WO2024104322A1 - 15-pgdh inhibitor - Google Patents

15-pgdh inhibitor Download PDF

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WO2024104322A1
WO2024104322A1 PCT/CN2023/131441 CN2023131441W WO2024104322A1 WO 2024104322 A1 WO2024104322 A1 WO 2024104322A1 CN 2023131441 W CN2023131441 W CN 2023131441W WO 2024104322 A1 WO2024104322 A1 WO 2024104322A1
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alkyl
alkylene
group
pharmaceutically acceptable
solvate
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PCT/CN2023/131441
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French (fr)
Chinese (zh)
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张学军
臧杨
李群
汤亚敏
王猛
丁肖华
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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    • 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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    • A61K31/437—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 containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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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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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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Definitions

  • the present invention belongs to the field of medicine, and in particular, relates to a 15-PGDH inhibitor.
  • 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, a solvate, a pharmaceutically acceptable salt, a solvate of a pharmaceutically acceptable salt or a prodrug of Formula I is provided:
  • Ring A is a C 3 -C 20 alicyclic hydrocarbon group
  • Ra is H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1 - C6 alkyl, -NH( C1 - C6 alkyl), C1 - C6 deuterated alkyl, C2 - C6 alkynyl, halogenated C1 - C6 alkyl, hydroxyl C1 - C6 alkyl, C1 - C6 alkylcarbonyl, C1 - C6 alkoxy or halogenated C1 - C6 alkoxy; when Ra is a plurality of substituents, the substituents are the same or different;
  • R1 is C1 - C6 alkyl, C1 - C6 deuterated alkyl, halogenated C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl) alkyl), C 1 -C 6 alkoxy, -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), 3-11-membered heterocycloalkyl, or -(C 1 -C 6 alkylene)-(3-11-membered heterocycloalkyl); 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;
  • R 1-1 is H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or deuterated C 1 -C 6 alkoxy;
  • R2 is amino, CN or -NHC(O)alkyl
  • R 3 is an aryl group, a 3-11-membered heterocycloalkyl group or a 3-11-membered heteroaryl group, which is optionally substituted by one or more R 3-1 ; when there are multiple substituents, the substituents are the same or different; the heteroatom is selected from one or more of N, O, and S;
  • R 3-1 is H, halogen, hydroxy, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-N(R 3-1-1 ) 2 , -N(R 3-1-1 ) 2 , -N(R 3-1-1 )(alkylene-OH), -N(R 3-1-1 )(alkylene-O-alkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-11 membered heterocycloalkyl, -C(O)N(R 3-1-1 ) 2 , -C(O)N(R 3-1-1 )(al
  • 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 3-1-3 ) 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 -O-alkylene-N(R 3-1-1 ) 2 or -N(R 3-1-1 ) 2 , two R 3-1-1 together with the N atom to which they are attached form a 4-7 membered heterocyclic ring, which optionally contains an additional heteroatom selected from O, S, or N, and wherein the 4-7 membered heterocyclic ring is optionally substituted by R 3-1-4 ; or alternatively, in -S(
  • R 3-1-2 is hydroxy, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • R 3-1-3 is H or C 1 -C 6 alkyl, or two R 3-1-3 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;
  • R 3-1-4 is halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • n, p, and r are 0, 1, or 2 respectively.
  • 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, R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, the substituents are the same or different; the heteroatoms of the heterocycloalkyl are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2 or 3.
  • R 1-1 is H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or deuterated C 1 -C 6 alkoxy; the alkylene is C 1 -C 6 alkylene.
  • R 2 is amino, CN or -NHC(O)alkyl; the alkyl is C 1 -C 6 alkyl.
  • R 3 is an aryl group, a 3-11-membered heterocycloalkyl group or a 3-11-membered heteroaryl group, which is optionally substituted by one or more R 3-1 ; when there are multiple substituents, the substituents are the same or different; the heteroatoms in the heterocycloalkyl group and the heteroaryl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2 or 3; the aryl group is a 6-10-membered aryl group.
  • R 3-1 is H, halogen, hydroxy, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-N(R 3-1-1 ) 2 , -N(R 3-1-1 ) 2 , -N(R 3-1-1 )(alkylene-OH), -N(R 3-1-1 )(alkylene-O-alkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-11 membered heterocycloalkyl, -C(O)N(R 3-1-1 ) 2 , -C(O)N
  • 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 3-1-3 ) 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 -O-alkylene-N(R 3-1-1 ) 2 or -N(R 3-1-1 ) 2 , two R 3-1-1 together with the N atom to which they are attached form a 4-7 membered heterocyclic ring containing N and optionally a heteroatom containing O or S, and wherein the 4-7 membered heterocyclic ring is optionally substituted by R 3-1-4 ; or alternative
  • R 3-1-3 is H or C 1 -C 6 alkyl, or two R 3-1-3 together with the N atom to which they are attached can form a 4-7 membered heterocyclic ring containing N and optionally containing a heteroatom of O or S(O) r .
  • the ring A is a C 3 -C 12 alicyclic hydrocarbon group, preferably, the ring A is a C 3 -C 7 alicyclic hydrocarbon group.
  • the ring A is cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl or spiro[2.4]heptane.
  • the Ra is methyl
  • 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 ; 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 1-1 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, deuterated C 1 -C 3 alkoxy.
  • R 2 is -NH 2 , CN or -NH-C(O)-CH 3 .
  • 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 5-6 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.
  • X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a ring atom; X 1 , X 2 , X 3 , X 4 and X 5 each independently represent N, O, S, CH 2 , CH or C; the bond connecting X 4 and X 5 is a single bond or a double bond; B is absent, or B forms a 3-7 membered heterocycloalkyl, a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring together with the ring atoms of X 4 and X 5 ; the heteroatom is selected from one or more of N, O and S; R b and R c each independently represent H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-N(R 3-1-1 ) 2
  • B is absent, or B, together with X 4 and X 5 ring atoms, forms a 3-7 membered heterocycloalkyl, a 5 membered heteroaromatic ring or a 6 membered heteroaromatic ring; the heteroatoms in the heterocycloalkyl and heteroaromatic groups are selected from one or more of N, O and S.
  • the alkylene group is a C 1 -C 6 alkylene group.
  • It is selected from 6-membered heteroaryl, 6-membered heteroaryl and 3-7-membered heterocycloalkyl, 6-membered heteroaryl and 5-6-membered heteroaryl containing 1 or more heteroatoms; the heteroatom is selected from N, O or S.
  • pyridine selected from pyridine, pyrimidine, pyridazine, pyridocyclobutyl, pyridocyclopentyl, pyridoimidazole, pyridopyrazole, pyridofuran, pyridopyrimidine, pyridothiophene, pyridothiazole.
  • R b and R c are each independently H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-NH 2 , -NH(alkylene-OH), -NH(alkylene-O-alkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(O)NH 2 , -C(O)NH(alkylene-OH), -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alk
  • R b and R c are each independently H, oxo, C 1 -C 4 alkyl, -NH(C 1 -C 4 alkyl), C 1 -C 4 deuterated alkyl, C 2 -C 4 alkynyl, halogenated C 1 -C 4 alkyl, hydroxyl C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy.
  • X 1 , X 2 , X 3 and X 4 each independently represent a ring atom; X 1 , X 2 , X 3 and X 4 each independently represent N, O, S, CH 2 , CH or C; R b is H, halogen, hydroxy, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-N(R 3-1-1 ) 2 , -N(R 3-1-1 ) 2 , -N(R 3-1-1 )(alkylene-OH), -N(R 3-1-1 )(alkylene-O-alkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6
  • the alkylene group is a C 1 -C 6 alkylene group.
  • the halogen is F, Cl, Br or I.
  • the alkyl group is a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group.
  • the C 3 -C 8 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • the alkylene group is a C 1 -C 6 alkylene group, preferably a C 1 -C 4 alkylene group, such as methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene or tert-butylene.
  • the C 1 -C 6 alkoxy group is a C 1 -C 4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
  • the 3-11 membered heterocycloalkyl group is a 5-6 membered heterocycloalkyl group.
  • the heteroatoms of the 3-11 membered heterocycloalkyl are selected from one or more of N, O, and S; and the number of the heteroatoms is 1, 2 or 3.
  • the aryl group in R 3 is a 6-10 membered aryl group, such as phenyl or naphthyl.
  • the heteroatom in R 3 is a heteroatom in the 3-11-membered heterocycloalkyl or 3-11-membered heteroaryl.
  • the 4-7 membered heterocycle is a 4-7 membered heterocycloalkyl group.
  • the heteroatoms of the 4-7 membered heterocycle are selected from one or more of N, O, and S; and the number of the heteroatoms is 1, 2 or 3.
  • the heterocyclic compound represented by formula I has a structure represented by formula I-3:
  • R 1 , R 3 , Ra and m are as defined in the first aspect of the present invention.
  • the heterocyclic compound represented by formula I has a structure represented by formula I-4:
  • R 1 , R 3 , Ra and m are as defined in the first aspect of the present invention.
  • the heterocyclic compound represented by formula I has a structure represented by formula I-5:
  • R 1 , R 3 , Ra and m are as defined in the first aspect of the present invention.
  • the heterocyclic compound represented by formula I has a structure represented by formula I-6:
  • R 1 , R 3 , Ra and m are as defined in the first aspect of the present invention.
  • ring A is C 3 -C 7 cycloalkyl.
  • Ra is C1 - C6 alkyl.
  • 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 4 alkoxy, -(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;
  • 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).
  • R2 is amino
  • R3 is a 3-11 membered heterocycloalkyl or 3-11 membered heteroaryl, which is optionally substituted by one or more R3-1 ; when there are multiple substituents, the substituents are the same or different; the heteroatoms in the 3-11 membered heterocycloalkyl or 3-11 membered heteroaryl are selected from one or more of N, O, and S; and the number of heteroatoms is 1, 2 or 3.
  • each R 3-1 is independently C 1 -C 6 alkyl, oxo, —NH(C 1 -C 6 alkyl), or —S( ⁇ O)( ⁇ NR 3-1-1 )—R 3-1-1 .
  • each R 3-1-1 is independently H, C 1 -C 6 alkyl or C 1 -C 6 alkylene-OH.
  • R 1 is
  • R 3 is Each of which is optionally substituted with one or more of the above-mentioned R 3-1 .
  • R 3 is
  • the heterocyclic compound represented by formula I is a heterocyclic compound represented by formula I-7,
  • Ring A is a C 3 -C 7 alicyclic hydrocarbon group
  • Each Ra is independently C1 - C6 alkyl
  • n 0, 1 or 2;
  • R1 is C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy or -( C1 - C6 alkylene)-( C1 - C6 alkoxy);
  • R 2 is amino, CN or -NH-C(O)-CH 3 ;
  • 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 ;
  • the heteroatoms of the heterocycloalkyl and heteroaryl are selected from one or more of N, O, and S; the number of heteroatoms is 1, 2, or 3;
  • Each R 3-1 is independently hydroxy, oxo, C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), or -S( ⁇ O)( ⁇ NR 3-1-1 )-R 3-1-1 ;
  • Each R 3-1-1 is independently a C 1 -C 6 alkyl group.
  • the heterocyclic compound represented by formula I is a heterocyclic compound represented by formula I-8,
  • Ring A is C 3 -C 7 cycloalkyl
  • each Ra is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
  • n 0, 1 or 2;
  • R1 is C1 - C4 alkyl, C3 - C6 cycloalkyl, -( C1 - C4 alkylene)-( C3 - C6 cycloalkyl) or -( C1 - C4 alkylene)-( C1 - C4 alkoxy);
  • 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 ;
  • the heteroatom of the heteroaryl group is selected from one or more of N, O, and S; the number of heteroatoms is 1, 2 or 3;
  • Each R 3-1 is independently oxo, C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), or -S( ⁇ O)( ⁇ NR 3-1-1 )-R 3-1-1 ;
  • Each R 3-1-1 is independently a C 1 -C 6 alkyl group.
  • the heterocyclic compound represented by formula I is a heterocyclic compound represented by formula I-9,
  • Ring A is cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl or spiro[2.4]heptane;
  • each Ra is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
  • n 0, 1 or 2;
  • R1 is C1 - C4 alkyl, C3 - C6 cycloalkyl, -( C1 - C4 alkylene)-( C3 - C6 cycloalkyl) or -( C1 - C4 alkylene)-( C1 - C4 alkoxy);
  • R3 is a 5-6 membered heteroaryl group optionally substituted by one or more R3-1 , or an 8-10 membered bicyclic heteroaryl group optionally substituted by one or more R3-1 ;
  • the heteroatom of the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2;
  • the heteroatom of the 8-10 membered bicyclic heteroaryl group is N, and the number of heteroatoms is 1, 2 or 3;
  • Each R 3-1 is independently oxo or C 1 -C 6 alkyl.
  • heterocyclic compound as shown in Formula I is selected from any of the following compounds:
  • Ra , R1 , R3 , n and m are as defined in the first aspect of the present invention.
  • the present invention provides a pharmaceutical composition, comprising: a compound of formula I as described in the first aspect, the second aspect, or the third 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 fifth aspect of the present invention provides a use of a substance, wherein the substance is a heterocyclic compound of formula I as described in any one of the first aspect, the second aspect, or the third aspect of the present invention, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, a prodrug thereof, or the pharmaceutical composition described in the fourth aspect of the present invention; 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.
  • 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, one, two or more of: fibrotic diseases, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host diseases, 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 and kidney disease.
  • fibrotic diseases include, but are not limited to, one, two or more of: fibrotic diseases, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host diseases, 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 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 ulcers), autoinflammatory diseases (such as Behcet's disease), vasculitic syndromes, acute liver injury, acute kidney injury, nonalcoholic fatty liver disease (NASH), atopic dermatitis, psoriasis, interstitial cystitis, prostatitis syndromes (such as chronic prostatitis/chronic pelvic pain syndrome)], cardiovascular diseases (such as fibrotic diseases
  • 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 may be the same as described above.
  • a substance X for treating 15-PGDH-related diseases is provided; the substance X is a compound represented by formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • a substance X for treating a disease is provided;
  • the substance X is a compound represented by formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof;
  • the disease is a fibrotic disease and/or an inflammatory disease.
  • the fibrotic disease and the inflammatory disease may be the same as described above.
  • the content of the compound represented by formula I, its solvate, its pharmaceutically acceptable 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 .
  • plurality may mean, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.
  • 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.
  • Ring A In the case where ring A is a cycloalkyl group, Ring A in is represented by a cycloalkyl group. Ring A in all of the above is cyclopentyl.
  • 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”)
  • alkylene is understood to mean a straight-chain divalent hydrocarbon group having 1 to 6 carbon atoms or a branched divalent hydrocarbon group having 3 to 6 carbon atoms, unless otherwise specified, such as methylene, ethylene, propylene, 1-methylpropylene, butylene, etc.
  • cycloalkyl refers to a cyclic alkyl group when used alone or as part of other substituents.
  • mn-membered cycloalkyl or "C m -C n cycloalkyl” should be understood to mean a saturated carbocyclic ring having m to n 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.
  • mn-membered heterocycloalkyl or "C m -C n heterocycloalkyl” is understood to mean a saturated ring having m to n atoms, wherein the heteroatoms are selected from N, O, S, P, preferably N, O or S.
  • the term "4-8-membered heterocycloalkyl” or “C 4 -C 8 heterocycloalkyl” is understood to mean a saturated ring having 4 to 8 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 atoms.
  • the number of carbons is also meant to include the heteroatoms.
  • Monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings are included.
  • heterocycloalkyl examples include pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, etc.
  • heterocycloalkyl can be used interchangeably with the term “heteroalkane 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 refers to the replacement of two hydrogen atoms on a methylene group by oxygen atoms, that is, the methylene group is replaced by a carbonyl group; for example, when the pyridine 2 position in a heteroaryl group is replaced by oxygen atoms, that is, Oxygen
  • pyridine 2 is replaced by oxygen
  • NH is replaced by methyl
  • 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) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.
  • 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, etc.
  • the reagent, starting material, reagent, etc. are appropriately selected.
