WO2021239049A1 - Novel glutamine analogs - Google Patents

Novel glutamine analogs Download PDF

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Publication number
WO2021239049A1
WO2021239049A1 PCT/CN2021/096306 CN2021096306W WO2021239049A1 WO 2021239049 A1 WO2021239049 A1 WO 2021239049A1 CN 2021096306 W CN2021096306 W CN 2021096306W WO 2021239049 A1 WO2021239049 A1 WO 2021239049A1
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membered
alkyl
heteroaryl
cycloalkyl
heterocyclyl
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PCT/CN2021/096306
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French (fr)
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Cunbo Ma
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Jacobio Pharmaceuticals Co., Ltd.
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the invention relates to a novel glutamine analogs shown as the formula (I) , a composition containing the glutamine analogs and the use thereof.
  • Glutamine analogs such as 6-diazo-5-oxo-L-norleucine (DON) have been shown to exhibit anti-cancer activities.
  • severe toxicity e.g., dose limiting GI toxicities, such as oral mucositis, gastric bleeding, nausea and vomiting, and abdominal pain
  • administering such glutamine antagonists at therapeutic dose levels has hampered their clinical development.
  • X is selected from -C 1-6 alkylene-or -C 1-6 alkylene-O-C 0-6 alkylene-, wherein the -C 0-6 alkylene-in the -C 1-6 alkylene-O-C 0-6 alkylene-is connected with the moiety said -C 1-6 alkylene-or -C 1-6 alkylene-O-C 0-6 alkylene-is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3 alkyl, haloC 1-3 alkyl, -C 1-3 alkoxy, haloC 1-3 alkoxy, -OH, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , oxo, -CO (C 1-3 alkyl) , -COOC 1-3 alkyl, -CONH 2 , -CONH (C 1-3 alkyl) , -
  • R 1 is selected from hydrogen, -C 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 3-6 membered cycloalkenyl, tri (C 1-6 alkyl) ammonium, tetra (C 1-6 alkyl) ammonium, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 3-10 membered cycloalkenyl, 3-10 membered heterocyclyl, tri (C 1-6 alkyl) ammonium, tetra (C 1-6 alkyl) ammonium, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or
  • Each of R 2 , R 4 , R 51 and R 52 is independently selected from hydrogen or -C 1-6 alkyl; said -C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form halogen, -C 1-3 alkyl, haloC 1-3 alkyl, -C 1-3 alkoxy, haloC 1-3 alkoxy, -OH, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , oxo, -CO (C 1-3 alkyl) , -COOC 1-3 alkyl, -CONH 2 , -CONH (C 1-3 alkyl) , -CON (C 1-3 alkyl) 2 , 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
  • R 3 , R 6 and R 8 is independently selected from hydrogen, -C 1-6 alkyl, -CO (C 1-6 alkyl) , -COOC 1-6 alkyl, -CONH 2 , -CONH (C 1-6 alkyl) , -CON (C 1-6 alkyl) 2 , 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6 alkyl, -CO (C 1-6 alkyl) , -COOC 1-6 alkyl, -CONH 2 , -CONH (C 1-6 alkyl) , -CON (C 1-6 alkyl) 2 , 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen,
  • R 7 is selected from hydrogen, -C 1-6 alkyl, -CO (C 1-6 alkyl) , -COOC 1-6 alkyl, -CONH 2 , -CONH (C 1-6 alkyl) , -CON (C 1-6 alkyl) 2 , 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6 alkyl, -CO (C 1-6 alkyl) , -COOC 1-6 alkyl, -CONH 2 , -CONH (C 1-6 alkyl) , -CON (C 1-6 alkyl) 2 , 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3 alkyl, hal
  • R 9 is selected from -C 1-20 alkly, -C 2-20 alkenyl, -C 2-20 alkynyl, 3-20 membered cycloalkyl, -C 1-6 alkylene- (3-20 membered cycloalkyl) , 3-20 membered heterocyclyl, -C 1-6 alkylene- (3-20 membered heterocyclyl) , 6-10 membered aryl, -C 1-6 alkylene- (6-10 membered aryl) , 5-10 membered heteroaryl, -C 1-6 alkylene- (5-10 membered heteroaryl) , each of which is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3 alkyl, haloC 1-3 alkyl, -C 1-3 alkoxy, haloC 1-3 alkoxy, -OH, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 al
  • R 91 is independently selected from hydrogen or -C 1-6 alkyl; said -C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form halogen, -C 1-3 alkyl, haloC 1-3 alkyl, -C 1-3 alkoxy, haloC 1-3 alkoxy, -OH, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , oxo, -CO (C 1-3 alkyl) , -COOC 1-3 alkyl, -CONH 2 , -CONH (C 1-3 alkyl) , -CON (C 1-3 alkyl) 2 , 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
  • R 93 is selected from hydrogen, -C 1-6 alkyl, -C 1-6 alkoxyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6 alkyl, -C 1-6 alkoxyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3 alkyl, haloC 1-3 alkyl, -C 1-3 alkoxy, haloC 1-3 alkoxy, -OH, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , oxo, -CO (C 1-3 alkyl) , -COOC 1-3 alkyl, -
  • R 93 and R 92 together with the atom they respectively are attached to form a 4-6 membered heterocyclyl, said heterocyclyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3 alkyl, haloC 1-3 alkyl, -C 1-3 alkoxy, haloC 1-3 alkoxy, -OH, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , oxo, -CO (C 1-3 alkyl) , -CONH 2 , -CONH (C 1-3 alkyl) , -CON (C 1-3 alkyl) 2 , 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
  • R 94 is selected from hydrogen, -C 1-6 alkyl, -CO (C 1-6 alkyl) , -COOC 1-6 alkyl, -CONH 2 , -CONH (C 1-6 alkyl) , -CON (C 1-6 alkyl) 2 , 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6 alkyl, -CO (C 1-6 alkyl) , -COOC 1-6 alkyl, -CONH 2 , -CONH (C 1-6 alkyl) , -CON (C 1-6 alkyl) 2 , 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3 alkyl,
  • n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • the compound is of formula (Ia) - (Id) :
  • X is selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 -O-, -CH 2 CH 2 -O-or -CH 2 CH 2 CH 2 -O-, wherein the -O-in -CH 2 -O-, -CH 2 CH 2 -O-or -CH 2 CH 2 CH 2 -O-is connected with the moiety each of which is independently optionally substituted with 1, 2 or 3 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3 , -OCH 3 , -OCF 3 , -OH, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , oxo, -COCH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON (CH 3 ) 2 , 3 membered
  • X is -CH 2 CH 2 -.
  • R 1 is selected from hydrogen, -C 1-3 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, -C 2-3 alkenyl, -C 2-3 alkynyl, 3-6 membered cycloalkenyl, tri (C 1-3 alkyl) ammonium, tetra (C 1-3 alkyl) ammonium, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said -C 1-3 alkyl, 3-6 membered cycloalkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, 3-6 membered cycloalkenyl, 3-6 membered heterocyclyl, tri (C 1-3 alkyl) ammonium, tetra (C 1-3 alkyl) ammonium, phenyl, naphthyl, 5 membered
  • R 1 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, 3 membered cycloalkyl, 4 membered cycloalyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, ethenyl, propenyl, ethynyl, propynyl, 5 membered cycloalkenyl, 6 membered cycloalkenyl, tri (methyl) ammonium, tetra (methyl) ammonium, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, said methyl, ethyl, propyl, isopropyl, 3 membered cycloalkyl, 4 membered cycloalyl, 5 membered cycloalkyl, 4
  • R 1 is selected from methyl, ethyl, propyl or isopropyl.
  • R 1 is isopropyl
  • each of R 2 , R 4 , R 51 and R 52 is independently selected from hydrogen or -C 1-3 alkyl; said -C 1-3 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form -F, -Cl, methyl, ethyl, propyl, -CF 3 , -OCH 3 , -OCF 3 , -OH, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , oxo, -COCH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON (CH 3 ) 2 , 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 laminated cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocycly
  • each of R 2 , R 4 , R 51 and R 52 is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl; said methyl, ethyl, propyl or isopropyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form -F, -Cl, methyl, ethyl, propyl, -CF 3 , -OCH 3 , -OCF 3 , -OH, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , oxo, -COCH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON (CH 3 ) 2 , 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 laminated cycloalkyl, 3 membered heterocyclyl, 4 membered hetero
  • each of R 2 , R 4 , R 51 and R 52 is independently hydrogen.
