WO2022078462A1 - Novel glutamine analogs - Google Patents

Novel glutamine analogs Download PDF

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Publication number
WO2022078462A1
WO2022078462A1 PCT/CN2021/123878 CN2021123878W WO2022078462A1 WO 2022078462 A1 WO2022078462 A1 WO 2022078462A1 CN 2021123878 W CN2021123878 W CN 2021123878W WO 2022078462 A1 WO2022078462 A1 WO 2022078462A1
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Prior art keywords
alkyl
alkylene
aryl
coo
membered heterocyclyl
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PCT/CN2021/123878
Other languages
French (fr)
Inventor
Runze LI
Cunbo Ma
Zhenchang LIAN
Jing XIONG
Yanping Wang
Wei LONG
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Jacobio Pharmaceuticals Co., Ltd.
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Publication of WO2022078462A1 publication Critical patent/WO2022078462A1/en

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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
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    • C07C245/18—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
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    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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    • C—CHEMISTRY; METALLURGY
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the invention relates to a novel glutamine analogs, 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
  • dose limiting GI toxicities such as oral mucositis, gastric bleeding, nausea and vomiting, and abdominal pain
  • a compound of formula I and a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotope substitutant thereof:
  • Z is (OR 1 ) 1-2 , (C (R 1 ) 2 ) 1-6 , (N (R 1 ) ) 1-2 R 1 ’, or (SR 1 ) 1-2 ;
  • R 1 and R 1 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -NH 2 , -CN, -OH, -C 1-6 alkyl, -C 2-6 alkenyl, C 2-6 alkynyl, -C 5-12 aryl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkylene-5-12 membered aryl, -C 0-6 alkylene-C 5-12 aryl, -C 0-6 alkylene -5-12 membered heteroaryl, -C 0-6 alkylene-5-12 membered heterocyclyl, -C 1-6 alkylene-N (C 1-6 alkyl) 2 , -C 1-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene-CO-NH-C 1-6 alkyl, -C 1-6 alkylene-CO-5-12 membered hetero
  • R 1 and R 1 ’ together with the nitrogen atom to which they are both attached form 4-8 membered heterocyclyl, and wherein said 4-8 membered heterocyclyl can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2 , and said 4-8 membered heterocyclyl can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6
  • W is oxygen, CO or a bond
  • n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
  • p and q are each independently selected from 0, 1 or 2, provided that the sum of p and q is 2;
  • R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, halogen, C 1-6 alkyl, -C 1-6 alkylene-SH, -C 1-6 alkylene-C 2-6 alkenyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 3-8 cycloalkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-CONH 2 , -C 1-6 alkylene-Se-C 1-6 alkyl, -C 1-6 alkylene-SH, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-CO 2 -C 1-6 alkyl, C 5-12 aryl, -C 1-6 alkylene-C 5-12 aryl, -C 1-6 alkylene-5-12 membered heteroaryl, -C 1-6 alkylene-5-12 membered heterocyclyl
  • R X1 and R X2 together with the carbon atom to which they are attached form C 3-10 carbocyclic ring, C 5-10 aryl, C 5-10 heteroaryl, C 2-4 alkenyl, C 3-10 heterocyclyl, and wherein said C 3-10 carbocyclic ring, C 5-10 aryl, C 5-10 heteroaryl, C 2-4 alkenyl, C 3-10 heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2 , -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-
  • R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5-12 membered heterocyclyl, and wherein said 5-12 membered heterocyclyl can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2 , and said 5-12 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -
  • each of R 6 is independently selected from the group consisting of hydrogen, deuterium, -C 1-6 alkyl, -C 3-8 cycloalkyl, 5-12 membered heterocyclyl, -C 2-6 alkenyl, and -C 3-8 cycloalkenyl, and wherein said -C 1-6 alkyl, said -C 3-8 cycloalkyl, said 5-12 membered heterocyclyl, said -C 1-6 alkenyl, and said -C 3-8 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl,
  • each of R 7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered heterocyclyl, C 1-6 alkenyl, C 3-8 cycloalkenyl, C 5-12 aryl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said C 3-8 cycloalkyl, said 5-12 membered heterocyclyl, said C 1-6 alkenyl, said C 3-8 cycloalkenyl, said C 5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2 , -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8
  • R 8 and R 9 are each independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, monosaccharide, acylated monosaccharide, C 5-12 aryl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said C 3-8 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C 5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -C
  • R 11 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C
  • G is C 5-12 aryl, or 5-12 membered heteroaryl, and wherein said C 5-12 aryl, and said 5-12 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2 , -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alky
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C
  • R 3 and R 3 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alky
  • Y is a bond, oxygen, or - (CR Y1 R Y2 ) n -;
  • n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
  • R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C
  • R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C
  • R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C
  • provided here is a compound of formula Ia or Ib, and a pharmaceutically acceptable salt thereof or a stereoisomer thereof
  • R 1 and R 1 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, C 2-6 alkynyl, -C 5-12 aryl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-C 5-12 aryl, -5-12 membered heteroaryl, -5-12 membered heterocyclyl, -C 1-6 alkylene-N (C 1-6 alkyl) 2 , -C 1-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene-CO-NH-C 1-6 alkyl, -C 1-6 alkylene-CO-5-12 membered heterocyclyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl and C 3-8 cycloalkyl-C 5-12 aryl,
  • R 1 and R 1 ’ together with the nitrogen atom to which they are both attached form 4-8 membered heterocyclic ring, and wherein said 4-8 membered heterocyclic ring can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2 , and said 4-8 membered heterocyclic ring can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -
  • W is oxygen or a bond
  • n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
  • p and q are each independently selected from 0, 1 or 2, provided that the sum of p and q is 2;
  • R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, halogen, C 1-6 alkyl, -C 1-6 alkylene-SH, -C 1-6 alkylene-C 2-6 alkenyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 3-8 cycloalkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-CONH 2 , -C 1-6 alkylene-Se-C 1-6 alkyl, -C 1-6 alkylene-SH, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-CO 2 -C 1-6 alkyl, C 5-12 aryl, -C 1-6 alkylene-C 5-12 aryl, -C 1-6 alkylene-5-12 membered heteroaryl, -C 1-6 alkylene-5-12 membered heterocyclyl
  • R X1 and R X2 together with the carbon atom to which they are attached form 5-10 membered carbocyclic ring, C 3-8 cycloalkyl, C 2-4 alkenyl, 5-10 membered heterocyclic ring, and wherein said 5-10 membered carbocyclic ring, said C 2-4 alkenyl, said 5-10 membered heterocyclic ring can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2 , -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6
  • R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5-12 membered heterocyclic ring, and wherein said 5-12 membered heterocyclic ring can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2 , and said 5-12 membered heterocyclic ring can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO
  • each of R 6 is independently selected from the group consisting of hydrogen, deuterium, -C 1-6 alkyl, -C 3-8 cycloalkyl, 5-12 membered heterocyclyl ring, -C 1-6 alkenyl, and -C 3-8 cycloalkenyl, and wherein said -C 1-6 alkyl, said -C 3-8 cycloalkyl, said 5-12 membered heterocyclyl ring, said -C 1-6 alkenyl, and said -C 3-8 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alken
  • each of R 7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered heterocyclyl ring, C 1-6 alkenyl, C 3-8 cycloalkenyl, C 5-12 aryl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said C 3-8 cycloalkyl, said 5-12 membered heterocyclyl ring, said C 1-6 alkenyl, said C 3-8 cycloalkenyl, said C 5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2 , -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -
  • R 8 and R 9 are each independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, monosaccharide, acylated monosaccharide, C 5-12 aryl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said C 3-8 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C 5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -C
  • R 11 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C
  • G is C 5-12 aryl, or 5-12 membered heteroaryl, and wherein said C 5-12 aryl, and said 5-12 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2 , -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alky
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C
  • R 3 and R 3 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alky
  • Y is a bond, oxygen, or - (CR Y1 R Y2 ) n -;
  • n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
  • R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C
  • R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C
  • R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C
  • R 1 and R 1 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, C 2-3 alkynyl, -C 5-10 aryl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-C 5-10 aryl, -5-10 membered heteroaryl, -5-10 membered heterocyclyl, -C 1-3 alkylene-N (C 1-3 alkyl) 2 , -C 1-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene-CO-NH-C 1-3 alkyl, -C 1-3 alkylene-CO-5-10 membered heterocyclyl, -C 1-3 alkylene-SO 2 -C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl and C 3-6 cycloalkyl-C 5-10 aryl, and where
  • R 1 and R 1 ’ together with the nitrogen atom to which they are both attached form 4-6 membered heterocyclyl, and wherein said 4-6 membered heterocyclyl can further contains 1, or 2 heteroatoms selected from N, O, S, SO or SO 2 , and said 4-6 membered heterocyclyl can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alky
  • R 1 and R 1 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, C 2-3 alkynyl, -C 5-10 aryl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-C 5-10 aryl, -5-10 membered heteroaryl, -5-10 membered heterocyclyl, -C 1-3 alkylene-N (C 1-3 alkyl) 2 , -C 1-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene-CO-NH-C 1-3 alkyl, -C 1-3 alkylene-CO-5-10 membered heterocyclyl, -C 1-3 alkylene-SO 2 -C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl and C 3-6 cycloalkyl-C 5-10 aryl, and where
  • R 1 and R 1 ’ together with the nitrogen atom to which they are both attached form 4-6 membered heterocyclyl, and wherein said 4-6 membered heterocyclyl can further contains 1, or 2 heteroatoms selected from N, O, S, SO or SO 2 , and said 4-6 membered heterocyclyl can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2 -C 1-3 alkyl,
  • R 1 and R 1 ’ are each independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, vinyl, allyl, ethyne, propyne, C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, -CH 2 -COO-CH 3 , - (CH 2 ) 2 -COO-CH 3 , - (CH 2 ) 3 -COO-CH 3 , -CH 2 -COO-CH 2 CH 3 , - (CH 2 ) 2 -COO-CH 2 CH 3 , - (CH 2 ) 2 -COO-CH 2 CH 3 , - (CH 2 ) 3 -COO-CH 2 CH 3 , - (CH 2 ) 3 -COO-CH 2 CH 3 , -CH 2 ) 3 -COO-
  • R 1 and R 1 ’ together with the nitrogen atom to which they are both attached form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, can further contains 1, or 2 heteroatoms selected from N, O, S, SO or SO 2 , and said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered
  • R 1 and R 1 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, vinyl, allyl, ethyne, propyne, C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, -CH 2 -COO-CH 3 , - (CH 2 ) 2 -COO-CH 3 , - (CH 2 ) 3 -COO-CH 3 , -CH 2 -COO-CH 2 CH 3 , - (CH 2 ) 2 -COO-CH 2 CH 3 , - (CH 2 ) 2 -COO-CH 2 CH 3 , - (CH 2 ) 3 -COO-CH 2 CH 3 , - (CH 2 ) 3 -COO-CH 2 CH 3 , -CH 2 -COO-CH 2 CH 3 ,
  • R 1 and R 1 ’ together with the nitrogen atom to which they are both attached form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, can further contains 1, or 2 heteroatoms selected from N, O, S, SO or SO 2 , and said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -
  • R 1 and R 1 ’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl,
  • R 1 and R 1 ’ together with the nitrogen atom to which they are both attached form said and wherein said and said said can be optionally substituted with one or more substituents, said which are independently selected from the group consisting of F, Cl, Br, I, -OH, oxo, -CN, -C 1-4 alkyl, -C 1-4 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -4-6 membered heterocyclyl, -COO-C 1-3 alkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
  • substituents said which are independently selected from the group consisting of F, Cl, Br, I, -OH, oxo, -
  • R 1 and R 1 ’ together with the nitrogen atom to which they are both attached form said and wherein said and said said can be optionally substituted with one or more substituents, said which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3 , -COO-CH 2 CH 3 , -COO-CH 2 CH 2 CH 3 , -COO-CH (CH 3 ) 2
  • W is oxygen or a bond
  • n is selected from 1, 2, or 3;
  • R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, halogen, C 1-3 alkyl, -C 1-3 alkylene-SH, -C 1-3 alkylene-C 2-3 alkenyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-CONH 2 , -C 1-3 alkylene-Se-C 1-3 alkyl, -C 1-3 alkylene-SH, -C 1-3 alkylene-SO 2 -C 1-3 alkyl, -C 1-3 alkylene-CO 2 -C 1-3 alkyl, C 5-10 aryl, -C 1-3 alkylene-C 5-10 aryl, -C 1-3 alkylene-5-10 membered heteroaryl, -C 1-3 alkylene-5-10 membered heterocyclyl,
  • R X1 and R X2 together with the carbon atom to which they are attached form 5-8 membered carbocyclic ring, C 3-6 cycloalkyl, C 2-3 alkenyl, 5-8 membered heterocyclyl, and wherein said 5-8 membered carbocyclic ring, said C 3-6 cycloalkyl, said C 2-3 alkenyl, and said 5-8 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2 , -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 al
  • R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5-10 membered heterocyclyl, and wherein said 5-10 membered heterocyclyl can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2 , and said 5-12 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -
  • R 11 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C
  • the compound of formula I or Ia a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein
  • W is oxygen or a bond
  • n is selected from 1, 2, or 3;
  • R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, halogen, C 1-3 alkyl, -C 0-3 alkylene-SH, -C 0-3 alkylene-C 2-3 alkenyl, -C 3-6 cycloalkyl, -C 0-3 alkylene-C 3-6 cycloalkyl, -C 0-3 alkylene-S-C 1-3 alkyl, -C 0-3 alkylene-CONH 2 , -C 0-3 alkylene-Se-C 1-3 alkyl, -C 0-3 alkylene-SH, -C 0-3 alkylene-SO 2 -C 1-3 alkyl, -C 0-3 alkylene-CO 2 -C 1-3 alkyl, C 5-10 aryl, -C 0-3 alkylene-C 5-10 aryl, -C 0-3 alkylene-5-10 membered heteroaryl, -C 0-3 al
  • R X1 and R X2 together with the carbon atom to which they are attached form 5-8 membered carbocyclic ring, C 3-6 cycloalkyl, C 2-3 alkenyl, 5-8 membered heterocyclyl, and wherein said 5-8 membered carbocyclic ring, said C 3-6 cycloalkyl, said C 2-3 alkenyl, and said 5-8 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2 , -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-4 al
  • R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5-10 membered heterocyclyl, and wherein said 5-10 membered heterocyclyl can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2 , and said 5-12 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-6 cycloalkyl, -C 1-4 alkylene-C 2-4 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-4 alkylene-COO-C 1-3 alkyl, -C 1-4 alkylene-SO 2 -
  • R 11 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-6 cycloalkyl, -C 1-4 alkylene-C 2-4 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-4 alkylene-COO-C 1-3 alkyl, -C 1-4 alkylene-SO 2 -C 1-3 alkyl, -C 1-4 alkylene-SO-C 1-3 alkyl, -C
  • W is a bond
  • n 1;
  • R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, -CO-CH 3 , -SO-CH 3 , -SO 2 -CH 3 , -NH-CO-CH 3 , and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6
  • W is a bond
  • n 1;
  • R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, -CO-CH 3 , -SO-CH 3 , -SO 2 -CH 3 , -NH-CO-CH 3 , and each of which can be optional substituted with one or more substituents, said which are independently selected from the group consisting of can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalky
  • R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, and wherein said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2 , and said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium,
  • R 11 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; and each of which is optional substituted with one or more substituents, which are independently selected from deuterium, halogen, -OH, oxo, -CN, -NO 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy -C 2-4 alkenyl, -C 2-4 alkynyl, -C 1-4 alkylene-C 2-4 alkenyl, -NH-CO-CH 3 , -CO-NH-CH 3 , -CO-N (CH 3 ) 2 , -COO-CH 3 , -CH 2 -COO-CH 3 , -CH 2 -SO 2 -CH 3 , -CH 2 e-SO-CH 3
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2 -C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alky
  • R 3 and R 3 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alky
  • R 3 and R 3 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2 -C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl,
  • R 3 and R 3 ’ are each independently hydrogen, or deuterium.
  • Y is - (CR Y1 R Y2 ) n -;
  • n is selected from 1, 2, or 3;
  • R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C
  • Y is - (CR Y1 R Y2 ) n -;
  • n 1;
  • R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2 -C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alky
  • Y is - (CR Y1 R Y2 ) n -;
  • n 1;
  • R Y1 and R Y2 are each independently hydrogen or deuterium.
  • R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C
  • R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2 -C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alky
  • R 4 is hydrogen or deuterium.
  • R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2 -C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C
  • R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2 -C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alky
  • the compound of formula I, Ia, Ib or Ic a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein
  • R 10 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-4 alkyl, -C 1-4 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -4-6 membered heterocyclyl, -COO-C 1-3 alkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 ,
  • R 10 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -4 membered heterocycl
  • provided here is a compound of formula Ia-1-3, Ib-1-3 or Ic-1-2, and a pharmaceutically acceptable salt thereof or a stereoisomer thereof
  • the stereoisomer thereof, the tautomer thereof defined herein wherein the configuration of the chiral atom in the compound represented by the general formula I, Ia, Ib, Ia-1, Ia-2, Ia-3, Ib-1, Ib-2, Ib-3, Ic-1, Ic-2, is S-or R-configuration.
  • provided here is a compound of formula Id-1-4, Ie-1-4, If 1-4. Ig 1-4, Ih 1-4, Ii 1-4, Ij 1-4, or Ik 1-4, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, the tautomer thereof
  • the compound is of formula Ia-3, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof:
  • a compound of formula II or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, the tautomer thereof
  • R 1 , R 1 ’, R X1 , R X2 , R 5 , and R 5’ is the same as defined herein.
  • R 1 and R 1 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, C 2-3 alkynyl, -C 5-10 aryl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-C 5-10 aryl, -5-10 membered heteroaryl, -5-10 membered heterocyclyl, -C 1-3 alkylene-N (C 1-3 alkyl) 2 , -C 1-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene-CO-NH-C 1-3 alkyl, -C 1-3 alkylene-CO-5-10 membered heterocyclyl, -C 1-3 alkylene-SO 2 -C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl and C 3-6 cycloalkyl-C 5-10 aryl; each of
  • R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, halogen, C 1-3 alkyl, -C 1-3 alkylene-SH, -C 1-3 alkylene-C 2-3 alkenyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-CONH 2 , -C 1-3 alkylene-Se-C 1-3 alkyl, -C 1-3 alkylene-SH, -C 1-3 alkylene-SO 2 -C 1-3 alkyl, -C 1-3 alkylene-CO 2 -C 1-3 alkyl, C 5-10 aryl, -C 1-3 alkylene-C 5-10 aryl, -C 1-3 alkylene-5-10 membered heteroaryl, -C 1-3 alkylene-5-10 membered heterocyclyl,
  • R 1 and R 1 ’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, vinyl, allyl, ethyne, propyne, C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, -CH 2 -COO-CH 3 , - (CH 2 ) 2 -COO-CH 3 , - (CH 2 ) 3 -COO-CH 3 , -CH 2 -COO-CH 2 CH 3 , - (CH 2 ) 2 -COO-CH 2 CH 3 , - (CH 2 ) 2 -COO-CH 2 CH 3 , - (CH 2 ) 3 -COO-CH 2 CH 3 , - (CH 2 ) 3 -COO-CH 2 CH 3 , -CH 2 -COO-CH 2 CH 3 ,
  • R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, -CO-CH 3 , -SO-CH 3 , -SO 2 -CH 3 , -NH-CO-CH 3 , and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; or
  • R 1 and R 1 ’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl,
  • R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium methyl, ethyl, propyl, isopropyl, tert-butyl,
  • 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 presently disclosed subject matter provides the use of a compound of the present invention, or a pharmaceutical composition thereof, for treating a disease or condition.
  • the disease or condition is selected from the group consisting of an infection, cancer, an autoimmune disease, an inflammatory disease, and a neurodegenerative or neurological disease.
  • a "cancer” in a patient refers to the presence of cells possessing characteristics typical of cancer-causing cells, for example, uncontrolled proliferation, loss of specialized functions, immortality, significant metastatic potential, significant increase in anti-apoptotic activity, rapid growth and proliferation rate, and certain characteristic morphology and cellular markers.
  • cancer cells will be in the form of a tumor; such cells may exist locally within an animal, or circulate in the blood stream as independent cells, for example, leukemic cells.
  • a “tumor, " as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues.
  • a "solid tumor, " as used herein, is an abnormal mass of tissue that generally does not contain cysts or liquid areas.
  • a solid tumor may be in the brain, colon, breasts, prostate, liver, kidneys, lungs, esophagus, head and neck, ovaries, cervix, stomach, colon, rectum, bladder, uterus, testes, and pancreas, as non-limiting examples.
  • the solid tumor regresses or its growth is slowed or arrested after the solid tumor is treated with the presently disclosed methods.
  • the solid tumor is malignant.
  • the cancer comprises Stage 0 cancer.
  • the cancer comprises Stage I cancer.
  • the cancer comprises Stage II cancer.
  • the cancer comprises Stage III cancer. In some embodiments, the cancer comprises Stage IV cancer. In some embodiments, the cancer is refractory and/or metastatic. For example, the cancer may be refractory to treatment with radiotherapy, chemotherapy or monotreatment with immunotherapy.
  • Cancer as used herein includes newly diagnosed or recurrent cancers, including without limitation, acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, breast carcinoma, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, colorectal carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung carcinoma, Lewis lung carcinoma, lymphoma, malignant fibrous histiocytoma, a mammary tumor, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, a pontine tumor, premen
  • the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer.
  • provided here is 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.
  • the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer.
  • the medicament is used as a glutamine antagonist.
  • glutamine antagonist refers to a glutamine analog that interfers with a glutamine metabolic pathway, e.g., the inhibition or blocking of a metabolic pathway downstream of glutamine in which glutamine acts as a precursor of one or more non-glutamine compounds.
  • glutamine metabolic pathway e.g., the inhibition or blocking of a metabolic pathway downstream of glutamine in which glutamine acts as a precursor of one or more non-glutamine compounds.
  • Examples of such metabolic pathways are well known (see, e.g., Hensley et al, "Glutamine and cancer: cell biology, physiology, and clinical opportunities” J Clin Invest. 2013; 123 (9) : 3678-3684; DeBerardinis et al, "Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer” Oncogene.
  • glutamine antagonist also includes glutamine analogs that inhibit glutamine uptake by cells, thereby reducing its biological activity. Diseases or conditions wherein excess and/or aberrant glutamine.
  • the compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of the present invention for use in treating the disease or condition.
  • the disease or condition is selected from the group consisting of an infection, cancer, an autoimmune disease, an inflammatory disease, and a neurodegenerative or neurological disease.
  • provided here is the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention; or the pharmaceutical composition of the present invention for use in therapy.
  • provided here is the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention; or the pharmaceutical composition of the present invention for use as a medicament.
  • the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention for use in treating the disease or condition.
  • the disease or condition is selected from the group consisting of an infection, cancer, an autoimmune disease, an inflammatory disease, and a neurodegenerative or neurological disease.
  • 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 lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer.
  • FIG. 1 is a graph showing the concentrations of DON and reference compound over time after IV infusion.
  • FIG. 2 is a graph showing the concentrations of DON and compound 2 over time after IV infusion.
  • FIG. 3 is a graph showing the concentrations of DON and compound 1 over time after IV infusion.
  • FIG. 4 is a bar graph showing the stability of compounds after incubation for 60 minutes in the presence of human microsomes.
  • FIG. 5 is a bar graph showing the stability of compounds after incubation for 60 minutes in the presence of human microsomes.
  • FIG. 6 is a graph showing the body weight changes of the mice in the different groups.
  • FIG. 7 is a graph showing anti-tumor activity of test compounds in MC38 syngeneic model.
  • 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 heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl or sipro heterocyclyl.
  • 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.
  • carbocycle refers to a substituted or unsubstituted monocyclic ring, bicyclic ring bridged ring, fused ring, sipiro ring non-aromatic ring system only containing carbon atoms ( (i.e., C 3-14 ) .
  • Non-limiting exemplary carbocycle groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and cyclopentenyl, cyclohexenyl.
  • the term "carbocycle" as used by itself or as part of another group means that the carbocycle as defined above substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino) alkyl, (carboxamido) alkyl, mercaptoalkyl, and (heter
  • fused ring refers to a cyclic group formed by substituents on separate atoms in a straight or branched alkane, or to a cyclic group formed by substituents on separate atoms in another ring.
  • spirocycle or "spirocyclic ring” refers to a pendant cyclic group formed by substituents on a single atom.
  • 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.
  • Step a To a solution of (S) -2- (l2-azaneyl) butanoic acid (1023 mg, 9.9205 mmol) in acetic acid (10 mL) was added acetic anhydride (1769 mg, 17.3281 mmol) . The mixture was stirred for 2h at 100 °C. The reaction mixture was concentrated under reduced pressure. The residue was stirred in EA, then filtered and the solid was collected to afford (S) -2-acetamidobutanoic acid (628 mg, 4.3264 mmol) . MS: m/z 144 (M-H) -
  • Step b To a solution of (S) -2-acetamidobutanoic acid (0.628 g, 4.3264 mmol) and methyl (S) -2-amino-6-diazo-5-oxohexanoate (498 mg, 2.6893 mmol) in DCM (5 mL) was added ethyl cyanoglyoxylate-2-oxime (624 mg, 4.3909 mmol) , N, N'-Diisopropylcarbodiimide (539 mg, 4.2710 mmol) and 2, 4, 6-Collidine (679 mg, 5.6033 mmol) at 0 °C. The mixture was stirred at RT for 1 h.
  • Step c To a solution of methyl (S) -2- ( (S) -2-acetamidobutanamido) -6-diazo-5-oxohexanoate (1.269 g, 4.0631 mmol) in THF (10 mL) added LiOH (156.2 mg, 6.5224 mmol) in water (5 mL) at 0°C. The mixture was stirred for 1h at RT and the reaction mixture was purified by FLASH (MeCN/H2O, 0 ⁇ 10%) . The product’s solution was concentrated under reduced pressure and the residue was further purified by pre-HPLC.
  • Step a To a solution of DL-Serine (1.64 g, 15.6054 mmol) , 5-Fluoroindole (1.01 g, 7.4738 mmol) was added acetic anhydride (5 mL) and acetic acid (20mL) under N 2 protection. The mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC. The product’s solution was concentrated under reduced pressure to afford 2-acetamido-3- (5-fluoro-1H-indol-3-yl) propanoic acid (2044 mg, 7.7350 mmol) . MS: m/z 265 (M+H) + ,
  • Step a To a solution of Nalpha-Fmoc-L-Tryptophan (1348 mg, 3.161 mmol) , isopropyl (S) -2-amino-6-diazo-5-oxohexanoate (452 mg, 2.120 mmol) and 4-Methylmorpholine (666 mg, 6.584 mmol) in DMF (10 mL) was added HATU (1226 mg, 3.224 mmol) at 0°C. The mixture was stirred for 3h at 0 °C ⁇ RT, then to the mixture was added water (10 mL) and DCM (10 mL) . The reaction mixture was filtered and the organic phase was collected.
  • Step b To a solution of isopropyl (S) -2- ( (S) -2- ( ( ( (9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (1H-indol-3-yl) propanamido) -6-diazo-5-ox ohexanoate (469 mg, 754.406 ⁇ mol) in DCM (50 mL) was added piperidine (224 mg, 2.631 mmol) at 0 °C. The mixture was stirred for 6h at 0 °C ⁇ RT. The reaction mixture was concentrated under reduced pressure.
  • Step c To a solution of isobutyric acid (0.0813 g, 922.765 ⁇ mol) , N, N'-Diisopropylcarbodiimide (0.1202 g, 952.464 ⁇ mol) 2, 4, 6-Collidine (0.1642 g, 1.355 mmol) and Ethyl cyanoglyoxylate-2-oxi (0.1876 g, 1.320 mmol) in DMF (5 mL) was added isopropyl (S) -2- ( (S) -2-amino-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoate (0.0938 g, 234.827 ⁇ mol) at 0 °C.
  • the mixture was stirred for 5 h at 0 °C ⁇ RT and to the mixture was added water (10 mL) and DCM (10 mL) , then the reaction mixture was filtered and the organic phase was collected. The aqueous solution was extracted with DCM (10 mL ⁇ 2) and the organic phase was combined. The combined organic phase washed with brine (10 mL ⁇ 3) and dried over anhydrous Na 2 SO 4 . The resulting mixture was concentrated under reduced pressure.
  • Step d To a solution of
  • Step b To a 0°C solution of methyl (S) -2-hydroxy-3- (1H-indol-3-yl) propanoate (0.283g, 1.291 mmol) in DCM (3 mL) was added TEA (498 mg, 4.921 mmol) , then 4-methylbenzenesulfonyl chloride was added dropwise. The mixture was stirred for 1 h at this temperature and the reaction mixture was quenched with NaHCO 3 (aq) (10 mL) . The aqueous layer was separated and extracted with DCM (2 ⁇ 10 mL) .
  • Step c To a 0°C solution of ethanethiol (327 mg, 5.263 mmol) and MeONa (286 mg, 5.294 mmol) in MeOH (3 mL) under nitrogen atmosphere was added methyl (S) -3- (1H-indol-3-yl) -2- (tosyloxy) propanoate (482. mg, 1.291 mmol) in MeOH (2 mL) dropwise. Then the resulting solution was stirred for 2 hours at room temperature. HCl (4M solution in EA, 3 mL) was added, the solid was filtered through a pad of Celite followed by MeOH washing and the filtrate was concentrated under reduced pressure.
  • Step d To a solution of methyl (R) -2- (ethylthio) -3- (1H-indol-3-yl) propanoate (125 mg, 474.644 ⁇ mol) in THF (2 mL) was added LiOH (2M solution in water, 1 mL) . The mixture was stirred for 2 h at room temperature. After citric acid (solid) was added, the reaction was diluted with water (5mL) and extracted with EA (2 ⁇ 10 mL) .