  • 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 Synthesis of ethyl 2-morpholinocyclopent-1-ene-1-carboxylate (B1-3)
  • Step 3 Synthesis of 1-hydroxy-3-(((((2-methoxyethyl)thio)methyl)thio)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (B1-7)
  • Step 4 Synthesis of 4-cyano-3-((((2-methoxyethyl)thio)methyl)thio)-6,7-dihydro-5H-cyclopentadi[c]pyridin-1-yl trifluoromethanesulfonate (B1-8)
  • Step 5 Synthesis of 3-((((2-methoxyethyl)thio)methyl)thio)-1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (B1-10)
  • Step 6 Synthesis of 3-((((2-methoxyethyl)sulfinyl)methyl)thio)-1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (B1-11)
  • 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 Synthesis of 6-(1-amino-2-((2-methoxyethyl)sulfinyl)-7,8-dihydro-6H-cyclopentyl[d]thieno[2,3-b]pyridin-5-yl)-3-methylpyrimidin-4(3H)-one (1)
  • the synthetic route of target compound 11 is as follows:
  • Step 1 Synthesis of ethyl 3-methyl-2-oxyylidenecyclopentane-1-carboxylate (B11-3)
  • 2-methylcyclopentan-1-one (B11-1) (1.5 g, 15.3 mmol) was dissolved in tetrahydrofuran (20 mL), and NaH (1.34 g, 33.4 mmol, 60%) and diethyl carbonate (3.16 g, 26.8 mmol) were added thereto, and the mixture was reacted at 60°C for 10 h. After the reaction, the mixture 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.
  • Step 3 Synthesis of 1-hydroxy-5-methyl-3-(2-oxa-5-thiahexyl-6-thio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B11-5)
  • Step 4 Synthesis of 4-cyano-5-methyl-3-(2-oxa-5-thiahex-6-ylthio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridin-1-yl trifluoromethanesulfonate (B11-6)
  • Step 5 Synthesis of 5-methyl-1-(1-methyl-6-oxo-pyrimidin-4-yl)-3-(2-oxa-5-thiahex-6-ylthio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B11-7)
  • Step 6 Synthesis of 3-((((2-methoxyethyl)(oxyylidene)- ⁇ 4 -thio]methyl ⁇ thio)-5-methyl-1-(1-methyl-6-oxyylidenepyrimidin-4-yl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B11-8)
  • the mixture was diluted with water (10 mL), quenched by adding saturated sodium sulfite solution (10 mL), neutralized by 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 obtain a crude product.
  • Step 7 Synthesis of 6-(1-amino-2-((2-methoxyethyl)sulfinyl)-8-methyl-7,8-dihydro-6H-cyclopentadienyl[d]thieno[2,3-b]pyridin-5-yl)-3-methylpyrimidin-4(3H)-one (Compound 11)
  • the synthetic route of target compound 12 is as follows:
  • Step 1 Synthesis of ethyl 3,3-dimethyl-2-oxyylidenecyclopentane-1-carboxylate (B12-2)
  • Step 2 Synthesis of 1-hydroxy-5,5-dimethyl-3-mercapto-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-3)
  • Step 3 Synthesis of 1-hydroxy-5,5-dimethyl-3-(2-oxa-5-thiahexyl-6-thio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-4)
  • Step 4 Synthesis of 4-cyano-5,5-dimethyl-3-(2-oxa-5-thiahexane-6-ylthio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridin-1-yl trifluoromethanesulfonate (B12-5)
  • Step 5 Synthesis of 5,5-dimethyl-1-(1-methyl-6-oxo-pyrimidin-4-yl)-3-(2-oxa-5-thiahex-6-ylthio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-6)
  • Step 6 Synthesis of 3-((((2-methoxyethyl)(oxyylidene)- ⁇ 4 -thio)methyl)thio)-5,5-dimethyl-1-(1-methyl-6-oxyylidenepyrimidin-4-yl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-7)
  • the mixture was diluted with water (10.0 mL), quenched by adding saturated sodium sulfite solution (10 mL), neutralized by 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 Synthesis of 6-(1-amino-2-((2-methoxyethyl)sulfinyl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[1,2-d]thieno[2,3-b]pyridin-5-yl)-3-methyl-3,4-dihydropyrimidin-4-one (Compound 12)
  • Test Example 1 Compound Inhibition Test on 15-PGDH Enzyme
  • 15-PGDH (R&D Systems, catalog number 5660-DH-010) was prepared with Assay Buffer (50mM Tris-HCl, pH 7.5, 0.01% Tween 20 by volume) to twice the final concentration, i.e. 30nM. Then, it was added to a 384 white plate (Cisbio Bioassays, catalog number 66PL384025) at 8 ⁇ l/well. A negative control well was set up, with only Assay Buffer added without enzyme. Then, the compound was prepared with Assay Buffer to 4 times the final concentration, i.e. 4000nM starting, 3-fold dilution, and 10 concentrations.
  • Assay Buffer 50mM Tris-HCl, pH 7.5, 0.01% Tween 20 by volume
  • 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. 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.
  • IPF model idiopathic pulmonary fibrosis model
  • the animals were euthanized, the lungs were removed from the thyroid cartilage (no perfusion was required), 10% formalin was slowly perfused into the lungs until both lungs were filled, the main trachea was ligated and fixed in 10% formalin with a volume of 5-10 times the tissue volume, paraffin tissue sections were made for the left lung, HE staining, Masson Trichrome staining, and the slices were panoramically scanned using a Hamamatsu NanoZoomer Digital Pathology (S210) slice scanner for pathological analysis.
  • S210 Hamamatsu NanoZoomer Digital Pathology
  • 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 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 weight. Oral gavage was started every day on 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 weighed twice a week.
  • IPF model idiopathic pulmonary fibrosis model
  • the animals were euthanized, the lungs were removed from the thyroid cartilage (no perfusion was required), 10% formalin was slowly perfused into the lungs until both lungs were filled, the main trachea was ligated and fixed in 10% formalin with a volume of 5-10 times the tissue volume, paraffin tissue sections were made for the left lung, HE staining, Masson Trichrome staining, and the slices were panoramically scanned using a Hamamatsu NanoZoomer Digital Pathology (S210) slice scanner for pathological analysis.
  • S210 Hamamatsu NanoZoomer Digital Pathology
  • 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 6800g for 6 minutes at 2-8°C, 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

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

Description

15-PGDH抑制剂15-PGDH inhibitors
本申请要求申请日为2022/11/14的中国专利申请2022114199903和申请日为2023/11/3的中国专利申请2023114672465的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese Patent Application No. 2022114199903 filed on November 14, 2022 and Chinese Patent Application No. 2023114672465 filed on November 3, 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15-PGDH抑制剂。The present invention belongs to the field of medicine, and in particular, relates to a 15-PGDH inhibitor.
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，提供了式I所示杂环类化合物、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：
In the first aspect of the present invention, a heterocyclic compound, a solvate, a pharmaceutically acceptable salt, a solvate of a pharmaceutically acceptable salt or a prodrug of Formula I is provided:
其中，in,
环A为C3-C20脂环烃基；Ring A is a C 3 -C 20 alicyclic hydrocarbon group;
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烷氧基或卤代C1-C6烷氧基；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, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1 - C6 alkyl, -NH( C1 - C6 alkyl), C1 - C6 deuterated alkyl, C2 - C6 alkynyl, halogenated C1 - C6 alkyl, hydroxyl C1 - C6 alkyl, C1 - C6 alkylcarbonyl, C1 - C6 alkoxy or halogenated C1 - C6 alkoxy; when 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) alkyl), C 1 -C 6 alkoxy, -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), 3-11-membered heterocycloalkyl, or -(C 1 -C 6 alkylene)-(3-11-membered heterocycloalkyl); 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;
R1-1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、C1-C6氘代烷基、卤代C1-C6烷基、C1-C6烷氧基或氘代C1-C6烷氧基；R 1-1 is H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or deuterated C 1 -C 6 alkoxy;
R2为氨基、CN或-NHC(O)烷基； R2 is amino, CN or -NHC(O)alkyl;
R3为芳基、3-11元杂环烷基或3-11元杂芳基，其任选地被一个或多个R3-1取代；当取代基为多个时，所述的取代基相同或不同；所述杂原子选自N、O、S中的一种或多种；R 3 is an aryl group, a 3-11-membered heterocycloalkyl group or a 3-11-membered heteroaryl group, which is optionally substituted by one or more R 3-1 ; when there are multiple substituents, the substituents are the same or different; the heteroatom is selected from one or more of N, O, and S;
R3-1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、-O-亚烷基-N(R3-1-1)2、-N(R3-1-1)2、-N(R3-1-1)(亚烷基-OH)、-N(R3-1-1)(亚烷基-O-烷基)、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、-亚烷基-OH、卤代C1-C6烷基、羟基C1-C6烷基、C3-C8环烷基、3-11元杂环烷基、-C(O)N(R3-1-1)2、-C(O)N(R3-1-1)(亚烷基-OH)、-C(O)-C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-C(O)O-C1-C6烷基、-S(O)p-C1-C6烷基或-S(＝O)(＝NR3-1-1)-R3-1-1，其中所述C3-C8环烷基和所述3-11元杂环烷基各自任选地被R3-1-2取代；R 3-1 is H, halogen, hydroxy, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-N(R 3-1-1 ) 2 , -N(R 3-1-1 ) 2 , -N(R 3-1-1 )(alkylene-OH), -N(R 3-1-1 )(alkylene-O-alkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-11 membered heterocycloalkyl, -C(O)N(R 3-1-1 ) 2 , -C(O)N(R 3-1-1 )(alkylene-OH), -C(O)-C 1 -C R 3-1-1 ; ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​
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(R3-1-3)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-O-亚烷基-N(R3-1-1)2或-N(R3-1-1)2中，两个R3-1-1连同它们所附接的N原子一起形成4-7元杂环，该杂环任选地含有选自O、S、或N的另外的杂原子，并且其中该4-7元杂环任选地被R3-1-4取代；或可替代地，在-S(＝O)(＝NR3-1-1)-R3-1-1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 3-1-3 ) 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 -O-alkylene-N(R 3-1-1 ) 2 or -N(R 3-1-1 ) 2 , two R 3-1-1 together with the N atom to which they are attached form a 4-7 membered heterocyclic ring, which optionally contains an additional heteroatom selected from O, S, or N, and wherein the 4-7 membered heterocyclic ring is optionally substituted by R 3-1-4 ; or alternatively, in -S(＝O)(＝NR 3-1-1 )-R 3-1-1 , 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为羟基、卤素、C1-C6烷基或C1-C6烷氧基；R 3-1-2 is hydroxy, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
R3-1-3是H或C1-C6烷基，或者两个R3-1-3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 3-1-3 is H or C 1 -C 6 alkyl, or two R 3-1-3 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;
R3-1-4为卤素、C1-C6烷基或C1-C6烷氧基；R 3-1-4 is halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
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，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；所述杂环烷基的杂原子选自N、O、S中的一种或多种，杂原子的个数为1、2或3个。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), 3-11-membered heterocycloalkyl, or -( C1 - C6 alkylene)-(3-11 - membered heterocycloalkyl); and, R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, the substituents are the same or different; the heteroatoms of the heterocycloalkyl are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2 or 3.
在本发明一优选实施方案中，R1-1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、C1-C6氘代烷基、卤代C1-C6烷基、C1-C6烷氧基或氘代C1-C6烷氧基；所述亚烷基为C1-C6亚烷基。 In a preferred embodiment of the present invention, R 1-1 is H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or deuterated C 1 -C 6 alkoxy; the alkylene is C 1 -C 6 alkylene.
在本发明一优选实施方案中，R2为氨基、CN或-NHC(O)烷基；所述烷基为C1-C6烷基。In a preferred embodiment of the present invention, R 2 is amino, CN or -NHC(O)alkyl; the alkyl is C 1 -C 6 alkyl.
在本发明一优选实施方案中，R3为芳基、3-11元杂环烷基或3-11元杂芳基，其任选地被一个或多个R3-1取代；当取代基为多个时，所述的取代基相同或不同；所述杂环烷基和杂芳基中的杂原子选自N、O、S中的一种或多种，杂原子的个数为1、2或3个；所述芳基为6-10元芳基。In a preferred embodiment of the present invention, R 3 is an aryl group, a 3-11-membered heterocycloalkyl group or a 3-11-membered heteroaryl group, which is optionally substituted by one or more R 3-1 ; when there are multiple substituents, the substituents are the same or different; the heteroatoms in the heterocycloalkyl group and the heteroaryl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2 or 3; the aryl group is a 6-10-membered aryl group.
在本发明一优选实施方案中，R3-1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、-O-亚烷基-N(R3-1-1)2、-N(R3-1-1)2、-N(R3-1-1)(亚烷基-OH)、-N(R3-1-1)(亚烷基-O-烷基)、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、-亚烷基-OH、卤代C1-C6烷基、羟基C1-C6烷基、C3-C8环烷基、3-11元杂环烷基、-C(O)N(R3-1-1)2、-C(O)N(R3-1-1)(亚烷基-OH)、-C(O)-C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-C(O)O-C1-C6烷基、-S(O)p-C1-C6烷基或-S(＝O)(＝NR3-1-1)-R3-1-1，其中所述C3-C8环烷基和所述3-11元杂环烷基各自任选地被R3-1-2取代；所述亚烷基为C1-C6亚烷基；所述烷基为C1-C6烷基；所述杂环烷基的杂原子选自N、O、S中的一种或多种，杂原子的个数为1、2或3个。In a preferred embodiment of the present invention, R 3-1 is H, halogen, hydroxy, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-N(R 3-1-1 ) 2 , -N(R 3-1-1 ) 2 , -N(R 3-1-1 )(alkylene-OH), -N(R 3-1-1 )(alkylene-O-alkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-11 membered heterocycloalkyl, -C(O)N(R 3-1-1 ) 2 , -C(O)N(R 3-1-1 )(alkylene-OH), -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, -C(O)OC 1 -C 6 alkyl, -S(O) p -C 1 -C 6 alkyl or -S(＝O)(＝NR 3-1-1 )-R 3-1-1 , wherein the C 3 -C 8 cycloalkyl and the 3-11 membered heterocycloalkyl are each optionally substituted by R 3-1-2 ; the alkylene is C 1 -C 6 alkylene; the alkyl is C 1 -C 6 alkyl; the heteroatoms of the heterocycloalkyl are selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3.
在本发明一优选实施方案中，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(R3-1-3)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-O-亚烷基-N(R3-1-1)2或-N(R3-1-1)2中，两个R3-1-1连同它们所附接的N原子一起形成4-7元杂环，该杂环含有N和任选的含有O或S的杂原子，并且其中该4-7元杂环任选地被R3-1-4取代；或可替代地，在-S(＝O)(＝NR3-1-1)-R3-1-1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；所述亚烷基为C1-C6亚烷基；所述烷基为C1-C6烷基。In a preferred embodiment of the present invention, 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 3-1-3 ) 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 -O-alkylene-N(R 3-1-1 ) 2 or -N(R 3-1-1 ) 2 , two R 3-1-1 together with the N atom to which they are attached form a 4-7 membered heterocyclic ring containing N and optionally a heteroatom containing O or S, and wherein the 4-7 membered heterocyclic ring is optionally substituted by R 3-1-4 ; or alternatively, in -S(＝O)(＝NR 3-1-1 )-R 3-1-1 , 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 alkylene group is a C 1 -C 6 alkylene group; and the alkyl group is a C 1 -C 6 alkyl group.
在本发明一优选实施方案中，R3-1-3是H或C1-C6烷基，或者两个R3-1-3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元杂环含有N和任选地含有O或S(O)r的杂原子。In a preferred embodiment of the present invention, R 3-1-3 is H or C 1 -C 6 alkyl, or two R 3-1-3 together with the N atom to which they are attached can form a 4-7 membered heterocyclic ring containing N and optionally containing a heteroatom of O or S(O) r .
在本发明一优选实施方案中，所述环A为C3-C12脂环烃基，较佳地，环A为C3-C7脂环烃基。In a preferred embodiment of the present invention, the ring A is a C 3 -C 12 alicyclic hydrocarbon group, preferably, the ring A is a C 3 -C 7 alicyclic hydrocarbon group.
在本发明一优选实施方案中，所述环A为环戊基、环己基、双环[3.1.0]己基或螺[2.4]庚烷。In a preferred embodiment of the present invention, the ring A is cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl or spiro[2.4]heptane.
在本发明一优选实施方案中，所述Ra为甲基。In a preferred embodiment of the present invention, the Ra is methyl.
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；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 ; 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R1-1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、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, deuterated C 1 -C 3 alkoxy.
在本发明一优选实施方案中，所述R2为-NH2、CN或-NH-C(O)-CH3。In a preferred embodiment of the present invention, R 2 is -NH 2 , CN or -NH-C(O)-CH 3 .
