figure PCTCN2022130697-appb-000067
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000068
Figure PCTCN2022130697-appb-000068
步骤1：化合物008的合成Step 1: Synthesis of Compound 008
在室温和氮气保护氛围下，将002_1(124mg)溶解于无水四氢呋喃(1mL)中，加入碳酸铯(447.27mg)，25℃加入2–氯–5-(三氟甲基)–嘧啶(102.10mg)，反应体系升温到75℃搅拌12小时。反应完毕后，将反应体系降温到室温，加入水(10mL)稀释，使用3M的稀盐酸调节pH到3～4，乙酸乙酯(15mL×3)萃取，合并有机相。有机相经饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得残余物经制备HPLC分离(流动相：乙腈/水；酸性：HCl)分离纯化得到化合物008.MS-ESI m/z:526.1[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.91(s,1H),9.02(d,J＝0.8Hz,2H),8.51(s,1H),6.89(d,J＝8.0Hz,1H),6.75–6.64(m,2H),6.02(s,2H),4.70(s,4H),3.30–3.25(m,1H),1.11–0.95(m,4H). At room temperature and under a nitrogen atmosphere, 002_1 (124 mg) was dissolved in anhydrous tetrahydrofuran (1 mL), cesium carbonate (447.27 mg) was added, and 2-chloro-5-(trifluoromethyl)-pyrimidine (102.10 mg), the reaction system was heated to 75°C and stirred for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, diluted with water (10 mL), adjusted to pH 3-4 with 3M dilute hydrochloric acid, extracted with ethyl acetate (15 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was separated and purified by preparative HPLC (mobile phase: acetonitrile/water; acidic: HCl) to obtain compound 008. MS-ESI m/z: 526.1[M+H] + . 1 H NMR (400MHz, DMSO_d 6 )δ :9.91(s,1H),9.02(d,J＝0.8Hz,2H),8.51(s,1H),6.89(d,J＝8.0Hz,1H),6.75–6.64(m,2H),6.02( s,2H),4.70(s,4H),3.30–3.25(m,1H),1.11–0.95(m,4H).
实施例9Example 9
Figure PCTCN2022130697-appb-000069
Figure PCTCN2022130697-appb-000069
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000070
Figure PCTCN2022130697-appb-000070
步骤1：化合物009的合成Step 1: Synthesis of Compound 009
在室温和氮气保护氛围下，将002_1(300mg)溶解于无水四氢呋喃(6mL)中，加入碳酸铯(1.08g)，25℃加入2–氯–5–溴吡啶(304.35mg)，反应体系升温到75℃搅拌12小时。反应完毕后，将反应体系降温到室温，加入水(10mL)稀释，使用3M的稀盐酸调节pH到3～4，乙酸乙酯(15mL×3)萃取，合并有机相。有机相经饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得残余物经制备HPLC分离(流动相：乙腈/水；酸性：HCl)分离纯化得到化合物009.MS-ESI m/z:535.1,537.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.91(s,1H),8.51(s,1H),8.22(d,J＝2.4Hz,1H),7.88(dd,J＝2.4,8.8Hz,1H),6.91(d,J＝8.0Hz,1H),6.79(d,J＝8.8Hz,1H),6.74(s,1H),6.69(d,J＝8.0Hz,1H),6.03(s,2H),4.71–4.58(m,2H),4.56–4.45(m,2H),3.30–3.25(m,1H)，1.13–0.95(m,4H). At room temperature and under a nitrogen atmosphere, dissolve 002_1 (300mg) in anhydrous THF (6mL), add cesium carbonate (1.08g), add 2-chloro-5-bromopyridine (304.35mg) at 25°C, and heat up the reaction system Stir at 75°C for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, diluted with water (10 mL), adjusted to pH 3-4 with 3M dilute hydrochloric acid, extracted with ethyl acetate (15 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was separated and purified by preparative HPLC (mobile phase: acetonitrile/water; acidic: HCl) to obtain compound 009. MS-ESI m/z: 535.1, 537.0 [M+H] + . 1 H NMR (400MHz, DMSO_d 6 )δ: 9.91(s, 1H), 8.51(s, 1H), 8.22(d, J=2.4Hz, 1H), 7.88(dd, J=2.4, 8.8Hz, 1H), 6.91(d, J=8.0 Hz,1H),6.79(d,J=8.8Hz,1H),6.74(s,1H),6.69(d,J=8.0Hz,1H),6.03(s,2H),4.71–4.58(m,2H ), 4.56–4.45(m,2H), 3.30–3.25(m,1H), 1.13–0.95(m,4H).
实施例10Example 10
Figure PCTCN2022130697-appb-000071
Figure PCTCN2022130697-appb-000071
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000072
Figure PCTCN2022130697-appb-000072
步骤1：化合物010的合成Step 1: Synthesis of Compound 010
在室温和氮气保护氛围下，将002_1(110mg)和6–氯咪唑并[1,2–b]哒嗪(57.88mg)溶解于无水N,N–二甲基甲酰胺(2mL)中，25℃加入碳酸铯(377.87mg)，反应体系升温到120℃搅拌12小时。反应完毕后，将反应体系降温到室温，使用3M的稀盐酸调节pH到3～4，乙酸乙酯(10mL×3)萃取，合并有机相。有机相经半饱和食盐水(10mL×2)洗涤，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液45℃减压浓缩除去溶剂。所得残余物经制备HPLC分离(流动相：乙腈/水；酸性：HCl)分离纯化得到化合物010.MS-ESI m/z:497.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.74(s,1H),8.48(s,1H),8.35(s,1H),8.27(d,J＝10.0Hz,1H),8.07(s,1H),7.36(d,J＝9.6Hz,1H),6.95(d,J＝8.0Hz,1H),6.77(s,1H),6.75–6.71(m,1H),6.03(s,2H),4.66(t,J＝4.4Hz,2H),4.38(t,J＝4.4Hz,2H),3.17–3.13(m,1H),1.08–0.96(m,4H). 002_1 (110 mg) and 6-chloroimidazo[1,2-b]pyridazine (57.88 mg) were dissolved in anhydrous N,N-dimethylformamide (2 mL) at room temperature under a nitrogen atmosphere, Cesium carbonate (377.87 mg) was added at 25°C, and the reaction system was heated to 120°C and stirred for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, and the pH was adjusted to 3-4 with 3M dilute hydrochloric acid, extracted with ethyl acetate (10 mL×3), and the organic phases were combined. The organic phase was washed with semi-saturated brine (10 mL×2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C to remove the solvent. The resulting residue was separated and purified by preparative HPLC (mobile phase: acetonitrile/water; acidic: HCl) to obtain compound 010. MS-ESI m/z: 497.2[M+H] + . 1 H NMR (400MHz, DMSO_d 6 )δ :9.74(s,1H),8.48(s,1H),8.35(s,1H),8.27(d,J=10.0Hz,1H),8.07(s,1H),7.36(d,J=9.6Hz, 1H), 6.95(d, J=8.0Hz, 1H), 6.77(s, 1H), 6.75–6.71(m, 1H), 6.03(s, 2H), 4.66(t, J=4.4Hz, 2H), 4.38(t,J=4.4Hz,2H),3.17–3.13(m,1H),1.08–0.96(m,4H).
实施例11Example 11
Figure PCTCN2022130697-appb-000073
Figure PCTCN2022130697-appb-000073
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000074
Figure PCTCN2022130697-appb-000074
步骤1：化合物011的合成Step 1: Synthesis of Compound 011
在室温和氮气保护氛围下，将002_1(500mg)溶解于无水N,N–二甲基甲酰胺(3mL)，将反应体系在氮气保护氛围下降温至0℃，向其中分批加入氢化钠(131.78mg,含量60％)，反应体系在0℃搅拌0.5小时，向其中加入2,5–二溴噻唑(480.22mg)，反应升温至20℃搅拌12小时。反应结束，向反应液中加入1M稀盐酸调节pH到2～3，乙酸乙酯(10mL×2)萃取，合并有机相，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经制备HPLC分离(流动相：乙腈/水；中性：NH 4HCO 3)分离纯化冻干后，所得固体经制备HPLC分离(流动相：乙腈/水；酸性HCl)分离纯化得到化合物011.MS-ESI m/z:541.0,543.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.92(s,1H),8.52(s,1H),7.27(s,1H),6.93(d,J＝8.0Hz,1H),6.75(s,1H),6.69(d,J＝7.6Hz,1H),6.05(s,2H),4.64(s,4H),3.31–3.23(m,1H),1.14–0.94(m,4H). 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. After the reaction, add 1M dilute hydrochloric acid to the reaction solution to adjust the pH to 2-3, extract with ethyl acetate (10mL×2), combine the organic phases, wash with saturated brine (20mL), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure to remove solvent. The obtained residue was separated and purified by preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4 HCO 3 ) and lyophilized, and the obtained solid was separated and purified by preparative HPLC (mobile phase: acetonitrile/water; acidic HCl) to obtain the compound 011.MS-ESI m/z:541.0,543.0[M+H] + . 1 H NMR (400MHz,DMSO_d 6 )δ:9.92(s,1H),8.52(s,1H),7.27(s,1H) ,6.93(d,J=8.0Hz,1H),6.75(s,1H),6.69(d,J=7.6Hz,1H),6.05(s,2H),4.64(s,4H),3.31–3.23( m,1H),1.14–0.94(m,4H).
实施例12Example 12
Figure PCTCN2022130697-appb-000075
Figure PCTCN2022130697-appb-000075
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000076
Figure PCTCN2022130697-appb-000076
步骤1：化合物012_1的合成Step 1: Synthesis of compound 012_1
室温和氮气的保护下，将2-氯-5-溴嘧啶(14g)溶解于四氢呋喃(210mL)中，加入碳酸钾(47.01g)。反应体系升温至45℃后加入乙二醇(6.74g)，45℃搅拌12小时。反应结束后，将反应液倒入水(500mL)中淬灭，乙酸乙酯(200mL×3)萃取，有机相用饱和食盐水(500mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂，得到化合物012_1，粗品直接投下一步。At room temperature under the protection of nitrogen, 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. After the reaction, the 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.
步骤2：化合物012_3的合成Step 2: Synthesis of Compound 012_3
室温和氮气的保护下，将012_2(5g)溶解于无水甲苯(75mL)中，在25℃下向其中加入丙二酸二乙酯(4.38g)，三叔丁基膦(2.01g，10％-14％的甲苯溶液)和磷酸钾(15.84g)，置换氮气三次后加入双(二亚苄基丙酮)钯(286.05mg)，再次置换氮气后反应体系升温到70℃并搅拌12小时。反应结束，使用3M的稀盐酸调节pH到5～6，加水(50mL)稀释，乙酸乙酯(80mL×3)萃取，合并有机相。有机相经饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–4/1，体积比)，得到化合物012_3。 1H NMR(400MHz,DMSO_d 6)δ:6.95(d,J＝1.8Hz,1H),6.83–6.73(m,2H),5.94(s,2H),4.51(s,1H),4.26–4.15(m,4H),1.28–1.23(m,6H). Under the protection of room temperature and nitrogen, 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. After the reaction, the pH was adjusted to 5-6 with 3M dilute hydrochloric acid, diluted with water (50 mL), extracted with ethyl acetate (80 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-4/1, volume ratio) to obtain compound 012_3. 1 H NMR (400MHz, DMSO_d 6 ) δ: 6.95 (d, J=1.8Hz, 1H), 6.83–6.73 (m, 2H), 5.94 (s, 2H), 4.51 (s, 1H), 4.26–4.15 ( m,4H),1.28–1.23(m,6H).
步骤3：化合物012_4的合成Step 3: Synthesis of compound 012_4
室温和氮气保护下，将乙醇钠(1.04g)溶解到无水乙醇(2.5mL)中，加入醋酸甲脒(144.87mg)。反应体系在25℃下搅拌20分钟后加入溶解于无水乙醇(1.1mL)的012_3(0.3g)，加料完毕后反应体系在25℃下继续搅拌12小时。反应结束后，反应体系直接减压浓缩除去溶剂，加水(5mL)稀释后，加3M稀盐酸调pH到6～7，过滤，收集固体，固体真空干燥除去溶剂得到化合物012_4，粗品直接投下一步。At room temperature under nitrogen protection, sodium ethoxide (1.04 g) was dissolved in absolute ethanol (2.5 mL), and formamidine acetate (144.87 mg) was added. After the reaction system was stirred at 25°C for 20 minutes, 012_3 (0.3 g) dissolved in absolute ethanol (1.1 mL) was added. After the addition, the reaction system was stirred at 25°C for 12 hours. After the reaction, the reaction system was directly concentrated under reduced pressure to remove the solvent, diluted with water (5 mL), adjusted to pH 6-7 by adding 3M dilute hydrochloric acid, filtered, collected the solid, dried in vacuum to remove the solvent to obtain compound 012_4, and the crude product was directly injected into the next step.
步骤4：化合物012_5的合成Step 4: Synthesis of compound 012_5
室温和氮气保护下，将012_4(110mg)溶解于三氯氧磷(0.5mL)中，将反应体系升温至90℃搅拌1小时。反应结束后，将反应体系降温到室温后缓慢倒入水(5mL)中淬灭，使用氨水调节pH到7～8，二氯甲烷(5mL×3)萃取，合并有机相，饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–5/1，体积比)，得到化合物012_5。 1H NMR(400MHz,CDCl 3)δ:8.77(s,1H),6.95(d,J＝8.3Hz,1H),6.82–6.73(m,2H),6.08(s,2H). At room temperature and under the protection of nitrogen, 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. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-5/1, volume ratio) to obtain compound 012_5. 1 H NMR (400MHz, CDCl 3 ) δ: 8.77(s, 1H), 6.95(d, J=8.3Hz, 1H), 6.82–6.73(m, 2H), 6.08(s, 2H).