  • Step a To a solution of methyl (S) -2-hydroxy-3- (1H-indol-3-yl) propanoate (2 g, 9.123 mmol) in DCM (20 mL) was added Imidazole (2061 mg, 30.274 mmol) and TBDMS-Cl (2980 mg, 19.772 mmol) . The mixture was stirred for overnight at RT. The reaction mixture was quenched with Water (10 mL) and extracted with DCM (10 mL) . The reaction mixture was separated and organic extracts were collected. The aqueous solution was extracted with DCM (2 ⁇ 10 mL) . The residue was purified by wet column chromatography with EA/Hex (0-20%) .
  • Step b To a -78°C solution of methyl (S) -2- ( (tert-butyldimethylsilyl) oxy) -3- (1H-indol-3-yl) propanoate (3.099g, 9.292 mmol) in THF (30 mL) was added LiHMDS (10.5 mL, 10.491 mmol) . The mixture was stirred for 30min at -78°C. Then Carbobenzyloxy chloride (4623 mg, 27.100 mmol) was dropped into the mixture at -78°C. The reaction mixture was stirred for 1h at this temperature. The reaction was quenched with sat.
  • Step c To a solution of benzyl (S) -3- (2- ( (tert-butyldimethylsilyl) oxy) -3-methoxy-3-oxopropyl) -1H-indole-1-carboxylate (4.345 g, 9.292 mmol) in THF (30 mL) was added Tetrabutylammonium fluoride (5 mL) . The mixture was stirred for overnight at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by FLASH with EA/Hex (0-60%) . The product’s solution was concentrated under reduced pressure.
  • Step d To a solution of benzyl 3- [ (2S) -2-hydroxy-3-methoxy-3-oxo-propyl] indole-1-carboxylate (103 mg, 291.481 ⁇ mol) , and 4A molecular sieve in CH 3 I (1mL) was added Silver oxide (216 mg, 932.098 ⁇ mol) . The mixture was stirred for overnight at RT. The reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with EA (5mL) and filtered, the filtrate was concentrated to afford benzyl (S) -3- (2, 3-dimethoxy-3-oxopropyl) -1H-indole-1-carboxylate (107.088 mg, 100.000%yield) . MS: m/z 368 (M+H) + .
  • Step e To a solution of benzyl (S) -3- (2, 3-dimethoxy-3-oxopropyl) -1H-indole-1-carboxylate (0.107g, 291.240 ⁇ mol) in THF (5 mL) and MeOH (5mL) was added NaOH (3mL, 3M/L) . The mixture was stirred for 1h at RT. The reaction mixture was adjusted the pH to 3 with 1M HCl. The aqueous solution was extracted with EA (2 ⁇ 10 mL) . The combined organic extracts were washed with brine (3 ⁇ 10 mL) , dried over anhydrous Na 2 SO 4 . The organic phase was concentrated under reduced pressure and (S) -3- (1H-indol-3-yl) -2-methoxypropanoic acid (71 mg) was obtained. MS: m/z 220 (M+H) + .
  • Ethyl cyanoglyoxylate-2-oxime (0.1079 g, 759.2576 ⁇ mol) and Glycine methyl ester hydrochloride (0.1582 g, 1.2600mmol) at 0 °C.
  • the mixture was stirred at 0 °C ⁇ RT for 3h.
  • the aqueous solution was extracted with DCM (10 mL ⁇ 2) .
  • the combined organic extracts were washed with brine (10 mL ⁇ 3) and dried over anhydrous Na 2 SO 4 .
  • the reaction mixture was purified by FLASH.
  • the residue was further purified by pre-HPLC.
  • Step b To a solution of 2-acetamido-3- (7-fluoro-1H-indol-3-yl) propanoic acid (0.122 g,461.681 ⁇ mol) , isopropyl (S) -2-amino-6-diazo-5-oxohexanoate (101 mg, 473.660 ⁇ mol) and DIPEA (164 mg, 1.269 mmol) in DCM was added HATU (182 mg, 478.659 ⁇ mol) . The mixture was stirred at RT for one night. The reaction mixture was concentrated under reduced pressure.
  • the dog pharmacokinetic study was conducted in accordance with the guidelines recommended in Guide for the Care and Use of Laboratory Animals and approved by the Beijing Piroma Biotech Inc.
  • Blood sample were collected at 0min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h, post dose, in tubes with EDTA-K2. Blood samples were centrifuged at a temperature of 4 °C at 3000g for 10 min. All samples were kept chilled throughout processing. Plasma samples were collected in polypropylene tubes and stored at -80 °C until bioanalysis.
  • plasma samples 50 ⁇ L were processed using a single liquid extraction method by addition of 200 ⁇ L of acetonitrile containing internal standard (Dexamethasone 100 ng/mL) , followed by vortex-mixing for 30 s and then centrifugation at 15000g for 5 min at 4 °C. 100 ⁇ L of the supernatant was diluted with 100 ⁇ L of water and transferred to a 250 ⁇ L polypropylene vial sealed with a Teflon cap. Prodrug and DON disappearance was monitored over time using a liquid chromatography and tandem mass spectrometry (LC-MS/MS) .
  • LC-MS/MS liquid chromatography and tandem mass spectrometry
  • DON was analyzed on an ExionLC system coupled with a REF Triple Quad 5500+ mass spectrometer. Separation was achieved at 25 °C using an HALO Penta-HILIC 2.7 ⁇ M 90A (2.1x100 mm) .
  • the mass spectrometer controlled by Analyst software 1.6.3 was operated with a heated ESI ionsource in positive ionization mode.
  • FIG. 1 is a graph showing the concentrations of DON and reference compound over time after IV infusion (intravenous infusion) .
  • FIG. 2 is a graph showing the concentrations of DON and compound 2 over time after IV infusion.
  • FIG. 3 is a graph showing the concentrations of DON and compound 1 over time after IV infusion. The pharmacokinetic data was shown in the following Table 1.
  • Reference compound, reference compound 1, compound 494, compound 495, compound 499, compound 501, compound 527 and compound 530 were provided for metabolic stability in human plasma and microsomes, and they were shown as below:
  • Reference compound reference compound 1, compound 494, compound 495, compound 499, compound 501, compound 527 and compound 530 (the concentration of the each compound was 1 ⁇ M) were spiked in each microsomes matrix and incubated in an orbital shaker at 37 °C respectively.
  • 50 ⁇ L aliquots of the mixture in duplicate were obtained, and 200 ⁇ L of ice cold acetonitrile spiked with the internal standard (Dexamethasone 100 ng/mL) was added into the obtained mixture to quench the reaction of the obtained mixture.
  • the samples were vortexed for 30 s and centrifuged at 15000g for 5 min.
  • FIG. 4 and FIG. 5 is a bar graph showing the stability of compounds after incubation for 60 minutes in the presence of human microsomes.
  • the MC38 tumor cells were maintained in vitro in DMEM medium supplemented with 10%FBS at 37 °C, 5%CO 2 .
  • the cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
  • the culture MC38 were harvested, re-suspended in PBS containing 50%Matrigel at a density of 1 ⁇ 10 7 cells/mL.
  • Each mouse was inoculated subcutaneously in the right flank region with 1 ⁇ 10 6 cells in 0.1 mL of PBS containing 50%Matrigel for tumor development.
  • the treatments were started when the mean tumor size reached 46-132mm 3 (average tumor size 95 mm 3 ) .
  • Each group contained 5 tumor bearing mice.
  • Group 1 was treated with Vehicle (10%DMSO + 90%Saline) , S.C., QD (Subcutaneous injection, quaque die) .
  • Group 2 was given treatments with reference compound at 2 ⁇ mol/kg, S.C., QD.
  • Group 3 was given treatments with compound 35 at 2 ⁇ mol/kg, S.C., QD.
  • Group 4 was given treatments with compound 3 at 2 ⁇ mol/kg, S.C., QD.
  • Table 2 was treated with Vehicle (10%DMSO + 90%Saline) , S.C., QD (Subcutaneous injection, quaque die) .
  • Group 3 was given treatments with compound 35 at 2 ⁇ mol/kg, S.C., QD.
  • Group 4 was given treatments with compound 3 at 2 ⁇ mol/kg, S.C., QD.
  • Table 2 was given treatments with compound
  • TGI tumor growth inhibition
  • Group treated with reference compound showed some body weight loss, but the group treated with vehicle, the group treated with compound 505 and the group treated with compound 474 were well-tolerated by the tumor-bearing mice.
  • the results of the body weight changes in the tumor-bearing mice are shown in Table 3, FIG. 6.

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Abstract

Glutamine analogs are provided, a composition containing the glutamine analogs and the use thereof.

Description

Novel Glutamine Analogs
Cross Reference To Related Applications
The application claims the benefit of PCT application Ser. No. PCT/CN2020/121114 filed on Oct. 15, 2020; PCT application Ser. No. PCT/CN2021/072115 and PCT/CN2021/072122 filed on Jan. 15, 2021; and PCT application Ser. No. PCT/CN2021/076480 and PCT/CN2021/076483 filed on Feb. 10, 2021. The entire contents of these applications are incorporated herein by reference in their entirety.
Technical Field
The invention relates to a novel glutamine analogs, 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) has hampered their clinical development when administering such glutamine antagonists at therapeutic dose levels.
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, provided here is a compound of formula I, and a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotope substitutant thereof:
Figure PCTCN2021123878-appb-000001
Wherein,
Z is (OR 1)  1-2, (C (R 1)  2)  1-6, (N (R 1) )  1-2 R 1’, or (SR 1)  1-2;
R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -NH 2, -CN, -OH, -C 1-6 alkyl, -C 2-6 alkenyl, C 2-6 alkynyl, -C 5-12 aryl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkylene-5-12 membered aryl, -C 0-6 alkylene-C 5-12 aryl, -C 0-6 alkylene -5-12 membered heteroaryl, -C 0-6 alkylene-5-12 membered heterocyclyl, -C 1-6 alkylene-N (C 1-6 alkyl)  2, -C 1-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene-CO-NH-C 1-6 alkyl, -C 1-6 alkylene-CO-5-12 membered  heterocyclyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-SH, and C 3-8 cycloalkyl-C 5-12 aryl, and each of which can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6alkylene-5-12 membered aryl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6alkyl, -C 1-6alkylene-COO-C 1-6alkyl, -C 1-6 alkylene-SO 2-C 1-6alkyl, -C 1-6alkylene-SO-C 1-6alkyl, -C 1-6alkylene-SH, -C 1-6alkylene-S-C 1-6alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl; or
R 1 and R 1’ together with the nitrogen atom to which they are both attached form 4-8 membered heterocyclyl, and wherein said 4-8 membered heterocyclyl can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2, and said 4-8 membered heterocyclyl can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
X is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, –C (=O) -G, –C (=O) -W- (CR X1R X2)  m-G, –C (=O) -W- (CR X1R X2)  m-NR 5R 5’, –C (=O) -W- (CR X1R X2)  m-OR 11, –C (=O) -W- (CR X1R X2)  m-SR 11, , C (=O) -W- (CR X1R X2)  m-SOR 11, C (=O) -W- (CR X1R X2)  m-SO 2R 11, -P (=O) (OR 6)  p (NHR 7)  q, -P (=O) (OG)  p, –C (=O) -W- (CR X1R X2)  m-G-O-C (=O) -R 8, –C (=O) -W- (CR X1R X2)  m-G-O-R 8, –C (=O) -O- (CR X1R X2)  m-O-C (=O) -R 9, -C (=O) -O-R 7, –C (=O) -W- (CR X1R X2)  m-G-O-C (=O) -G, and –C (=O) -W- (CR X1R X2)  m-G-NR 5R 5’;
W is oxygen, CO or a bond;
m is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
p and q are each independently selected from 0, 1 or 2, provided that the sum of p and q is 2;
R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, halogen, C 1-6 alkyl, -C 1-6 alkylene-SH, -C 1-6 alkylene-C 2-6 alkenyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 3-8 cycloalkyl, -C 1-6alkylene-S-C 1-6alkyl, -C 1-6 alkylene-CONH 2, 
Figure PCTCN2021123878-appb-000002
-C 1-6 alkylene-Se-C 1-6 alkyl, -C 1-6alkylene-SH, -C 1-6alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-CO 2-C 1-6 alkyl, C 5-12aryl, -C 1-6 alkylene-C 5-12 aryl, -C 1-6 alkylene-5-12 membered heteroaryl, -C 1-6 alkylene-5-12 membered heterocyclyl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said -C 1-6 alkylene-SH, said -C 1-6 alkylene-C 2-6 alkenyl, said -C 3-8 cycloalkyl, said -C 1-6 alkylene-C 3-8 cycloalkyl, said -C 1-6 alkylene-S-C 1-6 alkyl, said -C 1-6 alkylene-CONH 2, said
Figure PCTCN2021123878-appb-000003
said 
Figure PCTCN2021123878-appb-000004
said -C 1-6 alkylene-Se-C 1-6 alkyl, said -C 1-6 alkylene-SH, said -C 1-6 alkylene-SO 2-C 1-6 alkyl, said -C 1-6 alkylene-CO 2-C 1-6 alkyl, said C 5-12aryl, said -C 1-6 alkylene-C 5-12 aryl, said -C 1-6 alkylene-5-12 membered heteroaryl, said -C 1-6 alkylene-5-12 membered heterocyclyl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
or R X1 and R X2 together with the carbon atom to which they are attached form C 3-10 carbocyclic ring, C 5-10 aryl, C 5-10 heteroaryl, C 2-4 alkenyl, C 3-10 heterocyclyl, and wherein said C 3-10 carbocyclic ring, C 5-10 aryl, C 5-10 heteroaryl, C 2-4 alkenyl, C 3-10heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl; R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, -C 1-6 alkyl, -C 3-8 cycloalkyl, -C (=O) -C 1-6 alkyl, -C (=O) -C 3-8 cycloalkyl, -C (=O) -5-12 membered heterocyclyl, -C (=O) -5-12 membered carbocyclic, -C (=O) -adamantanyl, -C (=O) -C 1-6  alkylene-O-C 1-6 alkyl, -C (=O) -C 1-6 alkylene-NH-C 1-6 alkyl, -C (=O) -C 1-6 alkylene-N (C 1-6 alkyl)  2, and wherein said -C 1-6 alkyl, said -C 3-8 cycloalkyl, said -C (=O) -C 1-6 alkyl, said -C (=O) -C 3-8 cycloalkyl, -C (=O) -5-12 membered heterocyclyl, -C (=O) -5-12 membered carbocyclic, -C (=O) -C 1-6 alkylene-O-C 1-6 alkyl, -C (=O) -C 1-6 alkylene-NH-C 1-6 alkyl, -C (=O) -C 1-6 alkylene-N (C 1-6 alkyl)  2, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted or unsubstituted with halogen and -C 1-6 haloalkyl;
or R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5-12 membered heterocyclyl, and wherein said 5-12 membered heterocyclyl can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2, and said 5-12 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted or unsubstituted with halogen and -C 1-6 haloalkyl;
each of R 6 is independently selected from the group consisting of hydrogen, deuterium, -C 1-6 alkyl, -C 3-8 cycloalkyl, 5-12 membered heterocyclyl, -C 2-6 alkenyl, and -C 3-8 cycloalkenyl, and wherein said -C 1-6 alkyl, said -C 3-8 cycloalkyl, said 5-12 membered heterocyclyl, said -C 1-6 alkenyl, and said -C 3-8 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl,  -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted or unsubstituted with halogen and -C 1-6 haloalkyl;
or R 6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
each of R 7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered heterocyclyl, C 1-6 alkenyl, C 3-8 cycloalkenyl, C 5-12 aryl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said C 3-8 cycloalkyl, said 5-12 membered heterocyclyl, said C 1-6 alkenyl, said C 3-8 cycloalkenyl, said C 5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted or unsubstituted with halogen and -C 1-6 haloalkyl;
R 8 and R 9 are each independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, monosaccharide, acylated monosaccharide, C 5-12 aryl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said C 3-8 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C 5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted or unsubstituted with halogen and -C 1-6 haloalkyl;
R 11 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6  alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted or unsubstituted with halogen and -C 1-6 haloalkyl;
G is C 5-12 aryl, or 5-12 membered heteroaryl, and wherein said C 5-12 aryl, and said 5-12 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
R 3 and R 3’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
or R 3 and R 3’ together with the atom to which they attached to form
Y is a bond, oxygen, or - (CR Y1R Y2)  n-;
n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl.
In some embodiments, provided here is a compound of formula Ia or Ib, and a pharmaceutically acceptable salt thereof or a stereoisomer thereof
Figure PCTCN2021123878-appb-000005
Figure PCTCN2021123878-appb-000006
In some embodiments of formula I, Ia, or Ib, wherein
R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, C 2-6 alkynyl, -C 5-12 aryl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-C 5-12 aryl, -5-12 membered heteroaryl, -5-12 membered heterocyclyl, -C 1-6 alkylene-N (C 1-6 alkyl)  2, -C 1-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene-CO-NH-C 1-6 alkyl, -C 1-6 alkylene-CO-5-12 membered heterocyclyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl and C 3-8 cycloalkyl-C 5-12 aryl, and wherein said -C 1-6 alkyl, said -C 1-6 alkenyl, said C 1-6 alkynyl, said -C 5-12 aryl, said -C 1-6 alkylene-COO-C 1-6 alkyl, said -C 1-6 alkylene-C 5-12 aryl, said -5-12 membered heteroaryl, said -5-12 membered heterocyclyl, said -C 1-6 alkylene-N (C 1-6 alkyl)  2, said -C 1-6 alkylene-O-C 1-6 alkyl, said -C 1-6 alkylene-CO-NH-C 1-6 alkyl, said -C 1-6 alkylene-CO-5-12 membered heterocyclyl, said -C 1-6 alkylene-SO 2-C 1-6 alkyl, said -C 1-6 alkylene-SO-C 1-6 alkyl, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl; or
R 1 and R 1’ together with the nitrogen atom to which they are both attached form 4-8 membered heterocyclic ring, and wherein said 4-8 membered heterocyclic ring can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2, and said 4-8 membered heterocyclic ring can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
X is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, –C (=O) -G, –C (=O) -W- (CR X1R X2)  m-G, –C (=O) -W- (CR X1R X2)  m-NR 5R 5’, C (=O) -W- (CR X1R X2)  m-SR 11, ,  C (=O) -W- (CR X1R X2)  m-SOR 11, C (=O) -W- (CR X1R X2)  m-SO 2R 11, –C (=O) -W- (CR X1R X2)  m-OR 11, -P (=O) (OR 6)  p (NHR 7)  q, –C (=O) -W- (CR X1R X2)  m-G-O-C (=O) -R 8, –C (=O) -W- (CR X1R X2)  m-G-O-R 8, –C (=O) -O- (CR X1R X2)  m-O-C (=O) -R 9, -C (=O) -O-R 7, –C (=O) -W- (CR X1R X2)  m-G-O-C (=O) -G, and –C (=O) -W- (CR X1R X2)  m-G-NR 5R 5’;
W is oxygen or a bond;
m is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
p and q are each independently selected from 0, 1 or 2, provided that the sum of p and q is 2;
R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, halogen, C 1-6 alkyl, -C 1-6 alkylene-SH, -C 1-6 alkylene-C 2-6 alkenyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 3-8 cycloalkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-CONH 2, 
Figure PCTCN2021123878-appb-000007
-C 1-6 alkylene-Se-C 1-6 alkyl, -C 1-6 alkylene-SH, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-CO 2-C 1-6 alkyl, C 5-12aryl, -C 1-6 alkylene-C 5-12 aryl, -C 1-6 alkylene-5-12 membered heteroaryl, -C 1-6 alkylene-5-12 membered heterocyclyl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said -C 1-6 alkylene-SH, said -C 1-6 alkylene-C 2-6 alkenyl, said -C 3-8 cycloalkyl, said -C 1-6 alkylene-C 3-8 cycloalkyl, said -C 1-6 alkylene-S-C 1-6 alkyl, said -C 1-6 alkylene-CONH 2, said
Figure PCTCN2021123878-appb-000008
said
Figure PCTCN2021123878-appb-000009
said -C 1-6 alkylene-Se-C 1-6 alkyl, said -C 1-6 alkylene-SH, said -C 1-6 alkylene-SO 2-C 1-6 alkyl, said -C 1-6 alkylene-CO 2-C 1-6 alkyl, said C 5-12aryl, said -C 1-6 alkylene-C 5-12 aryl, said -C 1-6 alkylene-5-12 membered heteroaryl, said -C 1-6 alkylene-5-12 membered heterocyclyl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
or R X1 and R X2 together with the carbon atom to which they are attached form 5-10 membered carbocyclic ring, C 3-8 cycloalkyl, C 2-4 alkenyl, 5-10 membered heterocyclic ring, and wherein said 5-10 membered carbocyclic ring, said C 2-4 alkenyl, said 5-10 membered heterocyclic ring can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl; R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, -C 1-6 alkyl, -C 3-8 cycloalkyl, -C (=O) -C 1-6 alkyl, -C (=O) -C 5-10 carbocyclic, -C (=O) -adamantanyl, -C (=O) -C 3-8 cycloalkyl, and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
or R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5-12 membered heterocyclic ring, and wherein said 5-12 membered heterocyclic ring can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2, and said 5-12 membered heterocyclic ring can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
each of R 6 is independently selected from the group consisting of hydrogen, deuterium, -C 1-6 alkyl, -C 3-8 cycloalkyl, 5-12 membered heterocyclyl ring, -C 1-6 alkenyl, and -C 3-8 cycloalkenyl,  and wherein said -C 1-6 alkyl, said -C 3-8 cycloalkyl, said 5-12 membered heterocyclyl ring, said -C 1-6 alkenyl, and said -C 3-8 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
or R 6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
each of R 7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered heterocyclyl ring, C 1-6 alkenyl, C 3-8 cycloalkenyl, C 5-12 aryl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said C 3-8 cycloalkyl, said 5-12 membered heterocyclyl ring, said C 1-6 alkenyl, said C 3-8 cycloalkenyl, said C 5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
R 8 and R 9 are each independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, monosaccharide, acylated monosaccharide, C 5-12 aryl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said C 3-8 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C 5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl,  -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
R 11 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
G is C 5-12 aryl, or 5-12 membered heteroaryl, and wherein said C 5-12 aryl, and said 5-12 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
R 3 and R 3’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8  cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
Y is a bond, oxygen, or - (CR Y1R Y2)  n-;
n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl; or
R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, C 2-3 alkynyl, -C 5-10 aryl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-C 5-10 aryl, -5-10 membered heteroaryl, -5-10 membered heterocyclyl, -C 1-3 alkylene-N (C 1-3 alkyl)  2, -C 1-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene-CO-NH-C 1-3 alkyl, -C 1-3 alkylene-CO-5-10 membered heterocyclyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl and C 3-6 cycloalkyl-C 5-10 aryl, and wherein said -C 1-3 alkyl, said -C 2-3 alkenyl, said C 2-3 alkynyl, said -C 5-10 aryl, said -C 1-3 alkylene-COO-C 1-3 alkyl, said -C 1-3 alkylene-C 5-10 aryl, said -5-10 membered heteroaryl, said -5-10 membered heterocyclyl, said -C 1-3 alkylene-N (C 1-3 alkyl)  2, said -C 1-3 alkylene-O-C 1-3 alkyl, said -C 1-3 alkylene-CO-NH-C 1-3 alkyl, said -C 1-3 alkylene-CO-5-10 membered heterocyclyl, said -C 1-3 alkylene-SO 2-C 1-3 alkyl, said C 3-6 cycloalkyl-C 5-10 aryl and said -C 1-3 alkylene-SO-C 1-3 alkyl, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl; or
R 1 and R 1’ together with the nitrogen atom to which they are both attached form 4-6 membered heterocyclyl, and wherein said 4-6 membered heterocyclyl can further contains 1, or 2 heteroatoms selected from N, O, S, SO or SO 2, and said 4-6 membered heterocyclyl can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, C 2-3 alkynyl, -C 5-10 aryl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3  alkylene-C 5-10 aryl, -5-10 membered heteroaryl, -5-10 membered heterocyclyl, -C 1-3 alkylene-N (C 1-3 alkyl)  2, -C 1-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene-CO-NH-C 1-3 alkyl, -C 1-3 alkylene-CO-5-10 membered heterocyclyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl and C 3-6 cycloalkyl-C 5-10 aryl, and wherein said -C 1-3 alkyl, said -C 2-3 alkenyl, said C 2-3 alkynyl, said -C 5-10 aryl, said -C 1-3 alkylene-COO-C 1-3 alkyl, said -C 1-3 alkylene-C 5-10 aryl, said -5-10 membered heteroaryl, said -5-10 membered heterocyclyl, said -C 1-3 alkylene-N (C 1-3 alkyl)  2, said -C 1-3 alkylene-O-C 1-3 alkyl, said -C 1-3 alkylene-CO-NH-C 1-3 alkyl, said -C 1-3 alkylene-CO-5-10 membered heterocyclyl, said -C 1-3 alkylene-SO 2-C 1-3 alkyl, said C 3-6 cycloalkyl-C 5-10 aryl and said -C 1-3 alkylene-SO-C 1-3 alkyl, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl; or