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R3-1为H、甲基、氧代、-NHCH3或-S(＝O)(＝NCH3)-CH3。In a preferred embodiment of the present invention, the R 3-1 is H, methyl, oxo, -NHCH 3 or -S(=O)(=NCH 3 )-CH 3 .
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.
在本发明的第二方面，提供了式I-1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 second aspect of the present invention, there is provided a compound of formula I-1, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof:
其中，X1、X2、X3、X4和X5各自独立地表示环原子；X1、X2、X3、X4和X5各自独立地为N、O、S、CH2、CH或C；X4、X5之间所连接的键为单键或双键；B不存在，或者B与X4、X5环原子一起形成3-7元杂环烷基、5元杂芳环或6元杂芳环；所述杂原子选自N、O、S中的一种或多种；Rb、Rc各自独立地为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、-O-亚烷基-N(R3-1-1)2、-N(R3-1-1)2、-N(R3-1-1)(亚烷基-OH)、-N(R3-1-1)(亚烷基-O-烷基)、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、-亚烷基-OH、卤代C1-C6烷基、羟基C1-C6烷基、C3-C8环烷基、3-11元杂环烷基、-C(O)N(R3-1-1)2、-C(O)N(R3-1-1)(亚烷基-OH)、-C(O)-C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-C(O)O-C1-C6烷基、-S(O)p-C1-C6烷基、或-S(＝O)(＝NR3-1-1)-R3-1-1；当所述Rb或Rc为多个取代基时，所述的取代基相同或不同；s、t分别为0、1或2；R1、R2、R3-1-1、Ra、p和m的定义如本发明第一方面中所述。 wherein X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a ring atom; X 1 , X 2 , X 3 , X 4 and X 5 each independently represent N, O, S, CH 2 , CH or C; the bond connecting X 4 and X 5 is a single bond or a double bond; B is absent, or B forms a 3-7 membered heterocycloalkyl, a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring together with the ring atoms of X 4 and X 5 ; the heteroatom is selected from one or more of N, O and S; R b and R c each independently represent H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-N(R 3-1-1 ) 2 , -N(R 3-1-1 ) 2 , -N(R 3-1-1 )(alkylene-OH), -N(R -C(O)-C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-11 membered heterocycloalkyl, -C(O)N(R 3-1-1 )2, -C(O)N(R 3-1-1 )(alkylene-OH), -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, -C(O)OC 1 -C 6 alkyl, -S(O) p -C 1 -C 6 alkyl, or -S(＝O)(＝NR 3-1-1 )-R 3-1-1 ; when said R b or R When c is a plurality of substituents, the substituents are the same or different; s and t are 0, 1 or 2 respectively; R 1 , R 2 , R 3-1-1 , Ra , p and m are defined as described in the first aspect of the present invention.
在本发明一优选实施方案中，B不存在，或者B与X4、X5环原子一起形成3-7元杂环烷基、5元杂芳环或6元杂芳环；所述杂环烷基和杂芳基中的杂原子选自N、O、S中的一种或多种。In a preferred embodiment of the present invention, B is absent, or B, together with X 4 and X 5 ring atoms, forms a 3-7 membered heterocycloalkyl, a 5 membered heteroaromatic ring or a 6 membered heteroaromatic ring; the heteroatoms in the heterocycloalkyl and heteroaromatic groups are selected from one or more of N, O and S.
在本发明一优选实施方案中，所述亚烷基为C1-C6亚烷基。In a preferred embodiment of the present invention, the alkylene group is a C 1 -C 6 alkylene group.
在本发明一优选实施方案中，所述选自含有1个或多个杂原子的6元杂芳基、6元杂芳基并3-7元杂环烷基、6元杂芳基并5-6元杂芳基；所述杂原子选自N、O或S。 In a preferred embodiment of the present invention, It is selected from 6-membered heteroaryl, 6-membered heteroaryl and 3-7-membered heterocycloalkyl, 6-membered heteroaryl and 5-6-membered heteroaryl containing 1 or more heteroatoms; the heteroatom is selected from N, O or S.
在本发明一优选实施方案中，所述选自吡啶、嘧啶、哒嗪、吡啶并环丁基、吡啶并环戊基、吡啶并咪唑、吡啶并吡唑、吡啶并呋喃、吡啶并嘧啶、吡啶并噻吩、吡啶并噻唑。In a preferred embodiment of the present invention, Selected from pyridine, pyrimidine, pyridazine, pyridocyclobutyl, pyridocyclopentyl, pyridoimidazole, pyridopyrazole, pyridofuran, pyridopyrimidine, pyridothiophene, pyridothiazole.
在本发明一优选实施方案中，所述选自吡啶、嘧啶、吡啶并吡唑。In a preferred embodiment of the present invention, Selected from pyridine, pyrimidine, pyridopyrazole.
在本发明一优选实施方案中，所述选自吡啶、嘧啶、 In a preferred embodiment of the present invention, Selected from pyridine, pyrimidine,
在本发明一优选实施方案中，所述Rb、Rc各自独立地为H、卤素、羟基、氨基、硝基、氰基、羰基、氧代、羧基、-NH(C1-C6烷基)、-O-亚烷基-OH、-O-亚烷基-NH2、-NH(亚烷基-OH)、-NH(亚烷基-O-烷基)、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、-亚烷基-OH、卤代C1-C6烷基、羟基C1-C6烷基、C3-C6环烷基、3-7元杂环烷基、-C(O)NH2、-C(O)NH(亚烷基-OH)、-C(O)-C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-C(O)O-C1-C6烷基、-S(O)2-C1-C6烷基或-S(＝O)(＝NCH3)-C1-C6烷基；优选地，所述亚烷基为C1-C6亚烷基。In a preferred embodiment of the present invention, R b and R c are each independently H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-NH 2 , -NH(alkylene-OH), -NH(alkylene-O-alkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(O)NH 2 , -C(O)NH(alkylene-OH), -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, -C(O)OC 1 -C 6 alkyl, -S(O) 2 -C 1 -C 6 alkyl or -S(═O)(═NCH 3 )-C 1 -C 6 alkyl; preferably, the alkylene group is a C 1 -C 6 alkylene group.
在本发明一优选实施方案中，所述Rb、Rc各自独立地为H、氧代、C1-C4烷基、-NH(C1-C4烷基)、C1-C4氘代烷基、C2-C4炔基、卤代C1-C4烷基、羟基C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基。In a preferred embodiment of the present invention, R b and R c are each independently H, oxo, C 1 -C 4 alkyl, -NH(C 1 -C 4 alkyl), C 1 -C 4 deuterated alkyl, C 2 -C 4 alkynyl, halogenated C 1 -C 4 alkyl, hydroxyl C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy.
在本发明一优选实施方案中，所述Rb、Rc各自独立地为H、氧代、甲基、-NHCH3、-S(＝O)(＝NCH3)-CH3。In a preferred embodiment of the present invention, R b and R c are each independently H, oxo, methyl, -NHCH 3 , or -S(=O)(=NCH 3 )-CH 3 .
在本发明的第三方面，提供了式I-2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 third aspect of the present invention, there is provided a compound of formula I-2, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof:
其中，X1、X2、X3和X4各自独立地表示环原子；X1、X2、X3和X4各自独立地为N、O、S、CH2、CH或C；Rb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、-O-亚烷基-N(R3-1-1)2、-N(R3-1-1)2、-N(R3-1-1)(亚烷基-OH)、-N(R3-1-1)(亚烷基-O-烷基)、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、-亚烷基-OH、卤代C1-C6烷基、羟基C1-C6烷基、C3-C8环烷基、3-11元杂环烷基、-C(O)N(R3-1-1)2、-C(O)N(R3-1-1)(亚烷基-OH)、-C(O)-C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-C(O)O-C1-C6烷基、-S(O)p-C1-C6烷基、或-S(＝O)(＝NR3- 1-1)-R3-1-1；当所述Rb为多个取代基时，所述的取代基相同或不同；s为0、1或2；R1、R2、R3-1-1、Ra、 p和m的定义如本发明第一方面中所述。 wherein X 1 , X 2 , X 3 and X 4 each independently represent a ring atom; X 1 , X 2 , X 3 and X 4 each independently represent N, O, S, CH 2 , CH or C; R b is H, halogen, hydroxy, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-N(R 3-1-1 ) 2 , -N(R 3-1-1 ) 2 , -N(R 3-1-1 )(alkylene-OH), -N(R 3-1-1 )(alkylene-O-alkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 6 8- cycloalkyl, 3-11-membered heterocycloalkyl, -C(O)N(R 3-1-1 )2, -C(O)N(R 3-1-1 )(alkylene-OH), -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, -C(O)OC 1 -C 6 alkyl, -S(O) p -C 1 -C 6 alkyl, or -S(＝O)(＝NR 3-1-1 )-R 3-1-1 ; when R b is a plurality of substituents, the substituents are the same or different; s is 0, 1 or 2; R 1 , R 2 , R 3-1-1 , Ra , p and m are as defined in the first aspect of the present invention.
在本发明一优选实施方案中，所述亚烷基为C1-C6亚烷基。In a preferred embodiment of the present invention, the alkylene group is a C 1 -C 6 alkylene group.
在本发明一优选实施方案中，所述为 In a preferred embodiment of the present invention, for
在本发明一优选实施方案中，所述卤素为F、Cl、Br或I。In a preferred embodiment of the present invention, the halogen is F, Cl, Br or I.
在本发明一优选实施方案中，所述烷基为C1-C6烷基，优选为C1-C4烷基，优选为甲基、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, the alkyl group is a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group.
在本发明一优选实施方案中，所述C1-C6卤代烷基为-CvFw，其中v＝1至3，w＝1至(2v+1)，例如三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基或七氯丙基。In a preferred embodiment of the present invention, the C 1 -C 6 haloalkyl group is -CvFw, wherein v=1 to 3, w=1 to (2v+1), such as trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl or heptachloropropyl.
在本发明一优选实施方案中，所述C3-C8环烷基为环丙基、环丁基、环戊基、环己基或环庚基。In a preferred embodiment of the present invention, the C 3 -C 8 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
在本发明一优选实施方案中，所述亚烷基为C1-C6亚烷基，优选为C1-C4亚烷基，例如亚甲基、亚乙基、亚正丙基、亚异丙基、亚正丁基、亚异丁基、亚仲丁基或亚叔丁基。In a preferred embodiment of the present invention, the alkylene group is a C 1 -C 6 alkylene group, preferably a C 1 -C 4 alkylene group, such as methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene or tert-butylene.
在本发明一优选实施方案中，所述C1-C6烷氧基为C1-C4烷氧基，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。In a preferred embodiment of the present invention, the C 1 -C 6 alkoxy group is a C 1 -C 4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
在本发明一优选实施方案中，所述3-11元杂环烷基为5-6元杂环烷基。In a preferred embodiment of the present invention, the 3-11 membered heterocycloalkyl group is a 5-6 membered heterocycloalkyl group.
在本发明一优选实施方案中，所述3-11元杂环烷基的杂原子选自N、O、S中的一种或多种；杂原子的个数为1、2或3。In a preferred embodiment of the present invention, the heteroatoms of the 3-11 membered heterocycloalkyl are selected from one or more of N, O, and S; and the number of the heteroatoms is 1, 2 or 3.
在本发明一优选实施方案中，R3中所述芳基为6-10元芳基，例如苯基或萘基。In a preferred embodiment of the present invention, the aryl group in R 3 is a 6-10 membered aryl group, such as phenyl or naphthyl.
在本发明一优选实施方案中，R3中所述杂原子为所述3-11元杂环烷基或3-11元杂芳基中的杂原子。In a preferred embodiment of the present invention, the heteroatom in R 3 is a heteroatom in the 3-11-membered heterocycloalkyl or 3-11-membered heteroaryl.
在本发明一优选实施方案中，所述4-7元杂环为4-7元杂环烷基。In a preferred embodiment of the present invention, the 4-7 membered heterocycle is a 4-7 membered heterocycloalkyl group.
在本发明一优选实施方案中，所述4-7元杂环的杂原子选自N、O、S中的一种或多种；杂原子的个数为1、2或3。In a preferred embodiment of the present invention, the heteroatoms of the 4-7 membered heterocycle are selected from one or more of N, O, and S; and the number of the heteroatoms is 1, 2 or 3.
在本发明一优选实施方案中，所述式I所示杂环类化合物具有式I-3所示结构：
In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I has a structure represented by formula I-3:
其中，R1、R3、Ra、m的定义如本发明第一方面中所述。Wherein, R 1 , R 3 , Ra and m are as defined in the first aspect of the present invention.
在本发明一优选实施方案中，所述式I所示杂环类化合物具有式I-4所示结构：
In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I has a structure represented by formula I-4:
其中，R1、R3、Ra、m的定义如本发明第一方面中所述。Wherein, R 1 , R 3 , Ra and m are as defined in the first aspect of the present invention.
在本发明一优选实施方案中，所述式I所示杂环类化合物具有式I-5所示结构：
In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I has a structure represented by formula I-5:
其中，R1、R3、Ra、m的定义如本发明第一方面中所述。Wherein, R 1 , R 3 , Ra and m are as defined in the first aspect of the present invention.
在本发明一优选实施方案中，所述式I所示杂环类化合物具有式I-6所示结构：
In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I has a structure represented by formula I-6:
其中，R1、R3、Ra、m的定义如本发明第一方面中所述。Wherein, R 1 , R 3 , Ra and m are as defined in the first aspect of the present invention.
在本发明一优选实施方案中，环A为C3-C7环烷基。In a preferred embodiment of the present invention, ring A is C 3 -C 7 cycloalkyl.
在本发明一优选实施方案中，Ra为C1-C6烷基。In a preferred embodiment of the present invention, Ra is C1 - C6 alkyl.
在本发明一优选实施方案中，R1为C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、C1-C4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；In a preferred embodiment of the present invention, 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 4 alkoxy, -(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;
优选的，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)。Preferably, 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).
在本发明一优选实施方案中，R2为氨基。In a preferred embodiment of the present invention, R2 is amino.
在本发明一优选实施方案中，R3为3-11元杂环烷基或3-11元杂芳基，其任选地被一个或多个R3- 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元杂环烷基或3-11元杂芳基中的杂原子选自N、O、S中的一种或多种；杂原子的个数为1、2或3。In a preferred embodiment of the present invention, R3 is a 3-11 membered heterocycloalkyl or 3-11 membered heteroaryl, which is optionally substituted by one or more R3-1 ; when there are multiple substituents, the substituents are the same or different; the heteroatoms in the 3-11 membered heterocycloalkyl or 3-11 membered heteroaryl are selected from one or more of N, O, and S; and the number of heteroatoms is 1, 2 or 3.
在本发明一优选实施方案中，各个R3-1独立地为C1-C6烷基、氧代、-NH(C1-C6烷基)、或-S(＝O)(＝NR3-1-1)-R3-1-1。In a preferred embodiment of the present invention, each R 3-1 is independently C 1 -C 6 alkyl, oxo, —NH(C 1 -C 6 alkyl), or —S(═O)(═NR 3-1-1 )—R 3-1-1 .
在本发明一优选实施方案中，各个R3-1-1独立地为H、C1-C6烷基或C1-C6亚烷基-OH。In a preferred embodiment of the present invention, each R 3-1-1 is independently H, C 1 -C 6 alkyl or C 1 -C 6 alkylene-OH.
在本发明一优选实施方案中，R1为 In a preferred embodiment of the present invention, R 1 is
在本发明一优选实施方案中，R3为 其各自任选地被一个或多个上述R3-1取代。In a preferred embodiment of the present invention, R 3 is Each of which is optionally substituted with one or more of the above-mentioned R 3-1 .
在本发明一优选实施方案中，R3为 In a preferred embodiment of the present invention, R 3 is
在本发明一优选实施方案中，所述式I所示杂环类化合物为式I-7所示杂环类化合物，
In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is a heterocyclic compound represented by formula I-7,
其中，环A为C3-C7脂环烃基；Wherein, Ring A is a C 3 -C 7 alicyclic hydrocarbon group;
各个Ra独立地为C1-C6烷基；Each Ra is independently C1 - C6 alkyl;
m为0、1或2；m is 0, 1 or 2;
R1为C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、C1-C6烷氧基或-(C1-C6亚烷基)-(C1-C6烷氧基)； R1 is C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy or -( C1 - C6 alkylene)-( C1 - C6 alkoxy);
R2为氨基、CN或-NH-C(O)-CH3；R 2 is amino, CN or -NH-C(O)-CH 3 ;
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；所述杂环烷基和杂芳基的杂原子选自N、O、S中的一种或多种；杂原子的个数为1、2或3；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 ; the heteroatoms of the heterocycloalkyl and heteroaryl are selected from one or more of N, O, and S; the number of heteroatoms is 1, 2, or 3;
各个R3-1独立地为羟基、氧代、C1-C6烷基、-NH(C1-C6烷基)或-S(＝O)(＝NR3-1-1)-R3-1-1；Each R 3-1 is independently hydroxy, oxo, C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), or -S(═O)(═NR 3-1-1 )-R 3-1-1 ;
各个R3-1-1独立地为C1-C6烷基。Each R 3-1-1 is independently a C 1 -C 6 alkyl group.
