WO2020108579A1 - 氨基取代的吡啶酮衍生物、其制法与医药上的用途 - Google Patents

氨基取代的吡啶酮衍生物、其制法与医药上的用途 Download PDF

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WO2020108579A1
WO2020108579A1 PCT/CN2019/121726 CN2019121726W WO2020108579A1 WO 2020108579 A1 WO2020108579 A1 WO 2020108579A1 CN 2019121726 W CN2019121726 W CN 2019121726W WO 2020108579 A1 WO2020108579 A1 WO 2020108579A1
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alkyl
compound
ring
alkoxy
hydrogen
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PCT/CN2019/121726
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French (fr)
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蒋涛
关慧平
周福生
刘力锋
达晨啸
王海龙
童忠安
唐望期
王胜元
陈永刚
李少博
许峰
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Priority to CN201980009578.4A priority Critical patent/CN111712490A/zh
Publication of WO2020108579A1 publication Critical patent/WO2020108579A1/zh

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    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
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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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to the technical field of medicine, in particular to an amino-substituted pyridone derivative and a preparation method and application as an IDO inhibitor, as well as a pharmaceutical composition and a pharmaceutical composition prepared therefrom.
  • IDO Indoleamine 2,3-dioxygenase
  • Tryptophan is one of the eight essential amino acids. Tryptophan can be used to synthesize proteins in the body. Tryptophan can also be used as a precursor substrate to synthesize serotonin and melatonin (N- Acetyl-5-methoxytryptamine). Serotonin and melatonin are neurotransmitters and neuroendocrine hormones, which are involved in the regulation of various neurological and physiological processes in the body. In addition, tryptophan can also produce kynurenine and other metabolites through the kynurenine metabolism pathway.
  • the first step in the kynurenine metabolic pathway is the degradation of L-tryptophan into catalysis by indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase (TDO).
  • N-formyl-kynurenine, N-formyl-kynurenine is catalyzed by kynurenine formamide enzyme to form kynurenine, which can be further metabolized to form 3-hydroxyl Anthranilic acid, quinolinic acid, picolinic acid.
  • Quinolinic acid is neurotoxic, while picolinic acid has neuroprotective effects.
  • Kynurenine and 3-hydroxyanthranilic acid are involved in the regulation of lymphocyte activity and cause the immune system to be suppressed.
  • indolamine 2,3-dioxygenase is basically not expressed in most tissue cells under normal health conditions.
  • inflammatory cytokines such as interferon ⁇ can induce an increase in the expression of indoleamine 2,3-dioxygenase.
  • Various experimental results prove that the high expression of indoleamine 2,3-dioxygenase in tissue cells can cause the immune system of the tissue microenvironment to be suppressed, or the immune suppression or immune checkpoint (immune checkpoint) .
  • the high expression of indoleamine 2,3-dioxygenase in placental tissue can prevent immune rejection of the fetus.
  • indoleamine 2,3-dioxygenase in the inflammation area can prevent excessive immune response and prevent excessive damage to cell tissues.
  • One of the mechanisms leading to immune suppression is that high expression of indoleamine 2,3-dioxygenase causes local L-tryptophan depletion, which is felt by surrounding lymphocytes through GCN2 and other mechanisms, causing CD8+ cytotoxic T cells Cell cycle arrest or apoptosis occurs.
  • Another mechanism that leads to the suppression of immunity is the high expression of indoleamine 2,3-dioxygenase causing kynurenine to increase.
  • kynurenine After the formation of kynurenine, it can leave the cell and enter the extracellular matrix, and then enter the nearby lymph Cells regulate CD8+ T cells and regulatory Treg cells by combining AHR transcription factors.
  • the activity of CD8+ cytotoxic T cells is suppressed, while the number of regulatory Treg cells increases and is activated, resulting in immune suppression.
  • Indoleamine 2,3-dioxygenase is abnormally highly expressed in many different types of tumors, including hematological tumors and solid tumors such as colon cancer, liver cancer, lung cancer, pancreatic cancer, and throat cancer.
  • the abnormally high expression of indoleamine 2,3-dioxygenase was positively correlated with poor tumor prognosis.
  • the escape of immune monitoring of tumor cells is a key step in the development of cancer and cancer.
  • the abnormally high expression of indoleamine 2,3-dioxygenase in tumors may be the escape of tumor cells.
  • IDO indoleamine 2,3-dioxygenases
  • TDO Tryptophan 2,3-dioxygenase
  • IDO Tryptophan 2,3-dioxygenase
  • TDO Tryptophan 2,3-dioxygenase
  • the purpose of cancer treatment Because normal liver cells express TDO, it is not clear whether TDO inhibitors will affect liver function and normal tryptophan metabolism, but the mouse model of TDO knockout is not abnormal, indicating that TDO inhibitors may not affect liver function and normal Of tryptophan metabolism.
  • the mechanism by which IDO and TDO cause immune suppression is basically the same, so the IDO/TDO dual specific inhibitors have also attracted the interest of the pharmaceutical industry.
  • the IDO/TDO dual specific inhibitors will be applicable to IDO positive, TDO positive, IDO/TDO double positive Patient.
  • Indoleamine 2,3-dioxygenase inhibitors may also be used in the treatment of these diseases. Under the catalytic action of kynurenine aminotransferase, kynurenine can be converted into kynurenine, which is an NMDA antagonist, which is common to high in the central nervous system of patients with schizophrenia The level of quinolinic acid in dogs. Quinolinic acid is neurotoxic and can cause neuronal apoptosis and neurodegeneration. Indoleamine 2,3-dioxygenase is not only involved in the metabolism of tryptophan, but also in the metabolism of tryptophan, etc. 5-hydroxytryptamine can be converted into 5- under the catalysis of indoleamine 2,3-dioxygenase Hydroxyindole acetic acid, serotonin decline may be one of the factors leading to depression.
  • indoleamine 2,3-dioxygenase inhibitors are still in the early stage of research and development, and it is of great clinical significance to develop IDO inhibitors with better activity and lower toxicity on the existing basis.
  • the object of the present invention is to provide a class of novel IDO inhibitors, their preparation method and use.
  • the first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:
  • a ring is C 6-10 aromatic ring (preferably benzene ring), C 3-8 cycloalkyl ring (preferably C 3-6 cycloalkyl ring), 8 to 10 membered bicyclic heteroaryl ring, 4 to 7 Elementally saturated or partially unsaturated single heterocycle, spiro ring, spiro heterocycle, bridged ring or bridged heterocycle;
  • R 0 is hydrogen, cyano, hydroxy, carboxy, hydroxymethyl, hydroxyethyl, halogen, C 1-10 alkyl, -O(CH 2 ) p -C 1-10 alkoxy, -(CH 2 ) t -NR a R b , -(CH 2 ) q -NR c S(O) 2 NR a R b , -NR c C(O)C 1-10 alkyl, pyridine-2(1H)-one, 1 -Methylpyridine-2(1H)-one or -L 0 -Y 0 ; where L 0 is a bond, O, (CR 01 R 02 ) r , C(O)NR c , or NR 03 ; Y 0 is C 6-10 aryl (preferably phenyl), 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, 4 to 7 membered saturated monoheterocycle or
  • n 1, 2 or 3;
  • L is a bond, O, NR c , C(R d R e ), -CH 2 NR c -, -NHC(O)NH-, -CH 2 NHC(O)NH-, -C(O)NH- , -NHC(O)- or -CH 2 CH(OH)-;
  • R 1 is hydrogen or -L 1 -Y 1 ; where L 1 is (CR 11 R 12 ) s ; Y 1 is hydroxy, cyano, carboxy, halogen, C 1-10 alkyl, C 6-10 aryl ( (Preferably phenyl), 4- to 7-membered saturated or partially unsaturated monoheterocycle, 5- to 6-membered monocyclic heteroaryl, C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 1 -10 alkoxy; the C 6-10 aryl group, 4 to 7 membered saturated or partially unsaturated monoheterocycle, 5 to 6 membered monocyclic heteroaryl group is unsubstituted or selected by 1, 2 or 3 Substitution from the following group of substituents: cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkyl Oxygen
  • R 3 is -L 3 -Y 3 ; where L 3 is a bond, (CR 31 R 32 ) t , O or NR 33 ; Y 3 is hydrogen, R 34 , 5- to 6-membered monocyclic heteroaryl, C 6 -10 aryl (preferably phenyl), 4 to 7 membered saturated or partially unsaturated monoheterocycle or C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl); the 5 to 6 membered mono Cycloheteroaryl, C 6-10 aryl, 4- to 7-membered saturated or partially unsaturated monoheterocycle is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, Hydroxymethyl, hydroxyethyl, carboxyl, oxo, halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkoxy, 4 to 7 membered
  • p, q, t, r, s are each independently 0, 1, 2 or 3;
  • R a , R b and R c are each independently hydrogen, C 3-6 cycloalkyl or C 1-8 alkyl, or R a , R b and the attached N atom together form a 4- to 7-membered saturated monoheterocycle ;
  • R d and R e are each independently hydrogen, hydroxyl or C 1-8 alkyl
  • R 01 and R 02 are each independently hydrogen, hydroxyl or C 1-8 alkyl
  • R 03 is hydrogen or C 1-8 alkyl
  • R 11 and R 12 are each independently hydrogen, hydroxyl or C 1-8 alkyl
  • R 31 and R 32 are each independently hydrogen, hydroxyl or C 1-8 alkyl
  • R 33 is hydrogen or C 1-8 alkyl
  • R 34 is the structure shown in formula (a), formula (b), formula (c) or formula (d):
  • R a′ , R b′ and R 35 are each independently hydrogen, C 3-6 cycloalkyl or C 1-8 alkyl; or R 35 is hydrogen or C 1-8 alkyl, R a′ , R b′ and the connected N atom together form a 4- to 7-membered saturated single heterocyclic ring; or R a′ is hydrogen or C 1-8 alkyl, R 35 and R b′ together with the connected nitrogen and carbon atom atoms form 4 To 7-membered saturated monoheterocycle;
  • R 36 and R 37 are each independently hydrogen or C 1-8 alkyl, or R 37 is hydrogen or C 1-8 alkyl; R 36 and the C or N atom in L 3 together form the formula (b1) The ring:
  • R 36 is hydrogen or C 1-8 alkyl; R 37 and the C or N atom in L 3 together form a ring represented by formula (b2):
  • R 38 is hydrogen or C 1-8 alkyl
  • L 31 and L 32 are each independently N or CH, and y1 and y2 are independently 0, 1, 2 or 3;
  • R 2 and R 4 are each independently hydrogen, cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkoxy Group, halogenated C 1-10 alkoxy;
  • R 5 and R 6 are each independently hydrogen, hydroxyl, C 1-10 alkyl or oxo; or R 5 and R 6 together with the connected carbon atoms form a 3- to 7-membered saturated monoheterocycle or 3 to 7-membered Saturated single ring
  • n 0, 1, 2 or 3.
  • R a , R b , and R c are each independently hydrogen, C 3-6 cycloalkyl or C 1-3 alkyl, or R a , R b and the connected N atom together form 4 To 7-membered saturated monoheterocycle.
  • R a, R b are each independently hydrogen, cyclopropyl, methyl, ethyl, n-propyl or isopropyl, or R a, R b together with the N atom selected from the group formed From azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and 4- to 7-membered saturated monoheterocycle of tetrahydropyran; R c is hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • R d, R e are each independently hydrogen, hydroxy or C 1-3 alkyl.
  • the C 6-10 aromatic ring described in the A ring is selected from a benzene ring and a naphthalene ring, more preferably a benzene ring.
  • the C 3-8 cycloalkyl ring in the A ring is selected from cyclooctyl ring, cycloheptyl ring, cyclohexyl ring, cyclopentyl ring, cyclobutyl ring or cyclopropyl ring, More preferred is a cyclohexyl ring, cyclopentyl ring or cyclobutyl ring, and most preferred is a cyclohexyl ring.
  • the 8 to 10 membered bicyclic heteroaryl ring in ring A is a benzoaromatic heterocyclic ring, such as indole, benzimidazole, isoquinoline or quinoline; more preferably a quinoline ring.
  • the spiro ring in ring A is an 8-membered spiro ring, more preferably spiro[2,5]octane.
  • the spiro heterocycle in ring A is a 10-12 membered spiro heterocycle, more preferably 3-azaspiro[5,5]undecane.
  • the bridge ring in ring A is a 7-10 member bridge ring, more preferably adamantane.
  • the 4- to 7-membered saturated or partially unsaturated monocyclic heterocycle described in ring A is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, Piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • ring A is a cyclohexyl ring.
  • R 3 is -L 3 -Y 3 ; wherein L 3 is a bond, Y 3 is a 5-membered or 6-membered monocyclic heteroaryl group, C 6-10 aryl group, 4 to 7 membered saturated Or partially unsaturated monoheterocycle or C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl); the 5-membered or 6-membered monocyclic heteroaryl, C 6-10 aryl, 4 to 7 Single-membered saturated heterocycle is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1- 10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkoxy, 4 to 7 membered saturated or partially unsatur
  • R 3 is -L 3 -Y 3 ; wherein L 3 is a bond, and Y 3 is a 5- to 6-membered monocyclic heteroaryl group, a phenyl group, a 6-membered saturated or partially unsaturated monocyclic heterocyclic ring (Preferably 1,2,3,6-tetrahydropyridine or cyclohexene) or C 3-6 cycloalkyl; the 5- to 6-membered monocyclic heteroaryl, phenyl, 6-membered saturated or partially unsaturated
  • the single heterocyclic ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-3 alkyl Group, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, piperidine, piperazine, morpholine, t
  • R 3 is -L 3 -Y 3 ; wherein L 3 is a bond, Y 3 is a 5 to 6 membered monocyclic heteroaryl group, and the 5 to 6 membered monocyclic heteroaryl group is Substituted or substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, oxo, halogen, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, piperidine, piperazine, morpholine, tetrahydropyran, -S(O) 2 C 1-3 alkyl , -S(O) 2 NR a R b , -C(O)NR a R b , -NR a R b , -NR c C(O)C 1-3 alkyl, -NR c S(O) 2
  • Y 3 is a 5- to 6-membered monocyclic heteroaryl group selected from pyrazole, 1-methylpyrazole, imidazole, pyrrole, 1-methyl Pyrrole, isothiazole, thiazole, isoxazole, 1,2,3-triazole, 2-methyl-1,2,3-triazole, 1,2,4-triazole, thiophene, pyridine , Pyrimidine and pyridazine.
  • R 3 is -L 3 -Y 3 ; wherein L 3 is a bond, Y 3 is pyrazole, 1-methylpyrazole, imidazole, pyrrole, 1-methylpyrrole, thiazole, iso Thiazole, isoxazole, 1,2,3-triazole, 2-methyl-1,2,3-triazole, 1,2,4-triazole, thiophene, pyridine, pyrimidine and pyridazine.
  • R 3 is selected from the following structures:
  • R 3 is -L 3 -Y 3 ; wherein L 3 is (CR 31 R 32 ) t or NR 33 ; Y 3 is R 34 .
  • R 1 is hydrogen or -L 1 -Y 1 ; wherein L 1 is (CR 11 R 12 ) s , Y 1 is hydroxyl, cyano, carboxyl, halogen, C 1-10 alkyl, C 6-10 aryl (preferably phenyl), 4- to 7-membered saturated monoheterocycle, C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 1-10 alkoxy; Said C 6-10 aryl, 4 to 7 membered saturated monoheterocycle is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, Carboxy, oxo, halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkoxy, 4- to 7-membered saturated or partially Saturated monoheterocycle, 5- to 6-membere
  • R 11 and R 12 are each independently hydrogen, hydroxy or C 1-8 alkyl; s is 0, 1, 2 or 3.
  • R 1 is hydrogen or -L 1 -Y 1 ; wherein L 1 is (CR 11 R 12 ) s , Y 1 is hydroxyl, cyano, carboxyl, halogen, C 1-3 alkyl, Phenyl, 4- to 7-membered saturated monoheterocycle, C 3-6 cycloalkyl, C 1-3 alkoxy; the phenyl, 4- to 7-membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 Or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, -S(O) 2 C 1-3 alkyl, -S(O) 2 NR a R b , -C(O)NR a R b , -
  • R 11 and R 12 are each independently hydrogen, hydroxyl or C 1-3 alkyl; s is 0, 1, 2 or 3.
  • R 1 is hydrogen or -L 1 -Y 1 ; wherein L 1 is (CR 11 R 12 ) s , Y 1 is hydroxyl, cyano, carboxyl, halogen, C 1-3 alkyl, Phenyl, 4- to 6-membered saturated monoheterocycle, C 3-6 cycloalkyl, C 1-3 alkoxy; the phenyl, 4- to 6-membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 Or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, -S(O) 2 C 1-3 alkyl, -S(O) 2 NR a R b , -C(O)NR a R b , -NR
  • R 11 and R 12 are each independently hydrogen, hydroxyl or C 1-3 alkyl; s is 0, 1, 2 or 3;
  • the 4- to 6-membered saturated monoheterocycle is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, sulfur Dimorpholine-1,1-dioxide, tetrahydropyran;
  • the C 3-6 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R 1 is hydrogen or -L 1 -Y 1 ; wherein L 1 is (CR 11 R 12 ) s , Y 1 is hydroxyl, cyano, carboxy, halogen, C 1-3 alkoxy Or C 1-3 alkyl; wherein R 11 and R 12 are each independently hydrogen or C 1-3 alkyl; s is 0, 1, 2 or 3.
  • R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
  • R 0 is hydrogen, cyano, hydroxy, carboxy, hydroxymethyl, hydroxyethyl, halogen, C 1-3 alkyl, -O(CH 2 ) p -C 1-3 alkoxy Radical, -(CH 2 ) t -NH 2 , -(CH 2 ) t -N(CH 3 ) 2 , -(CH 2 ) q -NHS(O) 2 NH 2 , -NR c C(O)C 1 -3 alkyl, pyridin-2(1H)-one, 1-methylpyridine-2(1H)-one or -L 0 -Y 0 ; where L 0 is a bond, O, (CR 01 R 02 ) r Or C(O)NR c , Y 0 is phenyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, 4 to 7 membered saturated monoheterocycle or benzo
  • R 0 is cyano, hydroxy, carboxy, hydroxymethyl, hydroxyethyl, halogen, C 1-3 alkyl, -O(CH 2 ) p -C 1-3 alkoxy, -CH 2 -NH 2 , -CH 2 -N(CH 3 ) 2 , -CH 2 -NHS(O) 2 NH 2 , -NHC(O)C 1-3 alkyl, pyridine-2(1H)-one , 1-Methylpyridine-2(1H)-one or -L 0 -Y 0 ; where L 0 is a bond or O, Y 0 is phenyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered Bicyclic heteroaryl, benzo 5- to 6-membered saturated or partially unsaturated heterocyclic ring; the phenyl group, 5- to 6-membered monocyclic heteroaryl, 8 to 10-membered bicyclic heteroaryl,
  • R a and R b are each independently hydrogen, cyclopropyl, methyl, ethyl, n-propyl or isopropyl, or R a and R b together with the attached N atom form a group selected from azetidine , Oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and tetrahydropyran 4 To 7-membered saturated monoheterocycle;
  • R c is hydrogen, methyl, ethyl, n-propyl or isopropyl
  • p 0, 1, 2 or 3.