R 1 and R 1’ together with the nitrogen atom to which they are both attached form 4-6 membered heterocyclyl, and wherein said 4-6 membered heterocyclyl can further contains 1, or 2 heteroatoms selected from N, O, S, SO or SO 2, and said 4-6 membered heterocyclyl can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, vinyl, allyl, ethyne, propyne, C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2,  - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-C 5 aryl, -CH 2-C 6 aryl, - (CH 2)  2-C 6 aryl, - (CH 2)  3-C 6 aryl, -CH 2-C 7 aryl, - (CH 2)  2-C 7 aryl, - (CH 2)  3-C 7 aryl, -CH 2-C 8 aryl, - (CH 2)  2-C 8 aryl, - (CH 2)  3-C 8 aryl, -CH 2-C 9 aryl, - (CH 2)  2-C 9 aryl, - (CH 2)  3-C 9 aryl, -CH 2-C 10 aryl, - (CH 2)  2-C 10 aryl, - (CH 2)  3-C 10 aryl, -5 membered heteroaryl, -6 membered heteroaryl, -7 membered heteroaryl, -8 membered heteroaryl, -9 membered heteroaryl, -10 membered heteroaryl, -5 membered heterocyclyl, -6 membered heterocyclyl, -7 membered heterocyclyl, -8 membered heterocyclyl, -9 membered heterocyclyl, -10 membered heterocyclyl, -CH 2-N (CH 3)  2, - (CH 2)  2-N (CH 3)  2, - (CH 2)  3-N (CH 3)  2, -CH 2-N (CH 2CH 3)  2, - (CH 2)  2-N (CH 2CH 3)  2, - (CH 2)  3-N (CH 2CH 3)  2, -CH 2-N (CH 2CH 2CH 3)  2, - (CH 2)  2-N (CH 2CH 2CH 3)  2, - (CH 2)  3-N (CH 2CH 2CH 3)  2, -CH 2-N (CH (CH 3)  2)  2, - (CH 2)  2-N (CH (CH 3)  2)  2, - (CH 2)  3-N (CH (CH 3)  2)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2, - (CH 2)  3-O-CH (CH 3)  2, -CH 2-CO-NH-CH 3, - (CH 2)  2-CO-NH-CH 3, - (CH 2)  3-CO-NH-CH 3, -CH 2-CO-NH-CH 2CH 3, - (CH 2)  2-CO-NH-CH 2CH 3, - (CH 2)  3-CO-NH-CH 2CH 3, -CH 2-CO-NH-CH 2CH 2CH 3, - (CH 2)  2-CO-NH-CH 2CH 2CH 3, - (CH 2)  3-CO-NH-CH 2CH 2CH 3, -CH 2-CO-NH-CH (CH 3)  2, - (CH 2)  2-CO-NH-CH (CH 3)  2, - (CH 2)  3-CO-NH-CH (CH 3)  2, -CH 2-CO-5 membered heterocyclyl, - (CH 2)  2-CO-5 membered heterocyclyl, - (CH 2)  3-CO-5 membered heterocyclyl, -CH 2-CO-6 membered heterocyclyl, - (CH 2)  2-CO-6 membered heterocyclyl, - (CH 2)  3-CO-6 membered heterocyclyl, -CH 2-CO-7 membered heterocyclyl, - (CH 2)  2-CO-7 membered heterocyclyl, - (CH 2)  3-CO-7 membered heterocyclyl, -CH 2-CO-8 membered heterocyclyl, - (CH 2)  2-CO-8 membered heterocyclyl, - (CH 2)  3-CO-8 membered heterocyclyl, -CH 2-CO-9 membered heterocyclyl, - (CH 2)  2-CO-9 membered heterocyclyl, - (CH 2)  3-CO-9 membered heterocyclyl, -CH 2-CO-10 membered heterocyclyl, - (CH 2)  2-CO-10 membered heterocyclyl, - (CH 2)  3-CO-10 membered heterocyclyl, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3, -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, and - (CH 2)  3-SO-CH (CH 3)  2, -C 3 cycloalkyl-C 5 aryl, -C 4 cycloalkyl-C 5 aryl, -C 5 cycloalkyl-C 5 aryl, -C 6 cycloalkyl-C 5 aryl, -C 3 cycloalkyl-C 6 aryl, -C 4 cycloalkyl-C 6 aryl, -C 5  cycloalkyl-C 6 aryl, -C 6 cycloalkyl-C 6 aryl, -C 3 cycloalkyl-C 7 aryl, -C 4 cycloalkyl-C 7 aryl, -C 5 cycloalkyl-C 7 aryl, -C 6 cycloalkyl-C 7 aryl, -C 3 cycloalkyl-C 8 aryl, -C 4 cycloalkyl-C 8 aryl, -C 5 cycloalkyl-C 8 aryl, -C 6 cycloalkyl-C 8 aryl, -C 3 cycloalkyl-C 9 aryl, -C 4 cycloalkyl-C 9 aryl, -C 5 cycloalkyl-C 9 aryl, -C 6 cycloalkyl-C 9 aryl, -C 3 cycloalkyl-C 10 aryl, -C 4 cycloalkyl-C 10 aryl, -C 5 cycloalkyl-C 10 aryl, -C 6 cycloalkyl-C 10 aryl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said vinyl, said allyl, said ethyne, said propyne, said C 5 aryl, C 6 aryl, said C 7 aryl, said C 8 aryl, said C 9 aryl, said C 10 aryl, said -CH 2-COO-CH 3, said - (CH 2)  2-COO-CH 3, said - (CH 2)  3-COO-CH 3, said -CH 2-COO-CH 2CH 3, said - (CH 2)  2-COO-CH 2CH 3, said - (CH 2)  3-COO-CH 2CH 3, said -CH 2-COO-CH 2CH 2CH 3, said - (CH 2)  2-COO-CH 2CH 2CH 3, said - (CH 2)  3-COO-CH 2CH 2CH 3, said -CH 2-COO-CH (CH 3)  2, said - (CH 2)  2-COO-CH (CH 3)  2, said - (CH 2)  3-COO-CH (CH 3)  2, said -CH 2-C 5 aryl, said -CH 2-C 6 aryl, said - (CH 2)  2-C 6 aryl, said - (CH 2)  3-C 6 aryl, said -CH 2-C 7 aryl, said - (CH 2)  2-C 7 aryl, said - (CH 2)  3-C 7 aryl, said -CH 2-C 8 aryl, said - (CH 2)  2-C 8 aryl, said - (CH 2)  3-C 8 aryl, said -CH 2-C 9 aryl, said - (CH 2)  2-C 9 aryl, said - (CH 2)  3-C 9 aryl, said -CH 2-C 10 aryl, said - (CH 2)  2-C 10 aryl, said - (CH 2)  3-C 10 aryl, said -5 membered heteroaryl, said -6 membered heteroaryl, said -7 membered heteroaryl, said -8 membered heteroaryl, said -9 membered heteroaryl, said -10 membered heteroaryl, said -5 membered heterocyclyl, said -6 membered heterocyclyl, said -7 membered heterocyclyl, said -8 membered heterocyclyl, said -9 membered heterocyclyl, said -10 membered heterocyclyl, said -CH 2-N (CH 3)  2, said - (CH 2)  2-N (CH 3)  2, said - (CH 2)  3-N (CH 3)  2, said -CH 2-N (CH 2CH 3)  2, said - (CH 2)  2-N (CH 2CH 3)  2, said - (CH 2)  3-N (CH 2CH 3)  2, said -CH 2-N (CH 2CH 2CH 3)  2, said - (CH 2)  2-N (CH 2CH 2CH 3)  2, said - (CH 2)  3-N (CH 2CH 2CH 3)  2, said -CH 2-N (CH (CH 3)  2)  2, said - (CH 2)  2-N (CH (CH 3)  2)  2, said - (CH 2)  3-N (CH (CH 3)  2)  2, said -CH 2-O-CH 3, said - (CH 2)  2-O-CH 3, said - (CH 2)  3-O-CH 3, said -CH 2-O-CH 2CH 3, said - (CH 2)  2-O-CH 2CH 3, said - (CH 2)  3-O-CH 2CH 3, said -CH 2-O-CH 2CH 2CH 3, said - (CH 2)  2-O-CH 2CH 2CH 3, said - (CH 2)  3-O-CH 2CH 2CH 3, said -CH 2-O-CH (CH 3)  2, said - (CH 2)  2-O-CH (CH 3)  2, said - (CH 2)  3-O-CH (CH 3)  2, said -CH 2-CO-NH-CH 3, said - (CH 2)  2-CO-NH-CH 3, said - (CH 2)  3-CO-NH-CH 3, said -CH 2-CO-NH-CH 2CH 3, said - (CH 2)  2-CO-NH-CH 2CH 3, said - (CH 2)  3-CO-NH-CH 2CH 3, said -CH 2-CO-NH-CH 2CH 2CH 3, said - (CH 2)  2-CO-NH-CH 2CH 2CH 3, said - (CH 2)  3-CO-NH-CH 2CH 2CH 3, said -CH 2-CO-NH-CH (CH 3)  2, said - (CH 2)  2-CO-NH-CH (CH 3)  2, said - (CH 2)  3-CO-NH-CH (CH 3)  2, said -CH 2-CO-5 membered heterocyclyl, said - (CH 2)  2-CO-5 membered heterocyclyl, said - (CH 2)  3-CO-5 membered heterocyclyl, said -CH 2-CO-6 membered heterocyclyl, said - (CH 2)  2-CO-6 membered  heterocyclyl, said - (CH 2)  3-CO-6 membered heterocyclyl, said -CH 2-CO-7 membered heterocyclyl, said - (CH 2)  2-CO-7 membered heterocyclyl, said - (CH 2)  3-CO-7 membered heterocyclyl, said -CH 2-CO-8 membered heterocyclyl, said - (CH 2)  2-CO-8 membered heterocyclyl, said - (CH 2)  3-CO-8 membered heterocyclyl, said -CH 2-CO-9 membered heterocyclyl, said - (CH 2)  2-CO-9 membered heterocyclyl, said - (CH 2)  3-CO-9 membered heterocyclyl, said -CH 2-CO-10 membered heterocyclyl, said - (CH 2)  2-CO-10 membered heterocyclyl, said - (CH 2)  3-CO-10 membered heterocyclyl, said -CH 2-SO 2-CH 3, said - (CH 2)  2-SO 2-CH 3, said - (CH 2)  3-SO 2-CH 3, said -CH 2-SO 2-CH 2CH 3, said - (CH 2)  2-SO 2-CH 2CH 3, said - (CH 2)  3-SO 2-CH 2CH 3, said -CH 2-SO 2-CH 2CH 2CH 3, said - (CH 2)  2-SO 2-CH 2CH 2CH 3, said - (CH 2)  3-SO 2-CH 2CH 2CH 3, said -CH 2-SO 2-CH (CH 3)  2, said - (CH 2)  2-SO 2-CH (CH 3)  2, said - (CH 2)  3-SO 2-CH (CH 3)  2, said -CH 2-SO-CH 3, said - (CH 2)  2-SO-CH 3, said - (CH 2)  3-SO-CH 3, said -CH 2-SO-CH 2CH 3, said - (CH 2)  2-SO-CH 2CH 3, said - (CH 2)  3-SO-CH 2CH 3, said -CH 2-SO-CH 2CH 2CH 3, said - (CH 2)  2-SO-CH 2CH 2CH 3, said - (CH 2)  3-SO-CH 2CH 2CH 3, said -CH 2-SO-CH (CH 3)  2, said - (CH 2)  2-SO-CH (CH 3)  2, said -C 3 cycloalkyl-C 5 aryl, said -C 4 cycloalkyl-C 5 aryl, said -C 5 cycloalkyl-C 5 aryl, said -C 6 cycloalkyl-C 5 aryl, said -C 3 cycloalkyl-C 6 aryl, said -C 4 cycloalkyl-C 6 aryl, said -C 5 cycloalkyl-C 6 aryl, said -C 6 cycloalkyl-C 6 aryl, said -C 3 cycloalkyl-C 7 aryl, said -C 4 cycloalkyl-C 7 aryl, said -C 5 cycloalkyl-C 7 aryl, said -C 6 cycloalkyl-C 7 aryl, said -C 3 cycloalkyl-C 8 aryl, said -C 4 cycloalkyl-C 8 aryl, said -C 5 cycloalkyl-C 8 aryl, said -C 6 cycloalkyl-C 8 aryl, said -C 3 cycloalkyl-C 9 aryl, said -C 4 cycloalkyl-C 9 aryl, said -C 5 cycloalkyl-C 9 aryl, said -C 6 cycloalkyl-C 9 aryl, said -C 3 cycloalkyl-C 10 aryl, said -C 4 cycloalkyl-C 10 aryl, said -C 5 cycloalkyl-C 10 aryl, and said -C 6 cycloalkyl-C 10 aryl, and said - (CH 2)  3-SO-CH (CH 3)  2, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl; or
R 1 and R 1’ together with the nitrogen atom to which they are both attached form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, can further contains 1, or 2 heteroatoms selected from N, O, S, SO or SO 2, and said 4 membered heterocyclyl, said 5  membered heterocyclyl, said 6 membered heterocyclyl, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, vinyl, allyl, ethyne, propyne, C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-C 5 aryl, -CH 2-C 6 aryl, - (CH 2)  2-C 6 aryl, - (CH 2)  3-C 6 aryl, -CH 2-C 7 aryl, - (CH 2)  2-C 7 aryl, - (CH 2)  3-C 7 aryl, -CH 2-C 8 aryl, - (CH 2)  2-C 8 aryl, - (CH 2)  3-C 8 aryl, -CH 2-C 9 aryl, - (CH 2)  2-C 9 aryl, - (CH 2)  3-C 9 aryl, -CH 2-C 10 aryl, - (CH 2)  2-C 10 aryl, - (CH 2)  3-C 10 aryl, -5 membered heteroaryl, -6 membered heteroaryl, -7 membered heteroaryl, -8 membered heteroaryl, -9 membered heteroaryl, -10 membered heteroaryl, -5 membered heterocyclyl, -6 membered heterocyclyl, -7 membered heterocyclyl, -8 membered heterocyclyl, -9 membered heterocyclyl, -10 membered heterocyclyl, -CH 2-N (CH 3)  2, - (CH 2)  2-N (CH 3)  2, - (CH 2)  3-N (CH 3)  2, -CH 2-N (CH 2CH 3)  2, - (CH 2)  2-N (CH 2CH 3)  2, - (CH 2)  3-N (CH 2CH 3)  2, -CH 2-N (CH 2CH 2CH 3)  2, - (CH 2)  2-N (CH 2CH 2CH 3)  2, - (CH 2)  3-N (CH 2CH 2CH 3)  2, -CH 2-N (CH (CH 3)  2)  2, - (CH 2)  2-N (CH (CH 3)  2)  2, - (CH 2)  3-N (CH (CH 3)  2)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2, - (CH 2)  3-O-CH (CH 3)  2, -CH 2-CO-NH-CH 3, - (CH 2)  2-CO-NH-CH 3, - (CH 2)  3-CO-NH-CH 3, -CH 2-CO-NH-CH 2CH 3, - (CH 2)  2-CO-NH-CH 2CH 3, - (CH 2)  3-CO-NH-CH 2CH 3, -CH 2-CO-NH-CH 2CH 2CH 3, - (CH 2)  2-CO-NH-CH 2CH 2CH 3, - (CH 2)  3-CO-NH-CH 2CH 2CH 3, -CH 2-CO-NH-CH (CH 3)  2, - (CH 2)  2-CO-NH-CH (CH 3)  2, - (CH 2)  3-CO-NH-CH (CH 3)  2, -CH 2-CO-5 membered heterocyclyl, - (CH 2)  2-CO-5 membered heterocyclyl, - (CH 2)  3-CO-5 membered  heterocyclyl, -CH 2-CO-6 membered heterocyclyl, - (CH 2)  2-CO-6 membered heterocyclyl, - (CH 2)  3-CO-6 membered heterocyclyl, -CH 2-CO-7 membered heterocyclyl, - (CH 2)  2-CO-7 membered heterocyclyl, - (CH 2)  3-CO-7 membered heterocyclyl, -CH 2-CO-8 membered heterocyclyl, - (CH 2)  2-CO-8 membered heterocyclyl, - (CH 2)  3-CO-8 membered heterocyclyl, -CH 2-CO-9 membered heterocyclyl, - (CH 2)  2-CO-9 membered heterocyclyl, - (CH 2)  3-CO-9 membered heterocyclyl, -CH 2-CO-10 membered heterocyclyl, - (CH 2)  2-CO-10 membered heterocyclyl, - (CH 2)  3-CO-10 membered heterocyclyl, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3, -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, - (CH 2)  3-SO-CH (CH 3)  2, -C 3 cycloalkyl-C 5 aryl, -C 4 cycloalkyl-C 5 aryl, -C 5 cycloalkyl-C 5 aryl, -C 6 cycloalkyl-C 5 aryl, -C 3 cycloalkyl-C 6 aryl, -C 4 cycloalkyl-C 6 aryl, -C 5 cycloalkyl-C 6 aryl, -C 6 cycloalkyl-C 6 aryl, -C 3 cycloalkyl-C 7 aryl, -C 4 cycloalkyl-C 7 aryl, -C 5 cycloalkyl-C 7 aryl, -C 6 cycloalkyl-C 7 aryl, -C 3 cycloalkyl-C 8 aryl, -C 4 cycloalkyl-C 8 aryl, -C 5 cycloalkyl-C 8 aryl, -C 6 cycloalkyl-C 8 aryl, -C 3 cycloalkyl-C 9 aryl, -C 4 cycloalkyl-C 9 aryl, -C 5 cycloalkyl-C 9 aryl, -C 6 cycloalkyl-C 9 aryl, -C 3 cycloalkyl-C 10 aryl, -C 4 cycloalkyl-C 10 aryl, -C 5 cycloalkyl-C 10 aryl, and -C 6 cycloalkyl-C 10 aryl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said vinyl, said allyl, said ethyne, said propyne, said C 5 aryl, C 6 aryl, said C 7 aryl, said C 8 aryl, said C 9 aryl, said C 10 aryl, said -CH 2-COO-CH 3, said - (CH 2)  2-COO-CH 3, said - (CH 2)  3-COO-CH 3, said -CH 2-COO-CH 2CH 3, said - (CH 2)  2-COO-CH 2CH 3, said - (CH 2)  3-COO-CH 2CH 3, said -CH 2-COO-CH 2CH 2CH 3, said - (CH 2)  2-COO-CH 2CH 2CH 3, said - (CH 2)  3-COO-CH 2CH 2CH 3, said -CH 2-COO-CH (CH 3)  2, said - (CH 2)  2-COO-CH (CH 3)  2, said - (CH 2)  3-COO-CH (CH 3)  2, said -CH 2-C 5 aryl, said -CH 2-C 6 aryl, said - (CH 2)  2-C 6 aryl, said - (CH 2)  3-C 6 aryl, said -CH 2-C 7 aryl, said - (CH 2)  2-C 7 aryl, said - (CH 2)  3-C 7 aryl, said -CH 2-C 8 aryl, said - (CH 2)  2-C 8 aryl, said - (CH 2)  3-C 8 aryl, said -CH 2-C 9 aryl, said - (CH 2)  2-C 9 aryl, said - (CH 2)  3-C 9 aryl, said -CH 2-C 10 aryl, said - (CH 2)  2-C 10 aryl, said - (CH 2)  3-C 10 aryl, said -5 membered heteroaryl, said -6 membered heteroaryl, said -7 membered heteroaryl, said -8 membered heteroaryl, said -9 membered heteroaryl, said -10 membered heteroaryl, said -5 membered heterocyclyl, said -6 membered heterocyclyl, said -7  membered heterocyclyl, said -8 membered heterocyclyl, said -9 membered heterocyclyl, said -10 membered heterocyclyl, said -CH 2-N (CH 3)  2, said - (CH 2)  2-N (CH 3)  2, said - (CH 2)  3-N (CH 3)  2, said -CH 2-N (CH 2CH 3)  2, said - (CH 2)  2-N (CH 2CH 3)  2, said - (CH 2)  3-N (CH 2CH 3)  2, said -CH 2-N (CH 2CH 2CH 3)  2, said - (CH 2)  2-N (CH 2CH 2CH 3)  2, said - (CH 2)  3-N (CH 2CH 2CH 3)  2, said -CH 2-N (CH (CH 3)  2)  2, said - (CH 2)  2-N (CH (CH 3)  2)  2, said - (CH 2)  3-N (CH (CH 3)  2)  2, said -CH 2-O-CH 3, said - (CH 2)  2-O-CH 3, said - (CH 2)  3-O-CH 3, said -CH 2-O-CH 2CH 3, said - (CH 2)  2-O-CH 2CH 3, said - (CH 2)  3-O-CH 2CH 3, said -CH 2-O-CH 2CH 2CH 3, said - (CH 2)  2-O-CH 2CH 2CH 3, said - (CH 2)  3-O-CH 2CH 2CH 3, said -CH 2-O-CH (CH 3)  2, said - (CH 2)  2-O-CH (CH 3)  2, said - (CH 2)  3-O-CH (CH 3)  2, said -CH 2-CO-NH-CH 3, said - (CH 2)  2-CO-NH-CH 3, said - (CH 2)  3-CO-NH-CH 3, said -CH 2-CO-NH-CH 2CH 3, said - (CH 2)  2-CO-NH-CH 2CH 3, said - (CH 2)  3-CO-NH-CH 2CH 3, said -CH 2-CO-NH-CH 2CH 2CH 3, said - (CH 2)  2-CO-NH-CH 2CH 2CH 3, said - (CH 2)  3-CO-NH-CH 2CH 2CH 3, said -CH 2-CO-NH-CH (CH 3)  2, said - (CH 2)  2-CO-NH-CH (CH 3)  2, said - (CH 2)  3-CO-NH-CH (CH 3)  2, said -CH 2-CO-5 membered heterocyclyl, said - (CH 2)  2-CO-5 membered heterocyclyl, said - (CH 2)  3-CO-5 membered heterocyclyl, said -CH 2-CO-6 membered heterocyclyl, said - (CH 2)  2-CO-6 membered heterocyclyl, said - (CH 2)  3-CO-6 membered heterocyclyl, said -CH 2-CO-7 membered heterocyclyl, said - (CH 2)  2-CO-7 membered heterocyclyl, said - (CH 2)  3-CO-7 membered heterocyclyl, said -CH 2-CO-8 membered heterocyclyl, said - (CH 2)  2-CO-8 membered heterocyclyl, said - (CH 2)  3-CO-8 membered heterocyclyl, said -CH 2-CO-9 membered heterocyclyl, said - (CH 2)  2-CO-9 membered heterocyclyl, said - (CH 2)  3-CO-9 membered heterocyclyl, said -CH 2-CO-10 membered heterocyclyl, said - (CH 2)  2-CO-10 membered heterocyclyl, said - (CH 2)  3-CO-10 membered heterocyclyl, said -CH 2-SO 2-CH 3, said - (CH 2)  2-SO 2-CH 3, said - (CH 2)  3-SO 2-CH 3, said -CH 2-SO 2-CH 2CH 3, said - (CH 2)  2-SO 2-CH 2CH 3, said - (CH 2)  3-SO 2-CH 2CH 3, said -CH 2-SO 2-CH 2CH 2CH 3, said - (CH 2)  2-SO 2-CH 2CH 2CH 3, said - (CH 2)  3-SO 2-CH 2CH 2CH 3, said -CH 2-SO 2-CH (CH 3)  2, said - (CH 2)  2-SO 2-CH (CH 3)  2, said - (CH 2)  3-SO 2-CH (CH 3)  2, said -CH 2-SO-CH 3, said - (CH 2)  2-SO-CH 3, said - (CH 2)  3-SO-CH 3, said -CH 2-SO-CH 2CH 3, said - (CH 2)  2-SO-CH 2CH 3, said - (CH 2)  3-SO-CH 2CH 3, said -CH 2-SO-CH 2CH 2CH 3, said - (CH 2)  2-SO-CH 2CH 2CH 3, said - (CH 2)  3-SO-CH 2CH 2CH 3, said -CH 2-SO-CH (CH 3)  2, said - (CH 2)  2-SO-CH (CH 3)  2, said - (CH 2)  3-SO-CH (CH 3)  2, said -C 3 cycloalkyl-C 5 aryl, said -C 4 cycloalkyl-C 5 aryl, said -C 5 cycloalkyl-C 5 aryl, said -C 6 cycloalkyl-C 5 aryl, said -C 3 cycloalkyl-C 6 aryl, said -C 4 cycloalkyl-C 6 aryl, said -C 5 cycloalkyl-C 6 aryl, said -C 6  cycloalkyl-C 6 aryl, said -C 3 cycloalkyl-C 7 aryl, said -C 4 cycloalkyl-C 7 aryl, said -C 5 cycloalkyl-C 7 aryl, said -C 6 cycloalkyl-C 7 aryl, said -C 3 cycloalkyl-C 8 aryl, said -C 4 cycloalkyl-C 8 aryl, said -C 5 cycloalkyl-C 8 aryl, said -C 6 cycloalkyl-C 8 aryl, said -C 3 cycloalkyl-C 9 aryl, said -C 4 cycloalkyl-C 9 aryl, said -C 5 cycloalkyl-C 9 aryl, said -C 6 cycloalkyl-C 9 aryl, said -C 3 cycloalkyl-C 10 aryl, said -C 4 cycloalkyl-C 10 aryl, said -C 5 cycloalkyl-C 10 aryl, and said -C 6 cycloalkyl-C 10 aryl, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -CH 2-vinyl, - (CH 2)  2-vinyl, - (CH 2)  3-vinyl, -CH 2-allyl, - (CH 2)  2-allyl, - (CH 2)  3-allyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3, -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, - (CH 2)  3-SO-CH (CH 3)  2, -CH 2-S-CH 3, - (CH 2)  2-S-CH 3, - (CH 2)  3-S-CH 3, -CH 2-S-CH 2CH 3, - (CH 2)  2-S-CH 2CH 3, - (CH 2)  3-S-CH 2CH 3, -CH 2-S-CH 2CH 2CH 3, - (CH 2)  2-S-CH 2CH 2CH 3, - (CH 2)  3-S-CH 2CH 2CH 3, -CH 2-S-CH (CH 3)  2, - (CH 2)  2-S-CH (CH 3)  2, - (CH 2)  3-S-CH (CH 3)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2, - (CH 2)  3-O-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, -C 5 aryl, -C 6 aryl, -C 7 aryl, -C 8 aryl, -C 9 aryl, -C 10 aryl, -C 5 aryl substituted by F, -C 6 aryl substituted by F, -C 7 aryl substituted by F, -C 8 aryl substituted by F, -C 9 aryl substituted by F, -C 10 aryl substituted by F, -C 5 aryl substituted by Cl, -C 6 aryl  substituted by Cl, -C 7 aryl substituted by Cl, -C 8 aryl substituted by Cl, -C 9 aryl substituted by Cl, -C 10 aryl substituted by Cl, -C 1 haloalkyl, -C 2 haloalkyl, and –C 3 haloalkyl; or
R 1 and R 1’ together with the nitrogen atom to which they are both attached form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, can further contains 1, or 2 heteroatoms selected from N, O, S, SO or SO 2, and said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -CH 2-vinyl, - (CH 2)  2-vinyl, - (CH 2)  3-vinyl, -CH 2-allyl, - (CH 2)  2-allyl, - (CH 2)  3-allyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3, -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, - (CH 2)  3-SO-CH (CH 3)  2, -CH 2-S-CH 3, - (CH 2)  2-S-CH 3, - (CH 2)  3-S-CH 3, -CH 2-S-CH 2CH 3, - (CH 2)  2-S-CH 2CH 3, - (CH 2)  3-S-CH 2CH 3, -CH 2-S-CH 2CH 2CH 3, - (CH 2)  2-S-CH 2CH 2CH 3, - (CH 2)  3-S-CH 2CH 2CH 3, -CH 2-S-CH (CH 3)  2, - (CH 2)  2-S-CH (CH 3)  2, - (CH 2)  3-S-CH (CH 3)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2, - (CH 2)  3-O-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, -C 5 aryl, -C 6 aryl, -C 7 aryl, -C 8 aryl, -C 9 aryl, -C 10 aryl, -C 5 aryl substituted by F, -C 6 aryl substituted by F, -C 7 aryl substituted by F, -C 8 aryl substituted by F, -C 9 aryl substituted by F, -C 10 aryl substituted by F, -C 5  aryl substituted by Cl, -C 6 aryl substituted by Cl, -C 7 aryl substituted by Cl, -C 8 aryl substituted by Cl, -C 9 aryl substituted by Cl, -C 10 aryl substituted by Cl, -C 1 haloalkyl, -C 2 haloalkyl, and –C 3 haloalkyl. In some embodiments of formula I, Ia, or Ib, wherein
R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, 
Figure PCTCN2021123878-appb-000010
Figure PCTCN2021123878-appb-000011
Figure PCTCN2021123878-appb-000012
R 1 and R 1’ together with the nitrogen atom to which they are both attached form
Figure PCTCN2021123878-appb-000013
Figure PCTCN2021123878-appb-000014
said and wherein said
Figure PCTCN2021123878-appb-000015
and said
Figure PCTCN2021123878-appb-000016
said can be optionally substituted with one or more substituents, said which are independently selected from the group consisting of F, Cl, Br, I, -OH, oxo, -CN, -C 1-4 alkyl, -C 1-4 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -4-6 membered heterocyclyl, -COO-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl. Preferably, R 1 and R 1’ together with the nitrogen atom to which they are both attached form
Figure PCTCN2021123878-appb-000017
said and wherein said 
Figure PCTCN2021123878-appb-000018
and said
Figure PCTCN2021123878-appb-000019
said can be optionally substituted with one or more substituents, said which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -4 membered heterocyclyl,  -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, -C 5 aryl, -C 6 aryl, -C 7 aryl, -C 8 aryl, -C 9 aryl, -C 10 aryl, -C 5 aryl substituted by F, -C 6 aryl substituted by F, -C 7 aryl substituted by F, -C 8 aryl substituted by F, -C 9 aryl substituted by F, -C 10 aryl substituted by F, -C 5 aryl substituted by Cl, -C 6 aryl substituted by Cl, -C 7 aryl substituted by Cl, -C 8 aryl substituted by Cl, -C 9 aryl substituted by Cl, -C 10 aryl substituted by Cl, -C 1 haloalkyl, -C 2 haloalkyl, and –C 3 haloalkyl. Most preferably, R 1 and R 1’ together with the nitrogen atom to which they are both attached form
Figure PCTCN2021123878-appb-000020
In some embodiments of formula I, Ia, or Ib, wherein
X is selected from the group consisting of –C (=O) -W- (CR X1R X2)  m-NR 5R 5’, C (=O) -W- (CR X1R X2)  m-SR 11, C (=O) -W- (CR X1R X2)  m-SOR 11, C (=O) -W- (CR X1R X2)  m-SO 2R 11, and –C (=O) -W- (CR X1R X2)  m-OR 11;
W is oxygen or a bond;
m is selected from 1, 2, or 3;
R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, halogen, C 1-3 alkyl, -C 1-3 alkylene-SH, -C 1-3alkylene-C 2-3 alkenyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-CONH 2, 
Figure PCTCN2021123878-appb-000021
Figure PCTCN2021123878-appb-000022
-C 1-3 alkylene-Se-C 1-3 alkyl, -C 1-3 alkylene-SH, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-CO 2-C 1-3 alkyl, C 5-10aryl, -C 1-3 alkylene-C 5-10 aryl, -C 1-3 alkylene-5-10 membered heteroaryl, -C 1-3 alkylene-5-10 membered heterocyclyl, and 5-10 membered heteroaryl, and wherein said C 1-3 alkyl, said -C 1-3 alkylene-SH, said -C 1-3alkylene-C 2-3 alkenyl, said -C 3-6 cycloalkyl, said -C 1-3 alkylene-C 3-6 cycloalkyl, said -C 1-3 alkylene-S-C 1-3 alkyl, said -C 1-3 alkylene-CONH 2, said
Figure PCTCN2021123878-appb-000023
said
Figure PCTCN2021123878-appb-000024
said -C 1-3 alkylene-Se-C 1-3 alkyl, said -C 1-3 alkylene-SH, said -C 1-3 alkylene-SO 2-C 1-3 alkyl, said -C 1-3 alkylene-CO 2-C 1-3 alkyl, said C 5-10aryl, said -C 1-3 alkylene-C 5-10 aryl, said -C 1-3 alkylene-5-10  membered heteroaryl, said -C 1-3 alkylene-5-10 membered heterocyclyl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
or R X1 and R X2 together with the carbon atom to which they are attached form 5-8 membered carbocyclic ring, C 3-6 cycloalkyl, C 2-3 alkenyl, 5-8 membered heterocyclyl, and wherein said 5-8 membered carbocyclic ring, said C 3-6 cycloalkyl, said C 2-3 alkenyl, and said 5-8 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, -C 1-3 alkyl, -C 3-6cycloalkyl, -C (=O) -C 1-3 alkyl, -C (=O) -5-10 membered heterocyclyl, -C (=O) -5-10 membered carbocyclic, -C (=O) -adamantanyl, -C (=O) -C 1-3 alkylene-O-C 1-3 alkyl, -C (=O) -C 1-3 alkylene-NH-C 1-3 alkyl, -C (=O) -C 1-3 alkylene-N (C 1-3 alkyl)  2, -C (=O) -C 3-6 cycloalkyl, and wherein said -C 1-3 alkyl, said -C 3-6 cycloalkyl, -C (=O) -5-10 membered heterocyclyl, -C (=O) -5-10 membered carbocyclic, -C (=O) -C 1-3 alkylene-O-C 1-3 alkyl, -C (=O) -C 1-3 alkylene-NH-C 1-3 alkyl, -C (=O) -C 1-3 alkylene-N (C 1-3 alkyl)  2, said -C (=O) -C 1-3 alkyl, and said -C (=O) -C 3-6 cycloalkyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
or R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5-10 membered heterocyclyl, and wherein said 5-10 membered heterocyclyl can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2, and said 5-12 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
R 11 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl.
