WO2024104317A1 - Compound for inhibiting 15-pgdh and use thereof - Google Patents

Compound for inhibiting 15-pgdh and use thereof Download PDF

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WO2024104317A1
WO2024104317A1 PCT/CN2023/131424 CN2023131424W WO2024104317A1 WO 2024104317 A1 WO2024104317 A1 WO 2024104317A1 CN 2023131424 W CN2023131424 W CN 2023131424W WO 2024104317 A1 WO2024104317 A1 WO 2024104317A1
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alkyl
alkylene
group
pharmaceutically acceptable
solvate
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Chinese (zh)
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张学军
臧杨
李群
汤亚敏
卓君明
李莉娥
杨俊�
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武汉人福创新药物研发中心有限公司
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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Definitions

  • the present invention belongs to the field of medicine, and in particular, relates to a compound for inhibiting 15-PGDH and a use thereof.
  • the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) gene is located on chromosome 4, 4q34-q35, with a span of approximately 31kb, a total of 7 exons, and a molecular weight of 29kD.
  • 15-PGDH is composed of 266 amino acids and belongs to the short-chain dehydrogenase (SDR) family. It is a dimer composed of two identical subunits, but some people believe that it is only enzymatically active when it exists as a monomer.
  • 15-PGDH is a key enzyme for the degradation and inactivation of prostaglandins (PGs) and related eicosane bioactive substances.
  • the object of the present invention is to provide a novel compound useful as a 15-PGDH inhibitor.
  • a heterocyclic compound as shown in Formula I a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof is provided:
  • Ra is H, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1 - C6 alkyl, -NH( C1 - C6 alkyl), C1 - C6 deuterated alkyl, C2 - C6 alkynyl, halogenated C1 - C6 alkyl, hydroxyC1 - C6 alkyl, C1 -C6 alkylcarbonyl, C1 - C6 alkoxy, halogenated C1 - C6 alkoxy, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), aryl, 3-11 membered heterocycloalkyl or 5-11 membered heteroaryl; wherein the C1 - C6 alkyl, C3 - C8 cycloalkyl, aryl, 3-11 membered heterocycloalkyl or 5
  • R1 is C1 - C6 alkyl, C1 - C6 deuterated alkyl, halogenated C1 - C6 alkyl, C3 -C8 cycloalkyl , -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy, -( C1 - C6 alkylene)-( C1 - C6 alkoxy), 3-11-membered heterocycloalkyl, or -( C1 - C6 alkylene)-(3-11-membered heterocycloalkyl); and, said R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, said substituents are the same or different;
  • Each R 1-1 is independently H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy;
  • R 2 is amino, CN, or -NHC(O)(C 1 -C 6 alkyl);
  • R 3-1-2 is H or C 1 -C 6 alkyl, or two R 3-1-2 together with the N atom to which they are attached can form a 4-7 membered heterocyclic ring, which optionally contains an additional heteroatom selected from O, S(O) r , or N;
  • X is N or CH
  • n, p, and r are 0, 1, or 2 respectively.
  • Ra is isopropyl
  • R 3 is a 5-11 membered heteroaryl group, which is substituted by one or more R 3-1 ;
  • the 5-11 membered heteroaryl group is a 5-11 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from O, N and S.
  • Ra is H, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1 - C6 alkyl, -NH( C1 - C6 alkyl), C1 - C6 deuterated alkyl, C2 - C6 alkynyl, halogenated C1 - C6 alkyl, hydroxyC1 - C6 alkyl, C1 -C6 alkylcarbonyl, C1 - C6 alkoxy, halogenated C1 - C6 alkoxy, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), aryl, 3-11 membered heterocycloalkyl or 5-11 membered heteroaryl; wherein the C1 - C6 alkyl, C3 - C8 cycloalkyl, aryl, 3-11 membered heterocycloalkyl or 5
  • R1 is C1 - C6 alkyl, C1 - C6 deuterated alkyl, halogenated C1 - C6 alkyl, C3 -C8 cycloalkyl , -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy, -( C1 - C6 alkylene)-( C1 - C6 alkoxy), 3-11 membered heterocycloalkyl, or -( C1 - C6 alkylene)-(3-11 membered heterocycloalkyl); and, said R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, said substituents are the same or different; said 3-11 membered heterocycloalkyl is 1, 2 or 3 heteroatoms selected from O, N and S, and the number of heteroatoms is 1, 2 or 3 3-11 membered heterocycloalkyl; each R 1-1 is independently H,
  • R 2 is amino, CN, or -NHC(O)(C 1 -C 6 alkyl);
  • R 3 is an aryl group, a 3-11-membered heterocycloalkyl group or a 5-11-membered heteroaryl group, which is optionally substituted by one or more R 3-1 ;
  • the 3-11-membered heterocycloalkyl group is a 3-11-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S;
  • the 5-11-membered heteroaryl group is a 5-11-membered heteroaryl group having 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S;
  • Each R 3-1-2 is H or C 1 -C 6 alkyl, or two R 3-1-2 together with the N atom to which they are attached can form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring contains a heteroatom or heteroatom group selected from O, S(O) r , and N; a 4-7 membered heterocyclic ring having 1, 2 or 3 heteroatoms or heteroatom groups;
  • X is N or CH
  • n, p, and r are 0, 1, or 2 respectively.
  • X is CH.
  • n 1
  • n 1
  • Ra is H, C1 - C6 alkyl, aryl or 5-11 membered heteroaryl; wherein the C1 - C6 alkyl, aryl and 5-11 membered heteroaryl are each optionally substituted by R1-1 ; when Ra is a plurality of substituents, the substituents are the same or different; the aryl is C6 - C10 aryl; the 5-11 membered heteroaryl is a 5-11 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S; preferably, Ra is C1 - C6 alkyl.
  • R1 is C1 - C6 alkyl, C1 - C6 deuterated alkyl, halogenated C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy, -( C1 - C6 alkylene)-( C1 - C6 alkoxy); and, R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, the substituents are the same or different; preferably, R1 is C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), -( C1 - C6 alkylene)-( C1 - C6 alkoxy); more preferably, R1 is -( C1 - C6 alkyl,
  • R 3-1-1 is independently H or C 1 -C 6 alkyl, or the two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocycle, wherein the heteroatom is S and/or N and the number of heteroatoms is 1 or 2.
  • the C1 - C6 alkyl group is independently a C1 - C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the C1 - C6 deuterated alkyl group is independently a C1 - C4 deuterated alkyl group.
  • the halogenated C1 - C6 alkyl group is independently a halogenated C1 - C4 alkyl group.
  • the C3 - C8 cycloalkyl group is independently a C3 - C6 cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the C3 -C8 cycloalkyl in the -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl) is independently C3 -C6 cycloalkyl , for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the C1 - C6 alkylene in the -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl) is independently C1 - C4 alkylene, preferably -( CH2 ) x- , where x is 1, 2, or 3.
  • the C1 - C6 alkoxy group is independently a C1 - C4 alkoxy group, for example, a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.
  • the C 1 -C 6 alkoxy group in the -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy) group is a C 1 -C 4 alkoxy group, for example, a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.
  • the C 1 -C 6 alkylene in the -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy ) is C 1 -C 4 alkylene, preferably -(CH 2 ) x -, where x is 1, 2, or 3, such as -CH 2 -, -(CH 2 ) 2 -, or -(CH 2 ) 3 -.
  • the -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy) is -(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy).
  • the 3-11 membered heterocycloalkyl is a 3-6 membered heterocycloalkyl, preferably a 3-6 membered heterocycloalkyl having one or two heteroatoms selected from O, N and S and one or two heteroatoms.
  • the 3-11-membered heterocycloalkyl in the -( C1 - C6 alkylene)-(3-11-membered heterocycloalkyl) is a 3-6-membered heterocycloalkyl, preferably a 3-6-membered heterocycloalkyl having one or two heteroatoms selected from O, N and S and one or two heteroatoms.
  • the C1 - C6 alkylene in the -( C1 - C6 alkylene)-(3-11-membered heterocycloalkyl) is C1 - C4 alkylene.
  • the C 1 -C 6 alkyl in the -NH(C 1 -C 6 alkyl), C 1 -C 6 alkyl and halogenated C 1 -C 6 alkyl is C 1 -C 3 alkyl.
  • the C 1 -C 6 alkoxy group among the -NH(C 1 -C 6 alkyl), C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl , C 1 -C 6 alkoxy and deuterated C 1 -C 6 alkoxy is C 1 -C 3 alkoxy.
  • the C6 - C10 aryl group is a phenyl group.
  • the 5-11 membered heteroaryl is a 5-6 membered heteroaryl
  • the heteroatom is preferably selected from O, N and S, and a 5- to 6-membered heteroaryl group having 1 or 2 heteroatoms.
  • the 5-11 membered heteroaryl is a 5-10 membered heteroaryl; preferably, the 5-11 membered heteroaryl is a 5-6 membered heteroaryl or an 8-10 membered bicyclic heteroaryl; more preferably, the 5-11 membered heteroaryl is a 5-6 membered heteroaryl having 1 or 2 heteroatoms selected from one or two of O, N and S, or an 8-10 membered bicyclic heteroaryl having 1 or 2 heteroatoms selected from one or two of O, N and S; for example, pyridine.
  • the C 1 -C 6 alkyl group is independently a C 1 -C 3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl.
  • R 3-1-1 in R 3-1-1 , the two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7-membered heterocyclic ring, in which the 4-7-membered heterocyclic ring is a 5-6-membered heterocyclic ring, preferably a 5-membered heterocyclic ring; for example
  • R 1 is C 1 -C 4 alkyl, C 1 -C 4 deuterated alkyl, halogenated C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, -(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), C 1 -C 4 alkoxy, -(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy), 3-6 membered heterocycloalkyl or -(C 1 -C 4 alkylene)-(3-6 membered heterocycloalkyl); and R 1 is optionally substituted by one or more R 1-1 ; when there are multiple substituents, the substituents are the same or different; the definition of R 1-1 is as described in the first aspect of the present invention.
  • R 1 is butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) x -cyclopropyl, -(CH 2 ) x -cyclobutyl, -(CH 2 ) x -cyclopentyl, -(CH 2 ) x -cyclohexyl or -(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy); wherein x is 1, 2, or 3.
  • R 1 is -(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy).
  • said Ra is methyl or
  • R 1 is -CH 2 CH 2 -O-CH 3 .
  • R 1-1 is H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 3 alkyl), -O-alkylene-OH, C 1 -C 3 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy or deuterated C 1 -C 3 alkoxy.
  • said R 1-1 is H.
  • R 2 is -NH 2 , CN or -NH-C(O)-CH 3 ; preferably -NH 2 .
  • R 3 is a 5-6 membered heterocycloalkyl or a 5-10 membered heteroaryl, which is optionally substituted by one or more R 3-1 , and the definition of R 3-1 is as described in the first aspect of the present invention.
  • R 3 is a 5-10 membered heteroaryl group, which is optionally substituted by one or more R 3-1 , and the definition of R 3-1 is as described in the first aspect of the present invention.
  • R 3 is a 5-6 membered heteroaryl group optionally substituted by one or more R 3-1 , or an 8-10 membered bicyclic heteroaryl group optionally substituted by one or more R 3-1 , and the definition of R 3-1 is as described in the first aspect of the present invention.
  • R 3 is pyridine, which is substituted by one or more R 3-1 , and the definition of R 3-1 is as described in the first aspect of the present invention.
  • said R 3 is
  • said R 3-1-1 is independently H or C 1 -C 3 alkyl, or said two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocycle.
  • said R 3-1 is
  • Ra is H, C1 - C6 alkyl, aryl or 5-11 membered heteroaryl; wherein the C1 -C6 alkyl, aryl and 5-11 membered heteroaryl are each optionally substituted by R1-1 ; when Ra is a plurality of substituents, the substituents are the same or different; the aryl is C6 - C10 aryl; the 5-11 membered heteroaryl is a 5-11 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S;
  • R 1 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -(C 1 -C 6 alkylene)-(C 3 -C 8 cycloalkyl), -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy); and, said R 1 is optionally substituted by one or more R 1-1 ; when there are multiple substituents, said substituents are the same or different;
  • Each R 1-1 is independently C 1 -C 6 alkyl
  • R2 is an amino group
  • R 3 is a 5-11 membered heteroaryl group, which is substituted by one R 3-1 ;
  • the 5-11 membered heteroaryl group is a 5-11 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S;
  • X is N or CH
  • n 0 or 1
  • n 1.
  • Ra is a C1 - C6 alkyl group
  • R1 is -( C1 - C6 alkylene)-( C1 - C6 alkoxy);
  • R2 is an amino group
  • R 3 is a 5-11 membered heteroaryl group, which is substituted by one R 3-1 ;
  • the 5-11 membered heteroaryl group is a heteroatom selected from 1, 2 or 3 of O, N and S, and the number of heteroatoms is 1, 2 or 3 5-11 membered heteroaryl;
  • X is CH
  • n 1;
  • n 1.
  • the heterocyclic compound of formula I is characterized in that the compound of formula I is a compound of formula IA, formula IB or formula IC:
  • heterocyclic compound as shown in Formula I is selected from any of the following compounds:
  • heterocyclic compound as shown in Formula I is selected from any of the following compounds:
  • heterocyclic compound as shown in Formula I is selected from any of the following compounds:
  • the retention time is 1.327 min. and/or at a retention time of 1.731 min
  • chromatographic column Chiralcel OD-3 50 ⁇ 4.6mm ID3 ⁇ m
  • mobile phase A CO 2
  • mobile phase B IPA (0.05 vol% DEA), isocratic elution: 40 vol% IPA (0.05 vol% DEA) in CO 2
  • flow rate 3mL/min
  • detector PDA
  • column temperature 35°C
  • column pressure 100Bar.
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises: a compound of formula I as described in the first aspect of the present invention, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof; and a pharmaceutically acceptable carrier.
  • the third aspect of the present invention provides the use of the compound of formula I as described in the first aspect of the present invention, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt or its prodrug, or the use of the pharmaceutical composition as described in the second aspect of the present invention, the uses including: inhibiting 15-PGDH; and/or, preventing and/or treating 15-PGDH related diseases; and/or, for preparing 15-PGDH inhibitors, and/or for preparing drugs, pharmaceutical compositions or preparations for preventing and/or treating 15-PGDH related diseases.
  • the 15-PGDH-related diseases include, but are not limited to, one, two or more of: fibrotic diseases, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host disease, hair growth, osteoporosis, ear diseases, eye diseases, neutropenia, diabetes, underactive bladder, implant promotion in stem cell or bone marrow transplantation or organ transplantation, neurogenesis and neuronal cell death, blood cell reconstitution, tissue damage, cervical disease and kidney disease.
  • the 15-PGDH-related diseases include, but are not limited to, fibrotic diseases, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host disease, hair growth, osteoporosis, ear diseases, eye diseases, neutropenia, diabetes, underactive bladder, implant promotion in stem cell or bone marrow transplantation or organ transplantation, neurogenesis and neuronal cell death, One, two or more of blood cell remodeling, tissue damage, cervical disease, and kidney disease.
  • the 15-PGDH-related diseases include but are not limited to: fibrotic diseases (such as pulmonary fibrosis, including idiopathic pulmonary fibrosis, etc., liver fibrosis, renal fibrosis, myocardial fibrosis, scleroderma and myelofibrosis), inflammatory diseases [such as chronic obstructive pulmonary disease (COPD), acute lung injury, sepsis, asthma and exacerbation of lung disease, inflammatory bowel disease (IBD) (such as ulcerative colitis and Crohn's disease), peptic ulcer (such as NSAID-induced ulcer), autoinflammatory diseases (such as Behcet's disease), vasculitis syndrome, acute liver injury, acute kidney injury, non-alcoholic fatty liver disease (NASH), atopic dermatitis, psoriasis, interstitial cystitis, prostatitis syndrome (such as chronic prostatitis/chronic pelvic pain syndrome)], cardiovascular diseases (such as pulmonary hypertension, an fibrotic
  • the tissue damage is liver damage and/or muscle damage (such as muscle atrophy and muscular dystrophy).
  • the 15-PGDH-related diseases include but are not limited to idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the 15-PGDH-related diseases include but are not limited to: liver damage.
  • the 15-PGDH-related diseases include but are not limited to: IBD.
  • the prevention and/or treatment of 15-PGDH related diseases includes but is not limited to: liver regeneration.
  • the use is for preparing a medicament for preventing and/or treating the following diseases; the diseases are one or more of fibrotic diseases, inflammatory diseases or tissue damage.
  • the fibrotic disease, the inflammatory disease and the tissue damage may all be the same as described above.
  • a method for inhibiting 15-PGDH, or preventing and/or treating 15-PGDH-related diseases comprising the steps of administering to a subject in need thereof the compound of formula I described in the first aspect of the present invention, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt, or a prodrug thereof.
  • a method for preventing or treating the following diseases comprising the steps of: administering the compound of formula I described in the first aspect of the present invention, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt, or a prodrug thereof to a subject in need thereof; the disease is a fibrotic disease and/or an inflammatory disease.
  • the fibrotic disease and the inflammatory disease are as described above.
  • the compound represented by formula I in the above-mentioned application and pharmaceutical composition, the compound represented by formula I, its solvate, its pharmaceutically acceptable
  • the content of the salt, its pharmaceutically acceptable salt solvate or its prodrug is a therapeutically effective amount.
  • the manufacturer's instructions for the use of the kit can be used, or the reactions and purifications can be carried out in a manner known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.
  • substituents When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, CH 2 O is equivalent to OCH 2 .
  • a number from 1 to 10 should be understood as recording not only each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording the sum of each integer and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 respectively; for example, 1 to 3 should be understood as 1, 2 and 3.
  • C 3 -C 20 alicyclic hydrocarbon group refers to a cyclic hydrocarbon group with aliphatic properties, containing a closed carbon ring in the molecule, which can represent a saturated or partially unsaturated monovalent monocyclic, bicyclic or polycyclic hydrocarbon ring, and also includes a bridged ring or a spirocyclic ring.
  • the alicyclic hydrocarbon group when the alicyclic hydrocarbon group contains two or more carbon rings, they can be connected in a variety of ways: two rings in the molecule can share a carbon atom, and this system is called a spirocyclic ring; two carbon atoms on the ring can be connected by a carbon bridge to form a bicyclic or polycyclic system, which is called a bridged ring; several rings can also be connected to each other to form a cage-like structure.
  • the alicyclic hydrocarbon group can have 3 to 20 carbon atoms, preferably "C 3 -C 12 alicyclic hydrocarbon group", and can also be "C 3 -C 7 alicyclic hydrocarbon group", which can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms.
  • the alicyclic hydrocarbon group may be a "cycloalkyl", “cycloalkenyl”, “cycloalkynyl” or the like (the carbon number may be selected from any integer between 3 and 20 as mentioned above), and the alicyclic hydrocarbon group may be a monocyclic hydrocarbon group, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decalin ring.
  • C 3 -C 7 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which may be a spirocyclic or bridged ring, having 3, 4, 5, 6 or 7 carbon atoms.
  • the C 3 -C 7 cycloalkyl group may be, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.0]butyl, spiropentyl, spiro[2.3]hexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl or bicyclo[3.1.0]hexyl.
  • halogen alone or as part of another substituent refers to fluorine, chlorine, bromine, iodine; preferably fluorine or chlorine.
  • alkyl when alone or as part of another substituent, means a straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing no unsaturated bonds, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by a single bond.
  • C 1 -C 6 alkyl when alone or as part of another substituent, is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or isomers thereof.
  • the group has 1, 2 or 3 carbon atoms ("C 1 -C 3 alkyl”)
  • cycloalkyl refers to a cyclic alkyl group when used alone or as part of another substituent.
  • mn-membered cycloalkyl or "C m -C n cycloalkyl” should be understood to mean a saturated carbocyclic ring having m to n ring atoms.
  • 3-15-membered cycloalkyl or "C 3 -C 15 cycloalkyl” refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which may contain 1 to 4 rings.
  • 3-10-membered cycloalkyl contains 3-10 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring.
  • cycloalkyl can be used interchangeably with the term "carbocyclic group”.
  • heterocycloalkyl when used alone or as part of another substituent refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as, but not limited to, N, O, S, and P.
  • heteroatoms such as, but not limited to, N, O, S, and P.
  • mn-membered heterocycloalkyl or Cm - Cn heterocycloalkyl is understood to mean a saturated ring having m to n ring atoms, wherein the heteroatoms are selected from N, O, S, P, preferably N, O or S.
  • the term "4-8 membered heterocycloalkyl” or " C4 - C8 heterocycloalkyl” is understood to mean a saturated ring having 4 to 8 ring atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, S, P, preferably N, O or S.
  • "4-10 membered heterocycloalkyl” then means a saturated ring having 4 to 10 ring atoms.
  • the number of carbons is also meant to include the heteroatoms. Including monocyclic, bicyclic, tricyclic, spirocyclic or bridged ring.
  • heterocycloalkyl examples include: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, etc.
  • heterocycloalkyl can be used interchangeably with the term “heteroalkyl ring”.
  • alkynyl when used alone or as part of another substituent refers to a linear or branched monovalent hydrocarbon radical of two to forty carbon atoms (e.g., C2 - C6 alkynyl, for example, C2 - C4 alkynyl) with at least one carbon-carbon sp triple bond.
  • alkynyl groups include, but are not limited to, ethynyl and propynyl.
  • alkoxy by itself or as part of another substituent refers to the group -ORX , wherein RX is "alkyl” as defined above.
  • oxo when used alone or as part of another substituent refers to the replacement of two hydrogen atoms on a methylene group by oxygen, ie, the methylene group is replaced by a carbonyl group.
  • aryl when used alone or as part of another substituent refers to a monocyclic or polycyclic carbon ring having from 6 to 20 carbon atoms, wherein at least one ring is aromatic. When one of the rings is non-aromatic, the group may be attached via the aromatic ring or via the non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthenyl.
  • heteromatic ring refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, and the remaining ring atoms are C, wherein at least one ring is an aromatic ring.
  • the group may be a carbon group or a heteroatom group (i.e., it may be C-connected or N-connected, as long as it is possible).
  • the group may be connected through an aromatic ring or through a non-aromatic ring.
  • heteroaryl examples include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl and tetrahydroquinoline.
  • heteroaryl examples include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl,
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • Deuterated alkyl by itself or as part of another substituent refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • Deuterated alkoxy when used alone or as part of another substituent refers to an alkoxy group ( -ORX ) wherein the RX portion is substituted with one or more deuterium atoms, wherein RX is an "alkyl" group as defined above.
  • salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable acid addition salts” refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salts” refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects.
  • other salts are contemplated by the present invention. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization or purification of the compounds of the present invention.
  • amine salt refers to the product obtained by neutralizing an alkyl primary amine, secondary amine or tertiary amine with an acid.
  • the acid includes the inorganic acid or organic acid described in the present application.
  • solvate means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent forces between molecules.
  • the solvent is water, it is a hydrate.
  • pharmaceutically acceptable solvate of a salt refers to a substance formed by the combination of a compound with a pharmaceutically acceptable acid or base and a solvent (including but not limited to water, methanol, ethanol, etc.). The amount of the solvent may be stoichiometric or non-stoichiometric. Pharmaceutically acceptable solvates of salts include but are not limited to monohydrochloride monohydrate.
  • prodrug refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis.
  • the prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group.
  • pharmaceutical composition refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • excipient include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and/or adhesion.
  • treatment refers to therapeutic treatment.
  • treatment means: (1) alleviating one or more biological manifestations, (2) interfere with (a) one or more points in the biological cascade that leads to or causes the disorder or (b) one or more biological manifestations of the disorder, (3) ameliorate one or more symptoms, effects, or side effects associated with the disorder, or one or more symptoms, effects, or side effects associated with the disorder or its treatment, or (4) slow the progression of the disorder or one or more biological manifestations of the disorder.
  • prevent refers to the reduction of the risk of acquiring or developing a disease or disorder.
  • patient refers to any animal, preferably a mammal, that is about to or has been administered the compound or composition according to embodiments of the present invention.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., preferably humans.
  • terapéuticaally effective amount refers to an amount of a compound that is effective in treating a disease or condition described herein when administered to a patient.”
  • Therapeutically effective amount will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and can be adjusted as needed by those skilled in the art.
  • IBD inflammatory bowel disease
  • Ulcerative colitis causes inflammation and ulcers in the superficial lining of the large intestine (colon) and rectum.
  • Crohn's disease is characterized by inflammation of the lining of the digestive tract, which often affects deeper layers of the digestive tract.
  • the reaction temperature of each step can be appropriately selected according to the solvent, starting materials, reagents, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting materials, reagents, etc.
  • the target compound can be separated and purified from the reaction system by common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography, etc. In the case of not affecting the next step reaction, the target compound can also be directly used in the next step reaction without separation and purification.
  • the present inventors have unexpectedly developed a heterocyclic compound or a pharmaceutically acceptable salt thereof, a preparation method and a use thereof through extensive and in-depth research.
  • the present invention provides a compound, a solvate, a pharmaceutically acceptable salt, a solvate of a pharmaceutically acceptable salt or a prodrug of a compound of formula I, wherein the compound of formula I has a significant inhibitory effect on 15-PGDH.
  • the production of PGE2 can be significantly increased in a dose-dependent manner, and has a significant effect on IPF and liver regeneration. Combined with the pharmacokinetic data of mice, it can be seen that the compounds of the present invention exhibit excellent pharmacokinetic properties in mice, and have high safety and drug properties.
  • the present invention provides a method for preparing the compound shown in I, a solvate, a pharmaceutically acceptable salt, a solvate of a pharmaceutically acceptable salt or a prodrug and an intermediate.
  • the method is simple to operate, has a high yield and high purity, and can be used for industrial production of medicines.
  • IC 50 Half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved
  • n-butyllithium 14.56 mL, 29.1 mmol, 2.5 M n-hexane solution
  • n-butyllithium n-hexane solution means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol/L
  • N equivalent concentration, for example, 2N hydrochloric acid means 2 mol/L hydrochloric acid solution
  • the synthetic route of target compound 1 is as follows:
  • Step 1 (5-bromopyridin-2-yl)(imino)(methyl)- ⁇ 6 -sulfone
  • Step 2 (5-bromopyridin-2-yl)(methyl)(methylimino)- ⁇ 6 -sulfone
  • Step 3 Methyl(methylimino)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)- ⁇ 6 -sulfone
  • the target compound methyl(methylimino)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-2-yl)- ⁇ 6 -sulfone 130 mg, yield 30.3% was obtained by concentration and preparative chromatography.