  • R 0 is cyano, hydroxy, carboxy, hydroxymethyl, hydroxyethyl, halogen, C 1-3 alkyl, -O(CH 2 ) p -C 1-3 alkoxy, -CH 2 -NH 2 , -CH 2 -N(CH 3 ) 2 , -CH 2 -NHS(O) 2 NH 2 , -NHC(O)C 1-3 alkyl, pyridine-2(1H)-one , 1-Methylpyridine-2(1H)-one or -L 0 -Y 0 ; wherein L 0 is a bond or O; Y 0 is phenyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered Bicyclic heteroaryl, benzo 5- to 6-membered saturated or partially unsaturated heterocyclic ring; the phenyl group, 5- to 6-membered monocyclic heteroaryl, 8 to 10-membered bicyclic heteroaryl
  • R a and R b are each independently hydrogen, cyclopropyl, methyl, ethyl, n-propyl or isopropyl, or R a and R b together with the attached N atom form a group selected from azetidine , Oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and tetrahydropyran 4 To 7-membered saturated monoheterocycle;
  • R c is hydrogen, methyl, ethyl, n-propyl or isopropyl
  • p 0, 1, 2 or 3.
  • R 2 and R 4 are each independently hydrogen, halogen, C 1-10 alkyl or C 1-10 alkoxy.
  • R 2 is hydrogen or C 1-3 alkyl
  • R 4 is hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy.
  • R 2 is hydrogen or C 1-3 alkyl
  • R 4 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy.
  • R 2 is hydrogen; R 4 is hydrogen or methoxy.
  • R 2 and R 4 are hydrogen.
  • ring A is a benzene ring, C 3-6 cycloalkyl ring, cyclohexene, 9 to 10 membered bicyclic heteroaryl ring, 5 to 6 membered saturated or partially unsaturated monoheterocycle, 7 -10 membered spiro ring, 7-10 membered spiro heterocycle or 7-10 membered bridge ring.
  • the A ring is a benzene ring, a C 3-6 cycloalkyl ring, a 5-6 membered saturated or partially unsaturated monoheterocycle, and a 7-10 membered spiro ring.
  • ring A is a C 3-8 cycloalkyl ring (preferably a C 3-6 cycloalkyl ring), a 4- to 7-membered saturated or partially unsaturated single heterocyclic ring or spiro ring.
  • the A ring is a benzene ring, a cyclohexyl ring, a piperidine ring, a tetrahydropyran ring or a spiro heterocyclic ring.
  • ring A is a cyclohexyl ring, spiro[2,5]octane or quinoline ring.
  • W 1 is N or CR a3 ;
  • W 2 is a bond, O, NR a4 or CR a5 R a6 ;
  • W 3 is O, NR a7 or CR a8 R a9 ;
  • W 4 is CR a10 R a11 ;
  • W 5 is O or CR a2 R a12 ;
  • v 0, 1 or 2;
  • R a0 is as defined in R 0 above;
  • R a1, R a2, R a3 , R a5, R a6, R a8, R a9, R a10, R a11, R a12 are each independently hydrogen or - (CH 2) u -L a ; wherein L a is hydroxy , methyl, cyano, NH 2, or -NR c S (O) 2 NR a R b; u is 0, 1 or 2; R a, R b, R c, R 0, m as defined in the specification; R a4 and R a7 are each independently hydrogen or C 1-10 alkyl.
  • ring A is a benzene ring; R 0 is halogen or -O(CH 2 ) p -C 1-3 alkoxy.
  • W 1 is CR a3 ;
  • W 2 is CH 2 ;
  • W 3 is CH 2 ;
  • W 4 is CHR a10 ;
  • W 5 is CHR a2 ;
  • v 1;
  • R a1 , R a2 , R a3 and R a10 are each independently hydrogen or -(CH 2 ) u -L a ; wherein L a is hydroxy, methyl, cyano, NH 2 or -NHS(O) 2 NH 2 ;
  • u is 0 or 1
  • R a0 is -L 0 -Y 0 ; where L 0 is a bond or O, Y 0 is phenyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, benzo 5 to 6 membered Saturated or partially unsaturated heterocyclic ring; the phenyl group, 5 to 6 membered monocyclic heteroaryl group, 8 to 10 membered bicyclic heteroaryl group, benzo 5 to 6 membered saturated or partially unsaturated heterocyclic ring is unsubstituted or Substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, fluorine, chlorine, bromine, methyl, ethyl, n-propyl , Isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroeth
  • R a and R b are each independently hydrogen, cyclopropyl, methyl, ethyl, n-propyl or isopropyl, or R a and R b together with the attached N atom form a group selected from azetidine , Oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and tetrahydropyran 4 To 7-membered saturated monoheterocycle;
  • R c is hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • L is a bond, O, NH, -CH 2 NH -, - NHC (O) NH -, - CH 2 NHC (O) NH -, - C (O) NH -, - NHC (O)- or -CH 2 CH(OH)-.
  • L is O, NR c or C(R d R e ); R c , R d and R e are as defined in the specification.
  • L is NR c ; R c is hydrogen, methyl or ethyl. More preferably, L is NH.
  • L is NH or -C(O)NH-.
  • L is C(R d R e ); R d and R e are as defined in the specification.
  • n 0.
  • n is 1, 2 or 3, R 5 and R 6 are each independently hydrogen and hydroxyl, when n is 2 or 3, R 5 may be the same or different from each other, R 6 may be the same, It can also be different from each other.
  • W 1 is CR a3 ;
  • W 2 is a bond or CR a5 R a6 ;
  • W 3 is O or NR a7 ;
  • W 4 is CR a10 R a11 ;
  • W 5 is O Or CR a2 R a12 ;
  • v is 0 or 1;
  • R a0 is as defined above in R 0 ;
  • R a1 , R a2 , R a3 , R a5 , R a6 , R a10 , R a11 , R a12 are each independently hydrogen or - (CH 2) u -L a ; wherein L a is hydroxy, cyano, methyl, NH 2, or -NR c
  • W 1 is CR a3 ;
  • W 2 is a bond or CR a5 R a6 ;
  • W 3 is CR a8 R a9 ;
  • W 4 is CR a10 R a11 ;
  • W 5 is CHR a2 ;
  • R a0 is as defined above R 0 ;
  • R a1 , R a2 , R a3 , R a5 , R a6 , R a8 , R a9 , R a10 , R a11 are each independently hydrogen or- (CH 2) u -L a; wherein L a is hydroxy, cyano, methyl, NH 2, or -NR c S (O) 2 NR a R b; u is 0, 1 or 2; R a, R b , R c as defined in the specification.
  • W 1 is N or CR a3 ;
  • W 2 is a bond, O, NR a4 or CR a5 R a6 ;
  • W 3 is CR a8 R a9 ;
  • W 4 is CR a10 R a11 ;
  • W 5 is CHR a2 ;
  • R a0 is as defined above in R 0 ;
  • W 1 is N or CR a3 ;
  • W 2 is a bond or CR a5 R a6 ;
  • W 3 is CR a8 R a9 ;
  • W 4 is CR a10 R a11 ;
  • W 5 Is CHR a2 ;
  • v is 0 or 1;
  • R a0 is as defined in R 0 above;
  • R a1 , R a2 , R a3 , R a5 , R a8 , R a9 , R a10 , R a11 are each independently hydrogen or- (CH 2) u -L a; wherein L a is hydroxy, cyano, methyl, NH 2, or -NR c S (O) 2 NR a R b; u is 0, 1 or 2;
  • R a6 is hydrogen;
  • R a , R b and R c are as defined in the specification.
  • W 1 is N or CR a3 ;
  • W 2 is a bond or CR a5 R a6 ;
  • W 3 is CR a8 R a9 ;
  • W 4 is CR a10 R a11 ;
  • W 5 Is CHR a2 ;
  • v is 0 or 1;
  • R a0 is as defined in the above R 0 ;
  • R a1 , R a3 , R a5 , R a8 , R a9 , R a10 , R a11 are each independently hydrogen or -(CH 2 ) u -L a ; where L a is hydroxy, cyano, methyl, NH 2 or -NR c S(O) 2 NR a R b ; u is 0, 1 or 2;
  • R a2 is hydrogen or hydroxy;
  • R a6 is hydrogen;
  • R a, R b, R c is as defined in the specification.
  • W 1 is CR a3 ; W 2 is a bond, O or NR a4 ; W 3 is CR a8 R a9 ; W 4 is CR a10 R a11 ; W 5 is CHR a2 ; v is 0 or 1; R a0 is as defined in R 0 above; R a1 , R a2 , R a3 , R a8 , R a9 , R a10 , R a11 are each independently hydrogen or -(CH 2 ) u -L a ; where L a is hydroxy, cyano, methyl, NH 2 or -NR c S(O) 2 NR a R b ; u is 0, 1 or 2; R a , R b and R c are as specified Definition; R a4 is hydrogen or C 1-10 alkyl.
  • the compound of formula (I) has the structure shown in formula (II):
  • R 1 is hydrogen or -L 1 -Y 1 ; where L 1 is (CR 11 R 12 ) s ; Y 1 is hydroxyl, cyano, carboxyl, halogen, C 1-3 alkyl, phenyl, 4 to 7 members Saturated monoheterocycle, C 3-6 cycloalkyl, C 1-3 alkoxy; the phenyl, 4- to 7-membered saturated monoheterocycle is unsubstituted or is selected from 1, 2 or 3 Substituted by: cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, Halogenated C 1-3 alkoxy, -S(O) 2 C 1-3 alkyl, -S(O) 2 NR a R b , -C(O)NR a R b , -NR a R b , -
  • R 2 and R 4 are each independently hydrogen, cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy Group, halogenated C 1-3 alkoxy;
  • R 3 is -L 3 -Y 3 ; wherein L 3 is a bond; Y 3 is a 5- to 6-membered monocyclic heteroaryl, phenyl, 6-membered saturated or partially unsaturated monocyclic heterocycle (preferably 1, 2, 3,6-tetrahydropyridine or cyclohexene) or C 3-6 cycloalkyl; the 5- to 6-membered monocyclic heteroaryl, phenyl, 6-membered saturated or partially unsaturated monoheterocycle is unsubstituted Or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-3 alkyl, halo C 1- 3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, piperidine, piperazine, morpholine, tetrahydropyran, -S(O) 2 C 1-3 alkyl
  • L 3 is (CR 31 R 32 ) t or NR 33 ;
  • Y 3 is R 34 ;
  • R 34 is the structure shown in formula (a), formula (b), formula (c) or formula (d):
  • R a′ , R b′ and R 35 are each independently hydrogen, C 3-6 cycloalkyl or C 1-8 alkyl; or R 35 is hydrogen or C 1-8 alkyl, R a′ , R b′ and the connected N atom together form a 4- to 7-membered saturated single heterocyclic ring; or R a′ is hydrogen or C 1-8 alkyl, R 35 and R b′ together with the connected nitrogen and carbon atom atoms form 4 To 7-membered saturated monoheterocycle;
  • R 36 and R 37 are each independently hydrogen or C 1-8 alkyl, or R 37 is hydrogen or C 1-8 alkyl; R 36 and the C or N atom in L 3 together form the formula (b1) The ring:
  • R 36 is hydrogen or C 1-8 alkyl; R 37 and the C or N atom in L 3 together form a ring represented by formula (b2):
  • R 38 is hydrogen or C 1-8 alkyl
  • L 31 and L 32 are each independently N or CH, and y1 and y2 are independently 0, 1, 2 or 3;
  • R 31 and R 32 are each independently hydrogen, hydroxyl or C 1-8 alkyl
  • R 33 is hydrogen or C 1-8 alkyl
  • t 0, 1, 2 or 3;
  • W 1 is N or CR a3 ;
  • W 2 is a bond, O, NR a4 or CR a5 R a6 ;
  • W 3 is O, NR a7 or CR a8 R a9 ;
  • W 4 is CR a10 R a11 ;
  • W 5 is O or CR a2 R a12 ;
  • v 0, 1 or 2;
  • R a0 is hydrogen, cyano, hydroxy, carboxy, hydroxymethyl, hydroxyethyl, C 1-3 alkyl, -O(CH 2 ) p -C 1-3 alkoxy, -(CH 2 ) t- NH 2 , -(CH 2 ) t -N(CH 3 ) 2 , -(CH 2 ) q -NHS(O) 2 NH 2 , -NR c C(O)C 1-3 alkyl, pyridine-2( 1H)-ketone, 1-methylpyridine-2(1H)-one or -L 0 -Y 0 ; wherein L 0 is a bond, O, (CR 01 R 02 ) r or C(O)NR c ; Y 0 is phenyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, 4 to 7 membered saturated monoheterocycle or benzo 4 to 7 membered saturated or partially
  • R a1, R a2, R a3 , R a5, R a6, R a8, R a9, R a10, R a11, R a12 are each independently hydrogen or - (CH 2) u -L a ; wherein L a is hydroxy , Cyano, methyl, halogen, NH 2 or -NR c S(O) 2 NR a R b ; u is 0, 1 or 2;
  • R a4 and R a7 are each independently hydrogen or C 1-10 alkyl
  • p, q, t, r, s are each independently 0, 1, 2 or 3;
  • R a , R b and R c are each independently hydrogen, C 3-6 cycloalkyl or C 1-8 alkyl, or R a , R b and the attached N atom together form a 4- to 7-membered saturated monoheterocycle ;
  • R 01 and R 02 are each independently hydrogen, hydroxyl or C 1-3 alkyl
  • R 11 and R 12 are each independently hydrogen, hydroxyl or C 1-3 alkyl.
  • n 0, 1, 2 or 3.
  • the compound of formula (II) has the structure shown in formula (II-1) or formula (II-2):
  • L 1 is CH 2 , CH 2 CH 2 , CH 2 C(CH 3 ) 2 , CH 2 CH(OH).
  • R 2 is hydrogen or C 1-3 alkyl
  • R 4 is hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy.
  • R 2 is hydrogen; R 4 is hydrogen or methoxy.
  • the 4- to 7-membered saturated or partially unsaturated monoheterocycle described in Y 3 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, Piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2,3,6-tetrahydropyridine or cyclohexene.
  • the 4- to 7-membered saturated or partially unsaturated monocyclic heterocycle described in Y 3 is selected from the following structures:
  • the above groups are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-3 alkyl , Halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, piperidine, piperazine, morpholine, tetrahydropyran, -S(O) 2 C 1 -3 alkyl, -S(O) 2 NR a R b , -C(O)NR a R b , -NR a R b , -NR c C(O)C 1-3 alkyl, -NR c S (O) 2 NR a R b ; R a , R b and R c are as defined in the specification.
  • the 5- to 6-membered monocyclic heteroaryl group described in Y 3 is selected from: thiophene ring, N-alkane ring pyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring , Pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetra Azole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3, 4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring.
  • the 5- to 6-membered monocyclic heteroaryl group described in Y 3 is selected from the following structures:
  • the above groups are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-3 alkyl , Halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, piperidine, piperazine, morpholine, tetrahydropyran, -S(O) 2 C 1 -3 alkyl, -S(O) 2 NR a R b , -C(O)NR a R b , -NR a R b , -NR c C(O)C 1-3 alkyl, -NR c S (O) 2 N R a R b ; R a , R b and R c are as defined in the specification.
  • the 5- to 6-membered monocyclic heteroaryl group described in Y 3 is selected from the following structures:
  • the 4- to 7-membered saturated or partially unsaturated monoheterocycle described in Y 1 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, Piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • the 4- to 7-membered saturated or partially unsaturated monocyclic heterocycle described in Y 1 is selected from the following structures:
  • the above groups are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-3 alkyl , Halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, -S(O) 2 C 1-3 alkyl, -S(O) 2 NR a R b , -C(O)NR a R b , -NR a R b , -NHC(O)C 1-3 alkyl or -NHS(O) 2 NR a R b ; R a and R b are as described in the instruction manual definition.
  • the 5- to 6-membered monocyclic heteroaryl group described in Y 1 is selected from: thiophene ring, N-alkane ring pyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring , Pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetra Azole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3, 4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring.
  • the 5- to 6-membered monocyclic heteroaryl group described in Y 1 is selected from the following structures:
  • the above groups are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-3 alkyl , Halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, -S(O) 2 C 1-3 alkyl, -S(O) 2 NR a R b , -C(O)NR a R b , -NR a R b , -NHC(O)C 1-3 alkyl or -NHS(O) 2 NR a R b ; R a and R b are as described in the instruction manual definition.
  • the 4- to 7-membered saturated monoheterocycle described in Y 0 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piper Azine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • the 4- to 7-membered saturated monoheterocycle described in Y 0 is selected from the following structures:
  • the above groups are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-3 alkyl , Halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, amidino, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetra Hydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, thiophene, N-alkanepyrrole, furan, thiazole, imidazole, oxazole Azole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole
  • the 5- to 6-membered monocyclic heteroaryl group described in Y 0 is selected from: thiophene, N-alkane ring pyrrole, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2 ,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine .
  • the 5- to 6-membered monocyclic heteroaryl group described in Y 0 is selected from the following structures:
  • the above groups are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-3 alkyl , Halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, amidino, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetra Hydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, thiophene, N-alkanepyrrole, furan, thiazole, imidazole, oxazole Azole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole
  • the 8 to 10 membered bicyclic heteroaryl ring in Y 0 is a benzo 5 or 6 membered aromatic heterocyclic ring and contains 1, 2 or 3 heteroatoms selected from N, S or O, Selected from: benzofuran, benzothiophene, indole, benzimidazole, benzothiazole, purine, isoquinoline, quinoline, cinnoline ring, quinoxaline.
  • the benzo 4- to 7-membered (or benzo 5- to 6-membered) saturated or partially unsaturated heterocyclic ring in Y 0 contains 1, 2 or 3 heterocycles selected from N, S or O Atom, selected from: isoindolin-1-one, phthalimide, 3,4-dihydroquinolin-1(2H)-one, 4-hydroxyquinoline, 2,4-quinoline Oxadione, 1,3-benzodioxolane (pepper ring), 2-benzoxazolone (oxazole).
  • the 8 to 10 membered bicyclic heteroaryl or benzo 4 to 7 membered saturated or partially unsaturated heterocyclic ring (or benzo 5 to 6 membered saturated or partially unsaturated heterocyclic ring described in Y 0 ) Selected from the following structures:
  • the above groups are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-3 alkyl , Halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, amidino, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetra Hydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, thiophene, N-alkanepyrrole, furan, thiazole, imidazole, oxazole Azole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole
  • Y 0 is a structure selected from the group consisting of:
  • the above groups are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, oxo, halogen, C 1-3 alkyl , Halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, amidino, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetra Hydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, thiophene, N-alkanepyrrole, furan, thiazole, imidazole, oxazole Azole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole
  • W 1 is CR a3 ;
  • W 2 is a bond or CR a5 R a6 ;
  • W 3 is O or NR a7 ;
  • W 4 is CR a10 R a11 ;
  • W 5 is O Or CR a2 R a12 ;
  • v is 0 or 1;
  • R a0 is as defined in the specification;
  • R a1 , R a2 , R a3 , R a5 , R a6 , R a10 , R a11 , R a12 are each independently hydrogen or- (CH 2) u -L a; wherein L a is hydroxy, cyano, methyl, NH 2, or -NR c S (O) 2 NR a R b; u is 0, 1 or 2;
  • R a, R b , R c is as defined in the specification;
  • R a7 is hydrogen or C 1-10 alkyl.