In some embodiments, the compound of formula I or Ia, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein
X is selected from the group consisting of –C (=O) -W- (CR X1R X2)  m-NR 5R 5’, C (=O) -W- (CR X1R X2)  m-SR 11, C (=O) -W- (CR X1R X2)  m-SOR 11, C (=O) -W- (CR X1R X2)  m-SO 2R 11, and –C (=O) -W- (CR X1R X2)  m-OR 11;
W is oxygen or a bond;
m is selected from 1, 2, or 3;
R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, halogen, C 1-3 alkyl, -C 0-3 alkylene-SH, -C 0-3alkylene-C 2-3 alkenyl, -C 3-6 cycloalkyl, -C 0-3 alkylene-C 3-6 cycloalkyl, -C 0-3 alkylene-S-C 1-3 alkyl, -C 0-3 alkylene-CONH 2, 
Figure PCTCN2021123878-appb-000025
Figure PCTCN2021123878-appb-000026
-C 0-3 alkylene-Se-C 1-3 alkyl, -C 0-3 alkylene-SH, -C 0-3 alkylene-SO 2-C 1-3 alkyl, -C 0-3 alkylene-CO 2-C 1-3 alkyl, C 5-10aryl, -C 0-3 alkylene-C 5-10 aryl, -C 0-3  alkylene-5-10 membered heteroaryl, -C 0-3 alkylene-5-10 membered heterocyclyl, and 5-10 membered heteroaryl, and wherein said C 1-3 alkyl, said –C 0-3 alkylene-SH, said –C 0-3alkylene-C 2-3 alkenyl, said -C 3-6 cycloalkyl, said –C 0-3 alkylene-C 3-6 cycloalkyl, said –C 0-3 alkylene-S-C 1-3 alkyl, said –C 0-3 alkylene-CONH 2, said
Figure PCTCN2021123878-appb-000027
said
Figure PCTCN2021123878-appb-000028
said –C 0-3 alkylene-Se-C 1-3 alkyl, said –C 0-3 alkylene-SH, said –C 0-3 alkylene-SO 2-C 1-3 alkyl, said –C 0-3 alkylene-CO 2-C 1-3 alkyl, said C 5-10aryl, said -C 1-3 alkylene-C 5-10 aryl, said –C 0-3 alkylene-5-10 membered heteroaryl, said –C 0-3 alkylene-5-10 membered heterocyclyl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-6 cycloalkyl, -C 1-4 alkylene-C 2-4 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-4 alkylene-COO-C 1-3 alkyl, -C 1-4alkylene-SO 2-C 1-3 alkyl, -C 1-4 alkylene-SO-C 1-3 alkyl, -C 1-4 alkylene-S-C 1-3 alkyl, -C 1-4 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3haloalkyl;
or R X1 and R X2 together with the carbon atom to which they are attached form 5-8 membered carbocyclic ring, C 3-6 cycloalkyl, C 2-3 alkenyl, 5-8 membered heterocyclyl, and wherein said 5-8 membered carbocyclic ring, said C 3-6 cycloalkyl, said C 2-3 alkenyl, and said 5-8 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-4 alkylene-COO-C 1-3 alkyl, -C 1-4alkylene-SO 2-C 1-3 alkyl, -C 1-4alkylene-SO-C 1-3 alkyl, -C 1-4 alkylene-S-C 1-3 alkyl, -C 1-4 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl;
R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, -C 1-3 alkyl, -C 3-6cycloalkyl, -C (=O) -C 1-3 alkyl, -C (=O) -5-10 membered heterocyclyl, -C (=O) -5-10 membered carbocyclic, -C (=O) -adamantanyl, -C (=O) -C 1-3 alkylene-O-C 1-3 alkyl, -C (=O) -C 1-3 alkylene-NH-C 1-3 alkyl, -C (=O) -C 1-3 alkylene-N (C 1-3 alkyl)  2, -C (=O) -C 3-1 cycloalkyl, and wherein said -C 1-3 alkyl, said -C 3-6 cycloalkyl, -C (=O) -5-10 membered heterocyclyl, -C (=O) -5-10 membered carbocyclic, -C (=O) -C 1-3 alkylene-O-C 1-3 alkyl, -C (=O) -C 1-3 alkylene-NH-C 1-3 alkyl, -C (=O) -C 1-3 alkylene-N (C 1-3 alkyl)  2, said -C (=O) -C 1-3 alkyl, and said -C (=O) -C 3-6 cycloalkyl, can be optional substituted with one or more substituents, which are independently selected from the group  consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-6 cycloalkyl, -C 1-4 alkylene-C 2-4 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-4 alkylene-COO-C 1-3 alkyl, -C 1-4alkylene-SO 2-C 1-3 alkyl, -C 1-4alkylene-SO-C 1-3 alkyl, -C 1-4 alkylene-S-C 1-3 alkyl, -C 1-4 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3haloalkyl;
or R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5-10 membered heterocyclyl, and wherein said 5-10 membered heterocyclyl can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2, and said 5-12 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3alkoxy, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-6 cycloalkyl, -C 1-4 alkylene-C 2-4alkenyl, -4-10 membered heterocyclyl, -COO-C 1-3alkyl, -C 1-4 alkylene-COO-C 1-3 alkyl, -C 1-4 alkylene-SO 2-C 1-3 alkyl, -C 1-4alkylene-SO-C 1-3alkyl, -C 1-4 alkylene-S-C 1-3 alkyl, -C 1-4 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-6 haloalkyl;
R 11 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-4alkenyl, -C 2-4 alkynyl, -C 3-6cycloalkyl, -C 1-4 alkylene-C 2-4alkenyl, -4-10 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-4alkylene-COO-C 1-3 alkyl, -C 1-4alkylene-SO 2-C 1-3alkyl, -C 1-4 alkylene-SO-C 1-3 alkyl, -C 1-4 alkylene-S-C 1-3 alkyl, -C 1-4 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
X is selected from the group consisting of –C (=O) -W- (CR X1R X2)  m-NR 5R 5’, C (=O) -W- (CR X1R X2)  m-SR 11 , C (=O) -W- (CR X1R X2)  m-SOR 11, C (=O) -W- (CR X1R X2)  m-SO 2R 11, and –C (=O) -W- (CR X1R X2)  m-OR 11;
W is a bond;
m is 1;
R X1 and R X2 are each independently selected from the group consisting from  hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, 
Figure PCTCN2021123878-appb-000029
Figure PCTCN2021123878-appb-000030
Figure PCTCN2021123878-appb-000031
-CO-CH 3, -SO-CH 3, -SO 2-CH 3, -NH-CO-CH 3, 
Figure PCTCN2021123878-appb-000032
Figure PCTCN2021123878-appb-000033
Figure PCTCN2021123878-appb-000034
Figure PCTCN2021123878-appb-000035
and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -CO-CH 3, -NH-CO-CH 3, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, -C 5 aryl, -C 6 aryl, -C 7 aryl, -C 8 aryl, -C 9 aryl, -C 10 aryl, -C 5 aryl substituted by F, -C 6 aryl substituted by F, -C 7 aryl substituted by F, -C 8 aryl substituted by F, -C 9 aryl substituted by F, -C 10 aryl substituted by F, -C 5 aryl substituted by Cl, -C 6 aryl substituted by Cl, -C 7 aryl substituted by Cl, -C 8 aryl substituted by Cl, -C 9 aryl substituted by Cl, -C 10 aryl substituted by Cl, -C 1 haloalkyl, -C 2 haloalkyl, and –C 3 haloalkyl;
or R X1 and R X2 together with the carbon atom to which they are attached form
5 membered carbocyclic ring, 6 membered carbocyclic ring, 7 membered carbocyclic ring, 8 membered carbocyclic ring, C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 2 alkenyl, C 3 alkenyl, C 4 alkenyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, and wherein said 5 membered carbocyclic ring, said 6 membered carbocyclic ring, said 7 membered carbocyclic ring, said 8 membered carbocyclic ring, said C 3 cycloalkyl, said C 4 cycloalkyl, said C 5 cycloalkyl, said C 6 cycloalkyl, said C 2 alkenyl, said C 3 alkenyl, said C 4 alkenyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, can be optional substituted with one or more  substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -CH 2-vinyl, - (CH 2)  2-vinyl, - (CH 2)  3-vinyl, -CH 2-allyl, - (CH 2)  2-allyl, - (CH 2)  3-allyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3, -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, - (CH 2)  3-SO-CH (CH 3)  2, -CH 2-S-CH 3, - (CH 2)  2-S-CH 3, - (CH 2)  3-S-CH 3, -CH 2-S-CH 2CH 3, - (CH 2)  2-S-CH 2CH 3, - (CH 2)  3-S-CH 2CH 3, -CH 2-S-CH 2CH 2CH 3, - (CH 2)  2-S-CH 2CH 2CH 3, - (CH 2)  3-S-CH 2CH 2CH 3, -CH 2-S-CH (CH 3)  2, - (CH 2)  2-S-CH (CH 3)  2, - (CH 2)  3-S-CH (CH 3)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2, - (CH 2)  3-O-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, -C 5 aryl, -C 6 aryl, -C 7 aryl, -C 8 aryl, -C 9 aryl, -C 10 aryl, -C 5 aryl substituted by F, -C 6 aryl substituted by F, -C 7 aryl substituted by F, -C 8 aryl substituted by F, -C 9 aryl substituted by F, -C 10 aryl substituted by F, -C 5 aryl substituted by Cl, -C 6 aryl substituted by Cl, -C 7 aryl substituted by Cl, -C 8 aryl substituted by Cl, -C 9 aryl substituted by Cl, -C 10 aryl substituted by Cl, -C 1 haloalkyl, -C 2 haloalkyl, and –C 3 haloalkyl; R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C (=O) -CH 3, -C (=O) -CH 2CH 3, -C (=O) -CH 2CH 2CH 3, -C (=O) -CH (CH 3)  2, 
Figure PCTCN2021123878-appb-000036
-C(=O) -5 membered heterocyclyl, -C (=O) -6 membered heterocyclyl, -C (=O) -7 membered heterocyclyl, -C (=O) -8 membered heterocyclyl, -C (=O) -9 membered heterocyclyl, -C (=O) -10  membered heterocyclyl, -C (=O) -5 membered carbocyclic, -C (=O) -6 membered carbocyclic, -C (=O) -7 membered carbocyclic, -C (=O) -8 membered carbocyclic, -C (=O) -9 membered carbocyclic, -C (=O) -10 membered carbocyclic, -C (=O) -adamantanyl, -C (=O) -CH 2-O-CH 3, -C (=O) - (CH 2)  2-O-CH 3, -C (=O) - (CH 2)  3-O-CH 3, -C (=O) -CH 2-O-CH 2CH 3, -C (=O) - (CH 2)  2-O-CH 2CH 3, -C (=O) - (CH 2)  3-O-CH 2CH 3, -C (=O) -CH 2-O-CH 2CH 2CH 3, -C (=O) - (CH 2)  2-O-CH 2CH 2CH 3, -C (=O) - (CH 2)  3-O-CH 2CH 2CH 3, -C (=O) -CH 2-O-CH (CH 3)  2, -C (=O) - (CH 2)  2-O-CH (CH 3)  2, -C (=O) - (CH 2)  3-O-CH (CH 3)  2, -C (=O) -CH 2-NH-CH 3, -C (=O) - (CH 2)  2-NH-CH 3, -C (=O) - (CH 2)  3-NH-CH 3, -C (=O) -CH 2-NH-CH 2CH 3, -C (=O) - (CH 2)  2-NH-CH 2CH 3, -C (=O) - (CH 2)  3-NH-CH 2CH 3, -C (=O) -CH 2-NH-CH 2CH 2CH 3, -C (=O) - (CH 2)  2-NH-CH 2CH 2CH 3, -C (=O) - (CH 2)  3-NH-CH 2CH 2CH 3, -C (=O) -CH 2-NH-CH (CH 3)  2, -C (=O) - (CH 2)  2-NH-CH (CH 3)  2, -C (=O) - (CH 2)  3-NH-CH (CH 3)  2, -C (=O) -CH 2-N (CH 3)  2, -C (=O) - (CH 2)  2-N (CH 3)  2, -C (=O) - (CH 2)  3-N (CH 3)  2, -C (=O) -CH 2-N (CH 2CH 3)  2, -C (=O) - (CH 2)  2-N (CH 2CH 3)  2, -C (=O) - (CH 2)  3-N (CH 2CH 3)  2, -C (=O) -CH 2-N (CH 2CH 2CH 3)  2, -C (=O) - (CH 2)  2-N (CH 2CH 2CH 3)  2, -C (=O) - (CH 2)  3-N (CH 2CH 2CH 3)  2, -C (=O) -CH 2-N (CH (CH 3)  2)  2, -C (=O) - (CH 2)  2-N (CH (CH 3)  2)  2, -C (=O) - (CH 2)  3-N (CH (CH 3)  2)  2, -C (=O) -C 3 cycloalkyl, -C (=O) -C 4 cycloalkyl, -C (=O) -C 5 cycloalkyl, and -C (=O) -C 6 cycloalkyl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said -C (=O) -CH 3, said -C (=O) -CH 2CH 3, said -C (=O) -CH 2CH 2CH 3, said -C (=O) -CHCH 3)  2, said -C (=O) -5 membered heterocyclyl, said -C (=O) -6 membered heterocyclyl, said -C (=O) -7 membered heterocyclyl, said -C (=O) -8 membered heterocyclyl, said -C (=O) -9 membered heterocyclyl, said -C (=O) -10 membered heterocyclyl, said -C (=O) -5 membered carbocyclic, said -C (=O) -6 membered carbocyclic, said -C (=O) -7 membered carbocyclic, said -C (=O) -8 membered carbocyclic, said -C (=O) -9 membered carbocyclic, said -C (=O) -10 membered carbocyclic, said -C (=O) -CH 2-O-CH 3, said -C (=O) - (CH 2)  2-O-CH 3, said -C (=O) - (CH 2)  3-O-CH 3, said -C (=O) -CH 2-O-CH 2CH 3, said -C (=O) - (CH 2)  2-O-CH 2CH 3, said -C (=O) - (CH 2)  3-O-CH 2CH 3, said -C (=O) -CH 2-O-CH 2CH 2CH 3, said -C (=O) - (CH 2)  2-O-CH 2CH 2CH 3, said -C (=O) - (CH 2)  3-O-CH 2CH 2CH 3, said -C (=O) -CH 2-O-CH (CH 3)  2, said -C (=O) - (CH 2)  2-O-CH (CH 3)  2, said -C (=O) - (CH 2)  3-O-CH (CH 3)  2, said -C (=O) -CH 2-NH-CH 3, said -C (=O) - (CH 2)  2-NH-CH 3, said -C (=O) - (CH 2)  3-NH-CH 3, said -C (=O) -CH 2-NH-CH 2CH 3, said -C (=O) - (CH 2)  2-NH-CH 2CH 3, said -C (=O) - (CH 2)  3-NH-CH 2CH 3, said -C (=O) -CH 2-NH-CH 2CH 2CH 3, said -C (=O) - (CH 2)  2-NH-CH 2CH 2CH 3, said -C (=O) - (CH 2)  3-NH-CH 2CH 2CH 3, said  -C (=O) -CH 2-NH-CH (CH 3)  2, said -C (=O) - (CH 2)  2-NH-CH (CH 3)  2, said -C (=O) - (CH 2)  3-NH-CH (CH 3)  2, said -C (=O) -CH 2-N (CH 3)  2, said -C (=O) - (CH 2)  2-N (CH 3)  2, said -C (=O) - (CH 2)  3-N (CH 3)  2, said -C (=O) -CH 2-N (CH 2CH 3)  2, said -C (=O) - (CH 2)  2-N (CH 2CH 3)  2, said -C (=O) - (CH 2)  3-N (CH 2CH 3)  2, said -C (=O) -CH 2-N (CH 2CH 2CH 3)  2, said -C (=O) - (CH 2)  2-N (CH 2CH 2CH 3)  2, said -C (=O) - (CH 2)  3-N (CH 2CH 2CH 3)  2, said -C (=O) -CH 2-N (CH (CH 3)  2)  2, said -C (=O) - (CH 2)  2-N (CH (CH 3)  2)  2, said -C (=O) - (CH 2)  3-N (CH (CH 3)  2)  2, said -C (=O) -C 3 cycloalkyl, said -C (=O) -C 4 cycloalkyl, said -C (=O) -C 5 cycloalkyl, and said -C (=O) -C 6 cycloalkyl, can be optional substituted with one or more substituents, said which are independently selected from the group consisting of can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, -C 5 aryl, -C 6 aryl, -C 7 aryl, -C 8 aryl, -C 9 aryl, -C 10 aryl, -C 5 aryl substituted by F, -C 6 aryl substituted by F, -C 7 aryl substituted by F, -C 8 aryl substituted by F, -C 9 aryl substituted by F, -C 10 aryl substituted by F, -C 5 aryl substituted by Cl, -C 6 aryl substituted by Cl, -C 7 aryl substituted by Cl, -C 8 aryl substituted by Cl, -C 9 aryl substituted by Cl, -C 10 aryl substituted by Cl, -C 1 haloalkyl, -C 2 haloalkyl, and –C 3 haloalkyl; or R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, and wherein said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2, and said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -CH 2-vinyl, - (CH 2)  2-vinyl, - (CH 2)  3- vinyl, -CH 2-allyl, - (CH 2)  2-allyl, - (CH 2)  3-allyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3, -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, - (CH 2)  3-SO-CH (CH 3)  2, -CH 2-S-CH 3, - (CH 2)  2-S-CH 3, - (CH 2)  3-S-CH 3, -CH 2-S-CH 2CH 3, - (CH 2)  2-S-CH 2CH 3, - (CH 2)  3-S-CH 2CH 3, -CH 2-S-CH 2CH 2CH 3, - (CH 2)  2-S-CH 2CH 2CH 3, - (CH 2)  3-S-CH 2CH 2CH 3, -CH 2-S-CH (CH 3)  2, - (CH 2)  2-S-CH (CH 3)  2, - (CH 2)  3-S-CH (CH 3)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2, - (CH 2)  3-O-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, -C 5 aryl, -C 6 aryl, -C 7 aryl, -C 8 aryl, -C 9 aryl, -C 10 aryl, -C 5 aryl substituted by F, -C 6 aryl substituted by F, -C 7 aryl substituted by F, -C 8 aryl substituted by F, -C 9 aryl substituted by F, -C 10 aryl substituted by F, -C 5 aryl substituted by Cl, -C 6 aryl substituted by Cl, -C 7 aryl substituted by Cl, -C 8 aryl substituted by Cl, -C 9 aryl substituted by Cl, -C 10 aryl substituted by Cl, -C 1 haloalkyl, -C 2 haloalkyl, and –C 3 haloalkyl; R 11 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, 
Figure PCTCN2021123878-appb-000037
methoxy, ethoxy, propoxy, isopropoxy; and each of which is optional substituted with one or more substituents, which are independently selected from deuterium, halogen, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy -C 2-4alkenyl, -C 2-4 alkynyl, -C 1-4 alkylene-C 2-4alkenyl, 
Figure PCTCN2021123878-appb-000038
Figure PCTCN2021123878-appb-000039
-NH-CO-C 1-3alkyl, -CO-NH-C 1-3alkyl, -CO-N (CH 3)  2, -COO-C 1-3 alkyl,  -C 1-4alkylene-COO-C 1-3 alkyl, -C 1-4alkylene-SO 2-C 1-3alkyl, -C 1-4 alkylene-SO-C 1-3 alkyl, -C 1-4 alkylene-S-C 1-3 alkyl, -C 1-4 alkylene-O-C 1-3alkyl, -NH 2, -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl, -N (CH 3)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein X is selected from the group consisting of –C (=O) -W- (CR X1R X2)  m-NR 5R 5’, C (=O) -W- (CR X1R X2)  m-SR 11 , C (=O) -W- (CR X1R X2)  m-SOR 11, C (=O) -W- (CR X1R X2)  m-SO 2R 11, and –C (=O) -W- (CR X1R X2)  m-OR 11;
W is a bond;
m is 1;
R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, 
Figure PCTCN2021123878-appb-000040
Figure PCTCN2021123878-appb-000041
Figure PCTCN2021123878-appb-000042
-CO-CH 3, -SO-CH 3, -SO 2-CH 3, -NH-CO-CH 3, 
Figure PCTCN2021123878-appb-000043
Figure PCTCN2021123878-appb-000044
Figure PCTCN2021123878-appb-000045
Figure PCTCN2021123878-appb-000046
and each of which can be optional substituted with one or more substituents, said which are independently selected from the group consisting of can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl
or R X1 and R X2 together with the carbon atom to which they are attached form
5 membered carbocyclic ring, 6 membered carbocyclic ring, 7 membered carbocyclic ring, 8 membered carbocyclic ring, C 3cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 2 alkenyl, C 3 alkenyl, C 4 alkenyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, and wherein said 5 membered carbocyclic ring, said 6 membered carbocyclic ring, said 7 membered carbocyclic ring, said 8 membered carbocyclic ring, said C 3  cycloalkyl, said C 4 cycloalkyl, said C 5 cycloalkyl, said C 6 cycloalkyl, said C 2 alkenyl, said C 3 alkenyl, said C 4 alkenyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -CH 2-vinyl, - (CH 2)  2-vinyl, - (CH 2)  3-vinyl, -CH 2-allyl, - (CH 2)  2-allyl, - (CH 2)  3-allyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3, -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, - (CH 2)  3-SO-CH (CH 3)  2, -CH 2-S-CH 3, - (CH 2)  2-S-CH 3, - (CH 2)  3-S-CH 3, -CH 2-S-CH 2CH 3, - (CH 2)  2-S-CH 2CH 3, - (CH 2)  3-S-CH 2CH 3, -CH 2-S-CH 2CH 2CH 3, - (CH 2)  2-S-CH 2CH 2CH 3, - (CH 2)  3-S-CH 2CH 2CH 3, -CH 2-S-CH (CH 3)  2, - (CH 2)  2-S-CH (CH 3)  2, - (CH 2)  3-S-CH (CH 3)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2, - (CH 2)  3-O-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, -C 5 aryl, -C 6 aryl, -C 7 aryl, -C 8 aryl, -C 9 aryl, -C 10 aryl, -C 5 aryl substituted by F, -C 6 aryl substituted by F, -C 7 aryl substituted by F, -C 8 aryl substituted by F, -C 9 aryl substituted by F, -C 10 aryl substituted by F, -C 5 aryl substituted by Cl, -C 6 aryl substituted by Cl, -C 7 aryl substituted by Cl, -C 8 aryl substituted by Cl, -C 9 aryl substituted by Cl, -C 10 aryl substituted by Cl, -C 1 haloalkyl, -C 2 haloalkyl, and –C 3 haloalkyl; R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C (=O) -CH 3, -C (=O) -CH 2CH 3, -C (=O) -CH 2CH 2CH 3, -C (=O) -CH (CH 3)  2, 
Figure PCTCN2021123878-appb-000047
-C (=O) -5 membered heterocyclyl, -C (=O) -6 membered heterocyclyl, -C (=O) -7 membered heterocyclyl, -C (=O) -8 membered heterocyclyl, -C (=O) -9 membered heterocyclyl, -C (=O) -10 membered heterocyclyl, -C (=O) -5 membered carbocyclic, -C (=O) -6 membered carbocyclic, -C (=O) -7 membered carbocyclic, -C (=O) -8 membered carbocyclic, -C (=O) -9 membered carbocyclic, -C (=O) -10 membered carbocyclic, -C (=O) -adamantanyl, -C (=O) -CH 2-O-CH 3, -C (=O) - (CH 2)  2-O-CH 3, -C (=O) - (CH 2)  3-O-CH 3, -C (=O) -CH 2-O-CH 2CH 3, -C (=O) - (CH 2)  2-O-CH 2CH 3, -C (=O) - (CH 2)  3-O-CH 2CH 3, -C (=O) -CH 2-O-CH 2CH 2CH 3, -C (=O) - (CH 2)  2-O-CH 2CH 2CH 3, -C (=O) - (CH 2)  3-O-CH 2CH 2CH 3, -C (=O) -CH 2-O-CH (CH 3)  2, -C (=O) - (CH 2)  2-O-CH (CH 3)  2, -C (=O) - (CH 2)  3-O-CH (CH 3)  2, -C (=O) -CH 2-NH-CH 3, -C (=O) - (CH 2)  2-NH-CH 3, -C (=O) - (CH 2)  3-NH-CH 3, -C (=O) -CH 2-NH-CH 2CH 3, -C (=O) - (CH 2)  2-NH-CH 2CH 3, -C (=O) - (CH 2)  3-NH-CH 2CH 3, -C (=O) -CH 2-NH-CH 2CH 2CH 3, -C (=O) - (CH 2)  2-NH-CH 2CH 2CH 3, -C (=O) - (CH 2)  3-NH-CH 2CH 2CH 3, -C (=O) -CH 2-NH-CH (CH 3)  2, -C (=O) - (CH 2)  2-NH-CH (CH 3)  2, -C (=O) - (CH 2)  3-NH-CH (CH 3)  2, -C (=O) -CH 2-N (CH 3)  2, -C (=O) - (CH 2)  2-N (CH 3)  2, -C (=O) - (CH 2)  3-N (CH 3)  2, -C (=O) -CH 2-N (CH 2CH 3)  2, -C (=O) - (CH 2)  2-N (CH 2CH 3)  2, -C (=O) - (CH 2)  3-N (CH 2CH 3)  2, -C (=O) -CH 2-N (CH 2CH 2CH 3)  2, -C (=O) - (CH 2)  2-N (CH 2CH 2CH 3)  2, -C (=O) - (CH 2)  3-N (CH 2CH 2CH 3)  2, -C (=O) -CH 2-N (CH (CH 3)  2)  2, -C (=O) - (CH 2)  2-N (CH (CH 3)  2)  2, -C (=O) - (CH 2)  3-N (CH (CH 3)  2)  2, -C (=O) -C 3 cycloalkyl, -C (=O) -C 4 cycloalkyl, -C (=O) -C 5 cycloalkyl, and -C (=O) -C 6 cycloalkyl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said -C (=O) -CH 3, said -C (=O) -CH 2CH 3, said -C (=O) -CH 2CH 2CH 3, said -C (=O) -CHCH 3)  2, said -C (=O) -5 membered heterocyclyl, said -C (=O) -6 membered heterocyclyl, said -C (=O) -7 membered heterocyclyl, said -C (=O) -8 membered heterocyclyl, said -C (=O) -9 membered heterocyclyl, said -C (=O) -10 membered heterocyclyl, said -C (=O) -5 membered carbocyclic, said -C (=O) -6 membered carbocyclic, said -C (=O) -7 membered carbocyclic, said -C (=O) -8 membered carbocyclic, said -C (=O) -9 membered carbocyclic, said -C (=O) -10 membered carbocyclic, said -C (=O) -CH 2-O-CH 3, said -C (=O) - (CH 2)  2-O-CH 3, said -C (=O) - (CH 2)  3-O-CH 3, said -C (=O) -CH 2-O-CH 2CH 3, said -C (=O) - (CH 2)  2-O-CH 2CH 3, said -C (=O) - (CH 2)  3-O-CH 2CH 3, said -C (=O) -CH 2-O-CH 2CH 2CH 3, said -C (=O) - (CH 2)  2-O-CH 2CH 2CH 3, said -C (=O) - (CH 2)  3-O-CH 2CH 2CH 3, said -C (=O) -CH 2-O-CH (CH 3)  2, said -C (=O) - (CH 2)  2-O-CH (CH 3)  2, said -C (=O) - (CH 2)  3-O-CH (CH 3)  2, said -C (=O) -CH 2-NH-CH 3, said  -C (=O) - (CH 2)  2-NH-CH 3, said -C (=O) - (CH 2)  3-NH-CH 3, said -C (=O) -CH 2-NH-CH 2CH 3, said -C (=O) - (CH 2)  2-NH-CH 2CH 3, said -C (=O) - (CH 2)  3-NH-CH 2CH 3, said -C (=O) -CH 2-NH-CH 2CH 2CH 3, said -C (=O) - (CH 2)  2-NH-CH 2CH 2CH 3, said -C (=O) - (CH 2)  3-NH-CH 2CH 2CH 3, said -C (=O) -CH 2-NH-CH (CH 3)  2, said -C (=O) - (CH 2)  2-NH-CH (CH 3)  2, said -C (=O) - (CH 2)  3-NH-CH (CH 3)  2, said -C (=O) -CH 2-N (CH 3)  2, said -C (=O) - (CH 2)  2-N (CH 3)  2, said -C (=O) - (CH 2)  3-N (CH 3)  2, said -C (=O) -CH 2-N (CH 2CH 3)  2, said -C (=O) - (CH 2)  2-N (CH 2CH 3)  2, said -C (=O) - (CH 2)  3-N (CH 2CH 3)  2, said -C (=O) -CH 2-N (CH 2CH 2CH 3)  2, said -C (=O) - (CH 2)  2-N (CH 2CH 2CH 3)  2, said -C (=O) - (CH 2)  3-N (CH 2CH 2CH 3)  2, said -C (=O) -CH 2-N (CH (CH 3)  2)  2, said -C (=O) - (CH 2)  2-N (CH (CH 3)  2)  2, said -C (=O) - (CH 2)  3-N (CH (CH 3)  2)  2, said -C (=O) -C 3 cycloalkyl, said -C (=O) -C 4 cycloalkyl, said -C (=O) -C 5 cycloalkyl, and said -C (=O) -C 6 cycloalkyl, can be optional substituted with one or more substituents, and said substituents are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, phenyl, phenyl substituted by F, phenyl substituted by Cl;
or R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, and wherein said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2, and said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -CH 2-vinyl, - (CH 2)  2-vinyl, - (CH 2)  3-vinyl, -CH 2-allyl, - (CH 2)  2-allyl, - (CH 2)  3-allyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl,  -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3, -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, - (CH 2)  3-SO-CH (CH 3)  2, -CH 2-S-CH 3, - (CH 2)  2-S-CH 3, - (CH 2)  3-S-CH 3, -CH 2-S-CH 2CH 3, - (CH 2)  2-S-CH 2CH 3, - (CH 2)  3-S-CH 2CH 3, -CH 2-S-CH 2CH 2CH 3, - (CH 2)  2-S-CH 2CH 2CH 3, - (CH 2)  3-S-CH 2CH 2CH 3, -CH 2-S-CH (CH 3)  2, - (CH 2)  2-S-CH (CH 3)  2, - (CH 2)  3-S-CH (CH 3)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2, - (CH 2)  3-O-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, phenyl, phenyl substituted by F, phenyl substituted by Cl; or
R 11 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, 
Figure PCTCN2021123878-appb-000048
methoxy, ethoxy, propoxy, isopropoxy; and each of which is optional substituted with one or more substituents, which are independently selected from deuterium, halogen, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy -C 2-4alkenyl, -C 2-4 alkynyl, -C 1-4 alkylene-C 2-4alkenyl, 
Figure PCTCN2021123878-appb-000049
Figure PCTCN2021123878-appb-000050
-NH-CO-CH 3, -CO-NH-CH 3, -CO-N (CH 3)  2, -COO-CH 3, -CH 2-COO-CH 3, -CH 2-SO 2-CH 3, -CH 2e-SO-CH 3, -CH 2-S-CH 3, -CH 2-O-CH 3, -NH 2, -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl, -N (CH 3)  2, carboxyl, phenyl, phenyl substituted by halogen . the halogen is F, Cl, or Br.
In some embodiments of formula I, Ia, or Ib, wherein
R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein R 2 is hydrogen, or deuterium.