  • Step 4 6'-(N,S-dimethylsulfonylimino)-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile
  • Step 5 6'-(N,S-dimethylsulfonylimino)-4-isopropyl-6-((((2-methoxyethyl)sulfinyl)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile
  • the mixture was diluted with water (10 mL), quenched with saturated sodium sulfite solution (10 mL), neutralized with saturated sodium bicarbonate (3 mL), extracted with dichloromethane (20 mL ⁇ 3), and the organic phases were combined, washed with saturated sodium sulfite solution (20 mL) and saturated brine (20 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product.
  • Step 6 (5-(3-amino-4-isopropyl-2-((2-methoxyethyl)sulfinyl)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)(methyl)(methylimino)- ⁇ 6 -sulfone
  • the synthetic route of target compound 2 is as follows:
  • Step 1 tert-butyl ((5-bromopyridin-2-yl)(methyl)(oxo)- ⁇ 6 -sulfylidene)carbamate
  • Step 2 tert-butyl (methyl(oxo)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-yl)- ⁇ 6 -sulfylidene)carbamate
  • ethyl isobutyrylate (10.0 g, 63.21 mmol) and cyanothioacetamide (6.33 g, 63.21 mmol) were dissolved in methanol (50 mL), potassium hydroxide (7.09 g, 126.42 mmol) was added thereto, and stirred at 70°C for 18 h. After the reaction was completed, it was directly spin-dried, and the pH of the residue was adjusted to about 1 with concentrated hydrochloric acid, and filtered to obtain the target compound 6-hydroxy-4-isopropyl-2-mercaptonicotinonitrile (8.11 g, yield 66%).
  • Step 4 6-Hydroxy-4-isopropyl-2-((((2-methoxyethyl)thio)methyl)thio)nicotinonitrile
  • 6-Hydroxy-4-isopropyl-2-mercaptonicotinonitrile (5.0 g, 25.74 mmol) was dissolved in acetonitrile (10 mL), triethylamine (5.21 g, 51.48 mmol) and (chloromethyl)(2-methoxyethyl)sulfane (4.34 mg, 30.89 mmol) were added thereto, and stirred at room temperature for 16 h.
  • Step 5 5-cyano-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)pyridin-2-yl trifluoromethanesulfonate
  • 6-Hydroxy-4-isopropyl-2-((((2-methoxyethyl)thio)methyl)thio)nicotinonitrile (3.0 g, 10.05 mmol) was dissolved in tetrahydrofuran (30 mL), 1.0 M potassium tert-butoxide solution (15.08 mL, 15.08 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (4.7 g, 12.06 mmol) were added thereto, and stirred at room temperature for 16 h.
  • Step 6 tert-butyl ((5-cyano-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-[2,3'-bipyridyl]-6'-yl)(methyl)(oxo)- ⁇ 6 -sulfanylide)carbamate
  • Step 7 tert-butyl ((5-cyano-4-isopropyl-6-((((2-methoxyethyl)sulfoxide)methyl)thio)-[2,3'-bipyridyl]-6'-yl)(methyl)(oxo)- ⁇ 6 -sulfenyl)carbamate
  • the mixture was diluted with water (10 mL), quenched with saturated sodium sulfite solution (10 mL), neutralized with saturated sodium bicarbonate (3 mL), extracted with dichloromethane (20 mL ⁇ 3), and the organic phases were combined, washed with saturated sodium sulfite solution (20 mL) and saturated brine (20 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product.
  • Step 8 (5-(3-amino-4-isopropyl-2-((2-methoxyethylidene)sulfinyl)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)(imino)(methyl)- ⁇ 6 -sulfone
  • the mixture was diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL ⁇ 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • the crude product was dissolved in a 4 mol/L hydrogen chloride solution in 1,4-dioxane (5 mL), stirred at room temperature for 2 h, and directly concentrated to dryness after the reaction was completed.
  • a saturated aqueous sodium bicarbonate solution (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL*3).
  • the organic phases were combined and concentrated to dryness under reduced pressure.
  • the synthetic route of target compound 3 is as follows:
  • Step 1 ((5-bromopyridin-2-yl)imino)dimethyl- ⁇ 6 -sulfone
  • Dimethylsulfenyl imide (2.05 g, 22.0 mmol), cesium carbonate (8.61 g, 26.4 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (877 mg, 1.41 mmol) and palladium acetate (198 mg, 881 umol) were added to a solution of 5-bromo-2-iodopyridine (5.0 g, 17.6 mmol) in anhydrous toluene (80 mL). Stir at 120 ° C for 12 hours.
  • reaction solution was added to water (50 mL), then extracted with ethyl acetate (50 mL ⁇ 3), the organic layer phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude product.
  • Step 2 Dimethyl((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)imino)- ⁇ 6 -sulfone
  • Step 3 6'-((dimethyl(oxy)- ⁇ 6 -sulfaneylidene)amino)-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile
  • 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride 55.1 mg, 67.5 umol was added and reacted at 100° C. for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (30 mL), extracted three times with ethyl acetate (30 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • Step 4 6'-((dimethyl(oxy)- ⁇ 6 -sulfaneylidene)amino)-4-isopropyl-6-((((2-methoxyethyl)sulfinyl)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile
  • reaction mixture was quenched and neutralized with saturated sodium bicarbonate (3 mL), extracted with dichloromethane (20 mL ⁇ 3), and the organic phases were combined and washed with saturated sodium sulfite solution (20 mL) and saturated brine (20 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 6'-((dimethyl(oxyylidene)- ⁇ 6 -sulfaneylidene)amino)-4-isopropyl-6-((((2-methoxyethyl)sulfinyl)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile (220 mg, yield 70.8%).
  • Step 5 ((5-(3-amino-4-isopropyl-2-((2-methoxyethyl)sulfinyl)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)imino)dimethyl- ⁇ 6 -sulfone
  • the synthetic route of target compound 4 is as follows:
  • Step 2 (5-bromopyridin-2-yl)(3-chloropropyl)(imino)- ⁇ 6 -sulfone
  • Step 4 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-4,5-dihydro-3H-isothiazole 1-oxide
  • Step 5 4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-6'-(1-oxido-4,5-dihydro-3H-1 ⁇ 6 -isothiazol-1-yl)-[2,3'-bipyridine]-5-carbonitrile
  • Step 6 4-isopropyl-6-((((2-methoxyethyl)sulfoxide)methyl)thio)-6'-(1-oxide-4,5-dihydro-3H-1 ⁇ 6 -isothiazole-1- 2,3'-Bipyridine-5-carbonitrile
  • the mixture was diluted with water (10 mL), quenched with saturated sodium sulfite solution (10 mL), neutralized with saturated sodium bicarbonate (3 mL), extracted with dichloromethane (20 mL ⁇ 3), and the organic phases were combined, washed with saturated sodium sulfite solution (20 mL) and saturated brine (20 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product.
  • Step 7 1-(5-(3-amino-4-isopropyl-2-((2-methoxyethyl)sulfoxide)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)-4,5-dihydro-3H-isothiazole 1-oxide
  • Test Example 1 Compound Inhibition Test on 15-PGDH Enzyme
  • NAD + and PGE 2 were prepared into 4 times of the final concentration, i.e. 2mM and 0.12mM, respectively, using Assay Buffer.
  • 4 ⁇ L/well was added to the above white plate, mixed, centrifuged at 1000rpm for 1min, and incubated at 25°C for 30min for reaction.
  • the instrument TECAN SPARK 20M was used for detection at an excitation wavelength of 340nm and an emission wavelength of 485nm.
  • GraphPad Prism 8.0 was used for four-parameter fitting to calculate the IC 50 value.
  • Test Example 2 Effect of Compounds on PGE2 Levels in A549 Cell Supernatant
  • A549 cells (Wuhan Punosai) were cultured in F12K + 10% FBS. Cells in good logarithmic phase were used for experiments. The cells were digested and counted, and the cells were inoculated into 24-well plates, 8000 cells/well. The cells were placed in a 37°C, 5% CO2 incubator for overnight culture. After the cells adhered to the wall, the medium containing 0.5% FBS was changed to treat for about 10 hours, and IL-1 ⁇ (final concentration 20ng/mL, 1mL/well) was added to each well, and a control group was set up at the same time (the control group did not add IL-1 ⁇ ).
  • mice Male mice were adaptively fed for 1-2 weeks and after reaching the target body weight (25g), an IPF model (idiopathic pulmonary fibrosis model) was induced with a certain dose of bleomycin.
  • the mice On the day of modeling, the mice were randomly divided into a model group and a treatment group according to their body weight, and oral gavage was started every day.
  • the vehicle control group was given a blank vehicle for 21 consecutive days.
  • the body weight was measured every 3 days.
  • the animals were euthanized, the lungs were removed from the thyroid cartilage (no perfusion was required), and 10% formalin was slowly perfused into the lungs until both lungs were filled.
  • the experimental results show that the compounds of the present invention can significantly reduce the degree of fibrosis in the IPF prevention model of mice.
  • Test Example 4 Efficacy experiment on mouse IPF treatment model
  • mice Male mice were adaptively fed for 1-2 weeks and after reaching the target body weight (25g), an IPF model (idiopathic pulmonary fibrosis model) was induced with a certain dose of bleomycin.
  • the mice On the day of modeling, the mice were randomly divided into a model group and a treatment group according to their body weight. Oral gavage was performed daily starting from Day 7, and the vehicle control group was given a blank vehicle for 14 consecutive days. During the drug administration period, the body weight was measured twice a week. At the end of the last day of drug administration, the animals were euthanized, the lungs were removed from the thyroid cartilage (no perfusion was required), and 10% formalin was slowly perfused into the lungs until both lungs were filled.
  • the experimental results show that the compounds of the present invention can significantly reduce the degree of fibrosis in the IPF treatment model of mice.
  • Test Example 5 Mouse liver resection and regeneration efficacy experiment
  • mice The pharmacokinetic properties of the compounds of the present invention in mice were determined according to the following experimental methods.
  • mice Male CD-1 mice were used, with a dose of 10 mg/kg, and the administration route was oral gavage.
  • the solvent was 5% DMSO + 10% Solutol + 85% Saline.
  • the mice were fasted overnight, and blood was collected before administration and 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration.
  • the blood samples were centrifuged at 6800g2-8°C for 6 minutes, and the plasma was collected and stored at -80°C.
  • 10 ⁇ L of plasma at each time point was added to 200 ⁇ L of methanol containing 100ng/mL internal standard, vortexed and mixed, and centrifuged at 18000g for 7 minutes at 2-8°C. 200 ⁇ L was transferred to a 96-well sample plate for LC-MS/MS quantitative analysis.
  • the main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
  • mice The experimental results show that the compound of the present invention exhibits excellent pharmacokinetic properties in mice.

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Abstract

The present invention provides a heterocyclic compound represented by formula I, and a solvate, pharmaceutically acceptable salt, solvate of the pharmaceutically acceptable salt, or prodrug thereof. The compound has a good 15-PGDH inhibitory effect.

Description

抑制15-PGDH的化合物及其用途Compounds inhibiting 15-PGDH and uses thereof
本申请要求申请日为2022年11月14日的中国专利申请2022114274923，申请日为2023年11月2日的中国专利申请202311462383X的优先权。本申请引用上述中国专利申请的全文。This application claims priority to Chinese patent application 2022114274923, filed on November 14, 2022, and Chinese patent application 202311462383X, filed on November 2, 2023. This application cites the full text of the above Chinese patent application.
技术领域Technical Field
本发明属于医药领域，具体地，本发明涉及到一种抑制15-PGDH的化合物及其用途。The present invention belongs to the field of medicine, and in particular, relates to a compound for inhibiting 15-PGDH and a use thereof.
背景技术Background technique
15-羟基前列腺素脱氢酶(15-PGDH)基因位于4号染色体4q34～q35上，大约跨度为31kb，共有7个外显子，分子量为29kD。15-PGDH由266个氨基酸组成，属于短链脱氢酶(short-chain dehydrogenases，SDR)家族，由两个相同亚单位构成二聚体，但也有人认为它以单体存在时才有酶活性。15-PGDH是前列腺素(Prostaglandins，PGs)和相关二十烷类生物活性物质降解、灭活的关键酶，广泛存在于人和哺乳动物的肺、肾、胃肠道、甲状腺、前列腺和胎盘等正常组织中，它一方面可催化有活性的15-羟基前列腺素氧化成为活性大大减弱的15-酮基前列腺素，另一方面能在NAD+辅酶因子存在的情况下，降解其他一些非前列腺素的多环芳香烃，通过氧化反应减少生理或病理情况下产生的致癌物和前致癌物。The 15-hydroxyprostaglandin dehydrogenase (15-PGDH) gene is located on chromosome 4, 4q34-q35, with a span of approximately 31kb, a total of 7 exons, and a molecular weight of 29kD. 15-PGDH is composed of 266 amino acids and belongs to the short-chain dehydrogenase (SDR) family. It is a dimer composed of two identical subunits, but some people believe that it is only enzymatically active when it exists as a monomer. 15-PGDH is a key enzyme for the degradation and inactivation of prostaglandins (PGs) and related eicosane bioactive substances. It is widely present in normal tissues such as the lungs, kidneys, gastrointestinal tract, thyroid, prostate, and placenta of humans and mammals. On the one hand, it can catalyze the oxidation of active 15-hydroxyprostaglandins into 15-ketoprostaglandins with greatly weakened activity. On the other hand, it can degrade some other non-prostaglandin polycyclic aromatic hydrocarbons in the presence of NAD + coenzyme factors, reducing carcinogens and pro-carcinogens produced under physiological or pathological conditions through oxidation reactions.
目前尚无15-PGDH抑制途径治疗包括纤维化在内的众多病症的药物上市。因此，开发新的可抑制15-PGDH活性的化合物对于疾病的治疗具有积极意义。Currently, there is no drug on the market that inhibits the 15-PGDH pathway to treat a variety of diseases including fibrosis. Therefore, the development of new compounds that can inhibit the activity of 15-PGDH has positive significance for the treatment of diseases.
发明内容Summary of the invention
本发明的目的是提供一种新的化合物，用作15-PGDH抑制剂。The object of the present invention is to provide a novel compound useful as a 15-PGDH inhibitor.
在本发明的第一方面，提供了如式I所示杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药：
In the first aspect of the present invention, a heterocyclic compound as shown in Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof is provided:
其中，in,
Ra为H、卤素、羟基、氨基、硝基、氰基、羰基、氧代、羧基、C1-C6烷基、-NH(C1-C6烷基)、C1-C6氘代烷基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、芳基、3-11元杂环烷基或5-11元杂芳基；其中所述C1-C6烷基、C3-C8环烷基、芳基、3-11元杂环烷基和所述5-11元杂芳基各自任选地 被R1-1取代；当所述Ra为多个取代基时，所述的取代基相同或不同； Ra is H, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1 - C6 alkyl, -NH( C1 - C6 alkyl), C1 - C6 deuterated alkyl, C2 - C6 alkynyl, halogenated C1 - C6 alkyl, hydroxyC1 - C6 alkyl, C1 -C6 alkylcarbonyl, C1 - C6 alkoxy, halogenated C1 - C6 alkoxy, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), aryl, 3-11 membered heterocycloalkyl or 5-11 membered heteroaryl; wherein the C1 - C6 alkyl, C3 - C8 cycloalkyl, aryl, 3-11 membered heterocycloalkyl and the 5-11 membered heteroaryl are each optionally is substituted by R 1-1 ; when the Ra is a plurality of substituents, the substituents are the same or different;
R1为C1-C6烷基、C1-C6氘代烷基、卤代C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、C1-C6烷氧基、-(C1-C6亚烷基)-(C1-C6烷氧基)、3-11元杂环烷基、或-(C1-C6亚烷基)-(3-11元杂环烷基)；并且，所述R1任选地被一个或多个R1-1取代；当取代基为多个时，所述的取代基相同或不同； R1 is C1 - C6 alkyl, C1 - C6 deuterated alkyl, halogenated C1 - C6 alkyl, C3 -C8 cycloalkyl , -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy, -( C1 - C6 alkylene)-( C1 - C6 alkoxy), 3-11-membered heterocycloalkyl, or -( C1 - C6 alkylene)-(3-11-membered heterocycloalkyl); and, said R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, said substituents are the same or different;
每个R1-1独立地为H、卤素、羟基、硝基、氰基、羰基、氧代、羧基、-NH(C1-C6烷基)、-O-亚烷基-OH、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、氘代C1-C6烷氧基；Each R 1-1 is independently H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy;
R2为氨基、CN、或-NHC(O)(C1-C6烷基)；R 2 is amino, CN, or -NHC(O)(C 1 -C 6 alkyl);
R3为芳基、3-11元杂环烷基或5-11元杂芳基，其任选地被一个或多个R3-1取代；所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2；R 3 is aryl, 3-11-membered heterocycloalkyl or 5-11-membered heteroaryl, which is optionally substituted by one or more R 3-1 ; said R 3-1 is -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 ;
每个R3-1-1独立地为H、C1-C6烷基或亚烷基-OH，其任选地被以下取代：-OH、-亚烷基-NH2、-亚烷基-N(R3-1-2)2、-亚烷基-O-亚烷基-OH、-亚烷基-O-亚烷基-NH2、-C(O)-烷基、-C(O)O-烷基、-亚烷基-COOH或-S(O)p-烷基；或可替代地，在-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2中，两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环；each R 3-1-1 is independently H, C 1 -C 6 alkyl, or alkylene-OH, which is optionally substituted by: -OH, -alkylene-NH 2 , -alkylene-N(R 3-1-2 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 , -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O) p -alkyl; or alternatively, in -S(＝O)(＝NR 3-1-1 )-R 3-1-1 or -N＝S(＝O)(R 3-1-1 ) 2 , two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocyclic ring;
R3-1-2是H或C1-C6烷基，或者两个R3-1-2连同它们所附接的N原子一起可以形成4-7元杂环，该4-7元杂环任选地含有选自O、S(O)r、或N的另外的杂原子；R 3-1-2 is H or C 1 -C 6 alkyl, or two R 3-1-2 together with the N atom to which they are attached can form a 4-7 membered heterocyclic ring, which optionally contains an additional heteroatom selected from O, S(O) r , or N;
X为N或CH；X is N or CH;
m、n、p、r分别为0、1或2。m, n, p, and r are 0, 1, or 2 respectively.
在本发明一优选实施方案中，Ra为异丙基。In a preferred embodiment of the present invention, Ra is isopropyl.
在本发明一优选实施方案中，R3为5-11元杂芳基，其被一个或多个R3-1取代；所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-11元杂芳基。In a preferred embodiment of the present invention, R 3 is a 5-11 membered heteroaryl group, which is substituted by one or more R 3-1 ; the R 3-1 is -S(＝O)(＝NR 3-1-1 )-R 3-1-1 or -N＝S(＝O)(R 3-1-1 ) 2 ; the 5-11 membered heteroaryl group is a 5-11 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from O, N and S.
在本发明一优选实施方案中，In a preferred embodiment of the present invention,
Ra为H、卤素、羟基、氨基、硝基、氰基、羰基、氧代、羧基、C1-C6烷基、-NH(C1-C6烷基)、C1-C6氘代烷基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、芳基、3-11元杂环烷基或5-11元杂芳基；其中所述C1-C6烷基、C3-C8环烷基、芳基、3-11元杂环烷基和所述5-11元杂芳基各自任选地被R1-1取代；当所述Ra为多个取代基时，所述的取代基相同或不同；所述芳基为C6-C10芳基；所述3-11元杂环烷基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-11元杂环烷基；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-11元杂芳基； Ra is H, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1 - C6 alkyl, -NH( C1 - C6 alkyl), C1 - C6 deuterated alkyl, C2 - C6 alkynyl, halogenated C1 - C6 alkyl, hydroxyC1 - C6 alkyl, C1 -C6 alkylcarbonyl, C1 - C6 alkoxy, halogenated C1 - C6 alkoxy, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), aryl, 3-11 membered heterocycloalkyl or 5-11 membered heteroaryl; wherein the C1 - C6 alkyl, C3 - C8 cycloalkyl, aryl, 3-11 membered heterocycloalkyl and the 5-11 membered heteroaryl are each optionally substituted by R1-1 ; when the R When a is a plurality of substituents, the substituents are the same or different; the aryl group is a C 6 -C 10 aryl group; the 3-11 membered heterocycloalkyl group is a 3-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from O, N and S; the 5-11 membered heteroaryl group is a 5-11 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from O, N and S;
R1为C1-C6烷基、C1-C6氘代烷基、卤代C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、C1-C6烷氧基、-(C1-C6亚烷基)-(C1-C6烷氧基)、3-11元杂环烷基、或-(C1-C6亚烷基)-(3-11元杂环烷基)；并且，所述R1任选地被一个或多个R1-1取代；当取代基为多个时，所述的取代基相同或不同；所述3-11元杂环烷基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个 的3-11元杂环烷基；每个R1-1独立地为H、卤素、羟基、硝基、氰基、羰基、氧代、羧基、-NH(C1-C6烷基)、-O-亚烷基-OH、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、氘代C1-C6烷氧基；所述-O-亚烷基-OH中亚烷基为C1-C6亚烷基； R1 is C1 - C6 alkyl, C1 - C6 deuterated alkyl, halogenated C1 - C6 alkyl, C3 -C8 cycloalkyl , -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy, -( C1 - C6 alkylene)-( C1 - C6 alkoxy), 3-11 membered heterocycloalkyl, or -( C1 - C6 alkylene)-(3-11 membered heterocycloalkyl); and, said R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, said substituents are the same or different; said 3-11 membered heterocycloalkyl is 1, 2 or 3 heteroatoms selected from O, N and S, and the number of heteroatoms is 1, 2 or 3 3-11 membered heterocycloalkyl; each R 1-1 is independently H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy; the alkylene in the -O-alkylene-OH is C 1 -C 6 alkylene;
R2为氨基、CN、或-NHC(O)(C1-C6烷基)；R 2 is amino, CN, or -NHC(O)(C 1 -C 6 alkyl);
R3为芳基、3-11元杂环烷基或5-11元杂芳基，其任选地被一个或多个R3-1取代；所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2；所述3-11元杂环烷基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-11元杂环烷基；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-11元杂芳基；R 3 is an aryl group, a 3-11-membered heterocycloalkyl group or a 5-11-membered heteroaryl group, which is optionally substituted by one or more R 3-1 ; the R 3-1 is -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 ; the 3-11-membered heterocycloalkyl group is a 3-11-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S; the 5-11-membered heteroaryl group is a 5-11-membered heteroaryl group having 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S;
每个R3-1-1独立地为H、C1-C6烷基或亚烷基-OH，其任选地被以下取代：-OH、-亚烷基-NH2、-亚烷基-N(R3-1-2)2、-亚烷基-O-亚烷基-OH、-亚烷基-O-亚烷基-NH2、-C(O)-烷基、-C(O)O-烷基、-亚烷基-COOH或-S(O)p-烷基；或可替代地，在-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2中，两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环；所述亚烷基-OH、-亚烷基-NH2、-亚烷基-N(R3-1-2)2、-亚烷基-O-亚烷基-OH、-亚烷基-O-亚烷基-NH2和-亚烷基-COOH中亚烷基为C1-C6亚烷基；所述-C(O)-烷基、-C(O)O-烷基和-S(O)p-烷基中烷基为C1-C6烷基；所述4-7元杂环为杂原子为S和/或N，杂原子个数为1个或2个的4-7元杂环；Each R 3-1-1 is independently H, C 1 -C 6 alkyl or alkylene-OH, which is optionally substituted by: -OH, -alkylene-NH 2 , -alkylene-N(R 3-1-2 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 , -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH or -S(O) p -alkyl; or alternatively, in -S(＝O)(＝NR 3-1-1 )-R 3-1-1 or -N＝S(＝O)(R 3-1-1 ) 2 , two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocycle; the alkylene-OH, -alkylene-NH 2 , -alkylene-N(R 3-1-2 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 and -alkylene-COOH, the alkylene is C 1 -C 6 alkylene; the alkyl in the -C(O)-alkyl, -C(O)O-alkyl and -S(O) p -alkyl is C 1 -C 6 alkyl; the 4-7 membered heterocycle is a 4-7 membered heterocycle with S and/or N as the heteroatom and 1 or 2 heteroatoms;
每个R3-1-2是H或C1-C6烷基，或者两个R3-1-2连同它们所附接的N原子一起可以形成4-7元杂环，所述4-7元杂环含有选自O、S(O)r、和N的杂原子或杂原子团；杂原子和杂原子团个数为1个、2个或3个的4-7元杂环；Each R 3-1-2 is H or C 1 -C 6 alkyl, or two R 3-1-2 together with the N atom to which they are attached can form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring contains a heteroatom or heteroatom group selected from O, S(O) r , and N; a 4-7 membered heterocyclic ring having 1, 2 or 3 heteroatoms or heteroatom groups;
X为N或CH；X is N or CH;
m、n、p、r分别为0、1或2。m, n, p, and r are 0, 1, or 2 respectively.
在本发明中，所述的如式I所示的杂环类化合物中某些取代基的定义可如下所述，未提及的取代基的定义均如上任一方案所述。In the present invention, the definitions of certain substituents in the heterocyclic compound as shown in Formula I can be as described below, and the definitions of substituents not mentioned are as described in any of the above schemes.
在本发明一优选实施方案中，所述X为CH。In a preferred embodiment of the present invention, X is CH.
在本发明一优选实施方案中，m为1。In a preferred embodiment of the present invention, m is 1.
在本发明一优选实施方案中，n为1。In a preferred embodiment of the present invention, n is 1.
在本发明一优选实施方案中，所述Ra为H、C1-C6烷基、芳基或5-11元杂芳基；其中所述C1-C6烷基、芳基和所述5-11元杂芳基各自任选地被R1-1取代；当所述Ra为多个取代基时，所述的取代基相同或不同；所述芳基为C6-C10芳基；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-11元杂芳基；优选地，所述Ra为C1-C6烷基。In a preferred embodiment of the present invention, Ra is H, C1 - C6 alkyl, aryl or 5-11 membered heteroaryl; wherein the C1 - C6 alkyl, aryl and 5-11 membered heteroaryl are each optionally substituted by R1-1 ; when Ra is a plurality of substituents, the substituents are the same or different; the aryl is C6 - C10 aryl; the 5-11 membered heteroaryl is a 5-11 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S; preferably, Ra is C1 - C6 alkyl.