步骤5：化合物012_6的合成Step 5: Synthesis of compound 012_6
室温和氮气保护下，将012_5(92.7mg)溶解于无水甲苯(3mL)中，加入012_1(67.91mg)。将反应体系降温至0℃，加入叔丁醇钾(77.31mg)并在0℃下搅拌0.5小时。反应结束后，使用3M稀盐酸调节pH到4～5，加水(10mL)稀释，乙酸乙酯(15mL×3)萃取，合并有机相，饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–5/1，体积比)，得到化合物012_6。 1H NMR(400MHz,CDCl 3)δ:8.59–8.46(m,3H),6.87–6.81(m,1H),6.79–6.75(m,2H),6.02(s,2H),4.80–4.73(m,2H),4.71–4.65(m,2H). At room temperature under nitrogen protection, 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. After the reaction, 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. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-5/1, volume ratio) to obtain compound 012_6. 1 H NMR (400MHz, CDCl 3 ) δ: 8.59–8.46(m,3H), 6.87–6.81(m,1H), 6.79–6.75(m,2H), 6.02(s,2H), 4.80–4.73(m ,2H),4.71–4.65(m,2H).
步骤6：化合物012_7的合成Step 6: Synthesis of compound 012_7
室温和氮气保护下，将4-氨磺酰基哌啶-1-羧酸叔丁酯(0.5g)和012_6(533.94mg)溶解于二甲基亚砜(10mL)中，向其中加入碳酸钾(735.23mg)和四丁基氟化铵(1M,2.36mL)反应体系在70℃搅拌5小时。反应结束，加水(10mL)稀释，加3M稀盐酸调pH到3-4，乙酸乙酯(15mL×3)萃取，合并有机相，依次加入饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂。所得粗产物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–1/4，体积比)，得到化合物012_7，粗品直接投下一步。Under room temperature and nitrogen protection, tert-butyl 4-sulfamoylpiperidine-1-carboxylate (0.5 g) and 012_6 (533.94 mg) were dissolved in dimethyl sulfoxide (10 mL), and potassium carbonate ( 735.23mg) and tetrabutylammonium fluoride (1M, 2.36mL) was stirred at 70°C for 5 hours. After the reaction, add water (10mL) to dilute, add 3M dilute hydrochloric acid to adjust the pH to 3-4, extract with ethyl acetate (15mL×3), combine the organic phases, add saturated brine (10mL×2) successively for washing, anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-1/4, volume ratio) to obtain compound 012_7, and the crude product was directly sent to the next step.
步骤7：化合物012_8的合成Step 7: Synthesis of Compound 012_8
室温和氮气保护下，将012_7(0.2g)溶解于盐酸乙酸乙酯(4M,4mL)中，反应体系在25℃下搅拌12小时。反应完毕后将反应体系减压浓缩除去溶剂得到化合物012_8，粗品直接投下一步。At room temperature and under the protection of nitrogen, 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.
步骤8：化合物012的合成Step 8: Synthesis of compound 012
在室温和氮气保护氛围下，将012_8(120mg)溶解于二氯甲烷(2mL)中。反应体系在氮气保护氛围下降温到0℃，加入氯甲酸甲酯(23.94mg)及N,N-二异丙基乙胺(75.55mg)，反应体系升温到25℃，并搅拌2小时。反应结束，加入甲醇(1mL)淬灭反应，直接减压浓缩除去溶剂。所得残余物经制备HPLC分离(流动相：乙腈/水；酸性：HCl)分离纯化得到化合物012.MS-ESI m/z:636.8,638.8[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.02(s,1H),8.71(s,2H),8.50(s,1H),6.92(d,J＝7.6Hz,1H),6.77–6.64(m,2H),6.05(s,2H),4.66(s,2H),4.62–4.55(m,2H),4.12–3.94(m,3H),3.59(s,3H),2.99–2.75(m,2H),2.04–1.93(m,2H),1.59–1.44(m,2H). 012_8 (120 mg) was dissolved in dichloromethane (2 mL) at room temperature under a nitrogen atmosphere. The reaction system was cooled down to 0°C under a nitrogen atmosphere, methyl chloroformate (23.94mg) and N,N-diisopropylethylamine (75.55mg) were added, the reaction system was heated to 25°C and stirred for 2 hours. After the reaction was completed, methanol (1 mL) was added to quench the reaction, and the solvent was directly concentrated under reduced pressure to remove the solvent. The resulting residue was separated and purified by preparative HPLC (mobile phase: acetonitrile/water; acidic: HCl) to obtain compound 012. MS-ESI m/z: 636.8,638.8[M+H] + . 1 H NMR (400MHz, DMSO_d 6 )δ: 10.02(s, 1H), 8.71(s, 2H), 8.50(s, 1H), 6.92(d, J=7.6Hz, 1H), 6.77–6.64(m, 2H), 6.05(s, 2H ),4.66(s,2H),4.62–4.55(m,2H),4.12–3.94(m,3H),3.59(s,3H),2.99–2.75(m,2H),2.04–1.93(m,2H ),1.59–1.44(m,2H).
实施例13Example 13
Figure PCTCN2022130697-appb-000077
Figure PCTCN2022130697-appb-000077
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000078
Figure PCTCN2022130697-appb-000078
步骤1：化合物013的合成Step 1: Synthesis of Compound 013
在室温和氮气保护氛围下，将化合物002_1(900mg)溶解于N,N-二甲基甲酰胺(15mL)中，将反应体系降温至0℃。向反应体系中加入氢化钠(284.64mg,含量60％)，0℃下搅拌0.5小时，加入3-甲硫基-1,2,4-三嗪(452.51mg)，升温到20℃并搅拌2小时。反应完毕后，将反应液缓慢倒入冰水(20mL)中淬灭反应，用2M稀盐酸pH调节至2～3，加乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(20mL×2)洗，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过柱层析(洗脱剂：石油醚/乙酸乙酯＝17/3–3/2，体积比)分离纯化得到粗品，粗品经制备HPLC(流动相：乙腈/水；中性：NH 4HCO 3)分离纯化，得到化合物013。MS–ESI m/z:459.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.13(d,J＝2.4Hz,1H),8.65(d,J＝2.4Hz,1H),8.00(s,1H),6.81(d,J＝1.2Hz,1H),6.76–6.72(m,1H),6.71–6.67(m,1H),6.33(s,1H),5.94(s,2H),4.63–4.51(m,4H),3.12–3.00(m,1H),0.78–0.67(m,2H),0.64–0.54(m,2H). Compound 002_1 (900 mg) was dissolved in N,N-dimethylformamide (15 mL) at room temperature under a nitrogen atmosphere, and the reaction system was cooled to 0°C. Add sodium hydride (284.64mg, content 60%) to the reaction system, stir at 0°C for 0.5 hours, add 3-methylthio-1,2,4-triazine (452.51mg), raise the temperature to 20°C and stir for 2 Hour. 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. The resulting residue was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=17/3-3/2, volume ratio) to obtain a crude product, which was subjected to preparative HPLC (mobile phase: acetonitrile/water; neutral: NH 4 HCO 3 ) separation and purification to obtain compound 013. MS-ESI m/z: 459.2[M+H] + . 1 H NMR (400MHz, DMSO_d 6 ) δ: 9.13(d, J=2.4Hz, 1H), 8.65(d, J=2.4Hz, 1H), 8.00(s,1H),6.81(d,J=1.2Hz,1H),6.76–6.72(m,1H),6.71–6.67(m,1H),6.33(s,1H),5.94(s,2H) ,4.63–4.51(m,4H),3.12–3.00(m,1H),0.78–0.67(m,2H),0.64–0.54(m,2H).
实施例14Example 14
Figure PCTCN2022130697-appb-000079
Figure PCTCN2022130697-appb-000079
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000080
Figure PCTCN2022130697-appb-000080
步骤1：化合物014_2的合成Step 1: Synthesis of Compound 014_2
在室温和氮气保护氛围下，将化合物014_1(3g)溶解于二氯甲烷(60mL)中，在25℃下加入N-甲基吗啡啉(1.94mL)。反应体系在氮气保护下降温至-30℃，滴加氯甲酸异丁酯(2.41g)并在0℃下搅拌15分钟，避光条件下向反应液中加入2-巯基吡啶氮氧化物钠盐(2.90g)，0℃下避光搅拌2小时。反应完毕后，反应体系直接减压浓缩除去溶剂得到化合物014_2，粗品直接投下一步。Compound 014_1 (3 g) was dissolved in dichloromethane (60 mL) at room temperature under a nitrogen atmosphere, and N-methylmorpholine (1.94 mL) was added at 25°C. The reaction system was cooled down to -30°C under the protection of nitrogen, and isobutyl chloroformate (2.41g) was added dropwise and stirred at 0°C for 15 minutes, and 2-mercaptopyridine nitrogen oxide sodium salt was added to the reaction solution under dark conditions (2.90 g), and stirred at 0°C for 2 hours in the dark. After the reaction was completed, the reaction system was directly concentrated under reduced pressure to remove the solvent to obtain compound 014_2, and the crude product was directly sent to the next step.
步骤2:化合物014_3的合成Step 2: Synthesis of Compound 014_3
在室温和氮气保护氛围下，将化合物014_2(4.93g)溶解于氯苯(100mL)中，20℃下加入化合物2,2-二吡啶二硫(5.83g)。在氮气保护下反应体系用金卤灯(500W)照射搅拌2小时。反应完毕后，反应液直接减压浓缩除去溶剂。所得残余物经柱层析(洗脱剂:石油醚/乙酸乙酯＝1/0–23/2，体积比)分离纯化，得到化合物014_3。 1H NMR(400MHz,CDCl 3)δ:8.53–8.39(m,1H),7.56–7.47(m,1H),7.26–7.21(m,1H),7.09–7.00(m,1H),3.70(s,3H),2.46(s,6H). Compound 014_2 (4.93g) was dissolved in chlorobenzene (100mL) at room temperature under a nitrogen atmosphere, and compound 2,2-dipyridyldisulfide (5.83g) was added at 20°C. Under nitrogen protection, the reaction system was irradiated with a metal halide lamp (500W) and stirred for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-23/2, volume ratio) to obtain compound 014_3. 1 H NMR (400MHz, CDCl 3 ) δ: 8.53–8.39(m,1H), 7.56–7.47(m,1H), 7.26–7.21(m,1H), 7.09–7.00(m,1H), 3.70(s ,3H),2.46(s,6H).
步骤3:化合物014_4的合成Step 3: Synthesis of Compound 014_4
在室温和氮气保护氛围下，将化合物014_3(1.2g)溶解于二氯甲烷(15mL)中，氮气保护下降温至0℃。向反应体系中加入间氯过氧苯甲酸(3.11g,含量85％)，升温到20℃并搅拌12小时。反应完毕后，将反应体系过滤，滤饼用二氯甲烷(10mL)淋洗，合并滤液减压浓缩除去溶剂。所得残余物经柱层析(洗脱剂:石油醚/乙酸乙酯＝19/1–7/3，体积比)分离纯化，得到化合物014_4。 1H NMR(400MHz,CDCl 3)δ:8.79(d,J＝4.8Hz,1H),8.11–8.06(m,1H),7.99(dt,J＝1.2,7.6Hz,1H),7.58(dd,J＝5.2,7.2Hz,1H),3.69(s,3H),2.45(s,6H). Compound 014_3 (1.2 g) was dissolved in dichloromethane (15 mL) at room temperature under a nitrogen atmosphere, and the temperature was lowered to 0 °C under a nitrogen atmosphere. Add m-chloroperoxybenzoic acid (3.11 g, content 85%) to the reaction system, raise the temperature to 20°C and stir for 12 hours. After the reaction was completed, the reaction system was filtered, the filter cake was rinsed with dichloromethane (10 mL), and the combined filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-7/3, volume ratio) to obtain compound 014_4. 1 H NMR (400MHz, CDCl 3 ) δ: 8.79(d, J=4.8Hz, 1H), 8.11–8.06(m, 1H), 7.99(dt, J=1.2, 7.6Hz, 1H), 7.58(dd, J＝5.2,7.2Hz,1H),3.69(s,3H),2.45(s,6H).
步骤4:化合物014_5的合成Step 4: Synthesis of Compound 014_5
在室温和氮气保护氛围下，将化合物014_4(1g)溶解于四氢呋喃(15mL)，甲醇(5mL)和水(5mL)的混合溶剂中。向反应体系中加入一水合氢氧化锂(392.48mg)并在20℃下搅拌12小时。反应完毕后，反应液直接减压浓缩除去溶剂，所得残余物加水(10mL)稀释，用1M的稀盐酸调节pH至2～3，乙酸乙酯(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物014_5，粗品直接投下一步。Compound 014_4 (1 g) was dissolved in a mixed solvent of tetrahydrofuran (15 mL), methanol (5 mL) and water (5 mL) at room temperature under a nitrogen atmosphere. Lithium hydroxide monohydrate (392.48 mg) was added to the reaction system and stirred at 20°C for 12 hours. After the reaction was complete, the reaction solution 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 obtain compound 014_5. The crude product is directly sent to the next step.