  • each of R 3 , R 6 and R 8 is independently selected from hydrogen, -C 1-3 alkyl, -CO (C 1-3 alkyl) , -COOC 1-3 alkyl, -CONH 2 , -CONH (C 1-3 alkyl) , -CON (C 1-3 alkyl) 2 , 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered aryl, 9 membered aryl or 10 membered heteroaryl; said -C 1-3 alkyl, -CO (C 1-3 alkyl) , -COOC 1-3 alkyl, -CONH 2 , -CONH (C 1-3 alkyl) , -CON (C 1-3 1-3 alky
  • each of R 3 , R 6 and R 8 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CO (CH 3 ) , -COOCH 3 , -CONH 2 , -CONH (CH 3 ) , -CON (CH 3 ) 2 , 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered aryl, 9 membered aryl or 10 membered heteroaryl; said methyl, ethyl, propyl, isopropyl, -CO (CH 3 ) , -COOCH 3 , -CONH 2 , -CONH (CH 3 ) , -CON (CH 3 ) 2 , 5 membered cycloalkyl, 6 membered cycl
  • each of R 3 , R 6 and R 8 is independently hydrogen.
  • R 7 is selected from hydrogen, -C 1-3 alkyl, -CO (C 1-3 alkyl) , -COOC 1-3 alkyl, -CONH 2 , -CONH (C 1-3 alkyl) , -CON (C 1-3 alkyl) 2 , 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said -C 1-3 alkyl, -CO (C 1-3 alkyl) , -COOC 1-3 alkyl, -CONH 2 , -CONH (C 1-3 alkyl) , -CON (C 1-3 alkyl) 2 , 3
  • R 7 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, -COCH 3 , -COCH 2 CH 3 , -COCH 2 CH 2 CH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON (CH 3 ) 2 , 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said methyl, ethyl, propyl, isopropyl, -COCH 3 , -COCH 2 CH 3 , -COCH 2 CH 2 CH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON (CH 3 )
  • R 7 is -COCH 3 .
  • the moiety in the formula (I) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 9 is selected from -C 1-20 alkly, -C 2-20 alkenyl, -C 2-20 alkynyl, 5-20 membered cycloalkyl, -C 1-3 alkylene- (5-20 membered cycloalkyl) , 5-20 membered heterocyclyl, -C 1-3 alkylene- (5-20 membered heterocyclyl) , phenyl, naphthyl, -C 1-3 alkylene-phenyl, -C 1-3 alkylene-naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, -C 1-3 alkylene- (5 membered heteroaryl) , -C 1-3 alkylene- (6 membered heteroaryl) , -C 1-3 alkylene- (9 membered heteroaryl) , -C 1-3 alkylene- (10 membered heteroaryl) ,
  • R 91 is independently selected from hydrogen or -C 1-3 alkyl; said -C 1-3 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form -F, -Cl, methyl, ethyl, propyl, -CF 3 , -OCH 3 , -OCF 3 , -OH, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , oxo, -COCH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON (CH 3 ) 2 , 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 laminated cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl
  • R 91 is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl; said methyl, ethyl, propyl or isopropyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form -F, -Cl, methyl, ethyl, propyl, -CF 3 , -OCH 3 , -OCF 3 , -OH, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , oxo, -COCH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON (CH 3 ) 2 , 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 laminated cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 5 membere
  • R 91 is hydrogen
  • R 93 is selected from hydrogen, -C 1-3 alkyl, -C 1-3 alkoxyl, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said -C 1-3 alkyl, -C 1-3 alkoxyl, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 6 membered
  • R 93 and R 92 together with the atom they respectively are attached to form a 4 membered heterocyclyl, 5 membered heterocyclyl or 6 membered heterocyclyl; said heterocyclyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3 , -OCH 3 , -OCF 3 , -OH, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , oxo, -COCH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON (CH 3 ) 2 , 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 laminated cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocycly
  • R 93 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is independently optionally
  • R 93 and R 92 together with the atom they respectively are attached to form a 5 membered heterocyclyl or 6 membered heterocyclyl; said heterocyclyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3 , -OCH 3 , -OCF 3 , -OH, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , oxo, -COCH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON (CH 3 ) 2 , 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 laminated cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocycly
  • R 93 is hydrogen; or R 93 and R 92 together with the atom they respectively are attached to form
  • R 93 is hydrogen; or R 93 and R 92 together with the atom they respectively are attached to form
  • R 94 is selected from hydrogen, -C 1-3 alkyl, -CO (C 1-3 alkyl) , -COOC 1-3 alkyl, -CONH 2 , -CONH (C 1-3 alkyl) , -CON (C 1-3 alkyl) 2 , 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said -C 1-3 alkyl, -CO (C 1-3 alkyl) , -COOC 1-3 alkyl, -CONH 2 , -CONH (C 1-3 alkyl) , -CON (C 1-3 alkyl) 2 ,
  • R 94 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, -COCH 3 , -COCH 2 CH 3 , -COCH 2 CH 2 CH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON (CH 3 ) 2 , 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said methyl, ethyl, propyl, isopropyl, -COCH 3 , -COCH 2 CH 3 , -COCH 2 CH 2 CH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON (CH 3 ) 2 ,
  • R 94 is -COCH 3 .
  • R 9 is selected form:
  • m is selected from 1, 2, 3, 4, 5, 6 or 7.
  • m is selected from 3, 4, 5 or 6.
  • m is selected from 3, 4, 5 or 6.
  • m is 4.
  • the compound is selected from:
  • a pharmaceutical composition comprising the compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of the present invention; and a pharmaceutically acceptable carrier, diluent or excipient.
  • a method of treating a subject having a cancer comprising administering to the subject a therapeutically effective amount of the compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of the present invention; or the pharmaceutical composition of the present invention.
  • the cancer is selected from colon cancer, glioblastoma or head and neck cancer.
  • the compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of the present invention or the pharmaceutical composition of the present invention for the manufacture of a medicament for the treatment of a cancer.
  • the cancer is selected from colon cancer, glioblastoma or head and neck cancer.
  • the compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of the present invention or the pharmaceutical composition of the present invention for use in the treatment of a cancer.
  • the cancer is selected from colon cancer, glioblastoma or head and neck cancer.
  • halogen or “halo” , as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include -F, -Cl and -Br.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl.
  • C 1-6 as in C 1-6 alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
  • alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • methylene i.e., -CH 2 -
  • ethylene i.e., -CH 2 -CH 2 -or -CH (CH 3 ) -
  • propylene i.e., -CH 2 -CH 2 -CH 2 -, -CH (-CH 2 -CH 3 ) -or -CH 2 -CH (CH 3 ) -
  • alkenyl means a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length.
  • C 2-6 alkenyl contains from 2 to 6 carbon atoms.
  • Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
  • alkynyl contains a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length.
  • C 2-6 alkynyl contains from 2 to 6 carbon atoms.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • alkoxy radicals are oxygen ethers formed from the previously described alkyl groups.
  • aryl refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
  • heterocyclyl refers to unsubstituted and substituted mono or polycyclic non-aromatic ring system containing one or more heteroatoms, which comprising moncyclic heterocyclic ring, bicyclic heterocyclic ring, bridged heterocyclic ring, fused heterocyclic ring or sipro heterocyclic ring.
  • Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition.
  • heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
  • heteroaryl represents an aromatic ring system containing carbon (s) and at least one heteroatom.
  • Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
  • a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclic heteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) .
  • heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.
  • cycloalkyl refers to a substituted or unsubstituted monocyclic ring, bicyclic ring bridged ring, fused ring, sipiro ring non-aromatic ring system onle containing carbon atoms.
  • Examplary “cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
  • the compounds of the present invention may also be present in the form of pharmaceutically acceptable salt (s) .
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salt (s) " .
  • the pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • the pharmaceutically acceptable acidic/anionic salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid.
  • organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic.
  • Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
  • the present invention includes within its scope the prodrugs of the compounds of this invention.
  • such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs” , ed. H. Bundgaard, Elsevier, 1985.
  • the present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • stereoisomer refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and conformational isomers.
  • the configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.
  • the invention includes all possible stereoisomers of the compound.
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the isotopes of hydrogen can be denoted as 1 H (hydrogen) , 2 H (deuterium) and 3 H (tritium) . They are also commonly denoted as D for deuterium and T for tritium.
  • CD 3 denotes a methyl group wherein all of the hydrogen atomsare deuterium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
  • the present invention includes any possible solvates and polymorphic forms.
  • a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone or the like can be used.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
  • compositions of the present invention comprise a compound (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous) .
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compound or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt.
  • the compounds or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about 0.0lmg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or l000mg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound of this invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
  • dosage levels on the order of from about 0.001mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or alternatively about 0.05mg to about 7g per patient per day.
  • inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) may be effectively treated by the administration of from about 0.001 to 50mg of the compound per kilogram of body weight per day or alternatively about 0.05mg to about 3.5g per patient per day.

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Abstract

A novel glutamine analogs shown as the formula (I), a composition containing the glutamine analogs and the use thereof.

Description

Novel Glutamine Analogs Technical Field
The invention relates to a novel glutamine analogs shown as the formula (I) , a composition containing the glutamine analogs and the use thereof.
Background Art
Glutamine analogs, such as 6-diazo-5-oxo-L-norleucine (DON) have been shown to exhibit anti-cancer activities. However, the occurrence of severe toxicity (e.g., dose limiting GI toxicities, such as oral mucositis, gastric bleeding, nausea and vomiting, and abdominal pain) when administering such glutamine antagonists at therapeutic dose levels has hampered their clinical development.
Prior attempts to mitigate the severe toxicity associated with glutamine antagonists such as DON, have been unsuccessful. Therefore, it’s needed to develop novel glutamine antagonists to meet the clinical needs.
Summary of Invention
In one aspect, there is provided a compound of formula (I) :
Figure PCTCN2021096306-appb-000001
a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt of the stereoisomer thereof;
wherein:
X is selected from -C 1-6alkylene-or -C 1-6alkylene-O-C 0-6alkylene-, wherein the -C 0-6alkylene-in the -C 1-6alkylene-O-C 0-6alkylene-is connected with the moiety
Figure PCTCN2021096306-appb-000002
said -C 1-6alkylene-or -C 1-6alkylene-O-C 0-6alkylene-is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
R 1 is selected from hydrogen, -C 1-6alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, -C 2-6alkenyl, -C 2-6alkynyl, 3-6 membered cycloalkenyl, tri (C 1-6alkyl) ammonium, tetra (C 1-6alkyl) ammonium, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, -C 2-6alkenyl, -C 2-6alkynyl, 3-10 membered cycloalkenyl, 3-10 membered heterocyclyl, tri (C 1-6alkyl) ammonium, tetra (C 1-6alkyl) ammonium, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Each of R 2, R 4, R 51 and R 52 is independently selected from hydrogen or -C 1-6alkyl; said -C 1-6alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Each of R 3, R 6 and R 8 is independently selected from hydrogen, -C 1-6alkyl, -CO (C 1-6alkyl) , -COOC 1-6alkyl, -CONH 2, -CONH (C 1-6alkyl) , -CON (C 1-6alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6alkyl, -CO (C 1-6alkyl) , -COOC 1-6alkyl, -CONH 2,  -CONH (C 1-6alkyl) , -CON (C 1-6alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
R 7 is selected from hydrogen, -C 1-6alkyl, -CO (C 1-6alkyl) , -COOC 1-6alkyl, -CONH 2, -CONH (C 1-6alkyl) , -CON (C 1-6alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6alkyl, -CO (C 1-6alkyl) , -COOC 1-6alkyl, -CONH 2, -CONH (C 1-6alkyl) , -CON (C 1-6alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
R 9 is selected from -C 1-20alkly, -C 2-20alkenyl, -C 2-20alkynyl, 3-20 membered cycloalkyl, -C 1-6alkylene- (3-20 membered cycloalkyl) , 3-20 membered heterocyclyl, -C 1-6alkylene- (3-20 membered heterocyclyl) , 6-10 membered aryl, -C 1-6alkylene- (6-10 membered aryl) , 5-10 membered heteroaryl, -C 1-6alkylene- (5-10 membered heteroaryl) , 
Figure PCTCN2021096306-appb-000003
Figure PCTCN2021096306-appb-000004
each of which is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered  heteroaryl;
R 91 is independently selected from hydrogen or -C 1-6alkyl; said -C 1-6alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
R 92 is selected from hydrogen, -C 1-6alkyl, -C 1-6alkylene- (6-10 membered aryl) , -C 1-6alkylene- (5-10 membered heteroaryl) , -C 1-6alkylene-S-C 1-3alkyl, -C 1-6alkylene-OH, -C 1-6alkylene-SH, -C 1-6alkylene-C (=O) NH 2, -C 1-6alkylene-C (=O) NH (C 1-3alkyl) , -C 1-6alkylene-C (=O) N (C 1-3alkyl)  2, -C 1-6alkylene-NH 2, -C 1-6alkylene-NH (C 1-3alkyl) , -C 1-6alkylene-N (C 1-3alkyl)  2, -C 1-6alkylene-NH-C (=NH) -NH 2, -C 1-6alkylene-NH-C (=NH) -NH (C 1-3alkyl) , -C 1-6alkylene-NH-C (=NH) -N (C 1-3alkyl)  2, -C 1-6alkylene-COOH, -C 1-6alkylene-COOC 1-3alkyl; said -C 1-6alkyl, -C 1-6alkylene- (6-10 membered aryl) , -C 1-6alkylene- (5-10 membered heteroaryl) , -C 1-6alkylene-S-C 1-3alkyl, -C 1-6alkylene-OH, -C 1-6alkylene-SH, -C 1-6alkylene-C (=O) NH 2, -C 1-6alkylene-C (=O) NH (C 1-3alkyl) , -C 1-6alkylene-C (=O) N (C 1-3alkyl)  2, -C 1-6alkylene-NH 2, -C 1-6alkylene-NH (C 1-3alkyl) , -C 1-6alkylene-N (C 1-3alkyl)  2, -C 1-6alkylene-NH-C (=NH) -NH 2, -C 1-6alkylene-NH-C (=NH) -NH (C 1-3alkyl) , -C 1-6alkylene-NH-C (=NH) -N (C 1-3alkyl)  2, -C 1-6alkylene-COOH, -C 1-6alkylene-COOC 1-3alkyl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
R 93 is selected from hydrogen, -C 1-6alkyl, -C 1-6alkoxyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6alkyl, -C 1-6alkoxyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo,  -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; or
R 93 and R 92 together with the atom they respectively are attached to form a 4-6 membered heterocyclyl, said heterocyclyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
R 94 is selected from hydrogen, -C 1-6alkyl, -CO (C 1-6alkyl) , -COOC 1-6alkyl, -CONH 2, -CONH (C 1-6alkyl) , -CON (C 1-6alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6alkyl, -CO (C 1-6alkyl) , -COOC 1-6alkyl, -CONH 2, -CONH (C 1-6alkyl) , -CON (C 1-6alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloalkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
In some embodiments, the compound is of formula (Ia) - (Id) :
Figure PCTCN2021096306-appb-000005
Figure PCTCN2021096306-appb-000006
In some embodiments, X is selected from -C 1-3alkylene-or -C 1-3alkylene-O-, wherein the -O-in the -C 1-6alkylene-O-is connected with the moiety
Figure PCTCN2021096306-appb-000007
said -C 1-6alkylene-or -C 1-6alkylene-O-is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, X is selected from -CH 2-, -CH 2CH 2-, -CH 2CH 2CH 2-, -CH 2-O-, -CH 2CH 2-O-or -CH 2CH 2CH 2-O-, wherein the -O-in -CH 2-O-, -CH 2CH 2-O-or -CH 2CH 2CH 2-O-is connected with the moiety
Figure PCTCN2021096306-appb-000008
each of which is independently optionally substituted with 1, 2 or 3 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9  membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, X is -CH 2CH 2-.
In some embodiments, R 1 is selected from hydrogen, -C 1-3alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, -C 2-3alkenyl, -C 2-3alkynyl, 3-6 membered cycloalkenyl, tri (C 1-3alkyl) ammonium, tetra (C 1-3alkyl) ammonium, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said -C 1-3alkyl, 3-6 membered cycloalkyl, -C 2-3alkenyl, -C 2-3alkynyl, 3-6 membered cycloalkenyl, 3-6 membered heterocyclyl, tri (C 1-3alkyl) ammonium, tetra (C 1-3alkyl) ammonium, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 1 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, 3 membered cycloalkyl, 4 membered cycloalyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, ethenyl, propenyl, ethynyl, propynyl, 5 membered cycloalkenyl, 6 membered cycloalkenyl, tri (methyl) ammonium, tetra (methyl) ammonium, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, said methyl, ethyl, propyl, isopropyl, 3 membered cycloalkyl, 4 membered cycloalyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, ethenyl, propenyl, ethynyl, propynyl, 5 membered cycloalkenyl, 6 membered cycloalkenyl, tri (methyl) ammonium, tetra (methyl) ammonium, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 1 is selected from methyl, ethyl, propyl or isopropyl.
In some embodiments, R 1 is isopropyl.