在本发明一优选实施方案中，所述R1为C1-C6烷基、C1-C6氘代烷基、卤代C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、C1-C6烷氧基、-(C1-C6亚烷基)-(C1-C6烷氧基)；并且，所述R1任选地被一个或多个R1-1取代；当取代基为多个时，所述的取代基相同或不同；优选地，所述R1为C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、-(C1-C6亚烷基)-(C1-C6烷氧基)；更优选地，所述R1为-(C1-C6亚烷基)-(C1-C6烷氧基)。 In a preferred embodiment of the present invention, R1 is C1 - C6 alkyl, C1 - C6 deuterated alkyl, halogenated C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy, -( C1 - C6 alkylene)-( C1 - C6 alkoxy); and, R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, the substituents are the same or different; preferably, R1 is C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), -( C1 - C6 alkylene)-( C1 - C6 alkoxy); more preferably, R1 is -( C1 - C6 alkylene)-( C1 - C6 alkoxy).
在本发明一优选实施方案中，所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2，所述R3-1-1独立地是H或C1-C6烷基，或者所述两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环，所述4-7元杂环为杂原子为S和/或N，杂原子个数为1个或2个的4-7元杂环。In a preferred embodiment of the present invention, R 3-1 is -S(＝O)(＝NR 3-1-1 )-R 3-1-1 or -N＝S(＝O)(R 3-1-1 ) 2 , R 3-1-1 is independently H or C 1 -C 6 alkyl, or the two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocycle, wherein the heteroatom is S and/or N and the number of heteroatoms is 1 or 2.
在本发明一优选实施方案中，Ra、R1和R3-1-2中，所述C1-C6烷基独立地为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。In a preferred embodiment of the present invention, in Ra , R1 and R3-1-2 , the C1 - C6 alkyl group is independently a C1 - C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在本发明一优选实施方案中，Ra和R1中，所述C1-C6氘代烷基独立地为C1-C4氘代烷基。In a preferred embodiment of the present invention, in Ra and R1 , the C1 - C6 deuterated alkyl group is independently a C1 - C4 deuterated alkyl group.
在本发明一优选实施方案中，Ra和R1中，所述卤代C1-C6烷基独立地为卤代C1-C4烷基。In a preferred embodiment of the present invention, in Ra and R1 , the halogenated C1 - C6 alkyl group is independently a halogenated C1 - C4 alkyl group.
在本发明一优选实施方案中，Ra和R1中，所述C3-C8环烷基独立地为C3-C6环烷基，例如，环丙基、环丁基、环戊基或环己基。In a preferred embodiment of the present invention, in Ra and R1 , the C3 - C8 cycloalkyl group is independently a C3 - C6 cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
在本发明一优选实施方案中，Ra和R1中，所述-(C1-C6亚烷基)-(C3-C8环烷基)里的C3-C8环烷基独立地为C3-C6环烷基，例如，环丙基、环丁基、环戊基或环己基。In a preferred embodiment of the present invention, in Ra and R1 , the C3 -C8 cycloalkyl in the -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl) is independently C3 -C6 cycloalkyl , for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
在本发明一优选实施方案中，Ra和R1中，所述-(C1-C6亚烷基)-(C3-C8环烷基)里的C1-C6亚烷基独立地为C1-C4亚烷基，优选-(CH2)x-，x为1、2、或3。In a preferred embodiment of the present invention, in Ra and R1 , the C1 - C6 alkylene in the -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl) is independently C1 - C4 alkylene, preferably -( CH2 ) x- , where x is 1, 2, or 3.
在本发明一优选实施方案中，Ra和R1中，所述C1-C6烷氧基独立地为C1-C4烷氧基，例如，甲氧基、乙氧基、正丙氧基或异丙氧基。In a preferred embodiment of the present invention, in Ra and R1 , the C1 - C6 alkoxy group is independently a C1 - C4 alkoxy group, for example, a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.
在本发明一优选实施方案中，R1中，所述-(C1-C6亚烷基)-(C1-C6烷氧基)里的C1-C6烷氧基为C1-C4烷氧基，例如，甲氧基、乙氧基、正丙氧基或异丙氧基。In a preferred embodiment of the present invention, in R 1 , the C 1 -C 6 alkoxy group in the -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy) group is a C 1 -C 4 alkoxy group, for example, a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.
在本发明一优选实施方案中，R1中，所述-(C1-C6亚烷基)-(C1-C6烷氧基)里的C1-C6亚烷基为C1-C4亚烷基，优选-(CH2)x-，x为1、2、或3，例如-CH2-、-(CH2)2-或-(CH2)3-。In a preferred embodiment of the present invention, in R 1 , the C 1 -C 6 alkylene in the -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy ) is C 1 -C 4 alkylene, preferably -(CH 2 ) x -, where x is 1, 2, or 3, such as -CH 2 -, -(CH 2 ) 2 -, or -(CH 2 ) 3 -.
在本发明一优选实施方案中，R1中，所述-(C1-C6亚烷基)-(C1-C6烷氧基)为-(C1-C4亚烷基)-(C1-C4烷氧基)。In a preferred embodiment of the present invention, in R 1 , the -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy) is -(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy).
在本发明一优选实施方案中，Ra和R1中，所述3-11元杂环烷基为3-6元杂环烷基，优选为杂原子选自O、N和S中的1种或2种、杂原子数为1个或2个的3-6元杂环烷基。In a preferred embodiment of the present invention, in Ra and R1 , the 3-11 membered heterocycloalkyl is a 3-6 membered heterocycloalkyl, preferably a 3-6 membered heterocycloalkyl having one or two heteroatoms selected from O, N and S and one or two heteroatoms.
在本发明一优选实施方案中，Ra和R1中，所述-(C1-C6亚烷基)-(3-11元杂环烷基)里的3-11元杂环烷基为3-6元杂环烷基，优选为杂原子选自O、N和S中的1种或2种、杂原子数为1个或2个的3-6元杂环烷基。In a preferred embodiment of the present invention, in Ra and R1 , the 3-11-membered heterocycloalkyl in the -( C1 - C6 alkylene)-(3-11-membered heterocycloalkyl) is a 3-6-membered heterocycloalkyl, preferably a 3-6-membered heterocycloalkyl having one or two heteroatoms selected from O, N and S and one or two heteroatoms.
在本发明一优选实施方案中，Ra和R1中，所述-(C1-C6亚烷基)-(3-11元杂环烷基)里的C1-C6亚烷基为C1-C4亚烷基。In a preferred embodiment of the present invention, in Ra and R1 , the C1 - C6 alkylene in the -( C1 - C6 alkylene)-(3-11-membered heterocycloalkyl) is C1 - C4 alkylene.
在本发明一优选实施方案中，R1-1中，所述-NH(C1-C6烷基)、C1-C6烷基和卤代C1-C6烷基里的C1-C6烷基为C1-C3烷基。In a preferred embodiment of the present invention, in R 1-1 , the C 1 -C 6 alkyl in the -NH(C 1 -C 6 alkyl), C 1 -C 6 alkyl and halogenated C 1 -C 6 alkyl is C 1 -C 3 alkyl.
在本发明一优选实施方案中，R1-1中，所述-NH(C1-C6烷基)、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基和氘代C1-C6烷氧基里的C1-C6烷氧基为C1-C3烷氧基。In a preferred embodiment of the present invention, in R 1-1 , the C 1 -C 6 alkoxy group among the -NH(C 1 -C 6 alkyl), C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl , C 1 -C 6 alkoxy and deuterated C 1 -C 6 alkoxy is C 1 -C 3 alkoxy.
在本发明一优选实施方案中，Ra中，所述C6-C10芳基为苯基。In a preferred embodiment of the present invention, in Ra , the C6 - C10 aryl group is a phenyl group.
在本发明一优选实施方案中，Ra中，所述5-11元杂芳基为5-6元杂芳基，优选杂原子选自O、N 和S中的1种或2种，杂原子数为1个或2个的5-6元杂芳基。In a preferred embodiment of the present invention, in Ra , the 5-11 membered heteroaryl is a 5-6 membered heteroaryl, and the heteroatom is preferably selected from O, N and S, and a 5- to 6-membered heteroaryl group having 1 or 2 heteroatoms.
在本发明一优选实施方案中，R3中，所述5-11元杂芳基为5-10元杂芳基；优选地，所述5-11元杂芳基为5-6元杂芳基或8-10元双环杂芳基；更优选地，所述5-11元杂芳基为杂原子选自O、N和S中的1种或2种，杂原子数为1个或2个的5-6元杂芳基或杂原子选自O、N和S中的1种或2种，杂原子数为1个或2个的8-10元双环杂芳基；例如，吡啶。In a preferred embodiment of the present invention, in R 3 , the 5-11 membered heteroaryl is a 5-10 membered heteroaryl; preferably, the 5-11 membered heteroaryl is a 5-6 membered heteroaryl or an 8-10 membered bicyclic heteroaryl; more preferably, the 5-11 membered heteroaryl is a 5-6 membered heteroaryl having 1 or 2 heteroatoms selected from one or two of O, N and S, or an 8-10 membered bicyclic heteroaryl having 1 or 2 heteroatoms selected from one or two of O, N and S; for example, pyridine.
在本发明一优选实施方案中，R3-1-1中，所述C1-C6烷基独立地为C1-C3烷基，例如甲基、乙基、正丙基或异丙基。In a preferred embodiment of the present invention, in R 3-1-1 , the C 1 -C 6 alkyl group is independently a C 1 -C 3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl.
在本发明一优选实施方案中，R3-1-1中，所述两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环里的4-7元杂环为5-6元杂环，优选5元杂环；例如 In a preferred embodiment of the present invention, in R 3-1-1 , the two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7-membered heterocyclic ring, in which the 4-7-membered heterocyclic ring is a 5-6-membered heterocyclic ring, preferably a 5-membered heterocyclic ring; for example
在本发明一优选实施方案中，所述R1为C1-C4烷基、C1-C4氘代烷基、卤代C1-C4烷基、C3-C6环烷基、-(C1-C6亚烷基)-(C3-C6环烷基)、C1-C4烷氧基、-(C1-C4亚烷基)-(C1-C4烷氧基)、3-6元杂环烷基或-(C1-C4亚烷基)-(3-6元杂环烷基)；并且，所述R1任选地被一个或多个R1-1取代；当取代基为多个时，所述的取代基相同或不同；所述R1-1的定义如本发明第一方面中所述。In a preferred embodiment of the present invention, R 1 is C 1 -C 4 alkyl, C 1 -C 4 deuterated alkyl, halogenated C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, -(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), C 1 -C 4 alkoxy, -(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy), 3-6 membered heterocycloalkyl or -(C 1 -C 4 alkylene)-(3-6 membered heterocycloalkyl); and R 1 is optionally substituted by one or more R 1-1 ; when there are multiple substituents, the substituents are the same or different; the definition of R 1-1 is as described in the first aspect of the present invention.
在本发明一优选实施方案中，所述R1为丁基、环丙基、环丁基、环戊基、环己基、-(CH2)x-环丙基、-(CH2)x-环丁基、-(CH2)x-环戊基、-(CH2)x-环己基或-(C1-C4亚烷基)-(C1-C4烷氧基)；其中x是1、2、或3。In a preferred embodiment of the present invention, R 1 is butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) x -cyclopropyl, -(CH 2 ) x -cyclobutyl, -(CH 2 ) x -cyclopentyl, -(CH 2 ) x -cyclohexyl or -(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy); wherein x is 1, 2, or 3.
在本发明一优选实施方案中，所述R1为-(C1-C4亚烷基)-(C1-C4烷氧基)。In a preferred embodiment of the present invention, R 1 is -(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy).
在本发明一优选实施方案中，所述Ra为甲基或 In a preferred embodiment of the present invention, said Ra is methyl or
在本发明一优选实施方案中，所述R1为-CH2CH2-O-CH3。In a preferred embodiment of the present invention, R 1 is -CH 2 CH 2 -O-CH 3 .
在本发明一优选实施方案中，所述R1-1为H、卤素、羟基、硝基、氰基、羰基、氧代、羧基、-NH(C1-C3烷基)、-O-亚烷基-OH、C1-C3烷基、氘代C1-C6烷基、卤代C1-C3烷基、C1-C3烷氧基或氘代C1-C3烷氧基。In a preferred embodiment of the present invention, R 1-1 is H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 3 alkyl), -O-alkylene-OH, C 1 -C 3 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy or deuterated C 1 -C 3 alkoxy.
在本发明一优选实施方案中，所述R1-1为H。In a preferred embodiment of the present invention, said R 1-1 is H.
在本发明一优选实施方案中，所述R2为-NH2、CN或-NH-C(O)-CH3；优选-NH2。In a preferred embodiment of the present invention, R 2 is -NH 2 , CN or -NH-C(O)-CH 3 ; preferably -NH 2 .
在本发明一优选实施方案中，所述R3为5-6元杂环烷基或5-10元杂芳基，其任选地被一个或多个R3-1取代，所述R3-1的定义如本发明第一方面中所述。In a preferred embodiment of the present invention, R 3 is a 5-6 membered heterocycloalkyl or a 5-10 membered heteroaryl, which is optionally substituted by one or more R 3-1 , and the definition of R 3-1 is as described in the first aspect of the present invention.
在本发明一优选实施方案中，所述R3为5-10元杂芳基，其任选地被一个或多个R3-1取代，所述R3-1的定义如本发明第一方面中所述。In a preferred embodiment of the present invention, R 3 is a 5-10 membered heteroaryl group, which is optionally substituted by one or more R 3-1 , and the definition of R 3-1 is as described in the first aspect of the present invention.
在本发明一优选实施方案中，所述R3为任选地被一个或多个R3-1取代的5-6元杂芳基，或者为任选地被一个或多个R3-1取代的8-10元双环杂芳基，所述R3-1的定义如本发明第一方面中所述。In a preferred embodiment of the present invention, R 3 is a 5-6 membered heteroaryl group optionally substituted by one or more R 3-1 , or an 8-10 membered bicyclic heteroaryl group optionally substituted by one or more R 3-1 , and the definition of R 3-1 is as described in the first aspect of the present invention.
在本发明一优选实施方案中，所述R3为吡啶，其被一个或多个R3-1取代，所述R3-1的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, R 3 is pyridine, which is substituted by one or more R 3-1 , and the definition of R 3-1 is as described in the first aspect of the present invention.
在本发明一优选实施方案中，所述R3为 In a preferred embodiment of the present invention, said R 3 is
在本发明一优选实施方案中，所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2，所述R3-1-1独立地是H或C1-C3烷基，或者，所述两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环。In a preferred embodiment of the present invention, said R 3-1 is -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 , said R 3-1-1 is independently H or C 1 -C 3 alkyl, or said two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocycle.
在本发明一优选实施方案中，所述R3-1为 In a preferred embodiment of the present invention, said R 3-1 is
在本发明一优选实施方案中，所述R3-1为-S(＝O)(＝NCH3)-CH3或-N＝S(＝O)(CH3)2。In a preferred embodiment of the present invention, the R 3-1 is -S(=O)(=NCH 3 )-CH 3 or -N=S(=O)(CH 3 ) 2 .
本领域技术人员可以理解，根据本领域中使用的惯例，在本申请的结构式中，用于描绘化学键，所述化学键为部分或取代基与核心结构或骨架结构相连的点。Those skilled in the art will appreciate that, according to the conventions used in the art, in the structural formula of the present application, Used to depict chemical bonds, which are the points at which a moiety or substituent is attached to a core or backbone structure.
在本发明一优选实施方案中，In a preferred embodiment of the present invention,
Ra为H、C1-C6烷基、芳基或5-11元杂芳基；其中所述C1-C6烷基、芳基和所述5-11元杂芳基各自任选地被R1-1取代；当所述Ra为多个取代基时，所述的取代基相同或不同；所述芳基为C6-C10芳基；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-11元杂芳基； Ra is H, C1 - C6 alkyl, aryl or 5-11 membered heteroaryl; wherein the C1 -C6 alkyl, aryl and 5-11 membered heteroaryl are each optionally substituted by R1-1 ; when Ra is a plurality of substituents, the substituents are the same or different; the aryl is C6 - C10 aryl; the 5-11 membered heteroaryl is a 5-11 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S;
R1为C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、-(C1-C6亚烷基)-(C1-C6烷氧基)；并且，所述R1任选地被一个或多个R1-1取代；当取代基为多个时，所述的取代基相同或不同；R 1 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -(C 1 -C 6 alkylene)-(C 3 -C 8 cycloalkyl), -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy); and, said R 1 is optionally substituted by one or more R 1-1 ; when there are multiple substituents, said substituents are the same or different;
每个R1-1独立地为C1-C6烷基；Each R 1-1 is independently C 1 -C 6 alkyl;
R2为氨基； R2 is an amino group;
R3为5-11元杂芳基，其被一个R3-1取代；所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-11元杂芳基；R 3 is a 5-11 membered heteroaryl group, which is substituted by one R 3-1 ; the R 3-1 is -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 ; the 5-11 membered heteroaryl group is a 5-11 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S;
每个R3-1-1独立地为H或C1-C6烷基；或可替代地，在-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2中，两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环；所述4-7元杂环为杂原子为S和N的4-7元杂环；Each R 3-1-1 is independently H or C 1 -C 6 alkyl; or alternatively, in -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 , two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocyclic ring; the 4-7 membered heterocyclic ring is a 4-7 membered heterocyclic ring wherein the heteroatoms are S and N;
X为N或CH；X is N or CH;
m为0或1；m is 0 or 1;
n为1。n is 1.
在本发明一优选实施方案中，In a preferred embodiment of the present invention,
Ra为C1-C6烷基； Ra is a C1 - C6 alkyl group;
R1为-(C1-C6亚烷基)-(C1-C6烷氧基)； R1 is -( C1 - C6 alkylene)-( C1 - C6 alkoxy);
R2为氨基； R2 is an amino group;
R3为5-11元杂芳基，其被一个R3-1取代；所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的 5-11元杂芳基；R 3 is a 5-11 membered heteroaryl group, which is substituted by one R 3-1 ; the R 3-1 is -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 ; the 5-11 membered heteroaryl group is a heteroatom selected from 1, 2 or 3 of O, N and S, and the number of heteroatoms is 1, 2 or 3 5-11 membered heteroaryl;
每个R3-1-1独立地为H或C1-C6烷基；或可替代地，在-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2中，两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环；所述4-7元杂环为杂原子为S和N的4-7元杂环；Each R 3-1-1 is independently H or C 1 -C 6 alkyl; or alternatively, in -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 , two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocyclic ring; the 4-7 membered heterocyclic ring is a 4-7 membered heterocyclic ring wherein the heteroatoms are S and N;
X为CH；X is CH;
m为1；m is 1;
n为1。n is 1.
在本发明一优选实施方案中，所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述的如式I所示的化合物为如式I-A、如式I-B或如式I-C所示的化合物：
In a preferred embodiment of the present invention, the heterocyclic compound of formula I, its solvate, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt solvate or its prodrug, is characterized in that the compound of formula I is a compound of formula IA, formula IB or formula IC:
在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自下列任一化合物：
In a preferred embodiment of the present invention, the heterocyclic compound as shown in Formula I is selected from any of the following compounds:
在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自下列任一化合物：

In a preferred embodiment of the present invention, the heterocyclic compound as shown in Formula I is selected from any of the following compounds:

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自下列任一化合物：In a preferred embodiment of the present invention, the heterocyclic compound as shown in Formula I is selected from any of the following compounds:
在下述手性制备条件下保留时间为1.327min的和/或在保留时间为1.731min的 Under the following chiral preparation conditions, the retention time is 1.327 min. and/or at a retention time of 1.731 min
所述的手性制备条件：色谱柱：手性柱Chiralcel OD-3 50×4.6mm I.D.3μm；流动相A：CO2，流动相B：IPA(0.05体积％DEA)，等度洗脱：40体积％IPA(0.05体积％DEA)在CO2中；流速：3mL/min；检测器：PDA；柱温：35℃；柱压：100Bar。The chiral preparation conditions are as follows: chromatographic column: Chiralcel OD-3 50×4.6mm ID3μm; mobile phase A: CO 2 , mobile phase B: IPA (0.05 vol% DEA), isocratic elution: 40 vol% IPA (0.05 vol% DEA) in CO 2 ; flow rate: 3mL/min; detector: PDA; column temperature: 35°C; column pressure: 100Bar.
本发明第二方面，提供一种药物组合物，所述的药物组合物包括：如本发明第一方面中所述的式I所示化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药；和药学上可接受的载体。The second aspect of the present invention provides a pharmaceutical composition, which comprises: a compound of formula I as described in the first aspect of the present invention, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof; and a pharmaceutically acceptable carrier.
本发明第三方面，提供了如本发明第一方面中所述的式I所示化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药的用途，或本发明第二方面所述的药物组合物的用途，所述用途包括：抑制15‐PGDH；和/或，预防和/或治疗15‐PGDH相关的疾病；和/或，用于制备15‐PGDH抑制剂，和/或制备用于预防和/或治疗15‐PGDH相关的疾病的药物、药物组合物或制剂。The third aspect of the present invention provides the use of the compound of formula I as described in the first aspect of the present invention, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt or its prodrug, or the use of the pharmaceutical composition as described in the second aspect of the present invention, the uses including: inhibiting 15-PGDH; and/or, preventing and/or treating 15-PGDH related diseases; and/or, for preparing 15-PGDH inhibitors, and/or for preparing drugs, pharmaceutical compositions or preparations for preventing and/or treating 15-PGDH related diseases.
较佳的，所述15‐PGDH相关的疾病包括但不限于：纤维化疾病、炎性疾病、心血管疾病、创伤、自身免疫性疾病、移植物抗宿主疾病、毛发生长、骨质疏松症、耳病、眼病、中性白细胞减少、糖尿病、膀胱活动低下症、在干细胞或骨髓移植或器官移植中的植入物促进、神经发生和神经细胞死亡、血细胞重建、组织损伤、宫颈疾病和肾病中的一种、两种或更多种。Preferably, the 15-PGDH-related diseases include, but are not limited to, one, two or more of: fibrotic diseases, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host disease, hair growth, osteoporosis, ear diseases, eye diseases, neutropenia, diabetes, underactive bladder, implant promotion in stem cell or bone marrow transplantation or organ transplantation, neurogenesis and neuronal cell death, blood cell reconstitution, tissue damage, cervical disease and kidney disease.
较佳的，所述15‐PGDH相关的疾病包括但不限于：纤维化疾病、炎性疾病、心血管疾病、创伤、自身免疫性疾病、移植物抗宿主疾病、毛发生长、骨质疏松症、耳病、眼病、中性白细胞减少、糖尿病、膀胱活动低下症、在干细胞或骨髓移植或器官移植中的植入物促进、神经发生和神经细胞死亡、 血细胞重建、组织损伤、宫颈疾病和肾病中的一种、两种或更多种。Preferably, the 15-PGDH-related diseases include, but are not limited to, fibrotic diseases, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host disease, hair growth, osteoporosis, ear diseases, eye diseases, neutropenia, diabetes, underactive bladder, implant promotion in stem cell or bone marrow transplantation or organ transplantation, neurogenesis and neuronal cell death, One, two or more of blood cell remodeling, tissue damage, cervical disease, and kidney disease.
较佳地，所述15‐PGDH相关的疾病包括但不限于：纤维化疾病(如肺纤维化，包括特发性肺纤维化等，肝纤维化，肾纤维化，心肌纤维化，硬皮病和骨髓纤维化)、炎性疾病[如慢性阻塞性肺病(COPD)、急性肺损伤、脓毒症、哮喘和肺病的恶化、炎症性肠病(IBD)(如溃疡性结肠炎和克罗恩氏病)、消化性溃疡(如NSAID诱导的溃疡)、自身炎性疾病(如贝切特氏病)、血管炎综合征、急性肝损伤、急性肾损伤、非酒精性脂肪肝(NASH)、特应性皮炎、牛皮癣、间质性膀胱炎、前列腺炎综合征(如慢性前列腺炎/慢性骨盆疼痛综合征)]、心血管疾病(如肺动脉高压、心绞痛、心肌梗死、心力衰竭、缺血性心脏病、脑卒中和周围循环紊乱)、肾病(例如慢性肾病和肾衰竭)、创伤(如糖尿病性溃疡、烧伤、压迫性溃疡、急性粘膜损伤、包括斯-约二氏综合征、粘膜损伤(如粘膜炎或口腔炎)、与抗癌化疗剂有关的损伤(抗癌化疗剂主要地如烷化剂、DNA合成抑制剂、DNA回旋酶抑制剂)或抗代谢物、细胞或体液免疫疗法或放射线有关的损伤)、自身免疫性疾病(如多发性硬化或类风湿性关节炎)、移植物抗宿主疾病(GVHD)、毛发生长、骨质疏松症、耳病(如听力损失、耳鸣、眩晕和平衡失调)、眼病(如青光眼和干眼)、中性白细胞减少、糖尿病、膀胱活动低下症、在干细胞或骨髓移植或器官移植中的植入物促进、神经发生和神经细胞死亡(如精神神经疾病、神经病、神经毒性疾病、神经性疼痛和神经变性疾病)、肝脏再生、肌肉再生(如肌肉萎缩、肌营养不良和肌肉损伤)和宫颈疾病中的一种、两种或更多种。Preferably, the 15-PGDH-related diseases include but are not limited to: fibrotic diseases (such as pulmonary fibrosis, including idiopathic pulmonary fibrosis, etc., liver fibrosis, renal fibrosis, myocardial fibrosis, scleroderma and myelofibrosis), inflammatory diseases [such as chronic obstructive pulmonary disease (COPD), acute lung injury, sepsis, asthma and exacerbation of lung disease, inflammatory bowel disease (IBD) (such as ulcerative colitis and Crohn's disease), peptic ulcer (such as NSAID-induced ulcer), autoinflammatory diseases (such as Behcet's disease), vasculitis syndrome, acute liver injury, acute kidney injury, non-alcoholic fatty liver disease (NASH), atopic dermatitis, psoriasis, interstitial cystitis, prostatitis syndrome (such as chronic prostatitis/chronic pelvic pain syndrome)], cardiovascular diseases (such as pulmonary hypertension, angina pectoris, myocardial infarction, heart failure, ischemic heart disease, stroke and peripheral circulatory disorders), kidney disease (such as chronic kidney disease and renal failure), trauma (such as diabetic ulcers, burns, etc.), Injury, pressure ulcer, acute mucosal injury, including Stevens-Johnson syndrome, mucosal injury (such as mucositis or stomatitis), injury associated with anticancer chemotherapeutic agents (anticancer chemotherapeutic agents are mainly such as alkylating agents, DNA synthesis inhibitors, DNA gyrase inhibitors) or antimetabolites, cellular or humoral immunotherapy or radiation-related injury), autoimmune diseases (such as multiple sclerosis or rheumatoid arthritis), graft-versus-host disease (GVHD), hair growth, osteoporosis, ear diseases (such as hearing loss, tinnitus, vertigo and balance disorders), eye diseases (such as glaucoma and dry eyes), neutropenia, diabetes, underactive bladder, implant promotion in stem cell or bone marrow transplantation or organ transplantation, neurogenesis and neural cell death (such as psychoneurological diseases, neuropathy, neurotoxic diseases, neuropathic pain and neurodegenerative diseases), liver regeneration, muscle regeneration (such as muscle atrophy, muscular dystrophy and muscle injury) and cervical disease.