  • W 1 is CR a3 ;
  • W 2 is a bond or CR a5 R a6 ;
  • W 3 is CR a8 R a9 ;
  • W 4 is CR a10 R a11 ;
  • W 5 is CHR a2 ;
  • v is 0 or 1;
  • Ra0 is as defined in the specification;
  • Ra1 , Ra2 , Ra3 , Ra5 , Ra6 , Ra8 , Ra9 , Ra10 , Ra11 are each independently hydrogen or -( CH 2) u -L a; wherein L a is hydroxy, cyano, methyl, NH 2, or -NR c S (O) 2 NR a R b; u is 0, 1 or 2;
  • R a, R b, R c is as defined in the specification.
  • W 1 is N or CR a3 ;
  • W 2 is a bond, O, NR a4 or CR a5 R a6 ;
  • W 3 is CR a8 R a9 ;
  • W 4 is CR a10 R a11 ;
  • W 5 is CHR a2 ;
  • v is 0 or 1;
  • R a0 is as defined in the specification;
  • W 1 is N or CR a3 ;
  • W 2 is a bond or CR a5 R a6 ;
  • W 3 is CR a8 R a9 ;
  • W 4 is CR a10 R a11 ;
  • W 5 Is CHR a2 ;
  • v is 0 or 1;
  • R a0 is as defined in the specification;
  • R a1 , R a2 , R a3 , R a5 , R a8 , R a9 , R a10 , R a11 are each independently hydrogen or -(CH 2) u -L a; wherein L a is hydroxy, cyano, methyl, NH 2, or -NR c S (O) 2 NR a R b; u is 0, 1 or 2;
  • R a6 is hydrogen;
  • R a , R b and R c are as defined in the specification.
  • W 1 is N or CR a3 ;
  • W 2 is a bond or CR a5 R a6 ;
  • W 3 is CR a8 R a9 ;
  • W 4 is CR a10 R a11 ;
  • W 5 Is CHR a2 ;
  • v is 0 or 1;
  • R a0 is as defined in the specification;
  • R a1 , R a3 , R a5 , R a8 , R a9 , R a10 , R a11 are each independently hydrogen or -(CH 2 ) u -L a; wherein L a is hydroxy, cyano, methyl, NH 2, or -NR c S (O) 2 NR a R b; u is 0, 1 or 2;
  • R a2 is hydrogen or hydroxy;
  • R a6 is hydrogen;
  • R a, R b, R c is as defined in the specification.
  • W 1 is CR a3 ; W 2 is a bond, O or NR a4 ; W 3 is CR a8 R a9 ; W 4 is CR a10 R a11 ; W 5 is CHR a2; v is 0 or 1; R a0 as defined in the specification; R a1, R a2, R a3, R a8, R a9, R a10, R a11 are each independently hydrogen or - (CH 2) u -L a ; where L a is hydroxy, cyano, methyl, NH 2 or -NR c S(O) 2 NR a R b ; u is 0, 1 or 2; R a , R b and R c are as described in the specification Definition; R a4 is hydrogen or C 1-10 alkyl.
  • W 1 is CR a3 ;
  • W 2 is CH 2 ;
  • W 3 is CH 2 ;
  • W 4 is CHR a10 ;
  • W 5 is CHR a2 ;
  • v is 1;
  • R a1 , R a2 , R a3 and R a10 are each independently hydrogen or -(CH 2 ) u -L a ; wherein L a is hydroxy, methyl, cyano, NH 2 or -NHS(O) 2 NH 2 ;
  • u is 0 or 1;
  • R a0 is -L 0 -Y 0 ; wherein L 0 is a bond or O;
  • Y 0 is phenyl, 5 to 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl, benzo 5 to 6 membered saturated or partially unsaturated heterocyclic ring; the phenyl group, 5 to 6 membered monocyclic heteroaryl
  • R a and R b are each independently hydrogen, cyclopropyl, methyl, ethyl, n-propyl or isopropyl, or R a and R b together with the attached N atom form a group selected from azetidine , Oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and tetrahydropyran 4 To 7-membered saturated monoheterocycle;
  • R c is hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • R a, R b together with the N atom attached form a 4 to 7 membered saturated monocyclic heterocyclic ring selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetra Hydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • the 4 to 7 membered saturated monoheterocycle formed by R 35 and R b together with the connected nitrogen and carbon atoms is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydro Thiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • the 3- to 7-membered saturated monoheterocycle formed by R 5 and R 6 together with the connected carbon atoms is selected from: aziridine, ethylene oxide, azetidine, oxetane Alkanes, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • the compound of formula (I) is selected from the structures of Table A or Table B.
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; and a pharmaceutically acceptable Carrier.
  • the third aspect of the present invention provides the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to the second aspect of the present invention in the preparation of a medicament
  • the drug is used to inhibit the activity of indoleamine 2,3-dioxygenase or to suppress the immunosuppression of patients.
  • the medicament is used to treat or prevent a patient's cancer or tumor, viral infection, depression, neurodegenerative disorder, trauma, age-related cataract, organ transplant rejection or autoimmune disease; preferably, wherein
  • the cancer or tumor is selected from lung cancer, bone cancer, stomach cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, Vulvar cancer, rectal cancer, colon cancer, anal cancer, breast cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, urethral cancer, penile cancer, prostate cancer, pancreatic cancer, brain Cancer, testicular cancer, lymphoma, transitional cell carcinoma, bladder cancer, kidney cancer or ureteral cancer, renal cell carcinoma, renal pelvis cancer, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sar
  • the application refers to combining a therapeutically effective dose of the aforementioned compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition with an anti-CTLA-4 antibody , Anti-PD-1 antibody, anti-PD-L1 antibody, antiviral agent, chemotherapeutic agent, immunosuppressive agent, radiation, anti-tumor vaccine, antiviral vaccine, cytokine therapy or tyrosine kinase inhibitor for combined use; preferred
  • the cytokine is preferably IL-2, IL-3, IL-4 or IL-5
  • the chemotherapeutic agent is preferably a cytotoxic agent
  • the anti-PD-1 antibody is preferably a Keytruda antibody.
  • the fourth aspect of the present invention provides a method for modulating the activity of indoleamine 2,3-dioxygenase, which comprises treating a therapeutically effective dose of the aforementioned compound of formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer Or a solvate, or the aforementioned pharmaceutical composition is contacted with indoleamine 2,3-dioxygenase.
  • the adjustment is preferably an inhibitory effect.
  • a fifth aspect of the present invention provides a method of suppressing immunosuppression of a patient, the method comprising treating a therapeutically effective dose of the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or The aforementioned pharmaceutical composition is administered to a patient.
  • a sixth aspect of the present invention provides a method for treating cancer, the method comprising administering to a patient a therapeutically effective dose of the compound of the general formula (I) of the present invention or a tautomer, a racemate, a racemate Rotation, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof.
  • the cancer or tumor is selected from lung cancer, bone cancer, gastric cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, Cervical cancer, vaginal cancer, vulvar cancer, rectal cancer, colon cancer, anal cancer, breast cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, urethral cancer, penile cancer, Prostate cancer, pancreatic cancer, brain cancer, testicular cancer, lymphoma, transitional cell carcinoma, bladder cancer, kidney cancer or ureteral cancer, renal cell carcinoma, renal pelvis cancer, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, Children's solid tumors, lymphocytic lymphomas, central nervous system (CNS) tumors, primary central nervous system lymphomas, tumor angiogenesis, spinal
  • alkyl refers to a linear and branched saturated aliphatic hydrocarbon group
  • C 1-10 alkyl is an alkyl group containing 1 to 10 carbon atoms, preferably C 1-6 alkyl, more preferably C 1-3 alkyl, similarly defined; non-limiting examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , N-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-d
  • cycloalkyl and “cycloalkyl ring” are used interchangeably, and each refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group, and "C 3-8 cycloalkyl” refers to containing 3 to 8
  • the cyclic hydrocarbon group of carbon atom preferably C 3-6 cycloalkyl, is similarly defined.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl , Cyclooctyl, etc., preferably cyclopropyl, cyclopentyl, cyclohexenyl.
  • spiro ring refers to a polycyclic group that shares a carbon atom (called a spiro atom) between single rings. These may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system.
  • the helical ring is divided into a double helical ring or a multiple helical ring, preferably a double helical ring. More preferably, it is 4 yuan/5 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan double spiral ring.
  • spiro heterocycle refers to a polycyclic hydrocarbon that shares an atom (called a spiro atom) between single rings, where one or two ring atoms are selected from nitrogen, oxygen, or S(O) n (where n is an integer) 0 to 2) heteroatoms, the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system.
  • spiro heterocycles are classified into bispiro heterocycles or polyspiro heterocycles, preferably dispiro heterocycles. More preferably, it is 4-membered/5-membered, 5-membered/5-membered, or 5-membered/6-membered bis-spiro heterocyclic ring.
  • bridge ring refers to a polycyclic group that shares two or more carbon atoms.
  • the shared carbon atom is called a bridgehead carbon, and the two bridgehead carbons may be a carbon chain or a bond. , Called the bridge. These may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system. It is preferably a bicyclic or tricyclic bridge ring.
  • bridge heterocycle refers to a polycyclic group that shares two or more atoms, where one or more ring atoms are selected from nitrogen, oxygen, or S(O) n (where n is an integer from 0 to 2) ), the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system. It is preferably a bicyclic or tricyclic bridged heterocyclic ring. E.g:
  • 8 to 10 membered bicyclic ring refers to a bridge ring containing 8 to 10 ring atoms containing two rings, the bicyclic ring may be a saturated all-carbon bicyclic ring or a partially unsaturated all-carbon bicyclic ring, an 8 to 10 membered bicyclic ring Examples include (but are not limited to):
  • C 1-8 alkoxy refers to -O-(C 1-8 alkyl), where alkyl is as defined above. C 1-6 alkoxy is preferred, and C 1-3 alkoxy is more preferred. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy, pentoxy, and the like.
  • C 6-10 aryl and C 6-10 aryl ring are used interchangeably, and all refer to an all-carbon monocyclic or fused polycyclic ring (ie, shared adjacent
  • the ring group of a carbon atom pair refers to an aryl group containing 6 to 10 carbon atoms; phenyl and naphthyl are preferred, and phenyl is more preferred.
  • a bond refers to two groups connected by a covalent bond.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • halo refers to the replacement of one or more (eg 1, 2, 3, 4, or 5) hydrogen in a group with a halogen.
  • halo C 1-10 alkyl means that the alkyl is substituted with one or more (eg 1, 2, 3, 4, or 5) halogens, where alkyl is as defined above.
  • the halogenated C 1-6 alkyl group is selected, and the halogenated C 1-3 alkyl group is more preferable.
  • halogenated C 1-8 alkyl examples include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.
  • halo C 1-10 alkoxy refers to alkoxy substituted by one or more (eg 1, 2, 3, 4 or 5) halogen, wherein alkoxy is defined as described above. It is preferably a halogenated C 1-6 alkoxy group, and more preferably a halogenated C 1-3 alkoxy group. Including (but not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, etc.
  • amino refers to NH 2
  • cyano refers to the CN
  • Niro refers to NO 2
  • benzyl refers to -CH 2 - phenyl
  • carbboxy Refers to -C(O)OH
  • acetyl refers to -C(O)CH 3
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CHOHCH 3
  • thiol refers to SH.
  • heteroaryl ring and “heteroaryl” are used interchangeably and refer to having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl ;
  • the ring array shares 6, 10, or 14 ⁇ electrons; and in addition to carbon atoms, it also has 1 to 5 heteroatom groups.
  • Hetero atom means nitrogen, oxygen or sulfur.
  • 4- to 7-membered saturated or partially unsaturated monoheterocycle means that 1, 2 or 3 carbon atoms in the 4- to 7-membered monocyclic ring are selected from nitrogen, oxygen, or S(O) t (where t is substituted by a hetero atom of integer 0 to 2), but does not include the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon; preferably 4 to 6 members, more preferably 5 to 6 members.
  • Examples of 4- to 7-membered saturated or partially unsaturated monoheterocycles include, but are not limited to, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazole Alkane, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydro nitrogen heterocycle Butadiene, 1,2-dihydrooxadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro -1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-
  • 5 to 6 membered monocyclic heteroaryl ring and “5 to 6 membered monocyclic heteroaryl group” are used interchangeably, and each refers to a monoheteroaryl ring containing 5 to 6 ring atoms
  • Examples include (but not limited to): thiophene ring, N-alkane ring pyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole Ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2, 3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole
  • 8 to 10 membered bicyclic heteroaryl ring and “8 to 10 membered bicyclic heteroaryl group” are used interchangeably, and each refers to a biheteroaryl ring containing 8 to 10 ring atoms, including, for example, (But not limited to): benzofuran, benzothiophene, indole, isoindole, quinoline, isoquinoline, indazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, cinnoline, Phthalazine, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8 -Naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-nap
  • benzo 4- to 7-membered saturated or partially unsaturated heterocyclic ring means a benzo ring and a 4- to 7-membered saturated or partially unsaturated heterocyclic ring with a single carbon-carbon double bond, and a benzo 4- to 7-membered saturated or 1, 2 or 3 carbon atoms of the heterocyclic moiety in the partially unsaturated heterocyclic ring are replaced by a heteroatom selected from nitrogen, oxygen or S(O) t (where t is an integer from 0 to 2), preferably benzo 5 To 6-membered saturated or partially unsaturated heterocycle.
  • benzo 4- to 7-membered saturated or partially unsaturated heterocycles include (but are not limited to) isoindolin-1-one, phthalimide, 3,4-dihydroquinoline-1(2H )-Ketone, 4-hydroxyquinoline, 2,4-quinolinazolone, 1,3-benzodioxolane (pepper ring), 2-benzoxazolinone (oxazole).
  • substituted refers to one or more hydrogen atoms in a group, preferably 1 to 5 hydrogen atoms are independently substituted with a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independent of each other Are replaced by a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without undue effort. For example, an amino group or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.
  • any group herein may be substituted or unsubstituted.
  • the substituent is preferably 1 to 5 or less groups, independently selected from CN, halogen, and C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 Alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogenated C 1- 6 alkyl, more preferably halo C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halo C 1-8 alkoxy (preferably halo C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amine group, amine group, halogenated C 1-8 alkyl substituted amine group, 4 To 6 membered saturated monoheterocycle, 5 to 6 membered monocyclic heteroaryl ring,
  • (R 0 ) m in the present invention means that the hydrogen on the A ring is substituted with m R 0 , each R 0 is the same or different, and each independently is a group defined in the specification.
  • L 0 when L 0 is (CR 01 R 02 ) r and r is 2 or 3, two or three of R 01 or R 02 may be the same or different, and are independent types,
  • L 0 can be C(CH 3 )(OH)-C(CH 2 CH 3 )(OH), C(CH 3 )(CH 3 )-C(CH 3 )(OH) or C(H)(CH 2 CH 3 )-C(OH)(CH 3 ).
  • L 1 is (CR 11 R 12 ) s or L 3 is (CR 31 R 32 ) t .
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond. As defined herein, the term “partially unsaturated” encompasses rings with multiple sites of unsaturation, but includes aryl or heteroaryl moieties.
  • heterocycle means that 1, 2, or 3 carbon atoms in the ring are replaced with a heteroatom selected from nitrogen, oxygen, or S(O) t (where t is an integer from 0 to 2), but The ring part of -OO-, -OS- or -SS- is not included, and the remaining ring atoms are carbon.
  • t is an integer from 0 to 2
  • compositions include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salts” include, but are not limited to, inorganic base salts such as sodium, potassium, calcium, and magnesium salts. Including but not limited to salts of organic bases, such as ammonium salts, triethylamine salts, lysine salts, arginine salts, etc.
  • solvate refers to a complex formed by the compound of the present invention and a solvent. They either react in a solvent or precipitate out or crystallize out of the solvent. For example, a complex formed with water is called “hydrate”. Solvates of compounds of formula (I) are within the scope of the present invention.
  • the two carbon atoms on the cyclohexyl group connected by a group of substituents 3-aminopyridone substituted in the para position on the cyclohexyl group and the phenyl group (or heteroaryl group) are not chiral centers.
  • the chemical bond representation is only to indicate that the two chemical bonds connected to a group of substituents substituted in the para position have a trans or cis structure relative to the cyclohexyl group, so these two chemical bonds
  • the compounds expressed by exchanging with each other also fall within the protection scope of the present invention.
  • the compound represented by formula (I) or formula (II) of the present invention may exist as a mixture containing trans and cis structures, or as a cis structure, or as a trans structure. It is preferably in the form of a cis structure.
  • a group of substituents 3-aminopyridone and phenyl (or heteroaryl) substituted in the para position on the cyclohexyl group pass through two carbon atoms on the connected cyclohexyl group
  • the structure represented by the bond is a mixture containing trans and cis structures, and its protection scope includes trans or cis structures.
  • a pair of chemical bonds connected to the para position of cyclohexyl in the compound structure are Or both When, it means the same meaning, and all mean cis structure.
  • the pair of chemical bonds connected to the para position of cyclohexyl are: Or respectively When, it means the same meaning, both means trans structure.
  • the compounds represented by formula (I) or formula (II) of the present invention may contain one or more chiral centers and exist in different optically active forms.
  • a compound contains a chiral center
  • the compound contains enantiomers.
  • the present invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography.
  • diastereomers may exist.
  • the invention includes resolved optically pure specific isomers and mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • the present invention includes prodrugs of the above compounds.
  • Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released via enzymatic reactions to obtain the parent compound.
  • the specific prodrug preparation method can refer to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • dosage forms are suitable for oral, rectal, topical, oral, and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups.
  • the compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like.
  • the above dosage forms can be made from the active compound and one or more carriers or adjuvants through general pharmacological methods.
  • the aforementioned carrier needs to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers used in liquid preparations include water, physiological saline, aqueous glucose solution, ethylene glycol, and polyethylene glycol.
  • the active compound may form a solution or suspension with the above-mentioned carrier.
  • composition of the present invention is formulated, quantified, and administered in a manner consistent with medical practice standards.
  • the "therapeutically effective amount" of the administered compound is determined by factors such as the specific disorder to be treated, the individual being treated, the cause of the disorder, the target of the drug, and the mode of administration.
  • terapéuticaally effective amount refers to a compound of the present invention that will elicit an individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or improving symptoms, relieving a disorder, slowing or delaying disease progression, or preventing disease, etc. the amount.
  • the therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof contained in the pharmaceutical composition of the present invention is preferably 0.1 mg to 5 g/kg (body weight).
  • pharmaceutically acceptable carrier refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or any type of auxiliary materials, which is compatible with the patient, most It is preferably a mammal, and more preferably a human, which is suitable for delivering an active agent to a target target without terminating the activity of the agent.
  • patient refers to an animal, preferably a mammal, and more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, and humans.
  • treatment refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or disorder (e.g., cancer). Treatment also includes curing, preventing or alleviating one or more symptoms of the disease or condition to some extent.
  • the compound represented by formula (I) of the present invention can be prepared by a known method, for example, by the following method, a method equivalent thereto, or the method described in the examples.
  • the raw material compound may be in the form of a salt
  • the salt may be any pharmaceutically acceptable salt exemplified by the compound represented by formula (I) of the present invention.
  • the compound represented by formula (IVa) can be prepared by the Suzuki reaction (also called Suzuki coupling reaction) of the compound of formula (IIa) and the compound of formula (IIIa), and the compound represented by (Va) is then passed through the compound of formula (IVa) Reaction preparation.