In some embodiments, each of R 2, R 4, R 51 and R 52 is independently selected from hydrogen or -C 1-3alkyl; said -C 1-3alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, each of R 2, R 4, R 51 and R 52 is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl; said methyl, ethyl, propyl or isopropyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred  heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, each of R 2, R 4, R 51 and R 52 is independently hydrogen.
In some embodiments, each of R 3, R 6 and R 8 is independently selected from hydrogen, -C 1-3alkyl, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered aryl, 9 membered aryl or 10 membered heteroaryl; said -C 1-3alkyl, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered aryl, 9 membered aryl or 10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, each of R 3, R 6 and R 8 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CO (CH 3) , -COOCH 3, -CONH 2, -CONH (CH 3) , -CON (CH 3)  2, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered aryl, 9 membered aryl or 10 membered heteroaryl; said methyl, ethyl, propyl, isopropyl, -CO (CH 3) , -COOCH 3, -CONH 2, -CONH (CH 3) , -CON (CH 3)  2, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered aryl, 9 membered aryl or 10 membered heteroaryl is independently  optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, each of R 3, R 6 and R 8 is independently hydrogen.
In some embodiments, R 7 is selected from hydrogen, -C 1-3alkyl, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said -C 1-3alkyl, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 7 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, -COCH 3, -COCH 2CH 3, -COCH 2CH 2CH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 5 membered cycloalkyl, 6 membered cycloalkyl, 5  membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said methyl, ethyl, propyl, isopropyl, -COCH 3, -COCH 2CH 3, -COCH 2CH 2CH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 7 is -COCH 3.
In some embodiments, the moiety
Figure PCTCN2021096306-appb-000009
in the formula (I) is
Figure PCTCN2021096306-appb-000010
In some embodiments, R 9 is selected from -C 1-20alkly, -C 2-20alkenyl, -C 2-20alkynyl, 5-20 membered cycloalkyl, -C 1-3alkylene- (5-20 membered cycloalkyl) , 5-20 membered heterocyclyl, -C 1-3alkylene- (5-20 membered heterocyclyl) , phenyl, naphthyl, -C 1-3alkylene-phenyl, -C 1-3alkylene-naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, -C 1-3alkylene- (5 membered heteroaryl) , -C 1-3alkylene- (6 membered heteroaryl) , -C 1-3alkylene- (9 membered heteroaryl) , -C 1-3alkylene- (10 membered heteroaryl) ,
Figure PCTCN2021096306-appb-000011
Figure PCTCN2021096306-appb-000012
each of which is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 91 is independently selected from hydrogen or -C 1-3alkyl; said -C 1-3alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 91 is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl; said methyl, ethyl, propyl or isopropyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl  independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 91 is hydrogen.
In some embodiments, R 92 is selected from hydrogen, -C 1-4alkyl, -C 1-3alkylene-phenyl, -C 1-3alkyl-naphthyl, -C 1-3alkylene- (5 membered heteroaryl) , -C 1-3alkylene- (6 membered heteroaryl) , -C 1-3alkylene- (9 membered heteroaryl) , -C 1-3alkylene- (10 membered heteroaryl) , -C 1-3alkylene-S-C 1-3alkyl, -C 1-3alkylene-OH, -C 1-3alkylene-SH, -C 1-3alkylene-C (=O) NH 2, -C 1-3alkylene-C (=O) NH (C 1-3alkyl) , -C 1-3alkylene-C (=O) N (C 1-3alkyl)  2, -C 1-3alkylene-NH 2, -C 1-3alkylene-NH (C 1-3alkyl) , -C 1-3alkylene-N (C 1-3alkyl)  2, -C 1-3alkylene-NH-C (=NH) -NH 2, -C 1-3alkylene-NH-C (=NH) -NH (C 1-3alkyl) , -C 1-3alkylene-NH-C (=NH) -N (C 1-3alkyl)  2, -C 1-3alkylene-COOH or -C 1-3alkylene-COOC 1-3alkyl; said -C 1-3alkyl, -C 1-3alkylene-phenyl, -C 1-3alkyl-naphthyl, -C 1-3alkylene- (5 membered heteroaryl) , -C 1-3alkylene- (6 membered heteroaryl) , -C 1-3alkylene- (9 membered heteroaryl) , -C 1-3alkylene- (10 membered heteroaryl) , -C 1-3alkylene-S-C 1-3alkyl, -C 1-3alkylene-OH, -C 1-3alkylene-SH, -C 1-3alkylene-C (=O) NH 2, -C 1-3alkylene-C (=O) NH (C 1-3alkyl) , -C 1-3alkylene-C (=O) N (C 1-3alkyl)  2, -C 1-3alkylene-NH 2, -C 1-3alkylene-NH (C 1-3alkyl) , -C 1-3alkylene-N (C 1-3alkyl)  2, -C 1-3alkylene-NH-C (=NH) -NH 2, -C 1-3alkylene-NH-C (=NH) -NH (C 1-3alkyl) , -C 1-3alkylene-NH-C (=NH) -N (C 1-3alkyl)  2, -C 1-3alkylene-COOH or -C 1-3alkylene-COOC 1-3alkyl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 92 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -methylene-phenyl, -methyl-naphthyl, -methylene- (5 membered heteroaryl) , -methylene- (6 membered heteroaryl) ,  -methylene- (9 membered heteroaryl) , -methylene- (10 membered heteroaryl) , -methylene-S-C 1-3alkyl, -ethylene-S-C 1-3alkyl, -propylene-S-C 1-3alkyl, -methylene-OH, -ethylene-OH, -propylene-OH, -methylene-SH, -ethylene-SH, -propylene-SH, -methylene-C (=O) NH 2, -ethylene-C (=O) NH 2, -propylene-C (=O) NH 2, -methylene-C (=O) NH (C 1-3alkyl) , -ethylene-C (=O) NH (C 1-3alkyl) , -propylene-C (=O) NH (C 1-3alkyl) , -methylene-C (=O) N (C 1-3alkyl)  2, -ethylene-C (=O) N (C 1-3alkyl)  2, -propylene-C (=O) N (C 1-3alkyl)  2, -methylene-NH 2, -ethylene-NH 2, -propylene-NH 2, -butylene-NH 2, -methylene-NH (C 1-3alkyl) , -ethylene-NH (C 1-3alkyl) , -propylene-NH (C 1-3alkyl) , -butylene-NH (C 1-3alkyl) , -methylene-N (C 1-3alkyl)  2, -ethylene-N (C 1-3alkyl)  2, -propylene-N (C 1-3alkyl)  2, -butylene-N (C 1-3alkyl)  2, -methylene-NH-C (=NH) -NH 2, -ethylene-NH-C (=NH) -NH 2, -propylene-NH-C (=NH) -NH 2, -methylene-NH-C (=NH) -NH (C 1-3alkyl) , -ethylene-NH-C (=NH) -NH (C 1-3alkyl) , -propylene-NH-C (=NH) -NH (C 1-3alkyl) , -methylene-NH-C (=NH) -N (C 1-3alkyl)  2, -ethylene-NH-C (=NH) -N (C 1-3alkyl)  2, -propylene-NH-C (=NH) -N (C 1-3alkyl)  2, -methylene-COOH, -ethylene-COOH, -propylene-COOH, -methylene-COOC 1-3alkyl, -ethylene-COOC 1-3alkyl or -propylene-COOC 1-3alkyl; said methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -methylene-phenyl, -methyl-naphthyl, -methylene- (5 membered heteroaryl) , -methylene- (6 membered heteroaryl) , -methylene- (9 membered heteroaryl) , -methylene- (10 membered heteroaryl) , -methylene-S-C 1-3alkyl, -ethylene-S-C 1-3alkyl, -propylene-S-C 1-3alkyl, -methylene-OH, -ethylene-OH, -propylene-OH, -methylene-SH, -ethylene-SH, -propylene-SH, -methylene-C (=O) NH 2, -ethylene-C (=O) NH 2, -propylene-C (=O) NH 2, -methylene-C (=O) NH (C 1-3alkyl) , -ethylene-C (=O) NH (C 1-3alkyl) , -propylene-C (=O) NH (C 1-3alkyl) , -methylene-C (=O) N (C 1-3alkyl)  2, -ethylene-C (=O) N (C 1-3alkyl)  2, -propylene-C (=O) N (C 1-3alkyl)  2, -methylene-NH 2, -ethylene-NH 2, -propylene-NH 2, -butylene-NH 2, -methylene-NH (C 1-3alkyl) , -ethylene-NH (C 1-3alkyl) , -propylene-NH (C 1-3alkyl) , -butylene-NH (C 1-3alkyl) , -methylene-N (C 1-3alkyl)  2, -ethylene-N (C 1-3alkyl)  2, -propylene-N (C 1-3alkyl)  2, -butylene-N (C 1-3alkyl)  2, -methylene-NH-C (=NH) -NH 2, -ethylene-NH-C (=NH) -NH 2,  -propylene-NH-C (=NH) -NH 2, -methylene-NH-C (=NH) -NH (C 1-3alkyl) , -ethylene-NH-C (=NH) -NH (C 1-3alkyl) , -propylene-NH-C (=NH) -NH (C 1-3alkyl) , -methylene-NH-C (=NH) -N (C 1-3alkyl)  2, -ethylene-NH-C (=NH) -N (C 1-3alkyl)  2, -propylene-NH-C (=NH) -N (C 1-3alkyl)  2, -methylene-COOH, -ethylene-COOH, -propylene-COOH, -methylene-COOC 1-3alkyl, -ethylene-COOC 1-3alkyl or -propylene-COOC 1-3alkyl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 92 is selected from hydrogen, -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -CH (CH 3)  2, -CH 2CH 2CH 2CH 3, -CH 2CH (CH 3)  2, -CH (CH 3) CH 2CH 3, 
Figure PCTCN2021096306-appb-000013
-CH 2CH 2SCH 3, -CH 2-OH, -CH (CH 3) -OH, -CH 2-SH, -CH 2-C (=O) NH 2, -CH 2CH 2-C (=O) NH 2, -CH 2CH 2CH 2CH 2-NH 2, -CH 2CH 2CH 2-NH-C (=NH) -NH 2, -CH 2-COOH, -CH 2CH 2-COOH; said -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -CH (CH 3)  2, -CH 2CH 2CH 2CH 3, -CH 2CH (CH 3)  2, -CH (CH 3) CH 2CH 3, 
Figure PCTCN2021096306-appb-000014
-CH 2CH 2SCH 3, -CH 2-OH, -CH (CH 3) -OH, -CH 2-SH, -CH 2-C (=O) NH 2, -CH 2CH 2-C (=O) NH 2, -CH 2CH 2CH 2CH 2-NH 2, -CH 2CH 2CH 2-NH-C (=NH) -NH 2, -CH 2-COOH, -CH 2CH 2-COOH is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered  heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 92 is selected from hydrogen, -CH 3, -CH (CH 3)  2, -CH 2CH (CH 3)  2, -CH (CH 3) CH 2CH 3, 
Figure PCTCN2021096306-appb-000015
-CH 2CH 2SCH 3, -CH 2-OH, -CH (CH 3) -OH, -CH 2-SH, -CH 2-C (=O) NH 2, -CH 2CH 2-C (=O) NH 2, -CH 2CH 2CH 2CH 2-NH 2, -CH 2CH 2CH 2-NH-C (=NH) -NH 2, -CH 2-COOH, -CH 2CH 2-COOH.