较佳地，所述组织损伤为肝损伤和/或肌肉损伤(如肌肉萎缩和肌营养不良)。Preferably, the tissue damage is liver damage and/or muscle damage (such as muscle atrophy and muscular dystrophy).
较佳地，所述15‐PGDH相关的疾病包括但不限于：特发性肺纤维化(IPF)。Preferably, the 15-PGDH-related diseases include but are not limited to idiopathic pulmonary fibrosis (IPF).
较佳地，所述15‐PGDH相关的疾病包括但不限于：肝损伤。Preferably, the 15-PGDH-related diseases include but are not limited to: liver damage.
较佳地，所述15‐PGDH相关的疾病包括但不限于：IBD。Preferably, the 15-PGDH-related diseases include but are not limited to: IBD.
较佳地，所述预防和/治疗15‐PGDH相关的疾病包括但不限于：肝脏再生。Preferably, the prevention and/or treatment of 15-PGDH related diseases includes but is not limited to: liver regeneration.
在本发明第四方面，提供一种所述的式I所示化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药的用途，所述的用途为用于制备预防和/或治疗如下疾病的药物；所述的疾病为纤维化疾病、炎性疾病或组织损伤中的一种或多种。In the fourth aspect of the present invention, there is provided a use of the compound of formula I, its solvate, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt solvate or its prodrug, wherein the use is for preparing a medicament for preventing and/or treating the following diseases; the diseases are one or more of fibrotic diseases, inflammatory diseases or tissue damage.
所述的纤维化疾病、所述的炎性疾病和所述组织损伤均可同前所述。The fibrotic disease, the inflammatory disease and the tissue damage may all be the same as described above.
在本发明第五方面，提供一种抑制15‐PGDH，或预防和/或治疗15‐PGDH相关的疾病的方法，包括步骤：给需要的对象施用本发明第一方面所述的式I所示化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药。In the fifth aspect of the present invention, a method for inhibiting 15-PGDH, or preventing and/or treating 15-PGDH-related diseases is provided, comprising the steps of administering to a subject in need thereof the compound of formula I described in the first aspect of the present invention, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt, or a prodrug thereof.
所述与15‐PGDH相关的疾病如前所述。The diseases associated with 15-PGDH are as described above.
在本发明第六方面，提供一种预防或治疗如下疾病的方法，包括步骤：给需要的对象施用本发明第一方面所述的式I所示化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药；所述的疾病为纤维化疾病和/或炎性疾病。In the sixth aspect of the present invention, a method for preventing or treating the following diseases is provided, comprising the steps of: administering the compound of formula I described in the first aspect of the present invention, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt, or a prodrug thereof to a subject in need thereof; the disease is a fibrotic disease and/or an inflammatory disease.
所述的纤维化疾病和所述的炎性疾病如前所述。The fibrotic disease and the inflammatory disease are as described above.
本发明中，上述应用和药物组合物中，所述的式I所示化合物、其溶剂化物、其药学上可接受的 盐、其药学上可接受的盐的溶剂合物或其前药的含量为治疗有效量。In the present invention, in the above-mentioned application and pharmaceutical composition, the compound represented by formula I, its solvate, its pharmaceutically acceptable The content of the salt, its pharmaceutically acceptable salt solvate or its prodrug is a therapeutically effective amount.
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention.
术语和定义Terms and Definitions
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The group definitions and compound structures after such combinations and combinations shall fall within the scope of the description of this application.
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. If there are multiple definitions of a term herein, the definition in this chapter shall prevail.
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular form used in this specification and claims includes the plural form of the referred thing. It should also be noted that unless otherwise stated, the "or" and "or" used mean "and/or". In addition, the term "including" and other forms, such as "including", "containing" and "containing" are not restrictive.
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。Definitions of standard chemical terms can be found in the references, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods, are used. Unless specific definitions are provided, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, drug preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for the use of the kit can be used, or the reactions and purifications can be carried out in a manner known in the art or as described in the present invention. The above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH2O等同于OCH2。如本文所用，表示基团的连接位点。如本文所用，“R1”、“R1”和“R1”的含义相同，可相互替换。对于R2等其它其他符号，类似定义的含义相同。When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, CH 2 O is equivalent to OCH 2 . As used herein, Indicates the attachment site of a group. As used herein, "R 1 ", "R1" and "R 1 " have the same meaning and can be replaced with each other. For other symbols such as R 2 , similar definitions have the same meaning.
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。The section headings used herein are only for the purpose of organizing the article and should not be interpreted as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are incorporated herein by reference in their entirety.
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。 In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically stated.
本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“1～6的整数”应当理解为记载了1、2、3、4、5和6的每一个整数。当该数值范围被理解为“数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数以及该范围内的每一个小数。例如，“1～10的数”应当被理解为不仅记载了1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和；例如，1至3个应当理解为1个、2个和3个。The numerical ranges recorded in the specification and claims of this application, when the numerical range is understood as an "integer", should be understood as recording the two endpoints of the range and each integer in the range. For example, "an integer from 1 to 6" should be understood as recording each integer of 1, 2, 3, 4, 5 and 6. When the numerical range is understood as a "number", it should be understood as recording the two endpoints of the range and each integer in the range and each decimal in the range. For example, "a number from 1 to 10" should be understood as recording not only each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording the sum of each integer and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 respectively; for example, 1 to 3 should be understood as 1, 2 and 3.
在本申请中，当取代基为多个时，优选为1、2或3个。In the present application, when there are multiple substituents, 1, 2 or 3 are preferred.
在单独或作为其他取代基一部分时，术语“C3-C20脂环烃基”是指具有脂肪族性质的环烃基，分子中含有闭合的碳环，可以表示饱和或部分不饱和的一价单环、双环或多环烃环，也包括桥环或螺环，例如当所述脂环烃基含有两个或两个以上的碳环，它们可用多种方式连接：分子中两个环可以共用一个碳原子，这种体系称为螺环；环上两个碳原子之间可以用碳桥连接，形成双环或多环体系，称为桥环；几个环也可以互相连接形成笼状结构。所述脂环烃基可以具有3～20个碳原子，优选“C3-C12脂环烃基”，还可以为“C3-C7脂环烃基”，其可以具有3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20个碳原子。所述脂环烃基可以为“环烷基”、“环烯基”、“环炔基”等(碳数可选自上述3-20之间任意一个整数)，所述脂环烃基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。例如，术语“C3-C7环烷基”应理解为表示饱和的一价单环或双环烃环，可以是螺环或桥环，其具有3、4、5、6或7个碳原子。所述C3-C7环烷基可以是，例如，环丙基、环丁基、环戊基、环己基、双环[1.1.0]丁基、螺戊基、螺[2.3]己基、双环[1.1.1]戊基、双环[2.1.0]戊基、双环[2.1.1]己基或双环[3.1.0]己基。When used alone or as part of other substituents, the term "C 3 -C 20 alicyclic hydrocarbon group" refers to a cyclic hydrocarbon group with aliphatic properties, containing a closed carbon ring in the molecule, which can represent a saturated or partially unsaturated monovalent monocyclic, bicyclic or polycyclic hydrocarbon ring, and also includes a bridged ring or a spirocyclic ring. For example, when the alicyclic hydrocarbon group contains two or more carbon rings, they can be connected in a variety of ways: two rings in the molecule can share a carbon atom, and this system is called a spirocyclic ring; two carbon atoms on the ring can be connected by a carbon bridge to form a bicyclic or polycyclic system, which is called a bridged ring; several rings can also be connected to each other to form a cage-like structure. The alicyclic hydrocarbon group can have 3 to 20 carbon atoms, preferably "C 3 -C 12 alicyclic hydrocarbon group", and can also be "C 3 -C 7 alicyclic hydrocarbon group", which can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms. The alicyclic hydrocarbon group may be a "cycloalkyl", "cycloalkenyl", "cycloalkynyl" or the like (the carbon number may be selected from any integer between 3 and 20 as mentioned above), and the alicyclic hydrocarbon group may be a monocyclic hydrocarbon group, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decalin ring. For example, the term "C 3 -C 7 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which may be a spirocyclic or bridged ring, having 3, 4, 5, 6 or 7 carbon atoms. The C 3 -C 7 cycloalkyl group may be, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.0]butyl, spiropentyl, spiro[2.3]hexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl or bicyclo[3.1.0]hexyl.
在本申请中，在单独或作为其他取代基一部分时，术语“卤素”是指氟、氯、溴、碘；优选氟或氯。As used herein, the term "halogen" alone or as part of another substituent refers to fluorine, chlorine, bromine, iodine; preferably fluorine or chlorine.
在单独或作为其他取代基一部分时，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至6个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。在单独或作为其他取代基一部分时，术语“C1-C6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C1-C3烷基”)，例如甲基、乙基、正丙基或异丙基。The term "alkyl", when alone or as part of another substituent, means a straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing no unsaturated bonds, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by a single bond. The term "C 1 -C 6 alkyl", when alone or as part of another substituent, is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or isomers thereof. In particular, the group has 1, 2 or 3 carbon atoms ("C 1 -C 3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.
在单独或作为其他取代基一部分时，术语“环烷基”是指一种环状烷基。术语“m-n元环烷基”或者“Cm-Cn环烷基”应理解为表示具有m至n个环原子的饱和的碳环。例如，“3-15元环烷基”或者“C3-C15环烷基”是指含有3至15，3至9，3至6或3至5个碳原子的环状烷基，它可能包含1至4个环。“3-10元环烷基”则含有3-10个碳原子。包括单环、二环、三环、螺环或桥环。环烷基的实例包括但不限于环丙基，环丁基，环戊基，环己基和金刚烷基，或者是双环烃基如十氢化萘环。术语“环烷基”可以和术语“碳环基”交换使用。 The term "cycloalkyl" refers to a cyclic alkyl group when used alone or as part of another substituent. The term "mn-membered cycloalkyl" or "C m -C n cycloalkyl" should be understood to mean a saturated carbocyclic ring having m to n ring atoms. For example, "3-15-membered cycloalkyl" or "C 3 -C 15 cycloalkyl" refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which may contain 1 to 4 rings. "3-10-membered cycloalkyl" contains 3-10 carbon atoms. It includes monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring. The term "cycloalkyl" can be used interchangeably with the term "carbocyclic group".
在单独或作为其他取代基一部分时，术语“杂环烷基”是指其中一个或多个(在一些实施方案中为1至3个)碳原子被杂原子替换的环烷基，所述杂原子例如但不限于N、O、S和P。术语“m-n元杂环烷基”或者“Cm-Cn杂环烷基”应理解为表示具有m至n个环原子的饱和的环，其中杂环原子选自N、O、S、P，优选地选自N、O或S。例如，术语“4-8元杂环烷基”或者“C4-C8杂环烷基”应理解为表示具有4至8个环原子的饱和的环，其中1、2、3、或4个环原子选自N、O、S、P，优选地选自N、O或S。“4-10元杂环烷基”则是表示具有4至10个环原子的饱和的环。当诸如4-8元或4-10元的前缀用于表示杂环烷基时，碳的数目也意味着包括杂原子。包括单环、二环、三环、螺环或桥环。杂环烷基的示例为：吡咯烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢吡咯基、氮杂环丁烷基、噻唑烷基、唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、氮杂环庚烷基、二氮杂环庚烷基、氧氮杂环庚烷基等。术语“杂环烷基”可以和术语“杂烷环”交换使用。The term "heterocycloalkyl" when used alone or as part of another substituent refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as, but not limited to, N, O, S, and P. The term "mn-membered heterocycloalkyl" or " Cm - Cn heterocycloalkyl" is understood to mean a saturated ring having m to n ring atoms, wherein the heteroatoms are selected from N, O, S, P, preferably N, O or S. For example, the term "4-8 membered heterocycloalkyl" or " C4 - C8 heterocycloalkyl" is understood to mean a saturated ring having 4 to 8 ring atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, S, P, preferably N, O or S. "4-10 membered heterocycloalkyl" then means a saturated ring having 4 to 10 ring atoms. When prefixes such as 4-8 membered or 4-10 membered are used to represent heterocycloalkyl, the number of carbons is also meant to include the heteroatoms. Including monocyclic, bicyclic, tricyclic, spirocyclic or bridged ring. Examples of heterocycloalkyl are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, etc. The term "heterocycloalkyl" can be used interchangeably with the term "heteroalkyl ring".
在单独或作为其他取代基一部分时，术语“炔基”是指具有至少一个碳-碳sp三键的二到四十个碳原子的直链或支链的单价烃基(例如C2-C6炔基，又例如C2-C4炔基)。炔基的实例包括但不限于乙炔基和丙炔基。The term "alkynyl" when used alone or as part of another substituent refers to a linear or branched monovalent hydrocarbon radical of two to forty carbon atoms (e.g., C2 - C6 alkynyl, for example, C2 - C4 alkynyl) with at least one carbon-carbon sp triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl and propynyl.
在单独或作为其他取代基一部分时，术语“烷氧基”是指基团-O-RX，其中，RX为如上文所定义的“烷基”。The term "alkoxy" by itself or as part of another substituent refers to the group -ORX , wherein RX is "alkyl" as defined above.
在单独或作为其他取代基一部分时，术语“氧代”是指亚甲基上的两个氢被氧取代，也即亚甲基被羰基替代。The term "oxo" when used alone or as part of another substituent refers to the replacement of two hydrogen atoms on a methylene group by oxygen, ie, the methylene group is replaced by a carbonyl group.
在单独或作为其他取代基一部分时，术语“芳基”是指具有6到20个碳原子的单环或多环碳环，其中至少一个环是芳香环。当其中一个环是非芳香环时，该基团可通过芳香环连接，也可通过非芳香环连接。芳基的实例包括但不限于：苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、菲基、蒽基和苊基。The term "aryl" when used alone or as part of another substituent refers to a monocyclic or polycyclic carbon ring having from 6 to 20 carbon atoms, wherein at least one ring is aromatic. When one of the rings is non-aromatic, the group may be attached via the aromatic ring or via the non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthenyl.
在单独或作为其他取代基一部分时，术语“杂芳环”是指单环或多环碳环，其中至少一个环原子为独立地选自氧、硫和氮的杂原子，其余的环原子为C，其中至少一个环是芳香环。该基团可为碳基团或杂原子基团(也即其可为C-连接的或N-连接的，只要其是可能的即可)。当其中一个环是非芳香环时，该基团可通过芳香环连接，也可通过非芳香环连接。杂芳基的实例包括但不限于：咪唑基、吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、N-甲基吡咯基和四氢喹啉。术语“杂芳环”可以和术语“杂芳香环”、“杂芳基”或“杂芳环基”交换使用。When alone or as part of other substituents, the term "heteroaromatic ring" refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, and the remaining ring atoms are C, wherein at least one ring is an aromatic ring. The group may be a carbon group or a heteroatom group (i.e., it may be C-connected or N-connected, as long as it is possible). When one of the rings is a non-aromatic ring, the group may be connected through an aromatic ring or through a non-aromatic ring. Examples of heteroaryl include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl and tetrahydroquinoline. The term "heteroaromatic ring" may be used interchangeably with the terms "heteroaromatic ring", "heteroaryl" or "heteroaromatic cyclyl".
在单独或作为其他取代基一部分时，“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw，其中v＝1至3，w＝1至(2v+1))。卤代烷基的实例包括，但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。"Haloalkyl" when used alone or as part of other substituents refers to saturated aliphatic hydrocarbon groups including branched and straight chains having the specified number of carbon atoms, substituted with one or more halogens (e.g., -CvFw, where v = 1 to 3, w = 1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
在单独或作为其他取代基一部分时，“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。 "Deuterated alkyl" by itself or as part of another substituent refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
在单独或作为其他取代基一部分时，“氘代烷氧基”指烷氧基(-O-RX)中的RX部分被一个或多个氘原子取代，其中RX为如上文所定义的“烷基”。"Deuterated alkoxy" when used alone or as part of another substituent refers to an alkoxy group ( -ORX ) wherein the RX portion is substituted with one or more deuterium atoms, wherein RX is an "alkyl" group as defined above.
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。In the present application, "optional" or "optionally" means that the event or situation described later may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl.
在本申请中，术语“盐”或“药学上可接受的盐”，包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。In the present application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。"Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization or purification of the compounds of the present invention.
术语“胺盐”是指用酸中和烷基伯胺、仲胺或叔胺得到的产物。所述酸包括本申请中所述的无机酸或有机酸。The term "amine salt" refers to the product obtained by neutralizing an alkyl primary amine, secondary amine or tertiary amine with an acid. The acid includes the inorganic acid or organic acid described in the present application.
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。The term "solvate" means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent forces between molecules. When the solvent is water, it is a hydrate.
术语“药学上可接受的盐的溶剂合物”是指化合物与药学上可接受的酸或碱、溶剂(包括但不限于：水、甲醇、乙醇等)结合形成的物质。其中，溶剂的数量可以是化学计量的，也可以是非化学计量的。药学上可接受的盐的溶剂合物包括但不限于：单盐酸盐一水合物。The term "pharmaceutically acceptable solvate of a salt" refers to a substance formed by the combination of a compound with a pharmaceutically acceptable acid or base and a solvent (including but not limited to water, methanol, ethanol, etc.). The amount of the solvent may be stoichiometric or non-stoichiometric. Pharmaceutically acceptable solvates of salts include but are not limited to monohydrochloride monohydrate.
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. The prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and/or adhesion.
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学 表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating one or more biological manifestations, (2) interfere with (a) one or more points in the biological cascade that leads to or causes the disorder or (b) one or more biological manifestations of the disorder, (3) ameliorate one or more symptoms, effects, or side effects associated with the disorder, or one or more symptoms, effects, or side effects associated with the disorder or its treatment, or (4) slow the progression of the disorder or one or more biological manifestations of the disorder.
术语“预防”是指获得或发生疾病或障碍的风险降低。The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.
术语“患者”是指根据本发明的实施例，即将或已经接受了该化合物或组合物给药的任何动物，哺乳动物为优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为优。The term "patient" refers to any animal, preferably a mammal, that is about to or has been administered the compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., preferably humans.
术语“治疗有效量”是指在给予患者时，足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，可由本领域技术人员根据需要进行调整。The term "therapeutically effective amount" refers to an amount of a compound that is effective in treating a disease or condition described herein when administered to a patient."Therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and can be adjusted as needed by those skilled in the art.
术语“炎症性肠病”是指IBD，用于描述涉及消化道慢性炎症的疾病。主要类型包括：溃疡性结肠炎和克罗恩氏病。溃疡性结肠炎。会在大肠(结肠)和直肠浅表层覆膜引起炎症和溃疡。而克罗恩氏病的特征是消化道内膜发炎，炎症通常会累及消化道的深层。The term "inflammatory bowel disease," or IBD, is used to describe diseases that involve chronic inflammation of the digestive tract. The main types include: ulcerative colitis and Crohn's disease. Ulcerative colitis causes inflammation and ulcers in the superficial lining of the large intestine (colon) and rectum. Crohn's disease is characterized by inflammation of the lining of the digestive tract, which often affects deeper layers of the digestive tract.
各步骤的反应，反应温度可因溶剂、起始原料、试剂等适宜选择，反应时间也可因反应温度、溶剂、起始原料、试剂等适宜选择。各步骤反应结束后，目标化合物可按常用方法自反应体系中进行分离、提纯等步骤，如过滤、萃取、重结晶、洗涤、硅胶柱层析等方法。在不影响下一步反应的情况下，目标化合物也可不经过分离、纯化直接进入下一步反应。The reaction temperature of each step can be appropriately selected according to the solvent, starting materials, reagents, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting materials, reagents, etc. After the reaction of each step is completed, the target compound can be separated and purified from the reaction system by common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography, etc. In the case of not affecting the next step reaction, the target compound can also be directly used in the next step reaction without separation and purification.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.
有益效果Beneficial Effects
本发明人经过广泛而深入地研究，意外地开发了一种杂环类化合物或其药学上可接受的盐及制备方法和用途。The present inventors have unexpectedly developed a heterocyclic compound or a pharmaceutically acceptable salt thereof, a preparation method and a use thereof through extensive and in-depth research.
本发明提供了式I所示化合物、溶剂化物、药学上可接受的盐、药学上可接受的盐的溶剂合物或前药，所述式I化合物对15‐PGDH具有显著的抑制作用。可以剂量依赖性的显著增加PGE2的生成，并且对IPF和肝脏再生效果显著。结合小鼠的药代动力学数据，可知本发明化合物分别在小鼠体内表现出优良的药代动力学性质，具备较高的安全性和成药性质。The present invention provides a compound, a solvate, a pharmaceutically acceptable salt, a solvate of a pharmaceutically acceptable salt or a prodrug of a compound of formula I, wherein the compound of formula I has a significant inhibitory effect on 15-PGDH. The production of PGE2 can be significantly increased in a dose-dependent manner, and has a significant effect on IPF and liver regeneration. Combined with the pharmacokinetic data of mice, it can be seen that the compounds of the present invention exhibit excellent pharmacokinetic properties in mice, and have high safety and drug properties.
本发明提供了制备I所示化合物、溶剂化物、药学上可接受的盐、药学上可接受的盐的溶剂合物或前药的方法及中间体，所述方法操作简单、收率高、纯度高，可用于医药工业化生产。The present invention provides a method for preparing the compound shown in I, a solvate, a pharmaceutically acceptable salt, a solvate of a pharmaceutically acceptable salt or a prodrug and an intermediate. The method is simple to operate, has a high yield and high purity, and can be used for industrial production of medicines.
具体实施方式Detailed ways
以下结合具体实施例，进一步说明本发明。需理解，以下的描述仅为本发明的最优选实The present invention is further described below in conjunction with specific embodiments. It should be understood that the following description is only the most preferred embodiment of the present invention.
施方式，而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上，下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件，本领域技术人员可以对本发明的技术方案作出非本质的改动，这样的改动应当被视为包括于本发明的保护范围之中 的。The present invention is not intended to limit the scope of protection of the present invention. Based on a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art may make non-essential changes to the technical solutions of the present invention, and such changes should be deemed to be included in the scope of protection of the present invention. of.
本申请具有如下定义：This application has the following definitions:
符号或单位：Symbol or unit:
IC50：半数抑制浓度，指达到最大抑制效果一半时的浓度IC 50 : Half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved
M：mol/L，例如正丁基锂(14.56mL，29.1mmol，2.5M的正己烷溶液)表示摩尔浓度为2.5mol/L的正丁基锂的正己烷溶液M: mol/L, for example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol/L
N：当量浓度，例如2N盐酸表示2mol/L盐酸溶液N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol/L hydrochloric acid solution
试剂：Reagents:
DCM：二氯甲烷DCM: dichloromethane
TEA：三乙胺TEA: triethylamine
DMSO：二甲基亚砜DMSO: dimethyl sulfoxide
Solutol：聚乙二醇-15羟基硬脂酸酯Solutol: Macrogol-15 Hydroxystearate
Saline：盐水Saline: Salt water
DMAP：4-二甲氨基吡啶DMAP: 4-dimethylaminopyridine
实施例1：(5-(3-氨基-4-异丙基-2-((2-甲氧基乙基)亚磺酰基)噻吩并[2,3-b]吡啶-6-基)吡啶-2-基)(甲基)(甲基亚氨基)-λ6-砜(化合物1)的制备Example 1: Preparation of (5-(3-amino-4-isopropyl-2-((2-methoxyethyl)sulfinyl)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)(methyl)(methylimino)-λ 6 -sulfone (Compound 1)
目标化合物1的合成路线如下：
The synthetic route of target compound 1 is as follows:
第一步：(5-溴吡啶-2-基)(亚氨基)(甲基)-λ6-砜
Step 1: (5-bromopyridin-2-yl)(imino)(methyl)-λ 6 -sulfone
氮气保护下，将5-溴-2-(甲硫基)吡啶(5.0g,24.5mmol)和醋酸铵(5.7g,73.5mmol)溶于甲醇(100mL)中，然后室温搅拌下加入二乙酰氧基碘苯(15.8g，49.0mmol)，室温搅拌过夜。旋干，硅胶柱层析纯化(PE/EA＝1/1)得到化合物(5-溴吡啶-2-基)(亚氨基)(甲基)-λ6-砜(5.5g,收率95.5％)。Under nitrogen protection, 5-bromo-2-(methylthio)pyridine (5.0 g, 24.5 mmol) and ammonium acetate (5.7 g, 73.5 mmol) were dissolved in methanol (100 mL), and then diacetoxy iodobenzene (15.8 g, 49.0 mmol) was added under stirring at room temperature, and stirred at room temperature overnight. The mixture was spin-dried and purified by silica gel column chromatography (PE/EA=1/1) to obtain compound (5-bromopyridin-2-yl)(imino)(methyl)-λ 6 -sulfone (5.5 g, yield 95.5%).