在本发明一优选实施方案中，所述式I所示杂环类化合物为式I-8所示杂环类化合物，
In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is a heterocyclic compound represented by formula I-8,
其中，环A为C3-C7环烷基；Wherein, Ring A is C 3 -C 7 cycloalkyl;
各个Ra独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；each Ra is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
m为0、1或2；m is 0, 1 or 2;
R1为C1-C4烷基、C3-C6环烷基、-(C1-C4亚烷基)-(C3-C6环烷基)或-(C1-C4亚烷基)-(C1-C4烷氧基)； R1 is C1 - C4 alkyl, C3 - C6 cycloalkyl, -( C1 - C4 alkylene)-( C3 - C6 cycloalkyl) or -( C1 - C4 alkylene)-( C1 - C4 alkoxy);
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；所述杂芳基的杂原子选自N、O、S中的一种或多种；杂原子的个数为1、2或3；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 ; the heteroatom of the heteroaryl group is selected from one or more of N, O, and S; the number of heteroatoms is 1, 2 or 3;
各个R3-1独立地为氧代、C1-C6烷基、-NH(C1-C6烷基)或-S(＝O)(＝NR3-1-1)-R3-1-1；Each R 3-1 is independently oxo, C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), or -S(═O)(═NR 3-1-1 )-R 3-1-1 ;
各个R3-1-1独立地为C1-C6烷基。Each R 3-1-1 is independently a C 1 -C 6 alkyl group.
在本发明一优选实施方案中，所述式I所示杂环类化合物为式I-9所示杂环类化合物，
In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is a heterocyclic compound represented by formula I-9,
其中，环A为环戊基、环己基、双环[3.1.0]己基或螺[2.4]庚烷；wherein Ring A is cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl or spiro[2.4]heptane;
各个Ra独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；each Ra is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
m为0、1或2；m is 0, 1 or 2;
R1为C1-C4烷基、C3-C6环烷基、-(C1-C4亚烷基)-(C3-C6环烷基)或-(C1-C4亚烷基)-(C1-C4烷氧基)； R1 is C1 - C4 alkyl, C3 - C6 cycloalkyl, -( C1 - C4 alkylene)-( C3 - C6 cycloalkyl) or -( C1 - C4 alkylene)-( C1 - C4 alkoxy);
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5-6元杂芳基的杂原子为N，杂原子的个数为1或2；所述8-10元双环杂芳基的杂原子为N，杂原子的个数为1、2或3； R3 is a 5-6 membered heteroaryl group optionally substituted by one or more R3-1 , or an 8-10 membered bicyclic heteroaryl group optionally substituted by one or more R3-1 ; the heteroatom of the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; the heteroatom of the 8-10 membered bicyclic heteroaryl group is N, and the number of heteroatoms is 1, 2 or 3;
各个R3-1独立地为氧代或C1-C6烷基。Each R 3-1 is independently oxo or C 1 -C 6 alkyl.
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:

本发明某一方面，提供了一种式II所示的化合物，
In one aspect of the present invention, there is provided a compound represented by formula II,
其中，Ra、R1、R3、n和m的定义如本发明第一方面中所述；wherein Ra , R1 , R3 , n and m are as defined in the first aspect of the present invention;
例如： For example:
本发明第四方面，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、或第二方面、或第三方面中所述的式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。In a fourth aspect, the present invention provides a pharmaceutical composition, comprising: a compound of formula I as described in the first aspect, the second aspect, or the third 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.
本发明第五方面，提供一种物质的用途，所述的物质为如本发明第一方面、或第二方面、或第三方面中任一所述的式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、其前药或本发明第四方面所述的药物组合物；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。The fifth aspect of the present invention provides a use of a substance, wherein the substance is a heterocyclic compound of formula I as described in any one of the first aspect, the second aspect, or the third aspect of the present invention, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, a prodrug thereof, or the pharmaceutical composition described in the fourth aspect of the present invention; 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.
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。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, one, two or more of: fibrotic diseases, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host diseases, 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 and kidney disease. 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 ulcers), autoinflammatory diseases (such as Behcet's disease), vasculitic syndromes, acute liver injury, acute kidney injury, nonalcoholic fatty liver disease (NASH), atopic dermatitis, psoriasis, interstitial cystitis, prostatitis syndromes (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), renal diseases (such as chronic kidney disease and renal failure), trauma (such as diabetic ulcers, burns, pressure ulcers, acute mucosal injury, including Stevens-Johnson syndrome, mucosal injury (such as mucositis or stomatitis), injury associated with anticancer chemotherapeutic agents (anticancer chemotherapeutic agents mainly such as alkylating agents, DNA synthesis inhibitors, DNA One, two or more of the following: gyrase inhibitors) or antimetabolites, cellular or humoral immunotherapy or radiation-related damage), 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.
在本发明第六方面，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 sixth 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.
在本发明第七方面，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 seventh 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相关的疾病同前所述。The diseases associated with 15-PGDH are the same as described above.
在本发明第八方面，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 eighth 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均可同前所述。The fibrotic disease and the inflammatory disease may be the same as described above.
在本发明第九方面，提供一种治疗15‐PGDH相关的疾病的物质X；所述物质X为式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 ninth aspect of the present invention, a substance X for treating 15-PGDH-related diseases is provided; the substance X is a compound represented by formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof.
所述与15‐PGDH相关的疾病同前所述。The diseases associated with 15-PGDH are the same as described above.
在本发明第九方面，提供一种治疗疾病的物质X；所述物质X为式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 ninth aspect of the present invention, a substance X for treating a disease is provided; the substance X is a compound represented by formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug 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均可同前所述。The fibrotic disease and the inflammatory disease may be the same 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 applications and pharmaceutical compositions, the content of the compound represented by formula I, its solvate, its pharmaceutically acceptable 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 for organizational purposes only and should not be construed as limitations of the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are incorporated herein by reference. The formula is incorporated into this article in its 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0、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。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 0, 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 therein and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.
术语“多个”可以表示例如2、3、4、5、6、7、8、9、10个或更多个。The term "plurality" may mean, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.
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，环A中，当环A为环烷基时， 中的环A均表示为环烷基。例如 中的环A均表示为环戊基。In this application, ring A In the case where ring A is a cycloalkyl group, Ring A in is represented by a cycloalkyl group. Ring A in all of the above is cyclopentyl.
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.
在本申请中，术语“亚烷基”应理解为表示具有1-6个碳原子的直链二价烃基或具有3-6个碳原子的支链二价烃基，除非另有说明，例如亚甲基、亚乙基、亚丙基、1-甲基亚丙基、亚丁基等。In the present application, the term "alkylene" is understood to mean a straight-chain divalent hydrocarbon group having 1 to 6 carbon atoms or a branched divalent hydrocarbon group having 3 to 6 carbon atoms, unless otherwise specified, such as methylene, ethylene, propylene, 1-methylpropylene, butylene, etc.
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 other substituents. The term "mn-membered cycloalkyl" or "C m -C n cycloalkyl" should be understood to mean a saturated carbocyclic ring having m to n 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)碳原子被杂原子取代的环烷基，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 "C m -C n heterocycloalkyl" is understood to mean a saturated ring having m to n 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 "C 4 -C 8 heterocycloalkyl" is understood to mean a saturated ring having 4 to 8 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 atoms. When a prefix such as 4-8 or 4-10 is used to represent a heterocycloalkyl group, the number of carbons is also meant to include the heteroatoms. Monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings are included. Examples of heterocycloalkyl are pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, etc. The term "heterocycloalkyl" can be used interchangeably with the term "heteroalkane 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；例如杂芳基中的吡啶2位被氧代时，即被氧代为再例如吡啶2位被氧代同 时NH被甲基取代时为 When used alone or as part of other substituents, the term "oxo" refers to the replacement of two hydrogen atoms on a methylene group by oxygen atoms, that is, the methylene group is replaced by a carbonyl group; for example, when the pyridine 2 position in a heteroaryl group is replaced by oxygen atoms, that is, Oxygen For example, pyridine 2 is replaced by oxygen When NH is replaced by methyl
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) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.
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, etc. The reagent, starting material, reagent, etc. are appropriately selected. 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 further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. On the basis of 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 solution of the present invention, and such changes should be deemed to be included in the scope of protection of the present invention.
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:
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：氯化钠Saline: Sodium chloride
实施例1：6-(1-氨基-2-((2-甲氧基乙基)亚磺酰基)-7,8-二氢-6H-环戊二烯[d]噻吩并[2,3-b]吡啶-5-基)-3-甲基嘧啶-4(3H)-酮(化合物1)的制备Example 1: Preparation of 6-(1-amino-2-((2-methoxyethyl)sulfinyl)-7,8-dihydro-6H-cyclopentadienyl[d]thieno[2,3-b]pyridin-5-yl)-3-methylpyrimidin-4(3H)-one (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：2-吗啉代环戊-1-烯-1-甲酸乙酯(B1-3)的合成
Step 1: Synthesis of ethyl 2-morpholinocyclopent-1-ene-1-carboxylate (B1-3)
氮气保护下，将2-氧代环戊烷-1-甲酸乙酯(1-1)(5.0g,32.01mmol)和三氯化铈(789mg,3.20mmol)溶于吗啉(4.18g,48.02mmol)中，室温下搅拌18h。旋干，硅胶柱层析(PE/EA(V/V)＝7/3)，得到2-吗啉代环戊-1-烯-1-甲酸乙酯(6.50g,产率90％)。Under nitrogen protection, ethyl 2-oxocyclopentane-1-carboxylate (1-1) (5.0 g, 32.01 mmol) and cerium trichloride (789 mg, 3.20 mmol) were dissolved in morpholine (4.18 g, 48.02 mmol) and stirred at room temperature for 18 h. The mixture was spin-dried and subjected to silica gel column chromatography (PE/EA (V/V) = 7/3) to obtain ethyl 2-morpholinocyclopent-1-ene-1-carboxylate (6.50 g, yield 90%).
LC-MS,M/Z(ESI):226.2[M+H]+。LC-MS, M/Z (ESI): 226.2 [M+H] + .
第二步：1-羟基-3-巯基-6,7-二氢-5H-环戊烷[c]吡啶-4-甲腈(B1-5)的合成
Step 2: Synthesis of 1-hydroxy-3-mercapto-6,7-dihydro-5H-cyclopentane[c]pyridine-4-carbonitrile (B1-5)
将2-吗啉代环戊-1-烯-1-甲酸乙酯(6.50g,28.85mmol)溶于乙醇(20mL)中，向其中加入2-氰基硫代乙酰胺(2.89g,28.85mmol)，室温下搅拌18h。直接过滤，滤饼用乙醇洗涤(5mL*2)，得到1-羟基-3-巯基-6,7-二氢-5H-环戊烷[c]吡啶-4-甲腈(2.21g，产率40％)。Dissolve 2-morpholinocyclopent-1-ene-1-carboxylic acid ethyl ester (6.50 g, 28.85 mmol) in ethanol (20 mL), add 2-cyanothioacetamide (2.89 g, 28.85 mmol), stir at room temperature for 18 h. Filter directly, wash the filter cake with ethanol (5 mL*2), and obtain 1-hydroxy-3-mercapto-6,7-dihydro-5H-cyclopentane[c]pyridine-4-carbonitrile (2.21 g, yield 40%).
LC-MS,M/Z(ESI):193.1[M+H]+。LC-MS, M/Z (ESI): 193.1 [M+H] + .
第三步：1-羟基-3-(((((2-甲氧基乙基)硫代)甲基)硫代)-6,7-二氢-5H-环戊烷[c]吡啶-4-甲腈(B1-7)的合成
Step 3: Synthesis of 1-hydroxy-3-(((((2-methoxyethyl)thio)methyl)thio)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (B1-7)
将1-羟基-3-巯基-6,7-二氢-5H-环戊烷[c]吡啶-4-甲腈(1.0g,5.20mmol)溶于乙腈中(10mL)，向其中加入三乙胺(1.05g,10.40mmol)和(氯甲基)(2-甲氧基乙基)硫烷(805mg,5.72mmol)，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。粗产品通过硅胶柱层析(PE/EA(v/v)＝1/1)得到1-羟基-3-(((((2-甲氧基乙基)硫代)甲基)硫代)-6,7-二氢-5H-环戊烷[c]吡啶-4-甲腈(1.20g，产率78％)。1-Hydroxy-3-mercapto-6,7-dihydro-5H-cyclopentane[c]pyridine-4-carbonitrile (1.0 g, 5.20 mmol) was dissolved in acetonitrile (10 mL), triethylamine (1.05 g, 10.40 mmol) and (chloromethyl)(2-methoxyethyl)sulfane (805 mg, 5.72 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 silica gel column chromatography (PE/EA (v/v) = 1/1) to obtain 1-hydroxy-3-(((((2-methoxyethyl)thio)methyl)thio)-6,7-dihydro-5H-cyclopentane[c]pyridine-4-carbonitrile (1.20 g, yield 78%).
LC-MS,M/Z(ESI):297.1[M+H]+。LC-MS, M/Z (ESI): 297.1 [M+H] + .
第四步：4-氰基-3-((((2-甲氧基乙基)硫代)甲基)硫代)-6,7-二氢-5H-环戊二[c]吡啶-1-基三氟甲磺酸酯(B1-8)的合成
Step 4: Synthesis of 4-cyano-3-((((2-methoxyethyl)thio)methyl)thio)-6,7-dihydro-5H-cyclopentadi[c]pyridin-1-yl trifluoromethanesulfonate (B1-8)
将1-羟基-3-(((((2-甲氧基乙基)硫代)甲基)硫代)-6,7-二氢-5H-环戊烷[c]吡啶-4-甲腈(1.10g,3.71mmol)溶于四氢呋喃中(10mL)，向其中加入1.0M叔丁醇钾溶液(5.57mL,5.57mmol)和N-苯基双(三氟甲烷磺酰)亚胺(1.59g,4.45mmol),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)＝5/1)得到4-氰基-3-((((2-甲氧基乙基)硫代)甲基)硫代)-6,7-二氢-5H-环戊二[c]吡啶-1-基三氟甲磺酸酯(1.21g，产率76％)。1-Hydroxy-3-(((((2-methoxyethyl)thio)methyl)thio)-6,7-dihydro-5H-cyclopentane[c]pyridine-4-carbonitrile (1.10 g, 3.71 mmol) was dissolved in tetrahydrofuran (10 mL), 1.0 M potassium tert-butoxide solution (5.57 mL, 5.57 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (1.59 g, 4.45 mmol) were added thereto, and stirred at room temperature for 16 h. After the reaction was completed, Dilute with water (10 mL), extract three times with ethyl acetate (10 mL), combine the organic phases, wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate to give a crude product. The crude product was purified by column chromatography (PE/EA (v/v) = 5/1) to give 4-cyano-3-((((2-methoxyethyl)thio)methyl)thio)-6,7-dihydro-5H-cyclopentadi[c]pyridin-1-yl trifluoromethanesulfonate (1.21 g, yield 76%).
LC-MS,M/Z(ESI):429.2[M+H]+。LC-MS, M/Z (ESI): 429.2 [M+H] + .