In some embodiments, R 93 is selected from hydrogen, -C 1-3alkyl, -C 1-3alkoxyl, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said -C 1-3alkyl, -C 1-3alkoxyl, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S; or
R 93 and R 92 together with the atom they respectively are attached to form a 4 membered heterocyclyl, 5 membered heterocyclyl or 6 membered heterocyclyl; said  heterocyclyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 93 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S; or
R 93 and R 92 together with the atom they respectively are attached to form a 5 membered heterocyclyl or 6 membered heterocyclyl; said heterocyclyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl,  4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 93 is hydrogen; or R 93 and R 92 together with the atom they respectively are attached to form
Figure PCTCN2021096306-appb-000016
In some embodiments, R 93 is hydrogen; or R 93 and R 92 together with the atom they respectively are attached to form
Figure PCTCN2021096306-appb-000017
In some embodiments, R 94 is selected from hydrogen, -C 1-3alkyl, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said -C 1-3alkyl, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 94 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, -COCH 3, -COCH 2CH 3, -COCH 2CH 2CH 3, -COOCH 3, -CONH 2,  -CONHCH 3, -CON (CH 3)  2, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said methyl, ethyl, propyl, isopropyl, -COCH 3, -COCH 2CH 3, -COCH 2CH 2CH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments, R 94 is -COCH 3.
In some embodiments, R 9 is selected form:
Figure PCTCN2021096306-appb-000018
In some embodiments, m is selected from 1, 2, 3, 4, 5, 6 or 7.
In some embodiments, m is selected from 3, 4, 5 or 6.
In some embodiments, m is selected from 3, 4, 5 or 6.
In some embodiments, m is 4.
In some embodiments, the compound is selected from:
Figure PCTCN2021096306-appb-000019
Figure PCTCN2021096306-appb-000020
In another aspect, there is provide a pharmaceutical composition comprising the  compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of the present invention; and a pharmaceutically acceptable carrier, diluent or excipient.
In another aspect, there is provided a method of treating a subject having a cancer, said method comprising administering to the subject a therapeutically effective amount of the compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of the present invention; or the pharmaceutical composition of the present invention. In some embodiments, the cancer is selected from colon cancer, glioblastoma or head and neck cancer.
In another aspect, there is provided use of the compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of the present invention; or the pharmaceutical composition of the present invention for the manufacture of a medicament for the treatment of a cancer. In some embodiments, the cancer is selected from colon cancer, glioblastoma or head and neck cancer.
In another aspect, there is provided the compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of the present invention; or the pharmaceutical composition of the present invention for use in the treatment of a cancer. In some embodiments, the cancer is selected from colon cancer, glioblastoma or head and neck cancer.
Definition
The term “halogen” or “halo” , as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. The preferred halogen groups include -F, -Cl and -Br.
The term “alkyl” , as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Similary, C 1-6, as in C 1-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
The term “alkylene” means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. For example, methylene (i.e., -CH 2-) , ethylene (i.e., -CH 2-CH 2-or -CH (CH 3) -) and propylene (i.e., -CH 2-CH 2-CH 2-, -CH (-CH 2-CH 3) -or -CH 2-CH (CH 3) -) .
The term “alkenyl” means a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length. For example, “C 2-6alkenyl” contains from 2 to 6 carbon atoms. Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
The term “alkynyl” contains a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. For example, “C 2-6alkynyl” contains from 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
The term “alkoxy” radicals are oxygen ethers formed from the previously described alkyl groups.
The term “aryl” , as used herein, unless otherwise indicated, refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
The term “heterocyclyl” , as used herein, unless otherwise indicated, refers to unsubstituted and substituted mono or polycyclic non-aromatic ring system containing one or more heteroatoms, which comprising moncyclic heterocyclic ring, bicyclic heterocyclic ring, bridged heterocyclic ring, fused heterocyclic ring or sipro heterocyclic ring. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition. Examples of such heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
The term “heteroaryl” , as used herein, unless otherwise indicated, represents an aromatic ring system containing carbon (s) and at least one heteroatom. Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms. A polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to  12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) . Examples of heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.
The term “cycloalkyl” refers to a substituted or unsubstituted monocyclic ring, bicyclic ring bridged ring, fused ring, sipiro ring non-aromatic ring system onle containing carbon atoms. Examplary “cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
The term “composition” , as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
The compounds of the present invention may also be present in the form of pharmaceutically acceptable salt (s) . For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salt (s) " . The pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. The pharmaceutically acceptable acidic/anionic salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic. Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
The present invention includes within its scope the prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various  disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs" , ed. H. Bundgaard, Elsevier, 1985.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.
The present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
The present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
The term “stereoisomer” as used in the present invention refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and conformational isomers. The configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers. The invention includes all possible stereoisomers of the compound.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. The isotopes of hydrogen can be denoted as  1H (hydrogen) ,  2H (deuterium) and  3H (tritium) . They are also commonly denoted as D for deuterium and T for tritium. In the application, CD 3 denotes a methyl group wherein all of the hydrogen atomsare deuterium. Isotopes of carbon include  13C and  14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
When a tautomer of the compound exists, the present invention includes any possible  tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
When the compound and pharmaceutically acceptable salts thereof exist in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
The pharmaceutical compositions of the present invention comprise a compound (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
In practice, the compounds or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous) . Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The  compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt. The compounds or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient. For example, a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 0.0lmg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or l000mg.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound of this invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
Generally, dosage levels on the order of from about 0.001mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or  alternatively about 0.05mg to about 7g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) , may be effectively treated by the administration of from about 0.001 to 50mg of the compound per kilogram of body weight per day or alternatively about 0.05mg to about 3.5g per patient per day.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
These and other aspects will become apparent from the following written description of the invention.