In some embodiments of formula I, Ia, or Ib, wherein
R 3 and R 3’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
R 3 and R 3’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional  substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
R 3 and R 3’ are each independently hydrogen, or deuterium.
In some embodiments of formula I, Ia, or Ib, wherein
Y is - (CR Y1R Y2)  n-;
n is selected from 1, 2, or 3;
R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
Y is - (CR Y1R Y2)  n-;
n is 1;
R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
Y is - (CR Y1R Y2)  n-;
n is 1;
R Y1 and R Y2 are each independently hydrogen or deuterium.
In some embodiments of formula I, Ia, or Ib, wherein
R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
R 4 is hydrogen or deuterium.
In some embodiments of formula I, Ia, or Ib, wherein
R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl,  -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
In some embodiments, the compound of formula I, Ia, Ib or Ic, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein
R 10 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-4 alkyl, -C 1-4 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -4-6 membered heterocyclyl, -COO-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein
R 10 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3,  -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, -C 5 aryl, -C 6 aryl, -C 7 aryl, -C 8 aryl, -C 9 aryl, -C 10 aryl, -C 5 aryl substituted by F, -C 6 aryl substituted by F, -C 7 aryl substituted by F, -C 8 aryl substituted by F, -C 9 aryl substituted by F, -C 10 aryl substituted by F, -C 5 aryl substituted by Cl, -C 6 aryl substituted by Cl, -C 7 aryl substituted by Cl, -C 8 aryl substituted by Cl, -C 9 aryl substituted by Cl, -C 10 aryl substituted by Cl, -C 1 haloalkyl, -C 2 haloalkyl, and –C 3 haloalkyl.
In some embodiments of formula I, Ia, or Ib, wherein R 10 is hydrogen or deuterium.
In some embodiments, provided here is a compound of formula Ia-1-3, Ib-1-3 or Ic-1-2, and a pharmaceutically acceptable salt thereof or a stereoisomer thereof
Figure PCTCN2021123878-appb-000051
Figure PCTCN2021123878-appb-000052
In some embodiments of the compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof defined herein, wherein the configuration of the chiral atom in the compound represented by the general formula I, Ia, Ib, Ia-1, Ia-2, Ia-3, Ib-1, Ib-2, Ib-3, Ic-1, Ic-2, is S-or R-configuration.
In some embodiments, provided here is a compound of formula Id-1-4, Ie-1-4, If 1-4. Ig 1-4, Ih 1-4, Ii 1-4, Ij 1-4, or Ik 1-4, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, the tautomer thereof
Figure PCTCN2021123878-appb-000053
Figure PCTCN2021123878-appb-000054
Figure PCTCN2021123878-appb-000055
Figure PCTCN2021123878-appb-000056
Figure PCTCN2021123878-appb-000057
In some embodiments of formula I, Ia, or Ib, the compound is of formula Ia-3, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof:
Figure PCTCN2021123878-appb-000058
wherein Y, R 1, R 1’, R X1, R X2, R 5, R 5’ and m is the same as defined herein.
In another aspect, provided herein is a compound of formula II, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, the tautomer thereof
Figure PCTCN2021123878-appb-000059
wherein m is 1or 2; R 1, R 1’, R X1, R X2, R 5, and R 5’ is the same as defined herein.
In some embodiments of formula II, wherein
R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, C 2-3 alkynyl, -C 5-10 aryl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-C 5-10 aryl, -5-10 membered heteroaryl, -5-10 membered heterocyclyl, -C 1-3 alkylene-N (C 1-3 alkyl)  2, -C 1-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene-CO-NH-C 1-3 alkyl, -C 1-3 alkylene-CO-5-10 membered heterocyclyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl and C 3-6 cycloalkyl-C 5-10 aryl;  each of which can be optionally substituted with one or more substituents, and said substituents are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl;
R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, halogen, C 1-3 alkyl, -C 1-3 alkylene-SH, -C 1-3alkylene-C 2-3 alkenyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-CONH 2, 
Figure PCTCN2021123878-appb-000060
Figure PCTCN2021123878-appb-000061
-C 1-3 alkylene-Se-C 1-3 alkyl, -C 1-3 alkylene-SH, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-CO 2-C 1-3 alkyl, C 5-10aryl, -C 1-3 alkylene-C 5-10 aryl, -C 1-3 alkylene-5-10 membered heteroaryl, -C 1-3 alkylene-5-10 membered heterocyclyl, and 5-10 membered heteroaryl, each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-6 cycloalkyl, -C 1-4 alkylene-C 2-4 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-4 alkylene-COO-C 1-3 alkyl, -C 1-4alkylene-SO 2-C 1-3 alkyl, -C 1-4 alkylene-SO-C 1-3 alkyl, -C 1-4 alkylene-S-C 1-3 alkyl, -C 1-4 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3haloalkyl; or
R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, -C 1-3 alkyl, -C 3-6cycloalkyl, -C (=O) -C 1-3 alkyl, -C (=O) -5-10 membered heterocyclyl, -C (=O) -5-10 membered carbocyclic, -C (=O) -adamantanyl, -C (=O) -C 1-3 alkylene-O-C 1-3 alkyl, -C (=O) -C 1-3 alkylene-NH-C 1-3 alkyl, -C (=O) -C 1-3 alkylene-N (C 1-3 alkyl)  2, -C (=O) -C 3-6 cycloalkyl, each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -COO-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl.
In some embodiments of formula II, wherein
R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, vinyl, allyl, ethyne, propyne, C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2,  -CH 2-C 5 aryl, -CH 2-C 6 aryl, - (CH 2)  2-C 6 aryl, - (CH 2)  3-C 6 aryl, -CH 2-C 7 aryl, - (CH 2)  2-C 7 aryl, - (CH 2)  3-C 7 aryl, -CH 2-C 8 aryl, - (CH 2)  2-C 8 aryl, - (CH 2)  3-C 8 aryl, -CH 2-C 9 aryl, - (CH 2)  2-C 9 aryl, - (CH 2)  3-C 9 aryl, -CH 2-C 10 aryl, - (CH 2)  2-C 10 aryl, - (CH 2)  3-C 10 aryl, -5 membered heteroaryl, -6 membered heteroaryl, -7 membered heteroaryl, -8 membered heteroaryl, -9 membered heteroaryl, -10 membered heteroaryl, each of which can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl;
R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, 
Figure PCTCN2021123878-appb-000062
Figure PCTCN2021123878-appb-000063
Figure PCTCN2021123878-appb-000064
-CO-CH 3, -SO-CH 3, -SO 2-CH 3, -NH-CO-CH 3, 
Figure PCTCN2021123878-appb-000065
Figure PCTCN2021123878-appb-000066
Figure PCTCN2021123878-appb-000067
and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; or
R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C (=O) -CH 3, -C (=O) -CH 2CH 3, -C (=O) -CH 2CH 2CH 3, -C (=O) -CH (CH 3)  2, 
Figure PCTCN2021123878-appb-000068
-C (=O) -CH 2-O-CH 3, -C (=O) - (CH 2)  2-O-CH 3, -C (=O) - (CH 2)  3-O-CH 3, -C (=O) -CH 2-O-CH 2CH 3, -C (=O) -CH 2-NH-CH 3, -C (=O) - (CH 2)  2-NH-CH 3, -C (=O) - (CH 2)  3-NH-CH 3, -C (=O) -CH 2-NH-CH 2CH 3, -C (=O) -CH 2-N (CH 3)  2, -C (=O) - (CH 2)  2-N (CH 3)  2, -C (=O) - (CH 2)  3-N (CH 3)  2,  -C (=O) -CH 2-N (CH 2CH 3)  2, each of which can be optional substituted with one or more substituents, and said substituents are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -COO-CH 3, -COO-CH 2CH 3, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl.
In some embodiments of formula II, wherein
R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, 
Figure PCTCN2021123878-appb-000069
Figure PCTCN2021123878-appb-000070
R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium methyl, ethyl, propyl, isopropyl, tert-butyl, 
Figure PCTCN2021123878-appb-000071
Figure PCTCN2021123878-appb-000072
R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C (=O) -CH 3, -C (=O) -CH 2CH 3, -C (=O) -CH 2CH 2CH 3, -C (=O) -CH (CH 3)  2, 
Figure PCTCN2021123878-appb-000073
In another aspect, provided here is a compound of formula III, IV, V, VI or VII, and a pharmaceutically acceptable salt thereof or a stereoisomer thereof
Figure PCTCN2021123878-appb-000074
Figure PCTCN2021123878-appb-000075
wherein Z, R 1, R 1’, R 4, R 10, R 3, R 3’, R X1, R X2, R 11, are as defined herein.
In some embodiments of formula I, Ia, Ib, Ia-1, Ia-2, Ia-3, Ib-1, Ib-2, Ib-3, Ic-1, Ic-2, Id-1-4, Ie-1-4, If 1-4. Ig 1-4, Ih 1-4, Ii 1-4, Ij 1-4, Ik 1-4, II, III, IV, V, VI, or VII, wherein the compound is selected from:
Figure PCTCN2021123878-appb-000076
Figure PCTCN2021123878-appb-000077
Figure PCTCN2021123878-appb-000078
Figure PCTCN2021123878-appb-000079
Figure PCTCN2021123878-appb-000080
Figure PCTCN2021123878-appb-000081
Figure PCTCN2021123878-appb-000082
Figure PCTCN2021123878-appb-000083
Figure PCTCN2021123878-appb-000084
Figure PCTCN2021123878-appb-000085
Figure PCTCN2021123878-appb-000086
Figure PCTCN2021123878-appb-000087
Figure PCTCN2021123878-appb-000088
Figure PCTCN2021123878-appb-000089
Figure PCTCN2021123878-appb-000090
Figure PCTCN2021123878-appb-000091
Figure PCTCN2021123878-appb-000092
Figure PCTCN2021123878-appb-000093
Figure PCTCN2021123878-appb-000094
Figure PCTCN2021123878-appb-000095
Figure PCTCN2021123878-appb-000096
Figure PCTCN2021123878-appb-000097
Figure PCTCN2021123878-appb-000098
Figure PCTCN2021123878-appb-000099
Figure PCTCN2021123878-appb-000100
Figure PCTCN2021123878-appb-000101
Figure PCTCN2021123878-appb-000102
Figure PCTCN2021123878-appb-000103
Figure PCTCN2021123878-appb-000104
Figure PCTCN2021123878-appb-000105
In another embodiment, provided here are the following compounds or pharmaceutically acceptable salt thereof of the invention:
Figure PCTCN2021123878-appb-000106
Figure PCTCN2021123878-appb-000107
Figure PCTCN2021123878-appb-000108
Figure PCTCN2021123878-appb-000109
Figure PCTCN2021123878-appb-000110
Figure PCTCN2021123878-appb-000111
Figure PCTCN2021123878-appb-000112
Figure PCTCN2021123878-appb-000113
Figure PCTCN2021123878-appb-000114
Figure PCTCN2021123878-appb-000115
Figure PCTCN2021123878-appb-000116
In another aspect, provided here is 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 yet another aspect, provided here is 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 still other aspects, the presently disclosed subject matter provides the use of a compound of the present invention, or a pharmaceutical composition thereof, for treating a disease or condition. In  some embodiments, the disease or condition is selected from the group consisting of an infection, cancer, an autoimmune disease, an inflammatory disease, and a neurodegenerative or neurological disease.
As used herein, a "cancer" in a patient refers to the presence of cells possessing characteristics typical of cancer-causing cells, for example, uncontrolled proliferation, loss of specialized functions, immortality, significant metastatic potential, significant increase in anti-apoptotic activity, rapid growth and proliferation rate, and certain characteristic morphology and cellular markers. In some circumstances, cancer cells will be in the form of a tumor; such cells may exist locally within an animal, or circulate in the blood stream as independent cells, for example, leukemic cells. A "tumor, " as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. A "solid tumor, " as used herein, is an abnormal mass of tissue that generally does not contain cysts or liquid areas. A solid tumor may be in the brain, colon, breasts, prostate, liver, kidneys, lungs, esophagus, head and neck, ovaries, cervix, stomach, colon, rectum, bladder, uterus, testes, and pancreas, as non-limiting examples. In some embodiments, the solid tumor regresses or its growth is slowed or arrested after the solid tumor is treated with the presently disclosed methods. In other embodiments, the solid tumor is malignant. In some embodiments, the cancer comprises Stage 0 cancer. In some embodiments, the cancer comprises Stage I cancer. In some embodiments, the cancer comprises Stage II cancer. In some embodiments, the cancer comprises Stage III cancer. In some embodiments, the cancer comprises Stage IV cancer. In some embodiments, the cancer is refractory and/or metastatic. For example, the cancer may be refractory to treatment with radiotherapy, chemotherapy or monotreatment with immunotherapy. Cancer as used herein includes newly diagnosed or recurrent cancers, including without limitation, acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, breast carcinoma, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, colorectal carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung carcinoma, Lewis lung carcinoma, lymphoma, malignant fibrous histiocytoma, a mammary tumor, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, a pontine tumor, premenopausal breast cancer, prostate cancer, rhabdomyosarcoma, reticulum cell sarcoma, sarcoma, small cell lung cancer, a solid tumor, stomach cancer, testicular cancer, and uterine carcinoma.
In some embodiments, the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer.
In another aspect, provided here is 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 lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer.
In some embodiments, the medicament is used as a glutamine antagonist.
As used herein, the term "glutamine antagonist" refers to a glutamine analog that interfers with a glutamine metabolic pathway, e.g., the inhibition or blocking of a metabolic pathway downstream of glutamine in which glutamine acts as a precursor of one or more non-glutamine compounds. Examples of such metabolic pathways are well known (see, e.g., Hensley et al, "Glutamine and cancer: cell biology, physiology, and clinical opportunities" J Clin Invest. 2013; 123 (9) : 3678-3684; DeBerardinis et al, "Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer" Oncogene. 2009; 29 (3) : 313-324; and Medina et al, "Relevance of glutamine metabolism to tumor cell growth" Mol Cell Biochem. 1992; 113 (1) : 1 -15) . In some contexts, the term glutamine antagonist also includes glutamine analogs that inhibit glutamine uptake by cells, thereby reducing its biological activity. Diseases or conditions wherein excess and/or aberrant glutamine.
In yet another aspect, provided here is 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 treating the disease or condition. In some embodiments, the disease or condition is selected from the group consisting of an infection, cancer, an autoimmune disease, an inflammatory disease, and a neurodegenerative or neurological disease.
In yet another aspect, provided here is the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention; or the pharmaceutical composition of the present invention for use in therapy.
In yet another aspect, provided here is the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present  invention; or the pharmaceutical composition of the present invention for use as a medicament.
In yet another aspect, provided here is the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention; or the pharmaceutical composition of the present invention, for use in treating the disease or condition. In some embodiments, the disease or condition is selected from the group consisting of an infection, cancer, an autoimmune disease, an inflammatory disease, and a neurodegenerative or neurological disease.
In yet 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 lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer.
Brief description of the Drawings
FIG. 1 is a graph showing the concentrations of DON and reference compound over time after IV infusion.
FIG. 2 is a graph showing the concentrations of DON and compound 2 over time after IV infusion.
FIG. 3 is a graph showing the concentrations of DON and compound 1 over time after IV infusion.
FIG. 4 is a bar graph showing the stability of compounds after incubation for 60 minutes in the presence of human microsomes.
FIG. 5 is a bar graph showing the stability of compounds after incubation for 60 minutes in the presence of human microsomes.
FIG. 6 is a graph showing the body weight changes of the mice in the different groups.
FIG. 7 is a graph showing anti-tumor activity of test compounds in MC38 syngeneic model.
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 heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl or sipro heterocyclyl. 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 “carbocycle” refers to a substituted or unsubstituted monocyclic ring, bicyclic ring bridged ring, fused ring, sipiro ring non-aromatic ring system only containing carbon atoms ( (i.e., C 3-14 ) . Non-limiting exemplary carbocycle groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and cyclopentenyl, cyclohexenyl.
For the purpose of the present disclosure, the term "carbocycle " as used by itself or as part of another group means that the carbocycle as defined above substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino) alkyl, (carboxamido) alkyl, mercaptoalkyl, and (heterocyclo) alkyl. In one embodiment, the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent.
As used herein, the term "fused ring" refers to a cyclic group formed by substituents on separate atoms in a straight or branched alkane, or to a cyclic group formed by substituents on separate atoms in another ring.
As used herein, the term "spirocycle" or "spirocyclic ring" refers to a pendant cyclic group formed by substituents on a single atom.
As used herein, "optional" or "optionally, " may mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" may encompass both "aryl" and "substituted aryl" as defined herein. It will be understood by those ordinarily skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and/or inherently unstable.
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 examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are degrees Celsius, unless explicitly stated otherwise. The following abbreviations have been used in the examples:
Figure PCTCN2021123878-appb-000117
Figure PCTCN2021123878-appb-000118
SERIES 1-COMPOUNDS OF Formula I or IaIntermediate A1
Figure PCTCN2021123878-appb-000119
Intermediate A1 was prepared refering to the compound 3 in WO2017023774 in Scheme 1 at page 82.
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.
Figure PCTCN2021123878-appb-000120
Intermediate B1
Figure PCTCN2021123878-appb-000121
Step a: To a solution of (S) -2- (l2-azaneyl) butanoic acid (1023 mg, 9.9205 mmol) in acetic acid (10 mL) was added acetic anhydride (1769 mg, 17.3281 mmol) . The mixture was stirred for 2h at 100 ℃. The reaction mixture was concentrated under reduced pressure. The residue was stirred in EA, then filtered and the solid was collected to afford (S) -2-acetamidobutanoic acid (628 mg, 4.3264 mmol) . MS: m/z 144 (M-H)  -
Step b: To a solution of (S) -2-acetamidobutanoic acid (0.628 g, 4.3264 mmol) and methyl (S) -2-amino-6-diazo-5-oxohexanoate (498 mg, 2.6893 mmol) in DCM (5 mL) was added ethyl cyanoglyoxylate-2-oxime (624 mg, 4.3909 mmol) , N, N'-Diisopropylcarbodiimide (539 mg, 4.2710 mmol) and 2, 4, 6-Collidine (679 mg, 5.6033 mmol) at 0 ℃. The mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by FLASH. The product’s solution was concentrated under reduced pressure to afford methyl (S) -2- ( (S) -2-acetamidobutanamido) -6-diazo-5-oxohexanoate (1269 mg, 4.0631 mmol) . MS: m/z 313 (M+H)  +
Step c: To a solution of methyl (S) -2- ( (S) -2-acetamidobutanamido) -6-diazo-5-oxohexanoate (1.269 g, 4.0631 mmol) in THF (10 mL) added LiOH (156.2 mg, 6.5224 mmol) in water (5 mL) at 0℃. The mixture was stirred for 1h at RT and the reaction mixture was purified by FLASH (MeCN/H2O, 0～10%) . The product’s solution was concentrated under reduced pressure and the residue was further purified by pre-HPLC. The product’s solution was concentrated under reduced pressure to afford (S) -2- ( (S) -2-acetamidobutanamido) -6-diazo-5-oxohexanoic acid (101 mg, 338.5917 μmol) . MS: m/z 299 (M+H)  +
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.
Figure PCTCN2021123878-appb-000122
Intermediate B2
Figure PCTCN2021123878-appb-000123
Intermediate B2 was prepared from known patent, WO2020150639, where it was as compound 3 in Scheme 1 at page 121.
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.
Figure PCTCN2021123878-appb-000124
Figure PCTCN2021123878-appb-000125
Figure PCTCN2021123878-appb-000126
Intermediate B3
Figure PCTCN2021123878-appb-000127
Step a: To a solution of DL-Serine (1.64 g, 15.6054 mmol) , 5-Fluoroindole (1.01 g, 7.4738 mmol) was added acetic anhydride (5 mL) and acetic acid (20mL) under N 2 protection. The mixture was stirred at 80 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC. The product’s solution was concentrated under reduced pressure to afford 2-acetamido-3- (5-fluoro-1H-indol-3-yl) propanoic acid (2044 mg, 7.7350 mmol) . MS: m/z 265 (M+H)  +,
Step b: Referenced B2
The following compound was synthesized using the above procedure or modification procedure with the corresponding starting materials.
Figure PCTCN2021123878-appb-000128
Intermediate C1
Figure PCTCN2021123878-appb-000129
Step a: To a solution of Nalpha-Fmoc-L-Tryptophan (1348 mg, 3.161 mmol) , isopropyl (S) -2-amino-6-diazo-5-oxohexanoate (452 mg, 2.120 mmol) and 4-Methylmorpholine (666 mg, 6.584 mmol) in DMF (10 mL) was added HATU (1226 mg, 3.224 mmol) at 0℃. The mixture was stirred for 3h at 0 ℃～RT, then to the mixture was added water (10 mL) and DCM (10 mL) . The reaction mixture was filtered and the organic phase was collected. The aqueous solution was extracted with DCM (10 mL×2) and the organic phase was combined. The combined organic phase was washed with brine (10 mL×3) and dried over anhydrous Na 2SO 4. The resulting mixture was concentrated under reduced pressure. The residue was purified by FLASH (MeCN/H2O, 0～60%) and the product’s solution was concentrated under reduced pressure to afford isopropyl (S) -2- ( (S) -2- ( ( ( (9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (1H-indol-3-yl) propanamido) -6-diazo-5-ox ohexanoate (742 mg, 1.194 mmol, 56.306%yield) . MS: m/z 622 (M+H)  +
Step b: To a solution of isopropyl (S) -2- ( (S) -2- ( ( ( (9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (1H-indol-3-yl) propanamido) -6-diazo-5-ox ohexanoate (469 mg, 754.406 μmol) in DCM (50 mL) was added piperidine (224 mg, 2.631 mmol) at  0 ℃. The mixture was stirred for 6h at 0 ℃～RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by FLASH (MeCN/H2O, 0～100%) and the product’s solution was concentrated under reduced pressure to afford isopropyl (S) -2- ( (S) -2-amino-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoate (189 mg, 473.159 μmol, 62.719%yield) . MS: m/z 400 (M+H)  +
Step c: To a solution of isobutyric acid (0.0813 g, 922.765 μmol) , N, N'-Diisopropylcarbodiimide (0.1202 g, 952.464 μmol) 2, 4, 6-Collidine (0.1642 g, 1.355 mmol) and Ethyl cyanoglyoxylate-2-oxi (0.1876 g, 1.320 mmol) in DMF (5 mL) was added isopropyl (S) -2- ( (S) -2-amino-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoate (0.0938 g, 234.827 μmol) at 0 ℃. The mixture was stirred for 5 h at 0 ℃～RT and to the mixture was added water (10 mL) and DCM (10 mL) , then the reaction mixture was filtered and the organic phase was collected. The aqueous solution was extracted with DCM (10 mL×2) and the organic phase was combined. The combined organic phase washed with brine (10 mL×3) and dried over anhydrous Na 2SO 4. The resulting mixture was concentrated under reduced pressure. The residue was purified by FLASH (MeCN/H2O, 0～45%) and the product’s solution was concentrated under reduced pressure to afford Isopropyl (S) -2- ( (S) -3- (1H-indol-3-yl) -2-isobutyramidopropanamido) -6-diazo-5-oxohexanoate (100 mg, 212.978 μmol, 90.696%yield) . MS: m/z 470 (M+H)  +
Step d: To a solution of
Isopropyl (S) -2- ( (S) -3- (1H-indol-3-yl) -2-isobutyramidopropanamido) -6-diazo-5-oxohexanoate (98 mg, 208.718 μmol) in THF (6 mL) was added NaOH (25 mg, 625.045 μmol) in water (2mL) at 0 ℃. The mixture was stirred for 1 h at RT. The reaction mixture was purified by FLASH (MeCN/H2O, 0～10%) and the product’s solution was concentrated under reduced pressure to afford
(S) -2- ( (S) -3- (1H-indol-3-yl) -2-isobutyramidopropanamido) -6-diazo-5-oxohexanoic acid (90 mg, 210.550 μmol) . MS: m/z 428 (M+H)  +
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.
Figure PCTCN2021123878-appb-000130
Figure PCTCN2021123878-appb-000131
Intermediate D1 and D2
Figure PCTCN2021123878-appb-000132
Step a: To a solution of Indole (2.33 g, 19.889 mmol) and Ytterbium (III) triflate hydrate (1.79 g, 2.804 mmol) in Ethylene chloride (15 mL) under nitrogen atmosphere was added (2S) -Methylglycidate (1.02 g, 9.991 mmol) . The mixture was heated to 85℃, stirred for 3 h at this temperature. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by FLASH (eluting with MeCN : H 2O=0-80%, v/v) . The product’s solution was concentrated under reduced pressure to remove MeCN. The product mixture was diluted with EA, dried over anhydrous Na 2SO 4, filtered and concentrated under reduced pressure to give methyl (S) -2-hydroxy-3- (1H-indol-3-yl) propanoate, Intermediate D1, (779 mg, 3.553 mmol) . MS: m/z 220 (M+H)  +.
Step b: To a 0℃ solution of methyl (S) -2-hydroxy-3- (1H-indol-3-yl) propanoate (0.283g, 1.291 mmol) in DCM (3 mL) was added TEA (498 mg, 4.921 mmol) , then 4-methylbenzenesulfonyl chloride was added dropwise. The mixture was stirred for 1 h at this temperature and the reaction mixture was quenched with NaHCO 3 (aq) (10 mL) . The aqueous layer was separated and extracted with DCM (2×10 mL) . The combined organic layers were dried over anhydrous Na 2SO 4, filtered and concentrated under reduced pressure to give methyl (S) -3- (1H-indol-3-yl) -2- (tosyloxy) propanoate (482 mg) which was used in next step without any further purification. MS: m/z (374)  +.
Step c: To a 0℃ solution of ethanethiol (327 mg, 5.263 mmol) and MeONa (286 mg, 5.294  mmol) in MeOH (3 mL) under nitrogen atmosphere was added methyl (S) -3- (1H-indol-3-yl) -2- (tosyloxy) propanoate (482. mg, 1.291 mmol) in MeOH (2 mL) dropwise. Then the resulting solution was stirred for 2 hours at room temperature. HCl (4M solution in EA, 3 mL) was added, the solid was filtered through a pad of Celite followed by MeOH washing and the filtrate was concentrated under reduced pressure. The residue was purified by FLASH (eluting with MeCN : H 2O=0-80%, v/v) . The product’s solution was concentrated under reduced pressure to give methyl (R) -2- (ethylthio) -3- (1H-indol-3-yl) propanoate (126 mg, 478.442 μmol) . MS: m/z (264)  +.
Step d: To a solution of methyl (R) -2- (ethylthio) -3- (1H-indol-3-yl) propanoate (125 mg, 474.644 μmol) in THF (2 mL) was added LiOH (2M solution in water, 1 mL) . The mixture was stirred for 2 h at room temperature. After citric acid (solid) was added, the reaction was diluted with water (5mL) and extracted with EA (2×10 mL) . The combined organic layers were dried over anhydrous Na 2SO 4, filtered, and concentrated under reduced pressure to give (R) -2- (ethylthio) -3- (1H-indol-3-yl) propanoic acid, Intermediate D2 (118 mg) . MS: m/z (250)  +.
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.
Figure PCTCN2021123878-appb-000133
Figure PCTCN2021123878-appb-000134
Intermediate D3
Figure PCTCN2021123878-appb-000135
Step a: To a solution of methyl (S) -2-hydroxy-3- (1H-indol-3-yl) propanoate (2 g, 9.123 mmol) in DCM (20 mL) was added Imidazole (2061 mg, 30.274 mmol) and TBDMS-Cl (2980 mg, 19.772 mmol) . The mixture was stirred for overnight at RT. The reaction mixture was quenched with Water (10 mL) and extracted with DCM (10 mL) . The reaction mixture was separated and organic extracts were collected. The aqueous solution was extracted with DCM (2×10 mL) . The residue was purified by wet column chromatography with EA/Hex (0-20%) . The product’s solution was concentrated under reduced pressure. The methyl (2S) -2- [tert-butyl (dimethyl) silyl] oxy-3- (1H-indol-3-yl) propanoate (3099 mg) was obtained. MS: m/z 334 (M+H)  +.
Step b: To a -78℃ solution of methyl (S) -2- ( (tert-butyldimethylsilyl) oxy) -3- (1H-indol-3-yl) propanoate (3.099g, 9.292 mmol) in THF (30 mL) was added LiHMDS (10.5 mL, 10.491 mmol) . The mixture was stirred for 30min at -78℃. Then Carbobenzyloxy chloride (4623 mg, 27.100 mmol) was dropped into the mixture at -78℃. The reaction mixture was stirred for 1h at this temperature. The reaction was quenched with sat. NH 4Cl, and the aqueous solution was extracted with EA (2×10 mL) . The combined organic extracts were washed with brine (3×10 mL) , dried over anhydrous Na 2SO 4. The organic phase was concentrated under reduced pressure. The benzyl (S) -3- (2- ( (tert-butyldimethylsilyl) oxy) -3-methoxy-3-oxopropyl) -1H-indole-1-carboxylate (4345 mg) was obtained. MS: m/z 468 (M+H)  +.
Step c: To a solution of benzyl (S) -3- (2- ( (tert-butyldimethylsilyl) oxy) -3-methoxy-3-oxopropyl) -1H-indole-1-carboxylate (4.345 g, 9.292 mmol) in THF (30 mL) was added Tetrabutylammonium fluoride (5 mL) . The mixture was stirred for overnight at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by FLASH with EA/Hex (0-60%) . The product’s solution was concentrated under reduced pressure. The benzyl 3- [ (2S) -2-hydroxy-3-methoxy-3-oxo-propyl] indole-1-carboxylate (2.21 g) was obtained. MS: m/z 354 (M+H)  +.
Step d: To a solution of benzyl 3- [ (2S) -2-hydroxy-3-methoxy-3-oxo-propyl] indole-1-carboxylate (103 mg, 291.481 μmol) , and 4A molecular sieve in CH 3I (1mL) was added Silver oxide (216 mg, 932.098 μmol) . The mixture was stirred for overnight at RT. The reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with EA (5mL) and filtered, the filtrate was concentrated to afford benzyl (S) -3- (2, 3-dimethoxy-3-oxopropyl) -1H-indole-1-carboxylate (107.088 mg, 100.000%yield) . MS: m/z 368 (M+H)  +.