  • Suzuki reaction also called Suzuki coupling reaction
  • a compound represented by the formula (IIIb) may be prepared by formula (IIB) compound with acid pinacol ester Suzuki coupling reaction, (IVb) represented by formula and then a compound (IIIb), and the R 3 Br It is prepared by Suzuki coupling reaction, and the compound represented by (Vb) is prepared by reacting the compound of formula (IVb).
  • the compound represented by (IVc) is prepared by the substitution reaction of the compound of formula (IIc) and the compound of formula (IIIc), and the compound represented by (Vc) is prepared by the reaction of the compound of formula (IVc).
  • the compound represented by formula (IVd) can be prepared by reductive amination of the compound of formula (IId) and the compound of formula (IIId), and the compound represented by (Vd) is further prepared by reacting the compound of formula (IVd).
  • the compound represented by formula (IVe) can be prepared by reductive amination of the compound of formula (IIe) and the compound of formula (IIIe).
  • the compound represented by formula (IIIf) can be prepared by a known reaction by reacting a compound of formula (IIf) with a compound containing an R 1 group, for example,
  • the compound of formula (IIf) used as a starting material in the reaction scheme (If) can be passed through the reaction scheme (Ia), (Ib), (Ic) or (Id), or through the reaction scheme (Ie) where R 1 is H , Or other known methods.
  • the compound having an amino group, a carboxyl group or a hydroxyl group used in the present invention can be prepared using a compound that has been protected by a protecting group commonly used for the group as needed, and after the reaction process through the above reaction scheme, known desorption can be performed Protection reaction.
  • the main advantages of the present invention are better IDO inhibitory activity and lower toxicity.
  • DMB is 2,4-dimethoxybenzyl
  • THF is tetrahydrofuran
  • EA is ethyl acetate
  • PE is petroleum ether
  • Ac 2 O is acetic anhydride
  • NBS is N-bromosuccinimide
  • DCM is methylene chloride
  • AIBN is azobisisobutyronitrile
  • Pd(dppf)Cl 2 is 1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride
  • TFA is trifluoroacetic acid
  • TBSCl It is tert-butyldimethylchlorosilane
  • NCS is N-chlorosuccinimide
  • DHP is 3,4-dihydro-2H-pyran
  • LiAlH 4 is lithium aluminum hydride
  • PMB is p-methoxybenzyl Group
  • LiHMDS is lithium bis(trimethylsilyl)amide
  • room temperature refers to about 20-25°C.
  • Step 1 The compound 2a-1 (50g, 0.23mol) was dissolved in DMF (500ml), sodium hydrogen (18.4g, 0.4mol) was added in portions at 0°C, the reaction solution was stirred at room temperature for 30min, and the solution was added dropwise. Methoxybenzyl chloride (53.4g, 0.34mol), the reaction solution was stirred at room temperature overnight, followed by LC-MS until the reaction was complete.
  • Step 2 Compounds 1a and 2a-2 are used as reaction raw materials.
  • the preparation method is the same as the preparation method of compound 3a step 2, to obtain compound 2a-3.
  • Step 3 Dissolve compound 2a-3 (2.0g, 4.5mmol) in ethanol (10ml), add iron powder (1.0g, 18mmol), saturated ammonium chloride solution (2ml), and stir the reaction solution under reflux for 1h, LC-MS Follow until the reaction is complete. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated to dryness to obtain a crude compound 2a (1.6 g), which was directly used in the next reaction, MS m/z (ESI): 417 [M+H] + .
  • Step 1 Compound 3a-1 (32.7g, 150mmol) and ethyl iodide (46.8g, 300mmol) were dissolved in DMF (250ml), potassium carbonate (41.4g, 300mmol) was added, and the reaction solution was stirred at 60°C for 5h. LC-MS followed until the reaction was complete. The reaction solution was poured into ice water, filtered, and the filter cake was washed with water and dried to obtain compound 3a-2 (31 g, yield 84%), MSm/z (ESI): 247 [M+H] + .
  • Step 2 Dissolve compound 3a-2 (30g, 121.95mmol) and compound 3a-3 (28g, 134.15mmol) in 1,4-dioxane/water (500ml/100ml), add sodium carbonate (39g, 365.85 mmol), Pd(dppf)Cl 2 (6.24 mg, 8.54 mmol), and the reaction solution was stirred at 100° C. for 5 h under nitrogen protection, followed by LC-MS until the reaction was complete. The reaction solution was filtered, concentrated, and purified by column chromatography to obtain compound 3a-4 (21 g, yield 70%), MS m/z (ESI): 249 [M+H] + .
  • Step 3 Compound 3a-4 (21g, 84.68mmol) was dissolved in methanol, Pd/C (5g, 10%) was added, the reaction solution was stirred at room temperature under a hydrogen atmosphere for 48 hours, and LC-MS followed until the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to dryness to obtain crude compound 3a (16 g), which was directly used in the next reaction, MS m/z (ESI): 219 [M+H] + .
  • Step 1 Compound 4a-1 (9.4g, 50mmol) and bromoisobutane (34g, 250mmol) were dissolved in DMP (120ml), potassium carbonate (20.7g, 150mmol) was added, and the reaction solution was stirred at 100°C for 5h , LC-MS followed until the reaction was complete. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried, concentrated, and purified by column chromatography to obtain compound 4a-2 (5.6 g, yield 46%) , MS m/z (ESI): 245 [M+H] + .
  • Step 2 Dissolve compound 4a-2 (2.44g, 10mmol), compound 4a-4 (5.08g, 20mmol) in 1,4-dioxane, add potassium acetate (2.94g, 30mmol), Pd(dppf) Cl 2 (732 mg, 1 mmol), the reaction solution was stirred at 85° C. under nitrogen for 4 h, and LC-MS followed until the reaction was complete. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, the organic phases were combined, dried, concentrated, and purified by column chromatography to obtain compound 4a-5 (2.51g, yield 86%), MS m/z ( ESI): 293[M+H] + .
  • Step 3 Compound 4a-5 (2.13g, 7.32mmol) and compound 4a-6 (1g, 6.10mmol) were dissolved in 1,4-dioxane/water (40ml/10ml), and sodium carbonate (1.94g) was added , 18.29mmol), Pd (dppf) Cl 2 (445mg, 0.61mmol), the reaction solution was stirred at 100 °C 6h, LC-MS until the reaction was complete tracking. The reaction solution was cooled to room temperature and then filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 4a (0.91 g, yield 60%), MS m/z (ESI): 250 [M+H] + .
  • Step 1 Compound 1a-1 (500mg, 2.58mmol) was dissolved in DMF (15ml), sodium hydrogen (257mg, 6.45mmol) was added in portions at 0°C, the reaction solution was stirred at room temperature for 20min, and compound 5a-1 was added (896mg, 5.15mmol), the reaction solution was stirred at room temperature for 4h, followed by LC-MS until the reaction was complete. The reaction solution was poured into water, extracted with methyl tert-butyl ether, the organic phases were combined, washed with water, dried, and concentrated to dryness to obtain crude compound 5a-2 (270 mg), MS m/z (ESI): 241 [M+H ] + .
  • Step 2 The preparation method is the same as that of step 2 of intermediate 3a to obtain compound 5a.
  • Step 1 Compound 6a-1 (2g, 12.81mmol), sodium hydrogen (564mg, 14.09mmol) were dissolved in DMF (25ml), the reaction solution was stirred at 50°C for 1h, and iodoisobutane (3.63g, 19.22) was added mmol), and the reaction solution was stirred at 50°C overnight, followed by LC-MS until the reaction was complete. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with water, dried, concentrated, and purified by column chromatography to obtain compound 6a-2 (311mg, yield 11%), MS m/z (ESI): 213 [M+H] + .
  • Step 2 Compound 6a-2 (310mg, 1.46mmol), methyl iodide (622mg, 4.38mmol) was dissolved in tetrahydrofuran (10ml), potassium carbonate (1g, 7.30mmol) was added, and the reaction solution was sealed at 100°C overnight. , LC-MS followed until the reaction was complete. The reaction solution was cooled to room temperature and washed with saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate and the combined organic phase was dried and concentrated to dryness to obtain crude compound 6a-3 (412 mg), which was directly used in the next reaction, MS m/ z(ESI):227[M+H] + .
  • Step 3 The compound 6a-3 (412 mg, 1.82 mmol), NBS (357 mg, 2 mmol) was dissolved in acetonitrile (15 ml), the reaction solution was stirred at 60° C. overnight, and LC-MS followed until the reaction was complete. The reaction solution was washed with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried, and concentrated to dryness to obtain crude compound 6a (582 mg), which was directly used in the next reaction, MS m/z (ESI) :305[M+H] + .
  • Step 1 Dissolve compound 8a-1 (2.98g, 17.13mmol) in carbon tetrachloride (20ml), add NBS (2.73mg, 15.33mmol), BPO (5mg, 0.02mmol), the reaction solution was refluxed for 20min, LC- MS followed until the reaction was complete. The reaction solution was cooled to room temperature and filtered, and the filter cake was recrystallized with cyclohexane from compound 8a-2 (0.91 g, Y: 21%).
  • Step 2 Compound 8a-2 (800 mg, 3.17 mmol) was dissolved in glacial acetic acid (15 ml), potassium acetate (436 mg, 4.44 mmol) was added, and the reaction solution was stirred at 150° C. for 15 h, followed by LC-MS until the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The pH value of the reaction solution was neutralized to about 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, dried, and concentrated to dryness to obtain crude compound 8a (817 mg ), used directly in the next reaction, MS m/z (ESI): 233 [M+H] + .
  • the preparation method is the same as the preparation method of step 2 of intermediate 5a to obtain compound 10a, MS m/z (ESI): 354 [M+H] + .
  • Step 1 Dissolve lithium aluminum hydrogen (0.604g, 15.9mmol) in dichloromethane (35ml), and slowly add compound 10a (1.87g, 5.30mmol) in dichloromethane (15ml) at 0°C. After warming to room temperature, stirring was continued for 4h, and LC-MS followed until the reaction was complete. To the reaction solution, 0.6 ml of water, 0.6 ml of 15% sodium hydroxide solution, 1.8 ml of water were filtered, and the filtrate was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain crude compound 11a-1 (1.53 g). MS m/z (ESI): 326 [M+H] + .
  • Step 2 Dissolve compound 11a-1 (1.42g, 4.37mmol) in dichloromethane (25ml), slowly add Dess-Martin at 0 °C, the reaction solution is naturally raised to room temperature and continue to stir overnight, LC-MS tracking Until the reaction is complete. Saturated sodium carbonate solution was added to the reaction solution, the layers were separated, the organic phase was dried, and concentrated to obtain crude compound 11a-2 (678 mg), MS m/z (ESI): 324 [M+H] + .
  • Step 3 To a solution of sodium hydrogen (240mg, 10.0mmol) in tetrahydrofuran (15ml) was added methoxymethyltriphenylphosphonium chloride salt (2.05g, 6.0mmol), and the reaction solution was stirred at room temperature for 30min, slowly A solution of compound 11a-2 (646 mg, 2.0 mmol) in tetrahydrofuran (10 ml) was added, and the reaction solution was stirred at room temperature overnight, followed by LC-MS until the reaction was complete.
  • methoxymethyltriphenylphosphonium chloride salt 2.05g, 6.0mmol
  • Step 4 Compound 11a-3 (451mg, 1.28mmol) was dissolved in tetrahydrofuran (8ml), hydrochloric acid solution (2M, 8ml) was added, the reaction solution was stirred at 80°C for 2h under nitrogen protection, and LC-MS followed until the reaction was complete. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, dried, concentrated and purified by column chromatography to obtain compound 11a-4 (370 mg, Y: 85%), MS m/z (ESI): 338 [M +H] + .
  • Step 5 Dissolve compound 11a-4 (302mg, 0.90mmol) in tetrahydrofuran (10ml), add 11a-5 (1ml) at 0°C under nitrogen protection, the reaction solution was naturally raised to room temperature and continue to stir overnight, LC-MS tracking Until the reaction is complete. Saturated ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, dried, concentrated, and purified by column chromatography to obtain compound 11a (112mg, Y: 29%), MS m/z (ESI): 422[M+H] + .
  • reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, saturated brine, dried, concentrated, and subjected to column chromatography (preparation column: 21.2x250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength : 254/214nm, gradient: 48%-53% change in acetonitrile) purification to obtain compound 12a-a (600mg), compound 12a-b (800mg), yield 77%, MS m/z (ESI): 361 [M+ H] + .
  • Step 1 Dissolve compound 13a-1 (3.636g, 20.0mmol), phosphorus oxychloride (1.84g, 12.0mmol) in ether (10ml), and add styrene (1.042g, 10.0mmol), zinc copper reagent dropwise (3.868g, 30mmol) in diethyl ether solution (10ml). After the reaction solution was stirred at 40°C for 3h, it was stirred at room temperature overnight. LC-MS followed until the reaction was complete. The reaction solution was filtered, added with n-hexane and stirred at room temperature for 1 h, washed with water, saturated sodium bicarbonate solution, saturated brine, dried, and concentrated to obtain crude compound 13a-2 (1.303g).
  • Step 2 Compound 13a-2 (1.303g, 6.06mmol) and zinc powder (1.584g, 24.23mmol) were dissolved in glacial acetic acid, and the reaction solution was stirred at 90°C overnight, followed by LC-MS until the reaction was complete. After cooling the reaction solution to room temperature, water, MTBE, liquid separation was added, the organic phase was washed with water, saturated sodium bicarbonate solution, saturated brine, dried, concentrated and purified by column chromatography to obtain compound 13a (400 mg, Y: 44%) , MS m/z(ESI): 147[M+H] + .
  • the preparation method is the same as the preparation method of intermediate 13a to obtain compound 14a, MS m/z (ESI): 181 [M+H] + .
  • the preparation method is the same as the preparation method of 11a-2 in the middle to obtain compound 15a, MS m/z (ESI): 218 [M+H] + .
  • Step 1 Dissolve compound 16a-1 (1.05g, 5mmol) in tetrahydrofuran (40ml), add borane-dimethyl sulfide (2M, 8ml), the reaction solution was stirred at room temperature overnight, followed by LC-MS until the reaction was complete . Water was slowly added to the reaction solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried, and concentrated to dryness to obtain compound 16a-2 (800 mg).
  • Step 2 Compound 16a-2 (800 mg, 4.1 mmol) was dissolved in dichloromethane (30 ml), DMP (2.5 g, 8.2 mmol) was added, the reaction solution was stirred at 30° C. for 3 h, and LC-MS followed until the reaction was complete. The pH value of the reaction solution was adjusted to about 8 with saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined, dried, concentrated, and purified by column chromatography to obtain compound 16a-3 (420 mg).
  • Step 3 Dissolve compound 16a-3 (420mg, 2.16mmol) in 1,4-dioxane/water (12ml/4ml), add selenium dioxide (1.2g, 10.82mmol), and the reaction solution at 110°C After 3 hours of reaction, LC-MS followed until the reaction was complete. The reaction solution was concentrated and purified by column chromatography to obtain compound 16a (150 mg).
  • Step 1 Compound 17a-1 (5g, 44mmol) was dissolved in dichloromethane (100ml), benzyl bromide (8.5g, 49.6mmol) was added dropwise, and the reaction solution was stirred at room temperature for 3h, followed by LC-MS until the reaction was complete . The reaction solution was filtered, and the filter cake was washed with ethyl acetate and dried to obtain compound 17a-2 (12.01 g), MS m/z (ESI): 222 [M+H] + .
  • Step 2 Compound 17a-3 (4.92g, 40mmol) and potassium carbonate (11.04g, 80mmol) were dissolved in ethanol (100ml), and an aqueous solution (20ml) of compound 17a-2 (11.32mg, 40mmol) was added dropwise to react The solution was stirred at 100°C for 2h, and LC-MS followed until the reaction was complete. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, the organic phases were combined, dried, concentrated, and purified by column chromatography to obtain compound 17a (5g, Y: 60%), MS m/z (ESI): 206[M+H] + .
  • Step 1 Compound 18a-1 (5.31g, 30mmol), 18a-2 (5.16g, 60mmol), potassium tert-butoxide (10g, 90mmol) were dissolved in tetrahydrofuran (100ml), the reaction solution was stirred at room temperature for 6h, LC -MS trace until the reaction is complete. Saturated sodium bicarbonate solution was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined, dried, concentrated, and purified by column chromatography to obtain compound 18a-3 (3.5g, Y: 37%), MS m/z (ESI ):318[M+H] + .
  • Step 2 The compound 18a-3 (3.5g, 11mmol), sodium chloride (12.86g, 220mmol), water (10ml) was dissolved in DMSO (100ml), the reaction solution was stirred at 150 °C for 24h, LC-MS tracking to The reaction is complete. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, concentrated, and purified by column chromatography to obtain compound 18a (1.2 g, Y: 42%), MS m/z (ESI): 260[M+H] + .
  • Step 1 The preparation method is the same as that of intermediate 5a, step 2 to obtain compound 19a-3, MS m/z (ESI): 243 [M+H] + .
  • Step 2 Compound 19a-3 (600mg, 0.25mmol) was dissolved in ethanol/water (6ml/6ml), potassium carbonate (3.4mg, 0.025mmol) was added, the reaction solution was refluxed for 18h, and LC-MS was followed until the reaction was complete. After the reaction liquid was cooled to room temperature, the layers were separated, and the organic phase was filtered to obtain compound 19a-4 (421 mg, yield 65%), MS m/z (ESI): 261 [M+H] + .
  • Step 3 Compound 19a-4 (400mg, 1.54mmol) was dissolved in methanol (15ml), palladium on carbon (40mg) was added, the reaction solution was stirred at room temperature under a hydrogen atmosphere for 4h, and LC-MS followed until the reaction was complete. The reaction solution was filtered, and the crude compound 19a-5 (417 mg) concentrated in the filtrate was directly used in the next reaction, MS m/z (ESI): 263 [M+H] + .
  • Step 4 Compound 19a-5 (417g, 1.59mmol) was dissolved in dichloromethane (6ml), trifluoroacetic acid (6ml) was added, and the reaction solution was stirred at room temperature overnight, followed by LC-MS until the reaction was complete. Saturated sodium bicarbonate solution was added to adjust the pH of the reaction solution to about 8, extracted with ethyl acetate, the organic phases were combined, dried, and concentrated to obtain crude compound 19a-6 (360 mg), which was directly used in the next reaction, MS m/z (ESI):219[M+H] + .
  • Step 5 Dissolve compound 19a-6 (259mg, 1.19mmol) in chloroform (10ml), add NBS (254mg, 1.43mmol), p-TsOCl (20mg, 0.12mmol), reflux the reaction solution for 8h, LC-MS tracking Until the reaction is complete. The reaction solution was concentrated to dryness to obtain crude compound 19a-7 (0.67 g), which was directly used in the next reaction, MS m/z (ESI): 297 [M+H] + .
  • Step 6 Dissolve compound 19a-7 (0.67g, 1.19mmol) in glacial acetic acid (8ml), add potassium acetate (0.58g, 5.94mmol), and stir the reaction solution at 100°C for 12h, followed by LC-MS until the reaction is complete .
  • the reaction solution was concentrated, saturated sodium bicarbonate solution was added to adjust the pH to 8, extracted with ethyl acetate, the organic phases were combined, dried, and concentrated to dryness to obtain crude compound 19a (0.34g), which was directly used in the next reaction, MS m/z(ESI):277[M+H] + .