EXAMPLES
The following compounds can be synthesized:
Figure PCTCN2021096306-appb-000021
Figure PCTCN2021096306-appb-000022
Figure PCTCN2021096306-appb-000023
Figure PCTCN2021096306-appb-000024
Figure PCTCN2021096306-appb-000025
Figure PCTCN2021096306-appb-000026
It is to be understood that, if any prior art publication is referred to herein; such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art in any country.
The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and Examples should not be construed as limiting the scope of the invention.

Claims (47)

  1. A compound of formula (I) :
    Figure PCTCN2021096306-appb-100001
    a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt of the stereoisomer thereof;
    wherein:
    X is selected from -C 1-6alkylene-or -C 1-6alkylene-O-C 0-6alkylene-, wherein the -C 0-6alkylene-in the -C 1-6alkylene-O-C 0-6alkylene-is connected with the moiety
    Figure PCTCN2021096306-appb-100002
    said -C 1-6alkylene-or -C 1-6alkylene-O-C 0-6alkylene-is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
    R 1 is selected from hydrogen, -C 1-6alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, -C 2-6alkenyl, -C 2-6alkynyl, 3-6 membered cycloalkenyl, tri (C 1-6alkyl) ammonium, tetra (C 1-6alkyl) ammonium, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6alkyl, 3-10 membered cycloalkyl, -C 2-6alkenyl, -C 2-6alkynyl, 3-10 membered cycloalkenyl, 3-10 membered heterocyclyl, tri (C 1-6alkyl) ammonium, tetra (C 1-6alkyl) ammonium, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) ,  -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
    Each of R 2, R 4, R 51 and R 52 is independently selected from hydrogen or -C 1-6alkyl; said -C 1-6alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
    Each of R 3, R 6 and R 8 is independently selected from hydrogen, -C 1-6alkyl, -CO (C 1-6alkyl) , -COOC 1-6alkyl, -CONH 2, -CONH (C 1-6alkyl) , -CON (C 1-6alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6alkyl, -CO (C 1-6alkyl) , -COOC 1-6alkyl, -CONH 2, -CONH (C 1-6alkyl) , -CON (C 1-6alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
    R 7 is selected from hydrogen, -C 1-6alkyl, -CO (C 1-6alkyl) , -COOC 1-6alkyl, -CONH 2, -CONH (C 1-6alkyl) , -CON (C 1-6alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6alkyl, -CO (C 1-6alkyl) , -COOC 1-6alkyl, -CONH 2, -CONH (C 1-6alkyl) , -CON (C 1-6alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered  heteroaryl;
    R 9 is selected from -C 1-20alkly, -C 2-20alkenyl, -C 2-20alkynyl, 3-20 membered cycloalkyl, -C 1-6alkylene- (3-20 membered cycloalkyl) , 3-20 membered heterocyclyl, -C 1-6alkylene- (3-20 membered heterocyclyl) , 6-10 membered aryl, -C 1-6alkylene- (6-10 membered aryl) , 5-10 membered heteroaryl, -C 1-6alkylene- (5-10 membered heteroaryl) , 
    Figure PCTCN2021096306-appb-100003
    Figure PCTCN2021096306-appb-100004
    each of which is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
    R 91 is independently selected from hydrogen or -C 1-6alkyl; said -C 1-6alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
    R 92 is selected from hydrogen, -C 1-6alkyl, -C 1-6alkylene- (6-10 membered aryl) , -C 1-6alkylene- (5-10 membered heteroaryl) , -C 1-6alkylene-S-C 1-3alkyl, -C 1-6alkylene-OH, -C 1-6alkylene-SH, -C 1-6alkylene-C (=O) NH 2, -C 1-6alkylene-C (=O) NH (C 1-3alkyl) , -C 1-6alkylene-C (=O) N (C 1-3alkyl)  2, -C 1-6alkylene-NH 2, -C 1-6alkylene-NH (C 1-3alkyl) , -C 1-6alkylene-N (C 1-3alkyl)  2, -C 1-6alkylene-NH-C (=NH) -NH 2, -C 1-6alkylene-NH-C (=NH) -NH (C 1-3alkyl) , -C 1-6alkylene-NH-C (=NH) -N (C 1-3alkyl)  2, -C 1-6alkylene-COOH, -C 1-6alkylene-COOC 1-3alkyl; said -C 1-6alkyl, -C 1-6alkylene- (6-10 membered aryl) , -C 1-6alkylene- (5-10 membered heteroaryl) , -C 1-6alkylene-S-C 1-3alkyl, -C 1-6alkylene-OH, -C 1-6alkylene-SH, -C 1-6alkylene-C (=O) NH 2, -C 1-6alkylene-C (=O) NH (C 1-3alkyl) , -C 1-6alkylene-C (=O) N (C 1-3alkyl)  2, -C 1-6alkylene-NH 2, -C 1-6alkylene-NH (C 1-3alkyl) , -C 1-6alkylene-N (C 1-3alkyl)  2,  -C 1-6alkylene-NH-C (=NH) -NH 2, -C 1-6alkylene-NH-C (=NH) -NH (C 1-3alkyl) , -C 1-6alkylene-NH-C (=NH) -N (C 1-3alkyl)  2, -C 1-6alkylene-COOH, -C 1-6alkylene-COOC 1-3alkyl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
    R 93 is selected from hydrogen, -C 1-6alkyl, -C 1-6alkoxyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6alkyl, -C 1-6alkoxyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; or
    R 93 and R 92 together with the atom they respectively are attached to form a 4-6 membered heterocyclyl, said heterocyclyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy, haloC 1-3alkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
    R 94 is selected from hydrogen, -C 1-6alkyl, -CO (C 1-6alkyl) , -COOC 1-6alkyl, -CONH 2, -CONH (C 1-6alkyl) , -CON (C 1-6alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; said -C 1-6alkyl, -CO (C 1-6alkyl) , -COOC 1-6alkyl, -CONH 2, -CONH (C 1-6alkyl) , -CON (C 1-6alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C 1-3alkyl, haloC 1-3alkyl, -C 1-3alkoxy,  haloalkoxy, -OH, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, oxo, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
    m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  2. The compound according to claim 1, wherein the compound is of formula (Ia) - (Id) :
    Figure PCTCN2021096306-appb-100005
  3. The compound of claim 1 or 2, wherein X is selected from -C 1-3alkylene-or -C 1-3alkylene-O-, wherein the -O-in the -C 1-6alkylene-O-is connected with the moiety
    Figure PCTCN2021096306-appb-100006
    said -C 1-6alkylene-or -C 1-6alkylene-O-is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl,  phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  4. The compound of any one of claims 1-3, wherein X is selected from -CH 2-, -CH 2CH 2-, -CH 2CH 2CH 2-, -CH 2-O-, -CH 2CH 2-O-or -CH 2CH 2CH 2-O-, wherein the -O-in -CH 2-O-, -CH 2CH 2-O-or -CH 2CH 2CH 2-O-is connected with the moiety 
    Figure PCTCN2021096306-appb-100007
    each of which is independently optionally substituted with 1, 2 or 3 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  5. The compound of any one of claims 1-4, wherein X is -CH 2CH 2-.
  6. The compound of any one of claims 1-5, wherein R 1 is selected from hydrogen, -C 1-3alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, -C 2-3alkenyl, -C 2-3alkynyl, 3-6 membered cycloalkenyl, tri (C 1-3alkyl) ammonium, tetra (C 1-3alkyl) ammonium, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said -C 1-3alkyl, 3-6 membered cycloalkyl, -C 2-3alkenyl, -C 2-3alkynyl, 3-6 membered cycloalkenyl, 3-6 membered heterocyclyl, tri (C 1-3alkyl) ammonium, tetra (C 1-3alkyl) ammonium, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered  cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  7. The compound of any one of claims 1-6, wherein R 1 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, 3 membered cycloalkyl, 4 membered cycloalyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, ethenyl, propenyl, ethynyl, propynyl, 5 membered cycloalkenyl, 6 membered cycloalkenyl, tri (methyl) ammonium, tetra (methyl) ammonium, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, said methyl, ethyl, propyl, isopropyl, 3 membered cycloalkyl, 4 membered cycloalyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, ethenyl, propenyl, ethynyl, propynyl, 5 membered cycloalkenyl, 6 membered cycloalkenyl, tri (methyl) ammonium, tetra (methyl) ammonium, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  8. The compound of any one of claims 1-7, wherein R 1 is selected from methyl, ethyl, propyl or isopropyl.