步骤5:化合物014_6的合成Step 5: Synthesis of Compound 014_6
在室温和氮气保护氛围下，将化合物014_5(840mg)溶解于二氯甲烷(10mL)中，向反应体系依次加入三乙胺(1.68g,2.31mL)和4-二甲氨基吡啶(141.81mg)。反应体系在氮气保护氛围下降温至0℃，向其中滴加溶解于二氯甲烷(5mL)的二碳酸二叔丁酯(3.05mL)。滴加完毕后反应体系在20℃下搅拌12小时。反应完毕后，反应体系直接减压浓缩除去溶剂。所得残余物经柱层析(洗脱剂:石油醚/乙酸乙酯＝19/1–7/3，体积比)分离纯化，得到化合物014_6。 1H NMR(400MHz,CDCl 3)δ:8.79(d,J＝4.8Hz,1H),8.08(d,J＝8.0Hz,1H),8.01–7.95(m,1H),7.60–7.55(m,1H),2.39(s,6H),1.43(s,9H) At room temperature and under a nitrogen atmosphere, 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. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-7/3, volume ratio) to obtain compound 014_6. 1 H NMR (400MHz, CDCl 3 ) δ: 8.79(d, J=4.8Hz, 1H), 8.08(d, J=8.0Hz, 1H), 8.01–7.95(m, 1H), 7.60–7.55(m, 1H),2.39(s,6H),1.43(s,9H)
步骤6:化合物014_7的合成Step 6: Synthesis of compound 014_7
在室温和氮气保护氛围下，将四氢呋喃(3.5mL)放入反应瓶中，氮气保护下降温至0℃，加入氢化钠(95.02mg,含量60％)。在0℃和氮气保护氛围下向反应体系中滴加乙硫醇(196.82mg)，滴加完毕后在0℃下搅拌1小时。在0℃下向反应体系滴加溶解于四氢呋喃(1.5mL)的014_6(490mg)，滴加完毕后升温到20℃搅拌12小时。反应完毕后，向反应体系中加入甲基叔丁基醚(10mL)稀释，过滤，滤饼用甲基叔丁基醚(10mL)淋洗，收集滤饼真空干燥除去溶剂，得到化合物014_7，粗品直接投下一步。At room temperature and under a nitrogen atmosphere, 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. Add 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. After the reaction was completed, add methyl tert-butyl ether (10mL) to the reaction system to dilute, filter, rinse the filter cake with methyl tert-butyl ether (10mL), collect the filter cake and vacuum dry to remove the solvent to obtain compound 014_7, crude product Go straight to the next step.
步骤7:化合物014_8的合成Step 7: Synthesis of Compound 014_8
在室温和氮气保护氛围下，将化合物014_7(400mg)溶解于水(5mL)中，依次加入羟胺-O-磺酸(222.38mg)和醋酸钾(192.98mg)，反应体系在20℃下搅拌12小时。反应完毕后，将反应体系降温至0℃，过滤，滤饼用水(5mL)淋洗，滤饼用乙酸乙酯(20mL)溶解，无水硫酸钠干燥，过滤，滤液减压浓缩。得到化合物014_8。 1H NMR(400MHz,DMSO_d 6)δ:6.93(s,2H),2.20(s,6H),1.40(s,9H). At room temperature and under a nitrogen atmosphere, compound 014_7 (400mg) was dissolved in water (5mL), and hydroxylamine-O-sulfonic acid (222.38mg) and potassium acetate (192.98mg) were added successively, and the reaction system was stirred at 20°C for 12 Hour. After the reaction was completed, the reaction system was cooled to 0°C, filtered, and the filter cake was rinsed with water (5 mL), dissolved in ethyl acetate (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 014_8 was obtained. 1 H NMR (400MHz, DMSO_d 6 ) δ: 6.93(s, 2H), 2.20(s, 6H), 1.40(s, 9H).
步骤8:化合物014_9的合成Step 8: Synthesis of compound 014_9
在室温和氮气保护氛围下，将化合物012_6(426.69mg)和化合物014_8(257mg)溶解于二甲基亚砜(7mL)中。向反应体系中依次加入碳酸钾(391.69mg)，1M的四丁基氟化铵四氢呋喃溶液(1.89mL)，反应体系升温至70℃并搅拌12小时。反应完毕后，向反应液中加水(10mL)稀释，用1M稀盐酸调节pH至3～4，乙酸乙酯(30mL×3)萃取，合并有机相，饱和食盐水(10mL×2)洗，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经柱层析(洗脱剂:石油醚/乙酸乙酯＝19/1–3/1，体积比)分离纯化，得到化合物014_9。 1H NMR(400MHz,CDCl 3)δ:8.52–8.44(m,3H),6.90–6.83(m,2H),6.75–6.66(m,2H),6.03(s,2H),4.76–4.61(m,4H),2.49(s,6H),1.45(s,9H). Compound 012_6 (426.69 mg) and Compound 014_8 (257 mg) were dissolved in dimethyl sulfoxide (7 mL) at room temperature under a nitrogen atmosphere. Potassium carbonate (391.69mg) and 1M tetrabutylammonium fluoride tetrahydrofuran solution (1.89mL) were successively added to the reaction system, and the reaction system was heated to 70°C and stirred for 12 hours. After the reaction was completed, add water (10 mL) to the reaction liquid to dilute, adjust the pH to 3-4 with 1M dilute hydrochloric acid, extract with ethyl acetate (30 mL×3), combine the organic phases, and wash with saturated brine (10 mL×2). Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-3/1, volume ratio) to obtain compound 014_9. 1 H NMR (400MHz, CDCl 3 ) δ: 8.52–8.44(m,3H), 6.90–6.83(m,2H), 6.75–6.66(m,2H), 6.03(s,2H), 4.76–4.61(m ,4H),2.49(s,6H),1.45(s,9H).
步骤9:化合物014的合成Step 9: Synthesis of Compound 014
在室温和氮气保护氛围下，将化合物014_9(60mg)溶解于4M的盐酸二氧六环溶液(1.20mL)加入中。反应体系在20℃下搅拌6小时。反应完毕后，将反应体系直接减压浓缩除去溶剂，所得残余物经制备HPLC(流动相：乙腈/水；酸性：HCl)纯化分离。得到化合物014。MS–ESI m/z:606.2,608.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:12.77(s,1H),10.06(s,1H),8.71(s,2H),8.48(s,1H),6.94–6.66(m,3H),6.03(s,2H),4.67(s,2H),4.62–4.52(m,2H),2.41–2.11(m,6H). Compound 014_9 (60 mg) dissolved in 4M dioxane hydrochloride solution (1.20 mL) was added at room temperature under a nitrogen atmosphere. The reaction system was stirred at 20°C for 6 hours. After the reaction was completed, the reaction system was directly concentrated under reduced pressure to remove the solvent, and the obtained residue was purified and separated by preparative HPLC (mobile phase: acetonitrile/water; acidic: HCl). Compound 014 was obtained. MS–ESI m/z:606.2,608.2[M+H] + . 1 H NMR (400MHz,DMSO_d 6 )δ:12.77(s,1H),10.06(s,1H),8.71(s,2H),8.48 (s,1H),6.94–6.66(m,3H),6.03(s,2H),4.67(s,2H),4.62–4.52(m,2H),2.41–2.11(m,6H).
实施例15Example 15
Figure PCTCN2022130697-appb-000081
Figure PCTCN2022130697-appb-000081
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000082
Figure PCTCN2022130697-appb-000082
步骤1：化合物015的合成Step 1: Synthesis of compound 015
在室温和氮气保护氛围下，将014(40mg)溶解于四氢呋喃(1mL)中，依次加入甲胺(2mol/L,49.47μL)四氢呋喃溶液，三乙胺(26.70mg)和正丙基磷酸苷(58.85μL,50％的乙酸乙酯溶液)。反应体系在20℃下搅拌1小时。反应完毕，反应体系直接减压浓缩除去溶剂。所得残余物经制备HPLC(流动相：乙腈/水；酸性：HCl)纯化分离，得到化合物015。MS–ESI m/z:619.1,621.1[M+H] +。 1H NMR(400MHz,DMSO_d 6)δ:10.25–9.68(m,1H),8.72(s,2H),8.44(s,1H),7.87(d,J＝4.8Hz,1H),6.89(d,J＝8.0Hz,1H),6.79–6.58(m,2H),6.03(s,2H),4.74–4.49(m,4H),2.55(d,J＝4.8Hz,3H),2.34–2.12(m,6H). At room temperature and under a nitrogen atmosphere, 014 (40mg) was dissolved in tetrahydrofuran (1mL), methylamine (2mol/L, 49.47μL) tetrahydrofuran solution, triethylamine (26.70mg) and n-propyl phosphate (58.85 μL, 50% ethyl acetate solution). The reaction system was stirred at 20°C for 1 hour. After the reaction was completed, the reaction system was directly concentrated under reduced pressure to remove the solvent. The resulting residue was purified and separated by preparative HPLC (mobile phase: acetonitrile/water; acidic: HCl) to obtain compound 015. MS-ESI m/z: 619.1, 621.1 [M+H] + . 1 H NMR (400MHz, DMSO_d 6 )δ: 10.25–9.68(m, 1H), 8.72(s, 2H), 8.44(s, 1H), 7.87(d, J=4.8Hz, 1H), 6.89(d, J＝8.0Hz, 1H), 6.79–6.58(m, 2H), 6.03(s, 2H), 4.74–4.49(m, 4H), 2.55(d, J＝4.8Hz, 3H), 2.34–2.12(m ,6H).
实施例16Example 16
Figure PCTCN2022130697-appb-000083
Figure PCTCN2022130697-appb-000083
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000084
Figure PCTCN2022130697-appb-000084
步骤1：化合物016的合成Step 1: Synthesis of compound 016
在室温和氮气保护氛围下，将014(100mg)溶解于四氢呋喃(1mL)中，向反应体系中加入三乙胺(25.03mg)。在氮气保护氛围下将反应体系降温到-15℃，滴加氯甲酸异丁酯(23.82μL)，反应体系升温到0℃搅拌1小时。向反应体系加入氨水(1.26mL,含量25％)，反应体系在20℃下搅拌1小时。反应完毕后，将反应体系直接减压浓缩除去溶剂，所得残余物经制备HPLC(流动相：乙腈/水；酸性：HCl)纯化分离。得到化合物016。MS–ESI m/z:605.2,607.2[M+H] +。 1H NMR(400MHz,DMSO_d 6)δ:10.12–9.78(m,1H),8.72(s,2H),8.46(s,1H),7.40(s,1H),7.11(s,1H),6.89(d,J＝8.4Hz,1H),6.81–6.64(m,2H),6.03(s,2H),4.72–4.54(m,4H),2.36–2.10(m,6H). 014 (100 mg) was dissolved in tetrahydrofuran (1 mL) at room temperature under a nitrogen atmosphere, and triethylamine (25.03 mg) was added to the reaction system. The temperature of the reaction system was lowered to -15°C under nitrogen protection atmosphere, isobutyl chloroformate (23.82 μL) was added dropwise, and the temperature of the reaction system was raised to 0°C and stirred for 1 hour. Aqueous ammonia (1.26 mL, content 25%) was added to the reaction system, and the reaction system was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction system was directly concentrated under reduced pressure to remove the solvent, and the obtained residue was purified and separated by preparative HPLC (mobile phase: acetonitrile/water; acidic: HCl). Compound 016 was obtained. MS-ESI m/z: 605.2, 607.2 [M+H] + . 1 H NMR (400MHz,DMSO_d 6 )δ:10.12–9.78(m,1H),8.72(s,2H),8.46(s,1H),7.40(s,1H),7.11(s,1H),6.89( d,J＝8.4Hz,1H),6.81–6.64(m,2H),6.03(s,2H),4.72–4.54(m,4H),2.36–2.10(m,6H).
实施例17Example 17
Figure PCTCN2022130697-appb-000085
Figure PCTCN2022130697-appb-000085
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000086
Figure PCTCN2022130697-appb-000086
步骤1：化合物017的合成Step 1: Synthesis of compound 017
在室温和氮气保护氛围下，将014(200mg)溶解于二氯甲烷(4mL)中，加入三苯基膦(108.13mg)和2-巯基吡啶氮氧化物(99.86mg)，反应体系在20℃避光条件下搅拌1小时。反应完毕后，反应体系在避光条件下减压浓缩除去溶剂。所得粗产物溶解于氯仿(4mL)中，在氮气保护氛围下置于金卤灯(500W)下照射2小时。反应完毕后，反应体系直接减压浓缩除去溶剂，所得残余物经柱层析(洗脱剂:石油醚/乙酸乙酯＝19/1–7/3,体积比)分离纯化得到粗品。粗品经制备HPLC(流动相:乙腈/水；酸性：HCl)分离纯化，得到化合物017。MS–ESI m/z:562.2,564.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.24–9.38(m,1H),8.71(s,2H),8.44(s,1H),6.89(d,J＝8.0Hz,1H),6.77–6.64(m,2H),6.03(s,2H),4.69–4.55(m,4H),2.65(s,1H),2.20–2.03(m,6H). At room temperature and under a nitrogen atmosphere, 014 (200mg) was dissolved in dichloromethane (4mL), triphenylphosphine (108.13mg) and 2-mercaptopyridine nitrogen oxide (99.86mg) were added, and the reaction system was heated at 20°C Stir for 1 hour in the dark. After the reaction was completed, the reaction system was concentrated under reduced pressure to remove the solvent under light-shielding conditions. The obtained crude product was dissolved in chloroform (4 mL), and irradiated under a metal halide lamp (500 W) under a nitrogen atmosphere for 2 hours. After the reaction was completed, the reaction system was directly concentrated under reduced pressure to remove the solvent, and the obtained residue was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-7/3, volume ratio) to obtain a crude product. The crude product was separated and purified by preparative HPLC (mobile phase: acetonitrile/water; acidic: HCl) to obtain compound 017. MS–ESI m/z:562.2,564.2[M+H] + . 1 H NMR (400MHz,DMSO_d 6 )δ:10.24–9.38(m,1H),8.71(s,2H),8.44(s,1H) ,6.89(d,J＝8.0Hz,1H),6.77–6.64(m,2H),6.03(s,2H),4.69–4.55(m,4H),2.65(s,1H),2.20–2.03(m ,6H).