  • Step 1 Compound 20a-1 (4.34g, 20mmol) was dissolved in tetrahydrofuran (50ml), n-butyllithium (2.5M, 8ml) was added dropwise at -78°C, and the reaction solution was stirred at -78°C for 1h, Compound 20a-2 (3.75 g, 24 mmol) was added, and the reaction solution was stirred at -78°C for 2 h, followed by LC-MS until the reaction was complete.
  • n-butyllithium 2.5M, 8ml
  • Step 2 The preparation method is the same as that of intermediate 19a, step 4 to obtain compound 20a, MS m/z (ESI): 251 [M+H] + .
  • Step 1 Compound 21a-1 (2.13g, 7.94mmol) was dissolved in methanol (15ml), hydrogen bromide solution (15ml) was added, and the reaction solution was stirred at 60°C for 12h, followed by LC-MS until the reaction was complete. The reaction solution was concentrated, neutralized with saturated sodium bicarbonate solution, extracted with dichloromethane, dried, and concentrated to obtain crude compound 21a-2 (1.8 g), MS m/z (ESI): 254 [M+H] + .
  • Step 2 Compound 21a-2 (1.8g, 7.1mmol), bromoisobutane (1.95g, 14.2mmol) were dissolved in DMF (20ml), potassium carbonate (2.94g, 21.3mmol) was added, the reaction solution was at 100 After stirring at °C for 12h, LC-MS followed until the reaction was complete. The reaction solution was concentrated and purified by column chromatography to obtain compound 21a (1.2 g, Y: 54%), MS m/z (ESI): 310 [M+H] + .
  • Step 1 Compound 22a-1 (6.1g, 20mmol) and potassium tert-butoxide (2.24g, 20mmol) were dissolved in tetrahydrofuran (50ml), the reaction solution was stirred at 0°C for 1h, and compound 8a-1 (1.74g, 10mmol), the reaction solution was stirred at room temperature for 12h, LC-MS followed until the reaction was complete. Saturated ammonium chloride solution was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined, dried, concentrated, and purified by column chromatography to obtain compound 22a-2 (430 mg, Y: 21%), MS m/z (ESI) :203[M+H] + .
  • Step 2 Compound 22a-2 (430 mg, 2.13 mmol), hydrochloric acid solution (2N, 10.6 ml) was dissolved in tetrahydrofuran (15 ml), and the reaction solution was stirred at 60° C. for 2 h, followed by LC-MS until the reaction was complete. The reaction solution was cooled to room temperature and extracted with dichloromethane. The organic phases were combined, dried and concentrated to obtain crude compound 22a (380 mg).
  • Step 1 Dissolve compound 24a-1 (5g, 26.31mmol) and sodium hypochlorite solution (200ml) in acetonitrile. The reaction solution was stirred at room temperature overnight, followed by LC-MS until the reaction was complete. The reaction solution was extracted with acetonitrile, the organic phases were combined, dried, and concentrated to dryness to obtain crude compound 24a-2 (2.03g), which was directly used in the next reaction, MS m/z (ESI): 238 [M+H] + .
  • Step 2 Dissolve compound 24a-2 (200mg, 0.84mmol), sulfoxide chloride (10ml), DMF (2ml) in dichloromethane, stir the reaction solution at 50°C for 1h, concentrate the solvent at 0-10
  • Dichloromethane (20 ml), dimethylamine hydrochloride (140 mg, 1.68 mmol), triethylamine (1 ml) were added at °C, the reaction solution was stirred at room temperature overnight, and LC-MS followed until the reaction was complete.
  • the reaction solution was concentrated, ethyl acetate was added, washed with saturated sodium bicarbonate solution, dried, and concentrated to obtain crude compound 24a (274 mg), MS m/z (ESI): 265 [M+H] + .
  • Step 1 Put sodium silk (4.15g, 0.18mmol) in methanol (50ml), reflux for 30min, concentrate the reaction solution, add ethanol (50ml), toluene (50ml), compound 27a-1 (8.0g, 72mmol) Then, compound 27a-2 (36g, 360mmol) was added dropwise to maintain the temperature of the reaction solution at 40-45°C. After the dropwise addition was completed, the reaction solution was stirred at 45°C for 18h, followed by LC-MS until the reaction was complete. Water was added to the reaction solution, the layers were separated, the organic phase was dried, and concentrated to obtain crude compound 27a-3 (17g) for the next reaction, MS m/z (ESI): 165 [M+H] + .
  • Step 2 Compound 27a-3 (17g, 102.41mmol) was dissolved in methanol (150ml), ferric chloride (16.6g, 102.41mmol) was added, and the reaction solution was stirred at room temperature for 18h, followed by LC-MS until the reaction was complete. The reaction solution was concentrated, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 27a-4 (4.3 g, yield 26%), MS m/z (ESI): 165 [M+H] + .
  • Step 3 To the nitric acid solution (65%, 4ml), compound 27a-4 (797mg, 4.8mmol) was added dropwise at 0°C. The reaction solution was stirred at 0°C for 2h and then raised to room temperature and stirred for 10min. LC-MS tracking Until the reaction is complete. The reaction solution was poured into ice water, filtered, and the filter cake was washed with water and dried to obtain compound 27a-5 (412 mg, yield 41%), MS m/z (ESI): 210 [M+H] + .
  • Step 4 Compound 27a-5 (412mg, 1.97mmol) was dissolved in methanol (20ml), palladium on carbon (40mg) was added, and the reaction solution was stirred at room temperature under a hydrogen atmosphere for 5h, followed by LC-MS until the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to obtain a crude compound 27a (271 mg), which was directly used in the next reaction, MS m/z (ESI): 180 [M+H] + .
  • the intermediate compound 29a in the following table was prepared by referring to the method of intermediate 3a, except that the compound 3a-1 in step 1 was replaced with 5-bromo-4-methoxy-3-nitropyridine-2(1H) -Ketone, replacing iodoethane with bromoisobutane.
  • the compound 38a was prepared by referring to the method of the intermediate 3a, except that the ethyl iodide in step 1 was replaced with methyl iodide, and the compound 3a-3 in step 2 was replaced with 47a-1.
  • Compound 45a was prepared by referring to the method of intermediate 3a, except that the ethyl iodide in Step 1 was replaced with bromoisobutane, and the compound 3a-1 was replaced with 5-bromo-4-methyl-3-nitropyridine -2(1H)-one.
  • the compound 46a was prepared by referring to the method of the intermediate 3a, except that the compound 3a-1 in Step 1 was replaced with 5-bromo-6-methyl-3-nitropyridine-2(1H)-one.
  • the intermediate compound 50a in the following table is prepared by referring to the method of compound 19a-6, except that step 2 is omitted.
  • Compounds 54a, 56a, 57a, 58a, 60a, 61a, 64a were prepared by referring to compound 19a-6, except that compound 19a-1 in step 1 was replaced with 6-bromonicotinonitrile and 5-bromo-6- Methoxy-2-cyanopyridine, 5-bromo-6-methyl-2-cyanopyridine, 5-bromo-4-methoxy-2-cyanopyridine, 5-bromo-3-methyl- 2-cyanopyridine, 5-bromo-3-methoxy-2-cyanopyridine, 5-bromo-3-fluoro-2-cyanopyridine.
  • Step 1 Add 5-bromopyridine-2-sulfonyl chloride (500mg, 0.19mmol) to the NH 3 /EtOH (5mL, 10mmol, 2M) solution at 0°C and stir for 1 hour. The reaction solution was concentrated and dichloromethane was used. (5 mL) was redissolved, washed with water, washed with brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a solid crude product 5-bromopyridine-2-sulfonamide (450 mg, 97%). MS(ESI)237[M+H] + .
  • Step 2-4 Refer to the method for compound 66a to prepare compound 59a. MS (ESI) 255 [M+H] + .
  • Step 1 Dissolve 4-bromopyridic acid (1000mg, 4.95mmol) and DMF (3ml) in dichloromethane (20ml), slowly add oxalyl chloride (5ml) dropwise, and stir at 40°C for 2h. After the reaction was completed, the solvent was evaporated under pressure to obtain a solid crude product (1051 mg), which was directly used in the next reaction.
  • Step 3-5 Prepare compound 63a according to the method of compound 77a-3. MS (ESI) 247.1 [M+H] + .
  • Step 1 Compound 66a-1 (666 mg, 3.0 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl) -1,3,2-Dioxaborane (798mg, 3.0mmol), sodium carbonate (318mg, 3.0mmol) was added 1,1'- under the protection of argon in a mixed solvent of 20ml of dioxane and 6ml of water Bis(diphenylphosphino)ferrocene]palladium dichloride (109mg, 0.015mmol), the reaction solution was heated to 100 degrees for 5 hours, and the reaction was detected by LC-MS. The reaction solution was concentrated and dried under reduced pressure, and separated and purified using a silica gel column to obtain product 66a-2 (900 mg, brown solid). MS (ESI) 281 [M+H] + .
  • Step 2 Compound 66a-2 (900mg, 3.21mmol) was dissolved in 40ml of ethyl acetate, 300mg Pd/C was added, and the mixture was reacted at room temperature for 4h under the protection of hydrogen. The reaction was detected by LC-MS. The reaction was concentrated under reduced pressure using silica gel Column separation and purification gave product 66a-3 (800 mg, Y: 62.06%). MS(ESI)283[M+H] + .
  • Step 3 Compound 66a-3 (800 mg, 2.82 mmol) was dissolved in 20 ml of tetrahydrofuran, 30 ml of 4M hydrochloric acid was added, the mixture was stirred at room temperature for 4 hours, and concentrated to dryness to obtain product 66a (770 mg, Y: 100%). MS (ESI) 239 [M+H] + .
  • Step 1 Dissolve 5-bromopyrimidine-2-carboxylic acid (950 mg, 4.68 mmol) and DMF (1 ml) in sulfoxide chloride (5 ml), stir at 40°C for 1 h, evaporate the solvent under reduced pressure and add two Methyl chloride (25ml) was dissolved, and the solution was added dropwise at 0-10°C to a mixed system mixed with triethylamine (5ml), dimethylamino hydrochloride (572mg, 7.02mmol) and dichloromethane (25ml). Stir at -10°C for 1h, slowly warm to room temperature and stir for 2h.
  • Step 2-4 Prepare compound 70a according to the method of compound 77a-3. MS (ESI) 248.1 [M+H]+.
  • Step 1 To a mixed solution of sodium hydride (61 mg, 1.5 mmol, 60% wt) and tetrahydrofuran (3 mL) at 0°C, add 5-bromo-1H-pyrazolo[3,4-B]pyridine (198 mg , 1mmol) and tetrahydrofuran (2mL), stirred for 30 minutes, and then added iodomethane (187mg, 1.3mmol).
  • Step 2-4 Prepare compound 73a according to the method of compound 66a. MS (ESI) 230 [M+H]+.
  • Step 1 Combine 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxa Borane (1064mg, 4.00mmol), 2-bromobenzothiazole (864mg, 4.00mmol), anhydrous sodium carbonate (848mg, 8.00mmol), 1,1'-bis(diphenylphosphine ferrocene) di Palladium chloride (42 mg, 0.04 mmol) was added to a mixture solution of dioxane (50 mL) and water (10 mL), and then reacted under nitrogen at 100° C. for 2 hours.
  • Step 2 Compound 76a-1 (600 mg, 2.20 mmol) was dissolved in methanol (50 mL), 10% palladium carbon (100 mg) was added, hydrogen was replaced, and the overtime reaction was performed under a hydrogen atmosphere overnight. After the reaction was completed, the diatomite was filtered to remove palladium-carbon, washed once with methanol, and the filtrate was concentrated to obtain compound 76a-2 (600 mg, 100%) directly into the next reaction.
  • Step 3 Compound 76a-2 (600 mg, 2.18 mmol) was dissolved in tetrahydrofuran (10 mL), 5 mL of concentrated hydrochloric acid was added, and the reaction was carried out at room temperature for three hours. Concentrate under reduced pressure. The white solid hydrochloride compound 76a (500 mg, 100%) was obtained.
  • Step 1 Combine 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxa Borane (14.0g, 52.5mmol), 4-bromo-1,2-dimethoxybenzene (10.8g, 50.0mmol), [1,1'-bis(diphenylphosphino)ferrocene] di Palladium chloride (2.2g, 3.0mmol) and sodium carbonate (15.9g, 300mmol) were added to the mixed solution of 1,4-dioxane (200mL) and water (50mL), and the mixed solution was at 100 °C After stirring for 16 hours, after the reaction of the raw materials was completed, the reaction solution was cooled and filtered.
  • Step 2 Palladium carbon (10%, 2.0g) was added to a solution of 77a-1 (10.4g, 37.68mmol) in methanol (250mL), and the reaction solution was stirred under hydrogen at room temperature for 18 hours, filtered to remove insoluble The filtrate was evaporated to dryness under reduced pressure to obtain crude product 77a-2 (10.5 g, 100%). MS(ESI)279[M+H] + .
  • Step 4 Compound 77a-3 (2.34g, 10.0mmol) and copper bromide (2.23g, 10.0mmol) were added to ethyl acetate (100mL), heated to 40 °C and stirred for 4 hours, after the reaction of the raw materials was completed, The reaction liquid was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product 77a-4 (3.12 g, 100%). MS(ESI)313[M+H] + .
  • Step 5 Compound 77a-4 (3.12g, 10.0mmol) and potassium acetate (1.84g, 20.0mmol) were added to acetic acid (30mL), and heated to 110 °C and stirred for 18 hours.
  • MS (ESI) 293 [M+H] + MS (ESI) 293 [M+H] + .
  • Compound 78a was prepared according to the method of compound 77a.
  • Compound 80a was prepared according to the method of compound 79a.
  • Step 1 Dissolve 6-fluoro-4-hydroxyquinoline (815 mg, 5 mmol) and ethyl 4-hydroxycyclohexanecarboxylate (860 mg, 5 mmol) in THF (20 ml), add PPh 3 and DIAD at room temperature, and stir Overnight reaction. The reaction solution was poured into water, extracted with EA, the organic phases were combined, dried, concentrated, and purified by column chromatography to obtain compound 90a-1.
  • Step 2 Compound 90a-1 (600 mg, 2 mmol) in THF (20 ml) was added lithium aluminum hydrogen (160 mg, 4 mmol) slowly at 0°C. The reaction solution was naturally raised to room temperature and stirred for 10 min. Water and potassium hydroxide solution were added to the reaction solution, filtered, the filtrate was extracted with EA, the organic phases were combined, dried, concentrated and purified by column chromatography to obtain compound 90a-2.
  • Step 3 Add DMP (1.2g, 4mmol) to the solution of compound 90a-2 (500mg, 2mmol) in DCM (20ml), react at room temperature for 3h, adjust the pH to about 8 with sodium bicarbonate solution, extract with EA, and combine organic phase , Dried, concentrated and purified by column chromatography to obtain compound 90a.
  • Step 1 Dissolve 2-amino-4-bromobenzonitrile (2000 mg, 10.15 mmol) and potassium carbonate (2104 mg, 15.23 mmol) in DMSO (10 ml) and stir, add 30% H 2 O 2 (10 ml) and stir at room temperature for 30 min . After the reaction was completed, water (30 ml) was added, extracted with EA, dried, concentrated, and purified by column chromatography to obtain compound 91a-1. MS (ESI) 215 [M+H] + .
  • Step 2-3 Refer to step 1-2 of the method of compound 77a to prepare compound 91a. MS (ESI) 277 [M+H] + .
  • Step 1 Dissolve 2-amino-5-bromopyridine (5.16g, 30mmol) and DIPEA (15.5g, 120mmol) in DCM (150ml) solution, add acetyl chloride (3.51g, 45mmol), and stir at room temperature for 8h. Purification gave compound 94a-1 (4.28 g, Y: 67%). MS (ESI) 215 [M+H] + .
  • Step 2 Compound 94a-1 (4.28g, 20mmol) was dissolved in DMF (30ml), NaH (1.2g, 30mmol) was added at 0°C, and reacted at room temperature for 30min. Add iodomethane (8.52g, 60mmol) and react at room temperature for 2h. Water (60 ml) was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, dried, concentrated, and purified by column chromatography to obtain compound 94a-2 (3.62 g, Y: 79%), MS m/z (ESI) :229[M+H] + .
  • Step 3 Refer to the preparation method of compound 19a-3 to obtain compound 94a-3. MS m/z (ESI): 289 [M+H] + .
  • Step 4-5 Refer to step 3-4 of the method of compound 19a to obtain compound 94a. MS(ESI)247[M+H] + .
  • Step 1 Refer to the preparation method of compound 19a-3 to obtain compound 95a-1.
  • Step 2 Compound 95a-1 (1.5g, 6.2mmol) was dissolved in a mixed solution of methanol (20ml) and water (10ml), potassium hydroxide (700mg, 12.4mmol) was added, and the reaction solution was stirred at 100°C overnight After that, LC-MS followed until the reaction was complete. The reaction solution was concentrated and purified by pre-HPLC to obtain compound 95a-2.
  • Step 3 Dissolve compound 95a-2 (783mg, 3mmol), cyclopropylamine (171mg, 3mmol) in DMF (15ml), add TEA (606mg, 6mmol) and HATU (1.7g, 4.5mmol). After stirring at room temperature for 2h, LC-MS followed until the reaction was complete. The reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried, concentrated and purified by column chromatography to obtain compound 95a-3. MS m/z (ESI): 301 [M+H] + .
  • Step 4-5 Refer to step 3-4 of the method of compound 19a to obtain compound 95a. MS (ESI) 259 [M+H] + .
  • Step 1-2 Refer to steps 1 and 3 of the preparation method of compound 19a to obtain compound 96a-2.
  • Step 3 Refer to step 1 of the method for preparing compound 94a to obtain compound 96a-3.
  • Step 4 Refer to step 4 of the preparation method of compound 19a to obtain compound 96a. MS (ESI) 233 [M+H] + .
  • Compound 93a was prepared using 28a-1 as the starting material, and referring to method steps 5-6 of compound 19a.
  • Step 1 6,7-dihydro-5H-pyrrole [3,4-b]pyridine hydrochloride (1g, 5.3mmol) and 1,4-cyclohexanedione monoethylene glycol ketal (2g, 2.5mmol) ) was dissolved in dichloromethane (15 ml) and methanol (50 ml), acetic acid (21 ml) and sodium cyanoborohydride (668 mg, 10.6 mmol) were added, and the mixture was stirred at room temperature overnight. Sodium bicarbonate solution was added to adjust the pH to about 8, and the compound 99a-1 was purified.
  • Step 2 Refer to Step 4 of Compound 19a method to obtain Compound 99a. MS(ESI)217[M+H] + .
  • Example 13/14 3-[[(4S)-2-hydroxy-4-phenyl-cyclohexyl]amino]-5-(1-methylpyrazol-4-yl)-1H-pyridine-2- Ketone (P-13) and 3-[[(4R)-2-hydroxy-4-phenyl-cyclohexyl]amino]-5-(1-methylpyrazol-4-yl)-1H-pyridine-2 -Preparation of ketone (P-14)
  • Step 1 Compound 7a (616mg, 3.02mmol), compound 8a (700mg, 3.02mmol), trifluoroacetic acid (4ml) were dissolved in 1,4-dioxane, the reaction solution was stirred at 50 °C for 1.5h, added Sodium borohydride acetate (2.56g, 12.07mmol), and the reaction solution was stirred at 35-40°C for 2h, followed by LC-MS until the reaction was complete.