第五步：3-((((2-甲氧乙基)硫基)甲基)硫代)-1-(1-甲基-6-氧代-1,6-二氢嘧啶-4-基)-6,7-二氢-5H-环戊烷[c]吡啶-4-甲腈(B1-10)的合成
Step 5: Synthesis of 3-((((2-methoxyethyl)thio)methyl)thio)-1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (B1-10)
将4-氰基-3-((((2-甲氧基乙基)硫代)甲基)硫代)-6,7-二氢-5H-环戊二[c]吡啶-1-基三氟甲磺酸酯(1.20g，2.80mmol)，3-甲基-6-(三丁基锡基)嘧啶-4(3H)-酮(1.23g，3.08mmol)溶于甲苯(20mL)，加入 双三环己基膦二氯化钯(206mg，0.28mmol)，反应液在110℃反应16h。反应结束后，冷却至室温，向体系中加入饱和氟化钾溶液(50mL)，继续搅拌1h，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(PE/EA(v/v)＝1/2)得到化合物3-((((2-甲氧乙基)硫基)甲基)硫代)-1-(1-甲基-6-氧代-1,6-二氢嘧啶-4-基)-6,7-二氢-5H-环戊烷[c]吡啶-4-甲腈(150mg，产率14％)。4-Cyano-3-((((2-methoxyethyl)thio)methyl)thio)-6,7-dihydro-5H-cyclopentadi[c]pyridin-1-yl trifluoromethanesulfonate (1.20 g, 2.80 mmol) and 3-methyl-6-(tributyltinyl)pyrimidin-4(3H)-one (1.23 g, 3.08 mmol) were dissolved in toluene (20 mL) and added. Bistricyclohexylphosphine palladium dichloride (206 mg, 0.28 mmol), the reaction solution was reacted at 110 ° C for 16 h. After the reaction was completed, it was cooled to room temperature, saturated potassium fluoride solution (50 mL) was added to the system, and stirring was continued for 1 h. 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 subjected to silica gel column chromatography (PE/EA (v/v) = 1/2) to obtain compound 3-((((2-methoxyethyl)thio)methyl)thio)-1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-6,7-dihydro-5H-cyclopentane[c]pyridine-4-carbonitrile (150 mg, yield 14%).
LC-MS,M/Z(ESI):389.2[M+H]+。LC-MS, M/Z (ESI): 389.2 [M+H] + .
第六步：3-((((2-甲氧基乙基)亚磺酰基)甲基)硫代)-1-(1-甲基-6-氧代-1,6-二氢嘧啶-4-基)-6,7-二氢-5H-环戊烷[c]吡啶-4-甲腈(B1-11)的合成
Step 6: Synthesis of 3-((((2-methoxyethyl)sulfinyl)methyl)thio)-1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (B1-11)
将3-((((2-甲氧乙基)硫基)甲基)硫代)-1-(1-甲基-6-氧代-1,6-二氢嘧啶-4-基)-6,7-二氢-5H-环戊烷[c]吡啶-4-甲腈(150mg,386umol)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，粗产品通过柱层析，DCM/MeOH(v/v)＝10/1，得到3-((((2-甲氧基乙基)亚磺酰基)甲基)硫代)-1-(1-甲基-6-氧代-1,6-二氢嘧啶-4-基)-6,7-二氢-5H-环戊烷[c]吡啶-4-甲腈(130mg，产率83％)。3-((((2-methoxyethyl)thio)methyl)thio)-1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (150 mg, 386 umol) 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 column chromatography, and DCM/MeOH (v/v) = 10/1 to give 3-((((2-methoxyethyl)sulfinyl)methyl)thio)-1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-6,7-dihydro-5H-cyclopentane[c]pyridine-4-carbonitrile (130 mg, yield 83%).
LC-MS,M/Z(ESI):405.2[M+H]+。LC-MS, M/Z (ESI): 405.2 [M+H] + .
第七步：6-(1-氨基-2-((2-甲氧基乙基)亚磺酰基)-7,8-二氢-6H-环戊基[d]噻吩并[2,3-b]吡啶-5-基)-3-甲基嘧啶-4(3H)-酮(1)的合成
Step 7: Synthesis of 6-(1-amino-2-((2-methoxyethyl)sulfinyl)-7,8-dihydro-6H-cyclopentyl[d]thieno[2,3-b]pyridin-5-yl)-3-methylpyrimidin-4(3H)-one (1)
将3-((((2-甲氧基乙基)亚磺酰基)甲基)硫代)-1-(1-甲基-6-氧代-1,6-二氢嘧啶-4-基)-6,7-二氢-5H-环戊烷[c]吡啶-4-甲腈(130mg,321μmol)溶于N,N-二甲基甲酰胺(5mL)和甲醇(3mL)，加入氢氧化钾(18mg,321μmol)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，得到6-(1-氨基-2-((2-甲氧基乙基)亚磺酰 基)-7,8-二氢-6H-环戊基[d]噻吩并[2,3-b]吡啶-5-基)-3-甲基嘧啶-4(3H)-酮(化合物1)(52mg,产率40％)。3-((((2-methoxyethyl)sulfinyl)methyl)thio)-1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-6,7-dihydro-5H-cyclopentane[c]pyridine-4-carbonitrile (130 mg, 321 μmol) was dissolved in N,N-dimethylformamide (5 mL) and methanol (3 mL), and an aqueous solution (150 μL) of potassium hydroxide (18 mg, 321 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 chromatographed on a silica gel column with DCM/MeOH (v/v) = 10/1 to obtain 6-(1-amino-2-((2-methoxyethyl)sulfinyl)methyl)thio)-1-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-6,7-dihydro-5H-cyclopentane[c]pyridine-4-carbonitrile 4-(4-(4-(4-(4-(4-(4-(4-(4-thiazolyl)-2-yl)-7,8-dihydro-6H-cyclopentyl[d]thieno[2,3-b]pyridin-5-yl)-3-methylpyrimidin-4(3H)-one (Compound 1) (52 mg, yield 40%).
1H NMR(600MHz,CDCl3)δ8.21(s,1H),7.26(s,1H),5.05(s,2H),3.89–3.84(m,1H),3.70–3.66(m,1H),3.60–3.55(m,4H),3.39(s,3H),3.39–3.32(m,4H),3.30–3.24(m,1H),2.28–2.22(m,2H). 1 H NMR (600 MHz, CDCl 3 ) δ 8.21 (s, 1H), 7.26 (s, 1H), 5.05 (s, 2H), 3.89–3.84 (m, 1H), 3.70–3.66 (m, 1H), 3.60–3.55 (m, 4H), 3.39 (s, 3H), 3.39–3.32 (m, 4H), 3.30–3.24 (m, 1H), 2.28–2.22 (m, 2H).
LC-MS,M/Z(ESI):405.1[M+H]+。LC-MS, M/Z (ESI): 405.1 [M+H] + .
实施例2:6-(1-氨基-2-((2-甲氧基乙基)亚磺酰基)-8-甲基-7,8-二氢-6H-环戊二烯[d]噻吩并[2,3-b]吡啶-5-基)-3-甲基嘧啶-4(3H)-酮(化合物11)的制备Example 2: Preparation of 6-(1-amino-2-((2-methoxyethyl)sulfinyl)-8-methyl-7,8-dihydro-6H-cyclopentadienyl[d]thieno[2,3-b]pyridin-5-yl)-3-methylpyrimidin-4(3H)-one (Compound 11)
目标化合物11的合成路线如下：
The synthetic route of target compound 11 is as follows:
第一步：3-甲基-2-氧亚基环戊烷-1-甲酸乙酯(B11-3)的合成
Step 1: Synthesis of ethyl 3-methyl-2-oxyylidenecyclopentane-1-carboxylate (B11-3)
氮气保护下，将2-甲基环戊-1-酮(B11-1)(1.5g,15.3mmol)溶于四氢呋喃(20mL)中，向其中加入NaH(1.34g,33.4mmol,60％)和碳酸二乙酯(3.16g,26.8mmol),60℃反应10h。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。粗产品通过硅胶柱层析(PE/EA(v/v)＝10/1)，得到3-甲基-2-氧亚基环戊烷-1-甲酸乙酯(B11-3)(2.28g,收率88％)。Under nitrogen protection, 2-methylcyclopentan-1-one (B11-1) (1.5 g, 15.3 mmol) was dissolved in tetrahydrofuran (20 mL), and NaH (1.34 g, 33.4 mmol, 60%) and diethyl carbonate (3.16 g, 26.8 mmol) were added thereto, and the mixture was reacted at 60°C for 10 h. After the reaction, the mixture 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 chromatographed on a silica gel column (PE/EA (v/v) = 10/1) to obtain 3-methyl-2-oxyylidenecyclopentane-1-carboxylic acid ethyl ester (B11-3) (2.28 g, yield 88%).
第二步：1-羟基-5-甲基-3-巯基-6,7-二氢-5H-环戊[c]吡啶-4-甲腈(B11-4)的合成
Step 2: Synthesis of 1-hydroxy-5-methyl-3-mercapto-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (B11-4)
将3-甲基-2-氧亚基环戊烷-1-甲酸乙酯(B11-3)(2g,11.75mmol),叔丁醇钾(2.64g,23.5mmol),2-氰基硫代乙酰胺(1.76g,17.63mmol)溶于10mL二甲基亚砜中，100℃搅拌18h。反应结束后，用水(20mL)稀释，用乙酸乙酯(20mL)萃取三次，合并有机相，用饱和食盐水(20mL)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(DCM/MeOH(v/v)＝8/1)，得1-羟基-5-甲基-3-巯基-6,7-二氢-5H-环戊[c]吡啶-4-甲腈(B11-4)(350mg，收率14％)。3-Methyl-2-oxocyclopentane-1-carboxylic acid ethyl ester (B11-3) (2g, 11.75mmol), potassium tert-butoxide (2.64g, 23.5mmol), 2-cyanothioacetamide (1.76g, 17.63mmol) were dissolved in 10mL dimethyl sulfoxide and stirred at 100°C for 18h. After the reaction was completed, it was diluted with water (20mL), extracted three times with ethyl acetate (20mL), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (DCM/MeOH (v/v) = 8/1) to obtain 1-hydroxy-5-methyl-3-mercapto-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (B11-4) (350mg, yield 14%).
LC-MS,M/Z(ESI):207.1[M+H]+。LC-MS, M/Z (ESI): 207.1 [M+H] + .
第三步：1-羟基-5-甲基-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B11-5)的合成
Step 3: Synthesis of 1-hydroxy-5-methyl-3-(2-oxa-5-thiahexyl-6-thio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B11-5)
将1-羟基-5-甲基-3-巯基-6,7-二氢-5H-环戊[c]吡啶-4-甲腈(B11-4)(1.0g,4.85mmol)溶于乙腈中(10mL)，向其中加入三乙胺(0.98g,9.70mmol)和(氯甲基)(2-甲氧基乙基)硫烷(750mg,5.33mmol)，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1-羟基-5-甲基-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B11-5)(1.10g，收率73％)。1-Hydroxy-5-methyl-3-mercapto-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (B11-4) (1.0 g, 4.85 mmol) was dissolved in acetonitrile (10 mL), triethylamine (0.98 g, 9.70 mmol) and (chloromethyl)(2-methoxyethyl)sulfane (750 mg, 5.33 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 give 1-hydroxy-5-methyl-3-(2-oxa-5-thiahexan-6-ylsulfanyl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B11-5) (1.10 g, yield 73%).
LC-MS,M/Z(ESI):311.1[M+H]+。LC-MS, M/Z (ESI): 311.1 [M+H] + .
第四步：4-氰基-5-甲基-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-1-基三氟甲烷磺酸酯(B11-6)的合成
Step 4: Synthesis of 4-cyano-5-methyl-3-(2-oxa-5-thiahex-6-ylthio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridin-1-yl trifluoromethanesulfonate (B11-6)
将1-羟基-5-甲基-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B11-5)(1.15g,3.70mmol)溶于四氢呋喃中(10mL)，向其中加入1.0M叔丁醇钾溶液(5.57mL,5.57mmol)和N-苯基双(三氟甲烷磺酰)亚胺(1.59g,4.45mmol),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)＝5/1),得到4-氰基-5-甲基-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-1-基三氟甲烷磺酸酯(B11-6)(1.05g，收率64％)。1-Hydroxy-5-methyl-3-(2-oxa-5-thiahex-6-ylthio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B11-5) (1.15 g, 3.70 mmol) was dissolved in tetrahydrofuran (10 mL), 1.0 M potassium tert-butoxide solution (5.57 mL, 5.57 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (1.59 g, 4.45 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) = 5/1) to give 4-cyano-5-methyl-3-(2-oxa-5-thiahexan-6-ylsulfanyl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridin-1-yl trifluoromethanesulfonate (B11-6) (1.05 g, yield 64%).
LC-MS,M/Z(ESI):443.1[M+H]+。LC-MS, M/Z (ESI): 443.1 [M+H] + .
第五步：5-甲基-1-(1-甲基-6-氧亚基嘧啶-4-基)-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B11-7)的合成
Step 5: Synthesis of 5-methyl-1-(1-methyl-6-oxo-pyrimidin-4-yl)-3-(2-oxa-5-thiahex-6-ylthio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B11-7)
将4-氰基-5-甲基-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-1-基三氟甲烷磺酸酯(B11-6)(1.00g，2.26mmol)，3-甲基-6-(三丁基锡基)嘧啶-4(3H)-酮(1.35g，3.39mmol)溶于甲苯(10mL)，加入双三环己基膦二氯化钯(181mg，0.23mmol)，反应液在110℃反应16h。反应结束后，冷却至室温，向体系中加入饱和氟化钾溶液(50mL)，继续搅拌1h，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。粗产品通过柱层析(PE/EA(v/v)＝1/2),得到5-甲基-1-(1-甲基-6-氧亚基嘧啶-4-基)-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B11-7)(120mg，收率13％)。4-Cyano-5-methyl-3-(2-oxa-5-thiahex-6-ylthio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridin-1-yl trifluoromethanesulfonate (B11-6) (1.00 g, 2.26 mmol), 3-methyl-6-(tributyltinyl)pyrimidin-4(3H)-one (1.35 g, 3.39 mmol) were dissolved in toluene (10 mL), bistricyclohexylphosphine palladium dichloride (181 mg, 0.23 mmol) was added, and the reaction solution was reacted at 110°C for 16 h. After the reaction was completed, it was cooled to room temperature, saturated potassium fluoride solution (50 mL) was added to the system, and stirring was continued for 1 h, and 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 column chromatography (PE/EA (v/v) = 1/2) to give 5-methyl-1-(1-methyl-6-oxopyrimidin-4-yl)-3-(2-oxa-5-thiahexan-6-ylsulfanyl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B11-7) (120 mg, yield 13%).
LC-MS,M/Z(ESI):403.2[M+H]+。LC-MS, M/Z (ESI): 403.2 [M+H] + .
第六步：3-((((2-甲氧基乙基)(氧亚基)-λ4-硫基]甲基}硫基)-5-甲基-1-(1-甲基-6-氧亚基嘧啶-4-基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B11-8)的合成
Step 6: Synthesis of 3-((((2-methoxyethyl)(oxyylidene)-λ 4 -thio]methyl}thio)-5-methyl-1-(1-methyl-6-oxyylidenepyrimidin-4-yl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B11-8)
将5-甲基-1-(1-甲基-6-氧亚基嘧啶-4-基)-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B11-7)(120mg,300μmol)溶于氯仿(10mL)和醋酸(1mL)，加入双氧水(20mg,0.60mmol,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3-((((2-甲氧基乙基)(氧亚基)-λ4-硫基]甲基}硫基)-5-甲基-1-(1-甲基-6-氧亚基嘧啶-4-基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B11-8)(100mg，收率80％)。5-Methyl-1-(1-methyl-6-oxoylidenepyrimidin-4-yl)-3-(2-oxa-5-thiahexan-6-ylsulfanyl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B11-7) (120 mg, 300 μmol) was dissolved in chloroform (10 mL) and acetic acid (1 mL), and hydrogen peroxide (20 mg, 0.60 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 by adding saturated sodium sulfite solution (10 mL), neutralized by 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 obtain a crude product. The crude product was purified by column chromatography (DCM/MeOH (v/v) = 10/1) to obtain 3-((((2-methoxyethyl)(oxyylidene)-λ 4 -thio]methyl}thio)-5-methyl-1-(1-methyl-6-oxyylidenepyrimidin-4-yl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B11-8) (100 mg, yield 80%).