实施例18Example 18
Figure PCTCN2022130697-appb-000087
Figure PCTCN2022130697-appb-000087
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000088
Figure PCTCN2022130697-appb-000088
步骤1:化合物018_2的合成Step 1: Synthesis of compound 018_2
在室温和氮气保护氛围下，将化合物018_1(1g)溶解于二氯甲烷(15mL)中，将反应体系降温到0℃。 向反应体系中分批加入氰基硼氢化钠(1.87g)，加料完毕后滴加两滴醋酸，反应体系在20℃下搅拌12小时。反应完毕后，向反应体系倒入饱和氯化铵水溶液(50mL)淬灭反应，分液收集有机相，水相用二氯甲烷(20mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物通过柱层析(洗脱剂：石油醚/乙酸乙酯＝1/0–3/2，体积比)分离纯化，得到化合物018_2。 1H NMR(400MHz,CDCl 3)δ:4.23–4.11(m,1H),3.67(s,3H),3.10–2.96(m,1H),2.54–2.44(m,1H),2.41–2.26(m,3H),2.25–2.13(m,2H),1.99–1.84(m,2H),1.72(s,1H). Compound 018_1 (1 g) was dissolved in dichloromethane (15 mL) at room temperature under a nitrogen atmosphere, and the reaction system was cooled to 0 °C. Sodium cyanoborohydride (1.87 g) was added in batches to the reaction system, and after the addition was completed, two drops of acetic acid were added dropwise, and the reaction system was stirred at 20° C. for 12 hours. After completion of the reaction, pour saturated ammonium chloride aqueous solution (50mL) into the reaction system to quench the reaction, collect the organic phase by liquid separation, extract the aqueous phase with dichloromethane (20mL × 3), combine the organic phases, and wash with saturated brine (30mL ), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-3/2, volume ratio) to obtain compound 018_2. 1 H NMR (400MHz, CDCl 3 ) δ: 4.23–4.11(m,1H), 3.67(s,3H), 3.10–2.96(m,1H), 2.54–2.44(m,1H), 2.41–2.26(m ,3H),2.25–2.13(m,2H),1.99–1.84(m,2H),1.72(s,1H).
步骤2:化合物018_3的合成Step 2: Synthesis of compound 018_3
在室温和氮气保护氛围下，将化合物018_2(927mg)溶解于二氯甲烷(15mL)中，在25℃下依次加入1,8-双(二甲氨基)萘(4.79g)和三甲基氧鎓四氟硼酸盐(2.50g)。反应体系在25℃下搅拌2小时。反应完毕后，将反应体系过滤，用二氯甲烷(10mL)淋洗滤饼，合并滤液。滤液用1M的稀盐酸调节pH到2～3，分液，收集有机相，水相用二氯甲烷(30mL)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液直接减压浓缩除去溶剂。所得残余物经柱层析(洗脱剂：石油醚/乙酸乙酯＝19/1–17/3，体积比)分离纯化，得到化合物018_3。 1H NMR(400MHz,CDCl 3)δ:3.80–3.70(m,1H),3.66(s,3H),3.20(s,3H),3.08–2.99(m,1H),2.45–2.35(m,1H),2.34–2.11(m,5H),1.99–1.83(m,2H). Compound 018_2 (927 mg) was dissolved in dichloromethane (15 mL) at room temperature under a nitrogen atmosphere, and 1,8-bis(dimethylamino)naphthalene (4.79 g) and trimethyloxy Onium tetrafluoroborate (2.50 g). The reaction system was stirred at 25°C for 2 hours. After the reaction was completed, the reaction system was filtered, the filter cake was rinsed with dichloromethane (10 mL), and the filtrates were combined. Adjust the pH of the filtrate to 2-3 with 1M dilute hydrochloric acid, separate the liquids, collect the organic phase, extract the aqueous phase with dichloromethane (30 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, and directly concentrate the filtrate under reduced pressure to remove the solvent . The resulting residue was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-17/3, volume ratio) to obtain compound 018_3. 1 H NMR (400MHz, CDCl 3 ) δ: 3.80–3.70(m,1H), 3.66(s,3H), 3.20(s,3H), 3.08–2.99(m,1H), 2.45–2.35(m,1H ),2.34–2.11(m,5H),1.99–1.83(m,2H).
步骤3:化合物018_4的合成Step 3: Synthesis of compound 018_4
在室温和氮气保护氛围下，将化合物018_3(880mg)溶解于四氢呋喃(10mL)，甲醇(3mL)和水(3mL)的混合溶剂中。向反应体系中加入一水合氢氧化锂(501.11mg)，在20℃下搅拌12小时。反应完毕后，将反应体系直接减压浓缩除去溶剂，所得残余物加水(10mL)稀释，用1M稀盐酸调节pH至2～3，乙酸乙酯(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂，得到化合物018_4，粗品直接投下一步。Compound 018_3 (880 mg) was dissolved in a mixed solvent of tetrahydrofuran (10 mL), methanol (3 mL) and water (3 mL) at room temperature under a nitrogen atmosphere. Lithium hydroxide monohydrate (501.11 mg) was added to the reaction system, followed by stirring at 20°C for 12 hours. After the reaction was completed, 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.
步骤4:化合物018_5的合成Step 4: Synthesis of compound 018_5
在室温和氮气保护氛围下，将化合物018_4(380mg)溶解于二氯甲烷(6mL)中，加入N-甲基吗啡啉(245.46μL)。反应体系在氮气保护下降温至-15℃，滴加氯甲酸异丁酯(293.19μL)，滴加完毕后反应体系在0℃下搅拌半小时。在避光保护条件下向反应体系中加入巯基吡啶氮氧化物钠盐(365.97mg)并在0℃下避光搅拌2小时。反应完毕后，反应体系直接减压浓缩除去溶剂，得到化合物018_5，粗品直接投下一步。At room temperature under a nitrogen atmosphere, compound 018_4 (380 mg) was dissolved in dichloromethane (6 mL), and N-methylmorpholine (245.46 μL) was added. The reaction system was cooled down to -15°C under the protection of nitrogen, and isobutyl chloroformate (293.19 μL) was added dropwise. After the dropwise addition, the reaction system was stirred at 0°C for half an hour. Pyridine nitroxide sodium salt (365.97 mg) was added to the reaction system under the condition of protecting from light and stirred at 0° C. for 2 hours in the dark. After the reaction was completed, the reaction system was directly concentrated under reduced pressure to remove the solvent to obtain compound 018_5, and the crude product was directly sent to the next step.
步骤5:化合物018_6的合成Step 5: Synthesis of compound 018_6
在室温和氮气保护氛围下，将化合物018_5(623mg)溶解于氯苯(15mL)中，加入2,2-二吡啶二硫(737.00mg)，在氮气保护氛围下置于金卤灯下(500W)照射2小时。反应液体系直接浓缩除去溶剂，所得粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝1/0–47/3，体积比)分离纯化，得到化合物物018_6。 1H NMR(400MHz,CDCl 3)δ:8.47–8.35(m,1H),7.49–7.45(m,1H),7.07(d,J＝8.0Hz,1H),6.98–6.95(m,1H),4.24–4.16(m,1H),3.82–3.75(m,1H),3.21(s,3H),2.66–2.53(m,2H),2.52–2.46(m,1H),2.38–2.30(m,1H),2.19–2.11(m,2H),2.04–1.94(m,2H). At room temperature and under a nitrogen atmosphere, 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 liquid system was directly concentrated to remove the solvent, and the resulting crude product was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=1/0–47/3, volume ratio) to obtain compound 018_6. 1 H NMR (400MHz, CDCl 3 ) δ: 8.47–8.35 (m, 1H), 7.49–7.45 (m, 1H), 7.07 (d, J=8.0Hz, 1H), 6.98–6.95 (m, 1H), 4.24–4.16(m,1H),3.82–3.75(m,1H),3.21(s,3H),2.66–2.53(m,2H),2.52–2.46(m,1H),2.38–2.30(m,1H ),2.19–2.11(m,2H),2.04–1.94(m,2H).
步骤6:化合物018_7的合成Step 6: Synthesis of Compound 018_7
在室温和氮气保护氛围下，将化合物018_6(205mg)溶解于二氯甲烷(5mL)中，氮气保护下降温至0℃。向反应体系中分批加入间氯过氧苯甲酸(530.53mg,含量85％)，室温下搅拌2小时。反应完毕后，向反应体系中加入二氯甲烷(10mL)稀释，加入饱和亚硫酸氢钠饱和水溶液(10mL)，搅拌10min淬灭反应。分液，收集有机相，有机相依次用1M的氢氧化钠水溶液(10mL)洗涤，饱和食盐水(5mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝1/0–9/1，体积比)分离纯化，得到化合物018_7。 1H NMR(400MHz,CDCl 3)δ:8.77–8.66(m,1H),8.07(d,J＝8.0Hz,1H),7.98–7.91(m,1H),7.60–7.47(m,1H),4.30–4.18(m,1H),3.83–3.71(m,1H),3.20(s,3H),2.72–2.57(m,2H),2.47–2.34(m,2H),2.33–2.15(m,2H),2.03–1.90(m,2H). Compound 018_6 (205 mg) was dissolved in dichloromethane (5 mL) at room temperature under a nitrogen atmosphere, and the temperature was lowered to 0 °C under nitrogen protection. m-Chloroperoxybenzoic acid (530.53 mg, content 85%) was added in batches to the reaction system, and stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane (10 mL) was added to the reaction system for dilution, and a saturated aqueous solution of sodium bisulfite (10 mL) was added, and the reaction was quenched by stirring for 10 min. The liquid was separated and the organic phase was collected. The organic phase was washed successively with 1M aqueous sodium hydroxide solution (10 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=1/0-9/1, volume ratio) to obtain compound 018_7. 1 H NMR (400MHz, CDCl 3 ) δ: 8.77–8.66 (m, 1H), 8.07 (d, J=8.0Hz, 1H), 7.98–7.91 (m, 1H), 7.60–7.47 (m, 1H), 4.30–4.18(m,1H),3.83–3.71(m,1H),3.20(s,3H),2.72–2.57(m,2H),2.47–2.34(m,2H),2.33–2.15(m,2H ),2.03–1.90(m,2H).
步骤7:化合物018_8的合成Step 7: Synthesis of Compound 018_8
在室温和氮气保护氛围下，将四氢呋喃(3mL)放于反应瓶中，氮气保护下降温至0℃，加入氢化钠(36.35mg,含量60％)。在0℃下向反应体系中滴加乙硫醇(89.64μL)，滴加完毕后在0℃搅拌1小时。向反应体系中加入溶解于(1mL)四氢呋喃的化合物018_7(162mg)，室温下搅拌12小时。反应完毕后，相反应体 系中加入甲基叔丁基醚(2mL)稀释，过滤，滤饼用甲基叔丁基醚(2mL)淋洗，收集滤饼真空干燥除去溶剂，得到化合物018_8，粗品直接投下一步。At room temperature and under a nitrogen atmosphere, tetrahydrofuran (3 mL) was placed in a reaction flask, the temperature was lowered to 0° C. under nitrogen protection, and sodium hydride (36.35 mg, content 60%) was added. Add ethanethiol (89.64 μL) dropwise to the reaction system at 0°C, and stir at 0°C for 1 hour after the dropwise addition. Compound 018_7 (162 mg) dissolved in tetrahydrofuran (1 mL) was added to the reaction system, and stirred at room temperature for 12 hours. After the reaction was completed, methyl tert-butyl ether (2 mL) was added to the phase reaction system for dilution, filtered, the filter cake was rinsed with methyl tert-butyl ether (2 mL), the filter cake was collected and vacuum-dried to remove the solvent to obtain compound 018_8, crude product Go straight to the next step.
步骤8:化合物018_9的合成Step 8: Synthesis of Compound 018_9
在室温和氮气保护氛围下，将化合物018_8(70mg)溶解于水(2mL)中，加入醋酸钾(40.46mg)和羟胺磺酸(46.62mg)，反应体系在室温下搅拌12小时。反应完毕后，反应体系直接减压浓缩除去溶剂。所得粗产物粗品经经柱层析(洗脱剂：二氯甲烷/甲醇＝1/0–9/1，体积比)分离纯化得到化合物018_9。 1H NMR(400MHz,DMSO_d 6)δ:6.69(s,2H),3.79–3.53(m,1H),3.08(s,3H),2.97–2.93(m,1H),2.38–2.16(m,6H),1.88–1.73(m,2H). Compound 018_8 (70mg) was dissolved in water (2mL) at room temperature and under a nitrogen atmosphere, potassium acetate (40.46mg) and azaminosulfonic acid (46.62mg) were added, and the reaction system was stirred at room temperature for 12 hours. After the reaction was completed, the reaction system was directly concentrated under reduced pressure to remove the solvent. The obtained crude product was separated and purified by column chromatography (eluent: dichloromethane/methanol=1/0-9/1, volume ratio) to obtain compound 018_9. 1 H NMR (400MHz,DMSO_d 6 )δ:6.69(s,2H),3.79–3.53(m,1H),3.08(s,3H),2.97–2.93(m,1H),2.38–2.16(m,6H ),1.88–1.73(m,2H).