Step e: To a solution of benzyl (S) -3- (2, 3-dimethoxy-3-oxopropyl) -1H-indole-1-carboxylate (0.107g, 291.240 μmol) in THF (5 mL) and MeOH (5mL) was added NaOH (3mL, 3M/L) . The mixture was stirred for 1h at RT. The reaction mixture was adjusted the pH to 3 with 1M HCl. The aqueous solution was extracted with EA (2×10 mL) . The combined organic extracts were washed with brine (3×10 mL) , dried over anhydrous Na 2SO 4. The organic phase was concentrated under reduced pressure and (S) -3- (1H-indol-3-yl) -2-methoxypropanoic acid (71 mg) was obtained. MS: m/z 220 (M+H)  +.
The following compounds were synthesized using the above procedure or modification  procedure with the corresponding starting materials.
Figure PCTCN2021123878-appb-000136
Figure PCTCN2021123878-appb-000137
Other Intermediates
Figure PCTCN2021123878-appb-000138
EXAMPLE 1
(S) -2- ( (S) -2-acetamido-3-phenylpropanamido) -6-diazo-N- (4-fluorobenzyl) -5-oxohexanamide (compound 1)
Figure PCTCN2021123878-appb-000139
To a solution of (2S) -2- [ [ (2S) -2-acetamido-3-phenyl-propanoyl] amino] -6-diazo-5-oxo-hexanoic acid (174 mg, 482.8451 μmol) , 4-Fluorobenzylamine (208 mg, 1.6621 mmol) and NMM (178 mg, 1.7598 mmol) in DMF (10 mL) was added HATU (292 mg, 767.9577μmol) at 0 ℃. The mixture was stirred at RT for 1 h. The reaction mixture was purified by FLASH. The residue was further purified by pre-HPLC and the product’s solution was concentrated under reduced pressure to afford (S) -2- ( (S) -2-acetamido-3-phenylpropanamido) -6-diazo-N- (4-fluorobenzyl) -5-oxohexanamide (0.1525 g, 326.2090 μmol) by lyophilization. MS: m/z 468 (M+H)  +,  1H NMR (400 MHz, CD 3OD) δδ 7.31 –7.26 (m, 2H) , 7.26 –7.21 (m, 4H) , 7.21 –7.15 (m, 1H) , 7.09 –6.97 (m, 2H) , 4.55 (dd, J = 8.8, 6 .0 Hz, 1H) , 4.38 –4.21 (m, 3H) , 3.10 (dd, J = 13.9, 6.0 Hz, 1H) , 2.89 (dd, J = 13.9, 8.8 Hz, 1H) , 2.37 (s, 2 H) , 2.17 –2.03 (m, 1H) , 1.97 –1.84 (m, 4H) .
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.
Figure PCTCN2021123878-appb-000140
Figure PCTCN2021123878-appb-000141
Figure PCTCN2021123878-appb-000142
Figure PCTCN2021123878-appb-000143
Figure PCTCN2021123878-appb-000144
Figure PCTCN2021123878-appb-000145
Figure PCTCN2021123878-appb-000146
Figure PCTCN2021123878-appb-000147
Figure PCTCN2021123878-appb-000148
Figure PCTCN2021123878-appb-000149
Figure PCTCN2021123878-appb-000150
Figure PCTCN2021123878-appb-000151
Figure PCTCN2021123878-appb-000152
Figure PCTCN2021123878-appb-000153
Figure PCTCN2021123878-appb-000154
Figure PCTCN2021123878-appb-000155
Figure PCTCN2021123878-appb-000156
Figure PCTCN2021123878-appb-000157
Figure PCTCN2021123878-appb-000158
Figure PCTCN2021123878-appb-000159
Figure PCTCN2021123878-appb-000160
Figure PCTCN2021123878-appb-000161
Figure PCTCN2021123878-appb-000162
Figure PCTCN2021123878-appb-000163
Figure PCTCN2021123878-appb-000164
Figure PCTCN2021123878-appb-000165
Figure PCTCN2021123878-appb-000166
Figure PCTCN2021123878-appb-000167
Figure PCTCN2021123878-appb-000168
Figure PCTCN2021123878-appb-000169
Figure PCTCN2021123878-appb-000170
Figure PCTCN2021123878-appb-000171
Figure PCTCN2021123878-appb-000172
Figure PCTCN2021123878-appb-000173
Figure PCTCN2021123878-appb-000174
Figure PCTCN2021123878-appb-000175
Figure PCTCN2021123878-appb-000176
Figure PCTCN2021123878-appb-000177
Figure PCTCN2021123878-appb-000178
Figure PCTCN2021123878-appb-000179
Figure PCTCN2021123878-appb-000180
Figure PCTCN2021123878-appb-000181
Figure PCTCN2021123878-appb-000182
Figure PCTCN2021123878-appb-000183
Figure PCTCN2021123878-appb-000184
Figure PCTCN2021123878-appb-000185
Figure PCTCN2021123878-appb-000186
Figure PCTCN2021123878-appb-000187
Figure PCTCN2021123878-appb-000188
Figure PCTCN2021123878-appb-000189
Figure PCTCN2021123878-appb-000190
Figure PCTCN2021123878-appb-000191
Figure PCTCN2021123878-appb-000192
Figure PCTCN2021123878-appb-000193
Figure PCTCN2021123878-appb-000194
Figure PCTCN2021123878-appb-000195
Figure PCTCN2021123878-appb-000196
Figure PCTCN2021123878-appb-000197
Figure PCTCN2021123878-appb-000198
Figure PCTCN2021123878-appb-000199
Figure PCTCN2021123878-appb-000200
Figure PCTCN2021123878-appb-000201
Figure PCTCN2021123878-appb-000202
Figure PCTCN2021123878-appb-000203
Figure PCTCN2021123878-appb-000204
Figure PCTCN2021123878-appb-000205
Figure PCTCN2021123878-appb-000206
Figure PCTCN2021123878-appb-000207
Figure PCTCN2021123878-appb-000208
Figure PCTCN2021123878-appb-000209
Figure PCTCN2021123878-appb-000210
Example 2
(S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -N-benzyl-6-diazo-5-oxohexanamide (compound 494)
Figure PCTCN2021123878-appb-000211
To a solution of (S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoic acid (0.0713 g, 178.518 μmol) , Benzylamine (0.0491 g, 458.225 μmol) and NMM (0.0589 g, 582.321 μmol) in DMF (5 mL) was added HATU (0.1462 g, 384.505 μmol) . The mixture was stirred at RT for 3 h. And the mixture was added water (10 mL) and DCM (10 mL) . The reaction mixture was filtered and the organic extracts were collected. The aqueous solution was extracted with DCM (10 mL×2) . The combined organic extracts were washed with brine (10 mL×3) and dried over anhydrous Na 2SO 4. The resulting mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC. The product’s solution was concentrated under reduced pressure. The (S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -N-benzyl-6-diazo-5-oxohexanamide (0.0507 g, 103.779 μmol) was obtained by lyophilization. MS: m/z 489 (M+H)  +,  1H NMR (400 MHz, CD 3OD) δ 7.58 (d, J = 7.9 Hz, 1H) , 7.34 –7.26 (m, 3H) , 7.25 –7.18 (m, 3H) , 7.14 (s, 1H) , 7.12 –7.05 (m, 1H) , 7.06 –6.98 (m, 1H) , 4.58 (t, J = 6.8 Hz, 1H) , 4.34 –4.16 (m, 3H) , 3.20 (ddd, J = 33.1, 14.5, 6.8 Hz, 2H) , 2.26 –2.07 (m, 2H) , 2.06 –1.96 (m, 1H) , 1.94 (s, 3H) , 1.87 –1.75 (m, 1H) .
EXAMPLE 3
Ethyl ( (S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoyl) -L-valinate (compound 495)
Figure PCTCN2021123878-appb-000212
To a solution of (S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoic acid (202 mg, 505.7856 μmol) , Ethyl L-valinate hydrochloride (215 mg, 1.1835 mmol) and NMM (168 mg,1.6609 mmol) in DMF (10 mL) was added HATU (408 mg, 1.073 mmol) at 0 ℃. The mixture was stirred at RT for 16 h. The reaction mixture was purified by FLASH. The residue was further purified by pre-HPLC. The product’s solution was concentrated under reduced pressure. Ethyl ( (S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoyl) -L-valinate (52.7 mg,100.0791 μmol) was obtained by lyophilization. MS: m/z 527 (M+H)  +,  1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H) , 7.69 (d, J = 7.9 Hz, 1H) , 7.38 (d, J = 8.0 Hz, 1H) , 7.23 (dd, J = 16.4, 8.6 Hz, 2H) , 7.15 (t, J = 7.5 Hz, 1H) , 7.10 (s, 1H) , 6.16 (d, J = 7.5 Hz, 1H) , 4.77 (m, J = 6.0 Hz, 1H) , 4.43 –4.37 (m, 1H) , 4.35 (m, J = 6.1 Hz, 1H) , 4.25 –4.16 (m, 2H) , 3.41 (m, J = 14.9 Hz, 1H) , 3.22 –3.09 (m, 1H) , 2.51 –2.34 (m, 1H) , 2.31 –2.15 (m, 2H) , 2.02 (s, J = 7.4 Hz, 3H) , 1.98 –1.84 (m, 2H) , 1.30 (t, J = 7.1 Hz, 3H) , 0.97 (t, J = 7.3  Hz, 6H) .
EXAMPLE 4
(S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-N- (4-fluorobenzyl) -5-oxohexanamide (compound 496)
Figure PCTCN2021123878-appb-000213
To a solution of (S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoic acid (203mg, 508.2628μmol) , (4-fluorophenyl) methanamine (128 mg, 1.0228mmol) and 1-Methylimidazole (141mg, 1.7173mmol) in DMF (2 mL) was added TCFH (219mg, 780.5288 μmol) . The mixture was stirred at RT for 16 h. The reaction mixture was purified by FLASH. The residue was further purified by pre-HPLC. The product’s solution was concentrated under reduced pressure. The (S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-N- (4-fluorobenzyl) -5-oxohexanamide (52 mg, 102.6597 μmol) was obtained by lyophilization. MS: m/z 507 (M+H)  +,  1H NMR (400 MHz, CDCl 3) δ 7.99 (s, 1H) , 7.61 –7.51 (m, 1H) , 7.28 (d, J = 8.1 Hz, 1H) , 7.13 (d, J = 7.2 Hz, 2H) , 6.98 (ddd, J = 24.6, 15.6, 7.8 Hz, 3H) , 6.77 –6.62 (m, 1H) , 5.97 (d, J = 5.5 Hz, 1H) , 4.53 (dd, J = 11.2, 5.6 Hz, 1H) , 4.18 (d, J = 22.1 Hz, 2H) , 3.76 (s, 1H) , 3.30 (dd, J = 14.6, 5.3 Hz, 1H) , 3.17 –3.01 (m, 1H) , 2.27 (s, 1H) , 2.11 (d, J = 17.1 Hz, 1H) , 1.88 (s, 1H) , 1.79 (s, 1H) , 1.48 (s, 3H) .
EXAMPLE 5
2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxo-N- (4- (trifluoromethyl) phenyl) hexanamide (compound 497)
Figure PCTCN2021123878-appb-000214
(S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoic acid (150 mg, 375.5636 μmol) , tetrahydrofura (3 mL) were added to a vial. Then to the mixture was added 4- (trifluoromethyl) aniline (124.8 mg, 774.5578 μmol) , XtalFluor-E (133 mg, 580.7990 μmol) at an ice water bath. The mixture was cloudy. The ice water bath was removed and the mixture was stirred at room  temperature for overnight. DMF (0.75 ml, 5V) was added into the vial, and the mixture was clean. Then the mixture was stirred overnight at room temperature. The reaction mixture was purified by flash (MeCN/H 2O=0%～70%) , and the product fractions were collected and concentrated. 2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxo-N- (4- (trifluoromethyl) phenyl) hexana mide (4.9 mg, 9.0321 μmol) was obtained by lyophilization as a white solid. MS: m/z 543 (M+H)  +,  1H NMR (400 MHz, CD 3OD ) δ 7.88 (d, J = 8.5 Hz, 1H) , 7.75 (d, J = 8.5 Hz, 1H) , 7.58 (t, J = 8.5 Hz, 3H) , 7.32 (dd, J = 36.1, 8.0 Hz, 1H) , 7.16 (d, J = 2.0 Hz, 1H) , 7.08 –7.01 (m, 1H) , 7.01 –6.95 (m, 1H) , 4.70 –4.41 (m, 1H) , 4.36 –4.06 (m, 1H) , 3.26 –3.05 (m, 2H) , 2.22 –2.02 (m, 1H) , 2.00 (d, J = 7.7 Hz, 3H) , 1.96 –1.79 (m, 1H) , 1.53 (m, J = 51.9 Hz, 1H) , 1.29 (m, 1H) .
EXAMPLE 6
methyl ( (S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoyl) glycinate (compound 498)
Figure PCTCN2021123878-appb-000215
To a solution of (S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoic acid (0.1526 g, 382.0734 μmol) in DMF (5mL) was added N, N'-Diisopropylcarbodiimide (0.0741 g, 587.1679 μmol) , 2, 4, 6-Collidine (0.0951g, 784.7881μmol)
Ethyl cyanoglyoxylate-2-oxime (0.1079 g, 759.2576μmol) and Glycine methyl ester hydrochloride (0.1582 g, 1.2600mmol) at 0 ℃. The mixture was stirred at 0 ℃～RT for 3h. The aqueous solution was extracted with DCM (10 mL×2) . The combined organic extracts were washed with brine (10 mL×3) and dried over anhydrous Na 2SO 4. The reaction mixture was purified by FLASH. The residue was further purified by pre-HPLC. The product’s solution was concentrated under reduced pressure to afford methyl ( (S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoyl) glycinate (0.0622 g, 132.2061 μmol, 34.6023%yield) . MS: m/z 471 (M+H)  + ,  1H NMR (400 MHz, CD 3OD) δ 7.58 (d, J = 7.9 Hz, 1H) , 7.33 (d, J = 8.1 Hz, 1H) , 7.16 (s, 1H) , 7.12 –7.06 (m, 1H) , 7.02 (m, 1H) , 4.59 (t, J = 7.0 Hz, 1H) , 4.27 (dd, J = 8.9, 4.8 Hz, 1H) , 3.76 (d, J = 10.8 Hz, 2H) , 3.70 (s, 3H) , 3.20 (ddd, J = 39.2, 14.5, 6.8 Hz, 2H) , 2.29 (m, 2H) , 2.10 –1.99 (m, 1H) , 1.97 (s, 3H) , 1.82 (m, 1H) .
The following compounds were synthesized using the above procedure (example 2 to example 6) or modification procedure with the corresponding starting materials.
Figure PCTCN2021123878-appb-000216
Figure PCTCN2021123878-appb-000217
Figure PCTCN2021123878-appb-000218
Figure PCTCN2021123878-appb-000219
Figure PCTCN2021123878-appb-000220
Figure PCTCN2021123878-appb-000221
Figure PCTCN2021123878-appb-000222
Figure PCTCN2021123878-appb-000223
Figure PCTCN2021123878-appb-000224
Figure PCTCN2021123878-appb-000225
Figure PCTCN2021123878-appb-000226
Figure PCTCN2021123878-appb-000227
Figure PCTCN2021123878-appb-000228
Figure PCTCN2021123878-appb-000229
Figure PCTCN2021123878-appb-000230
Figure PCTCN2021123878-appb-000231
Figure PCTCN2021123878-appb-000232
Figure PCTCN2021123878-appb-000233
Figure PCTCN2021123878-appb-000234
Figure PCTCN2021123878-appb-000235
Figure PCTCN2021123878-appb-000236
Figure PCTCN2021123878-appb-000237
Figure PCTCN2021123878-appb-000238
Figure PCTCN2021123878-appb-000239
Figure PCTCN2021123878-appb-000240
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.
Figure PCTCN2021123878-appb-000241
Figure PCTCN2021123878-appb-000242
Figure PCTCN2021123878-appb-000243
Figure PCTCN2021123878-appb-000244
Figure PCTCN2021123878-appb-000245
Figure PCTCN2021123878-appb-000246
Figure PCTCN2021123878-appb-000247
Figure PCTCN2021123878-appb-000248
Figure PCTCN2021123878-appb-000249
Figure PCTCN2021123878-appb-000250
Figure PCTCN2021123878-appb-000251
Figure PCTCN2021123878-appb-000252
Figure PCTCN2021123878-appb-000253
Figure PCTCN2021123878-appb-000254
EXAMPLE 7
S-isopropyl
2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanethioate
Figure PCTCN2021123878-appb-000255
To a solution of (S) -2- ( (S) -2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoic acid (190 mg, 475.714 μmol) , propane-2-thiol (76 mg, 997.895 μmol) and DIPEA (197 mg, 1.524 mmol) in DMF (5 mL) was added BOP (237 mg,535.860 μmol) . The mixture was stirred at RT for 2.5 h. Water (30 mL) and EA (30 mL×2) were added. The reaction mixture was filtered and the organic extracts were collected. The combined organic extracts were washed with brine (30 mL×2) . The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC. The product’s solution was concentrated under reduced pressure. The S-isopropyl 2- (2-acetamido-3- (1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanethioate (28.3 mg, 61.852 μmol) was obtained by lyophilization. MS: m/z 458 (M+H)  +,  1H NMR (400 MHz, CDCl 3) δ 8.09 (d, J = 19.0 Hz, 1H) , 7.60 (d, J = 5.6 Hz, 1H) , 7.29 (d, J = 7.9 Hz, 1H) , 7.16 –7.10 (m, 1H) , 7.10 –7.01 (m, 2H) , 6.09 (s, 1H) , 6.00 (s, 1H) , 5.02 (s, 1H) , 4.76 –4.63 (m, 1H) , 4.46 –4.34 (m, 1H) , 3.49 (dd, J = 13.1, 6.8 Hz, 2H) , 3.30 –3.20 (m, 1H) , 3.17 –3.06 (m, 1H) , 2.10 (dd, J = 25.3, 17.9 Hz, 2H) , 1.93 (t, J = 3.6 Hz, 3H) , 1.81 (d, J = 13.2 Hz, 2H) , 1.18 (d, J = 6.9 Hz, 6H) .
The following compounds were synthesized by using the above procedure or modification procedure with the corresponding starting materials.
Figure PCTCN2021123878-appb-000256
EXAMPLE 8
Isopropyl (S) -2- ( (S) -2-acetamido-3- (7-fluoro-1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoate and isopropyl (S) -2- ( (R) -2-acetamido-3- (7-fluoro-1H-indol-3-yl) propanamido) -6-diazo-5-oxohexanoate
Figure PCTCN2021123878-appb-000257
Step a: A flame-dried round bottom flask was charged with a solution of 7-fluoro-1H-indole (202 mg, 1.495 mmol) , serine (347 mg, 3.302 mmol) and acetic anhydride (0.8 mL) in acetic acid (5 mL) . The mixture was stirred at 80℃ under nitrogen atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel plate (eluting  with DCM : MeOH=10: 1, v/v) to give 2-acetamido-3- (7-fluoro-1H-indol-3-yl) propanoic acid (122 mg, 461.681 μmol) . MS: m/z 265 (M+H)  +.
Step b: To a solution of 2-acetamido-3- (7-fluoro-1H-indol-3-yl) propanoic acid (0.122 g,461.681 μmol) , isopropyl (S) -2-amino-6-diazo-5-oxohexanoate (101 mg, 473.660 μmol) and DIPEA (164 mg, 1.269 mmol) in DCM was added HATU (182 mg, 478.659μmol) . The mixture was stirred at RT for one night. The reaction mixture was concentrated under reduced pressure. The residue was purified by chiral separation (CHIRALPAK IA column, 2.12cm×15cm id, 5 μm particle size) to give the previous point (1.878min, 13.1 mg, 28.511μmol) , MS: m/z 460(M+H)  +,  1H NMR (400 MHz, CDCl 3) δ 8.30 (s, 1H) , 7.45 (t, J = 8.1 Hz, 1H) , 7.21 –7.14 (m, 1H) , 7.11 –7.00 (m, 1H) , 6.92 (dd, J = 11.1, 7.8 Hz, 1H) , 6.26 (d, J = 7.3 Hz, 1H) , 6.18 (d, J = 7.2 Hz, 1H) , 4.96 (dt, J = 18.7, 6.2 Hz, 1H) , 4.79 –4.65 (m, 1H) , 4.41 –4.31 (m, 1H) , 3.33 (ddd, J = 14.6, 9.2, 5.0 Hz, 1H) , 3.22 –3.11 (m, 1H) , 2.67 –2.43 (m, 2H) , 2.16 (ddd, J = 11.5, 6.1, 3.4 Hz, 2H) , 2.03 (d, J = 6.3 Hz, 3H) , 1.26 (dd, J = 6.3, 2.6 Hz, 3H) , 1.23 (dd, J = 6.2, 2.3 Hz, 3H) , and the back point (2.625min, 14.7 mg, 31.993μmol) ; MS: m/z 460 (M+H)  +,  1H NMR (400 MHz, CDCl 3) δ 8.25 (s, 1H) , 7.37 (d, J = 8.0 Hz, 1H) , 7.08 (s, 1H) , 6.99 (td, J = 7.9, 4.7 Hz, 1H) , 6.88 –6.81 (m, 1H) , 6.29 (d, J = 7.2 Hz, 1H) , 6.04 (d, J = 7.7 Hz, 1H) , 4.90 (dt, J = 15.8, 6.3 Hz, 1H) , 4.70 (dd, J = 13.1, 7.9 Hz, 1H) , 4.34 –4.23 (m, 1H) , 3.23 (dd, J = 14.6, 5.7 Hz, 1H) , 3.10 (dd, J = 14.6, 8.1 Hz, 1H) , 2.22 (td, J = 23.0, 15.8 Hz, 2H) , 2.12 –1.74 (m, 5H) , 1.20 –1.12 (m, 6H) .
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.
Figure PCTCN2021123878-appb-000258
Figure PCTCN2021123878-appb-000259
Figure PCTCN2021123878-appb-000260
Figure PCTCN2021123878-appb-000261
Synthesis of Control Compounds:
Compound 60 of WO2017023774 (named “reference compound” ) was obtained according to the synthesis route and operation steps of compound 60 on Page 124 in WO2017023774.
Compound 47 of WO2017023774 (named “reference compound 1” ) was obtained according to the synthesis route and operation steps of compound 47 on Page 115-116 in WO2017023774.
Example 9 Dog pharmacokinetic study
Reference compound, compound 1 and compound 2 were provided for Dog pharmacokinetic study, and they were shown as below:
Figure PCTCN2021123878-appb-000262
The dog pharmacokinetic study was conducted in accordance with the guidelines recommended in Guide for the Care and Use of Laboratory Animals and approved by the Beijing Piroma Biotech Inc. Reference compound, compound 2 and compound 1 were administered intravenously to a male and a female beagle dogs (n=2/group) at a dose of 500 nmoL/kg respectively. Blood sample were collected at 0min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h, post dose, in tubes with EDTA-K2. Blood samples were centrifuged at a temperature of 4 ℃ at 3000g for 10 min. All samples were kept chilled throughout processing. Plasma samples were collected in polypropylene tubes and stored at -80 ℃ until bioanalysis.
For quantifying intact compounds and DON in the pharmacokinetic samples, plasma samples (50 μL) were processed using a single liquid extraction method by addition of 200 μL of acetonitrile containing internal standard (Dexamethasone 100 ng/mL) , followed by vortex-mixing for 30 s and then centrifugation at 15000g for 5 min at 4 ℃. 100 μL of the supernatant was diluted with 100 μL of water and transferred to a 250 μL polypropylene vial sealed with a Teflon cap. Prodrug and DON disappearance was monitored over time using a liquid chromatography and tandem mass spectrometry (LC-MS/MS) .
For LC-MS/MS analysis, intact compounds were analyzed on an ExionLC system coupled to Accela open autosampler on a Phenomenex Kinetex 5 μm C18 100A (2.1*50) mm UPLC column. The temperature of autosampler was controlled and the autosampler was operated at 4 ℃. The mobile phase used for the chromatographic separation was composed of acetonitrile/water containing 0.1%formic acid and will run at a flow rate of 0.6 mL/min for 3.5 min using gradient elution. The column effluent was monitored using TSQ Vantage triple-quadrupole mass-spectrometric detector, equipped with an electrospray probe set in the positive ionization mode. Samples were introduced into the ionization source through a heated nebulized probe (450 ℃) . Disappearance of prodrugs will be measured from ratio of peak areas of analyte to IS (internal standard) .
DON was analyzed on an ExionLC system coupled with a REF Triple Quad 5500+ mass spectrometer. Separation was achieved at 25 ℃ using an HALO Penta-HILIC 2.7 μM 90A (2.1x100 mm) . The mobile phase consisted of 100%Water (5MM ammonium formate PH=3.0) and 100%Acetonitrile. Pumps were operated at a flow rate of 0.6 mL/min for 5.0 min using gradientelution. The mass spectrometer controlled by Analyst software 1.6.3 was operated with a heated ESI ionsource in positive ionization mode.
Reference compound, compound 2 and compound 1 were administrated intravenously to a beagle dog respectively. FIG. 1 is a graph showing the concentrations of DON and reference compound over time after IV infusion (intravenous infusion) . FIG. 2 is a graph showing the concentrations of DON and compound 2 over time after IV infusion. FIG. 3 is a graph showing the concentrations of DON and compound 1 over time after IV infusion. The pharmacokinetic data was shown in the following Table 1.
Table 1. Pharmacokinetic parameters intact compounds administration
Figure PCTCN2021123878-appb-000263
Example 10 Metabolic stability in human plasma and microsomes
Reference compound, reference compound 1, compound 494, compound 495, compound 499, compound 501, compound 527 and compound 530 were provided for metabolic stability in human plasma and microsomes, and they were shown as below:
Figure PCTCN2021123878-appb-000264
Figure PCTCN2021123878-appb-000265
For metabolic stability analysis, microsomes from human was used. Reference compound, reference compound 1, compound 494, compound 495, compound 499, compound 501, compound 527 and compound 530 (the concentration of the each compound was 1 μM) were spiked in each microsomes matrix and incubated in an orbital shaker at 37 ℃ respectively. At predetermined times (0 and 60 min) , 50 μL aliquots of the mixture in duplicate were obtained, and 200 μL of ice cold acetonitrile spiked with the internal standard (Dexamethasone 100 ng/mL) was added into the obtained mixture to quench the reaction of the obtained mixture. The samples were vortexed for 30 s and centrifuged at 15000g for 5 min. 100 μL of the supernatant was diluted with 100 μL of water and transferred to a 250 μL polypropylene vial sealed with a Teflon cap. Prodrug disappearance was monitored over time using a liquid chromatography and tandem mass spectrometry (LC-MS/MS) .
For LC-MS/MS analysis, intact compounds were analyzed on an ExionLC system coupled to Accela open autosampler on a Phenomenex Kinetex 5 μm C18 100A (2.1*50) mm UPLC column. The temperature of autosampler was controlled and the autosampler was operated at 4 ℃. The mobile phase used for the chromatographic separation was composed of acetonitrile/water containing 0.1%formic acid and at a flow rate of 0.5 mL/min for 3.5 min using gradient elution. The column effluent was monitored using TSQ Vantage triple-quadrupole mass-pectrometric detector, equipped with an electrospray probe set in the positive ionization mode. Samples were introduced into the ionization source through a heated nebulized probe (450 ℃) . Disappearance of the compounds will be measured from ratio of peak areas of analyte to IS (internal standard) .
FIG. 4 and FIG. 5 is a bar graph showing the stability of compounds after incubation for 60 minutes in the presence of human microsomes.
Example 11 Anti-tumor Efficacy of compound 496 and compound 527 the anti-tumor Efficacy in MC38 Syngeneics in CES1c -/-mouse
Compound 496, compound 527 and reference compound were provided for anti-tumor efficacy in MC38 Syngeneics in CES1c -/-mouse, and they were shown as below:
Figure PCTCN2021123878-appb-000266
Animal species: Mus musculus; Strain: C57BL/6-Ces1c em1Smoc; Age: 6-8 weeks; Sex: female. (Shanghai Model Organisms)
The MC38 tumor cells were maintained in vitro in DMEM medium supplemented with 10%FBS at 37 ℃, 5%CO 2. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. The culture MC38 were harvested, re-suspended in PBS containing 50%Matrigel at a density of 1×10 7 cells/mL. Each mouse was inoculated subcutaneously in the right flank region with 1×10 6 cells in 0.1 mL of PBS containing 50%Matrigel for tumor development.
The treatments were started when the mean tumor size reached 46-132mm 3 (average tumor size 95 mm 3) . Each group contained 5 tumor bearing mice. Group 1 was treated with Vehicle (10%DMSO + 90%Saline) , S.C., QD (Subcutaneous injection, quaque die) . Group 2 was given treatments with reference compound at 2 μmol/kg, S.C., QD. Group 3 was given treatments with compound 35 at 2 μmol/kg, S.C., QD. Group 4 was given treatments with compound 3 at 2 μmol/kg, S.C., QD. The administration of different compounds in each study group was shown in the following Table 2.
In vivo efficacy was examined according to absolute tumor growth inhibition (TGI) and the safety was evaluated according to weight change and survival in mice.
Table 2. Groups and treatments for efficacy study
Group Treatment Dose (μmol/kg) Dosing Route Schedule
1 Vehicle 2 S.C. QD×21
2 Reference compound 2 S.C. QD×21
3 Compound 527 2 S.C. QD×21
4 Compound 496 2 S.C. QD×21
Body Weight
Group treated with reference compound showed some body weight loss, but the group treated with vehicle, the group treated with compound 505 and the group treated with compound 474 were well-tolerated by the tumor-bearing mice. The results of the body weight changes in the tumor-bearing mice are shown in Table 3, FIG. 6.