LC-MS,M/Z(ESI):419.2[M+H]+ LC-MS, M/Z(ESI):419.2[M+H] +
第七步：6-(1-氨基-2-((2-甲氧基乙基)亚磺酰基)-8-甲基-7,8-二氢-6H-环戊二烯[d]噻吩并[2,3-b]吡啶-5-基)-3-甲基嘧啶-4(3H)-酮(化合物11)的合成
Step 7: Synthesis of 6-(1-amino-2-((2-methoxyethyl)sulfinyl)-8-methyl-7,8-dihydro-6H-cyclopentadienyl[d]thieno[2,3-b]pyridin-5-yl)-3-methylpyrimidin-4(3H)-one (Compound 11)
将3-((((2-甲氧基乙基)(氧亚基)-λ4-硫基]甲基}硫基)-5-甲基-1-(1-甲基-6-氧亚基嘧啶-4-基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B11-8)(100mg,0.24mmol)溶于N,N-二甲基甲酰胺(5mL)和甲醇(3mL)，加入氢氧化钾(10mg,0.24mmol)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)，冻干，得到6-(1-氨基-2-((2-甲氧基乙基)亚磺酰基)-8-甲基-7,8-二氢-6H-环戊二烯[d]噻吩并[2,3-b]吡啶-5-基)-3-甲基嘧啶-4(3H)-酮(化合物11)(50mg,收率50％)。3-((((2-methoxyethyl)(oxyylidene)-λ 4 -thio]methyl}thio)-5-methyl-1-(1-methyl-6-oxyylidenepyrimidin-4-yl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B11-8) (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (5 mL) and methanol (3 mL), and an aqueous solution (150 μL) of potassium hydroxide (10 mg, 0.24 mmol) 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), and the mixture was added with 1N dilute hydrochloric acid (1 mL) was neutralized, ethyl acetate (20 mL × 3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was lyophilized by column chromatography (DCM/MeOH (v/v) = 10/1) to give 6-(1-amino-2-((2-methoxyethyl)sulfinyl)-8-methyl-7,8-dihydro-6H-cyclopentadienyl[d]thieno[2,3-b]pyridin-5-yl)-3-methylpyrimidin-4(3H)-one (Compound 11) (50 mg, yield 50%).
LC-MS,M/Z(ESI):419.2[M+H]+ LC-MS, M/Z(ESI):419.2[M+H] +
1H NMR(400MHz,CDCl3)δ8.21(s,1H),7.28(d,1H),5.08(s,2H),3.92–3.84(m,1H),3.83–3.75(m,1H),3.70(dt,1H),3.65–3.55(m,4H),3.43–3.33(m,5H),3.32–3.24(m,1H),2.40–2.26(m,1H),2.02(dd,1H),1.35(dd,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (s, 1H), 7.28 (d, 1H), 5.08 (s, 2H), 3.92–3.84 (m, 1H), 3.83–3.75 (m, 1H), 3.70 (dt, 1H), 3.65–3.55 (m, 4H), 3.43–3.33 (m, 5H), 3.32–3.24 (m, 1H), 2.40–2.26 (m, 1H), 2.02 (dd, 1H), 1.35 (dd, 3H).
实施例3：6-(1-氨基-2-((2-甲氧基乙基)亚磺酰基)-8,8-二甲基-7,8-二氢-6H-环戊并[1,2-d]噻吩并 [2,3-b]吡啶-5-基)-3-甲基-3,4-二氢嘧啶-4-酮(化合物12)的制备Example 3: 6-(1-amino-2-((2-methoxyethyl)sulfinyl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[1,2-d]thieno Preparation of [2,3-b]pyridin-5-yl)-3-methyl-3,4-dihydropyrimidin-4-one (Compound 12)
目标化合物12的合成路线如下：
The synthetic route of target compound 12 is as follows:
第一步：3,3-二甲基-2-氧亚基环戊烷-1-甲酸乙酯(B12-2)的合成
Step 1: Synthesis of ethyl 3,3-dimethyl-2-oxyylidenecyclopentane-1-carboxylate (B12-2)
氮气保护下，将2,2-二甲基环戊-1-酮(B12-1)(2g,17.8mmol)溶于四氢呋喃(20mL)中，向其中加入NaH(1.43g,35.66mmol,60％)和碳酸二乙酯(10.53g,89.15mmol),60℃反应18h。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)＝10/1)，得到3,3-二甲基-2-氧亚基环戊烷-1-甲酸乙酯(B12-2)(2.50g,收率82％)。Under nitrogen protection, 2,2-dimethylcyclopentan-1-one (B12-1) (2g, 17.8mmol) was dissolved in tetrahydrofuran (20mL), and NaH (1.43g, 35.66mmol, 60%) and diethyl carbonate (10.53g, 89.15mmol) were added thereto, and the reaction was carried out at 60°C for 18h. After the reaction was completed, it was diluted with water (10mL), extracted three times with ethyl acetate (10mL), the organic phases were combined, washed with saturated brine (10mL), 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) = 10/1) to obtain 3,3-dimethyl-2-oxyylidenecyclopentane-1-carboxylic acid ethyl ester (B12-2) (2.50g, yield 82%).
第二步：1-羟基-5,5-二甲基-3-巯基-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B12-3)的合成
Step 2: Synthesis of 1-hydroxy-5,5-dimethyl-3-mercapto-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-3)
将3,3-二甲基-2-氧亚基环戊烷-1-甲酸乙酯(B12-2)(2g,10.86mmol),叔丁醇钾(3.05g,27.14mmol),2-氰基硫代乙酰胺(2.17g,21.71mmol)溶于二甲基亚砜(10mL)中，120℃搅拌18h。反应结束后，用水 (20mL)稀释，用乙酸乙酯(20mL)萃取三次，合并有机相，用饱和食盐水(20mL)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(DCM/MeOH(v/v)＝8/1)，得1-羟基-5,5-二甲基-3-巯基-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B12-3)(210mg，收率9％)。Dissolve 3,3-dimethyl-2-oxocyclopentane-1-carboxylic acid ethyl ester (B12-2) (2 g, 10.86 mmol), potassium tert-butoxide (3.05 g, 27.14 mmol), and 2-cyanothioacetamide (2.17 g, 21.71 mmol) in dimethyl sulfoxide (10 mL) and stir at 120 ° C for 18 h. After the reaction is completed, wash with water (20mL), extracted three times with ethyl acetate (20mL), combined organic phases, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (DCM/MeOH (v/v) = 8/1) to give 1-hydroxy-5,5-dimethyl-3-mercapto-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-3) (210 mg, yield 9%).
LC-MS,M/Z(ESI):221.1[M+H]+。LC-MS, M/Z (ESI): 221.1 [M+H] + .
第三步：1-羟基-5,5-二甲基-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B12-4)的合成
Step 3: Synthesis of 1-hydroxy-5,5-dimethyl-3-(2-oxa-5-thiahexyl-6-thio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-4)
将1-羟基-5,5-二甲基-3-巯基-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B12-3)(2.0g,9.1mmol)溶于乙腈中(20mL)，向其中加入三乙胺(1.84g,18.16mmol)和(氯甲基)(2-甲氧基乙基)硫烷(1.40g,9.99mmol),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1-羟基-5,5-二甲基-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B12-4)(1.88g，收率64％)。1-Hydroxy-5,5-dimethyl-3-mercapto-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-3) (2.0 g, 9.1 mmol) was dissolved in acetonitrile (20 mL), triethylamine (1.84 g, 18.16 mmol) and (chloromethyl)(2-methoxyethyl)sulfane (1.40 g, 9.99 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 give 1-hydroxy-5,5-dimethyl-3-(2-oxa-5-thiahexan-6-ylsulfanyl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-4) (1.88 g, yield 64%).
LC-MS,M/Z(ESI):325.1[M+H]+。LC-MS, M/Z (ESI): 325.1 [M+H] + .
第四步：4-氰基-5,5-二甲基-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-1-基三氟甲烷磺酸酯(B12-5)的合成
Step 4: Synthesis of 4-cyano-5,5-dimethyl-3-(2-oxa-5-thiahexane-6-ylthio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridin-1-yl trifluoromethanesulfonate (B12-5)
将1-羟基-5,5-二甲基-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B12-4)(1.20g,3.70mmol)溶于四氢呋喃中(10mL)，向其中加入1.0M叔丁醇钾溶液(5.57mL,5.57mmol)和N-苯基双(三氟甲烷磺酰)亚胺(1.59g,4.45mmol)，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)＝5/1),得到4-氰基-5,5-二甲基-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-1-基三氟甲烷磺酸酯(B12-5)(1.00g，收率59％)。1-Hydroxy-5,5-dimethyl-3-(2-oxa-5-thiahexane-6-ylthio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-4) (1.20 g, 3.70 mmol) was dissolved in tetrahydrofuran (10 mL), 1.0 M potassium tert-butoxide solution (5.57 mL, 5.57 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (1.59 g, 4.45 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) = 5/1) to give 4-cyano-5,5-dimethyl-3-(2-oxa-5-thiahexan-6-ylsulfanyl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridin-1-yl trifluoromethanesulfonate (B12-5) (1.00 g, yield 59%).
LC-MS,M/Z(ESI):457.1[M+H]+。 LC-MS, M/Z (ESI): 457.1 [M+H] + .
第五步：5,5-二甲基-1-(1-甲基-6-氧亚基嘧啶-4-基)-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B12-6)的合成
Step 5: Synthesis of 5,5-dimethyl-1-(1-methyl-6-oxo-pyrimidin-4-yl)-3-(2-oxa-5-thiahex-6-ylthio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-6)
将4-氰基-5,5-二甲基-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-1-基三氟甲烷磺酸酯(B12-5)(1.00g，2.19mmol)，3-甲基-6-(三丁基锡基)嘧啶-4(3H)-酮(1.20g，2.63mmol)溶于甲苯(10mL)，加入双三环己基膦二氯化钯(178mg，0.22mmol)，反应液在110℃反应16h。反应结束后，冷却至室温，向体系中加入饱和氟化钾溶液(50mL)，继续搅拌1h，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。粗产品通过柱层析(PE/EA(v/v)＝1/2),得到5,5-二甲基-1-(1-甲基-6-氧亚基嘧啶-4-基)-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B12-6)(90mg，收率10％)。4-cyano-5,5-dimethyl-3-(2-oxa-5-thiahexane-6-ylthio)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridin-1-yl trifluoromethanesulfonate (B12-5) (1.00 g, 2.19 mmol), 3-methyl-6-(tributyltinyl)pyrimidin-4(3H)-one (1.20 g, 2.63 mmol) were dissolved in toluene (10 mL), bistricyclohexylphosphine palladium dichloride (178 mg, 0.22 mmol) was added, and the reaction solution was reacted at 110 ° C for 16 h. After the reaction was completed, it was cooled to room temperature, saturated potassium fluoride solution (50 mL) was added to the system, and stirring was continued for 1 h, and 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 column chromatography (PE/EA (v/v) = 1/2) to give 5,5-dimethyl-1-(1-methyl-6-oxopyrimidin-4-yl)-3-(2-oxa-5-thiahexan-6-ylsulfanyl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-6) (90 mg, yield 10%).
LC-MS,M/Z(ESI):417.2[M+H]+。LC-MS, M/Z (ESI): 417.2 [M+H] + .
第六步：3-((((2-甲氧基乙基)(氧亚基)-λ4-硫基)甲基)硫基)-5,5-二甲基-1-(1-甲基-6-氧亚基嘧啶-4-基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B12-7)的合成
Step 6: Synthesis of 3-((((2-methoxyethyl)(oxyylidene)-λ 4 -thio)methyl)thio)-5,5-dimethyl-1-(1-methyl-6-oxyylidenepyrimidin-4-yl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-7)
将5,5-二甲基-1-(1-甲基-6-氧亚基嘧啶-4-基)-3-(2-氧杂-5-硫杂己-6-基硫基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B12-6)(90mg,0.22μmol)溶于氯仿(10mL)和醋酸(1mL)，加入双氧水(16mg,0.44mmol,30％纯度)，在30℃反应1小时。反应结束后，用水(10.0mL)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3-((((2-甲氧基乙基)(氧亚基)-λ4-硫基)甲基)硫基)-5,5-二甲基-1-(1-甲基-6-氧亚基嘧啶-4-基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B12-7)(70mg，收率75％)。5,5-Dimethyl-1-(1-methyl-6-oxoylidenepyrimidin-4-yl)-3-(2-oxa-5-thiahexan-6-ylsulfanyl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-6) (90 mg, 0.22 μmol) was dissolved in chloroform (10 mL) and acetic acid (1 mL), and hydrogen peroxide (16 mg, 0.44 mmol, 30% purity) was added and reacted at 30 ° C for 1 hour. After the reaction, the mixture was diluted with water (10.0 mL), quenched by adding saturated sodium sulfite solution (10 mL), neutralized by 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 (DCM/MeOH (v/v) = 10/1) to give 3-((((2-methoxyethyl)(oxyylidene)-λ 4 -thio)methyl)thio)-5,5-dimethyl-1-(1-methyl-6-oxyylidenepyrimidin-4-yl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-7) (70 mg, yield 75%).
LC-MS,M/Z(ESI):433.2[M+H]+ LC-MS, M/Z(ESI):433.2[M+H] +
第七步：6-(1-氨基-2-((2-甲氧基乙基)亚磺酰基)-8,8-二甲基-7,8-二氢-6H-环戊并[1,2-d]噻吩并[2,3-b]吡啶-5-基)-3-甲基-3,4-二氢嘧啶-4-酮(化合物12)的合成
Step 7: Synthesis of 6-(1-amino-2-((2-methoxyethyl)sulfinyl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[1,2-d]thieno[2,3-b]pyridin-5-yl)-3-methyl-3,4-dihydropyrimidin-4-one (Compound 12)
将3-((((2-甲氧基乙基)(氧亚基)-λ4-硫基)甲基)硫基)-5,5-二甲基-1-(1-甲基-6-氧亚基嘧啶-4-基)-6,7-二氢-5H-环戊并[1,2-c]吡啶-4-甲腈(B12-7)(70mg,0.16mmol)溶于N,N-二甲基甲酰胺(5mL)和甲醇(3mL)，加入氢氧化钾(10mg,0.24mmol)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)，冻干，得到6-(1-氨基-2-((2-甲氧基乙基)亚磺酰基)-8,8-二甲基-7,8-二氢-6H-环戊并[1,2-d]噻吩并[2,3-b]吡啶-5-基)-3-甲基-3,4-二氢嘧啶-4-酮(化合物12)(40mg,收率57％)。3-((((2-methoxyethyl)(oxyylidene)-λ 4 -thio)methyl)thio)-5,5-dimethyl-1-(1-methyl-6-oxyylidenepyrimidin-4-yl)-6,7-dihydro-5H-cyclopenta[1,2-c]pyridine-4-carbonitrile (B12-7) (70 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (5 mL) and methanol (3 mL), and an aqueous solution (150 μL) of potassium hydroxide (10 mg, 0.24 mmol) 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 (DCM/MeOH (v/v) = 10/1) and freeze-dried to give 6-(1-amino-2-((2-methoxyethyl)sulfinyl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[1,2-d]thieno[2,3-b]pyridin-5-yl)-3-methyl-3,4-dihydropyrimidin-4-one (Compound 12) (40 mg, yield 57%).
LC-MS,M/Z(ESI):433.2[M+H]+ LC-MS, M/Z(ESI):433.2[M+H] +
1H NMR(400MHz,CDCl3)δ8.28(s,1H),6.61(s,1H),5.03(s,2H),3.83(ddd,1H),3.67–3.60(m,4H),3.54(dd,1H),3.37(s,3H),3.26–3.17(m,1H),2.85(t,2H),2.01(t,2H),1.36(s,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.28 (s, 1H), 6.61 (s, 1H), 5.03 (s, 2H), 3.83 (ddd, 1H), 3.67–3.60 (m, 4H), 3.54 (dd, 1H), 3.37 (s, 3H), 3.26–3.17 (m, 1H), 2.85 (t, 2H), 2.01 (t, 2H), 1.36 (s, 6H).
以下目标化合物参照化合物1的合成方法类似制备得到。


The following target compounds were prepared similarly to the synthesis method of compound 1.