步骤9:化合物018的合成Step 9: Synthesis of Compound 018
在室温和氮气保护氛围下，将化合物012_6(60.01mg)和化合物018_9(30mg)溶解于二甲基亚砜(1.5mL)中。向反应体系中依次加入1M的四丁基氟化铵的四氢呋喃溶液(265.72μL)，碳酸钾(55.09mg)，在氮气保护氛围下升温至70℃搅拌5小时。反应完毕后，将反应体系降至室温，用1M稀盐酸调节pH至3～4，用乙酸乙酯(30mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得粗品经制备HPLC(流动相:乙腈/水；酸性：HCl)分离纯化，得到化合物018。MS–ESI m/z:619.8,621.9[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.81(s,1H),8.70(s,2H),8.47(s,1H),6.90(d,J＝8.0Hz,1H),6.72–6.62(m,2H),6.03(s,2H),4.69–4.55(m,4H),4.54–4.39(m,1H),3.73–3.62(m,1H),3.06(s,3H),2.42–2.16(m,6H),1.88–1.73(m,2H). Compound 012_6 (60.01 mg) and Compound 018_9 (30 mg) were dissolved in dimethyl sulfoxide (1.5 mL) at room temperature under a nitrogen atmosphere. 1M tetrabutylammonium fluoride solution in tetrahydrofuran (265.72 μL) and potassium carbonate (55.09 mg) were sequentially added to the reaction system, and the temperature was raised to 70° C. and stirred for 5 hours under a nitrogen atmosphere. After the reaction was completed, the reaction system was lowered to room temperature, adjusted to pH 3-4 with 1M dilute hydrochloric acid, extracted with ethyl acetate (30mL×3), combined the organic phases, washed with saturated brine (30mL), anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure to remove the solvent. The obtained crude product was separated and purified by preparative HPLC (mobile phase: acetonitrile/water; acidic: HCl) to obtain compound 018. MS–ESI m/z:619.8,621.9[M+H] + . 1 H NMR (400MHz,DMSO_d 6 )δ:9.81(s,1H),8.70(s,2H),8.47(s,1H),6.90 (d,J＝8.0Hz,1H),6.72–6.62(m,2H),6.03(s,2H),4.69–4.55(m,4H),4.54–4.39(m,1H),3.73–3.62(m ,1H),3.06(s,3H),2.42–2.16(m,6H),1.88–1.73(m,2H).
实施例19Example 19
Figure PCTCN2022130697-appb-000089
Figure PCTCN2022130697-appb-000089
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000090
Figure PCTCN2022130697-appb-000090
步骤1：化合物019_2的合成Step 1: Synthesis of Compound 019_2
室温和氮气的保护下，将甲醇钠(10.22g)溶于乙醇(120mL)中，加入019_1(4.07g)，反应体系在25℃下搅拌20分钟。向反应体系中加入溶解于乙醇(60mL)的012_3(5.3g)，并在25℃下搅拌2小时。反应完毕后，将反应体系直接减压浓缩除去溶剂，所得残余物加水(100mL)稀释后，用3M的稀盐酸调节pH到6～7，搅拌10分钟，过滤，收集滤饼，真空干燥除去溶剂，得到化合物019_2，粗品直接投下一步。At room temperature and under the protection of nitrogen, sodium methoxide (10.22g) was dissolved in ethanol (120mL), 019_1 (4.07g) was added, and the reaction system was stirred at 25°C for 20 minutes. 012_3 (5.3 g) dissolved in ethanol (60 mL) was added to the reaction system, and stirred at 25° C. for 2 hours. After the reaction was completed, 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.
步骤2：化合物019_3的合成Step 2: Synthesis of Compound 019_3
室温和氮气的保护下，将019_2(2g)溶解于三氯氧磷(16.50g)中，反应体系升温至90℃并搅拌6小时。反应完毕后，将反应体系直接减压浓缩，所得残余物加入二氯甲烷(20mL)稀释，用饱和碳酸氢钠水溶液调节pH至8～9，分液，收集有机相，水相用二氯甲烷(20mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经柱层析(洗脱剂：石油醚/乙酸乙酯＝19/1–7/3，体积比)分离纯化，得到019_3。 1H NMR(400MHz,CDCl 3)δ:6.91–6.86(m,1H),6.75–6.69(m,2H),6.03(s,2H),3.89–3.82(m,4H),3.81–3.72(m,4H). At room temperature and under the protection of nitrogen, 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. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-7/3, volume ratio) to obtain 019_3. 1 H NMR (400MHz, CDCl 3 ) δ: 6.91–6.86(m,1H),6.75–6.69(m,2H),6.03(s,2H),3.89–3.82(m,4H),3.81–3.72(m ,4H).
步骤3：化合物019_4的合成Step 3: Synthesis of Compound 019_4
室温和氮气保护下，将019_3(800mg)和012_1(593.68mg)溶解于四氢呋喃(14mL)中。将反应体系在氮气保护氛围下降温至0℃，分批加入氢化钠(108.41mg,含量：60％)，升温到20℃并搅拌12小时。反应完毕后，将反应体系倒入水(20mL)中淬灭反应，用2M稀盐酸调节pH至3～4，用乙酸乙酯(10mL×3)萃取，合并有机相，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经柱层析(洗脱剂：石油醚/乙酸乙酯＝19/1–3/1,体积比)分离纯化，得到化合物019_4。 1H NMR(400MHz,CDCl 3)δ:8.50(s,2H),6.81–6.76(m,1H),6.74–6.68(m,2H),5.98(s,2H),4.70–4.59(m,4H),3.77(d,J＝4.0Hz,8H). At room temperature under nitrogen protection, 019_3 (800 mg) and 012_1 (593.68 mg) were dissolved in 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%) was added in batches, the temperature was raised to 20°C and stirred for 12 hours. After the reaction is complete, pour the reaction system into water (20mL) to quench the reaction, adjust the pH to 3-4 with 2M dilute hydrochloric acid, extract with ethyl acetate (10mL×3), combine the organic phases, and saturated brine (10mL) Washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-3/1, volume ratio) to obtain compound 019_4. 1 H NMR (400MHz, CDCl 3 ) δ: 8.50(s,2H),6.81–6.76(m,1H),6.74–6.68(m,2H),5.98(s,2H),4.70–4.59(m,4H ),3.77(d,J＝4.0Hz,8H).
步骤4：化合物019的合成Step 4: Synthesis of compound 019
在室温和氮气保护氛围下，将019_4(560mg)溶解于二甲基亚砜(7mL)中，向反应体系中依次加入环丙烷磺酰胺(139.04mg)，碳酸钾(432.58mg)和四丁基氟化铵(1M的四氢呋喃溶液,2.09mL)，升温至100℃搅拌12小时。反应完毕后，向反应体系中加水(20mL)稀释，用1M稀盐酸调节pH到3～4，用乙酸乙酯(20mL×2)萃取，合并有机相，用饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经柱层析分离(洗脱剂:石油醚/乙酸乙酯＝19/1–7/3，体积比)纯化得到粗品，再经制备HPLC分离(流动相：乙腈/水；酸性：HCl)分离纯化得到化合物019。MS–ESI m/z:621.2,623.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.41(s,1H),8.73(s,2H),6.86(d,J＝8.0Hz,1H),6.70–6.53(m,2H),6.01(s,2H),4.71–4.51(m,4H),3.65(s,8H),3.24–3.10(m,1H),1.10–0.88(m,4H). At room temperature and under a nitrogen atmosphere, 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). Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-7/3, volume ratio) and purified to obtain a crude product, which was then separated by preparative HPLC (mobile phase: acetonitrile/water; acidic: HCl) separation and purification to obtain compound 019. MS–ESI m/z: 621.2, 623.2[M+H] + . 1 H NMR (400MHz, DMSO_d 6 ) δ: 9.41(s, 1H), 8.73(s, 2H), 6.86(d, J=8.0Hz ,1H),6.70–6.53(m,2H),6.01(s,2H),4.71–4.51(m,4H),3.65(s,8H),3.24–3.10(m,1H),1.10–0.88(m ,4H).
实施例20Example 20
Figure PCTCN2022130697-appb-000091
Figure PCTCN2022130697-appb-000091
合成路线：synthetic route:
Figure PCTCN2022130697-appb-000092
Figure PCTCN2022130697-appb-000092
步骤1：化合物020_1的合成Step 1: Synthesis of Compound 020_1
室温和氮气的保护下，将甲醇钠(11.57g)溶于乙醇(50mL)中，加入盐酸乙脒(2.63g)并在25℃下搅拌20分钟。向反应体系中加入012_3(6g)的乙醇(24mL)溶液，25℃搅拌3小时。反应结束后，反应体系直接减压浓缩除去溶剂，所得残余物加水(50mL)稀释，过滤，滤液用3M的稀盐酸调节pH到2～3，搅拌10分钟，过滤，收集滤饼，滤饼真空干燥除去溶剂，得到化合物020_1. 1H NMR(400MHz,DMSO_d 6)δ:12.76–11.60(m,2H),7.18–7.02(m,2H),6.89–6.76(m,2H),5.95(s,1H),2.27(s,3H). At room temperature under the protection of nitrogen, sodium methoxide (11.57 g) was dissolved in ethanol (50 mL), acetamidine hydrochloride (2.63 g) was added and stirred at 25° C. for 20 minutes. A solution of 012_3 (6 g) in ethanol (24 mL) was added to the reaction system, and stirred at 25° C. for 3 hours. After the reaction, the reaction system was directly concentrated under reduced pressure to remove the solvent, and the resulting residue was diluted with water (50 mL), filtered, and the filtrate was adjusted to pH 2 to 3 with 3M dilute hydrochloric acid, stirred for 10 minutes, filtered, and the filter cake was collected in a vacuum. The solvent was removed by drying to obtain compound 020_1.1 H NMR (400MHz, DMSO_d 6 ) δ: 12.76–11.60 (m, 2H), 7.18–7.02 (m, 2H), 6.89–6.76 (m, 2H), 5.95 (s, 1H), 2.27(s, 3H).
步骤2：化合物020_2的合成Step 2: Synthesis of Compound 020_2
室温和氮气的保护下，将020_1(2.8g)溶解于三氯氧磷(24.75g)中，反应体系升温至90℃搅拌2小时。反应完毕后，反应体系直接减压浓缩，所得残余物加入二氯甲烷(50mL)溶解，用加饱和碳酸氢钠水溶液调节pH至8～9，分液，收集有机相，水相用二氯甲烷(20mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经柱层析(洗脱剂：石油醚/乙酸乙酯＝19/1–9/1，体积比)分离纯化，得到化合物020_2。MS–ESI m/z:282.9，284.8。Under the protection of room temperature and nitrogen, 020_1 (2.8g) was dissolved in phosphorus oxychloride (24.75g), and the reaction system was heated to 90°C and stirred for 2 hours. After the reaction was completed, the reaction system was directly concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (50 mL), adjusted to pH 8-9 with saturated aqueous sodium bicarbonate solution, separated, and the organic phase was collected. (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. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-9/1, volume ratio) to obtain compound 020_2. MS–ESI m/z: 282.9, 284.8.
步骤3：化合物020_3的合成Step 3: Synthesis of Compound 020_3
室温和氮气保护下，将020_2(1.4g)和012_1(974.83mg)溶解于甲苯(25mL)中，氮气保护下降温至0℃。向反应体系中分批加入叔丁醇钾(1.11g)，0℃下搅拌1小时。反应完毕后，将反应体系倒入水(10mL)中淬灭反应，用2M稀盐酸将pH值调节至3～4，用乙酸乙酯(20mL×3)萃取，合并有机相，饱和食盐水(30mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经柱层析(洗脱剂：石油醚/乙酸乙酯＝19/1–13/7，体积比)分离纯化。得到020_3。 1H NMR(400MHz,CDCl 3)δ:8.50(s,2H),6.86–6.79(m,1H),6.78–6.70(m,2H),6.00(s,2H),4.80–4.71(m,2H),4.69–4.60(m,2H),2.59(s,3H). At room temperature and under the protection of nitrogen, 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. After the reaction was completed, 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. The resulting residue was separated and purified by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-13/7, volume ratio). Get 020_3. 1 H NMR (400MHz, CDCl 3 ) δ: 8.50(s,2H),6.86–6.79(m,1H),6.78–6.70(m,2H),6.00(s,2H),4.80–4.71(m,2H ),4.69–4.60(m,2H),2.59(s,3H).
步骤4：化合物020的合成Step 4: Synthesis of Compound 020
在室温和氮气保护氛围下，将020_3(1.5g)和环丙烷磺酰胺(429.28mg)溶解于二甲基亚砜(20mL)中。向反应体系中加入四丁基氟化铵(1M的四氢呋喃,6.44mL)和碳酸钾(1.34g)，氮气置换三次，氮气保护下升温至70℃搅拌12小时。反应完毕后，将反应体系倒入水(10mL)中淬灭反应，用3M稀盐酸调节pH到3～4，用乙酸乙酯(20mL×2)萃取，合并有机相合，饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过柱层析(洗脱剂：石油醚/乙酸乙酯＝19/1–3/2，体积比)分离得到粗产物，再经制备HPLC分离(流动相：乙腈/水；酸性：HCl)分离纯化，得到化合物020。MS–ESI m/z:549.8,551.8[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.73(s,1H),8.72(s,2H),6.90(d,J＝8.0Hz,1H),6.76–6.50(m,2H),6.03(s,2H),4.75–4.48(m,4H),3.31–3.23(m,1H),2.44(s,3H),1.13–0.90(m,4H). 020_3 (1.5 g) and cyclopropanesulfonamide (429.28 mg) were dissolved in dimethyl sulfoxide (20 mL) at room temperature under a nitrogen atmosphere. Tetrabutylammonium fluoride (1M tetrahydrofuran, 6.44mL) and potassium carbonate (1.34g) were added to the reaction system, replaced with nitrogen three times, heated to 70°C under nitrogen protection and stirred for 12 hours. After the reaction is complete, pour the reaction system into water (10mL) to quench the reaction, adjust the pH to 3-4 with 3M dilute hydrochloric acid, extract with ethyl acetate (20mL×2), combine organic phases, and saturated saline (50mL) Washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate=19/1-3/2, volume ratio) to obtain a crude product, which was then separated by preparative HPLC (mobile phase: acetonitrile/water; acidic: HCl) separation and purification to obtain compound 020. MS–ESI m/z: 549.8, 551.8[M+H] + . 1 H NMR (400MHz, DMSO_d 6 ) δ: 9.73(s, 1H), 8.72(s, 2H), 6.90(d, J=8.0Hz ,1H),6.76–6.50(m,2H),6.03(s,2H),4.75–4.48(m,4H),3.31–3.23(m,1H),2.44(s,3H),1.13–0.90(m ,4H).