Table 3. The body weight changes (%) of the mice in different groups
Figure PCTCN2021123878-appb-000267
Tumor Volumes
The results of tumor sizes in different groups at different time points post tumor inoculation were shown in Table 4 and FIG. 7. The tumor growth inhibition was summarized in Table 5. The result showed that all treatment groups had significant anti-tumor effect when compared to the vehicle group. Statistical analysis of difference in tumor volume among the groups was performed using one-way ANOVA followed by individual comparisons using Games-Howell post-hoc test (equal variance not assumed) . All data was analyzed using SPSS 22.0 software.
Table 4. Mean tumor volume in the different treatment groups
Figure PCTCN2021123878-appb-000268
Table 5: Anti-tumor activity of test compounds in MC38 syngeneic model
Figure PCTCN2021123878-appb-000269

Claims (25)

  1. A compound of formula I, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, the tautomer thereof
    Figure PCTCN2021123878-appb-100001
    Wherein,
    Z is (OR 1)  1-2, (C (R 1)  2)  1-6, (N (R 1) )  1-2 R 1’, or (SR 1)  1-2;
    R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, C 2-6 alkynyl, -C 5-12 aryl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-C 5-12 aryl, -5-12 membered heteroaryl, -5-12 membered heterocyclyl, -C 1-6 alkylene-N (C 1-6 alkyl)  2, -C 1-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene-CO-NH-C 1-6 alkyl, -C 1-6 alkylene-CO-5-12 membered heterocyclyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, and wherein said -C 1-6 alkyl, said -C 1-6 alkenyl, said C 1-6 alkynyl, said -C 5-12 aryl, said -C 1-6 alkylene-COO-C 1-6 alkyl, said -C 1-6 alkylene-C 5-12 aryl, said -5-12 membered heteroaryl, said -5-12 membered heterocyclyl, said -C 1-6 alkylene-N (C 1-6 alkyl)  2, said -C 1-6 alkylene-O-C 1-6 alkyl, said -C 1-6 alkylene-CO-NH-C 1-6 alkyl, said -C 1-6 alkylene-CO-5-12 membered heterocyclyl, said -C 1-6 alkylene-SO 2-C 1-6 alkyl, said -C 1-6 alkylene-SO-C 1-6 alkyl, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl; or
    R 1 and R 1’ together with the nitrogen atom to which they are both attached form 4-8 membered heterocyclyl, and wherein said 4-8 membered heterocyclyl can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2, and said 4-8 membered heterocyclyl can be optionally substituted with one or more substituents, which are independently selected from the group consisting  of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    X is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, –C (=O) -G, –C (=O) -W- (CR X1R X2)  m-G, –C (=O) -W- (CR X1R X2)  m-NR 5R 5’ , C (=O) -W- (CR X1R X2)  m-SR 11, , C (=O) -W- (CR X1R X2)  m-SOR 11, C (=O) -W- (CR X1R X2)  m-SO 2R 11, –C (=O) -W- (CR X1R X2)  m-OR 11, -P (=O) (OR 6)  p (NHR 7)  q, -P (=O) (OG)  p, –C (=O) -W- (CR X1R X2)  m-G-O-C (=O) -R 8, –C (=O) -W- (CR X1R X2)  m-G-O-R 8, –C (=O) -O- (CR X1R X2)  m-O-C (=O) -R 9, -C (=O) -O-R 7, –C (=O) -W- (CR X1R X2)  m-G-O-C (=O) -G, and –C (=O) -W- (CR X1R X2)  m-G-NR 5R 5’;
    W is oxygen, CO or a bond;
    m is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
    p and q are each independently selected from 0, 1 or 2, provided that the sum of p and q is 2;
    R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, halogen, C 1-6 alkyl, -C 1-6 alkylene-SH, -C 1-6 alkylene-C 2-6 alkenyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 3-8 cycloalkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-CONH 2, 
    Figure PCTCN2021123878-appb-100002
    -C 1-6 alkylene-Se-C 1-6 alkyl, -C 1-6 alkylene-SH, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-CO 2-C 1-6 alkyl, C 5-12aryl, -C 1-6 alkylene-C 5-12 aryl, -C 1-6 alkylene-5-12 membered heteroaryl, -C 1-6 alkylene-5-12 membered heterocyclyl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said -C 1-6 alkylene-SH, said -C 1-6 alkylene-C 2-6 alkenyl, said -C 3-8 cycloalkyl, said -C 1-6 alkylene-C 3-8 cycloalkyl, said -C 1-6 alkylene-S-C 1-6 alkyl, said -C 1-6 alkylene-CONH 2, said
    Figure PCTCN2021123878-appb-100003
    said 
    Figure PCTCN2021123878-appb-100004
    said -C 1-6 alkylene-Se-C 1-6 alkyl, said -C 1-6 alkylene-SH, said -C 1-6 alkylene-SO 2-C 1-6 alkyl, said -C 1-6 alkylene-CO 2-C 1-6 alkyl, said C 5-12aryl, said -C 1-6 alkylene-C 5-12 aryl, said -C 1-6 alkylene-5-12 membered heteroaryl, said -C 1-6 alkylene-5-12 membered heterocyclyl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl,  -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    or R X1 and R X2 together with the carbon atom to which they are attached form 5-10 membered carbocyclic ring, C 3-8 cycloalkyl, C 2-4 alkenyl, 5-10 membered heterocyclyl, and wherein said 5-10 membered carbocyclic ring, said C 2-4 alkenyl, said 5-10 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, -C 1-6 alkyl, -C 3-8 cycloalkyl, -C (=O) -C 1-6 alkyl, -C (=O) -C 5-10 carbocyclic, -C (=O) -adamantanyl, -C (=O) -C 3-6 cycloalkyl, and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    or R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5-12 membered heterocyclyl, and wherein said 5-12 membered heterocyclyl can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2, and said 5-12 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6  alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    each of R 6 is independently selected from the group consisting of hydrogen, deuterium, -C 1-6 alkyl, -C 3-8 cycloalkyl, 5-12 membered heterocyclyl, -C 1-6 alkenyl, and -C 3-8 cycloalkenyl, and wherein said -C 1-6 alkyl, said -C 3-8 cycloalkyl, said 5-12 membered heterocyclyl, said -C 1-6 alkenyl, and said -C 3-8 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    or R 6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
    each of R 7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, 5-12 membered heterocyclyl, C 1-6 alkenyl, C 3-8 cycloalkenyl, C 5-12 aryl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said C 3-8 cycloalkyl, said 5-12 membered heterocyclyl, said C 1-6 alkenyl, said C 3-8 cycloalkenyl, said C 5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    R 8 and R 9 are each independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, monosaccharide, acylated monosaccharide, C 5-12 aryl, and 5-12 membered heteroaryl, and wherein said C 1-6 alkyl, said C 3-8 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C 5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen,  -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    R 11 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    G is C 5-12 aryl, or 5-12 membered heteroaryl, and wherein said C 5-12 aryl, and said 5-12 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    R 3 and R 3’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    Y is a bond, oxygen, or - (CR Y1R Y2)  n-;
    n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
    R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, and C 1-6 alkoxy, and wherein said C 1-6 alkyl, and said C 1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6  alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl.
  2. The compound of claim 1, wherein the compound is of Formula Ia, or Ib, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotope substitutant thereof:
    Figure PCTCN2021123878-appb-100005
  3. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of claim 1 or 2, wherein
    R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, C 2-3 alkynyl, -C 5-10 aryl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-C 5-10 aryl, -5-10 membered heteroaryl, -5-10 membered heterocyclyl, -C 1-3 alkylene-N (C 1-3 alkyl)  2, -C 1-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene-CO-NH-C 1-3 alkyl, -C 1-3 alkylene-CO-5-10 membered heterocyclyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, and -C 1-3 alkylene-SO-C 1-3 alkyl, and wherein said -C 1-3 alkyl, said -C 2-3 alkenyl, said C 2-3 alkynyl, said -C 5-10 aryl, said -C 1-3 alkylene-COO-C 1-3 alkyl, said -C 1-3 alkylene-C 5-10 aryl, said -5-10 membered heteroaryl, said -5-10 membered heterocyclyl, said -C 1-3 alkylene-N (C 1-3 alkyl)  2, said -C 1-3 alkylene-O-C 1-3 alkyl, said -C 1-3 alkylene-CO-NH-C 1-3 alkyl, said -C 1-3 alkylene-CO-5-10 membered heterocyclyl, said -C 1-3 alkylene-SO 2-C 1-3 alkyl, and said -C 1-3 alkylene-SO-C 1-3 alkyl, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6  alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl; or
    R 1 and R 1’ together with the nitrogen atom to which they are both attached form 4-6 membered heterocyclyl, and wherein said 4-6 membered heterocyclyl can further contains 1, or 2 heteroatoms selected from N, O, S, SO or SO 2, and said 4-6 membered heterocyclyl can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl.
  4. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of any of claims 1-3, wherein
    R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, C 2-3 alkynyl, -C 5-10 aryl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-C 5-10 aryl, -5-10 membered heteroaryl, -5-10 membered heterocyclyl, -C 1-3 alkylene-N (C 1-3 alkyl)  2, -C 1-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene-CO-NH-C 1-3 alkyl, -C 1-3 alkylene-CO-5-10 membered heterocyclyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, and -C 1-3 alkylene-SO-C 1-3 alkyl, and wherein said -C 1-3 alkyl, said -C 2-3 alkenyl, said C 2-3 alkynyl, said -C 5-10 aryl, said -C 1-3 alkylene-COO-C 1-3 alkyl, said -C 1-3 alkylene-C 5-10 aryl, said -5-10 membered heteroaryl, said -5-10 membered heterocyclyl, said -C 1-3 alkylene-N (C 1-3 alkyl)  2, said -C 1-3 alkylene-O-C 1-3 alkyl, said -C 1-3 alkylene-CO-NH-C 1-3 alkyl, said -C 1-3 alkylene-CO-5-10 membered heterocyclyl, said -C 1-3 alkylene-SO 2-C 1-3 alkyl, and said -C 1-3 alkylene-SO-C 1-3 alkyl, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl; or
    R 1 and R 1’ together with the nitrogen atom to which they are both attached form 4-6 membered heterocyclyl, and wherein said 4-6 membered heterocyclyl can further contains 1, or 2 heteroatoms selected from N, O, S, SO or SO 2, and said 4-6 membered heterocyclyl can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
  5. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of any one of claims 1-4, wherein
    R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, vinyl, allyl, ethyne, propyne, C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-C 5 aryl, -CH 2-C 6 aryl, - (CH 2)  2-C 6 aryl, - (CH 2)  3-C 6 aryl, -CH 2-C 7 aryl, - (CH 2)  2-C 7 aryl, - (CH 2)  3-C 7 aryl, -CH 2-C 8 aryl, - (CH 2)  2-C 8 aryl, - (CH 2)  3-C 8 aryl, -CH 2-C 9 aryl, - (CH 2)  2-C 9 aryl, - (CH 2)  3-C 9 aryl, -CH 2-C 10 aryl, - (CH 2)  2-C 10 aryl, - (CH 2)  3-C 10 aryl, -5 membered heteroaryl, -6 membered heteroaryl, -7 membered heteroaryl, -8 membered heteroaryl, -9 membered heteroaryl, -10 membered heteroaryl, -5 membered heterocyclyl, -6 membered heterocyclyl, -7 membered heterocyclyl, -8 membered heterocyclyl, -9 membered heterocyclyl, -10 membered heterocyclyl, -CH 2-N (CH 3)  2, - (CH 2)  2-N (CH 3)  2, - (CH 2)  3-N (CH 3)  2, -CH 2-N (CH 2CH 3)  2, - (CH 2)  2-N (CH 2CH 3)  2, - (CH 2)  3-N (CH 2CH 3)  2, -CH 2-N (CH 2CH 2CH 3)  2, - (CH 2)  2-N (CH 2CH 2CH 3)  2, - (CH 2)  3-N (CH 2CH 2CH 3)  2, -CH 2-N (CH (CH 3)  2)  2, - (CH 2)  2-N (CH (CH 3)  2)  2, - (CH 2)  3-N (CH (CH 3)  2)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2, - (CH 2)  3-O-CH (CH 3)  2, -CH 2-CO-NH-CH 3, - (CH 2)  2-CO-NH-CH 3, - (CH 2)  3-CO-NH-CH 3, -CH 2-CO-NH-CH 2CH 3, - (CH 2)  2-CO-NH-CH 2CH 3, - (CH 2)  3-CO-NH-CH 2CH 3, -CH 2-CO-NH-CH 2CH 2CH 3,  - (CH 2)  2-CO-NH-CH 2CH 2CH 3, - (CH 2)  3-CO-NH-CH 2CH 2CH 3, -CH 2-CO-NH-CH (CH 3)  2, - (CH 2)  2-CO-NH-CH (CH 3)  2, - (CH 2)  3-CO-NH-CH (CH 3)  2, -CH 2-CO-5 membered heterocyclyl, - (CH 2)  2-CO-5 membered heterocyclyl, - (CH 2)  3-CO-5 membered heterocyclyl, -CH 2-CO-6 membered heterocyclyl, - (CH 2)  2-CO-6 membered heterocyclyl, - (CH 2)  3-CO-6 membered heterocyclyl, -CH 2-CO-7 membered heterocyclyl, - (CH 2)  2-CO-7 membered heterocyclyl, - (CH 2)  3-CO-7 membered heterocyclyl, -CH 2-CO-8 membered heterocyclyl, - (CH 2)  2-CO-8 membered heterocyclyl, - (CH 2)  3-CO-8 membered heterocyclyl, -CH 2-CO-9 membered heterocyclyl, - (CH 2)  2-CO-9 membered heterocyclyl, - (CH 2)  3-CO-9 membered heterocyclyl, -CH 2-CO-10 membered heterocyclyl, - (CH 2)  2-CO-10 membered heterocyclyl, - (CH 2)  3-CO-10 membered heterocyclyl, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3, -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, and - (CH 2)  3-SO-CH (CH 3)  2, and wherein said methyl, said ethyl, said propyl, said isopropyl, said vinyl, said allyl, said ethyne, said propyne, said C 5 aryl, C 6 aryl, said C 7 aryl, said C 8 aryl, said C 9 aryl, said C 10 aryl, said -CH 2-COO-CH 3, said - (CH 2)  2-COO-CH 3, said - (CH 2)  3-COO-CH 3, said -CH 2-COO-CH 2CH 3, said - (CH 2)  2-COO-CH 2CH 3, said - (CH 2)  3-COO-CH 2CH 3, said -CH 2-COO-CH 2CH 2CH 3, said - (CH 2)  2-COO-CH 2CH 2CH 3, said - (CH 2)  3-COO-CH 2CH 2CH 3, said -CH 2-COO-CH (CH 3)  2, said - (CH 2)  2-COO-CH (CH 3)  2, said - (CH 2)  3-COO-CH (CH 3)  2, said -CH 2-C 5 aryl, said -CH 2-C 6 aryl, said - (CH 2)  2-C 6 aryl, said - (CH 2)  3-C 6 aryl, said -CH 2-C 7 aryl, said - (CH 2)  2-C 7 aryl, said - (CH 2)  3-C 7 aryl, said -CH 2-C 8 aryl, said - (CH 2)  2-C 8 aryl, said - (CH 2)  3-C 8 aryl, said -CH 2-C 9 aryl, said - (CH 2)  2-C 9 aryl, said - (CH 2)  3-C 9 aryl, said -CH 2-C 10 aryl, said - (CH 2)  2-C 10 aryl, said - (CH 2)  3-C 10 aryl, said -5 membered heteroaryl, said -6 membered heteroaryl, said -7 membered heteroaryl, said -8 membered heteroaryl, said -9 membered heteroaryl, said -10 membered heteroaryl, said -5 membered heterocyclyl, said -6 membered heterocyclyl, said -7 membered heterocyclyl, said -8 membered heterocyclyl, said -9 membered heterocyclyl, said -10 membered heterocyclyl, said -CH 2-N (CH 3)  2, said - (CH 2)  2-N (CH 3)  2, said - (CH 2)  3-N (CH 3)  2, said -CH 2-N (CH 2CH 3)  2, said - (CH 2)  2-N (CH 2CH 3)  2, said - (CH 2)  3-N (CH 2CH 3)  2, said -CH 2-N (CH 2CH 2CH 3)  2, said - (CH 2)  2-N (CH 2CH 2CH 3)  2, said - (CH 2)  3-N (CH 2CH 2CH 3)  2, said  -CH 2-N (CH (CH 3)  2)  2, said - (CH 2)  2-N (CH (CH 3)  2)  2, said - (CH 2)  3-N (CH (CH 3)  2)  2, said -CH 2-O-CH 3, said - (CH 2)  2-O-CH 3, said - (CH 2)  3-O-CH 3, said -CH 2-O-CH 2CH 3, said - (CH 2)  2-O-CH 2CH 3, said - (CH 2)  3-O-CH 2CH 3, said -CH 2-O-CH 2CH 2CH 3, said - (CH 2)  2-O-CH 2CH 2CH 3, said - (CH 2)  3-O-CH 2CH 2CH 3, said -CH 2-O-CH (CH 3)  2, said - (CH 2)  2-O-CH (CH 3)  2, said - (CH 2)  3-O-CH (CH 3)  2, said -CH 2-CO-NH-CH 3, said - (CH 2)  2-CO-NH-CH 3, said - (CH 2)  3-CO-NH-CH 3, said -CH 2-CO-NH-CH 2CH 3, said - (CH 2)  2-CO-NH-CH 2CH 3, said - (CH 2)  3-CO-NH-CH 2CH 3, said -CH 2-CO-NH-CH 2CH 2CH 3, said - (CH 2)  2-CO-NH-CH 2CH 2CH 3, said - (CH 2)  3-CO-NH-CH 2CH 2CH 3, said -CH 2-CO-NH-CH (CH 3)  2, said - (CH 2)  2-CO-NH-CH (CH 3)  2, said - (CH 2)  3-CO-NH-CH (CH 3)  2, said -CH 2-CO-5 membered heterocyclyl, said - (CH 2)  2-CO-5 membered heterocyclyl, said - (CH 2)  3-CO-5 membered heterocyclyl, said -CH 2-CO-6 membered heterocyclyl, said - (CH 2)  2-CO-6 membered heterocyclyl, said - (CH 2)  3-CO-6 membered heterocyclyl, said -CH 2-CO-7 membered heterocyclyl, said - (CH 2)  2-CO-7 membered heterocyclyl, said - (CH 2)  3-CO-7 membered heterocyclyl, said -CH 2-CO-8 membered heterocyclyl, said - (CH 2)  2-CO-8 membered heterocyclyl, said - (CH 2)  3-CO-8 membered heterocyclyl, said -CH 2-CO-9 membered heterocyclyl, said - (CH 2)  2-CO-9 membered heterocyclyl, said - (CH 2)  3-CO-9 membered heterocyclyl, said -CH 2-CO-10 membered heterocyclyl, said - (CH 2)  2-CO-10 membered heterocyclyl, said - (CH 2)  3-CO-10 membered heterocyclyl, said -CH 2-SO 2-CH 3, said - (CH 2)  2-SO 2-CH 3, said - (CH 2)  3-SO 2-CH 3, said -CH 2-SO 2-CH 2CH 3, said - (CH 2)  2-SO 2-CH 2CH 3, said - (CH 2)  3-SO 2-CH 2CH 3, said -CH 2-SO 2-CH 2CH 2CH 3, said - (CH 2)  2-SO 2-CH 2CH 2CH 3, said - (CH 2)  3-SO 2-CH 2CH 2CH 3, said -CH 2-SO 2-CH (CH 3)  2, said - (CH 2)  2-SO 2-CH (CH 3)  2, said - (CH 2)  3-SO 2-CH (CH 3)  2, said -CH 2-SO-CH 3, said - (CH 2)  2-SO-CH 3, said - (CH 2)  3-SO-CH 3, said -CH 2-SO-CH 2CH 3, said - (CH 2)  2-SO-CH 2CH 3, said - (CH 2)  3-SO-CH 2CH 3, said -CH 2-SO-CH 2CH 2CH 3, said - (CH 2)  2-SO-CH 2CH 2CH 3, said - (CH 2)  3-SO-CH 2CH 2CH 3, said -CH 2-SO-CH (CH 3)  2, said - (CH 2)  2-SO-CH (CH 3)  2, and said - (CH 2)  3-SO-CH (CH 3)  2, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl; or
    R 1 and R 1’ together with the nitrogen atom to which they are both attached form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, can further contains 1, or 2 heteroatoms selected from N, O, S, SO or SO 2, and said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
  6. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of any one of claims 1-5, wherein
    R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, vinyl, allyl, ethyne, propyne, C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-C 5 aryl, -CH 2-C 6 aryl, - (CH 2)  2-C 6 aryl, - (CH 2)  3-C 6 aryl, -CH 2-C 7 aryl, - (CH 2)  2-C 7 aryl, - (CH 2)  3-C 7 aryl, -CH 2-C 8 aryl, - (CH 2)  2-C 8 aryl, - (CH 2)  3-C 8 aryl, -CH 2-C 9 aryl, - (CH 2)  2-C 9 aryl, - (CH 2)  3-C 9 aryl, -CH 2-C 10 aryl, - (CH 2)  2-C 10 aryl, - (CH 2)  3-C 10 aryl, -5 membered heteroaryl, -6 membered heteroaryl, -7 membered heteroaryl, -8 membered heteroaryl, -9 membered heteroaryl, -10 membered heteroaryl, -5 membered heterocyclyl, -6 membered heterocyclyl, -7 membered heterocyclyl, -8 membered heterocyclyl, -9 membered heterocyclyl, -10 membered heterocyclyl, -CH 2-N (CH 3)  2, - (CH 2)  2-N (CH 3)  2, - (CH 2)  3-N (CH 3)  2, -CH 2-N (CH 2CH 3)  2, - (CH 2)  2-N (CH 2CH 3)  2, - (CH 2)  3-N (CH 2CH 3)  2, -CH 2-N (CH 2CH 2CH 3)  2, - (CH 2)  2-N (CH 2CH 2CH 3)  2, - (CH 2)  3-N (CH 2CH 2CH 3)  2, -CH 2-N (CH (CH 3)  2)  2, - (CH 2)  2-N (CH (CH 3)  2)  2, - (CH 2)  3-N (CH (CH 3)  2)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2,  - (CH 2)  3-O-CH (CH 3)  2, -CH 2-CO-NH-CH 3, - (CH 2)  2-CO-NH-CH 3, - (CH 2)  3-CO-NH-CH 3, -CH 2-CO-NH-CH 2CH 3, - (CH 2)  2-CO-NH-CH 2CH 3, - (CH 2)  3-CO-NH-CH 2CH 3, -CH 2-CO-NH-CH 2CH 2CH 3, - (CH 2)  2-CO-NH-CH 2CH 2CH 3, - (CH 2)  3-CO-NH-CH 2CH 2CH 3, -CH 2-CO-NH-CH (CH 3)  2, - (CH 2)  2-CO-NH-CH (CH 3)  2, - (CH 2)  3-CO-NH-CH (CH 3)  2, -CH 2-CO-5 membered heterocyclyl, - (CH 2)  2-CO-5 membered heterocyclyl, - (CH 2)  3-CO-5 membered heterocyclyl, -CH 2-CO-6 membered heterocyclyl, - (CH 2)  2-CO-6 membered heterocyclyl, - (CH 2)  3-CO-6 membered heterocyclyl, -CH 2-CO-7 membered heterocyclyl, - (CH 2)  2-CO-7 membered heterocyclyl, - (CH 2)  3-CO-7 membered heterocyclyl, -CH 2-CO-8 membered heterocyclyl, - (CH 2)  2-CO-8 membered heterocyclyl, - (CH 2)  3-CO-8 membered heterocyclyl, -CH 2-CO-9 membered heterocyclyl, - (CH 2)  2-CO-9 membered heterocyclyl, - (CH 2)  3-CO-9 membered heterocyclyl, -CH 2-CO-10 membered heterocyclyl, - (CH 2)  2-CO-10 membered heterocyclyl, - (CH 2)  3-CO-10 membered heterocyclyl, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3, -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, and - (CH 2)  3-SO-CH (CH 3)  2, and wherein said methyl, said ethyl, said propyl, said isopropyl, said vinyl, said allyl, said ethyne, said propyne, said C 5 aryl, C 6 aryl, said C 7 aryl, said C 8 aryl, said C 9 aryl, said C 10 aryl, said -CH 2-COO-CH 3, said - (CH 2)  2-COO-CH 3, said - (CH 2)  3-COO-CH 3, said -CH 2-COO-CH 2CH 3, said - (CH 2)  2-COO-CH 2CH 3, said - (CH 2)  3-COO-CH 2CH 3, said -CH 2-COO-CH 2CH 2CH 3, said - (CH 2)  2-COO-CH 2CH 2CH 3, said - (CH 2)  3-COO-CH 2CH 2CH 3, said -CH 2-COO-CH (CH 3)  2, said - (CH 2)  2-COO-CH (CH 3)  2, said - (CH 2)  3-COO-CH (CH 3)  2, said -CH 2-C 5 aryl, said -CH 2-C 6 aryl, said - (CH 2)  2-C 6 aryl, said - (CH 2)  3-C 6 aryl, said -CH 2-C 7 aryl, said - (CH 2)  2-C 7 aryl, said - (CH 2)  3-C 7 aryl, said -CH 2-C 8 aryl, said - (CH 2)  2-C 8 aryl, said - (CH 2)  3-C 8 aryl, said -CH 2-C 9 aryl, said - (CH 2)  2-C 9 aryl, said - (CH 2)  3-C 9 aryl, said -CH 2-C 10 aryl, said - (CH 2)  2-C 10 aryl, said - (CH 2)  3-C 10 aryl, said -5 membered heteroaryl, said -6 membered heteroaryl, said -7 membered heteroaryl, said -8 membered heteroaryl, said -9 membered heteroaryl, said -10 membered heteroaryl, said -5 membered heterocyclyl, said -6 membered heterocyclyl, said -7 membered heterocyclyl, said -8 membered heterocyclyl, said -9 membered heterocyclyl, said -10  membered heterocyclyl, said -CH 2-N (CH 3)  2, said - (CH 2)  2-N (CH 3)  2, said - (CH 2)  3-N (CH 3)  2, said -CH 2-N (CH 2CH 3)  2, said - (CH 2)  2-N (CH 2CH 3)  2, said - (CH 2)  3-N (CH 2CH 3)  2, said -CH 2-N (CH 2CH 2CH 3)  2, said - (CH 2)  2-N (CH 2CH 2CH 3)  2, said - (CH 2)  3-N (CH 2CH 2CH 3)  2, said -CH 2-N (CH (CH 3)  2)  2, said - (CH 2)  2-N (CH (CH 3)  2)  2, said - (CH 2)  3-N (CH (CH 3)  2)  2, said -CH 2-O-CH 3, said- (CH 2)  2-O-CH 3, said - (CH 2)  3-O-CH 3, said -CH 2-O-CH 2CH 3, said - (CH 2)  2-O-CH 2CH 3, said - (CH 2)  3-O-CH 2CH 3, said -CH 2-O-CH 2CH 2CH 3, said - (CH 2)  2-O-CH 2CH 2CH 3, said - (CH 2)  3-O-CH 2CH 2CH 3, said -CH 2-O-CH (CH 3)  2, said - (CH 2)  2-O-CH (CH 3)  2, said - (CH 2)  3-O-CH (CH 3)  2, said -CH 2-CO-NH-CH 3, said - (CH 2)  2-CO-NH-CH 3, said - (CH 2)  3-CO-NH-CH 3, said -CH 2-CO-NH-CH 2CH 3, said - (CH 2)  2-CO-NH-CH 2CH 3, said - (CH 2)  3-CO-NH-CH 2CH 3, said -CH 2-CO-NH-CH 2CH 2CH 3, said - (CH 2)  2-CO-NH-CH 2CH 2CH 3, said - (CH 2)  3-CO-NH-CH 2CH 2CH 3, said -CH 2-CO-NH-CH (CH 3)  2, said - (CH 2)  2-CO-NH-CH (CH 3)  2, said - (CH 2)  3-CO-NH-CH (CH 3)  2, said -CH 2-CO-5 membered heterocyclyl, said - (CH 2)  2-CO-5 membered heterocyclyl, said - (CH 2)  3-CO-5 membered heterocyclyl, said -CH 2-CO-6 membered heterocyclyl, said - (CH 2)  2-CO-6 membered heterocyclyl, said - (CH 2)  3-CO-6 membered heterocyclyl, said -CH 2-CO-7 membered heterocyclyl, said - (CH 2)  2-CO-7 membered heterocyclyl, said - (CH 2)  3-CO-7 membered heterocyclyl, said -CH 2-CO-8 membered heterocyclyl, said - (CH 2)  2-CO-8 membered heterocyclyl, said - (CH 2)  3-CO-8 membered heterocyclyl, said -CH 2-CO-9 membered heterocyclyl, said - (CH 2)  2-CO-9 membered heterocyclyl, said - (CH 2)  3-CO-9 membered heterocyclyl, said -CH 2-CO-10 membered heterocyclyl, said - (CH 2)  2-CO-10 membered heterocyclyl, said - (CH 2)  3-CO-10 membered heterocyclyl, said -CH 2-SO 2-CH 3, said - (CH 2)  2-SO 2-CH 3, said - (CH 2)  3-SO 2-CH 3, said -CH 2-SO 2-CH 2CH 3, said - (CH 2)  2-SO 2-CH 2CH 3, said - (CH 2)  3-SO 2-CH 2CH 3, said -CH 2-SO 2-CH 2CH 2CH 3, said - (CH 2)  2-SO 2-CH 2CH 2CH 3, said - (CH 2)  3-SO 2-CH 2CH 2CH 3, said -CH 2-SO 2-CH (CH 3)  2, said - (CH 2)  2-SO 2-CH (CH 3)  2, said - (CH 2)  3-SO 2-CH (CH 3)  2, said -CH 2-SO-CH 3, said - (CH 2)  2-SO-CH 3, said - (CH 2)  3-SO-CH 3, said -CH 2-SO-CH 2CH 3, said - (CH 2)  2-SO-CH 2CH 3, said - (CH 2)  3-SO-CH 2CH 3, said -CH 2-SO-CH 2CH 2CH 3, said - (CH 2)  2-SO-CH 2CH 2CH 3, said - (CH 2)  3-SO-CH 2CH 2CH 3, said -CH 2-SO-CH (CH 3)  2, said - (CH 2)  2-SO-CH (CH 3)  2, and said - (CH 2)  3-SO-CH (CH 3)  2, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl,  -C 5 cycloalkyl, -C 6 cycloalkyl, -CH 2-vinyl, - (CH 2)  2-vinyl, - (CH 2)  3-vinyl, -CH 2-allyl, - (CH 2)  2-allyl, - (CH 2)  3-allyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3, -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, - (CH 2)  3-SO-CH (CH 3)  2, -CH 2-S-CH 3, - (CH 2)  2-S-CH 3, - (CH 2)  3-S-CH 3, -CH 2-S-CH 2CH 3, - (CH 2)  2-S-CH 2CH 3, - (CH 2)  3-S-CH 2CH 3, -CH 2-S-CH 2CH 2CH 3, - (CH 2)  2-S-CH 2CH 2CH 3, - (CH 2)  3-S-CH 2CH 2CH 3, -CH 2-S-CH (CH 3)  2, - (CH 2)  2-S-CH (CH 3)  2, - (CH 2)  3-S-CH (CH 3)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2, - (CH 2)  3-O-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, -C 5 aryl, -C 6 aryl, -C 7 aryl, -C 8 aryl, -C 9 aryl, -C 10 aryl, -C 5 aryl substituted by F, -C 6 aryl substituted by F, -C 7 aryl substituted by F, -C 8 aryl substituted by F, -C 9 aryl substituted by F, -C 10 aryl substituted by F, -C 5 aryl substituted by Cl, -C 6 aryl substituted by Cl, -C 7 aryl substituted by Cl, -C 8 aryl substituted by Cl, -C 9 aryl substituted by Cl, -C 10 aryl substituted by Cl, -C 1 haloalkyl, -C 2 haloalkyl, and –C 3 haloalkyl; or
    R 1 and R 1’ together with the nitrogen atom to which they are both attached form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, can further contains 1, or 2 heteroatoms selected from N, O, S, SO or SO 2, and said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy,  vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -CH 2-vinyl, - (CH 2)  2-vinyl, - (CH 2)  3-vinyl, -CH 2-allyl, - (CH 2)  2-allyl, - (CH 2)  3-allyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3, -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, - (CH 2)  3-SO-CH (CH 3)  2, -CH 2-S-CH 3, - (CH 2)  2-S-CH 3, - (CH 2)  3-S-CH 3, -CH 2-S-CH 2CH 3, - (CH 2)  2-S-CH 2CH 3, - (CH 2)  3-S-CH 2CH 3, -CH 2-S-CH 2CH 2CH 3, - (CH 2)  2-S-CH 2CH 2CH 3, - (CH 2)  3-S-CH 2CH 2CH 3, -CH 2-S-CH (CH 3)  2, - (CH 2)  2-S-CH (CH 3)  2, - (CH 2)  3-S-CH (CH 3)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2, - (CH 2)  3-O-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, -C 5 aryl, -C 6 aryl, -C 7 aryl, -C 8 aryl, -C 9 aryl, -C 10 aryl, -C 5 aryl substituted by F, -C 6 aryl substituted by F, -C 7 aryl substituted by F, -C 8 aryl substituted by F, -C 9 aryl substituted by F, -C 10 aryl substituted by F, -C 5 aryl substituted by Cl, -C 6 aryl substituted by Cl, -C 7 aryl substituted by Cl, -C 8 aryl substituted by Cl, -C 9 aryl substituted by Cl, -C 10 aryl substituted by Cl, -C 1 haloalkyl, -C 2 haloalkyl, and –C 3 haloalkyl.