第二步：(5-溴吡啶-2-基)(甲基)(甲基亚氨基)-λ6-砜
Step 2: (5-bromopyridin-2-yl)(methyl)(methylimino)-λ 6 -sulfone
将钠氢溶于无水DMF中，然后氮气保护冰浴下加入(5-溴吡啶-2-基)(亚氨基)(甲基)-λ6-砜(2.50g，10.6mmol)的无水DMF溶液中，保持温度搅拌30分钟，然后向其中加入碘甲烷(3.0g，21.3mmol)，室温下搅拌18h。制备色谱分离得到目标化合物(5-溴吡啶-2-基)(甲基)(甲基亚氨基)-λ6-砜(2.5g，收率94.4％)。Sodium hydroxide was dissolved in anhydrous DMF, and then (5-bromopyridin-2-yl)(imino)(methyl)-λ 6 -sulfone (2.50 g, 10.6 mmol) was added to an anhydrous DMF solution under nitrogen protection in an ice bath, and the temperature was maintained and stirred for 30 minutes, and then iodomethane (3.0 g, 21.3 mmol) was added thereto, and stirred at room temperature for 18 hours. The target compound (5-bromopyridin-2-yl)(methyl)(methylimino)-λ 6 -sulfone (2.5 g, yield 94.4%) was obtained by preparative chromatography.
第三步：甲基(甲基亚氨基)(5-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶-2-基)-λ6-砜
Step 3: Methyl(methylimino)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-λ 6 -sulfone
将(5-溴吡啶-2-基)(甲基)(甲基亚氨基)-λ6-砜(0.5g,2.0mmol)溶于1,4-二氧六环(10mL)和水(2mL)中，向其中加入醋酸钾(0.4g,4.0mmol)，双联频那醇硼酸酯(764mg，3.0mmol)和双三苯基膦二氯化钯(141mg，0.2mmol)，氮气保护下100℃搅拌16h。反应结束后，浓缩制备色谱分离得到目标化合物甲基(甲基亚氨基)(5-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶-2-基)-λ6-砜(130mg，收率30.3％)。(5-bromopyridin-2-yl)(methyl)(methylimino)-λ 6 -sulfone (0.5 g, 2.0 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL), potassium acetate (0.4 g, 4.0 mmol), bis-pinacol borate (764 mg, 3.0 mmol) and bistriphenylphosphine palladium dichloride (141 mg, 0.2 mmol) were added thereto, and stirred at 100°C for 16 h under nitrogen protection. After the reaction was completed, the target compound methyl(methylimino)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridin-2-yl)-λ 6 -sulfone (130 mg, yield 30.3%) was obtained by concentration and preparative chromatography.
第四步：6'-(N,S-二甲基磺酰亚胺基)-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)-[2,3'-联吡啶]-5-腈
Step 4: 6'-(N,S-dimethylsulfonylimino)-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile
将5-氰基-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)吡啶-2-基三氟甲磺酸酯(314mg，0.7mmol)，(甲基亚氨基)(5-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶-2-基)-λ6-砜(130mg，0.6mmol)溶于1,4-二氧六环(20mL)和水(5mL)中，加入双三苯基膦二氯化钯(51mg，0.07mmol)和Na2CO3(191mg，1.8mmol)，反应液在100℃反应16h。反应结束后，冷却至室温，向体系中浓缩，然后粗产品通过硅胶柱层析，PE/EA(v/v)＝1/1，得到目标化合物6'-(N,S-二甲基磺酰亚胺基)-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)-[2,3'-联吡啶]-5-腈(180mg，收率65.8％)。5-Cyano-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)pyridin-2-yl trifluoromethanesulfonate (314 mg, 0.7 mmol) and (methylimino)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-λ 6 -sulfone (130 mg, 0.6 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL), bistriphenylphosphinepalladium dichloride (51 mg, 0.07 mmol) and Na 2 CO 3 (191 mg, 1.8 mmol) were added, and the reaction solution was reacted at 100° C. for 16 h. After the reaction, the mixture was cooled to room temperature and concentrated to a certain extent. The crude product was then chromatographed on a silica gel column with PE/EA (v/v) = 1/1 to give the target compound 6'-(N,S-dimethylsulfonylimino)-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile (180 mg, yield 65.8%).
第五步：6'-(N,S-二甲基磺酰亚胺基)-4-异丙基-6-((((2-甲氧基乙基)亚磺酰基)甲基)硫代)-[2,3'-联吡啶]-5-腈
Step 5: 6'-(N,S-dimethylsulfonylimino)-4-isopropyl-6-((((2-methoxyethyl)sulfinyl)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile
将6'-(N,S-二甲基磺酰亚胺基)-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)-[2,3'-联吡啶]-5-腈(180mg，0.4mmol)溶于氯仿(10mL)和醋酸(1mL)，加入双氧水(66mg，0.58mmol,30％纯度)，在30℃反应1小时。反应结束后，用水(10mL)稀释，加入饱和亚硫酸钠溶液(10mL)淬灭，饱和碳酸氢钠(3mL)中和，用二氯甲烷(20mL×3)萃取，合并有机相，依次用饱和亚硫酸钠溶液(20mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗产品，粗产品通过硅胶柱层析，DCM/MeOH(v/v)＝10/1,得到目标化合物6'-(N,S-二甲基磺酰亚胺基)-4-异丙基-6-((((2-甲氧基乙基)亚磺酰基)甲基)硫代)-[2,3'-联吡啶]-5-腈(180mg，收率98％)。6'-(N,S-dimethylsulfonylimino)-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile (180 mg, 0.4 mmol) was dissolved in chloroform (10 mL) and acetic acid (1 mL), and hydrogen peroxide (66 mg, 0.58 mmol, 30% purity) was added and reacted at 30°C for 1 hour. After the reaction, the mixture was diluted with water (10 mL), quenched with saturated sodium sulfite solution (10 mL), neutralized with saturated sodium bicarbonate (3 mL), extracted with dichloromethane (20 mL×3), and the organic phases were combined, washed with saturated sodium sulfite solution (20 mL) and saturated brine (20 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography with DCM/MeOH (v/v) = 10/1 to give the target compound 6'-(N,S-dimethylsulfonylimino)-4-isopropyl-6-((((2-methoxyethyl)sulfinyl)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile (180 mg, yield 98%).
第六步：(5-(3-氨基-4-异丙基-2-((2-甲氧基乙基)亚磺酰基)噻吩并[2,3-b]吡啶-6-基)吡啶-2-基)(甲基)(甲基亚氨基)-λ6–砜
Step 6: (5-(3-amino-4-isopropyl-2-((2-methoxyethyl)sulfinyl)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)(methyl)(methylimino)-λ 6 -sulfone
将6'-(N,S-二甲基磺酰亚胺基)-4-异丙基-6-((((2-甲氧基乙基)亚磺酰基)甲基)硫代)-[2,3'-联吡啶]-5-腈(180mg,0.4mmol)溶于N,N-二甲基甲酰胺(5mL)和甲醇(3mL)，加入氢氧化钾(18mg,321umol)的水溶液(150μL)，在30℃反应10分钟。反应结束后，用水(20mL)和乙酸乙酯(20mL)稀释，用1N稀盐酸(1mL)中和，乙酸乙酯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过硅胶柱层析，DCM/MeOH(v/v)＝10/1，冻干，得到目标化合物(5-(3-氨基-4-异丙基-2-((2-甲氧基乙基)亚磺酰基)噻吩并[2,3-b]吡啶-6-基)吡啶-2-基)(甲基)(甲基亚氨基)-λ6–砜(化合物1)(90mg,收率50％)。6'-(N,S-dimethylsulfonylimino)-4-isopropyl-6-((((2-methoxyethyl)sulfinyl)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile (180 mg, 0.4 mmol) was dissolved in N,N-dimethylformamide (5 mL) and methanol (3 mL), and an aqueous solution (150 μL) of potassium hydroxide (18 mg, 321 umol) was added, and the mixture was reacted at 30°C for 10 minutes. After the reaction was completed, the mixture was diluted with water (20 mL) and ethyl acetate (20 mL), neutralized with 1N dilute hydrochloric acid (1 mL), extracted with ethyl acetate (20 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography, DCM/MeOH (v/v) = 10/1, and lyophilized to give the target compound (5-(3-amino-4-isopropyl-2-((2-methoxyethyl)sulfinyl)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)(methyl)(methylimino)-λ 6 -sulfone (Compound 1) (90 mg, yield 50%).
LC-MS,M/Z(ESI):467.0[M+H]+。LC-MS, M/Z (ESI): 467.0 [M+H] + .
1H NMR(400MHz,CDCl3)δ9.39(d,1H),8.63(dd,1H),8.22(d,1H),7.70(s,1H),5.12(s,2H),3.91–3.88(m,1H),3.84–3.81(m,1H),3.74–3.70(m,1H),3.67–3.63(m,1H),3.43(s,3H)，3.33-3.30(m,4H),2.72(s,3H),1.51(s,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.39 (d, 1H), 8.63 (dd, 1H), 8.22 (d, 1H), 7.70 (s, 1H), 5.12 (s, 2H), 3.91–3.88 (m, 1H), 3.84–3.81 (m, 1H), 3.74–3.70 (m, 1H), 3.67–3.63 (m, 1H), 3.43 (s, 3H), 3.33-3.30 (m, 4H), 2.72 (s, 3H), 1.51 (s, 6H).
实施例2：(5-(3-氨基-4-异丙基-2-((2-甲氧亚乙基)亚磺基)噻吩并[2,3-b]吡啶-6-基)吡啶-2-基)(亚氨 基)(甲基)-λ6-砜(化合物2)的制备Example 2: (5-(3-amino-4-isopropyl-2-((2-methoxyethylidene)sulfinyl)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)(imido Preparation of (methyl)-λ 6 -sulfone (Compound 2)
目标化合物2的合成路线如下：
The synthetic route of target compound 2 is as follows:
第一步：((5-溴吡啶-2-基)(甲基)(氧代)-λ6-亚硫基)氨基甲酸叔丁酯
Step 1: tert-butyl ((5-bromopyridin-2-yl)(methyl)(oxo)-λ 6 -sulfylidene)carbamate
将(5-溴吡啶-2-基)(亚氨基)(甲基)-λ6-砜(5.0g，1.27mmol)和DMAP(3.12g，25.52mmol)溶于二氯甲烷(50mL)中，向其中加入BOC酸酐(6.96g，31.90mmol)室温下搅拌18h。反应结束后，用水(50mL)稀释，用二氯甲烷(50mL)萃取三次，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品经过硅胶柱层析(PE/EA＝1/1)，得目标化合物为((5-溴吡啶-2-基)(甲基)(氧代)-λ6-亚硫基)氨基甲酸叔丁酯(5.3g，收率74％)。(5-bromopyridin-2-yl)(imino)(methyl)-λ 6 -sulfone (5.0 g, 1.27 mmol) and DMAP (3.12 g, 25.52 mmol) were dissolved in dichloromethane (50 mL), and BOC anhydride (6.96 g, 31.90 mmol) was added thereto and stirred at room temperature for 18 h. After the reaction was completed, it was diluted with water (50 mL), extracted three times with dichloromethane (50 mL), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was subjected to silica gel column chromatography (PE/EA=1/1) to obtain the target compound, tert-butyl ((5-bromopyridin-2-yl)(methyl)(oxo)-λ 6 -sulfylin)carbamate (5.3 g, yield 74%).
LC-MS,M/Z(ESI):335.2[M+H]+。LC-MS, M/Z (ESI): 335.2 [M+H] + .
第二步：(甲基(氧代)(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-吡啶-2-基)-λ6-亚硫基)氨基甲酸叔丁酯
Step 2: tert-butyl (methyl(oxo)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-yl)-λ 6 -sulfylidene)carbamate
将((5-溴吡啶-2-基)(甲基)(氧代)-λ6-磺烷基)氨基甲酸叔丁酯(3.0g，8.95mmol)，联硼酸频哪醇酯(4.55g，18.9mmol)，醋酸钾(2.63g，26.85mmol)溶于1,4-二氧六环(40mL)，加入1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(734mg，0.89mmol)，反应液在90℃反应16h。反应结束后，冷却至室温，向体系中加入水(50mL)，用乙酸乙酯(50mL)萃取三次，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过硅胶柱层析，DCM/MeOH(v/v)＝15/1,得到目标化合物(甲基(氧代)(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-吡啶-2-基)-λ6-亚硫基)氨基甲酸叔丁酯(2.88g，收率84％)。 Tert-butyl ((5-bromopyridin-2-yl)(methyl)(oxo)-λ 6 -sulfoalkyl)carbamate (3.0 g, 8.95 mmol), biboronic acid pinacol ester (4.55 g, 18.9 mmol), potassium acetate (2.63 g, 26.85 mmol) were dissolved in 1,4-dioxane (40 mL), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) dichloromethane complex (734 mg, 0.89 mmol) was added, and the reaction solution was reacted at 90° C. for 16 h. After the reaction was completed, the system was cooled to room temperature, water (50 mL) was added to the system, and the system was extracted three times with ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography with DCM/MeOH (v/v) = 15/1 to give the target compound (methyl(oxo)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-yl)-λ 6 -sulfanylide)carbamic acid tert-butyl ester (2.88 g, yield 84%).
LC-MS,M/Z(ESI):383.2[M+H]+。LC-MS, M/Z (ESI): 383.2 [M+H] + .
第三步：6-羟基-4-异丙基-2-巯基烟腈
Step 3: 6-Hydroxy-4-isopropyl-2-mercaptonicotinonitrile
氮气保护下，将异丁酰乙酸乙酯(10.0g，63.21mmol)和氰基硫代乙酰胺(6.33g，63.21mmol)溶于甲醇(50mL)中，向其中加入氢氧化钾(7.09g，126.42mmol)，70℃下搅拌18h。反应结束后，直接旋干，用浓盐酸将残留物pH调至1左右，过滤，得目标化合物6-羟基-4-异丙基-2-巯基烟腈(8.11g,收率66％)。Under nitrogen protection, ethyl isobutyrylate (10.0 g, 63.21 mmol) and cyanothioacetamide (6.33 g, 63.21 mmol) were dissolved in methanol (50 mL), potassium hydroxide (7.09 g, 126.42 mmol) was added thereto, and stirred at 70°C for 18 h. After the reaction was completed, it was directly spin-dried, and the pH of the residue was adjusted to about 1 with concentrated hydrochloric acid, and filtered to obtain the target compound 6-hydroxy-4-isopropyl-2-mercaptonicotinonitrile (8.11 g, yield 66%).
LC-MS,M/Z(ESI):195.1[M+H]+。LC-MS, M/Z (ESI): 195.1 [M+H] + .
第四步：6-羟基-4-异丙基-2-((((2-甲氧基乙基)硫代)甲基)硫代)烟腈
Step 4: 6-Hydroxy-4-isopropyl-2-((((2-methoxyethyl)thio)methyl)thio)nicotinonitrile
将6-羟基-4-异丙基-2-巯基烟腈(5.0g，25.74mmol)溶于乙腈中(10mL)，向其中加入三乙胺(5.21g，51.48mmol)和(氯甲基)(2-甲氧基乙基)硫烷(4.34mg，30.89mmol),室温下搅拌16h。反应结束后，用水(10mL)稀释，用乙酸乙酯(10mL)萃取三次，合并有机相，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过柱层析，PE/EA(v/v)＝1/1,得到目标化合物6-羟基-4-异丙基-2-((((2-甲氧基乙基)硫代)甲基)硫代)烟腈(3.31g，收率43％)。6-Hydroxy-4-isopropyl-2-mercaptonicotinonitrile (5.0 g, 25.74 mmol) was dissolved in acetonitrile (10 mL), triethylamine (5.21 g, 51.48 mmol) and (chloromethyl)(2-methoxyethyl)sulfane (4.34 mg, 30.89 mmol) were added thereto, and stirred at room temperature for 16 h. After the reaction was completed, it was diluted with water (10 mL), extracted three times with ethyl acetate (10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography, PE/EA (v/v) = 1/1, to obtain the target compound 6-hydroxy-4-isopropyl-2-((((2-methoxyethyl)thio)methyl)thio)nicotinonitrile (3.31 g, yield 43%).
LC-MS,M/Z(ESI):299.1[M+H]+。LC-MS, M/Z (ESI): 299.1 [M+H] + .
第五步：5-氰基-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)吡啶-2-基三氟甲烷磺酸酯
Step 5: 5-cyano-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)pyridin-2-yl trifluoromethanesulfonate
将6-羟基-4-异丙基-2-((((2-甲氧基乙基)硫代)甲基)硫代)烟腈((3.0g，10.05mmol)溶于四氢呋喃中(30mL)，向其中加入1.0M叔丁醇钾溶液(15.08mL，15.08mmol)和N-苯基双(三氟甲烷磺酰)亚胺(4.7g，12.06mmol),室温下搅拌16h。反应结束后，用水(30mL)稀释，用乙酸乙酯(130mL)萃取三次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过硅胶柱层析，PE/EA(v/v)＝5/1,得到目标化合物5-氰基-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)吡啶-2-基三氟甲烷磺酸酯(3.58g，收率83％)。6-Hydroxy-4-isopropyl-2-((((2-methoxyethyl)thio)methyl)thio)nicotinonitrile (3.0 g, 10.05 mmol) was dissolved in tetrahydrofuran (30 mL), 1.0 M potassium tert-butoxide solution (15.08 mL, 15.08 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (4.7 g, 12.06 mmol) were added thereto, and stirred at room temperature for 16 h. After the reaction was completed, water (30 m L), extracted three times with ethyl acetate (130 mL), combined the organic phases, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was chromatographed on a silica gel column with PE/EA (v/v) = 5/1 to give the target compound 5-cyano-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)pyridin-2-yl trifluoromethanesulfonate (3.58 g, yield 83%).
LC-MS,M/Z(ESI):431.1[M+H]+。LC-MS, M/Z (ESI): 431.1 [M+H] + .
第六步：((5-氰基-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)-[2,3'-联吡啶]-6'-基)(甲基)(氧代)-λ6-亚硫基)氨基甲酸叔丁酯
Step 6: tert-butyl ((5-cyano-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-[2,3'-bipyridyl]-6'-yl)(methyl)(oxo)-λ 6 -sulfanylide)carbamate
将5-氰基-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)吡啶-2-基三氟甲烷磺酸酯(500mg，1.16mmol)，(甲基(氧代)(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-吡啶-2-基)-λ6-亚硫基)氨基甲酸叔丁酯(444mg，1.16mmol)，碳酸钠(246mg，2.32mmol)溶于1,4-二氧六环(20mL)和水(2mL)，加入1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(90mg，0.11mmol)，反应液在90℃反应16h。反应结束后，冷却至室温，向体系中加入水(50mL)，用乙酸乙酯(50mL)萃取三次，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过硅胶柱层析，DCM/MeOH(v/v)＝15/1,得到目标化合物((5-氰基-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)-[2,3'-联吡啶]-6'-基)(甲基)(氧代)-λ6-亚硫基)氨基甲酸叔丁酯(310mg，收率50％)。5-Cyano-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)pyridin-2-yl trifluoromethanesulfonate (500 mg, 1.16 mmol), tert-butyl (methyl(oxo)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-yl)-λ 6 -sulfanylide)carbamate (444 mg, 1.16 mmol), and sodium carbonate (246 mg, 2.32 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL), and 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) dichloromethane complex (90 mg, 0.11 mmol) was added, and the reaction solution was reacted at 90° C. for 16 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added to the system, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was chromatographed on a silica gel column with DCM/MeOH (v/v) = 15/1 to obtain the target compound ((5-cyano-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-[2,3'-bipyridyl]-6'-yl)(methyl)(oxo)-λ 6 -sulfylin)carbamic acid tert-butyl ester (310 mg, yield 50%).
LC-MS,M/Z(ESI):537.1[M+H]+。LC-MS, M/Z (ESI): 537.1 [M+H] + .
第七步：((5-氰基-4-异丙基-6-((((2-甲氧基乙基)亚砜基)甲基)硫代)-[2,3'-联吡啶]-6'-基)(甲基)(氧代)-λ6-亚硫基)氨基甲酸叔丁酯
Step 7: tert-butyl ((5-cyano-4-isopropyl-6-((((2-methoxyethyl)sulfoxide)methyl)thio)-[2,3'-bipyridyl]-6'-yl)(methyl)(oxo)-λ 6 -sulfenyl)carbamate
将((5-氰基-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)-[2,3'-联吡啶]-6'-基)(甲基)(氧代)-λ6-亚硫基)氨基甲酸叔丁酯(300mg，559μmol)溶于氯仿(10mL)和醋酸(1mL)，加入双氧水(95mg，0.84mmol，30％纯度)，在30℃反应1小时。反应结束后，用水(10mL)稀释，加入饱和亚硫酸钠溶液(10mL)淬灭，饱和碳酸氢钠(3mL)中和，用二氯甲烷(20mL×3)萃取，合并有机相，依次用饱和亚硫酸钠溶液(20mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗产品，粗产品通过柱层析，DCM/MeOH(v/v)＝10/1，得到目标化合物((5-氰基-4-异丙基-6-((((2-甲氧基乙基)亚砜基)甲基)硫代)-[2,3'-联吡啶]-6'-基)(甲基)(氧代)-λ6-亚硫基)氨基甲酸叔丁酯(130mg，收率74％)。Tert-butyl ((5-cyano-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-[2,3'-bipyridyl]-6'-yl)(methyl)(oxo)-λ 6 -sulfanylide)carbamate (300 mg, 559 μmol) was dissolved in chloroform (10 mL) and acetic acid (1 mL), and hydrogen peroxide (95 mg, 0.84 mmol, 30% purity) was added and reacted at 30° C. for 1 hour. After the reaction, the mixture was diluted with water (10 mL), quenched with saturated sodium sulfite solution (10 mL), neutralized with saturated sodium bicarbonate (3 mL), extracted with dichloromethane (20 mL×3), and the organic phases were combined, washed with saturated sodium sulfite solution (20 mL) and saturated brine (20 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography with DCM/MeOH (v/v) = 10/1 to give the target compound ((5-cyano-4-isopropyl-6-((((2-methoxyethyl)sulfoxide)methyl)thio)-[2,3'-bipyridyl]-6'-yl)(methyl)(oxo)-λ 6 -sulfylidene)carbamic acid tert-butyl ester (130 mg, yield 74%).
LC-MS,M/Z(ESI):553.1[M+H]+。LC-MS, M/Z (ESI): 553.1 [M+H] + .
第八步：(5-(3-氨基-4-异丙基-2-((2-甲氧亚乙基)亚磺基)噻吩并[2,3-b]吡啶-6-基)吡啶-2-基)(亚氨基)(甲基)-λ6-砜
Step 8: (5-(3-amino-4-isopropyl-2-((2-methoxyethylidene)sulfinyl)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)(imino)(methyl)-λ 6 -sulfone
将((5-氰基-4-异丙基-6-((((2-甲氧基乙基)亚砜基)甲基)硫代)-[2,3'-联吡啶]-6'-基)(甲基)(氧代)-λ6-亚硫基)氨基甲酸叔丁酯(130mg，235μmol)溶于N,N-二甲基甲酰胺(5mL)和甲醇(3mL)，加入氢氧化钾(16mg，282μmol)的水溶液(150μL)，在30℃反应10分钟。反应结束后，用水(20mL)和乙酸乙酯(20mL)稀释，乙酸乙酯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品溶解于4mol/L的氯化氢的1,4-二氧六环溶液中(5mL)，室温下搅拌2h，反应结束后，直接浓缩干，加入饱和的碳酸氢钠水溶液(10mL),用乙酸乙酯(10mL*3)萃取三次。合并有机相，减压浓缩干，所得残留物通过硅胶柱层析，DCM/MeOH(v/v)＝10/1，得到目标化合物(5-(3-氨基-4-异丙基-2-((2-甲氧亚乙基)亚磺基)噻吩并[2,3-b]吡啶-6-基)吡啶-2-基)(亚氨基)(甲基)-λ6-砜(化合物2)(52mg,收率50％)。Tert-butyl ((5-cyano-4-isopropyl-6-((((2-methoxyethyl)sulfoxide)methyl)thio)-[2,3'-bipyridyl]-6'-yl)(methyl)(oxo)-λ 6 -sulfenyl)carbamate (130 mg, 235 μmol) was dissolved in N,N-dimethylformamide (5 mL) and methanol (3 mL), and an aqueous solution (150 μL) of potassium hydroxide (16 mg, 282 μmol) was added, and the mixture was reacted at 30°C for 10 minutes. After the reaction was completed, the mixture was diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was dissolved in a 4 mol/L hydrogen chloride solution in 1,4-dioxane (5 mL), stirred at room temperature for 2 h, and directly concentrated to dryness after the reaction was completed. A saturated aqueous sodium bicarbonate solution (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL*3). The organic phases were combined and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography with DCM/MeOH (v/v) = 10/1 to give the target compound (5-(3-amino-4-isopropyl-2-((2-methoxyethylidene)sulfinyl)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)(imino)(methyl)-λ 6 -sulfone (Compound 2) (52 mg, yield 50%).
LC-MS,M/Z(ESI):453.1[M+H]+。LC-MS, M/Z (ESI): 453.1 [M+H] + .
1H NMR(400MHz,CDCl3)δ9.34(s,1H),8.60(d,1H),8.23(s,1H),7.67(s,1H),4.20(s,4H),3.90–3.86(m,1H),3.82–3.78(m,1H),3.71–3.61(m,2H),3.42–3.38(m,2H),3.38(s,3H),3.33–3.27(m,1H),1.49(dd,6H). 1 H NMR (400 MHz, CDCl 3 ) δ9.34 (s, 1H), 8.60 (d, 1H), 8.23 (s, 1H), 7.67 (s, 1H), 4.20 (s, 4H), 3.90–3.86 (m, 1H), 3.82–3.78 (m, 1H), 3.71–3.61 (m, 2H), 3.42–3.38 (m, 2H), 3.38 (s, 3H), 3.33–3.27 (m, 1H), 1.49 (dd, 6H).