  9. The compound of any one of claims 1-7, wherein R 1 is isopropyl.
  10. The compound of any one of claims 1-9, wherein each of R 2, R 4, R 51 and R 52  is independently selected from hydrogen or -C 1-3alkyl; said -C 1-3alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  11. The compound of any one of claims 1-10, wherein each of R 2, R 4, R 51 and R 52 is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl; said methyl, ethyl, propyl or isopropyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  12. The compound of any one of claims 1-11, wherein each of R 2, R 4, R 51 and R 52 is independently hydrogen.
  13. The compound of any one of claims 1-12, wherein each of R 3, R 6 and R 8 is independently selected from hydrogen, -C 1-3alkyl, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered aryl, 9 membered aryl or 10 membered heteroaryl; said -C 1-3alkyl, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl,  5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered aryl, 9 membered aryl or 10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  14. The compound of any one of claims 1-13, wherein each of R 3, R 6 and R 8 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CO (CH 3) , -COOCH 3, -CONH 2, -CONH (CH 3) , -CON (CH 3)  2, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered aryl, 9 membered aryl or 10 membered heteroaryl; said methyl, ethyl, propyl, isopropyl, -CO (CH 3) , -COOCH 3, -CONH 2, -CONH (CH 3) , -CON (CH 3)  2, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered aryl, 9 membered aryl or 10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  15. The compound of any one of claims 1-14, wherein each of R 3, R 6 and R 8 is independently hydrogen.
  16. The compound of any one of claims 1-15, wherein R 7 is selected from  hydrogen, -C 1-3alkyl, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said -C 1-3alkyl, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  17. The compound of any one of claims 1-16, wherein R 7 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, -COCH 3, -COCH 2CH 3, -COCH 2CH 2CH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said methyl, ethyl, propyl, isopropyl, -COCH 3, -COCH 2CH 3, -COCH 2CH 2CH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered  cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  18. The compound of any one of claims 1-17, wherein R 7 is -COCH 3.
  19. The compound of any one of claims 1-18, wherein the moiety
    Figure PCTCN2021096306-appb-100008
    in the formula (I) is
    Figure PCTCN2021096306-appb-100009
  20. The compound of any one of claims 1-19, R 9 is selected from -C 1-20alkly, -C 2-20alkenyl, -C 2-20alkynyl, 5-20 membered cycloalkyl, -C 1-3alkylene- (5-20 membered cycloalkyl) , 5-20 membered heterocyclyl, -C 1-3alkylene- (5-20 membered heterocyclyl) , phenyl, naphthyl, -C 1-3alkylene-phenyl, -C 1-3alkylene-naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, -C 1-3alkylene- (5 membered heteroaryl) , -C 1-3alkylene- (6 membered heteroaryl) , -C 1-3alkylene- (9 membered heteroaryl) , -C 1-3alkylene- (10 membered heteroaryl) , 
    Figure PCTCN2021096306-appb-100010
    Figure PCTCN2021096306-appb-100011
    Figure PCTCN2021096306-appb-100012
    each of which is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl,  phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  21. The compound of any one of claims 1-20, wherein R 91 is independently selected from hydrogen or -C 1-3alkyl; said -C 1-3alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  22. The compound of any one of claims 1-21, wherein R 91 is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl; said methyl, ethyl, propyl or isopropyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected form -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  23. The compound of any one of claims 1-22, wherein R 91 is hydrogen.
  24. The compound of any one of claims 1-23, wherein R 92 is selected from hydrogen, -C 1-4alkyl, -C 1-3alkylene-phenyl, -C 1-3alkyl-naphthyl, -C 1-3alkylene- (5 membered heteroaryl) , -C 1-3alkylene- (6 membered heteroaryl) , -C 1-3alkylene- (9 membered heteroaryl) , -C 1-3alkylene- (10 membered heteroaryl) , -C 1-3alkylene-S-C 1-3alkyl, -C 1-3alkylene-OH, -C 1-3alkylene-SH, -C 1-3alkylene-C (=O) NH 2, -C 1-3alkylene-C (=O) NH (C 1-3alkyl) ,  -C 1-3alkylene-C (=O) N (C 1-3alkyl)  2, -C 1-3alkylene-NH 2, -C 1-3alkylene-NH (C 1-3alkyl) , -C 1-3alkylene-N (C 1-3alkyl)  2, -C 1-3alkylene-NH-C (=NH) -NH 2, -C 1-3alkylene-NH-C (=NH) -NH (C 1-3alkyl) , -C 1-3alkylene-NH-C (=NH) -N (C 1-3alkyl)  2, -C 1-3alkylene-COOH or -C 1-3alkylene-COOC 1-3alkyl; said -C 1-3alkyl, -C 1-3alkylene-phenyl, -C 1-3alkyl-naphthyl, -C 1-3alkylene- (5 membered heteroaryl) , -C 1-3alkylene- (6 membered heteroaryl) , -C 1-3alkylene- (9 membered heteroaryl) , -C 1-3alkylene- (10 membered heteroaryl) , -C 1-3alkylene-S-C 1-3alkyl, -C 1-3alkylene-OH, -C 1-3alkylene-SH, -C 1-3alkylene-C (=O) NH 2, -C 1-3alkylene-C (=O) NH (C 1-3alkyl) , -C 1-3alkylene-C (=O) N (C 1-3alkyl)  2, -C 1-3alkylene-NH 2, -C 1-3alkylene-NH (C 1-3alkyl) , -C 1-3alkylene-N (C 1-3alkyl)  2, -C 1-3alkylene-NH-C (=NH) -NH 2, -C 1-3alkylene-NH-C (=NH) -NH (C 1-3alkyl) , -C 1-3alkylene-NH-C (=NH) -N (C 1-3alkyl)  2, -C 1-3alkylene-COOH or -C 1-3alkylene-COOC 1-3alkyl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  25. The compound of any one of claims 1-24, wherein R 92 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -methylene-phenyl, -methyl-naphthyl, -methylene- (5 membered heteroaryl) , -methylene- (6 membered heteroaryl) , -methylene- (9 membered heteroaryl) , -methylene- (10 membered heteroaryl) , -methylene-S-C 1-3alkyl, -ethylene-S-C 1-3alkyl, -propylene-S-C 1-3alkyl, -methylene-OH, -ethylene-OH, -propylene-OH, -methylene-SH, -ethylene-SH, -propylene-SH, -methylene-C (=O) NH 2, -ethylene-C (=O) NH 2, -propylene-C (=O) NH 2, -methylene-C (=O) NH (C 1-3alkyl) , -ethylene-C (=O) NH (C 1-3alkyl) , -propylene-C (=O) NH (C 1-3alkyl) , -methylene-C (=O) N (C 1-3alkyl)  2, -ethylene-C (=O) N (C 1-3alkyl)  2,  -propylene-C (=O) N (C 1-3alkyl)  2, -methylene-NH 2, -ethylene-NH 2, -propylene-NH 2, -butylene-NH 2, -methylene-NH (C 1-3alkyl) , -ethylene-NH (C 1-3alkyl) , -propylene-NH (C 1-3alkyl) , -butylene-NH (C 1-3alkyl) , -methylene-N (C 1-3alkyl)  2, -ethylene-N (C 1-3alkyl)  2, -propylene-N (C 1-3alkyl)  2, -butylene-N (C 1-3alkyl)  2, -methylene-NH-C (=NH) -NH 2, -ethylene-NH-C (=NH) -NH 2, -propylene-NH-C (=NH) -NH 2, -methylene-NH-C (=NH) -NH (C 1-3alkyl) , -ethylene-NH-C (=NH) -NH (C 1-3alkyl) , -propylene-NH-C (=NH) -NH (C 1-3alkyl) , -methylene-NH-C (=NH) -N (C 1-3alkyl)  2, -ethylene-NH-C (=NH) -N (C 1-3alkyl)  2, -propylene-NH-C (=NH) -N (C 1-3alkyl)  2, -methylene-COOH, -ethylene-COOH, -propylene-COOH, -methylene-COOC 1-3alkyl, -ethylene-COOC 1-3alkyl or -propylene-COOC 1-3alkyl; said methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -methylene-phenyl, -methyl-naphthyl, -methylene- (5 membered heteroaryl) , -methylene- (6 membered heteroaryl) , -methylene- (9 membered heteroaryl) , -methylene- (10 membered heteroaryl) , -methylene-S-C 1-3alkyl, -ethylene-S-C 1-3alkyl, -propylene-S-C 1-3alkyl, -methylene-OH, -ethylene-OH, -propylene-OH, -methylene-SH, -ethylene-SH, -propylene-SH, -methylene-C (=O) NH 2, -ethylene-C (=O) NH 2, -propylene-C (=O) NH 2, -methylene-C (=O) NH (C 1-3alkyl) , -ethylene-C (=O) NH (C 1-3alkyl) , -propylene-C (=O) NH (C 1-3alkyl) , -methylene-C (=O) N (C 1-3alkyl)  2, -ethylene-C (=O) N (C 1-3alkyl)  2, -propylene-C (=O) N (C 1-3alkyl)  2, -methylene-NH 2, -ethylene-NH 2, -propylene-NH 2, -butylene-NH 2, -methylene-NH (C 1-3alkyl) , -ethylene-NH (C 1-3alkyl) , -propylene-NH (C 1-3alkyl) , -butylene-NH (C 1-3alkyl) , -methylene-N (C 1-3alkyl)  2, -ethylene-N (C 1-3alkyl)  2, -propylene-N (C 1-3alkyl)  2, -butylene-N (C 1-3alkyl)  2, -methylene-NH-C (=NH) -NH 2, -ethylene-NH-C (=NH) -NH 2, -propylene-NH-C (=NH) -NH 2, -methylene-NH-C (=NH) -NH (C 1-3alkyl) , -ethylene-NH-C (=NH) -NH (C 1-3alkyl) , -propylene-NH-C (=NH) -NH (C 1-3alkyl) , -methylene-NH-C (=NH) -N (C 1-3alkyl)  2, -ethylene-NH-C (=NH) -N (C 1-3alkyl)  2, -propylene-NH-C (=NH) -N (C 1-3alkyl)  2, -methylene-COOH, -ethylene-COOH, -propylene-COOH, -methylene-COOC 1-3alkyl, -ethylene-COOC 1-3alkyl or -propylene-COOC 1-3alkyl is independently optionally substituted with 1, 2, 3, 4, 5 or  6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  26. The compound of any one of claims 1-25, wherein R 92 is selected from hydrogen, -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -CH (CH 3)  2, -CH 2CH 2CH 2CH 3, -CH 2CH (CH 3)  2, -CH (CH 3) CH 2CH 3, 