  7. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of any one of claims 1-6, wherein
    R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, isopropyl, 
    Figure PCTCN2021123878-appb-100006
    Figure PCTCN2021123878-appb-100007
    Figure PCTCN2021123878-appb-100008
    Figure PCTCN2021123878-appb-100009
    or
    R 1 and R 1’ together with the nitrogen atom to which they are both attached form
    Figure PCTCN2021123878-appb-100010
    Figure PCTCN2021123878-appb-100011
  8. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of any one of claims 1-7, wherein
    X is selected from the group consisting of–C (=O) -W- (CR X1R X2)  m-NR 5R 5’, C (=O) -W- (CR X1R X2)  m-SR 11, C (=O) -W- (CR X1R X2)  m-SO 2R 11, C (=O) -W- (CR X1R X2)  m-SO 2R 11, and –C (=O) -W- (CR X1R X2)  m-OR 11;
    W is oxygen or a bond;
    m is selected from 1, 2, or 3;
    R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, halogen, C 1-3 alkyl, -C 1-3 alkylene-SH, -C 1-3alkylene-C 2-3 alkenyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-CONH 2, 
    Figure PCTCN2021123878-appb-100012
    Figure PCTCN2021123878-appb-100013
    -C 1-3 alkylene-Se-C 1-3 alkyl, -C 1-3 alkylene-SH, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-CO 2-C 1-3 alkyl, C 5-10aryl, -C 1-3 alkylene-C 5-10 aryl, -C 1-3 alkylene-5-10 membered heteroaryl, -C 1-3 alkylene-5-10 membered heterocyclyl, and 5-10 membered heteroaryl, and wherein said C 1-3 alkyl, said -C 1-3 alkylene-SH, said -C 1-3alkylene-C 2-3 alkenyl, said -C 3-6 cycloalkyl, said -C 1-3 alkylene-C 3-6 cycloalkyl, said -C 1-3 alkylene-S-C 1-3 alkyl, said -C 1-3 alkylene-CONH 2, said
    Figure PCTCN2021123878-appb-100014
    said
    Figure PCTCN2021123878-appb-100015
    said -C 1-3 alkylene-Se-C 1-3 alkyl, said -C 1-3 alkylene-SH, said -C 1-3 alkylene-SO 2-C 1-3 alkyl, said -C 1-3 alkylene-CO 2-C 1-3 alkyl, said C 5-10aryl, said -C 1-3 alkylene-C 5-10 aryl, said -C 1-3 alkylene-5-10 membered heteroaryl, said -C 1-3 alkylene-5-10 membered heterocyclyl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    or R X1 and R X2 together with the carbon atom to which they are attached form 5-8 membered carbocyclic ring, C 3-6 cycloalkyl, C 2-3 alkenyl, 5-8 membered heterocyclyl, and wherein said 5-8 membered carbocyclic ring, said C 3-6 cycloalkyl, said C 2-3 alkenyl, and said 5-8 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered  heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, -C 1-3 alkyl, -C 3-6 cycloalkyl, -C (=O) -C 1-3 alkyl, -C (=O) -C 5-10 carbocyclic, -C (=O) -adamantanyl, -C (=O) -C 3-6 cycloalkyl, and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    or R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5-10 membered heterocyclyl, and wherein said 5-10 membered heterocyclyl can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2, and said 5-12 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    R 11 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl.
  9. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of any one of claims 1-8, wherein
    X is selected from the group consisting of –C (=O) -W- (CR X1R X2)  m-NR 5R 5’,
    W is a bond;
    m is 1;
    R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, 
    Figure PCTCN2021123878-appb-100016
    Figure PCTCN2021123878-appb-100017
    Figure PCTCN2021123878-appb-100018
    or R X1 and R X2 together with the carbon atom to which they are attached form
    5 membered carbocyclic ring, 6 membered carbocyclic ring, 7 membered carbocyclic ring, 8 membered carbocyclic ring, C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 2 alkenyl, C 3 alkenyl, C 4 alkenyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, and wherein said 5 membered carbocyclic ring, said 6 membered carbocyclic ring, said 7 membered carbocyclic ring, said 8 membered carbocyclic ring, said C 3 cycloalkyl, said C 4 cycloalkyl, said C 5 cycloalkyl, said C 6 cycloalkyl, said C 2 alkenyl, said C 3 alkenyl, said C 4 alkenyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5 cycloalkyl, -C 6 cycloalkyl, -CH 2-vinyl, - (CH 2)  2-vinyl, - (CH 2)  3-vinyl, -CH 2-allyl, - (CH 2)  2-allyl, - (CH 2)  3-allyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3,  -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, - (CH 2)  3-SO-CH (CH 3)  2, -CH 2-S-CH 3, - (CH 2)  2-S-CH 3, - (CH 2)  3-S-CH 3, -CH 2-S-CH 2CH 3, - (CH 2)  2-S-CH 2CH 3, - (CH 2)  3-S-CH 2CH 3, -CH 2-S-CH 2CH 2CH 3, - (CH 2)  2-S-CH 2CH 2CH 3, - (CH 2)  3-S-CH 2CH 2CH 3, -CH 2-S-CH (CH 3)  2, - (CH 2)  2-S-CH (CH 3)  2, - (CH 2)  3-S-CH (CH 3)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2, - (CH 2)  3-O-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, -C 5 aryl, -C 6 aryl, -C 7 aryl, -C 8 aryl, -C 9 aryl, -C 10 aryl, -C 5 aryl substituted by F, -C 6 aryl substituted by F, -C 7 aryl substituted by F, -C 8 aryl substituted by F, -C 9 aryl substituted by F, -C 10 aryl substituted by F, -C 5 aryl substituted by Cl, -C 6 aryl substituted by Cl, -C 7 aryl substituted by Cl, -C 8 aryl substituted by Cl, -C 9 aryl substituted by Cl, -C 10 aryl substituted by Cl, -C 1 haloalkyl, -C 2 haloalkyl, and –C 3 haloalkyl; R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, -C (=O) -CH 3, -C (=O) -CH 2CH 3, -C (=O) -CH (CH 3)  2, 
    Figure PCTCN2021123878-appb-100019
    or R X1 and R 5 together with the carbon atom and nitrogen atom to which they are attached respectively form 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, and wherein said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can further contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, SO or SO 2, and said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, allyl, ethyne, propyne, -C 3 cycloalkyl, -C 4 cycloalkyl, -C 5  cycloalkyl, -C 6 cycloalkyl, -CH 2-vinyl, - (CH 2)  2-vinyl, - (CH 2)  3-vinyl, -CH 2-allyl, - (CH 2)  2-allyl, - (CH 2)  3-allyl, -4 membered heterocyclyl, -5 membered heterocyclyl, -6 membered heterocyclyl, -COO-CH 3, -COO-CH 2CH 3, -COO-CH 2CH 2CH 3, -COO-CH (CH 3)  2, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-SO 2-CH 3, - (CH 2)  2-SO 2-CH 3, - (CH 2)  3-SO 2-CH 3, -CH 2-SO 2-CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 3, -CH 2-SO 2-CH 2CH 2CH 3, - (CH 2)  2-SO 2-CH 2CH 2CH 3, - (CH 2)  3-SO 2-CH 2CH 2CH 3, -CH 2-SO 2-CH (CH 3)  2, - (CH 2)  2-SO 2-CH (CH 3)  2, - (CH 2)  3-SO 2-CH (CH 3)  2, -CH 2-SO-CH 3, - (CH 2)  2-SO-CH 3, - (CH 2)  3-SO-CH 3, -CH 2-SO-CH 2CH 3, - (CH 2)  2-SO-CH 2CH 3, - (CH 2)  3-SO-CH 2CH 3, -CH 2-SO-CH 2CH 2CH 3, - (CH 2)  2-SO-CH 2CH 2CH 3, - (CH 2)  3-SO-CH 2CH 2CH 3, -CH 2-SO-CH (CH 3)  2, - (CH 2)  2-SO-CH (CH 3)  2, - (CH 2)  3-SO-CH (CH 3)  2, -CH 2-S-CH 3, - (CH 2)  2-S-CH 3, - (CH 2)  3-S-CH 3, -CH 2-S-CH 2CH 3, - (CH 2)  2-S-CH 2CH 3, - (CH 2)  3-S-CH 2CH 3, -CH 2-S-CH 2CH 2CH 3, - (CH 2)  2-S-CH 2CH 2CH 3, - (CH 2)  3-S-CH 2CH 2CH 3, -CH 2-S-CH (CH 3)  2, - (CH 2)  2-S-CH (CH 3)  2, - (CH 2)  3-S-CH (CH 3)  2, -CH 2-O-CH 3, - (CH 2)  2-O-CH 3, - (CH 2)  3-O-CH 3, -CH 2-O-CH 2CH 3, - (CH 2)  2-O-CH 2CH 3, - (CH 2)  3-O-CH 2CH 3, -CH 2-O-CH 2CH 2CH 3, - (CH 2)  2-O-CH 2CH 2CH 3, - (CH 2)  3-O-CH 2CH 2CH 3, -CH 2-O-CH (CH 3)  2, - (CH 2)  2-O-CH (CH 3)  2, - (CH 2)  3-O-CH (CH 3)  2, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl, -C 5 aryl, -C 6 aryl, -C 7 aryl, -C 8 aryl, -C 9 aryl, -C 10 aryl, -C 5 aryl substituted by F, -C 6 aryl substituted by F, -C 7 aryl substituted by F, -C 8 aryl substituted by F, -C 9 aryl substituted by F, -C 10 aryl substituted by F, -C 5 aryl substituted by Cl, -C 6 aryl substituted by Cl, -C 7 aryl substituted by Cl, -C 8 aryl substituted by Cl, -C 9 aryl substituted by Cl, -C 10 aryl substituted by Cl, -C 1 haloalkyl, -C 2 haloalkyl, and –C 3 haloalkyl; or
    R 11 is selected from the group consisting of hydrogen, deuterium.
  10. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of any one of claims 1-9, wherein
    R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6  alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    R 3 and R 3’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    Y is - (CR Y1R Y2)  n-;
    n is selected from 1, 2, or 3;
    R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl;
    R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl; or
    R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-6 alkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, -C 1-6 alkylene-C 2-6 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-6 alkyl, -C 1-6 alkylene-COO-C 1-6 alkyl, -C 1-6 alkylene-SO 2-C 1-6 alkyl, -C 1-6 alkylene-SO-C 1-6 alkyl, -C 1-6 alkylene-S-C 1-6 alkyl, -C 1-6 alkylene-O-C 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl) , -N (C 1-6alkyl)  2, carboxyl, -C 5-12 aryl, -C 5-12 aryl substituted by halogen and -C 1-6 haloalkyl.
  11. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of any one of claims 1-10, wherein
    R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl;
    R 3 and R 3’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl;
    Y is - (CR Y1R Y2)  n-;
    n is 1;
    R Y1 and R Y2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional  substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl;
    R 4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl; or
    R 10 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl, and C 1-3 alkoxy, and wherein said C 1-3 alkyl, and said C 1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 2-3 alkenyl, -4-8 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3 haloalkyl.
  12. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of any one of claims 1-11, wherein
    R 2 is hydrogen, or deuterium;
    R 3 and R 3’ are each independently hydrogen, or deuterium;
    Y is - (CR Y1R Y2)  n-;
    n is 1;
    R Y1 and R Y2 are each independently hydrogen or deuterium;
    R 4 is hydrogen or deuterium; or
    R 10 is hydrogen or deuterium.
  13. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of any one of claims 1-12, wherein the compound is of formula Ia-3
    Figure PCTCN2021123878-appb-100020
    wherein Y, R 1, R 1’, R X1, R X2, R 5, R 5’ and m is the same as defined in claims 1-12.
  14. A compound, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof of formula II
    Figure PCTCN2021123878-appb-100021
    wherein m is 1or 2; R 1, R 1’, R X1, R X2, R 5, and R 5’ is the same as defined in claims 1-12.
  15. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of claim 14, wherein R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, C 2-3 alkynyl, -C 5-10 aryl, -C 1-3 alkylene-COO-C 1-3 alkyl, -C 1-3 alkylene-C 5-10 aryl, -5-10 membered heteroaryl, -5-10 membered heterocyclyl, -C 1-3 alkylene-N (C 1-3 alkyl)  2, -C 1-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene-CO-NH-C 1-3 alkyl, -C 1-3 alkylene-CO-5-10 membered heterocyclyl, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-SO-C 1-3 alkyl and C 3-6 cycloalkyl-C 5-10 aryl, each of which can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl;
    R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, halogen, C 1-3 alkyl, -C 1-3 alkylene-SH, -C 1-3alkylene-C 2-3 alkenyl, -C 3-6 cycloalkyl, -C 1-3 alkylene-C 3-6  cycloalkyl, -C 1-3 alkylene-S-C 1-3 alkyl, -C 1-3 alkylene-CONH 2, 
    Figure PCTCN2021123878-appb-100022
    Figure PCTCN2021123878-appb-100023
    -C 1-3 alkylene-Se-C 1-3 alkyl, -C 1-3 alkylene-SH, -C 1-3 alkylene-SO 2-C 1-3 alkyl, -C 1-3 alkylene-CO 2-C 1-3 alkyl, C 5-10aryl, -C 1-3 alkylene-C 5-10 aryl, -C 1-3 alkylene-5-10 membered heteroaryl, -C 1-3 alkylene-5-10 membered heterocyclyl, and 5-10 membered heteroaryl, each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 3-6 cycloalkyl, -C 1-4 alkylene-C 2-4 alkenyl, -4-10 membered heterocyclyl, -COO-C 1-3 alkyl, -C 1-4 alkylene-COO-C 1-3 alkyl, -C 1-4alkylene-SO 2-C 1-3 alkyl, -C 1-4 alkylene-SO-C 1-3 alkyl, -C 1-4 alkylene-S-C 1-3 alkyl, -C 1-4 alkylene-O-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl, -C 5-10 aryl, -C 5-10 aryl substituted by halogen and -C 1-3haloalkyl; or
    R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, -C 1-3 alkyl, -C 3-6cycloalkyl, -C (=O) -C 1-3 alkyl, -C (=O) -5-10 membered heterocyclyl, -C (=O) -5-10 membered carbocyclic, -C (=O) -adamantanyl, -C (=O) -C 1-3 alkylene-O-C 1-3 alkyl, -C (=O) -C 1-3 alkylene-NH-C 1-3 alkyl, -C (=O) -C 1-3 alkylene-N (C 1-3 alkyl)  2, -C (=O) -C 3-6 cycloalkyl, each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -NO 2, -C 1-3 alkyl, -C 1-3 alkoxy, -COO-C 1-3 alkyl, -NH 2, -NH (C 1-3 alkyl) , -N (C 1-3alkyl)  2, carboxyl.
  16. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of of claim 14 or 15, wherein R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, vinyl, allyl, ethyne, propyne, C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, -CH 2-COO-CH 3, - (CH 2)  2-COO-CH 3, - (CH 2)  3-COO-CH 3, -CH 2-COO-CH 2CH 3, - (CH 2)  2-COO-CH 2CH 3, - (CH 2)  3-COO-CH 2CH 3, -CH 2-COO-CH 2CH 2CH 3, - (CH 2)  2-COO-CH 2CH 2CH 3, - (CH 2)  3-COO-CH 2CH 2CH 3, -CH 2-COO-CH (CH 3)  2, - (CH 2)  2-COO-CH (CH 3)  2, - (CH 2)  3-COO-CH (CH 3)  2, -CH 2-C 5 aryl, -CH 2-C 6 aryl, - (CH 2)  2-C 6 aryl, - (CH 2)  3-C 6 aryl, -CH 2-C 7 aryl, - (CH 2)  2-C 7 aryl, - (CH 2)  3-C 7 aryl, -CH 2-C 8 aryl, - (CH 2)  2-C 8 aryl, - (CH 2)  3-C 8 aryl, -CH 2-C 9 aryl, - (CH 2)  2-C 9 aryl, - (CH 2)  3-C 9 aryl, -CH 2-C 10 aryl, - (CH 2)  2-C 10 aryl, - (CH 2)  3-C 10 aryl, -5 membered heteroaryl, -6 membered heteroaryl, -7 membered heteroaryl, -8 membered heteroaryl, -9 membered  heteroaryl, -10 membered heteroaryl, each of which can be optionally substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -NO 2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl;
    R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, 
    Figure PCTCN2021123878-appb-100024
    Figure PCTCN2021123878-appb-100025
    Figure PCTCN2021123878-appb-100026
    -CO-CH 3, -SO-CH 3, -SO 2-CH 3, -NH-CO-CH 3, 
    Figure PCTCN2021123878-appb-100027
    Figure PCTCN2021123878-appb-100028
    Figure PCTCN2021123878-appb-100029
    and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, ; or
    R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C (=O) -CH 3, -C (=O) -CH 2CH 3, -C (=O) -CH 2CH 2CH 3, -C (=O) -CH (CH 3)  2, 
    Figure PCTCN2021123878-appb-100030
    -C (=O) -CH 2-O-CH 3, -C (=O) - (CH 2)  2-O-CH 3, -C (=O) - (CH 2)  3-O-CH 3, -C (=O) -CH 2-O-CH 2CH 3,
    -C (=O) -CH 2-NH-CH 3, -C (=O) - (CH 2)  2-NH-CH 3, -C (=O) - (CH 2)  3-NH-CH 3,-C (=O) -CH 2-NH-CH 2CH 3, -C (=O) -CH 2-N (CH 3)  2, -C (=O) - (CH 2)  2-N (CH 3)  2, -C (=O) - (CH 2)  3-N (CH 3)  2, -C (=O) -CH 2-N (CH 2CH 3)  2, each of which can be optional substituted with one or more substituents, and said substituents are independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -COO-CH 3,  -COO-CH 2CH 3, -NH 2, -NHCH 3, -NHCH 2CH 3, -NHCH 2CH 2CH 3, -NHCH (CH 3)  2, -N (CH 3)  2, -N (CH 2CH 3)  2, -N (CH 2CH 2CH 3)  2, -N (CH (CH 3)  2)  2, carboxyl.
  17. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of any one of claims 14-16, wherein the compound is of formula Ia-3 R 1 and R 1’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, 
    Figure PCTCN2021123878-appb-100031
    Figure PCTCN2021123878-appb-100032
    R X1 and R X2 are each independently selected from the group consisting from hydrogen, deuterium methyl, ethyl, propyl, isopropyl, tert-butyl, 
    Figure PCTCN2021123878-appb-100033
    Figure PCTCN2021123878-appb-100034
    or
    R 5 and R 5’ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C (=O) -CH 3, -C (=O) -CH 2CH 3, -C (=O) -CH 2CH 2CH 3, -C (=O) -CH (CH 3)  2, 
    Figure PCTCN2021123878-appb-100035
  18. The compound, or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof of any one of claims 1-17, wherein the compound is selected from:
    Figure PCTCN2021123878-appb-100036
    Figure PCTCN2021123878-appb-100037
    Figure PCTCN2021123878-appb-100038
    Figure PCTCN2021123878-appb-100039
    Figure PCTCN2021123878-appb-100040
    Figure PCTCN2021123878-appb-100041
    Figure PCTCN2021123878-appb-100042
    Figure PCTCN2021123878-appb-100043
    Figure PCTCN2021123878-appb-100044
    Figure PCTCN2021123878-appb-100045
    Figure PCTCN2021123878-appb-100046
    Figure PCTCN2021123878-appb-100047
    Figure PCTCN2021123878-appb-100048
    Figure PCTCN2021123878-appb-100049
    Figure PCTCN2021123878-appb-100050
    Figure PCTCN2021123878-appb-100051
    Figure PCTCN2021123878-appb-100052
    Figure PCTCN2021123878-appb-100053
    Figure PCTCN2021123878-appb-100054
    Figure PCTCN2021123878-appb-100055
    Figure PCTCN2021123878-appb-100056
    Figure PCTCN2021123878-appb-100057
    Figure PCTCN2021123878-appb-100058
    Figure PCTCN2021123878-appb-100059
    Figure PCTCN2021123878-appb-100060
    Figure PCTCN2021123878-appb-100061
    Figure PCTCN2021123878-appb-100062
    Figure PCTCN2021123878-appb-100063
    Figure PCTCN2021123878-appb-100064
    Figure PCTCN2021123878-appb-100065
  19. 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 1-18; and a pharmaceutically acceptable carrier, diluent or excipient.
  20. 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 1-18; or the pharmaceutical composition of claim 19.
  21. The method of claim 20, wherein the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer..
  22. 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 1-18; or the pharmaceutical composition of claim 19 for the manufacture of a medicament for the treatment of a cancer.
  23. The use of claim 22, wherein the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer..
  24. The compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable salt of the stereoisomer thereof of any one of claims 1-18; or the pharmaceutical composition of claim 19 for use in the treatment of a cancer.
  25. 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 24, wherein the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer.
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WO2019071110A1 (en) * 2017-10-06 2019-04-11 The John Hopkins University Novel glutamine antagonists and uses thereof

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US20020132776A1 (en) * 2000-11-03 2002-09-19 N-Zyme Biotech Gmbh Inhibitors of transglutaminase
CN108290827A (en) * 2015-07-31 2018-07-17 约翰霍普金斯大学 The prodrug of glutamine analogues
CN108348492A (en) * 2015-07-31 2018-07-31 约翰霍普金斯大学 Use the method for cancer and immunotherapy of the glutamine analogues including DON
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DATABASE REGISTRY STN; 16 March 1933 (1933-03-16), ANONYMOUS : "Carbamic acid, [5-diazo-1-[(dimethylamino)carbonyl]-4-oxopentyl]-,phenylmethyl ester, (S)- (9CI)", XP055921369, Database accession no. N 146467-16-5 *
DATABASE REGISTRY STN; 16 March 1993 (1993-03-16), ANONYMOUS : "Carbamic acid, [5-diazo-1-[(dimethylamino)carbonyl]-4-oxopentyl]-,2-propenyl ester, (S)- (9CI)", XP055921366, Database accession no. RN 146467-17-6 *
DATABASE REGISTRY STN; 16 November 1984 (1984-11-16), ANONYMOUS : "Carbamic acid, [5-diazo-4-oxo-1-[[(phenylmethyl)amino]carbonyl]pentyl]-,phenylmethyl ester, (S)- (9CI)", XP055921397, Database accession no. RN 58456-29-4 *
DATABASE REGISTRY STN; 16 November 1984 (1984-11-16), ANONYMOUS : "Glycine, N-(6-diazo-5-oxo-L-norleucyl)- (9CI)", XP055921370, Database accession no. RN 78081-74-0 *
DATABASE REGISTRY STN; 16 November 1984 (1984-11-16), ANONYMOUS : "L-Serine, O-(2-diazoacetyl)-", XP055921415, Database accession no. RN 115-02-6 *
DATABASE REGISTRY STN; 16 November 1984 (1984-11-16), ANONYMOUS CH2 : "Carbamic acid, [5-diazo-4-oxo-1-[[(phenylmethyl)amino]carbonyl]pentyl](hydroxymethyl)-,phenylmethyl ester, (S)- (9CI)", XP055921399, Database accession no. RN 58456-28-3 *
DATABASE REGISTRY STN; 19 December 2005 (2005-12-19), ANONYMOUS : "Glycine, 6-diazo-5-oxo-N-[(phenylmethoxy)carbonyl]-L-norleucyl- (9CI)", XP055921355, Database accession no. RN 870152-23-1 *
DATABASE REGISTRY STN; 19 December 2005 (2005-12-19), ANONYMOUS : "Glycine, 6-diazo-5-oxo-N-[(phenylmethoxy)carbonyl]-L-norleucyl-,methyl ester (9CI)", XP055921359, Database accession no. RN 870152-22-0 *
DATABASE REGISTRY STN; 19-12-2005, ANONYMOUS : "L-Phenylalanine, 6-diazo-5-oxo-N-[(phenylmethoxy)carbonyl]-L-norleucyl-, methyl ester (9CI)", XP055921353, Database accession no. RN 870152-25-3 *
DATABASE REGISTRY STN; 2 March 2017 (2017-03-02), ANONYMOUS : "L-Norleucine, 6-diazo-5-oxo-, 1-methylethyl ester", XP055921404, Database accession no. RN 2079939-24-3 *
DATABASE REGISTRY STN; 2 March 2017 (2017-03-02), ANONYMOUS : "L-Norleucine, 6-diazo-5-oxo-N2-[(2-propen-1-yloxy)carbonyl]-", XP055921414, Database accession no. RN 2079939-15-2 *
DATABASE REGISTRY STN; 2 March 2017 (2017-03-02), ANONYMOUS : "L-Norleucine, 6-diazo-N-[[1-(2,2-dimethyl-1-oxopropoxy)-2-methylpropoxy]carbonyl]-5-oxo-, 1-methylethyl ester", XP055921407, Database accession no. RN 2079939-22-1 *
DATABASE REGISTRY STN; 2 March 2017 (2017-03-02), ANONYMOUS : "L-Norleucine, 6-diazo-N-[[1-(2,2-dimethyl-1-oxopropoxy)ethoxy]carbonyl]-5- oxo-,ethyl ester", XP055921410, Database accession no. RN 2079939-20-9 *
DATABASE REGISTRY STN; 2 March 2017 (2017-03-02), ANONYMOUS : "L-Norleucine, 6-diazo-N-[[1-(2-methyl-1-oxopropoxy)ethoxy]carbonyl]-5-oxo- ,ethyl ester", XP055921409, Database accession no. RN 2079939-21-0 *
DATABASE REGISTRY STN; 2 March 2017 (2017-03-02), ANONYMOUS : "L-Norleucine, 6-diazo-N2-[[(1S)-1-(2-methyl-1-oxopropoxy)ethoxy]carbonyl]-5-oxo-, ethyl ester", XP055921401, Database accession no. RN 2079939-28-7 *
DATABASE REGISTRY STN; 2 March 2017 (2017-03-02), ANONYMOUS : "L-Norleucine, N-[[[4-(acetyloxy)phenyl]methoxy]carbonyl]-6-diazo-5-oxo-,ethyl ester", XP055921402, Database accession no. RN 2079939-26-5 *
DATABASE REGISTRY STN; 2 March 2017 (2017-03-02), ANONYMOUS : "Norleucine, 6-diazo-N-[[1-(2-methyl-1-oxopropoxy)ethoxy]carbonyl]-5-oxo-, ethyl ester", XP055921412, Database accession no. RN 2079939-19-6 *
DATABASE REGISTRY STN; 28 May 2002 (2002-05-28), ANONYMOUS : "Glycine, 6-diazo-5-oxo-N-[(phenylmethoxy)carbonyl]-L-norleucyl-,phenylmethyl ester (9CI)", XP055921363, Database accession no. RN 422322-73-4 *

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