  • Step 2 The preparation method is the same as the method in Step 2 of Example 28 to obtain compound 13-2.
  • Step 3 Compound 13-2 (150mg, 0.37mmol) was dissolved in tetrahydrofuran (5ml), lithium hydroxide solution (4M, 3ml) was added, and the reaction solution was stirred at room temperature for 1h, followed by LC-MS until the reaction was complete.
  • reaction solution was neutralized to about 8 with hydrochloric acid (2M), extracted with ethyl acetate, the organic phases were combined, dried, concentrated, and subjected to pre-HPLC (preparative column: 21.2x250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 48%-53% acetonitrile purification) to obtain compound P-13 (21mg, Y: 16%), compound P-14 (6mg, Y: 4%), MS m /z(ESI):365[M+H] + .
  • 2M hydrochloric acid
  • compound P-16 refer to the preparation methods of step 1 and step 3 of Example 13/14, except that compound 77a was used instead of compound 8a, and compound 31a was used instead of compound 7a.
  • compound P-20 refer to the preparation methods of step 1 and step 3 in Example 13/14, except that compound 8a is used instead of compound 8a, and compound 4a is used instead of compound 7a.
  • Step 1 The compound 12a-a (361mg, 1.0mmol) , 7a-2 (228mg, 1.1mmol) was dissolved in 1,4-dioxane (40ml), was added Pd (dppf) Cl 2 (74mg , 0.1mmol ), saturated sodium carbonate solution (6ml), and the reaction solution was stirred at 80°C for 1 hour under nitrogen protection, followed by LC-MS until the reaction was complete. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain crude compound 28-1 (500 mg), which was directly used in the next reaction, MS m/z (ESI): 363 [M+H] + .
  • Step 2 Compound 28-1 (220mg, 0.61mmol) was dissolved in DMF (10ml), p-toluenesulfonic acid (524mg, 3.05mmol), lithium chloride (128mg, 3.04mmol) were added, and the reaction solution was stirred at 130°C 1h, LC-MS followed until the reaction was complete. The reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined, dried, concentrated, and purified by pre-HPLC to obtain compound P-28 (158.10 mg, Y: 60%), MS (ESI) 349.2 [M+H ] + .
  • Step 1 Refer to the reaction conditions in the preparation methods of intermediate compounds 12a-a and 12a-b to obtain compound 43a-1. MS “m/z(ESI): 387.2[M+H]+.
  • Step 2-3 Prepare according to the reaction conditions in Example 28 to obtain compound P-43. MS m/z (ESI): 361.2 [M+H] + .
  • Compound P-33 refers to the preparation method of Step 1 of Example 13/14, except that compound 38a is used instead of compound 7a, and compound 8a-1 is used instead of compound 8a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • compound P-35 refer to the preparation method in Step 1 of Example 13/14, except that compound 38a was used instead of compound 7a, and compound 8a-1 was used instead of compound 8a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-36 refers to the preparation method of Example 28, except that compound 1a-1 is used instead of compound 7a-2.
  • compound P-37 refer to the preparation method of Example 28, except that compound 1a-1 is used instead of compound 7a-2, and compound 12a-b is used instead of compound 12a-a.
  • Compound P-39 refers to the preparation method of Example 28, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) is used -1H-imidazole replaces compound 7a-2.
  • Compound P-40 was prepared according to Reference Example 28, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) was used -1H-imidazole replaces compound 7a-2, and compounds 12a-b replace compounds 12a-a.
  • Compound P-41 was prepared according to Reference Example 28, except that 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) was used -1H-pyrazole replaces compound 7a-2.
  • Compound P-42 refers to the preparation method of Example 28, except that 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) is used -1H-pyrazole replaces compound 7a-2, and compound 12a-b replaces compound 12a-a.
  • Compound P-44 refers to the preparation method of Example 30, except that methyl iodide is used instead of benzyl chloride.
  • Compound P-46 refers to the preparation method of Example 28, except that 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane is substituted Compound 7a-2.
  • Compound P-49 refers to the preparation method of Example 43, except that compound 74a is substituted for compound 50a, and compound 3a-3 is substituted for compound 1a-1.
  • Compound P-50 Refer to the preparation method of Example 28, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) is used -2H-1,2,3-triazole replaces compound 7a-2.
  • Compound P-51 refers to the preparation method of Example 43, except that compound 75a is substituted for compound 50a, and compound 3a-3 is substituted for compound 1a-1.
  • Compound P-52 refers to the preparation method of Example 43, except that compound 50a is replaced with compound 8a-1 and 1-methyl-3-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-1H-pyrrole replaces compound 1a-1.
  • Compound P-59 refers to the preparation methods of Step 1 and Step 2 of Example 13/14, except that Compound 7a is replaced with Intermediate 5a, and Compound 8a is replaced with Compound 8a-1.
  • compound P-60 refer to the preparation method of Example 43, except that compound 8a-1 is used instead of compound 50a, and 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1H-pyrazole replaces compound 1a-1.
  • Compound P-61 refers to the preparation method of Example 28, except that 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl)-1H-pyrazol-1-yl)piperidine replaces compound 7a-2.
  • Compound P-62 was prepared according to Reference Example 28, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) was used Isoxazole replaces compound 7a-2.
  • Compound P-63 was prepared according to Reference Example 28, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) was used Isothiazole replaces compound 7a-2.
  • Compound P-64 refers to the preparation method of Example 28, except that 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) is used Thiazole replaces compound 7a-2.
  • Compound P-67 refers to the preparation method of Example 28, except that compound 5a-2 is used instead of 7a-2.
  • Compounds P-68 and P-69 refer to the preparation methods of Examples 57 and 58, except that compound 8a-1 is substituted for 4-(pyridin-3-yl)cyclohexan-1-one and 1-isopropyl is used -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole replaces compound 1a-1.
  • Compound P-70 refers to the preparation method of Example 28, except that 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl)-1H-pyrazol-1-yl)ethan-1-ol replaces compound 7a-2.
  • Compound P-74 refers to the preparation methods of Steps 1 and 2 of Example 13/14, except that 4-(4-methoxyphenyl)cyclohexan-1-one is used instead of Compound 8a.
  • Compounds P-77 and P-78 refer to the preparation methods of Examples 57 and 58, except that compound 89a is substituted for 4-(pyridin-3-yl)cyclohexan-1-one, and compound 3a-3 is substituted for compound 1a -1.
  • Compound P-79 refers to the preparation methods of Steps 1 and 2 of Example 13/14, except that Compound 14a is used instead of Compound 8a.
  • Compound P-85 refers to the preparation methods of Steps 1 and 2 of Example 13/14, except that Compound 8a is replaced with Compound 17a.
  • Compounds P-87 and P-88 refer to the preparation method of Step 1 of Example 13/14, except that 4-(4-methoxyphenyl)cyclohexan-1-one is used instead of compound 8a, and compound 35a instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-94 refers to the preparation methods of steps 1 and 2 of Example 13/14, except that 4-(4-chlorophenyl)cyclohexan-1-one is used instead of compound 8a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-101 refers to the preparation method of Step 1 of Example 13, except that compound 8a is replaced with 1-phenyl-4-one, and compound 7a is replaced with compound 31a.
  • Compound P-103 refers to the preparation method of Example 30, except that compound P-46 is used instead of P-28, and methyl iodide is used instead of benzyl chloride.
  • Compound P-104 refers to the preparation method of Example 30, except that compound P-46 is used instead of compound P-28.
  • Compound P-105 refers to the preparation method of Example 30, except that compound P-74 is used instead of compound P-28.
  • Compound P-108 refers to the preparation method of Example 30, except that compound P-77 is used instead of P-28, and bromoisobutane is used instead of benzyl chloride.
  • Compound P-112 refers to the preparation method of Step 1 in Example 13, except that compound 39a is used instead of compound 7a, and compound 8a-1 is used instead of compound 8a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-116 refers to the preparation methods of Steps 1 and 2 of Example 13, except that 4-(4-(trifluoromethyl)phenyl)cyclohex-1-one is used instead of compound 8a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-117 refers to the preparation method of Step 1 in Example 13, except that 4-(4-oxocyclohexyl)benzonitrile is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-118 refers to the preparation method of Example 30, except that compound P-228 is used instead of P-28, and bromoisobutane is used instead of benzyl chloride.
  • Compound P-123 refers to the preparation method of Step 1 in Example 13 except that 4-(benzo[d][1,3]dioxol-5-yl)cyclohexan-1-one is substituted For compound 8a, replace compound 7a with compound 35a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-124 refers to the preparation method of Step 1 of Example 13, except that 4-(3-methoxyphenyl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-125 refers to the preparation method in Step 1 of Example 13, except that 4-(4-(dimethylamino)phenyl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-127 refers to the preparation method of Step 1 of Example 13, except that 4-(p-tolyl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-129 refers to the preparation method of Step 1 of Example 13, except that 4-(4-methoxyphenyl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-130 refers to the preparation method of Step 1 in Example 13, except that 4-(benzo[d][1,3]dioxol-5-yl)cyclohexan-1-one is used instead
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-131 refers to the preparation method of Step 1 of Example 13, except that 4-(3,4-dimethoxyphenyl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-132 refers to the preparation method of Step 1 in Example 13, except that 4-(6-methoxypyridin-3-yl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-133 refers to the preparation method of Step 1 of Example 13, except that 4-(pyridin-4-yl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-134 refers to the preparation method of Example 30, except that compound P-64 is used instead of P-28, and bromoisobutane is used instead of benzyl chloride.
  • Compound P-136 refers to the preparation method of Step 1 of Example 13, except that compound 8a-1 is used instead of compound 8a, and compound 41a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-144 refers to the preparation method in Step 1 of Example 13, except that 4-(4-(dimethylamino)phenyl)cyclohexan-1-one is used instead of compound 8a, and compound 3a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-146 refers to the preparation method in Step 1 of Example 13, except that 4-(5-methoxypyridin-3-yl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-147 refers to the preparation method of Step 1 of Example 13, except that 4-(3-methoxyphenyl)cyclohexan-1-one is used instead of compound 8a, and compound 3a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-149 refers to the preparation method of Step 1 of Example 13, except that 4-(5-methoxypyridin-3-yl)cyclohexan-1-one is used instead of compound 8a, and compound 3a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-151 refers to the preparation method of Step 1 in Example 13, except that compound 8a-1 is used instead of compound 8a, and compound 43a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-152 refers to the preparation method of Step 1 in Example 13, except that 4-(4-methoxyphenyl)cyclohexan-1-one is used instead of compound 8a, and compound 3a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-153 refers to the preparation method of Step 1 in Example 13 except that 4-(benzo[d][1,3]dioxol-5-yl)cyclohex-1-one is substituted For compound 8a, replace compound 7a with compound 3a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-157 refers to the preparation method of Step 1 of Example 13, except that 4-(4-isopropoxyphenyl)cyclohexan-1-one is used instead of compound 8a, and compound 3a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-160 refers to the preparation method of Step 1 of Example 13, except that 4-(pyrimidin-5-yl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-161 refers to the preparation method of Step 1 in Example 13, except that compound 8a-1 is used instead of compound 8a, and compound 44a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-162 refers to the preparation method of Step 1 of Example 13, except that 4-(3,4-dimethoxyphenyl)cyclohexan-1-one is used instead of compound 8a, and compound 3a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-164 refers to the preparation method of Step 1 of Example 13, except that 4-(2-methoxyphenyl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-167 refers to the preparation method of Step 1 in Example 13, except that 4-(2-isopropoxypyridin-4-yl)cyclohexan-1-one is used instead of compound 8a, and compound 3a is used instead of compound 7a .
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-168 refers to the preparation method of Step 1 of Example 13, except that 4-(2-methoxypyridin-4-yl)cyclohexan-1-one is used instead of compound 8a, and compound 3a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-171 refers to the preparation method in Step 1 of Example 13, except that 4-(2-methoxypyrimidin-5-yl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-172 refers to the preparation method of Step 1 of Example 13, except that 4-(2-methoxypyridin-4-yl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-174 refers to the preparation method of Step 1 in Example 13, except that 94a is used instead of 8a, and 31a is used instead of 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Example 177 1-isobutyl-5-(1-methyl-1H-pyrazol-4-yl)-3-(((1S,4S)-4-(3,4,5-trimethoxy Preparation of phenyl)cyclohexyl)amino)pyridine-2(1H)-one (P-177)
  • Step 1 Dissolve compound 7a (200 mg, 0.98 mmol), compound 79a (259 mg, 0.98 mmol) and TFA (1 ml) in 1,4-dioxane (10 ml), stir at 50°C for 1 h, at 0 Sodium triacetoxyborohydride (623 mg, 2.43 mmol) was added at -10°C, and stirring was continued at room temperature overnight. When the reaction was completed, the reaction solution was filtered to remove insoluble materials, the solution was evaporated to dryness under reduced pressure, and white solid product P-177-1 (50 mg) was prepared by column purification. Three-step yield: 11.3%. MS (ESI) 453.2 [M+H] + .
  • Step 2 A solution of compound P-177-1 (23 mg, 0.051 mmol) and hydrobromic acid aqueous solution (40%, 2 ml) in methanol 5 (ml) was stirred at room temperature overnight. At the end of the reaction, the solvent was evaporated under reduced pressure to a solid P-177-2 (20 mg). Without further purification, the crude product was directly used in the next reaction. MS (ESI) 439.3 [M+H] + .
  • Step 3 Dissolve compound P-177-2 (20mg, 0.046mmol), bromoisopropane (19mg, 0.137mmol) in anhydrous potassium carbonate (32mg, 0.23mmol) in DMF (5ml) and stir at 100°C overnight.
  • the reaction solution is filtered to remove insoluble materials, the solution is evaporated to dryness under reduced pressure, and prepared by high-performance liquid phase (preparation conditions: preparation column: 21.2x250mm C18 column system: 10mM NH 4 HCO 3 H 2 O wavelength: 254 /214nm gradient: 50%-55% acetonitrile change) to give white solid product P-177 (1.71 mg, purity 83.11%). Two-step yield: 7.6%.
  • Compound P-179 refers to the preparation method of Step 1 of Example 13, except that compound 8a-1 is used instead of compound 8a, and compound 45a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-182 refers to the preparation method of Step 1 in Example 13, except that compound 20a is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-183 refers to the preparation method in Step 1 of Example 13, except that 4-(4-(methylsulfonyl)phenyl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-185 refers to the preparation method of Step 1 of Example 13, except that compound 8a-1 is used instead of compound 8a, and compound 46a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-187 refers to the preparation method of Step 1 of Example 13, except that 4-(pyridin-2-yl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-189 refers to the preparation method of Step 1 of Example 13, except that 4-(pyridin-3-yl)cyclohexan-1-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-190 refers to the preparation method of Step 1 of Example 13, except that 6-phenyl-2H-pyran-3(4H)-one is used instead of compound 8a, and compound 31a is used instead of compound 7a.
  • Compound P-192 refers to the preparation method of Step 1 of Example 13, except that 4-(3,4-dimethoxyphenyl)cyclohexan-1-one is used instead of compound 8a, and compound 29a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-193 refers to the preparation method of Step 1 in Example 13, except that compound 8a is replaced with 28a-1, and compound 7a is replaced with compound 3a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Step 1 Compound 31a (800 mg, 3.25 mmol), compound 96a (1132 mg, 4.87 mmol) and TFA (1 ml) were dissolved in THF (20 ml) and stirred at 50°C for 1 h. Sodium triacetoxyborohydride (2066 mg, 9.75 mmol) was added at room temperature, and stirring at room temperature was continued overnight. When the reaction was completed, the reaction solution was filtered to remove insoluble materials, the solution was evaporated to dryness under reduced pressure, and white solid product P-194 (655 mg) was prepared by column purification.
  • Compound P-195 refers to the preparation method of Step 1 in Example 13 except that 6-(3,4-dimethoxyphenyl)dihydro-2H-pyran-3(4H)-one is used instead of compound 8a. Replace compound 7a with compound 31a.
  • Compound P-196 refers to the preparation method of Step 1 of Example 13, except that compound 20a is used instead of compound 8a, and compound 3a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-198 refers to the preparation method of Step 1 in Example 13 except that 6-(4-oxocyclohexyl)benzo[d]oxazol-2(3H)-one is used instead of compound 8a and compound 31a Instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compounds P-199 and P-200 refer to the preparation method of Step 1 in Example 13, except that compounds 19a-6 are used instead of compound 8a, and compounds 31a are used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-202 refers to the preparation method of Step 1 in Example 13, except that 95a is used instead of compound 8a, and 31a is used instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-203 refers to the preparation method of Step 1 of Example 13, except that compound 8a is replaced with 97a, and compound 7a is replaced with compound 31a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-204 refers to the preparation method in Step 1 of Example 13, except that 4-(3,4-dimethoxyphenyl)cyclohexan-1-one is used instead of compound 8a, and compound 29a instead of compound 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • compound P-205 refer to the preparation method of Step 1 in Example 13, except that compound 8a is replaced with 98a, and compound 7a is replaced with compound 31a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Compound P-208 refers to the preparation method of Example 294, except that compound 70a is substituted for compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one, and compound 31a is substituted for compound 4a.
  • Compound P-209 refers to the preparation method of Example 294, except that compound 100a is substituted for compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one, and compound 31a is substituted for compound 4a.
  • Compound P-250 refers to the preparation method of Step 1 in Example 13, except that 19a-6 is used instead of 8a, and 4a is used instead of 7a.
  • the separation conditions are the same as in step 3 of Example 13/14.
  • Example 220 3-(((1R,4R)-4-(aminomethyl)-4-(3,4-dimethoxyphenyl)cyclohexyl)amino)-1-isobutyl-5- Preparation of (1-methyl-1H-pyrazol-4-yl)pyridine-2(1H)-one (P-220)
  • Example 221 3-(((1S,4S)-4-(aminomethyl)-4-(3,4-dimethoxyphenyl)cyclohexyl)amino)-1-isobutyl-5- Preparation of (1-methyl-1H-pyrazol-4-yl)pyridine-2(1H)-one (P-221)
  • Example 224 2-(5-(1-methyl-1H-pyrazol-3-yl)-2-oxo-3-(((1s, 4s)-4-phenylcyclohexyl)amino)pyridine Preparation of -1(2H)-yl)acetic acid (P-224)
  • Step 1 Dissolve compound P-28 (200mg, 0.57mmol) in DMF (20ml), add ethyl bromoacetate (143mg, 0.86mmol), potassium carbonate (158mg, 1.14mmol), potassium iodide (10mg, 0.06mmol), The reaction solution was stirred at 120°C for 4h, followed by LC-MS until the reaction was complete. The reaction solution was concentrated and purified by pre-HPLC to obtain compound 224-1 (50 mg, yield 20%), MSm/z (ESI): 435 [M+H] + .
  • Step 2 Dissolve compound 224-1 (248 mg, 0.57 mmol) in 1,4-dioxane (10 ml), add lithium hydroxide monohydrate (239 mg, 5.7 mmol), water (10 ml), and the reaction solution is at room temperature After stirring overnight, LC-MS followed until the reaction was complete. The reaction solution was concentrated and purified by pre-HPLC to obtain compound P-224 (10 mg, yield 4%), MS m/z (ESI): 407.3 [M+H] + .