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, catalog number 5660-DH-010) was prepared with Assay Buffer (50mM Tris-HCl, pH 7.5, 0.01% Tween 20 by volume) to twice the final concentration, i.e. 30nM. Then, it was added to a 384 white plate (Cisbio Bioassays, catalog number 66PL384025) at 8μl/well. A negative control well was set up, with only Assay Buffer added without enzyme. Then, the compound was prepared with Assay Buffer to 4 times the final concentration, i.e. 4000nM starting, 3-fold dilution, and 10 concentrations. It was added to the above white plate at 4μl/well, mixed, centrifuged at 1000rpm for 1min, and incubated at 25°C for 10min. At the same time, a positive control well (with only 15-PGDH) and a negative control well (without 15-PGDH) were set up. Then use Assay Buffer to prepare a mixture of NAD + (Sellect. Product No. S2518) and PGE 2 (R&D Systems, Product No. 2296/10). Use Assay Buffer to prepare NAD + and PGE 2 to 4 times the final concentration, namely 2mM and 0.12mM, respectively. Then add 4μl/well to the above white plate, mix well, centrifuge at 1000rpm for 1min, and incubate at 25℃ for 30min for reaction. Use the instrument TECAN SPARK 20M to detect at an excitation wavelength of 340nm and an emission wavelength of 485nm. Use GraphPad Prism 8.0 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
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 production 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), 10% formalin was slowly perfused into the lungs until both lungs were filled, the main trachea was ligated and fixed in 10% formalin with a volume of 5-10 times the tissue volume, paraffin tissue sections were made for the left lung, HE staining, Masson Trichrome staining, and the slices were panoramically scanned 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 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 weight. Oral gavage was started every day on 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 weighed 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), 10% formalin was slowly perfused into the lungs until both lungs were filled, the main trachea was ligated and fixed in 10% formalin with a volume of 5-10 times the tissue volume, paraffin tissue sections were made for the left lung, HE staining, Masson Trichrome staining, and the slices were panoramically scanned 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 up. 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 hepatic 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 cleaning the residual blood in the abdominal cavity, the muscle layer and the fur layer were sutured layer by layer. Pay attention to postoperative care. Drugs were administered on the day of modeling, and the animals were killed on the 1st and 3rd day of administration, and the intact liver tissue was weighed and compared with the model group to evaluate the effect of the drug on 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6800g 2-8℃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 6800g for 6 minutes at 2-8℃, 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.
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 (31)

  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,
    环A为C3-C20脂环烃基；Ring A is a C 3 -C 20 alicyclic hydrocarbon group;
    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烷氧基或卤代C1-C6烷氧基；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, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1 - C6 alkyl, -NH( C1 - C6 alkyl), C1 - C6 deuterated alkyl, C2 - C6 alkynyl, halogenated C1 - C6 alkyl, hydroxyl C1 - C6 alkyl, C1 - C6 alkylcarbonyl, C1 - C6 alkoxy or halogenated C1 - C6 alkoxy; when 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;
    R1-1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、C1-C6氘代烷基、卤代C1-C6烷基、C1-C6烷氧基或氘代C1-C6烷氧基；R 1-1 is H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or deuterated C 1 -C 6 alkoxy;
    R2为氨基、CN或-NHC(O)烷基； R2 is amino, CN or -NHC(O)alkyl;
    R3为芳基、3-11元杂环烷基或3-11元杂芳基，其任选地被一个或多个R3-1取代；当取代基为多个时，所述的取代基相同或不同；所述杂原子选自N、O、S中的一种或多种；R 3 is an aryl group, a 3-11-membered heterocycloalkyl group or a 3-11-membered heteroaryl group, which is optionally substituted by one or more R 3-1 ; when there are multiple substituents, the substituents are the same or different; the heteroatom is selected from one or more of N, O, and S;
    R3-1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、-O-亚烷基-N(R3-1-1)2、-N(R3-1-1)2、-N(R3-1-1)(亚烷基-OH)、-N(R3-1-1)(亚烷基-O-烷基)、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、-亚烷基-OH、卤代C1-C6烷基、羟基C1-C6烷基、C3-C8环烷基、3-11元杂环烷基、-C(O)N(R3-1-1)2、-C(O)N(R3-1-1)(亚烷基-OH)、-C(O)-C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-C(O)O-C1-C6烷基、-S(O)p-C1-C6烷基或-S(＝O)(＝NR3-1-1)-R3-1-1，其中所述C3-C8环烷基和所述3-11元杂环烷基各自任选地被R3-1-2取代；R 3-1 is H, halogen, hydroxy, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-N(R 3-1-1 ) 2 , -N(R 3-1-1 ) 2 , -N(R 3-1-1 )(alkylene-OH), -N(R 3-1-1 )(alkylene-O-alkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-11 membered heterocycloalkyl, -C(O)N(R 3-1-1 ) 2 , -C(O)N(R 3-1-1 )(alkylene-OH), -C(O)-C 1 -C R 3-1-1 ; ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​
    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(R3-1-3)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-O-亚烷基-N(R3-1-1)2或-N(R3-1-1)2中，两个R3-1-1连同它们所附接的N原子一起形成4-7元杂环，该杂环任选地含有选自O、S、或N的另外的杂原子，并且其中该4-7元杂环任选地被R3-1-4取代；或可替代地，在-S(＝O)(＝NR3-1-1)-R3-1-1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 3-1-3 ) 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 -O-alkylene-N(R 3-1-1 ) 2 or -N(R 3-1-1 ) 2 , two R 3-1-1 together with the N atom to which they are attached form a 4-7 membered heterocyclic ring, which optionally contains an additional heteroatom selected from O, S, or N, and wherein the 4-7 membered heterocyclic ring is optionally substituted by R 3-1-4 ; or alternatively, in -S(＝O)(＝NR 3-1-1 )-R 3-1-1 , 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为羟基、卤素、C1-C6烷基或C1-C6烷氧基；R 3-1-2 is hydroxy, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
    R3-1-3是H或C1-C6烷基，或者两个R3-1-3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 3-1-3 is H or C 1 -C 6 alkyl, or two R 3-1-3 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;
    R3-1-4为卤素、C1-C6烷基或C1-C6烷氧基；R 3-1-4 is halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
    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，所述式I所示的杂环类化合物满足以下条件中的一种或多种：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 of formula I satisfies one or more of the following conditions:
    (1)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；所述杂环烷基的杂原子选自N、O、S中的一种或多种，杂原子的个数为1、2或3个；(1) 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 R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, the substituents are the same or different; the heteroatom of the heterocycloalkyl is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2 or 3;
    (2)R1-1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、C1-C6氘代烷基、卤代C1-C6烷基、C1-C6烷氧基或氘代C1-C6烷氧基；所述亚烷基为C1-C6亚烷基；(2) R 1-1 is H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or deuterated C 1 -C 6 alkoxy; the alkylene is C 1 -C 6 alkylene;
    (3)R2为氨基、CN或-NHC(O)烷基；所述烷基为C1-C6烷基；(3) R 2 is amino, CN or -NHC(O)alkyl; the alkyl is C 1 -C 6 alkyl;
    (4)R3为芳基、3-11元杂环烷基或3-11元杂芳基，其任选地被一个或多个R3-1取代；当取代基为多个时，所述的取代基相同或不同；所述杂环烷基和杂芳基中的杂原子选自N、O、S中的一种或多种，杂原子的个数为1、2或3个；所述芳基为6-10元芳基；(4) R 3 is an aryl group, a 3-11-membered heterocycloalkyl group or a 3-11-membered heteroaryl group, which is optionally substituted by one or more R 3-1 ; when there are multiple substituents, the substituents are the same or different; the heteroatoms in the heterocycloalkyl group and the heteroaryl group are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2 or 3; the aryl group is a 6-10-membered aryl group;
    (5)R3-1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、-O-亚烷基-N(R3-1-1)2、-N(R3-1-1)2、-N(R3-1-1)(亚烷基-OH)、-N(R3-1-1)(亚烷基-O-烷基)、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、-亚烷基-OH、卤代C1-C6烷基、羟基C1-C6烷基、C3-C8环烷基、3-11元杂环烷基、-C(O)N(R3-1-1)2、-C(O)N(R3-1-1)(亚烷基-OH)、-C(O)-C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-C(O)O-C1-C6烷基、-S(O)p-C1-C6烷基或-S(＝O)(＝NR3-1-1)-R3-1-1，其中所述C3-C8环烷基和所述3-11元杂环烷基各自任选地被R3-1-2取代；所述亚烷基为C1-C6亚烷基；所述烷基为C1-C6烷基；所述杂环烷基的杂原子选自N、O、S中的一种或多种，杂原子的个数为1、2或3个(5) R 3-1 is H, halogen, hydroxy, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-N(R 3-1-1 ) 2 , -N(R 3-1-1 ) 2 , -N(R 3-1-1 )(alkylene-OH), -N(R 3-1-1 )(alkylene-O-alkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-11 membered heterocycloalkyl, -C(O)N(R 3-1-1 ) 2 , -C(O)N(R 3-1-1 )(alkylene-OH), -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, -C(O)OC 1 -C 6 alkyl, -S(O) p -C 1 -C 6 alkyl or -S(＝O)(＝NR 3-1-1 )-R 3-1-1 , wherein the C 3 -C 8 cycloalkyl and the 3-11 membered heterocycloalkyl are each optionally substituted by R 3-1-2 ; the alkylene is C 1 -C 6 alkylene; the alkyl is C 1 -C 6 alkyl; the heteroatoms of the heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3
    (6)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(R3-1-3)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-O-亚烷基-N(R3-1-1)2或-N(R3-1-1)2中，两个R3-1-1连同它们所附接的N原子一起形成4-7元杂环，该杂环含有N和任选地含有O或S的杂原子，并且其中该4-7元杂环任选地被R3-1-4取代；或可替代地，在-S(＝O)(＝NR3-1-1)-R3-1-1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；所述亚烷基为C1-C6亚烷基；所述烷基为C1-C6烷基；和(6) 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 3-1-3 ) 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 -O-alkylene-N(R 3-1-1 ) 2 or -N(R 3-1-1 ) 2 , two R 3-1-1 together with the N atom to which they are attached form a 4-7 membered heterocyclic ring containing N and optionally containing a heteroatom of O or S, and wherein the 4-7 membered heterocyclic ring is optionally substituted by R 3-1-4 ; or alternatively, in -S(＝O)(＝NR 3-1-1 )-R 3-1-1 , 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 alkylene group is a C 1 -C 6 alkylene group; the alkyl group is a C 1 -C 6 alkyl group; and
    (7)R3-1-3是H或C1-C6烷基，或者两个R3-1-3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元杂环含有N和任选地含有O或S(O)r的杂原子。 (7) R 3-1-3 is H or C 1 -C 6 alkyl, or two R 3-1-3 together with the N atom to which they are attached can form a 4-7 membered heterocyclic ring containing N and optionally containing a heteroatom of O or S(O) r .
  3. 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，所述环A为C3-C12脂环烃基，较佳地，环A为C3-C7脂环烃基。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 ring A is a C 3 -C 12 alicyclic hydrocarbon group, preferably, ring A is a C 3 -C 7 alicyclic hydrocarbon group.
  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，所述环A为环戊基、环己基、双环[3.1.0]己基或螺[2.4]庚烷。The heterocyclic compound of formula I as claimed in claim 3, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt or its prodrug, characterized in that the ring A is cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl or spiro[2.4]heptane.
  5. 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。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 Ra is methyl.
  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, 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 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; R 1-1 has the definition as claimed 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.
  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R1-1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。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.
  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 .
  9. 如权利要求1或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，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或2所述的定义。The heterocyclic compound of formula I as claimed in claim 1 or 2, 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 or 2.
  10. 如权利要求1或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，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或2所述的定义。The heterocyclic compound of formula I as described in claim 1 or 2, 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 or 2.
  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R3-1为H、甲基、氧代、-NHCH3或-S(＝O)(＝NCH3)-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 3-1 is H, methyl, oxo, -NHCH 3 or -S(=O)(=NCH 3 )-CH 3 .
  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，所述的式I所示的杂环类化合物具有式I-1所示结构：
    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 has a structure as shown in formula I-1:
    其中，X1、X2、X3、X4和X5各自独立地表示环原子；wherein X 1 , X 2 , X 3 , X 4 and X 5 each independently represent a ring atom;
    X1、X2、X3、X4和X5各自独立地为N、O、S、CH2、CH或C；X 1 , X 2 , X 3 , X 4 and X 5 are each independently N, O, S, CH 2 , CH or C;
    X4、X5之间所连接的键为单键或双键；The bond between X 4 and X 5 is a single bond or a double bond;
    B不存在，或者B与X4、X5环原子一起形成3-7元杂环烷基、5元杂芳环或6元杂芳环；所述杂原子选自N、O、S中的一种或多种；B is absent, or B, together with X 4 and X 5 ring atoms, forms a 3-7 membered heterocycloalkyl, a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring; the heteroatom is selected from one or more of N, O and S;
    Rb、Rc各自独立地为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、-O-亚烷基-N(R3-1-1)2、-N(R3-1-1)2、-N(R3-1-1)(亚烷基-OH)、-N(R3-1-1)(亚烷基-O-烷基)、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、-亚烷基-OH、卤代C1-C6烷基、羟基C1-C6烷基、C3-C8环烷基、3-11元杂环烷基、-C(O)N(R3-1-1)2、-C(O)N(R3-1-1)(亚烷基-OH)、-C(O)-C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-C(O)O-C1-C6烷基、-S(O)p-C1-C6烷基、或-S(＝O)(＝NR3-1-1)-R3-1-1；当所述Rb或Rc为多个取代基时，所述的取代基相同或不同；R b and R c are each independently H, halogen, hydroxy, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-N(R 3-1-1 ) 2 , -N(R 3-1-1 ) 2 , -N(R 3-1-1 )(alkylene-OH), -N(R 3-1-1 )(alkylene-O-alkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-11 membered heterocycloalkyl, -C(O)N(R 3-1-1 ) 2 , -C(O)N(R 3-1-1 )(alkylene-OH), -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, -C(O)OC 1 -C 6 alkyl, -S(O) p -C 1 -C 6 alkyl, or -S(＝O)(＝NR 3-1-1 )-R 3-1-1 ; when R b or R c is a plurality of substituents, the substituents are the same or different;
    s、t分别为0、1或2；s and t are 0, 1 or 2 respectively;
    R1、R2、R3-1-1、Ra、p和m具有权利要求1所述的定义。R 1 , R 2 , R 3-1-1 , Ra , p and m have the same meanings as those defined in claim 1.
  13. 如权利要求12所述的式I-1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，所述式I-1所示的杂环类化合物满足以下条件中的一种或多种：The heterocyclic compound represented by formula I-1, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt, or its prodrug according to claim 12, characterized in that the heterocyclic compound represented by formula I-1 satisfies one or more of the following conditions:
    (1)B不存在，或者B与X4、X5环原子一起形成3-7元杂环烷基、5元杂芳环或6元杂芳环；所述杂环烷基和杂芳基中的杂原子选自N、O、S中的一种或多种；(1) B is absent, or B, together with the ring atoms of X 4 and X 5 , forms a 3-7-membered heterocycloalkyl, a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring; the heteroatoms in the heterocycloalkyl and heteroaromatic groups are selected from one or more of N, O and S;
    (2)所述亚烷基为C1-C6亚烷基；和(2) the alkylene group is a C 1 -C 6 alkylene group; and
    (3)所述选自含有1个或多个杂原子的6元杂芳基、6元杂芳基并3-7元杂环烷基、6元杂芳基并5-6元杂芳基；所述杂原子选自N、O或S；(3) is selected from 6-membered heteroaryl, 6-membered heteroaryl and 3-7-membered heterocycloalkyl, 6-membered heteroaryl and 5-6-membered heteroaryl containing 1 or more heteroatoms; the heteroatom is selected from N, O or S;
    较佳地，所述选自吡啶、嘧啶、哒嗪、吡啶并环丁基、吡啶并环戊基、吡啶并咪唑、吡啶并吡唑、吡啶并呋喃、吡啶并嘧啶、吡啶并噻吩、吡啶并噻唑； Preferably, the is selected from the group consisting of pyridine, pyrimidine, pyridazine, pyridocyclobutyl, pyridocyclopentyl, pyridoimidazole, pyridopyrazole, pyridofuran, pyridopyrimidine, pyridothiophene, and pyridothiazole;
    较佳地，所述选自吡啶、嘧啶、吡啶并吡唑；Preferably, the is selected from pyridine, pyrimidine, pyridopyrazole;
    更佳地，所述选自吡啶、嘧啶、 More preferably, the Selected from pyridine, pyrimidine,
  14. 如权利要求12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Rb、Rc各自独立地为H、卤素、羟基、氨基、硝基、氰基、羰基、氧代、羧基、-NH(C1-C6烷基)、-O-亚烷基-OH、-O-亚烷基-NH2、-NH(亚烷基-OH)、-NH(亚烷基-O-烷基)、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、-亚烷基-OH、卤代C1-C6烷基、羟基C1-C6烷基、C3-C6环烷基、3-7元杂环烷基、-C(O)NH2、-C(O)NH(亚烷基-OH)、-C(O)-C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-C(O)O-C1-C6烷基、-S(O)2-C1-C6烷基或-S(＝O)(＝NCH3)-C1-C6烷基；优选地，所述亚烷基为C1-C6亚烷基。The heterocyclic compound represented by formula I as claimed in claim 12, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt or its prodrug, characterized in that R b and R c are each independently H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-NH 2 , -NH(alkylene-OH), -NH(alkylene-O-alkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(O)NH 2 , -C(O)NH(alkylene-OH), -C(O)-C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 1 -C 6 alkoxy, -C(O)OC 1 -C 6 alkyl, -S(O) 2 -C 1 -C 6 alkyl or -S(═O)(═NCH 3 )-C 1 -C 6 alkyl; preferably, the alkylene group is a C 1 -C 6 alkylene group.