实施例3：((5-(3-氨基-4-异丙基-2-((2-甲氧基乙基)亚磺酰基)噻吩并[2,3-b]吡啶-6-基)吡啶-2-基)亚氨基)二甲基-λ6-砜(化合物3)的制备Example 3: Preparation of ((5-(3-amino-4-isopropyl-2-((2-methoxyethyl)sulfinyl)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)imino)dimethyl- λ 6 -sulfone (Compound 3)
目标化合物3的合成路线如下：
The synthetic route of target compound 3 is as follows:
第一步：((5-溴吡啶-2-基)亚氨基)二甲基-λ6-砜
Step 1: ((5-bromopyridin-2-yl)imino)dimethyl- λ 6 -sulfone
将二甲基亚磺酰亚胺(2.05g，22.0mmol)，碳酸铯(8.61g，26.4mmol)，1,1'-联萘-2,2'-双二苯膦(877mg，1.41mmol)和醋酸钯(198mg，881umol)加入5-溴-2-碘吡啶(5.0g，17.6mmol)的无水甲苯(80mL)溶液中。在120℃下搅拌12小时。将反应液加入水中(50mL)，然后用乙酸乙酯(50mL×3)萃取，合并有机层相，用食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-1:1)得到((5-溴吡啶-2-基)亚氨基)二甲基-λ6-砜(2.11g，产率45.4％)。Dimethylsulfenyl imide (2.05 g, 22.0 mmol), cesium carbonate (8.61 g, 26.4 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (877 mg, 1.41 mmol) and palladium acetate (198 mg, 881 umol) were added to a solution of 5-bromo-2-iodopyridine (5.0 g, 17.6 mmol) in anhydrous toluene (80 mL). Stir at 120 ° C for 12 hours. The reaction solution was added to water (50 mL), then extracted with ethyl acetate (50 mL × 3), the organic layer phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 10:1-1:1) to obtain ((5-bromopyridin-2-yl) imino) dimethyl- λ 6 -sulfone (2.11 g, yield 45.4%).
LC-MS,M/Z(ESI):249.1[M+H]+。 LC-MS, M/Z (ESI): 249.1 [M+H] + .
第二步：二甲基((5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)亚氨基)-λ6-砜
Step 2: Dimethyl((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)imino)-λ 6 -sulfone
将((5-溴吡啶-2-基)氨亚基)二甲基-λ6-硫烷酮(2.0g，7.57mmol)，联硼酸频那醇酯(2.11g，8.33mmol)和醋酸钾(2.23g，22.7mmol)溶于1,4-二氧六环(40mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(554mg，757μmol)，反应液在85℃反应3小时。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用反相制备色谱(0.1％盐酸为流动相)纯化，得到化合物二甲基((5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)亚氨基)-λ6-砜(400mg)。Dissolve ((5-bromopyridin-2-yl)aminoylidene)dimethyl- λ 6 -sulfanone (2.0 g, 7.57 mmol), biboronic acid pinacol ester (2.11 g, 8.33 mmol) and potassium acetate (2.23 g, 22.7 mmol) in 1,4-dioxane (40 mL), replace with nitrogen three times, add 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (II) (554 mg, 757 μmol), and react at 85° C. for 3 hours. After the reaction is completed, cool to room temperature, dilute with water (30 mL), extract three times with ethyl acetate (120 mL), combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product was purified by reverse phase preparative chromatography (0.1% hydrochloric acid as mobile phase) to give dimethyl((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)imino)-λ 6 -sulfone (400 mg).
LC-MS,M/Z(ESI):297.1[M+H]+。LC-MS, M/Z (ESI): 297.1 [M+H] + .
第三步：6'-((二甲基(氧亚基)-λ6-硫烷亚基)氨基)-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)-[2,3'-联吡啶]-5-甲腈
Step 3: 6'-((dimethyl(oxy)-λ 6 -sulfaneylidene)amino)-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile
将二甲基((5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)亚氨基)-λ6-砜(400mg,675μmol)，5-氰基-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)吡啶-2-基三氟甲磺酸(291mg，675μmol)和碳酸钠(143mg，1.35mmol)溶于1,4-二氧六环(30mL)和水(6mL)中，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(55.1mg,67.5umol)，100℃反应3小时。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(30mL)萃取三次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗品用硅胶柱分离纯化(乙酸乙酯:甲醇(V/V)＝1:0-10:1)得到化合物6'-((二甲基(氧亚基)-λ6-硫烷亚基)氨基)-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)-[2,3'-联吡啶]-5-甲腈(300mg,收率98.6％)。Dimethyl((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)imino)-λ 6 -sulfone (400 mg, 675 μmol), 5-cyano-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)pyridin-2-yltrifluoromethanesulfonic acid (291 mg, 675 μmol) and sodium carbonate (143 mg, 1.35 mmol) were dissolved in 1,4-dioxane (30 mL) and water (6 mL), and the atmosphere was replaced with nitrogen three times. 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (55.1 mg, 67.5 umol) was added and reacted at 100° C. for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (30 mL), extracted three times with ethyl acetate (30 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (ethyl acetate: methanol (V/V) = 1:0-10:1) to obtain compound 6'-((dimethyl(oxyylidene)-λ 6 -sulfaneylidene)amino)-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile (300 mg, yield 98.6%).
LC-MS,M/Z(ESI):451.2[M+H]+。LC-MS, M/Z (ESI): 451.2 [M+H] + .
第四步：6'-((二甲基(氧亚基)-λ6-硫烷亚基)氨基)-4-异丙基-6-((((2-甲氧基乙基)亚磺酰基)甲基)硫代)-[2,3'-联吡啶]-5-甲腈
Step 4: 6'-((dimethyl(oxy)-λ 6 -sulfaneylidene)amino)-4-isopropyl-6-((((2-methoxyethyl)sulfinyl)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile
将6'-((二甲基(氧亚基)-λ6-硫烷亚基)氨基)-4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)-[2,3'-联吡啶]-5-甲腈(300mg，666μmol)溶于氯仿(3mL)和醋酸(0.3mL)，加入双氧水(113mg,998μmol，95.9μL，30％纯度)，在30℃反应1小时。反应结束后，用水(10mL)稀释，加入饱和亚硫酸钠溶液(10mL) 淬灭，饱和碳酸氢钠(3mL)中和，用二氯甲烷(20mL×3)萃取，合并有机相，依次用饱和亚硫酸钠溶液(20mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物6'-((二甲基(氧亚基)-λ6-硫烷亚基)氨基)-4-异丙基-6-((((2-甲氧基乙基)亚磺酰基)甲基)硫代)-[2,3'-联吡啶]-5-甲腈(220mg，收率70.8％)。6'-((dimethyl(oxyylidene)-λ 6 -sulfaneylidene)amino)-4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile (300 mg, 666 μmol) was dissolved in chloroform (3 mL) and acetic acid (0.3 mL), and hydrogen peroxide (113 mg, 998 μmol, 95.9 μL, 30% purity) was added, and the mixture was reacted at 30°C for 1 hour. After the reaction was completed, the mixture was diluted with water (10 mL) and a saturated sodium sulfite solution (10 mL) was added. The reaction mixture was quenched and neutralized with saturated sodium bicarbonate (3 mL), extracted with dichloromethane (20 mL×3), and the organic phases were combined and washed with saturated sodium sulfite solution (20 mL) and saturated brine (20 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 6'-((dimethyl(oxyylidene)-λ 6 -sulfaneylidene)amino)-4-isopropyl-6-((((2-methoxyethyl)sulfinyl)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile (220 mg, yield 70.8%).
LC-MS,M/Z(ESI):467.2[M+H]+。LC-MS, M/Z (ESI): 467.2 [M+H] + .
第五步：((5-(3-氨基-4-异丙基-2-((2-甲氧基乙基)亚磺酰基)噻吩并[2,3-b]吡啶-6-基)吡啶-2-基)亚氨基)二甲基-λ6-砜
Step 5: ((5-(3-amino-4-isopropyl-2-((2-methoxyethyl)sulfinyl)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)imino)dimethyl-λ 6 -sulfone
将6'-((二甲基(氧亚基)-λ6-硫烷亚基)氨基)-4-异丙基-6-((((2-甲氧基乙基)亚磺酰基)甲基)硫代)-[2,3'-联吡啶]-5-甲腈(200mg，429μmol)溶于N,N-二甲基甲酰胺(5mL)和甲醇(2mL)中，加入氢氧化钾(14.9mg，266μmol)的水溶液(150μL)，在30℃反应10分钟。反应结束后，用水(20mL)和乙酸乙酯(20mL)稀释，用1N稀盐酸(1mL)中和，乙酸乙酯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过反相高效液相色谱法进行分离，分离方法为(柱子：Phenomenex C18 75*30mm*3μm；溶剂：A＝水+0.5体积％甲酸(99％)，B＝乙腈；梯度：10％-40％，总共洗脱7分钟)，得到化合物((5-(3-氨基-4-异丙基-2-((2-甲氧基乙基)亚磺酰基)噻吩并[2,3-b]吡啶-6-基)吡啶-2-基)亚氨基)二甲基-λ6-砜(化合物3)(100mg,产率47.5％)。6'-((dimethyl(oxyylidene)-λ 6 -sulfaneylidene)amino)-4-isopropyl-6-((((2-methoxyethyl)sulfinyl)methyl)thio)-[2,3'-bipyridine]-5-carbonitrile (200 mg, 429 μmol) was dissolved in N,N-dimethylformamide (5 mL) and methanol (2 mL), and an aqueous solution (150 μL) of potassium hydroxide (14.9 mg, 266 μmol) was added, and the mixture was reacted at 30°C for 10 minutes. After the reaction was completed, the mixture was diluted with water (20 mL) and ethyl acetate (20 mL), neutralized with 1N dilute hydrochloric acid (1 mL), extracted with ethyl acetate (20 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by reverse phase high performance liquid chromatography (column: Phenomenex C 18 75*30mm*3μm; solvent: A=water+0.5 volume% formic acid (99%), B=acetonitrile; gradient: 10%-40%, total elution time 7 minutes) to obtain compound ((5-(3-amino-4-isopropyl-2-((2-methoxyethyl)sulfinyl)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)imino)dimethyl- λ 6 -sulfone (compound 3) (100 mg, yield 47.5%).
所得产物经SFC拆分(色谱柱:Chiralcel OD-3 50×4.6mm I.D.,3μm，流动相A：CO2，流动相B：IPA(0.05体积％DEA)，等度洗脱:40体积％IPA(0.05体积％DEA)在CO2中；等度洗脱:40体积％IPA(0.05体积％DEA)在CO2中；流速:3mL/min；检测器：PDA，柱温:35℃；柱压:100Bar)。得两个异构体，化合物3-1(RT＝1.327min)和化合物3-2(RT＝1.731min).
The obtained product was separated by SFC (chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm, mobile phase A: CO 2 , mobile phase B: IPA (0.05 vol% DEA), isocratic elution: 40 vol% IPA (0.05 vol% DEA) in CO 2 ; isocratic elution: 40 vol% IPA (0.05 vol% DEA) in CO 2 ; flow rate: 3mL/min; detector: PDA, column temperature: 35°C; column pressure: 100Bar). Two isomers were obtained, compound 3-1 (RT=1.327min) and compound 3-2 (RT=1.731min).
LC-MS,M/Z(ESI):467.1[M+H]+。LC-MS, M/Z (ESI): 467.1 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ＝8.93(d,1H),8.30-8.33(m,1H),7.79(s,1H),6.76(d,1H),5.69(d,2H),3.85-3.91(m,1H),3.72-3.74(m,1H),3.59-3.62(m,1H),3.43(s,6H),3.38-3.40(m,1H),3.32(s,3H),3.20-3.28(m,1H),1.34-1.38(m,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ＝8.93 (d, 1H), 8.30-8.33 (m, 1H), 7.79 (s, 1H), 6.76 (d, 1H), 5.69 (d, 2H), 3.85-3.91 (m, 1H), 3.72-3.74 (m, 1H), 3.59-3.62 (m, 1H), 3.43 (s, 6H), 3.38-3.40 (m, 1H), 3.32 (s, 3H), 3.20-3.28 (m, 1H), 1.34-1.38 (m, 6H).
实施例4：1-(5-(3-氨基-4-异丙基-2-((2-甲氧基乙基)亚砜基)噻吩并[2,3-b]吡啶-6-基)吡啶-2-基)-4,5-二氢-3H-异噻唑1-氧化物(化合物4)的制备 Example 4: Preparation of 1-(5-(3-amino-4-isopropyl-2-((2-methoxyethyl)sulfoxide)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)-4,5-dihydro-3H-isothiazole 1-oxide (Compound 4)
目标化合物4的合成路线如下：
The synthetic route of target compound 4 is as follows:
第一步：5-溴-2-((3-氯丙基)硫代)吡啶
Step 1: 5-Bromo-2-((3-chloropropyl)thio)pyridine
氮气保护下，将5-溴吡啶-2-硫醇(5.0g，26.31mmol)和甲醇钠(2.13g，39.46mmol)溶于甲醇(50mL)中，向其中加入1-溴-3-氯丙烷(8.28g，52.62mmol)室温下搅拌18h。反应结束后，用水(50mL)稀释，用乙酸乙酯(50mL)萃取三次，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品经过柱层析(PE/EA＝5/1)，得到化合物5-溴-2-((3-氯丙基)硫代)吡啶(5.22g，收率74％)。Under nitrogen protection, 5-bromopyridine-2-thiol (5.0g, 26.31mmol) and sodium methoxide (2.13g, 39.46mmol) were dissolved in methanol (50mL), 1-bromo-3-chloropropane (8.28g, 52.62mmol) was added thereto and stirred at room temperature for 18h. After the reaction was completed, it was diluted with water (50mL), extracted three times with ethyl acetate (50mL), the organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (PE/EA=5/1) to obtain compound 5-bromo-2-((3-chloropropyl)thio)pyridine (5.22g, yield 74%).
LC-MS,M/Z(ESI):266.2[M+H]+。LC-MS, M/Z (ESI): 266.2 [M+H] + .
第二步：(5-溴吡啶2-基)(3-氯丙基)(亚氨基)-λ6-砜
Step 2: (5-bromopyridin-2-yl)(3-chloropropyl)(imino)-λ 6 -sulfone
将5-溴-2-((3-氯丙基)硫代)吡啶(5.0g，18.76mmol)和碘苯二乙酸(15.1g，46.89mmol)溶于甲醇(50mL)中，向其中加入氨基甲酸铵(3.66g，46.89mmol)室温下搅拌18h。反应结束后，用水(50mL)稀释，用乙酸乙酯(50mL)萃取三次，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品经过柱层析(PE/EA＝1/2)，得到化合物(5-溴吡啶2-基)(3-氯丙基)(亚氨基)-λ6-砜(3.2g,收率57％)。5-bromo-2-((3-chloropropyl)thio)pyridine (5.0g, 18.76mmol) and iodophenyl diacetic acid (15.1g, 46.89mmol) were dissolved in methanol (50mL), and ammonium carbamate (3.66g, 46.89mmol) was added thereto and stirred at room temperature for 18h. After the reaction was completed, it was diluted with water (50mL), extracted three times with ethyl acetate (50mL), the organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (PE/EA=1/2) to obtain compound (5-bromopyridin-2-yl)(3-chloropropyl)(imino)-λ 6 -sulfone (3.2g, yield 57%).
LC-MS,M/Z(ESI):297.2[M+H]+。LC-MS, M/Z (ESI): 297.2 [M+H] + .
第三步：1-(5-溴吡啶-2-基)-4,5-二氢-3H-异噻唑1-氧化物
Step 3: 1-(5-bromopyridin-2-yl)-4,5-dihydro-3H-isothiazole 1-oxide
将(5-溴吡啶2-基)(3-氯丙基)(亚氨基)-λ6-砜(3.0g,10.08mmol)溶于二甲基亚砜(20mL)中,向其中加入浓氨水(1mL)，50℃下搅拌18h。反应结束后，用水(50mL)稀释，用乙酸乙酯(50mL)萃取三次，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品经过硅胶柱层析(PE/EA＝1/5)，得到化合物1-(5-溴吡啶-2-基)-4,5-二氢-3H-异噻唑1-氧化物(1.88g，收率71％)。Dissolve (5-bromopyridin-2-yl)(3-chloropropyl)(imino)-λ 6 -sulfone (3.0 g, 10.08 mmol) in dimethyl sulfoxide (20 mL), add concentrated aqueous ammonia (1 mL), and stir at 50°C for 18 h. After the reaction is completed, dilute with water (50 mL), extract three times with ethyl acetate (50 mL), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product is subjected to silica gel column chromatography (PE/EA=1/5) to obtain compound 1-(5-bromopyridin-2-yl)-4,5-dihydro-3H-isothiazole 1-oxide (1.88 g, yield 71%).
第四步：1-(5-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶-2-基)-4,5-二氢-3H-异噻唑1-氧化物
Step 4: 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-4,5-dihydro-3H-isothiazole 1-oxide
将1-(5-溴吡啶-2-基)-4,5-二氢-3H-异噻唑1-氧化物(1.50g，5.74mmol)，联硼酸频哪醇酯(2.92g，11.49mmol)，醋酸钾(1.69g，17.23mmol)溶于1,4-二氧六环(20mL)，加入1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(470mg，0.57mmol)，反应液在90℃反应16h。反应结束后，冷却至室温，向体系中加入水(50mL)，用乙酸乙酯(50mL)萃取三次，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过硅胶柱层析，DCM/MeOH(v/v)＝10/1,得到1-(5-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶-2-基)-4,5-二氢-3H-异噻唑1-氧化物(510mg，收率39％)。1-(5-bromopyridin-2-yl)-4,5-dihydro-3H-isothiazole 1-oxide (1.50 g, 5.74 mmol), biboronic acid pinacol ester (2.92 g, 11.49 mmol), potassium acetate (1.69 g, 17.23 mmol) were dissolved in 1,4-dioxane (20 mL), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) dichloromethane complex (470 mg, 0.57 mmol) was added, and the reaction solution was reacted at 90 ° C for 16 h. After the reaction was completed, it was cooled to room temperature, water (50 mL) was added to the system, and it was extracted three times with ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography with DCM/MeOH (v/v) = 10/1 to give 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-4,5-dihydro-3H-isothiazole 1-oxide (510 mg, yield 39%).
LC-MS,M/Z(ESI):309.1[M+H]+。LC-MS, M/Z (ESI): 309.1 [M+H] + .
第五步：4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)-6'-(1-氧化-4,5-二氢-3H-1λ6-异噻唑-1-基)-[2,3'-联吡啶]-5-甲腈
Step 5: 4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-6'-(1-oxido-4,5-dihydro-3H-1λ 6 -isothiazol-1-yl)-[2,3'-bipyridine]-5-carbonitrile
将1-(5-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)吡啶-2-基)-4,5-二氢-3H-异噻唑1-氧化物(200mg，0.89mmol)，5-氰基-4-异丙基-6-((((2-2-甲氧亚乙基硫代)甲基)硫代)吡啶-2-基三氟甲磺酸酯(381mg，0.89mmol)，碳酸钠(188mg，1.77mmol)溶于1,4-二氧六环(20mL)和水(2mL)中，加入1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(82mg，0.10mmol)，反应液在90℃反应16h。反应结束后，冷却至室温，向体系中加入水(50mL)，用乙酸乙酯(50mL)萃取三次，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过硅胶柱层析，DCM/MeOH(v/v)＝15/1,得到4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)-6'-(1-氧化-4,5-二氢-3H-1λ6-异噻唑-1-基)-[2,3'-联吡啶]-5-甲腈(150mg，收率37％)。1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-4,5-dihydro-3H-isothiazole 1-oxide (200 mg, 0.89 mmol), 5-cyano-4-isopropyl-6-((((2-2-methoxyethylidenethio)methyl)thio)pyridin-2-yl trifluoromethanesulfonate (381 mg, 0.89 mmol), and sodium carbonate (188 mg, 1.77 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL), and 1,1'-bis(diphenylphosphino)ferrocene dichloride was added. Palladium (II) dichloromethane complex (82 mg, 0.10 mmol), the reaction solution was reacted at 90 ° C for 16 h. After the reaction was completed, it was cooled to room temperature, water (50 mL) was added to the system, and it was extracted three times with ethyl acetate (50 mL), the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was chromatographed on a silica gel column, DCM/MeOH (v/v) = 15/1 to obtain 4-isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-6'-(1-oxidized-4,5-dihydro-3H-1λ 6 -isothiazol-1-yl)-[2,3'-bipyridine]-5-carbonitrile (150 mg, yield 37%).
LC-MS,M/Z(ESI):463.2[M+H]+。LC-MS, M/Z (ESI): 463.2 [M+H] + .
第六步：4-异丙基-6-((((2-甲氧基乙基)亚砜)甲基)硫代)-6'-(1-氧化物-4,5-二氢-3H-1λ6-异噻唑-1- 基)-[2,3'-二吡啶]-5-甲腈
Step 6: 4-isopropyl-6-((((2-methoxyethyl)sulfoxide)methyl)thio)-6'-(1-oxide-4,5-dihydro-3H-1λ 6 -isothiazole-1- 2,3'-Bipyridine-5-carbonitrile
将4-异丙基-6-((((2-甲氧基乙基)硫代)甲基)硫代)-6'-(1-氧化-4,5-二氢-3H-1λ6-异噻唑-1-基)-[2,3'-联吡啶]-5-甲腈(150mg，324μmol)溶于氯仿(10mL)和醋酸(1mL)，加入双氧水(55mg，0.49mmol，30％纯度)，在30℃反应1小时。反应结束后，用水(10mL)稀释，加入饱和亚硫酸钠溶液(10mL)淬灭，饱和碳酸氢钠(3mL)中和，用二氯甲烷(20mL×3)萃取，合并有机相，依次用饱和亚硫酸钠溶液(20mL)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗产品，粗产品通过硅胶柱层析，DCM/MeOH(v/v)＝10/1,得到目标化合物4-异丙基-6-((((2-甲氧基乙基)亚砜)甲基)硫代)-6'-(1-氧化物-4,5-二氢-3H-1λ6-异噻唑-1-基)-[2,3'-二吡啶]-5-甲腈(120mg，收率77％)。4-Isopropyl-6-((((2-methoxyethyl)thio)methyl)thio)-6'-(1-oxido-4,5-dihydro-3H-1λ 6 -isothiazol-1-yl)-[2,3'-bipyridine]-5-carbonitrile (150 mg, 324 μmol) was dissolved in chloroform (10 mL) and acetic acid (1 mL), and hydrogen peroxide (55 mg, 0.49 mmol, 30% purity) was added and reacted at 30° C. for 1 hour. After the reaction, the mixture was diluted with water (10 mL), quenched with saturated sodium sulfite solution (10 mL), neutralized with saturated sodium bicarbonate (3 mL), extracted with dichloromethane (20 mL×3), and the organic phases were combined, washed with saturated sodium sulfite solution (20 mL) and saturated brine (20 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography with DCM/MeOH (v/v) = 10/1 to give the target compound 4-isopropyl-6-((((2-methoxyethyl)sulfoxide)methyl)thio)-6'-(1-oxide-4,5-dihydro-3H-1λ 6 -isothiazol-1-yl)-[2,3'-bipyridine]-5-carbonitrile (120 mg, yield 77%).
LC-MS,M/Z(ESI):479.1[M+H]+。LC-MS, M/Z (ESI): 479.1 [M+H] + .
第七步：1-(5-(3-氨基-4-异丙基-2-((2-甲氧基乙基)亚砜基)噻吩并[2,3-b]吡啶-6-基)吡啶-2-基)-4,5-二氢-3H-异噻唑1-氧化物
Step 7: 1-(5-(3-amino-4-isopropyl-2-((2-methoxyethyl)sulfoxide)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)-4,5-dihydro-3H-isothiazole 1-oxide
将4-异丙基-6-((((2-甲氧基乙基)亚砜)甲基)硫代)-6'-(1-氧化物-4,5-二氢-3H-1λ6-异噻唑-1-基)-[2,3'-二吡啶]-5-甲腈(120mg,251μmol)溶于N,N-二甲基甲酰胺(5mL)和甲醇(3mL)，加入氢氧化钾(14mg，251umol)的水溶液(150μL)，在30℃反应10分钟。反应结束后，用水(20mL)和乙酸乙酯(20mL)稀释，用1N稀盐酸(1mL)中和，乙酸乙酯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过柱层析，DCM/MeOH(v/v)＝10/1，得到化合物1-(5-(3-氨基-4-异丙基-2-((2-甲氧基乙基)亚砜基)噻吩并[2,3-b]吡啶-6-基)吡啶-2-基)-4,5-二氢-3H-异噻唑1-氧化物(化合物4)(12mg，产率10％)。4-Isopropyl-6-((((2-methoxyethyl)sulfoxide)methyl)thio)-6'-(1-oxide-4,5-dihydro-3H-1λ 6 -isothiazol-1-yl)-[2,3'-bipyridine]-5-carbonitrile (120 mg, 251 μmol) was dissolved in N,N-dimethylformamide (5 mL) and methanol (3 mL), and an aqueous solution (150 μL) of potassium hydroxide (14 mg, 251 μmol) was added, and the mixture was reacted at 30°C for 10 minutes. After the reaction was completed, the mixture was diluted with water (20 mL) and ethyl acetate (20 mL), neutralized with 1N dilute hydrochloric acid (1 mL), extracted with ethyl acetate (20 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography with DCM/MeOH (v/v) = 10/1 to give compound 1-(5-(3-amino-4-isopropyl-2-((2-methoxyethyl)sulfoxide)thieno[2,3-b]pyridin-6-yl)pyridin-2-yl)-4,5-dihydro-3H-isothiazole 1-oxide (Compound 4) (12 mg, 10% yield).
LC-MS,M/Z(ESI):479.1[M+H]+。LC-MS, M/Z (ESI): 479.1 [M+H] + .
1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.59(d,1H),8.30(d,1H),7.66(s,1H),5.11(s,2H),4.19–4.11(m,1H),4.00–3.77(m,4H),3.75–3.60(m,2H),3.42(s,3H),3.30(ddd,2H),2.53–2.42(m,2H),1.49(dd,6H). 1 H NMR (400 MHz, CDCl 3 ) δ9.32 (s, 1H), 8.59 (d, 1H), 8.30 (d, 1H), 7.66 (s, 1H), 5.11 (s, 2H), 4.19–4.11 (m, 1H), 4.00–3.77 (m, 4H), 3.75–3.60 (m, 2H), 3.42 (s, 3H), 3.30 (ddd, 2H), 2.53–2.42 (m, 2H), 1.49 (dd, 6H).