  • Example 225 ((1s, 4s)-4-((5-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl) Preparation of amino)cyclohexyl)benzoic acid (P-225)
  • Example 226 5-((4-((1-isobutyl-5-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3 -Yl)amino)cyclohexyl)nicotinic acid (P-226)
  • Step 1 Compound 12a-a (60mg, 0.17mmol) was dissolved in 1,4-dioxane (18ml), formaldehyde (0.6ml) and trifluoroacetic acid (6ml) were added, and the reaction solution was stirred at room temperature for 2h. Sodium borohydride acetate (106 mg, 0.5 mmol) was added, and the reaction solution was stirred at room temperature for 3 h, followed by LC-MS until the reaction was complete.
  • Step 2 The preparation method is the same as the step 1 method in Example 28, MS m/z (ESI): 377 [M+H] + .
  • Step 3 The preparation method is the same as the step 2 method in Example 28, MS m/z (ESI): 363 [M+H] + .
  • Step 1 Dissolve compound 12a-a (140mg, 0.39mmol), compound 4a-4 (198mg, 0.78mmol) in 1,4-dioxane, add tetrakistriphenylphosphine palladium (23mg, 0.05mmol), Potassium carbonate (108mg, 2mmol), the reaction solution was microwaved at 120 °C for 1h, LC-MS followed until the reaction was complete. The reaction solution was concentrated, and the crude product was purified by column chromatography to obtain compound 228-1 (112 mg, yield: 70%), MS m/z (ESI): 409 [M+H] + .
  • Step 2 Dissolve compound 228-1 (360 mg, 0.88 mmol) and compound 228-2 (166 mg, 1.06 mmol) in 1,4-dioxane/water (4 ml/1 ml), and add tetrakistriphenylphosphine palladium (105mg, 0.09mmol), potassium acetate (346mg, 3.53mmol), the reaction solution was reacted under microwave at 120 °C for 30min, LC-MS followed until the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 228-3 (267 mg, Y: 84%), MS m/z (ESI): 360 [M+H] + .
  • Step 3 The preparation method is the same as that of Example 28, Step 2, MS m/z (ESI): 346 [M+H] + .
  • Step 1 Prepared according to the conditions of Step 1 of Example 13/14, MS m/z (ESI): 343.2 [M+H] + .
  • Step 2 Dissolve compound 243-3 (376mg, 2mmol) in tetrahydrofuran (40ml), add n-butyl lithium solution (1M, 2ml) dropwise at -78°C, and stir the reaction solution at -78°C for 1h, add Compound 243-2 (342mg, 1mmol) in tetrahydrofuran solution, the reaction solution was stirred at -78 °C for 2h, LC-MS followed until the reaction was complete.
  • reaction was quenched by adding water, extracted with ethyl acetate, the organic phases were combined, dried, concentrated, and subjected to pre-HPLC (preparative column: 21.2x250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient : 48%-53% acetonitrile change) purification to obtain compound P-243 (19 mg, Y: 4%), MS m/z (ESI): 452.2 [M+H] + .
  • Example 244/245 3-((R)-hydroxy-((1R,4R)-4-phenylcyclohexyl)methyl)-1-isobutyl-5-(1-methyl-1H-pyridine Oxazol-4-yl)pyridine-2(1H)-one (P-244) and 3-((S)-hydroxy-((1S,4R)-4-phenylcyclohexyl)methyl)-1-iso Preparation of Butyl-5-(1-methyl-1H-pyrazol-4-yl)pyridine-2(1H)-one (P-245)
  • Step 1 Compound P-186 (210mg, 0.43mmol) was dissolved in dichloromethane (15ml), DIBAL-H (1M, 1.27ml) was added dropwise at -78°C, and the reaction solution was stirred at -78°C for 6h , LC-MS followed until the reaction was complete. The reaction was quenched by addition of water, extracted with ethyl acetate, the organic phases were combined, dried, and concentrated to dryness to give crude compound 246-1 (140 mg), MS m/z (ESI): 493 [M+H] + .
  • Step 2 The preparation method is the same as that of Example 257, Step 3, MS m/z (ESI): 495.3 [M+H] + .
  • Step 1 The preparation method is the same as the step 1 method in Example 13, MS m/z (ESI): 431 [M+H] + .
  • Step 2 Dissolve compound 247-2 (828mg, 1.8mmol) in ethanol/water (50ml/10ml), add hydroxylamine hydrochloride (373mg, 5.4mmol), sodium bicarbonate (900mg, 10.8mmol), and the reaction solution is protected under nitrogen Under reflux for 4 hours, LC-MS followed until the reaction was complete. The reaction solution was concentrated, water was added, extracted with ethyl acetate, the organic phases were combined, dried, and concentrated to dryness to obtain a crude compound 247-3 (900 mg), which was directly used in the next reaction. MS m/z (ESI): 464 [M+H] + .
  • Step 3 Dissolve compound 247-3 (900mg, 2.0mmol) in dichloromethane (100ml), add acetyl chloride (468mg, 6.0mmol), DIPEA (1032mg, 8.0mmol), and stir the reaction solution at room temperature under nitrogen for 2h , LC-MS followed until the reaction was complete.
  • Dichloromethane was added to dilute the reaction solution, washed with water and saturated brine, dried, concentrated, and purified by column chromatography to obtain compound 247-4 (800 mg, yield 83%), MS m/z (ESI): 506 [M+ H] + .
  • Step 4 Compound 247-4 (800 mg, 1.58 mmol) was dissolved in toluene, and the reaction solution was refluxed under nitrogen protection overnight, followed by LC-MS until the reaction was complete.
  • the reaction solution was concentrated and purified by pre-HPLC (preparation column: 21.2x250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 48%-53% acetonitrile change) to obtain compound P- 247 (17.48 mg, yield 3%), MS m/z (ESI): 488 [M+H] + .
  • Example 248 1-isobutyl-3-(((1R,4R)-4-(5-methyl-1,2,4-oxadiazol-3-yl)cyclohexyl)amino)-5- Preparation of (1-methyl-1H-pyrazol-4-yl)pyridine-2(1H)-one (P-248)
  • Example 247 for the preparation of the conditions, the difference is that 4-oxocyclohexanecarbonitrile is used to replace the 247-1 compound in Step 1 of Example 247, the separation conditions (preparation column: 21.2x250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214 nm, gradient: 48%-53% acetonitrile). MS m/z (ESI): 411.2 [M+H] + .
  • Example 249 1-isobutyl-5-(1-methyl-1H-pyrazol-4-yl)-3-(((1S,4S)-4-(6-(morpholine-4-carbonyl )Pyridin-3-yl)cyclohexyl)amino)pyridine-2(1H)-one (P-249)
  • Step 1 Prepare with reference to the conditions in Step 1 of Example 13/14, pre-HPLC (preparation column: 21.2x250mmC18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 48% -53% acetonitrile change). Purification gave compound 249-1, MS m/z (ESI): 431 [M+H] + .
  • Step 2 Prepare according to the conditions in Example 225 to obtain compound 249-2. MS m/z (ESI): 450 [M+H] + .
  • Step 3 Dissolve compound 249-2 (50mg, 0.10mmol), compound 249-3 (26mg, 0.3mmol), DIPEA (25mg, 0.20mmol) in dichloromethane (13ml), add HATU (57mg, 0.15mmol) The reaction solution was stirred at room temperature for 4h, and LC-MS followed until the reaction was complete. The reaction solution was diluted with dichloromethane, washed with saturated brine, dried, concentrated and purified by pre-HPLC to obtain compound P-249 (1.02 mg, Y: 2%), MS (ESI) 519.3 [M+H] + .
  • Example 257 5-((1S,4S)-4-(hydroxymethyl)-4—((1-isobutyl-5-(1-methyl-1H-pyrazol-4-yl)-2 -Oxo-1,2-dihydropyridin-3-yl)amino)cyclohexyl)-N,N-dimethylpyridine amide (P-257)
  • Step 1 Compound 28a-1 (200 mg, 0.82 mmol) and compound 31a (221 mg, 0.90 mmol) were dissolved in glacial acetic acid, the reaction solution was stirred at 0°C for 30 min, TMSCN (123 mg, 1.23 mmol) was added, and the reaction solution was at room temperature After stirring overnight, LC-MS followed until the reaction was complete.
  • reaction solution was poured into iced ammonia water, extracted with dichloromethane/methanol (10/1, v/v), the organic phases were combined, dried, concentrated, and subjected to column chromatography (preparation column: 21.2x250mm C18 column, system: 10 mM NH 4 HCO 3 H 2 O, wavelength: 254/214 nm, gradient: 48%-53% acetonitrile). Purification gave compound 257-1 (150 mg, 36% yield), MS m/z (ESI): 502 [M+H] + .
  • Step 2 Dissolve compound 257-1 (100mg, 0.2mmol) in dichloromethane (10ml), add 1.5M DIBAL-H (0.4ml, 0.6mmol) at -78°C under the protection of nitrogen, the reaction solution is at -78 Stir at °C for 3h, and follow the LC-MS until the reaction is complete. The reaction solution was concentrated to obtain a crude compound 257-2 (120 mg), MS m/z (ESI): 505 [M+H] + .
  • Step 3 Compound 257-2 (120 mg, 0.24 mmol) was dissolved in methanol, sodium borohydride (18 mg, 0.48 mmol) was added, the reaction solution was stirred at room temperature for 30 min, and LC-MS followed until the reaction was complete. The reaction solution was concentrated and purified by pre-HPLC to obtain compound P-257 (0.52 mg), MS m/z (ESI): 507.3 [M+H] + .
  • Step 1 Compound 66a (239 mg, 1.00 mmol) and compound 4a (249 mg, 1.00 mmol) were dissolved in dichloromethane 20 ml, 2 ml of acetic acid and sodium cyanoborohydride (63 mg, 1.00 mmol) were added, and the mixture was stirred at room temperature 4 Hours, separation and purification using a silica gel column to obtain compound P-281-1 (170 mg, brown solid). MS(ESI)472[M+H] + .
  • Step 2 Compound P-281-1 (47mg, 0.10mmol) was dissolved in 20ml of concentrated ammonia water, and the tube was heated at 100 degrees and stirred for 4 hours, concentrated to dryness, and prepared by Prep-HPLC to obtain cis-structure compound P-281 (15mg , Y: 37%), preparative column: 21.2X250mm C18 column system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254 214nm, gradient /: 48% -53% acetonitrile change. MS (ESI) 457.3 [M+H]+.
  • Example 302 5-((1s, 4s)-4-((1-isobutyl-5-(isothiazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl ) Preparation of amino) cyclohexyl) pyridinecarboximide (P-302)
  • Step 1 Add compound 4a (498 mg, 2.0 mmol) and compound 19a-6 (436 mg, 2.0 mmol) to a mixed solution of dioxane (15 mL) and trifluoroacetic acid (3 mL), and then stir at 0°C for 10 Minutes, add sodium triacetoxyborohydride (1260 mg, 6.0 mmol) to the reaction solution and stir at 0°C for 30 minutes, and then stir at room temperature for another hour.
  • Step 3 Lithium bismethylsilylamide (1M solution in tetrahydrofuran, 0.74ml, 0.74mmol) was added to a solution of compound P-302-2 (56mg, 0.11mmol) in tetrahydrofuran at 0°C. The reaction solution was at 0°C Stir for 1 hour, then warm to room temperature and stir for 1 hour. After the reaction of the raw materials is complete, pour the reaction solution into ice water and extract with ethyl acetate. Combine the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Example 306 3-((4-(3,4-dimethoxyphenyl)-2-hydroxycyclohexyl)amino)-1-ethyl-5-(1-methyl-1H-pyrazole- Preparation of 4-yl)pyridine-2(1H)-one (P-306)
  • Step 1 Compound 77a (2.45g, 8.39mmol) and compound 3a (1.41g, 6.45mmol) were added to the mixed solution of dioxane (30mL) and trifluoroacetic acid (5mL), and then stirred at 0°C for 15 Minutes, add sodium triacetoxyborohydride (4.10g, 19.36mmol) to the reaction solution and stir at 0°C for 30 minutes, warm to room temperature and stir for another hour.
  • Step 2 Add compound P-306-1 (1.7g, 3.44mmol) to the tetrahydrofuran (25mL) solution, then add lithium hydroxide (4M, 60mL, 240mmol) dropwise with stirring. After the dropwise addition, at room temperature After stirring for 6 hours, the reaction solution was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered.
  • lithium hydroxide 4M, 60mL, 240mmol
  • the filtrate was concentrated under reduced pressure and prepared by high-performance liquid phase (column: 21.2X250mm C18 column; system : 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30-35% acetonitrile) to give the cis structure P-306 (1.15 g, 74%).
  • Compound P-258 refers to the preparation method of Example 30, except that 2-bromoethanol is used instead of benzyl chloride.
  • Compound P-260 refers to the preparation method and separation conditions of Example 294, except that compound 85a is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-261 refers to the preparation method and separation conditions of Reference Example 294, except that compound 63a is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-262 refers to the preparation method and separation conditions of Example 294, except that compound 84a is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-263 Refer to the preparation method and separation conditions of Example 294, except that compound 19a-6 was used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one, and compound 49a Replaces compound 4a.
  • Compound P-264 refers to the preparation method and separation conditions of Reference Example 294, except that compound 19a-6 is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one, and compound 48a is used Replaces compound 4a.
  • Compound P-265 refers to the preparation method and separation conditions of Reference Example 281, except that compound 66a is replaced with compound 67a.
  • Compound P-266 refers to the preparation method and separation conditions of Example 294, except that compound 86a is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-267 refers to the preparation method and separation conditions of Example 294, except that compound 87a is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-268 refers to the preparation method and separation conditions of Reference Example 294, except that 4-(2-methoxypyridin-4-yl)cyclohexan-1-one is used instead of compound 4-(benzo[d] Thiazol-2-yl) cyclohex-1-one.
  • Compound P-269 refers to the preparation method and separation conditions of Reference Example 294, except that 4-(quinolin-6-yl)cyclohexan-1-one is used instead of compound 4-(benzo[d]thiazole-2- Radical) cyclohexan-1-one.
  • Compound P-270 refers to the preparation method and separation conditions of Reference Example 294, except that 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)cyclohexan-1-one is used instead of compound 4- (Benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-272 refers to the preparation method and separation conditions of Reference Example 297, except that compound 91a is replaced with 92a.
  • Compound P-273 refers to the preparation method and separation conditions of Reference Example 281, except that compound 68a is used instead of compound 66a.
  • Compound P-274 refers to the preparation method and separation conditions of Example 281, except that compound 69a is used instead of compound 66a.
  • Compound P-275 refers to the preparation method and separation conditions of Reference Example 294, except that 4-(4-oxocyclohexyl)benzamide is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexyl -1-one.
  • Compound P-276 refers to the preparation method and separation conditions of Reference Example 294, except that compound 72a is substituted for compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one, and compound 31a is substituted for compound 4a.
  • Compound P-277 refers to the preparation method and separation conditions of Reference Example 294, except that compound 63a is substituted for compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one, and compound 31a is substituted for compound 4a.
  • Compound P-278 refers to the preparation method and separation conditions of Reference Example 294, except that compound 71a is substituted for compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one, and compound 31a is substituted for compound 4a.
  • Compound P-279 refers to the preparation method and separation conditions of Example 294, except that compound 19a-6 is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one, and compound 47a is used instead of compound 4a.
  • Compound P-280 refers to the preparation method and separation conditions of Reference Example 294, except that compound 19a-6 is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one, and compound 43a is used instead of compound 4a.
  • Compound P-282 refers to the preparation method and separation conditions of Example 294, except that compound 99a is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-283 refers to the preparation method and separation conditions of Example 294, except that compound 19a-6 is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one, and compound 34a Instead of compound 4a.
  • Compound P-285 refers to the preparation method and separation conditions of Example 294, except that compound 62a is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-286 refers to the preparation method and separation conditions of Reference Example 294, except that 4-(6-methoxypyridin-3-yl)cyclohexan-1-one is used instead of compound 4-(benzo[d] Thiazol-2-yl) cyclohex-1-one.
  • Compound P-287 refers to the preparation method and separation conditions of Example 294, except that compound 61a is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-288 refers to the preparation method and separation conditions of Example 294, except that compound 4-a is substituted for compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-289 refers to the preparation method and separation conditions of Example 294, except that compound 82a is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Example 294 For compound P-290, refer to the preparation method and separation conditions of Example 294, except that compound 81a was used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-291 refers to the preparation method and separation conditions of Reference Example 294, except that compound 73a is used instead of compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-292 refers to the preparation method and separation conditions of Example 294, except that compound 4-a is substituted for compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-298 refers to the preparation method and separation conditions of Example 294, except that compound 4-a is substituted for compound 4-(benzo[d]thiazol-2-yl)cyclohexan-1-one.
  • Compound P-305 refers to the preparation method and separation conditions of Example 306, except that compound 93a is substituted for compound 77a, and compound 31a is substituted for compound 3a.
  • Example 307 5-(4-((1-isobutyl-5-(1-methyl-1H-pyrazole-4-yl)-2-oxo-1,2-dihydropyridine-3- Yl)amino)-3-methylcyclohexyl)-2-pyridinecarboxamide (P-307)
  • Step 1 Add 5-(4-carbonylcyclohexyl)pyridine-2-carboxylic acid methyl ester (800 mg, 3.43 mmol) to tetrahydrofuran (30 mL), and slowly add bistrimethylsilylamino group at -78°C Lithium (1M in THF, 4.12mL, 4.12mmol) and stir for 1 hour, then add methyl iodide (488mg, 3.43mmol) to the reaction solution at -78°C, and raise the reaction solution to room temperature and stir for 18 hours. After the reaction is complete, the reaction solution is added with saturated aqueous ammonium chloride solution, and then extracted with ethyl acetate.
  • Step 2 Combine 5-(3-methyl-4-carbonylcyclohexyl)pyridine-2-carboxylic acid methyl ester (47mg, 0.19mmol) and 3-amino-1-isobutyl-5-(1-methyl- 1H-pyrazol-4-yl)pyridone (31a) was added to the mixed solution of 1,4-dioxane (5mL) and trifluoroacetic acid (0.5mL), and the reaction solution was stirred at 50°C for 0.5 hour, then The reaction solution was cooled to room temperature, sodium triacetoxyborohydride (121 mg, 0.57 mmol) was added to the reaction solution and stirred for 0.5 hours.
  • 1,4-dioxane 5mL
  • trifluoroacetic acid 0.5mL
  • Step 3 The 5-(4-((1-isobutyl-5-(1-methyl-1H-pyrazole-4-yl)-2-oxo-1,2-dihydropyridine-3- Methyl)amino)-3-methylcyclohexyl)-2-picolinic acid methyl ester (91 mg, 0.19 mmol) was added to 7M ammonia gas (methanol solution, 8 mL), and then the reaction solution was stirred at 55° C.
  • Example 308 5-((1s,4s)-4-((1-isobutyl-5-(3-methylene-2-oxopyrrolidin-1-yl)-2-oxo-1 , 2-dihydropyridin-3-yl)amino)cyclohexyl)pyridine-2-carboxamide (P-308)
  • Step 1 Combine 5-bromo-2-methoxy-3-nitropyridine (11.6g, 50mmol), 2-pyrrolidone (5.1g, 60mmol), trans-(1R, 2R)-N,N'-di A solution of methyl 1,2-cyclohexanediamine (0.71g, 5mmol), CuI (0.95g, 5mmol) and potassium carbonate (13.8g, 100mmol) in 1,4-dioxane (150mL) was heated to reflux After stirring for 24 hours, the reaction solution was filtered to remove insoluble materials.