生物测试：Biological test:
实验例1：人体ETA受体拮抗效应的体外测试Experimental example 1: In vitro test of human ETA receptor antagonistic effect
实验目的：Purpose:
通过使用荧光检测方法测定化合物对人ET A受体激动剂诱导的胞质Ca 2+离子信号变化的作用来评估化合物在SK–N–MC细胞中内源表达的人ET A受体上的拮抗剂活性。ET A受体拮抗效应的功能活性在Eurofins-Cerep SA根据现行的标准操作程序进行测试。 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.
实验方案：Experimental program:
1.将细胞(human endogenous(SK-N-MC cells))悬浮于用1％FCSd补充的Dulbecco's改良的Eagle培养基溶液(DMEM,Invitrogen)中，然后以5×10 4个细胞/孔的密度分布在384板中(100μL/孔)； 1. Suspend the cells (human endogenous (SK-N-MC cells)) in Dulbecco's modified Eagle medium solution (DMEM, Invitrogen) supplemented with 1% FCSd, and then at a density of 5×10 4 cells/well Distributed in 384 plates (100μL/well);
2.将在20mM 4-(2-羟乙基)哌嗪-1-乙磺酸(Hepes,Invitrogen)(pH7.4)补充的Hank's平衡盐溶液(HBSS,Invitrogen)中羧苯磺胺与荧光探针(Fluo4NW,Invitrogen)混合，再加入到每个孔中，然后在37℃下与细胞平衡60分钟，再在22℃下与细胞平衡15分钟；2. In the Hank's balanced salt solution (HBSS, Invitrogen) supplemented in 20mM 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (Hepes, Invitrogen) (pH7.4), carbenzylsulfonamide and fluorescent probe Needles (Fluo4NW, Invitrogen) were mixed and then added to each well, then equilibrated with the cells at 37°C for 60 minutes, and then equilibrated with the cells at 22°C for 15 minutes;
3.将测定板置于微板读数器(CellLux，PerkinElmer)中，加入测试化合物与阳性对照的适当浓度的DMSO溶液或HBSS缓冲液，5分钟后再加入1nM内皮素–1或HBSS缓冲液(基底对照)，然后测量与游离细胞溶质的Ca 2+离子浓度成比例的荧光强度变化值； 3. Place the assay plate in a microplate reader (CellLux, PerkinElmer), add the DMSO solution or HBSS buffer solution of the appropriate concentration of the test compound and the positive control, and then add 1nM endothelin-1 or HBSS buffer solution ( base control), and then measure the fluorescence intensity change value proportional to the Ca 2+ ion concentration of the free cytosol;
4.结果是对1nM内皮素–1的对照响应的百分比抑制；4. Results are percent inhibition of control response to 1 nM endothelin-1;
5.标准阳性对照是BQ–123(CAS登录号：136553-81-6)，在每个实验中测试几个浓度，使用Prism分析数据，产生一个浓度–响应的曲线，计算化合物的IC 50值。 5. 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 .
实验例2：人体ETB受体拮抗效应的体外测试Experimental example 2: In vitro test of human ETB receptor antagonistic effect
实验目的：Purpose:
通过使用荧光检测方法测定化合物对人ET B受体激动剂诱导的胞质Ca 2+离子信号变化的作用来评估化合物在转染的CHO细胞中表达人的ET B受体上的拮抗剂活性。ET B受体拮抗效应的功能活性在Eurofins-Cerep SA根据现行的标准操作程序进行测试。 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.
实验方案：Experimental program:
1.将细胞(human recombinant(CHO cells))悬浮在DMEM缓冲液(Invitrogen)中，然后以3×10 4细胞/孔的密度分布在384板中(100μL/孔)； 1. Suspend the cells (human recombinant (CHO cells)) in DMEM buffer (Invitrogen), and then distribute them in 384 plates at a density of 3×10 4 cells/well (100 μL/well);
2.将在20mM Hepes(Invitrogen)(pH7.4)补充的HBSS缓冲液(Invitrogen)中羧苯磺胺与荧光探针(Fluo4 Direct,Invitrogen)混合，再加入到每个孔中，然后在37℃下与细胞平衡60分钟，再在22℃下与细胞平衡15分钟；2. In the HBSS buffer (Invitrogen) supplemented with 20mM Hepes (Invitrogen) (pH7.4), carbenzylsulfonamide was mixed with the fluorescent probe (Fluo4 Direct, Invitrogen), then added to each well, and then incubated at 37°C Equilibrate with the cells for 60 minutes at 22°C for 15 minutes;
3.将测定板置于微板读数器(CellLux，PerkinElmer)中，加入测试化合物与阳性对照的适当浓度的DMSO溶液或HBSS缓冲液，5分钟后再加入0.3nM内皮素–1或HBSS缓冲液(基底对照)，然后测3. Place the assay plate in a microplate reader (CellLux, PerkinElmer), add the appropriate concentration of the test compound and positive control in DMSO solution or HBSS buffer, and then add 0.3nM endothelin-1 or HBSS buffer after 5 minutes (basal control), and then measure
量与游离细胞溶质的Ca 2+离子浓度成比例的荧光强度变化值； Fluorescence intensity change value proportional to Ca 2+ ion concentration of free cytosol;
4.结果是对0.3nM内皮素–1的对照响应的百分比抑制；4. Results are percent inhibition of the control response to 0.3 nM endothelin-1;
5.标准阳性对照是BQ–788钠盐(CAS登录号：156161-89-6)，在每个实验中测试几个浓度，使用Prism5. The standard positive control is BQ-788 sodium salt (CAS accession number: 156161-89-6), test several concentrations in each experiment, use Prism
分析数据，产生一个浓度–响应的曲线，计算化合物的IC 50值。 The data are analyzed to generate a concentration-response curve and IC50 values for the compounds are calculated.
实验结果：部分实验结果见表1。Experimental results: Some experimental results are shown in Table 1.
表1.本公开化合物对人源ETA和ETB受体拮抗活性数据及其ETB受体的选择性Table 1. Data on the antagonistic activity of the disclosed compounds on human ETA and ETB receptors and their selectivity for ETB receptors
化合物compound ETA-IC 50(nM) ETA- IC50 (nM) ETB-IC 50(nM) ETB-IC 50 (nM) ETB/ETA选择系数ETB/ETA selection factor
002002 1.81.8 230000230000 127778127778
007007 6.56.5 8400084000 1292312923
008008 3.33.3 >300000>300000 >90909>90909
018018 3.13.1 >100000>100000 >32258>32258
020020 4.34.3 >100000>100000 >23255>23255
实验结论：本公开化合物在体外实验中展现了对人源ETA受体的高度抑制活性；同时部分化合物对人源ETA和ETB受体具有高度选择性，选择系数大于10000倍。Experimental conclusion: the disclosed compounds exhibited high inhibitory activity on human ETA receptors in vitro experiments; at the same time, some compounds were highly selective to human ETA and ETB receptors, with a selection coefficient greater than 10,000 times.
实验例3：体内药代动力学性质研究Experimental Example 3: Study on Pharmacokinetic Properties in Vivo
实验目的：测定化合物在SD大鼠中的药代动力学参数。Experimental purpose: To determine the pharmacokinetic parameters of the compound in SD rats.
实验材料：Experimental Materials:
Sprague Dawley大鼠(雄性,200-300g,7～9周龄，北京维通利华)Sprague Dawley rats (male, 200-300g, 7-9 weeks old, Beijing Weitong Lihua)
实验方法：experimental method:
1.该项目使用4只雄性SD大鼠，给药前称重，根据体重，计算给药量，然后将大鼠分成两组。一组2只SD大鼠进行静脉注射给药，给药剂量为2mg/kg，给药浓度0.5mg/mL；另外一组2只SD大鼠进行口服给药，给药剂量为10mg/kg，给药浓度1mg/mL；1. 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;
2.收集给药后0.083(仅静脉组)、0.25、0.5、1、2、4、6、8、24h的血浆样品。每个样品采集约0.05mL，肝素钠抗凝，采集后放置湿冰上。2. Collect plasma samples at 0.083 (only in the intravenous group), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. About 0.05mL of each sample was collected, anticoagulated with heparin sodium, and placed on wet ice after collection.
3.血液样本采集后置于冰上，并于1小时之内离心分离血浆(离心条件：6000g，3分钟，2-8℃)。血浆样本在分析前存放时则放于-80℃冰箱内。3. Place the blood sample on ice after collection, and centrifuge the plasma within 1 hour (centrifugation conditions: 6000g, 3 minutes, 2-8°C). Plasma samples were stored in a -80°C freezer until analysis.
4.对收集的样品进行LC-MS/MS分析并采集数据。采集的分析数据用Phoenix WinNonlin 8.2.0软件计算相关药代动力学参数。4. Perform LC-MS/MS analysis on the collected samples and collect data. The collected analytical data was calculated with Phoenix WinNonlin 8.2.0 software to calculate relevant pharmacokinetic parameters.
实验结果：部分实验结果见表2。Experimental results: Some experimental results are shown in Table 2.
表2体内药代动力学实验结果Table 2 In vivo pharmacokinetic test results
Figure PCTCN2022130697-appb-000093
Figure PCTCN2022130697-appb-000093
结论：本公开化合物具有较好的暴露量和生物利用度。Conclusion: The disclosed compound has better exposure and bioavailability.
实验例4：体内药效研究Experimental Example 4: In Vivo Drug Efficacy Study
试验目的：探索受试药物对Thy1肾炎治疗作用Purpose of the test: To explore the therapeutic effect of the tested drug on Thy1 nephritis
实验流程：experiment process:
1.取50只大鼠(SD大鼠，常州卡文斯试验动物有限公司)采用异氟烷气体麻醉。全身麻醉过后，在大鼠右侧行单侧肾脏切除术；切除右侧肾脏，之后缝合给予抗生素；对照组大鼠(Group-1)操作步骤同模型组但是不切除肾脏。单侧肾脏切除术后一周，模型组大鼠尾静脉注射1mg/kg anti-Thy1antibody，对照组大鼠尾静脉注射等体积生理盐水，注射后第三天，收集大鼠24h尿液，检测尿液中尿总蛋白含量；剔除造模未成功大鼠，并根据尿蛋白数据使用简单随机法分组，将造模大鼠随机分成6组，分别为Group-2、Group-3、Group-4、Group-5、Group-6、Group-7组。1. 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. One week after unilateral nephrectomy, 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.
2.抗体注射后第四天，Group-1、Group-2组大鼠灌胃等体积溶媒(5％DMSO+20％PEG400+10％HS)，一日一次，灌胃体积为1mL/100g，连续给药4周；Group-3组大鼠灌胃5mg/kg强的松，一日一次，灌胃体积为1mL/100g，连续给药4周；Group-4组大鼠灌胃阿曲生坦(10mg/kg)，一日一次，灌胃体积为1mL/100g，连续给药4周；Group-5组大鼠灌胃本公开实施例化合物(1mg/kg)，一日一次，灌胃体积为1mL/100g，连续给药4周；Group-6组大鼠灌胃本公开实施例化合物(3mg/kg)，一日一次，灌胃体积为1mL/100g，连续给药4周；Group-7组大鼠灌胃本公开实施例化合物(10mg/kg)，一日一次，灌胃体积为1mL/100g，连续给药4周。2. On the fourth day after antibody injection, 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; Group - Rats in Group 7 were gavaged with the compound of the present disclosure (10 mg/kg), once a day, with a gavage volume of 1 mL/100 g, and administered continuously for 4 weeks.
3.抗体注射后第三天(Day 0)、给药第7天、给药第28天分别收集大鼠24h尿液，检测24h尿蛋白含量；尿液收集完毕后，取各组大鼠血液样本检测红细胞压积。3. On the third day after antibody injection (Day 0), on the seventh day of administration, and on the 28th day of administration, the 24h urine of the rats was collected respectively, and the 24h urine protein content was detected; after the urine was collected, the blood of the rats in each group was collected Samples were tested for hematocrit.
4.取血结束后CO 2法安乐死大鼠，取肾脏组织，PAS染色观察肾脏组织的病变程度。 4. After the blood collection, the rats were euthanized by CO 2 method, and the kidney tissue was taken, and the lesion degree of the kidney tissue was observed by PAS staining.
统计分析：Statistical Analysis:
数据采用Graphpad Prism 5(Version 5.01)进行分析与作图，Adobe Illustrator CS6(Version 16.0.0)进行整理合图。所有数据均以means±SD表示，组间统计学差异采用one-way ANOVA和Tukey’s检验，P值小于0.05认为有显著性差异。The data were analyzed and drawn using Graphpad Prism 5 (Version 5.01), and Adobe Illustrator CS6 (Version 16.0.0) was used to organize and combine the pictures. All data are expressed as means ± SD, and statistical differences between groups were tested using one-way ANOVA and Tukey’s test, and a P value less than 0.05 was considered significant.