测试例1：化合物对15-PGDH酶抑制试验Test Example 1: Compound Inhibition Test on 15-PGDH Enzyme
用Assay Buffer(50mM Tris-HCl，pH 7.5，0.01体积％Tween 20)将15-PGDH(R&D Systems，货号 5660-DH-010)配置成终浓度的2倍，即30nM。然后按照8μL/孔，加入到384白板中(Cisbio Bioassays，货号66PL384025)。设定阴性对照孔，不加酶只加Assay Buffer。然后用Assay Buffer将化合物配置成终浓度的4倍，即4000nM起始，3倍稀释，10个浓度。按照4μl/孔加入上述的白板中，混匀后，1000rpm离心1min，25℃孵育10min。同时设定阳性对照孔(只加15-PGDH)和阴性对照孔(不加15-PGDH)。再用Assay Buffer配置NAD+(Sellect.货号S2518)和PGE2(R&D Systems，货号2296/10)的混合液。用Assay Buffer分别将NAD+和PGE2配置成终浓度的4倍，即2mM和0.12mM。然后按照4μL/孔加入到上述的白板中，混匀后，1000rpm离心1min，25℃孵育30min进行反应。采用仪器TECAN SPARK 20M在激发波长为340nm，发射波长为485nm处检测。用GraphPad Prism 8.0进行四参数拟合计算IC50值。15-PGDH (R&D Systems, Cat. No. 5660-DH-010) to 2 times the final concentration, i.e. 30nM. Then add it to a 384 white plate (Cisbio Bioassays, Cat. No. 66PL384025) at 8μL/well. Set up a negative control well, add only Assay Buffer without enzyme. Then use Assay Buffer to prepare the compound to 4 times the final concentration, i.e. 4000nM starting, 3-fold dilution, 10 concentrations. Add it to the above white plate at 4μl/well, mix well, centrifuge at 1000rpm for 1min, and incubate at 25℃ for 10min. At the same time, set up a positive control well (only 15-PGDH) and a negative control well (without 15-PGDH). Then use Assay Buffer to prepare a mixture of NAD + (Sellect. Cat. No. S2518) and PGE 2 (R&D Systems, Cat. No. 2296/10). NAD + and PGE 2 were prepared into 4 times of the final concentration, i.e. 2mM and 0.12mM, respectively, using Assay Buffer. Then, 4μL/well was added to the above white plate, mixed, centrifuged at 1000rpm for 1min, and incubated at 25℃ for 30min for reaction. The instrument TECAN SPARK 20M was used for detection at an excitation wavelength of 340nm and an emission wavelength of 485nm. GraphPad Prism 8.0 was used for four-parameter fitting to calculate the IC 50 value.
表1.化合物对15‐PGDH抑制试验结果
Table 1. Results of the 15-PGDH inhibition test of compounds
实验结果表明，本发明化合物对15‐PGDH具有显著的抑制作用。The experimental results show that the compounds of the present invention have a significant inhibitory effect on 15-PGDH.
测试例2：化合物对A549细胞上清中PGE2水平的影响Test Example 2: Effect of Compounds on PGE2 Levels in A549 Cell Supernatant
A549细胞(武汉普诺赛)在F12K+10％FBS进行培养，取对数期的细胞状态良好的细胞进行实验，将细胞消化、计数，将细胞接种到24孔板，8000个/孔。将细胞置37℃，5％CO2培养箱进行培养过夜。待细胞贴壁后，换含0.5％FBS的培养基处理约10h，向各孔添加IL-1β(终浓度20ng/mL，1mL/孔)，同时设置对照组(对照组不添加IL-1β)。IL-1β刺激约24h后，吸弃各孔细胞培养液，并用新鲜含0.5％FBS培养基轻轻清洗各孔，然后向各孔添加含各浓度的化合物(20nM和2500nM)的培养基400μL处理约12h。收集上清，采用ELISA试剂盒(R&D Systems，货号KGE004B)检测PGE2。A549 cells (Wuhan Punosai) were cultured in F12K + 10% FBS. Cells in good logarithmic phase were used for experiments. The cells were digested and counted, and the cells were inoculated into 24-well plates, 8000 cells/well. The cells were placed in a 37°C, 5% CO2 incubator for overnight culture. After the cells adhered to the wall, the medium containing 0.5% FBS was changed to treat for about 10 hours, and IL-1β (final concentration 20ng/mL, 1mL/well) was added to each well, and a control group was set up at the same time (the control group did not add IL-1β). After IL-1β stimulation for about 24 hours, the cell culture fluid in each well was aspirated and discarded, and each well was gently washed with fresh medium containing 0.5% FBS, and then 400μL of medium containing compounds of various concentrations (20nM and 2500nM) was added to each well for about 12 hours. The supernatant was collected and PGE2 was detected using an ELISA kit (R&D Systems, Cat. No. KGE004B).
表2.化合物对A549细胞上清中PGE2增加倍数
Table 2. Compounds increase PGE2 in A549 cell supernatant by multiple times
实验结果表明，本发明化合物可以显著增加PGE2的生成。The experimental results show that the compounds of the present invention can significantly increase the generation of PGE2 .
测试例3：小鼠IPF预防模型药效实验Test Example 3: Efficacy experiment on IPF prevention model in mice
雄性小鼠适应性饲养1-2周，并体重达标后(25g)，以一定剂量的博来霉素诱导IPF模型(特发性肺纤维化模型)，造模当天根据动物体重随机分为模型组和给药组，并开始每天口服灌胃给药，溶媒对照组给予空白溶媒，连续给药21天。给药期间，每3天称量一次体重。在最后一天给药结束对动物进行安乐死，自甲状软骨开始取下肺脏(无需灌注)，向肺内缓慢灌注10％福尔马林至双侧肺脏充盈， 结扎主气管后置于5-10倍组织体积的10％福尔马林中固定，对左肺进行石蜡组织切片制作、HE染色、Masson Trichrome染色，使用Hamamatsu NanoZoomer Digital Pathology(S210)切片扫描仪进行切片全景扫描，进行病理分析。Male mice were adaptively fed for 1-2 weeks and after reaching the target body weight (25g), an IPF model (idiopathic pulmonary fibrosis model) was induced with a certain dose of bleomycin. On the day of modeling, the mice were randomly divided into a model group and a treatment group according to their body weight, and oral gavage was started every day. The vehicle control group was given a blank vehicle for 21 consecutive days. During the drug administration period, the body weight was measured every 3 days. At the end of the last day of drug administration, the animals were euthanized, the lungs were removed from the thyroid cartilage (no perfusion was required), and 10% formalin was slowly perfused into the lungs until both lungs were filled. After ligation of the main trachea, the lungs were fixed in 10% formalin at 5-10 times the tissue volume. Paraffin tissue sections were prepared for the left lung, and HE and Masson Trichrome staining were performed. The sections were scanned panoramically using a Hamamatsu NanoZoomer Digital Pathology (S210) slice scanner for pathological analysis.
表3.肺纤维化病理评价指标
Table 3. Pathological evaluation indexes of pulmonary fibrosis
实验结果显示，本发明的化合物可以显著降低小鼠IPF预防模型的纤维化程度。The experimental results show that the compounds of the present invention can significantly reduce the degree of fibrosis in the IPF prevention model of mice.
测试例4：小鼠IPF治疗模型药效实验Test Example 4: Efficacy experiment on mouse IPF treatment model
雄性小鼠适应性饲养1-2周，并体重达标后(25g)，以一定剂量的博来霉素诱导IPF模型(特发性肺纤维化模型)，造模当天根据动物体重随机分为模型组和给药组，Day7开始每天口服灌胃给药，溶媒对照组给予空白溶媒，连续给药14天。给药期间，每周称量2次体重。在最后一天给药结束对动物进行安乐死，自甲状软骨开始取下肺脏(无需灌注)，向肺内缓慢灌注10％福尔马林至双侧肺脏充盈， 结扎主气管后置于5-10倍组织体积的10％福尔马林中固定，对左肺进行石蜡组织切片制作、HE染色、Masson Trichrome染色，使用Hamamatsu NanoZoomer Digital Pathology(S210)切片扫描仪进行切片全景扫描，进行病理分析。Male mice were adaptively fed for 1-2 weeks and after reaching the target body weight (25g), an IPF model (idiopathic pulmonary fibrosis model) was induced with a certain dose of bleomycin. On the day of modeling, the mice were randomly divided into a model group and a treatment group according to their body weight. Oral gavage was performed daily starting from Day 7, and the vehicle control group was given a blank vehicle for 14 consecutive days. During the drug administration period, the body weight was measured twice a week. At the end of the last day of drug administration, the animals were euthanized, the lungs were removed from the thyroid cartilage (no perfusion was required), and 10% formalin was slowly perfused into the lungs until both lungs were filled. After ligation of the main trachea, the lungs were fixed in 10% formalin at 5-10 times the tissue volume. Paraffin tissue sections were prepared for the left lung, and HE and Masson Trichrome staining were performed. The sections were scanned panoramically using a Hamamatsu NanoZoomer Digital Pathology (S210) slice scanner for pathological analysis.
表4.肺纤维化病理评价指标
Table 4. Pathological evaluation indexes of pulmonary fibrosis
实验结果显示，本发明的化合物可以显著降低小鼠IPF治疗模型的纤维化程度。The experimental results show that the compounds of the present invention can significantly reduce the degree of fibrosis in the IPF treatment model of mice.
测试例5：小鼠肝切除再生药效实验Test Example 5: Mouse liver resection and regeneration efficacy experiment
8周龄雄性C57BL/6J小鼠(20-24g)，动物麻醉，腹部朝上固定，手术部位剃毛并碘伏消毒；腹部横切开口约1.5-2cm，以止血夹夹住两侧的腹壁动脉；打开腹腔后将各肝叶游离，以手术线结扎需要切除的肝叶的肝门部，在其颜色变深后行肝脏左外叶及中叶切除；术后清理完腹腔残留血液后逐层缝合肌层以及皮毛层；注意术后护理。造模当天开始给药，分别在给药1天和3天各处死动物，取完整 肝组织称重，与模型组进行对比，评估药物促进肝再生的作用。8-week-old male C57BL/6J mice (20-24g) were anesthetized and fixed with the abdomen facing upward. The surgical site was shaved and disinfected with iodine. The abdominal transverse incision was about 1.5-2cm, and the abdominal wall arteries on both sides were clamped with hemostatic clips. After opening the abdominal cavity, each liver lobe was freed, and the hilum of the liver lobe to be removed was ligated with surgical thread. After the color of the liver lobe turned darker, the left lateral lobe and middle lobe of the liver were removed. After the residual blood in the abdominal cavity was cleaned up, the muscle layer and the fur layer were sutured layer by layer. Pay attention to postoperative care. Drug administration began on the day of modeling, and the animals were killed on the 1st and 3rd day of drug administration, and the intact The liver tissue was weighed and compared with the model group to evaluate the effect of the drug in promoting liver regeneration.
实验结果显示，本发明的化合物可以显著的促进肝再生。The experimental results show that the compounds of the present invention can significantly promote liver regeneration.
测试例6：小鼠药代动力学Test Example 6: Pharmacokinetics in mice
参照下述实验方法测定本发明化合物的小鼠药代动力学性质。The pharmacokinetic properties of the compounds of the present invention in mice were determined according to the following experimental methods.
采用雄性CD-1小鼠，剂量为10mg/kg，给药途径为灌胃，溶媒为5％DMSO+10％Solutol+85％Saline，禁食过夜，采血时间点为给药前和在给药后15、30分钟以及1、2、4、6、8、24小时。血液样品6800g2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆10μL加入200μL含100ng/mL内标的甲醇，涡旋混匀后2-8℃18000g离心7分钟。取200μL转移至96孔进样板中，进行LC-MS/MS定量分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。Male CD-1 mice were used, with a dose of 10 mg/kg, and the administration route was oral gavage. The solvent was 5% DMSO + 10% Solutol + 85% Saline. The mice were fasted overnight, and blood was collected before administration and 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration. The blood samples were centrifuged at 6800g2-8℃ for 6 minutes, and the plasma was collected and stored at -80℃. 10μL of plasma at each time point was added to 200μL of methanol containing 100ng/mL internal standard, vortexed and mixed, and centrifuged at 18000g for 7 minutes at 2-8℃. 200μL was transferred to a 96-well sample plate for LC-MS/MS quantitative analysis. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
表5.小鼠药代动力学数据
Table 5. Mouse pharmacokinetic data
实验结果表明，本发明化合物在小鼠体内表现出优良的药代动力学性质。The experimental results show that the compound of the present invention exhibits excellent pharmacokinetic properties in mice.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。 Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims (25)

  1. 一种如式I所示杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药：
    A heterocyclic compound as shown in Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof:
    其中，in,
    Ra为H、卤素、羟基、氨基、硝基、氰基、羰基、氧代、羧基、C1-C6烷基、-NH(C1-C6烷基)、C1-C6氘代烷基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、芳基、3-11元杂环烷基或5-11元杂芳基；其中所述C1-C6烷基、C3-C8环烷基、芳基、3-11元杂环烷基和所述5-11元杂芳基各自任选地被R1-1取代；当所述Ra为多个取代基时，所述的取代基相同或不同； Ra is H, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1 - C6 alkyl, -NH( C1 - C6 alkyl), C1 - C6 deuterated alkyl, C2 - C6 alkynyl, halogenated C1 - C6 alkyl, hydroxyC1 - C6 alkyl, C1 -C6 alkylcarbonyl, C1 - C6 alkoxy, halogenated C1 - C6 alkoxy, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), aryl, 3-11 membered heterocycloalkyl or 5-11 membered heteroaryl; wherein said C1 - C6 alkyl, C3 - C8 cycloalkyl, aryl, 3-11 membered heterocycloalkyl and said 5-11 membered heteroaryl are each optionally substituted by R1-1 ; when said Ra is a plurality of substituents, said substituents are the same or different;
    R1为C1-C6烷基、C1-C6氘代烷基、卤代C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、C1-C6烷氧基、-(C1-C6亚烷基)-(C1-C6烷氧基)、3-11元杂环烷基、或-(C1-C6亚烷基)-(3-11元杂环烷基)；并且，所述R1任选地被一个或多个R1-1取代；当取代基为多个时，所述的取代基相同或不同； R1 is C1 - C6 alkyl, C1 - C6 deuterated alkyl, halogenated C1 - C6 alkyl, C3 -C8 cycloalkyl , -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy, -( C1 - C6 alkylene)-( C1 - C6 alkoxy), 3-11-membered heterocycloalkyl, or -( C1 - C6 alkylene)-(3-11-membered heterocycloalkyl); and, said R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, said substituents are the same or different;
    每个R1-1独立地为H、卤素、羟基、硝基、氰基、羰基、氧代、羧基、-NH(C1-C6烷基)、-O-亚烷基-OH、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、氘代C1-C6烷氧基；Each R 1-1 is independently H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy;
    R2为氨基、CN、或-NHC(O)(C1-C6烷基)；R 2 is amino, CN, or -NHC(O)(C 1 -C 6 alkyl);
    R3为芳基、3-11元杂环烷基或5-11元杂芳基，其任选地被一个或多个R3-1取代；所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2；R 3 is aryl, 3-11-membered heterocycloalkyl or 5-11-membered heteroaryl, which is optionally substituted by one or more R 3-1 ; said R 3-1 is -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 ;
    每个R3-1-1独立地为H、C1-C6烷基或亚烷基-OH，其任选地被以下取代：-OH、-亚烷基-NH2、-亚烷基-N(R3-1-2)2、-亚烷基-O-亚烷基-OH、-亚烷基-O-亚烷基-NH2、-C(O)-烷基、-C(O)O-烷基、-亚烷基-COOH或-S(O)p-烷基；或可替代地，在-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2中，两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环；each R 3-1-1 is independently H, C 1 -C 6 alkyl, or alkylene-OH, which is optionally substituted by: -OH, -alkylene-NH 2 , -alkylene-N(R 3-1-2 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 , -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O) p -alkyl; or alternatively, in -S(＝O)(＝NR 3-1-1 )-R 3-1-1 or -N＝S(＝O)(R 3-1-1 ) 2 , two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocyclic ring;
    R3-1-2是H或C1-C6烷基，或者两个R3-1-2连同它们所附接的N原子一起可以形成4-7元杂环，该4-7元杂环任选地含有选自O、S(O)r、或N的另外的杂原子；R 3-1-2 is H or C 1 -C 6 alkyl, or two R 3-1-2 together with the N atom to which they are attached can form a 4-7 membered heterocyclic ring, which optionally contains an additional heteroatom selected from O, S(O) r , or N;
    X为N或CH；X is N or CH;
    m、n、p、r分别为0、1或2。m, n, p, and r are 0, 1, or 2 respectively.
  2. 如权利要求1所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述如式I所示杂环类化合物满足如下条件的一种或两种：The heterocyclic compound of formula I, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt, or its prodrug as claimed in claim 1, characterized in that the heterocyclic compound of formula I satisfies one or both of the following conditions:
    (1)Ra为异丙基；(1) Ra is isopropyl;
    (2)R3为5-11元杂芳基，其被一个或多个R3-1取代；所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或- N＝S(＝O)(R3-1-1)2；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-11元杂芳基。(2) R 3 is a 5-11 membered heteroaryl group, which is substituted by one or more R 3-1 ; said R 3-1 is -S(=O)(=NR 3-1-1 )-R 3-1-1 or - N=S(=O)(R 3-1-1 ) 2 ; the 5- to 11-membered heteroaryl group is a 5- to 11-membered heteroaryl group having 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, and having 1, 2 or 3 heteroatoms.
  3. 如权利要求2所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，The heterocyclic compound of formula I, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt, or its prodrug as claimed in claim 2, characterized in that:
    Ra为H、卤素、羟基、氨基、硝基、氰基、羰基、氧代、羧基、C1-C6烷基、-NH(C1-C6烷基)、C1-C6氘代烷基、C2-C6炔基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、芳基、3-11元杂环烷基或5-11元杂芳基；其中所述C1-C6烷基、C3-C8环烷基、芳基、3-11元杂环烷基和所述5-11元杂芳基各自任选地被R1-1取代；当所述Ra为多个取代基时，所述的取代基相同或不同；所述芳基为C6-C10芳基；所述3-11元杂环烷基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-11元杂环烷基；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-11元杂芳基； Ra is H, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1 - C6 alkyl, -NH( C1 - C6 alkyl), C1 - C6 deuterated alkyl, C2 - C6 alkynyl, halogenated C1 - C6 alkyl, hydroxyC1 - C6 alkyl, C1 -C6 alkylcarbonyl, C1 - C6 alkoxy, halogenated C1 - C6 alkoxy, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), aryl, 3-11 membered heterocycloalkyl or 5-11 membered heteroaryl; wherein the C1 - C6 alkyl, C3 - C8 cycloalkyl, aryl, 3-11 membered heterocycloalkyl and the 5-11 membered heteroaryl are each optionally substituted by R1-1 ; when the R When a is a plurality of substituents, the substituents are the same or different; the aryl group is a C 6 -C 10 aryl group; the 3-11 membered heterocycloalkyl group is a 3-11 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from O, N and S; the 5-11 membered heteroaryl group is a 5-11 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from O, N and S;
    R1为C1-C6烷基、C1-C6氘代烷基、卤代C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、C1-C6烷氧基、-(C1-C6亚烷基)-(C1-C6烷氧基)、3-11元杂环烷基、或-(C1-C6亚烷基)-(3-11元杂环烷基)；并且，所述R1任选地被一个或多个R1-1取代；当取代基为多个时，所述的取代基相同或不同；所述3-11元杂环烷基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-11元杂环烷基；每个R1-1独立地为H、卤素、羟基、硝基、氰基、羰基、氧代、羧基、-NH(C1-C6烷基)、-O-亚烷基-OH、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、氘代C1-C6烷氧基；所述-O-亚烷基-OH中亚烷基为C1-C6亚烷基； R1 is C1 - C6 alkyl, C1 - C6 deuterated alkyl, halogenated C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy, -( C1 - C6 alkylene)-( C1 - C6 alkoxy), 3-11-membered heterocycloalkyl, or -( C1 - C6 alkylene)-(3-11-membered heterocycloalkyl); and, said R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, said substituents are the same or different; said 3-11-membered heterocycloalkyl is a 3-11-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from O, N and S; each R 1-1 is independently H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy; the alkylene in the -O-alkylene-OH is C 1 -C 6 alkylene;
    R2为氨基、CN、或-NHC(O)(C1-C6烷基)；R 2 is amino, CN, or -NHC(O)(C 1 -C 6 alkyl);
    R3为芳基、3-11元杂环烷基或5-11元杂芳基，其任选地被一个或多个R3-1取代；所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2；所述3-11元杂环烷基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-11元杂环烷基；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-11元杂芳基；R 3 is an aryl group, a 3-11-membered heterocycloalkyl group or a 5-11-membered heteroaryl group, which is optionally substituted by one or more R 3-1 ; the R 3-1 is -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 ; the 3-11-membered heterocycloalkyl group is a 3-11-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S; the 5-11-membered heteroaryl group is a 5-11-membered heteroaryl group having 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S;
    每个R3-1-1独立地为H、C1-C6烷基或亚烷基-OH，其任选地被以下取代：-OH、-亚烷基-NH2、-亚烷基-N(R3-1-2)2、-亚烷基-O-亚烷基-OH、-亚烷基-O-亚烷基-NH2、-C(O)-烷基、-C(O)O-烷基、-亚烷基-COOH或-S(O)p-烷基；或可替代地，在-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2中，两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环；所述亚烷基-OH、-亚烷基-NH2、-亚烷基-N(R3-1-2)2、-亚烷基-O-亚烷基-OH、-亚烷基-O-亚烷基-NH2和-亚烷基-COOH中亚烷基为C1-C6亚烷基；所述-C(O)-烷基、-C(O)O-烷基和-S(O)p-烷基中烷基为C1-C6烷基；所述4-7元杂环为杂原子为S和/或N，杂原子个数为1个或2个的4-7元杂环；Each R 3-1-1 is independently H, C 1 -C 6 alkyl or alkylene-OH, which is optionally substituted by: -OH, -alkylene-NH 2 , -alkylene-N(R 3-1-2 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 , -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH or -S(O) p -alkyl; or alternatively, in -S(＝O)(＝NR 3-1-1 )-R 3-1-1 or -N＝S(＝O)(R 3-1-1 ) 2 , two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocycle; the alkylene-OH, -alkylene-NH 2 , -alkylene-N(R 3-1-2 ) 2 , -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH 2 and -alkylene-COOH, the alkylene is C 1 -C 6 alkylene; the alkyl in the -C(O)-alkyl, -C(O)O-alkyl and -S(O) p -alkyl is C 1 -C 6 alkyl; the 4-7 membered heterocycle is a 4-7 membered heterocycle with S and/or N as the heteroatom and 1 or 2 heteroatoms;
    每个R3-1-2是H或C1-C6烷基，或者两个R3-1-2连同它们所附接的N原子一起可以形成4-7元杂环，所述4-7元杂环含有选自O、S(O)r、和N的杂原子或杂原子团；杂原子和杂原子团个数为1个、2个或3个的4-7元杂环； Each R 3-1-2 is H or C 1 -C 6 alkyl, or two R 3-1-2 together with the N atom to which they are attached can form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring contains a heteroatom or heteroatom group selected from O, S(O) r , and N; a 4-7 membered heterocyclic ring having 1, 2 or 3 heteroatoms or heteroatom groups;
    X为N或CH；X is N or CH;
    m、n、p、r分别为0、1或2。m, n, p, and r are 0, 1, or 2 respectively.