  15. 如权利要求12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Rb、Rc各自独立地为H、氧代、C1-C4烷基、-NH(C1-C4烷基)、C1-C4氘代烷基、C2-C4炔基、卤代C1-C4烷基、羟基C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基；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 12, characterized in that R b and R c are each independently H, oxo, C 1 -C 4 alkyl, -NH(C 1 -C 4 alkyl), C 1 -C 4 deuterated alkyl, C 2 -C 4 alkynyl, halogenated C 1 -C 4 alkyl , hydroxyl C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy;
    较佳地，所述Rb、Rc各自独立地为H、氧代、甲基、-NHCH3、-S(＝O)(＝NCH3)-CH3。Preferably, R b and R c are each independently H, oxo, methyl, -NHCH 3 , or -S(=O)(=NCH 3 )-CH 3 .
  16. 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，所述的式I所示的杂环类化合物具有式I-2所示结构：
    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 has a structure as shown in formula I-2:
    其中，X1、X2、X3和X4各自独立地表示环原子；wherein X 1 , X 2 , X 3 and X 4 each independently represent a ring atom;
    X1、X2、X3和X4各自独立地为N、O、S、CH2、CH或C；X 1 , X 2 , X 3 and X 4 are each independently N, O, S, CH 2 , CH or C;
    Rb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、-O-亚烷基-N(R3-1-1)2、-N(R3-1-1)2、-N(R3-1-1)(亚烷基-OH)、-N(R3-1-1)(亚烷基-O-烷基)、C1-C6烷基、C1-C6氘代烷基、C2-C6炔基、-亚烷基-OH、卤代C1-C6烷基、羟基C1-C6烷基、C3-C8环烷基、3-11元杂环烷基、-C(O)N(R3-1-1)2、-C(O)N(R3-1-1)(亚烷基-OH)、-C(O)-C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-C(O)O-C1-C6烷基、-S(O)p-C1-C6烷基、或-S(＝O)(＝NR3-1-1)-R3-1-1；当所述Rb为多个取代基时，所述的 取代基相同或不同；R b is H, halogen, hydroxy, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, -O-alkylene-N(R 3-1-1 ) 2 , -N(R 3-1-1 ) 2 , -N(R 3-1-1 )(alkylene-OH), -N(R 3-1-1 )(alkylene-O-alkyl), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, -alkylene-OH, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-11 membered heterocycloalkyl, -C(O)N(R 3-1-1 )2, -C(O)N(R 3-1-1 )(alkylene-OH), -C(O)-C 1 -C 6 alkyl, C 2 -C 6 deuterated alkyl, 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, -C(O)OC 1 -C 6 alkyl, -S(O) p -C 1 -C 6 alkyl, or -S(＝O)(＝NR 3-1-1 )-R 3-1-1 ; when the R b is a plurality of substituents, the The substituents are the same or different;
    s为0、1或2；s is 0, 1, or 2;
    R1、R2、R3-1-1、Ra、p和m具有权利要求1所述的定义。R 1 , R 2 , R 3-1-1 , Ra , p and m have the same meanings as those defined in claim 1.
  17. 如权利要求16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，所述为 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 16, characterized in that: for
    和/或，所述亚烷基为C1-C6亚烷基。And/or, the alkylene group is a C 1 -C 6 alkylene group.
  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，所述式I所示的杂环类化合物满足以下条件中的一种或多种：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 of formula I satisfies one or more of the following conditions:
    (1)所述卤素为F、Cl、Br或I；(1) The halogen is F, Cl, Br or I;
    (2)所述烷基为C1-C6烷基，优选为C1-C4烷基，优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；(2) The alkyl group is a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group;
    (3)所述C1-C6卤代烷基为-CvFw，其中v＝1至3，w＝1至(2v+1)，例如三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基或七氯丙基；(3) The C 1 -C 6 haloalkyl group is -CvFw, wherein v=1 to 3, w=1 to (2v+1), such as trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl or heptachloropropyl;
    (4)所述C3-C8环烷基为环丙基、环丁基、环戊基、环己基或环庚基；(4) The C 3 -C 8 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
    (5)所述亚烷基为C1-C6亚烷基，优选为C1-C4亚烷基，例如亚甲基、亚乙基、亚正丙基、亚异丙基、亚正丁基、亚异丁基、亚仲丁基或亚叔丁基；(5) The alkylene group is a C 1 -C 6 alkylene group, preferably a C 1 -C 4 alkylene group, such as a methylene group, an ethylene group, a n-propylene group, an isopropylene group, a n-butylene group, an isobutylene group, a sec-butylene group or a tert-butylene group;
    (6)所述C1-C6烷氧基为C1-C4烷氧基，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基；(6) The C 1 -C 6 alkoxy group is a C 1 -C 4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;
    (7)所述3-11元杂环烷基为5-6元杂环烷基；(7) The 3-11-membered heterocycloalkyl group is a 5-6-membered heterocycloalkyl group;
    (8)所述3-11元杂环烷基的杂原子选自N、O、S中的一种或多种；杂原子的个数为1、2或3；(8) The heteroatoms of the 3-11 membered heterocycloalkyl group are selected from one or more of N, O, and S; the number of heteroatoms is 1, 2, or 3;
    (9)R3中所述芳基为6-10元芳基，例如苯基或萘基；(9) The aryl group in R 3 is a 6-10 membered aryl group, such as phenyl or naphthyl;
    (10)R3中所述杂原子为所述3-11元杂环烷基或3-11元杂芳基中的杂原子；(10) The heteroatom in R 3 is a heteroatom in the 3-11-membered heterocycloalkyl or 3-11-membered heteroaryl;
    (11)所述4-7元杂环为4-7元杂环烷基；和(11) the 4-7 membered heterocyclic ring is a 4-7 membered heterocycloalkyl ring; and
    (12)所述4-7元杂环的杂原子选自N、O、S中的一种或多种；杂原子的个数为1、2或3。(12) The heteroatom of the 4-7 membered heterocyclic ring is selected from one or more of N, O and S; the number of the heteroatom is 1, 2 or 3.
  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，所述式I所示的杂环类化合物满足以下条件中的一种或多种：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 of formula I satisfies one or more of the following conditions:
    (1)环A为C3-C7环烷基；(1) Ring A is C 3 -C 7 cycloalkyl;
    (2)R1为C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、C1-C4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； (2) R1 is C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C4 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;
    优选的，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)；Preferably, 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);
    更优选的，R1为 More preferably, R1 is
    (3)R2为氨基；(3) R2 is an amino group;
    (4)R3为3-11元杂环烷基或3-11元杂芳基，其任选地被一个或多个R3-1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元杂环烷基或3-11元杂芳基中的杂原子选自N、O、S中的一种或多种；杂原子的个数为1、2或3；(4) R 3 is a 3-11-membered heterocycloalkyl or 3-11-membered heteroaryl, which is optionally substituted by one or more R 3-1 ; when there are multiple substituents, the substituents are the same or different; the heteroatoms in the 3-11-membered heterocycloalkyl or 3-11-membered heteroaryl are selected from one or more of N, O, and S; the number of heteroatoms is 1, 2, or 3;
    优选的，R3为 其各自任选地被一个或多个上述R3-1取代；Preferably, R3 is each of which is optionally substituted with one or more of the above R 3-1 ;
    更优选的，R3为 More preferably, R3 is
    (5)各个R3-1独立地为C1-C6烷基、氧代、-NH(C1-C6烷基)、或-S(＝O)(＝NR3-1-1)-R3-1-1；和(5) each R 3-1 is independently C 1 -C 6 alkyl, oxo, -NH(C 1 -C 6 alkyl), or -S(=O)(=NR 3-1-1 )-R 3-1-1 ; and
    (6)各个R3-1-1独立地为H、C1-C6烷基或C1-C6亚烷基-OH。(6) Each R 3-1-1 is independently H, C 1 -C 6 alkyl or C 1 -C 6 alkylene-OH.
  20. 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，所述式I所示的杂环类化合物满足以下方案一、方案二和方案三中的一种：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 the heterocyclic compound of formula I satisfies one of the following schemes 1, 2 and 3:
    方案一：Option One:
    所述式I所示杂环类化合物为式I-7所示杂环类化合物，
    The heterocyclic compound represented by formula I is a heterocyclic compound represented by formula I-7,
    其中，环A为C3-C7脂环烃基；Wherein, Ring A is a C 3 -C 7 alicyclic hydrocarbon group;
    各个Ra独立地为C1-C6烷基；Each Ra is independently C1 - C6 alkyl;
    m为0、1或2； m is 0, 1 or 2;
    R1为C1-C6烷基、C3-C8环烷基、-(C1-C6亚烷基)-(C3-C8环烷基)、C1-C6烷氧基或-(C1-C6亚烷基)-(C1-C6烷氧基)； R1 is C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy, or -( C1 - C6 alkylene)-( C1 - C6 alkoxy);
    R2为氨基、CN或-NH-C(O)-CH3；R 2 is amino, CN or -NH-C(O)-CH 3 ;
    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；所述杂环烷基和杂芳基的杂原子选自N、O、S中的一种或多种；杂原子的个数为1、2或3；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 ; the heteroatoms of the heterocycloalkyl and heteroaryl are selected from one or more of N, O, and S; the number of heteroatoms is 1, 2, or 3;
    各个R3-1独立地为羟基、氧代、C1-C6烷基、-NH(C1-C6烷基)或-S(＝O)(＝NR3-1-1)-R3-1-1；Each R 3-1 is independently hydroxy, oxo, C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), or -S(═O)(═NR 3-1-1 )-R 3-1-1 ;
    各个R3-1-1独立地为C1-C6烷基；Each R 3-1-1 is independently a C 1 -C 6 alkyl group;
    方案二：Option II:
    所述式I所示杂环类化合物为式I-8所示杂环类化合物，
    The heterocyclic compound represented by formula I is a heterocyclic compound represented by formula I-8,
    其中，环A为C3-C7环烷基；Wherein, Ring A is C 3 -C 7 cycloalkyl;
    各个Ra独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；each Ra is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    m为0、1或2；m is 0, 1 or 2;
    R1为C1-C4烷基、C3-C6环烷基、-(C1-C4亚烷基)-(C3-C6环烷基)或-(C1-C4亚烷基)-(C1-C4烷氧基)； R1 is C1 - C4 alkyl, C3 - C6 cycloalkyl, -( C1 - C4 alkylene)-( C3 - C6 cycloalkyl) or -( C1 - C4 alkylene)-( C1 - C4 alkoxy);
    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；所述杂芳基的杂原子选自N、O、S中的一种或多种；杂原子的个数为1、2或3；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 ; the heteroatom of the heteroaryl group is selected from one or more of N, O, and S; the number of heteroatoms is 1, 2 or 3;
    各个R3-1独立地为氧代、C1-C6烷基、-NH(C1-C6烷基)或-S(＝O)(＝NR3-1-1)-R3-1-1；Each R 3-1 is independently oxo, C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), or -S(═O)(═NR 3-1-1 )-R 3-1-1 ;
    各个R3-1-1独立地为C1-C6烷基；Each R 3-1-1 is independently a C 1 -C 6 alkyl group;
    方案三：third solution:
    所述式I所示杂环类化合物为式I-9所示杂环类化合物，
    The heterocyclic compound represented by formula I is a heterocyclic compound represented by formula I-9,
    其中，环A为环戊基、环己基、双环[3.1.0]己基或螺[2.4]庚烷；wherein Ring A is cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl or spiro[2.4]heptane;
    各个Ra独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； each Ra is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    m为0、1或2；m is 0, 1 or 2;
    R1为C1-C4烷基、C3-C6环烷基、-(C1-C4亚烷基)-(C3-C6环烷基)或-(C1-C4亚烷基)-(C1-C4烷氧基)； R1 is C1 - C4 alkyl, C3 - C6 cycloalkyl, -( C1 - C4 alkylene)-( C3 - C6 cycloalkyl) or -( C1 - C4 alkylene)-( C1 - C4 alkoxy);
    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5-6元杂芳基的杂原子为N，杂原子的个数为1或2；所述8-10元双环杂芳基的杂原子为N，杂原子的个数为1、2或3； R3 is a 5-6 membered heteroaryl group optionally substituted by one or more R3-1 , or an 8-10 membered bicyclic heteroaryl group optionally substituted by one or more R3-1 ; the heteroatom of the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; the heteroatom of the 8-10 membered bicyclic heteroaryl group is N, and the number of heteroatoms is 1, 2 or 3;
    各个R3-1独立地为氧代或C1-C6烷基。Each R 3-1 is independently oxo or C 1 -C 6 alkyl.
  21. 如权利要求1-20中任一项所述的式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，所述的式I所示的杂环类化合物具有如下所示结构：
    The heterocyclic compound represented by Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof according to any one of claims 1 to 20, characterized in that the heterocyclic compound represented by Formula I has the following structure:
    其中，R1、R3、Ra、m具有如权利要求1-20中任一项所述的定义。wherein R 1 , R 3 , Ra and m have the meanings as defined in any one of claims 1-20.
  22. 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:

  23. 一种式II所示的化合物，
    A compound represented by formula II,
    其中，Ra、R1、R3、n和m的定义如权利要求22所述； wherein Ra , R1 , R3 , n and m are as defined in claim 22;
    例如： For example:
  24. 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1-22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 22, 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.
  25. 一种物质的用途，其特征在于，所述的物质为如权利要求1-22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、其前药或权利要求24所述的药物组合物；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 22, 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 24;
    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。The use is to prepare a 15-PGDH inhibitor, or to prepare a drug for preventing and/or treating a disease associated with 15-PGDH.
  26. 如权利要求25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 25, 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.
  27. 如权利要求26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；The use according to claim 26, 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;
    所述的肺纤维化优选为特发性肺纤维化；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；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;
    所述的炎症性肠病优选为溃疡性结肠炎和/或克罗恩氏病；The inflammatory bowel disease is preferably ulcerative colitis and/or Crohn's disease;
    所述的消化性溃疡优选为NSAID诱导的溃疡；The peptic ulcer is preferably an ulcer induced by NSAID;
    所述的自身炎性疾病优选为贝切特氏病；The autoinflammatory disease is preferably Behcet's disease;
    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；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 one or more of pulmonary hypertension, angina pectoris, myocardial infarction, heart failure, ischemic heart disease, stroke or peripheral circulatory disorder;
    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；And/or, the trauma is diabetic ulcer, burn, pressure ulcer, acute mucosal injury, including Stevens-Johnson syndrome, One or more of mucosal injury, injury associated with anticancer chemotherapeutic agents, antimetabolites, cellular or humoral immunotherapy, or radiation-related injury;
    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；The anticancer chemotherapeutic agent is preferably one or more of an alkylating agent, a DNA synthesis inhibitor or a DNA gyrase inhibitor;
    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；And/or, the tissue damage is liver damage and/or muscle damage;
    所述肌肉损伤优选为肌肉萎缩和/或肌营养不良；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.
  28. 如权利要求25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 25, characterized in that the disease prevented and/or treated by the method is liver regeneration.
  29. 一种如权利要求1-22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、其前药或权利要求24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 22, 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 24, 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，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27所述。Preferably, the fibrotic disease, the inflammatory disease and the tissue damage are all as described in claim 27.
  30. 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：给需要的对象施用如权利要求1-22中任一所述的式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；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 a compound of formula I as described in any one of claims 1 to 22, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof;
    优选，所述与15‐PGDH相关的疾病如权利要求26或27所述。Preferably, the disease associated with 15-PGDH is as described in claim 26 or 27.
  31. 一种预防或治疗如下疾病的方法，包括步骤：给需要的对象施用如权利要求1-22中任一所述的式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；A method for preventing or treating the following diseases, comprising the steps of: administering to a subject in need thereof a compound of formula I as described in any one of claims 1 to 22, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof; the disease is a fibrotic disease and/or an inflammatory disease;
    优选，所述的纤维化疾病和所述的炎性疾病如权利要求27所述。 Preferably, the fibrotic disease and the inflammatory disease are as described in claim 27.
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