实验结论：本公开化合物可以减少大鼠蛋白尿含量，提高血细胞压积，并且缓解大鼠肾损伤，抑制肾小球系膜细胞增生、肾小球系膜基质增多和肾小球囊壁增厚现象。Experimental conclusion: 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.

Claims (15)

  1. 式(A)化合物或其药学上可接受的盐，其选自：Formula (A) compound or its pharmaceutically acceptable salt, it is selected from:
    Figure PCTCN2022130697-appb-100001
    Figure PCTCN2022130697-appb-100001
    其中，in,
    Z 1选自N或CR Z1； Z1 is selected from N or CR Z1 ;
    Z 2选自N或CR Z2； Z2 is selected from N or CR Z2 ;
    R Z1或R Z2各自独立地选自H、卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1- 6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、或卤代二C 1-6烷基氨基； 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选自O或NH；X is selected from O or NH;
    环A选自任选地被一个或多个R a取代的以下基团：3-12元环烷基或3-12元杂环烷基； 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;
    R a各自独立地选自卤素、-OH、氧代、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-NHC(O)NR a1R a2、-NR a1C(O)OR a2、-OC(O)R a1、-C(O)OR a1、-OC(O)OR a1、-OC(O)NR a1R a2、-C 1-6亚烷基C(O)NR a1R a2、-C 1-6亚烷基NR a1C(O)R a2、-C 1-6亚烷基NHC(O)NR a1R a2、-C 1-6亚烷基NR a1C(O)OR a2、-C 1-6亚烷基OC(O)R a1、-C 1-6亚烷基C(O)OR a1、-C 1-6亚烷基OC(O)NR a1R a2、或任选地被1个或多个R a3取代的如下基团：C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、3-12元环烷基、3-12元杂环烷基、5-10元杂环基、6-10元芳基、或5-10元杂芳基； 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)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 C(O)OR a2 , -C 1-6 alkylene OC(O)R a1 , -C 1-6 alkylene C(O)OR a1 , -C 1-6 alkylene OC(O)NR a1 R a2 , or the following groups optionally substituted by one or more R a3 : C 1-6 alkyl, C 1-6 alkoxy Base, C 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl ;
    R a1、R a2各自独立地选自H或C 1-6烷基； R a1 and R a2 are each independently selected from H or C 1-6 alkyl;
    R a3各自独立地选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、或卤代二C 1-6烷基氨基； 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选自单键、-O-、-S-、-NH-、-C(O)-、或是任选地被一个或多个R L取代的以下基团：-CH 2-、-N(C 1- 6烷基)-、或-CH(C 1-6烷基)-； 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各自独立地选自卤素、-OH、-NH 2、-CN、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、或卤代二C 1-6烷基氨基； 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;
    环D选自任选地被一个或多个R b取代的以下基团：3-12元环烷基、3-12元杂环烷基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基； 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各自独立地选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、或卤代二C 1-6烷基氨基； 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;
    Y 1选自-O-、-S-、或-NH-； Y1 is selected from -O-, -S-, or -NH-;
    Y 2选自-O-、-S-、-NH-、-SO 2-、-NHSO 2-、-SO 2NH-、-NHSO 2NH-、-C(O)NH-、-NHC(O)-、-OC(O)NH-、-NHC(O)O-、或-NHC(O)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-;
    m选自1、2、3、4、5、或6；m is selected from 1, 2, 3, 4, 5, or 6;
    环C选自3-12元环烷基、3-12元杂环烷基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5- 10元杂芳基；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选自0、1、2、3、或4；n is selected from 0, 1, 2, 3, or 4;
    R 1各自独立地选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、或卤代二C 1-6烷基氨基； 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选自H、卤素、-OH、-NH 2、-CN、或是任选地被一个或多个R 2a取代的以下基团：C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、3-12元环烷基、3-12元杂环烷基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基； 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各自独立地选自氧代、卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、或卤代二C 1-6烷基氨基； 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、环A、环D或环C任选地被一个或多个取代基取代。 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.
  2. 根据权利要求1所述的式(A)化合物或其药学上可接受的盐，其中，环A选自任选地被一个或多个R a取代的以下基团：3-10元环烷基或3-10元杂环烷基； The compound of formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is selected from the following groups optionally substituted by one or more R a : 3-10 membered cycloalkyl Or 3-10 membered heterocycloalkyl;
    或者，环A选自任选地被一个或多个R a取代的以下基团：3-8元环烷基或3-8元杂环烷基； Alternatively, 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;
    或者，环A选自任选地被一个或多个R a取代的以下基团：环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、双环[1.1.1]戊基、双环[3.1.0]己基、双环[3.2.0]庚基、双环[2.2.2]辛基、双环[3.3.0]辛基、螺[3.3]庚基、螺[3.4]辛基、氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、氧杂环庚烷基、氮杂环庚烷基、氮杂双环[3.1.0]己基、氧杂双环[3.2.0]庚基、氮杂双环[3.2.0]庚基、氧杂双环[2.2.2]辛基、氮杂双环[2.2.2]辛基、氧杂双环[3.3.0]辛基、氮杂双环[3.3.0]辛基、氧杂螺[3.3]庚基、氮杂螺[3.3]庚基、氧杂螺[3.4]辛基、或氮杂螺[3.4]辛基； Alternatively, ring A is selected from the following groups optionally substituted by one or more R a : cyclopropyl, 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, oxepanyl, azepanyl , azabicyclo[3.1.0]hexyl, oxabicyclo[3.2.0]heptyl, azabicyclo[3.2.0]heptyl, oxabicyclo[2.2.2]octyl, azabicyclo[2.2. 2] Octyl, oxabicyclo[3.3.0]octyl, azabicyclo[3.3.0]octyl, oxaspiro[3.3]heptyl, azaspiro[3.3]heptyl, oxaspiro[3.4] ]octyl, or azaspiro[3.4]octyl;
    或者，环A选自任选地被一个或多个R a取代的以下基团：环丙烷基、螺[3.3]庚基、四氢呋喃基、哌啶基、或氧杂螺[3.3]庚基； Alternatively, ring A is selected from the following groups optionally substituted by one or more Ra : cyclopropanyl, spiro[3.3]heptyl, tetrahydrofuranyl, piperidinyl, or oxaspiro[3.3]heptyl;
    或者，环A选自任选地被一个或多个R a取代的以下基团：
    Figure PCTCN2022130697-appb-100002
    Figure PCTCN2022130697-appb-100003
    Alternatively, Ring A is selected from the following groups optionally substituted with one or more Ra :
    Figure PCTCN2022130697-appb-100002
    Figure PCTCN2022130697-appb-100003
    或者，环A选自任选地被一个或多个R a取代的以下基团：
    Figure PCTCN2022130697-appb-100004
    Figure PCTCN2022130697-appb-100005
    其中R a各自独立地选自-C(O)NH 2、-C(O)NHCH 3、-COOH、-COOCH 3、甲基、或甲氧基；     Alternatively, Ring A is selected from the following groups optionally substituted with one or more Ra :
    Figure PCTCN2022130697-appb-100004
    Figure PCTCN2022130697-appb-100005
    wherein each R a is independently selected from -C(O)NH 2 , -C(O)NHCH 3 , -COOH, -COOCH 3 , methyl, or methoxy;
    或者，环A选自以下基团：
    Figure PCTCN2022130697-appb-100006
    Figure PCTCN2022130697-appb-100007
    Alternatively, ring A is selected from the following groups:
    Figure PCTCN2022130697-appb-100006
    Figure PCTCN2022130697-appb-100007
  3. 根据权利要求1或2所述的式(A)化合物或其药学上可接受的盐，其中，R a各自独立地选自卤素、-OH、氧代、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-NHC(O)NR a1R a2、-NR a1C(O)OR a2、-OC(O)R a1、-C(O)OR a1、-OC(O)OR a1、-OC(O)NR a1R a2、-C 1-4亚烷基C(O)NR a1R a2、-C 1-4亚烷基NR a1C(O)R a2、-C 1-4亚烷基NHC(O)NR a1R a2、-C 1-4亚烷基NR a1C(O)OR a2、-C 1-4亚烷基OC(O)R a1、-C 1-4亚烷基C(O)OR a1、 -C 1-4亚烷基OC(O)NR a1R a2、或任选地被1个或多个R a3取代的如下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、3-6元环烷基、3-6元杂环烷基、5-6元杂环基、苯基、或5-6元杂芳基； The compound of formula (A) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein 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)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 NHC(O)NR a1 R a2 , -C 1-4 alkylene NR a1 C(O)OR a2 , -C 1 -4 alkylene OC (O) R a1 , -C 1-4 alkylene C (O) OR a1 , -C 1-4 alkylene OC (O) NR a1 R a2 , or optionally replaced by 1 The following groups substituted by one or more R a3 : C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkane Base, 5-6 membered heterocyclic group, phenyl, or 5-6 membered heteroaryl;
    或者，R a各自独立地选自卤素、-OH、氧代、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-OC(O)R a1、-C(O)OR a1、-C 1-4亚烷基C(O)NR a1R a2、-C 1-4亚烷基NR a1C(O)R a2、-C 1-4亚烷基OC(O)R a1、-C 1-4亚烷基C(O)OR a1、或任选地被1个或多个R a3取代的如下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、3-6元环烷基、3-6元杂环烷基、5-6元杂环基、苯基、或5-6元杂芳基； Alternatively, 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 the following groups optionally substituted by 1 or more R a3 : C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heterocyclyl, phenyl , or 5-6 membered heteroaryl;
    或者，R a各自独立地选自F、Cl、Br、-OH、氧代、-NH 2、-CN、-C(O)R a1、-C(O)NR a1R a2、-NR a1C(O)R a2、-OC(O)R a1、-C(O)OR a1、-C 1-2亚烷基C(O)NR a1R a2、-C 1-2亚烷基NR a1C(O)R a2、-C 1-2亚烷基OC(O)R a1、-C 1-2亚烷基C(O)OR a1、或任选地被1个或多个R a3取代的如下基团：甲基、乙基、甲氧基、乙氧基、甲基氨基、或二甲基氨基； Alternatively, 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 substituted by one or more R a3 The following groups: methyl, ethyl, methoxy, ethoxy, methylamino, or dimethylamino;
    或者，R a各自独立地选自F、Cl、Br、-OH、氧代、-NH 2、-CN、-C(O)NR a1R a2、-C(O)OR a1、或任选地被1个或多个R a3取代的如下基团：甲基、乙基、甲氧基、乙氧基、甲基氨基、或二甲基氨基； Alternatively, 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 optionally The following groups substituted by one or more R a3 : methyl, ethyl, methoxy, ethoxy, methylamino, or dimethylamino;
    或者，R a各自独立地选自F、Cl、Br、-OH、氧代、-NH 2、-CN、-C(O)NR a1R a2、-C(O)OR a1、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、甲基氨基、乙基氨基、二甲基氨基、三氟甲基、或三氟甲氧基； Alternatively, 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 radical, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy;
    或者，R a各自独立地选自-C(O)NH 2、-C(O)NHCH 3、-COOH、-COOCH 3、甲基、或甲氧基。 Alternatively, each R a is independently selected from -C(O)NH 2 , -C(O)NHCH 3 , -COOH, -COOCH 3 , methyl, or methoxy.
  4. 根据权利要求1-3任意一项所述的式(A)化合物或其药学上可接受的盐，其中，L选自单键、-O-、-S-、-NH-、-C(O)-、或是任选地被一个或多个R L取代的以下基团：-CH 2-、-N(C 1-3烷基)-、或-CH(C 1-3烷基)-； The compound of formula (A) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein L is selected from single bonds, -O-, -S-, -NH-, -C(O )-, or the following groups optionally substituted by one or more R L : -CH 2 -, -N(C 1-3 alkyl)-, or -CH(C 1-3 alkyl)- ;
    或者，L选自单键、-O-、-S-、-NH-、-C(O)-、或是任选地被一个或多个R L取代的以下基团：-CH 2-、-N(CH 3)-、或-CH(CH 3)-； Alternatively, L is selected from a single bond, -O-, -S-, -NH-, -C(O)-, or the following groups optionally substituted by one or more R L : -CH 2 -, -N(CH 3 )-, or -CH(CH 3 )-;
    或者，L选自单键、-O-、-S-、-NH-、-C(O)-、-CH 2-、-N(CH 3)-、或-CH(CH 3)-； Alternatively, L is selected from a single bond, -O-, -S-, -NH-, -C(O)-, -CH 2 -, -N(CH 3 )-, or -CH(CH 3 )-;
    或者，L选自单键。Alternatively, L is selected from single bonds.