    Figure PCTCN2021096306-appb-100013
    -CH 2CH 2SCH 3, -CH 2-OH, -CH (CH 3) -OH, -CH 2-SH, -CH 2-C (=O) NH 2, -CH 2CH 2-C (=O) NH 2, -CH 2CH 2CH 2CH 2-NH 2, -CH 2CH 2CH 2-NH-C (=NH) -NH 2, -CH 2-COOH, -CH 2CH 2-COOH; said -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -CH (CH 3)  2, -CH 2CH 2CH 2CH 3, -CH 2CH (CH 3)  2, -CH (CH 3) CH 2CH 3, 
    Figure PCTCN2021096306-appb-100014
    -CH 2CH 2SCH 3, -CH 2-OH, -CH (CH 3) -OH, -CH 2-SH, -CH 2-C (=O) NH 2, -CH 2CH 2-C (=O) NH 2, -CH 2CH 2CH 2CH 2-NH 2, -CH 2CH 2CH 2-NH-C (=NH) -NH 2, -CH 2-COOH, -CH 2CH 2-COOH is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  27. The compound of any one of claims 1-26, wherein R 92 is selected from  hydrogen, -CH 3, -CH (CH 3)  2, -CH 2CH (CH 3)  2, -CH (CH 3) CH 2CH 3, 
    Figure PCTCN2021096306-appb-100015
    Figure PCTCN2021096306-appb-100016
    -CH 2CH 2SCH 3, -CH 2-OH, -CH (CH 3) -OH, -CH 2-SH, -CH 2-C (=O) NH 2, -CH 2CH 2-C (=O) NH 2, -CH 2CH 2CH 2CH 2-NH 2, -CH 2CH 2CH 2-NH-C (=NH) -NH 2, -CH 2-COOH, -CH 2CH 2-COOH.
  28. The compound of any one of claims 1-27, wherein R 93 is selected from hydrogen, -C 1-3alkyl, -C 1-3alkoxyl, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said -C 1-3alkyl, -C 1-3alkoxyl, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S; or
    R 93 and R 92 together with the atom they respectively are attached to form a 4 membered heterocyclyl, 5 membered heterocyclyl or 6 membered heterocyclyl; said heterocyclyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3  membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  29. The compound of any one of claims 1-28, wherein R 93 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S; or
    R 93 and R 92 together with the atom they respectively are attached to form a 5 membered heterocyclyl or 6 membered heterocyclyl; said heterocyclyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl  independently contains 1 or 2 heteroatoms selected from N, O or S.
  30. The compound of any one of claims 1-29, wherein R 93 is hydrogen; or R 93 and R 92 together with the atom they respectively are attached to form
    Figure PCTCN2021096306-appb-100017
  31. The compound of any one of claims 1-30, wherein R 93 is hydrogen; or R 93 and R 92 together with the atom they respectively are attached to form
    Figure PCTCN2021096306-appb-100018
  32. The compound of any one of claims 1-31, wherein R 94 is selected from hydrogen, -C 1-3alkyl, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl; said -C 1-3alkyl, -CO (C 1-3alkyl) , -COOC 1-3alkyl, -CONH 2, -CONH (C 1-3alkyl) , -CON (C 1-3alkyl)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  33. The compound of any one of claims 1-32, wherein R 94 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, -COCH 3, -COCH 2CH 3, -COCH 2CH 2CH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10  membered heteroaryl; said methyl, ethyl, propyl, isopropyl, -COCH 3, -COCH 2CH 3, -COCH 2CH 2CH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 5 membered cycloalkyl, 6 membered cycloalkyl, 5 membered heterocyclyl, 6 membered hetercyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -Cl, methyl, ethyl, propyl, -CF 3, -OCH 3, -OCF 3, -OH, -NH 2, -NHCH 3, -N (CH 3)  2, oxo, -COCH 3, -COOCH 3, -CONH 2, -CONHCH 3, -CON (CH 3)  2, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membred cycloalkyl, 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membred heteroaryl or 10 membered heteroaryl; said each heterocyclyl or heteroaryl independently contains 1 or 2 heteroatoms selected from N, O or S.
  34. The compound of any one of claims 1-33, wherein R 94 is -COCH 3.
  35. The compound of any one of claims 1-34, wherein R 9 is selected form:
    Figure PCTCN2021096306-appb-100019
  36. The compound of any one of claims 1-35, wherein m is selected from 1, 2, 3, 4, 5, 6 or 7.
  37. The compound of any one of claims 1-36, wherein m is selected from 3, 4, 5 or 6.
  38. The compound of any one of claims 1-37, wherein m is selected from 3, 4, 5  or 6.
  39. The compound of any one of claims 1-38, wherein m is 4.
  40. The compound of any one of claims 1-39, wherein the compound is selected from:
    Figure PCTCN2021096306-appb-100020
    Figure PCTCN2021096306-appb-100021
    Figure PCTCN2021096306-appb-100022
  41. A pharmaceutical composition comprising the compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of any one of claims 1-40; and a pharmaceutically acceptable carrier, diluent or excipient.
  42. A method of treating a subject having a cancer, said method comprising administering to the subject a therapeutically effective amount of the compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of any one of claims 1-40; or the pharmaceutical composition of claim 41.
  43. The mehod of claim 42, wherein the cancer is selected from colon cancer, glioblastoma or head and neck cancer.
  44. Use of the compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of any one of claims 1-38; or the pharmaceutical composition of claim 43 for the manufacture of a medicament for the treatment of a cancer.
  45. The use of claim 44, wherein the cancer is selected from colon cancer, glioblastoma or head and neck cancer.
  46. The compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of any one of claims 1-40; or the pharmaceutical composition of claim 41 for use in the treatment of a cancer.
  47. The compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof; or the pharmaceutical composition of claim 46, wherein the cancer is selected from colon cancer, glioblastoma or head and neck cancer.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017023774A1 (en) * 2015-07-31 2017-02-09 The Johns Hopkins University Prodrugs of glutamine analogs
WO2019071110A1 (en) * 2017-10-06 2019-04-11 The John Hopkins University Novel glutamine antagonists and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017023774A1 (en) * 2015-07-31 2017-02-09 The Johns Hopkins University Prodrugs of glutamine analogs
WO2019071110A1 (en) * 2017-10-06 2019-04-11 The John Hopkins University Novel glutamine antagonists and uses thereof

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Title
TENORA LUK, ALT JESSE, DASH RANJEET P., GADIANO ALEXANDRA J., NOVOTNá KATEřINA, VEERAVALLI VIJAYABHASKAR, LAM JENNY, KIR: "-norleucine (DON) Using Substituted Acetylated Lysine Prodrugs", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 62, no. 7, 11 April 2019 (2019-04-11), US , pages 3524 - 3538, XP055805617, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.8b02009 *

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