  4. 如权利要求3所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述如式I所示的杂环类化合物满足以下条件中的一项或多项：The heterocyclic compound of formula I, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt, or its prodrug as claimed in claim 3, characterized in that the heterocyclic compound as shown in formula I satisfies one or more of the following conditions:
    (1)Ra、R1和R3-1-2中，所述C1-C6烷基独立地为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；(1) In Ra , R1 and R3-1-2 , the C1 - C6 alkyl group is independently a C1 - C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    (2)Ra和R1中，所述C1-C6氘代烷基独立地为C1-C4氘代烷基；(2) In Ra and R1 , the C1 - C6 deuterated alkyl group is independently a C1 - C4 deuterated alkyl group;
    (3)Ra和R1中，所述卤代C1-C6烷基独立地为卤代C1-C4烷基；(3) In Ra and R1 , the halogenated C1 - C6 alkyl group is independently a halogenated C1 - C4 alkyl group;
    (4)Ra和R1中，所述C3-C8环烷基独立地为C3-C6环烷基，例如，环丙基、环丁基、环戊基或环己基；(4) In Ra and R1 , the C3 - C8 cycloalkyl group is independently a C3 - C6 cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
    (5)Ra和R1中，所述-(C1-C6亚烷基)-(C3-C8环烷基)里的C3-C8环烷基独立地为C3-C6环烷基，例如，环丙基、环丁基、环戊基或环己基；(5) In Ra and R1 , the C3 - C8 cycloalkyl in the -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl) is independently C3 - C6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
    (6)Ra和R1中，所述-(C1-C6亚烷基)-(C3-C8环烷基)里的C1-C6亚烷基独立地为C1-C4亚烷基，优选-(CH2)x-，x为1、2、或3；(6) In Ra and R1 , the C1 - C6 alkylene in the - (C1-C6 alkylene)-(C3-C8 cycloalkyl) is independently C1-C4 alkylene , preferably - ( CH2 ) x- , where x is 1, 2, or 3;
    (7)Ra和R1中，所述C1-C6烷氧基独立地为C1-C4烷氧基，例如，甲氧基、乙氧基、正丙氧基或异丙氧基；(7) In Ra and R1 , the C1 - C6 alkoxy group is independently a C1 - C4 alkoxy group, for example, a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group;
    (8)R1中，所述-(C1-C6亚烷基)-(C1-C6烷氧基)里的C1-C6烷氧基为C1-C4烷氧基，例如，甲氧基、乙氧基、正丙氧基或异丙氧基；(8) In R 1 , the C 1 -C 6 alkoxy group in the -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy) group is a C 1 -C 4 alkoxy group, for example, a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group;
    (9)R1中，所述-(C1-C6亚烷基)-(C1-C6烷氧基)里的C1-C6亚烷基为C1-C4亚烷基，优选-(CH2)x-，x为1、2、或3，例如-CH2-、-(CH2)2-或-(CH2)3-；(9) In R1 , the C1 - C6 alkylene in the -(C1-C6 alkylene ) -( C1 - C6 alkoxy) is C1 - C4 alkylene, preferably -( CH2 ) x- , wherein x is 1, 2 , or 3, such as -CH2- , -( CH2 ) 2- , or -( CH2 ) 3- ;
    (10)R1中，所述-(C1-C6亚烷基)-(C1-C6烷氧基)为-(C1-C4亚烷基)-(C1-C4烷氧基)；(10) In R1 , the -( C1 - C6 alkylene)-( C1 - C6 alkoxy) is -( C1 - C4 alkylene)-( C1 - C4 alkoxy);
    (11)Ra和R1中，所述3-11元杂环烷基为3-6元杂环烷基，优选为杂原子选自O、N和S中的1种或2种、杂原子数为1个或2个的3-6元杂环烷基；(11) In Ra and R1 , the 3-11-membered heterocycloalkyl group is a 3-6-membered heterocycloalkyl group, preferably a 3-6-membered heterocycloalkyl group having one or two heteroatoms selected from O, N and S and having one or two heteroatoms;
    (12)Ra和R1中，所述-(C1-C6亚烷基)-(3-11元杂环烷基)里的3-11元杂环烷基为3-6元杂环烷基，优选为杂原子选自O、N和S中的1种或2种、杂原子数为1个或2个的3-6元杂环烷基；(12) In Ra and R1 , the 3-11-membered heterocycloalkyl in the -( C1 - C6 alkylene)-(3-11-membered heterocycloalkyl) is a 3-6-membered heterocycloalkyl, preferably a 3-6-membered heterocycloalkyl having one or two heteroatoms selected from O, N and S and one or two heteroatoms;
    (13)Ra和R1中，所述-(C1-C6亚烷基)-(3-11元杂环烷基)里的C1-C6亚烷基为C1-C4亚烷基；(13) In Ra and R1 , the C1 - C6 alkylene in the -( C1 - C6 alkylene)-(3-11-membered heterocycloalkyl) is C1 - C4 alkylene;
    (14)R1-1中，所述-NH(C1-C6烷基)、C1-C6烷基和卤代C1-C6烷基里的C1-C6烷基为C1-C3烷基；(14) In R 1-1 , the C 1 -C 6 alkyl in the -NH(C 1 -C 6 alkyl), C 1 -C 6 alkyl and halogenated C 1 -C 6 alkyl is C 1 -C 3 alkyl;
    (15)R1-1中，所述-NH(C1-C6烷基)、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基和氘代C1-C6烷氧基里的C1-C6烷氧基为C1-C3烷氧基；(15) In R 1-1 , the C 1 -C 6 alkoxy group in the -NH(C 1 -C 6 alkyl), C 1 -C 6 alkyl group, halogenated C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group and deuterated C 1 -C 6 alkoxy group is C 1 -C 3 alkoxy group;
    (16)Ra中，所述C6-C10芳基为苯基；(16) In Ra , the C6 - C10 aryl group is a phenyl group;
    (17)Ra中，所述5-11元杂芳基为5-6元杂芳基，优选杂原子选自O、N和S中的1种或2种，杂原子数为1个或2个的5-6元杂芳基；(17) In Ra , the 5-11-membered heteroaryl group is a 5-6-membered heteroaryl group, preferably a 5-6-membered heteroaryl group having one or two heteroatoms selected from O, N and S;
    (18)R3中，所述5-11元杂芳基为5-10元杂芳基；优选地，所述5-11元杂芳基为5-6元杂芳基 或8-10元双环杂芳基；更优选地，所述5-11元杂芳基为杂原子选自O、N和S中的1种或2种，杂原子数为1个或2个的5-6元杂芳基或杂原子选自O、N和S中的1种或2种，杂原子数为1个或2个的8-10元双环杂芳基；例如，吡啶；(18) In R 3 , the 5-11-membered heteroaryl group is a 5-10-membered heteroaryl group; preferably, the 5-11-membered heteroaryl group is a 5-6-membered heteroaryl group. or an 8-10 membered bicyclic heteroaryl group; more preferably, the 5-11 membered heteroaryl group is a 5-6 membered heteroaryl group having 1 or 2 heteroatoms selected from one or two of O, N and S, or an 8-10 membered bicyclic heteroaryl group having 1 or 2 heteroatoms selected from one or two of O, N and S; for example, pyridine;
    (19)R3-1-1中，所述C1-C6烷基独立地为C1-C3烷基，例如甲基、乙基、正丙基或异丙基；(19) In R 3-1-1 , the C 1 -C 6 alkyl group is independently a C 1 -C 3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl;
    (20)R3-1-1中，所述两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环里的4-7元杂环为5-6元杂环，优选5元杂环；例如 (20) In R 3-1-1 , the two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7-membered heterocyclic ring, wherein the 4-7-membered heterocyclic ring is a 5-6-membered heterocyclic ring, preferably a 5-membered heterocyclic ring; for example
  5. 如权利要求3所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述如式I所示的杂环类化合物满足以下条件中的一项或多项：The heterocyclic compound of formula I, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt, or its prodrug as claimed in claim 3, characterized in that the heterocyclic compound as shown in formula I satisfies one or more of the following conditions:
    (1)所述X为CH；(1) X is CH;
    (2)m为1；(2) m is 1;
    (3)n为1；(3) n is 1;
    (4)所述Ra为H、C1-C6烷基、芳基或5-11元杂芳基；其中所述C1-C6烷基、芳基和所述5-11元杂芳基各自任选地被R1-1取代；当所述Ra为多个取代基时，所述的取代基相同或不同；所述芳基为C6-C10芳基；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-11元杂芳基；优选地，所述Ra为C1-C6烷基；(4) Ra is H, C1 - C6 alkyl, aryl or 5-11 membered heteroaryl; wherein the C1 - C6 alkyl, aryl and 5-11 membered heteroaryl are each optionally substituted by R1-1 ; when Ra is a plurality of substituents, the substituents are the same or different; the aryl is C6 - C10 aryl; the 5-11 membered heteroaryl is a 5-11 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S; preferably, Ra is C1 - C6 alkyl;
    (5)所述R1为C1-C6烷基、C1-C6氘代烷基、卤代C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、C1-C6烷氧基、-(C1-C6亚烷基)-(C1-C6烷氧基)；并且，所述R1任选地被一个或多个R1- 1取代；当取代基为多个时，所述的取代基相同或不同；优选地，所述R1为C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、-(C1-C6亚烷基)-(C1-C6烷氧基)；更优选地，所述R1为-(C1-C6亚烷基)-(C1-C6烷氧基)；例如，所述R1为-(C1-C4亚烷基)-(C1-C4烷氧基)；(5) The R1 is C1 - C6 alkyl, C1 - C6 deuterated alkyl, halogenated C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1-C6 alkoxy , -( C1 - C6 alkylene)-( C1 - C6 alkoxy); and the R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, the substituents are the same or different; preferably, the R1 is C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), -( C1 - C6 alkylene)-( C1 - C6 alkoxy); more preferably, the R1 is -( C1 - C6 alkylene)-(C1- C6 6 alkoxy); for example, the R 1 is -(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy);
    (6)所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2，所述R3-1-1独立地是H或C1-C6烷基，或者所述两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环，所述4-7元杂环为杂原子为S和/或N，杂原子个数为1个或2个的4-7元杂环；(6) the R 3-1 is -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 , the R 3-1-1 is independently H or C 1 -C 6 alkyl, or the two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocyclic ring, wherein the heteroatom is S and/or N, and the number of heteroatoms is 1 or 2;
    (7)所述R3为5-10元杂芳基，其任选地被一个或多个R3-1取代；优选地，所述R3为 (7) R 3 is a 5-10 membered heteroaryl group, which is optionally substituted by one or more R 3-1 ; preferably, R 3 is
    (8)所述R2为-NH2。(8) The R 2 is -NH 2 .
  6. 如权利要求1所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述Ra为甲基或 The heterocyclic compound of formula I according to claim 1, its solvate, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt solvate or its prodrug, characterized in that Ra is methyl or
  7. 如权利要求1所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述R1为C1-C4烷基、C1-C4氘代烷基、卤代C1-C4烷基、C3-C6环烷基、-(C1-C6亚烷基)-(C3-C6环烷基)、C1-C4烷氧基、-(C1-C4亚烷基)-(C1-C4烷氧基)、3- 6元杂环烷基或-(C1-C4亚烷基)-(3-6元杂环烷基)；并且，所述R1任选地被一个或多个R1-1取代；当取代基为多个时，所述的取代基相同或不同；所述R1-1具有权利要求1所述的定义；The heterocyclic compound of formula I as claimed in claim 1, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt or its prodrug, characterized in that R1 is C1 - C4 alkyl, C1 - C4 deuterated alkyl, halogenated C1 - C4 alkyl, C3 - C6 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C6 cycloalkyl), C1 - C4 alkoxy, -( C1 - C4 alkylene)-( C1 - C4 alkoxy), 3- 6-membered heterocycloalkyl or -(C 1 -C 4 alkylene)-(3-6-membered heterocycloalkyl); and, the R 1 is optionally substituted by one or more R 1-1 ; when there are multiple substituents, the substituents are the same or different; the R 1-1 has the definition as described in claim 1;
    较佳地，所述R1为丁基、环丙基、环丁基、环戊基、环己基、-(CH2)x-环丙基、-(CH2)x-环丁基、-(CH2)x-环戊基、-(CH2)x-环己基或-(C1-C4亚烷基)-(C1-C4烷氧基)；其中x是1、2、或3；Preferably, R 1 is butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) x -cyclopropyl, -(CH 2 ) x -cyclobutyl, -(CH 2 ) x -cyclopentyl, -(CH 2 ) x -cyclohexyl or -(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy); wherein x is 1, 2, or 3;
    更佳地，所述R1为-CH2CH2-O-CH3。More preferably, the R 1 is -CH 2 CH 2 -O-CH 3 .
  8. 如权利要求1所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述R1-1为H、卤素、羟基、硝基、氰基、羰基、氧代、羧基、-NH(C1-C3烷基)、-O-亚烷基-OH、C1-C3烷基、氘代C1-C6烷基、卤代C1-C3烷基、C1-C3烷氧基或氘代C1-C3烷氧基；较佳地，所述R1-1为H。The heterocyclic compound of formula I as claimed in claim 1, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt or its prodrug, characterized in that R 1-1 is H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 3 alkyl), -O-alkylene-OH, C 1 -C 3 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy or deuterated C 1 -C 3 alkoxy; preferably, R 1-1 is H.
  9. 如权利要求1所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述R2为-NH2、CN或-NH-C(O)-CH3。The heterocyclic compound of formula I, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt, or its prodrug according to claim 1, characterized in that R 2 is -NH 2 , CN or -NH-C(O)-CH 3 .
  10. 如权利要求1所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述R3为5-6元杂环烷基或5-10元杂芳基，其任选地被一个或多个R3-1取代，所述R3-1具有权利要求1所述的定义。The heterocyclic compound of formula I as claimed in claim 1, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt or its prodrug, characterized in that R 3 is a 5-6 membered heterocycloalkyl or a 5-10 membered heteroaryl, which is optionally substituted by one or more R 3-1 , and R 3-1 has the definition as described in claim 1.
  11. 如权利要求1所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述R3为任选地被一个或多个R3-1取代的5-6元杂芳基，或者为任选地被一个或多个R3-1取代的8-10元双环杂芳基，所述R3-1具有权利要求1所述的定义。The heterocyclic compound of formula I as claimed in claim 1, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt or its prodrug, characterized in that R 3 is a 5-6-membered heteroaryl group optionally substituted by one or more R 3-1 , or an 8-10-membered bicyclic heteroaryl group optionally substituted by one or more R 3-1 , and R 3-1 has the definition as described in claim 1.
  12. 如权利要求1所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述R3-1为-S(＝O)(＝NCH3)-CH3或-N＝S(＝O)(CH3)2。The heterocyclic compound of formula I, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt or its prodrug as claimed in claim 1, characterized in that R 3-1 is -S(=O)(=NCH 3 )-CH 3 or -N=S(=O)(CH 3 ) 2 .
  13. 如权利要求10所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述R3为吡啶，其被一个或多个R3-1取代，所述R3-1具有权利要求6所述的定义。The heterocyclic compound of formula I, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt or its prodrug as claimed in claim 10, characterized in that R 3 is pyridine, which is substituted by one or more R 3-1 , and R 3-1 has the definition as described in claim 6.
  14. 如权利要求10所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1- 1)2，所述R3-1-1独立地是H或C1-C3烷基，或者所述两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环。The heterocyclic compound represented by formula I, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt or its prodrug as claimed in claim 10, characterized in that R 3-1 is -S(＝O)(＝NR 3-1-1 )-R 3-1-1 or -N＝S(＝O)(R 3-1- 1 ) 2 , the R 3-1-1 is independently H or C 1 -C 3 alkyl, or the two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocyclic ring.
  15. 如权利要求14所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述R3-1为 The heterocyclic compound of formula I, its solvate, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt solvate or its prodrug according to claim 14, characterized in that R 3-1 is
  16. 如权利要求3所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述的式I所示的杂环类化合物选自以下任一方案：The heterocyclic compound of formula I, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt, or its prodrug as claimed in claim 3, characterized in that the heterocyclic compound of formula I is selected from any of the following schemes:
    方案1：plan 1:
    Ra为H、C1-C6烷基、芳基或5-11元杂芳基；其中所述C1-C6烷基、芳基和所述5-11元杂芳基各 自任选地被R1-1取代；当所述Ra为多个取代基时，所述的取代基相同或不同；所述芳基为C6-C10芳基；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-11元杂芳基； Ra is H, C1 - C6 alkyl, aryl or 5-11 membered heteroaryl; wherein the C1 - C6 alkyl, aryl and 5-11 membered heteroaryl are each is optionally substituted by R 1-1 ; when the Ra is a plurality of substituents, the substituents are the same or different; the aryl is a C 6 -C 10 aryl; the 5-11 membered heteroaryl is a 5-11 membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, N and S;
    R1为C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、-(C1-C6亚烷基)-(C1-C6烷氧基)；并且，所述R1任选地被一个或多个R1-1取代；当取代基为多个时，所述的取代基相同或不同；R 1 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -(C 1 -C 6 alkylene)-(C 3 -C 8 cycloalkyl), -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy); and, said R 1 is optionally substituted by one or more R 1-1 ; when there are multiple substituents, said substituents are the same or different;
    每个R1-1独立地为C1-C6烷基；Each R 1-1 is independently C 1 -C 6 alkyl;
    R2为氨基； R2 is an amino group;
    R3为5-11元杂芳基，其被一个R3-1取代；所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-11元杂芳基；R 3 is a 5-11 membered heteroaryl group, which is substituted by one R 3-1 ; the R 3-1 is -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 ; the 5-11 membered heteroaryl group is a 5-11 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S;
    每个R3-1-1独立地为H或C1-C6烷基；或可替代地，在-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2中，两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环；所述4-7元杂环为杂原子为S和N的4-7元杂环；Each R 3-1-1 is independently H or C 1 -C 6 alkyl; or alternatively, in -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 , two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocyclic ring; the 4-7 membered heterocyclic ring is a 4-7 membered heterocyclic ring wherein the heteroatoms are S and N;
    X为N或CH；X is N or CH;
    m为0或1；m is 0 or 1;
    n为1；n is 1;
    方案2：Scenario 2:
    Ra为C1-C6烷基； Ra is a C1 - C6 alkyl group;
    R1为-(C1-C6亚烷基)-(C1-C6烷氧基)； R1 is -( C1 - C6 alkylene)-( C1 - C6 alkoxy);
    R2为氨基； R2 is an amino group;
    R3为5-11元杂芳基，其被一个R3-1取代；所述R3-1为-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2；所述5-11元杂芳基为杂原子选自O、N和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-11元杂芳基；R 3 is a 5-11 membered heteroaryl group, which is substituted by one R 3-1 ; the R 3-1 is -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 ; the 5-11 membered heteroaryl group is a 5-11 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from O, N and S;
    每个R3-1-1独立地为H或C1-C6烷基；或可替代地，在-S(＝O)(＝NR3-1-1)-R3-1-1或-N＝S(＝O)(R3-1-1)2中，两个R3-1-1与其所附接的N及S原子一起形成4-7元杂环；所述4-7元杂环为杂原子为S和N的4-7元杂环；Each R 3-1-1 is independently H or C 1 -C 6 alkyl; or alternatively, in -S(=O)(=NR 3-1-1 )-R 3-1-1 or -N=S(=O)(R 3-1-1 ) 2 , two R 3-1-1 together with the N and S atoms to which they are attached form a 4-7 membered heterocyclic ring; the 4-7 membered heterocyclic ring is a 4-7 membered heterocyclic ring wherein the heteroatoms are S and N;
    X为CH；X is CH;
    m为1；m is 1;
    n为1。n is 1.
  17. 如权利要求1-16任一项所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述的如式I所示的化合物为如式I-A、如式I-B或如式I-C所示的化合物：
    The heterocyclic compound of formula I according to any one of claims 1 to 16, its solvate, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt solvate or its prodrug, characterized in that the compound of formula I is a compound of formula IA, formula IB or formula IC:
  18. 如权利要求1所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述杂环类化合物选自下列任一化合物：
    The heterocyclic compound of formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof according to claim 1, characterized in that the heterocyclic compound is selected from any one of the following compounds:
    较佳地，所述如式I所示的杂环类化合物选自下列任一化合物：Preferably, the heterocyclic compound as shown in Formula I is selected from any of the following compounds:
    在如下手性制备条件下保留时间为1.327min的和保留时间为1.731min的 Under the following chiral preparation conditions, the retention time is 1.327 min. and retention time of 1.731 min
    所述的手性制备条件：色谱柱：手性柱Chiralcel OD-3 50×4.6mm I.D.3μm；流动相A：CO2，流动相B：IPA(0.05体积％DEA)，等度洗脱：40体积％IPA(0.05体积％DEA)在CO2中；流速：3mL/min；检测器：PDA；柱温：35℃；柱压：100Bar。The chiral preparation conditions are as follows: chromatographic column: Chiralcel OD-3 50×4.6mm ID3μm; mobile phase A: CO 2 , mobile phase B: IPA (0.05 vol% DEA), isocratic elution: 40 vol% IPA (0.05 vol% DEA) in CO 2 ; flow rate: 3mL/min; detector: PDA; column temperature: 35°C; column pressure: 100Bar.
  19. 如权利要求1所述的式I所示的杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药，其特征在于，所述杂环类化合物选自下列任一化合物：
    The heterocyclic compound of formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof according to claim 1, characterized in that the heterocyclic compound is selected from any one of the following compounds:
  20. 一种药物组合物，其特征在于，所述药物组合物包括：如权利要求1-19中任一所述的式I所示杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物或其前药；和药学上可接受的载体。A pharmaceutical composition, characterized in that the pharmaceutical composition comprises: a heterocyclic compound of formula I as described in any one of claims 1 to 19, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof; and a pharmaceutically acceptable carrier.
  21. 一种物质的用途，其特征在于，所述的物质为如权利要求1-19中任一所述的式I所示杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其前药或如权利要求20所述的药物组合物；所述的用途为制备15‐PGDH抑制剂、或、制备预防和/或治疗与15‐PGDH相关的疾病的药物。A use of a substance, characterized in that the substance is a heterocyclic compound of formula I as described in any one of claims 1 to 19, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, a prodrug thereof, or a pharmaceutical composition as described in claim 20; the use is for preparing a 15-PGDH inhibitor, or for preparing a drug for preventing and/or treating a disease associated with 15-PGDH.
  22. 如权利要求21所述的用途，其特征在于，所述的与15‐PGDH相关的疾病为纤维化疾病、炎性疾病、心血管疾病、创伤、自身免疫性疾病、移植物抗宿主疾病、毛发生长、骨质疏松症、耳病、眼病、中性白细胞减少、糖尿病、膀胱活动低下症、在干细胞或骨髓移植或器官移植中的植入物促进、神经发生和神经细胞死亡、血细胞重建、组织损伤、宫颈疾病或肾病中的一种、两种或更多种，优选为纤维化、炎性疾病或组织损伤中的一种或多种。The use as claimed in claim 21, characterized in that the disease associated with 15-PGDH is one, two or more of fibrotic diseases, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host disease, hair growth, osteoporosis, ear diseases, eye diseases, neutropenia, diabetes, underactive bladder, implant promotion in stem cell or bone marrow transplantation or organ transplantation, neurogenesis and nerve cell death, blood cell reconstruction, tissue damage, cervical disease or kidney disease, preferably one or more of fibrosis, inflammatory diseases or tissue damage.
  23. 如权利要求22所述的用途，其特征在于，所述的纤维化疾病为肺纤维化、肝纤维化、肾纤维化、心肌纤维化、硬皮病或骨髓纤维化中的一种或多种，优选为肺纤维化和/或肝纤维化，例如肺纤维化；其中，所述的肺纤维化优选为特发性肺纤维化；The use according to claim 22, characterized in that the fibrotic disease is one or more of pulmonary fibrosis, liver fibrosis, kidney fibrosis, myocardial fibrosis, scleroderma or myelofibrosis, preferably pulmonary fibrosis and/or liver fibrosis, such as pulmonary fibrosis; wherein the pulmonary fibrosis is preferably idiopathic pulmonary fibrosis;
    和/或，所述的炎性疾病为慢性阻塞性肺病、急性肺损伤、脓毒症、哮喘和肺病的恶化、炎症性肠病、消化性溃疡、自身炎性疾病、血管炎综合征、急性肝损伤、急性肾损伤、非酒精性脂肪肝、特应性皮炎、牛皮癣、间质性膀胱炎或前列腺炎综合征中的一种或多种，优选为炎症性肠病；其中，所述的炎症性肠病优选为溃疡性结肠炎和/或克罗恩氏病；所述的消化性溃疡优选为NSAID诱导的溃疡；所述的自身炎性疾病优选为贝切特氏病；所述的前列腺炎综合征优选为慢性前列腺炎和/或慢性骨盆疼痛综合征；And/or, the inflammatory disease is one or more of chronic obstructive pulmonary disease, acute lung injury, sepsis, asthma and exacerbation of lung disease, inflammatory bowel disease, peptic ulcer, autoinflammatory disease, vasculitis syndrome, acute liver injury, acute kidney injury, non-alcoholic fatty liver disease, atopic dermatitis, psoriasis, interstitial cystitis or prostatitis syndrome, preferably inflammatory bowel disease; wherein the inflammatory bowel disease is preferably ulcerative colitis and/or Crohn's disease; the peptic ulcer is preferably NSAID-induced ulcer; the autoinflammatory disease is preferably Behcet's disease; the prostatitis syndrome is preferably chronic prostatitis and/or chronic pelvic pain syndrome;
    和/或，所述的心血管疾病为肺动脉高压、心绞痛、心肌梗死、心力衰竭、缺血性心脏病、脑卒中 或周围循环紊乱中的一种或多种；And/or, the cardiovascular disease is pulmonary hypertension, angina pectoris, myocardial infarction, heart failure, ischemic heart disease, stroke or one or more of peripheral circulatory disorders;
    和/或，所述的创伤为糖尿病性溃疡、烧伤、压迫性溃疡、急性粘膜损伤、包括斯-约二氏综合征、粘膜损伤、抗癌化疗剂有关的损伤、抗代谢物、细胞或体液免疫疗法或放射线有关的损伤中的一种或多种；其中，所述的抗癌化疗剂优选为烷化剂、DNA合成抑制剂或DNA回旋酶抑制剂中的一种或多种；And/or, the trauma is one or more of diabetic ulcer, burn, pressure ulcer, acute mucosal injury, including Stevens-Johnson syndrome, mucosal injury, injury related to anticancer chemotherapy, antimetabolites, cellular or humoral immunotherapy or radiation-related injury; wherein the anticancer chemotherapy is preferably one or more of alkylating agents, DNA synthesis inhibitors or DNA gyrase inhibitors;
    和/或，所述的自身免疫性疾病为多发性硬化和/或类风湿性关节炎；and/or, the autoimmune disease is multiple sclerosis and/or rheumatoid arthritis;
    和/或，所述的耳病为听力损失、耳鸣、眩晕或平衡失调中的一种或多种；and/or, the ear disease is one or more of hearing loss, tinnitus, vertigo or imbalance;
    和/或，所述的眼病为青光眼和/或干眼；and/or, the eye disease is glaucoma and/or dry eye;
    和/或，所述的神经发生和神经细胞死亡为精神神经疾病、神经病、神经毒性疾病、神经性疼痛或神经变性疾病中的一种或多种；and/or, the neurogenesis and neuronal cell death are one or more of a psychiatric neurological disease, a neuropathy, a neurotoxic disease, a neuropathic pain or a neurodegenerative disease;
    和/或，所述的组织损伤为肝损伤和/或肌肉损伤；所述肌肉损伤优选为肌肉萎缩和/或肌营养不良；And/or, the tissue damage is liver damage and/or muscle damage; the muscle damage is preferably muscle atrophy and/or muscular dystrophy;
    和/或，所述的肾病为慢性肾病和/或肾衰竭。And/or, the kidney disease is chronic kidney disease and/or renal failure.
  24. 如权利要求21所述的用途，其特征在于，预防和/或治疗与15‐PGDH相关的疾病为肝脏再生。The use according to claim 21, characterized in that the disease prevented and/or treated by the method is liver regeneration.
  25. 一种如权利要求1-19中任一所述的式I所示杂环类化合物、其溶剂化物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其前药或如权利要求20所述的药物组合物的用途，所述的用途为用于制备预防和/或治疗如下疾病的药物；所述的疾病为纤维化疾病、炎性疾病或组织损伤中的一种或多种；A use of a heterocyclic compound of formula I as claimed in any one of claims 1 to 19, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, a prodrug thereof, or a pharmaceutical composition as claimed in claim 20, wherein the use is for preparing a medicament for preventing and/or treating the following diseases; the diseases are one or more of fibrotic diseases, inflammatory diseases, or tissue damage;
    优选地，所述的纤维化疾病、所述的炎性疾病和所述的组织损伤均如权利要求23所述。 Preferably, the fibrotic disease, the inflammatory disease and the tissue damage are all as described in claim 23.
PCT/CN2023/131424 2022-11-14 2023-11-14 Compound for inhibiting 15-pgdh and use thereof WO2024104317A1 (en)

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