  5. 根据权利要求1-4任意一项所述的式(A)化合物或其药学上可接受的盐，其中，环D选自任选地被一个或多个R b取代的以下基团：3-10元环烷基、3-10元杂环烷基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基； The compound of formula (A) or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein ring D is selected from the following groups optionally substituted by one or more R b : 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;
    或者，环D选自任选地被一个或多个R b取代的以下基团：5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基； Alternatively, ring D is selected from the following groups optionally substituted by one or more R b : 5-10 membered carbocyclyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered Heteroaryl;
    或者，环D选自任选地被一个或多个R b取代的以下基团：
    Figure PCTCN2022130697-appb-100008
    其中环B选自5-6元杂环烯基、或5-6元杂芳基，T 1选自C、或N；     Alternatively, ring D is selected from the following groups optionally substituted with one or more R b :
    Figure PCTCN2022130697-appb-100008
    Wherein ring B is selected from 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, T1 is selected from C or N;
    或者，环D选自任选地被一个或多个R b取代的以下基团：苯并5-6元环烯基、苯并5-6元杂环基、吡啶并5-6元杂环基、苯基、萘基、或9-10元杂芳基； Alternatively, ring D is selected from the following groups optionally substituted with one or more R b : benzo 5-6 membered cycloalkenyl, benzo 5-6 membered heterocyclyl, pyrido 5-6 membered heterocyclic Base, phenyl, naphthyl, or 9-10 membered heteroaryl;
    或者，环D选自任选地被一个或多个R b取代的如下基团：
    Figure PCTCN2022130697-appb-100009
    苯基、萘基、吲哚基、苯并吡唑基、苯并咪唑基、苯并噻唑基、
    Figure PCTCN2022130697-appb-100010
    喹 啉基、异喹啉基、或苯并嘧啶基；     Alternatively, ring D is selected from the following groups optionally substituted with one or more R b :
    Figure PCTCN2022130697-appb-100009
    Phenyl, naphthyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl,
    Figure PCTCN2022130697-appb-100010
    Quinolinyl, isoquinolinyl, or benzopyrimidinyl;
    或者，环D选自任选地被一个或多个R b取代的如下基团：
    Figure PCTCN2022130697-appb-100011
    苯并噻唑基、或
    Figure PCTCN2022130697-appb-100012
    Alternatively, ring D is selected from the following groups optionally substituted with one or more R b :
    Figure PCTCN2022130697-appb-100011
    benzothiazolyl, or
    Figure PCTCN2022130697-appb-100012
    或者，环D选自任选地被一个或多个R b取代的如下基团：
    Figure PCTCN2022130697-appb-100013
    Alternatively, ring D is selected from the following groups optionally substituted with one or more R b :
    Figure PCTCN2022130697-appb-100013
    或者，环D选自
    Figure PCTCN2022130697-appb-100014
    Alternatively, ring D is selected from
    Figure PCTCN2022130697-appb-100014
  6. 根据权利要求1-5任意一项所述的式(A)化合物或其药学上可接受的盐，其中，R b各自独立地选自卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1- 4烷基、卤代C 1-4烷氧基、卤代C 1-4烷硫基、卤代C 1-4烷基氨基、或卤代二C 1-4烷基氨基； The compound of formula (A) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein 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;
    或者，R b各自独立地选自卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二C 1- 4烷基氨基、卤代C 1-4烷基、或卤代C 1-4烷氧基； Alternatively, each R b is independently selected from halogen , -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkane Base amino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy;
    或者，R b各自独立地选自F、Cl、Br、-OH、-NH 2、-CN、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、甲基氨基、乙基氨基、二甲基氨基、三氟甲基、或三氟甲氧基； Alternatively, each R b is independently selected from F, Cl, Br, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methyl Amino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy;
    或者，R b各自独立地选自F、Cl、Br、-OH、-NH 2、-CN、甲基、甲氧基、甲基氨基、二甲基氨基、三氟甲基、或三氟甲氧基。 Alternatively, each R b is independently selected from F, Cl, Br, -OH, -NH 2 , -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethyl Oxygen.
  7. 根据权利要求1-6任意一项所述的式(A)化合物或其药学上可接受的盐，其中，Y 2选自-O-、-S-、-NH-、-SO 2-、-NHSO 2-、-SO 2NH-、-C(O)NH-、或-NHC(O)-； The compound of formula (A) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein Y 2 is selected from -O-, -S-, -NH-, -SO 2 -, - NHSO 2 -, -SO 2 NH-, -C(O)NH-, or -NHC(O)-;
    或者，Y 2选自-O-、-S-、或-NH-； Alternatively, Y2 is selected from -O-, -S-, or -NH-;
    或者，Y 2选自-O-。 Alternatively, Y2 is selected from -O-.
  8. 根据权利要求1-7任意一项所述的式(A)化合物或其药学上可接受的盐，其中，环C选自3-10元环烷基、3-10元杂环烷基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基；The compound of formula (A) or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein 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;
    或者，环C选自3-8元环烷基、3-8元杂环烷基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基；Alternatively, ring C is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered carbocyclyl, 5-10 membered heterocyclic group, 6-10 membered aryl, or 5-10 membered Metaheteroaryl;
    或者，环C选自6-10元芳基或5-10元杂芳基；Alternatively, ring C is selected from 6-10 membered aryl or 5-10 membered heteroaryl;
    或者，环C选自苯基、萘基、吡咯基、吡唑基、咪唑基、呋喃基、噁唑基、异噁唑基、噻吩基、噻唑基、异噻唑基、吡喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吲哚基、苯并吡唑基、苯并咪唑基、苯并噻唑基、咪唑并[1,2-b]哒嗪基、吡唑并[1,5-a]吡啶基、喹啉基、异喹啉基、或苯并嘧啶基；Alternatively, ring C is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyranyl, pyridyl , pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, imidazo[1,2-b]pyridazinyl, pyr Azolo[1,5-a]pyridyl, quinolinyl, isoquinolyl, or benzopyrimidinyl;
    或者，环C选自苯基、萘基、噻唑基、吡啶基、嘧啶基、三嗪基、或咪唑并[1,2-b]哒嗪基；Alternatively, ring C is selected from phenyl, naphthyl, thiazolyl, pyridyl, pyrimidinyl, triazinyl, or imidazo[1,2-b]pyridazinyl;
    或者，环C选自嘧啶基、吡啶基、噻唑基、咪唑并哒嗪基和三嗪基；Alternatively, ring C is selected from pyrimidyl, pyridyl, thiazolyl, imidazopyridazinyl and triazinyl;
    或者，环C选自
    Figure PCTCN2022130697-appb-100015
    Alternatively, Ring C is selected from
    Figure PCTCN2022130697-appb-100015
  9. 根据权利要求1-8任意一项所述的式(A)化合物或其药学上可接受的盐，其中，R 1各自独立地选自卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷基氨基、二C 1-4烷基氨基、卤代C 1- 4烷基、卤代C 1-4烷氧基、卤代C 1-4烷硫基、卤代C 1-4烷基氨基、或卤代二C 1-4烷基氨基； The compound of formula (A) or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein 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;
    或者，R 1各自独立地选自卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二C 1- 4烷基氨基、卤代C 1-4烷基、或卤代C 1-4烷氧基； Alternatively, each R 1 is independently selected from halogen , -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkane Base amino, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy;
    或者，R 1各自独立地选自F、Cl、Br、-OH、-NH 2、-CN、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、甲基氨基、乙基氨基、二甲基氨基、三氟甲基、或三氟甲氧基； Alternatively, each R1 is independently selected from F, Cl, Br, -OH, -NH2 , -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methyl Amino, ethylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy;
    或者，R 1各自独立地选自F、Cl、Br、-OH、-NH 2、-CN、甲基、甲氧基、甲基氨基、二甲基氨基、三氟甲基、或三氟甲氧基； Alternatively, each R1 is independently selected from F, Cl, Br, -OH, -NH2 , -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethyl Oxygen;
    或者，R 1各自独立地选自F、Cl、Br、或三氟甲氧基。 Alternatively, each R1 is independently selected from F, Cl, Br, or trifluoromethoxy.
  10. 根据权利要求1-9任意一项所述的式(A)化合物或其药学上可接受的盐，其中，R 2选自H、卤素、-OH、-NH 2、-CN、或是任选地被一个或多个R 2a取代的以下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷基氨基、二C 1-4烷基氨基、3-10元环烷基、3-10元杂环烷基、5-10元碳环基、5-10元杂环基、6-10元芳基、或5-10元杂芳基； The compound of formula (A) or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R 2 is selected from H, halogen, -OH, -NH 2 , -CN, or optionally The following groups substituted by 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, 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, 5-10-membered carbocyclyl, 5-10-membered heterocyclyl, 6-10-membered aryl, or 5-10-membered heterocyclyl Aryl;
    或者，R 2选自H、卤素、-OH、-NH 2、-CN、或是任选地被一个或多个R 2a取代的以下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷基氨基、二C 1-4烷基氨基、3-8元环烷基、3-8元杂环烷基、苯基、或5-6元杂芳基； Alternatively, R 2 is selected from H, halogen, -OH, -NH 2 , -CN, or the following groups optionally substituted by one or more R 2a : C 1-4 alkyl, C 1-4 alkane Oxygen, C 1-4 alkylthio, C 1-4 alkylamino, two C 1-4 alkylamino, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5 -6 membered heteroaryl;
    或者，R 2选自H、卤素、-OH、-NH 2、-CN、或是任选地被一个或多个R 2a取代的以下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二C 1-4烷基氨基、3-6元环烷基、3-6元杂环烷基、苯基、或5-6元杂芳基； Alternatively, R 2 is selected from H, halogen, -OH, -NH 2 , -CN, or the following groups optionally substituted by one or more R 2a : C 1-4 alkyl, C 1-4 alkane Oxygen, C 1-4 alkylamino, two C 1-4 alkylamino, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl;
    或者，R 2选自H、F、Cl、Br、-OH、-NH 2、-CN、或是任选地被一个或多个R 2a取代的以下基团：甲基、乙基、甲氧基、乙氧基、甲基氨基、乙基氨基、二甲基氨基、环丙烷基、环丁烷基、环戊烷基、环己烷基、氮杂环丁烷基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、苯基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、或吡嗪基； Alternatively, R 2 is selected from H, F, Cl, Br, -OH, -NH 2 , -CN, or the following groups optionally substituted by one or more R 2a : methyl, ethyl, methoxy ethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexane, azetidinyl, tetrahydrofuranyl, pyrrolidine Base, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl;
    或者，R 2选自H、F、Cl、Br、或是任选地被一个或多个R 2a取代的以下基团：甲基或吗啉基； Alternatively, R is selected from H, F, Cl, Br, or the following groups optionally substituted by one or more R 2a : methyl or morpholinyl;
    或者，R 2选自H、甲基、或吗啉基。 Alternatively, R is selected from H, methyl, or morpholinyl.
  11. 根据权利要求1-10任意一项所述的式(A)化合物或其药学上可接受的盐，其选自式(A-1)、式(A-2)、式(A-3)或式(A-4)化合物或其药学上可接受的盐，The compound of formula (A) or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, which is selected from formula (A-1), formula (A-2), formula (A-3) or A compound of formula (A-4) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022130697-appb-100016
    Figure PCTCN2022130697-appb-100016
    其中，R 1、R 2、Y 1、Y 2、X、m、n、L、环A、环D和环C如权利要求1-10任意一项所定义。 Wherein, R 1 , R 2 , Y 1 , Y 2 , X, m, n, L, ring A, ring D and ring C are as defined in any one of claims 1-10.
  12. 根据权利要求1-11任意一项所述的式(A)化合物或其药学上可接受的盐，其选自式(II)化合物或其药学上可接受的盐，The compound of formula (A) or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, which is selected from the compound of formula (II) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022130697-appb-100017
    Figure PCTCN2022130697-appb-100017
    其中，in,
    T 1选自C和N； T1 is selected from C and N;
    环B选自5-6元杂环烯基和5-6元杂芳基；Ring B is selected from 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
    结构单元
    Figure PCTCN2022130697-appb-100018
    任选地被一个或多个R b取代；     Structural units
    Figure PCTCN2022130697-appb-100018
    optionally substituted with one or more R b ;
    R 1、R 2、R b、X、n、环A和环C如权利要求1-10任意一项所定义。 R 1 , R 2 , R b , X, n, ring A and ring C are as defined in any one of claims 1-10.
  13. 下列化合物或其药学上可接受的盐，The following compounds or pharmaceutically acceptable salts thereof,
    Figure PCTCN2022130697-appb-100019
    Figure PCTCN2022130697-appb-100019
    Figure PCTCN2022130697-appb-100020
    Figure PCTCN2022130697-appb-100020
  14. 药物组合物，其包含权利要求1-13任意一项所述的式(A)化合物或其药学上可接受的盐；任选地，所述药物组合物还包括药学上可接受的辅料。A pharmaceutical composition comprising the compound of formula (A) or a pharmaceutically acceptable salt thereof according to any one of claims 1-13; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable auxiliary material.
  15. 权利要求1-13任意一项所述的式(A)化合物或其药学上可接受的盐、或权利要求14所述的药物组合物在制备治疗ETA受体相关疾病的药物中的用途；任选地，所述ETA受体相关疾病选自IgA肾病。The use of the compound of formula (A) or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, or the pharmaceutical composition described in claim 14 in the preparation of medicines for the treatment of ETA receptor-related diseases; any Optionally, the ETA receptor-related disease is selected from IgA nephropathy.
PCT/CN2022/130697 2021-11-08 2022-11-08 Azobenzene compound and application thereof WO2023078463A1 (en)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
US5292740A (en) * 1991-06-13 1994-03-08 Hoffmann-La Roche Inc. Sulfonamides
CN1095375A (en) * 1992-12-10 1994-11-23 霍夫曼-拉罗奇有限公司 Novel sulfonamides
CN1111242A (en) * 1993-12-17 1995-11-08 田边制药株式会社 Benzenesulfonamide derivative and process for preparing thereof
WO2002008200A2 (en) * 2000-07-21 2002-01-31 Actelion Pharmaceuticals Ltd Arylethene-sulfonamides, their preparation and their use as endothelin antagonists

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 (en) * 1992-12-10 1994-11-23 霍夫曼-拉罗奇有限公司 Novel sulfonamides
CN1111242A (en) * 1993-12-17 1995-11-08 田边制药株式会社 Benzenesulfonamide derivative and process for preparing thereof
WO2002008200A2 (en) * 2000-07-21 2002-01-31 Actelion Pharmaceuticals Ltd Arylethene-sulfonamides, their preparation and their use as endothelin antagonists

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