  • Step 2 Add hydrobromic acid (70 mL) to a solution of 1-(6-methoxy-5-nitropyridin-3-yl)pyrrolidin-2-one (8.1 g, 34.18 mmol) in methanol (70 mL) Then, the reaction solution was heated to 70°C and stirred for 3 hours. After the reaction of the raw materials was completed, the reaction solution was concentrated under reduced pressure to obtain an oily crude product 1-(6-hydroxy-5-nitropyridin-3-yl)pyrrole Alkan-2-one (21 g, >100%), MS (ESI): 224.1 [M+H] + .
  • Step 3 Combine 1-(6-hydroxy-5-nitropyridin-3-yl)pyrrolidin-2-one (18.8g, 84.30mmol), bromoisobutane (34.4g, 252.991mmol) and potassium carbonate (58.2g, 421.52mmol) of N,N-dimethylformamide (200mL) solution was heated to 100 °C and stirred for 6 hours, then the reaction solution was poured into water (800mL), ethyl acetate (200mL ⁇ 3 ) Extraction, the organic phases are combined, washed with saturated brine (200 mL ⁇ 4), dried over anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure and purified by column chromatography to obtain the oily product 1-isobutyl-3-nitrate Yl-5-(2-oxopyrrolidin-1-yl)pyridin-2(1H)-one (3.1 g, 33%), MS (ESI): 280.1 [M+H]
  • Step 4 A solution of 1-isobutyl-3-nitro-5-(2-oxopyrrolidin-1-yl)pyridine-2(1H)-one (2.79g, 10mmol) in tetrahydrofuran (10mL) was slowly added Add dropwise to a solution of sodium hydride (60%, 1.12 mg, 28 mmol) in tetrahydrofuran (50 mL), and then continue to add dropwise diethyl oxalate (2.92 g, 20 mmol). After the addition is complete, the reaction solution is heated to reflux and stirred for 18 hours.
  • reaction liquid was cooled to room temperature, acetic acid (1 mL) was added and stirred at room temperature for 1 hour, the reaction liquid was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and Purification by column chromatography gave the oily product 2-(1-(1-isobutyl-5-nitro-6-oxo-1,6-dihydropyridin-3-yl)-2-oxopyrrolidine -3-yl)-2-oxo ethyl acetate (210 mg, 6%), MS (ESI): 380.2 [M+H] + .
  • Step 5 Combine 2-(1-(1-isobutyl-5-nitro-6-oxo-1,6-dihydropyridin-3-yl)-2-oxopyrrolidin-3-yl) A mixed solution of ethyl-2-oxoacetate (150 mg, 0.40 mmol) and diethylamine (87 mg, 1.19 mmol) in tetrahydrofuran (10 mL) and water (4 mL) was cooled to 0°C, and then a formaldehyde aqueous solution (36.5) was slowly added dropwise %, 130 mg, 1.58 mmol), the addition is complete, the reaction solution is stirred at room temperature for 4 hours.
  • Step 6 Combine 1-isobutyl-5-(3-methylene-2-oxopyrrolidin-1-yl)-3-nitropyridone (160 mg, 0.55 mmol) in tetrahydrofuran (8 mL) and water Iron powder (308 mg, 5.50 mmol) and ammonium chloride (291 mg, 5.50 mmol) were added to the mixed solution (2 mL). The reaction solution was stirred at reflux for 1 hour. After the reaction of the raw materials was completed, the reaction solution was filtered to remove insoluble materials. The filtrate was extracted with ethyl acetate.
  • Step 7 Combine 3-amino-1-isobutyl-5-(3-methylene-2-pyrrolidone-1-yl)-2-pyridone (94 mg, 0.36 mmol) and 5-(4-cyclohexyl) Ketone)-2-pyridinecarboxamide (158 mg, 0.72 mmol) was added to the mixed solution of 1,4-dioxane (5 mL) and trifluoroacetic acid (0.5 mL), the reaction solution was stirred at room temperature for 1 hour, and then Sodium triacetoxyborohydride (230mg, 1.08mmol) was added to the reaction solution and stirred for 1 hour.
  • 1,4-dioxane 5 mL
  • trifluoroacetic acid 0.5 mL
  • the exemplary compounds of the present invention have good inhibitory activity against Hela and HEK-293 cells.

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Abstract

本发明涉及氨基取代的吡啶酮衍生物、其制法与医药上的用途。具体地，本发明公开了式(I)化合物或其药学上可接受的盐、立体异构体或溶剂化合物，及其制备方法和应用，式中各基团的定义详见说明书。

Description

氨基取代的吡啶酮衍生物、其制法与医药上的用途 技术领域
本发明涉及医药技术领域，特别涉及一种氨基取代的吡啶酮衍生物及其制备方法和作为IDO抑制剂的应用，以及由其制备的药物组合物和药用组合物。
背景技术
吲哚胺2,3-双加氧酶(indoleamine 2,3-dioxygenase,简写IDO)是一种与色氨酸代谢有关的蛋白酶。色氨酸是八种必需氨基酸之一，在体内色氨酸可用来合成蛋白质，色氨酸还可作为前体底物通过甲氧基吲哚代谢途径合成5-羟色胺和褪黑激素(N-乙酰-5-甲氧基色胺)。5-羟色胺和褪黑激素是神经递质和神经内分泌激素，参与体内的多种神经与生理过程的调节。此外，色氨酸还可通过犬尿氨酸代谢途径产生犬尿氨酸等代谢产物。犬尿氨酸代谢途径的第一步是在吲哚胺2,3-双加氧酶或色氨酸2，3-双加氧酶(TDO)的催化作用下，L-色氨酸降解为N-甲酰基-犬尿氨酸，N-甲酰基-犬尿氨酸在犬尿氨酸甲酰胺酶的催化作用下形成犬尿氨酸，犬尿氨酸还可被进一步代谢形成3-羟基邻氨基苯甲酸，喹啉酸，吡啶甲酸。喹啉酸具有神经毒性，而吡啶甲酸具有神经保护作用。犬尿氨酸和3-羟基邻氨基苯甲酸参与淋巴细胞活性调节从而引起免疫系统被抑制。
除胎盘组织外，正常健康状况下吲哚胺2,3-双加氧酶在多数组织细胞内基本不表达。在炎症发生区域，干扰素γ等炎性细胞因子可诱导吲哚胺2,3-双加氧酶表达量升高。多方面的实验结果证明，吲哚胺2,3-双加氧酶在组织细胞中的高表达可导致该组织微环境的免疫系统被抑制，或称免疫被抑制或免疫检查点(immune checkpoint)。胎盘组织吲哚胺2,3-双加氧酶的高表达可防止对胎儿的免疫排斥反应。炎症区域吲哚胺2,3-双加氧酶的高表达可防止过度的免疫反应，防止细胞组织受到过度的损伤。导致免疫被抑制的机制之一是吲哚胺2,3-双加氧酶高表达造成局部L-色氨酸耗竭，从而被周围的淋巴细胞通过GCN2等机制感受到，引起CD8+细胞毒性T细胞发生细胞周期停滞或凋亡。导致免疫被抑制的另一种机制是吲哚胺2,3-双加氧酶高表达造成犬尿氨酸升高，犬尿氨酸形成后可离开细胞进入细胞外基质，然后进入附近的淋巴细胞通过结合AHR转录因子对CD8+T细胞和调节性Treg细胞进行调节，CD8+细胞毒性T细胞的活性被抑制，而调节性Treg细胞的数量增多并且被激活，从而导致免疫被抑制。
在很多不同类型的肿瘤中吲哚胺2,3-双加氧酶发生异常高表达，包括血液肿瘤和直结肠癌、肝癌、肺癌、胰腺癌、咽喉癌等实体瘤。吲哚胺2,3-双加氧酶异常高表达与肿瘤不良预后呈正相关。肿瘤细胞逃脱免疫监控是癌变和癌症进一步发展的关键一步，肿瘤中吲哚胺2,3-双加氧酶的异常高表达可能是肿瘤细胞逃脱。
免疫监控的一种主要机制，抑制吲哚胺2,3-双加氧酶的活性有可能激活被抑制的免疫系统，达到抑制肿瘤生长的效果，所以吲哚胺2,3-双加氧酶抑制剂作为一种免疫检查点抑制剂(immune checkpoint inhibitor)引起了医药界很大的兴趣。吲哚胺2,3-双加氧酶(IDO)有两种， IDO-1和IDO-2，参与上述免疫被抑制的主要是IDO-1，IDO-2在免疫被抑制中的作用还不是很清楚。色氨酸2，3-双加氧酶(TDO)也在很多类型的肿瘤中发生异常高表达，有的肿瘤还呈现IDO和TDO双阳性，所以有人认为也可通过抑制TDO免疫检查点起到肿瘤治疗的目的。因为正常肝脏细胞表达TDO，尚不清楚TDO抑制剂是否会影响肝脏功能和正常的色氨酸代谢，但TDO敲除得小鼠模型未见异常，表明TDO抑制剂可能不会影响肝脏功能和正常的色氨酸代谢。IDO和TDO导致免疫被抑制的机理基本相同，所以IDO/TDO双特异抑制剂也同样引起了医药界的兴趣，IDO/TDO双特异抑制剂将适用于IDO阳性、TDO阳性、IDO/TDO双阳性的病人。
色氨酸的犬尿氨酸代谢途径的很多代谢产物与精神分裂症，抑郁症，神经元退化有关，吲哚胺2,3-双加氧酶抑制剂可能也可用于这些疾病的治疗。犬尿氨酸在犬尿氨酸氨基转移酶的催化作用下可转化为犬尿喹啉酸，犬尿喹啉酸是一种NMDA拮抗剂，在精神分裂症病人的中枢神经中常见到较高的犬尿喹啉酸水平。喹啉酸具有神经毒性，可导致神经细胞凋亡和神经退化。吲哚胺2,3-双加氧酶不仅参与色氨酸代谢，还参与色氨等的代谢，5-羟色胺在吲哚胺2,3-双加氧酶的催化作用下可转化为5-羟吲哚乙酸，5-羟色胺下降可能是导致抑郁症的因素之一。
目前吲哚胺2,3-双加氧酶抑制剂还处于早期研发阶段，在现有基础上开发活性更好毒性更低的IDO抑制剂具有重要的临床意义。
发明内容
本发明的目的是提供一类结构新颖的IDO抑制剂及其制备方法和用途。
本发明第一方面提供了一种式(I)所示的化合物，或其药学上可接受的盐、立体异构体或溶剂化物：
Figure PCTCN2019121726-appb-000001
式中，
A环为C 6-10芳环(优选为苯环)、C 3-8环烷基环(优选为C 3-6环烷基环)、8至10元双环杂芳基环、4至7元饱和或部分不饱和单杂环、螺环、螺杂环、桥环或桥杂环；
R 0为氢、氰基、羟基、羧基、羟甲基、羟乙基、卤素、C 1-10烷基、-O(CH 2) p-C 1-10烷氧基、-(CH 2) t-NR aR b、-(CH 2) q-NR cS(O) 2NR aR b、-NR cC(O)C 1-10烷基、吡啶-2(1H)-酮、1-甲基吡啶-2(1H)-酮或-L 0-Y 0；其中L 0为一个键、O、(CR 01R 02) r、C(O)NR c、或NR 03；Y 0为C 6-10芳基(优选为 苯基)、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环或苯并4至7元饱和或部分不饱和杂环；所述C 6-10芳基、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环、苯并4至7元饱和或部分不饱和杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、脒基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基、-CH(CH 3)C(O)NR aR b、-C(O)N(R c)-C 6-10芳基、-S(O) 2C 1-10烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-10烷基或-NR cS(O) 2N R aR b；
m为1、2或3；
L为一个键、O、NR c、C(R dR e)、-CH 2NR c-、-NHC(O)NH-、-CH 2NHC(O)NH-、-C(O)NH-、-NHC(O)-或-CH 2CH(OH)-；
R 1为氢或-L 1-Y 1；其中L 1为(CR 11R 12) s；Y 1为羟基、氰基、羧基、卤素、C 1-10烷基、C 6-10芳基(优选为苯基)、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基、C 3-8环烷基(优选为C 3-6环烷基)、C 1-10烷氧基；所述C 6-10芳基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基环、-S(O) 2C 1-10烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-10烷基或-NR cS(O) 2N R aR b；
R 3为-L 3-Y 3；其中L 3为一个键、(CR 31R 32) t、O或NR 33；Y 3为氢、R 34、5至6元单环杂芳基、C 6-10芳基(优选为苯基)、4至7元饱和或部分不饱和单杂环或C 3-8环烷基(优选为C 3-6环烷基)；所述5至6元单环杂芳基、C 6-10芳基、4至7元饱和或部分不饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基环、-S(O) 2C 1-10烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-10烷基或-NR cS(O) 2N R aR b；
p、q、t、r、s各自独立地为0、1、2或3；
R a、R b、R c各自独立地为氢、C 3-6环烷基或C 1-8烷基，或者R a、R b与连接的N原子共同形成4至7元饱和单杂环；
R d、R e各自独立地为氢、羟基或C 1-8烷基；
R 01、R 02各自独立地为氢、羟基或C 1-8烷基；
R 03为氢或C 1-8烷基；
R 11、R 12各自独立地为氢、羟基或C 1-8烷基；
R 31、R 32各自独立地为氢、羟基或C 1-8烷基；
R 33为氢或C 1-8烷基；
R 34为式(a)、式(b)、式(c)或式(d)所示结构：
Figure PCTCN2019121726-appb-000002
式中R a’、R b’、R 35各自独立地为氢、C 3-6环烷基或C 1-8烷基；或者R 35为氢或C 1-8烷基，R a’、R b’与连接的N原子共同形成4至7元饱和单杂环；或者R a’为氢或C 1-8烷基，R 35、R b’与连接的氮和碳原子原子共同形成4至7元饱和单杂环；
R 36、R 37各自独立地为氢或C 1-8烷基，或者R 37为氢或C 1-8烷基；R 36与L 3中的C或N原子共同形成式(b1)所示的环：
Figure PCTCN2019121726-appb-000003
或者R 36为氢或C 1-8烷基；R 37与L 3中的C或N原子共同形成式(b2)所示的环：
Figure PCTCN2019121726-appb-000004
R 38为氢或C 1-8烷基；
其中L 31、L 32各自独立地为N或CH，y1、y2各自独立地为0、1、2或3；
R 2、R 4各自独立地为氢、氰基、羟基、羟甲基、羟乙基、羧基、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基；
R 5、R 6各自独立地为氢、羟基、C 1-10烷基或氧代基；或R 5、R 6与相连的碳原子共同形成3至7元饱和单杂环或3至7元饱和单环；
n为0、1、2或3。
在另一优选例中，R a、R b、R c各自独立地为氢、C 3-6环烷基或C 1-3烷基，或者R a、R b与连接的N原子共同形成4至7元饱和单杂环。在另一优选例中，R a、R b各自独立地为氢、环丙基、甲基、乙基、正丙基或异丙基，或者R a、R b与连接的N原子共同形成选自氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物和四氢吡喃的4至7元饱和单杂环；R c为氢、甲基、乙基、正丙基或异丙基。
在另一优选例中，R d、R e各自独立地为氢、羟基或C 1-3烷基。
在另一优选例中，A环中所述的C 6-10芳环选自苯环、萘环，更优选苯环。
在另一优选例中，A环中所述的C 3-8环烷基环选自环辛基环、环庚基环、环己基环、环戊基环、环丁基环或环丙基环，更优选环己基环、环戊基环或环丁基环，最优选环己基环。
在另一优选例中，A环中所述的8至10元双环杂芳基环为苯并芳杂环，如吲哚、苯并咪 唑、异喹啉或喹啉；更优选喹啉环。
在另一优选例中，A环中所述的螺环为8元螺环，更优选螺[2,5]辛烷。
在另一优选例中，A环中所述的螺杂环为10-12元螺杂环，更优选3-氮螺环[5,5]十一烷。
在另一优选例中，A环中所述的桥环为7-10元桥环，更优选金刚烷。
在另一优选例中，A环中所述的4至7元饱和或部分不饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃。
在另一优选例中，A环为环己基环。在另一优选例中，R 3为-L 3-Y 3；其中L 3为一个键，Y 3为5元或6元单环杂芳基、C 6-10芳基、4至7元饱和或部分不饱和单杂环或C 3-8环烷基(优选为C 3-6环烷基)；所述5元或6元单环杂芳基、C 6-10芳基、4至7元饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基环、-S(O) 2C 1-10烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-10烷基或-NR cS(O) 2N R aR b；R a、R b、R c如说明书中所定义。
在另一优选例中，R 3为-L 3-Y 3；其中L 3为一个键，Y 3为5至6元单环杂芳基、苯基、6元饱和或部分不饱和单杂环(优选为1,2,3,6-四氢吡啶或环己烯)或C 3-6环烷基；所述5至6元单环杂芳基、苯基、6元饱和或部分不饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、哌啶、哌嗪、吗啉、四氢吡喃、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基、-NR cS(O) 2N R aR b；R a、R b、R c如说明书中所定义。
在另一优选例中，R 3为-L 3-Y 3；其中L 3为一个键，Y 3为5至6元单环杂芳基，所述5至6元单环杂芳基为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、哌啶、哌嗪、吗啉、四氢吡喃、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基、-NR cS(O) 2N R aR b；R a、R b、R c如说明书中所定义。
在另一优选例中，Y 3为5至6元单环杂芳基，所述5至6元单环杂芳基选自吡唑、1-甲基吡唑、咪唑、吡咯、1-甲基吡咯、异噻唑、噻唑、异恶唑、1,2,3-三氮唑、2-甲基-1,2,3-三氮唑、1,2,4-三氮唑、噻吩、吡啶、嘧啶和哒嗪。
在另一优选例中，R 3为-L 3-Y 3；其中L 3为一个键，Y 3为吡唑、1-甲基吡唑、咪唑、吡咯、1-甲基吡咯、噻唑、异噻唑、异恶唑、1,2,3-三氮唑、2-甲基-1,2,3-三氮唑、1,2,4-三氮唑、噻吩、吡啶、嘧啶和哒嗪。
在另一优选例中，R 3选自如下结构：
Figure PCTCN2019121726-appb-000005
Figure PCTCN2019121726-appb-000006
在另一优选例中，R 3为-L 3-Y 3；其中L 3为(CR 31R 32) t或NR 33；Y 3为R 34。
在另一优选例中，R 1为氢或-L 1-Y 1；其中L 1为(CR 11R 12) s，Y 1为羟基、氰基、羧基、卤素、C 1-10烷基、C 6-10芳基(优选为苯基)、4至7元饱和单杂环、C 3-8环烷基(优选为C 3-6环烷基)、C 1-10烷氧基；所述C 6-10芳基、4至7元饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基环、-S(O) 2C 1-10烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-10烷基或-NR cS(O) 2NR aR b；R a、R b、R c如说明书中所定义；
其中R 11、R 12各自独立地为氢、羟基或C 1-8烷基；s为0、1、2或3。
在另一优选例中，R 1为氢或-L 1-Y 1；其中L 1为(CR 11R 12) s，Y 1为羟基、氰基、羧基、卤素、C 1-3烷基、苯基、4至7元饱和单杂环、C 3-6环烷基、C 1-3烷氧基；所述苯基、4至7元饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NHC(O)C 1-3烷基或-NHS(O) 2NR aR b；R a、R b如说明书中所定义；
其中R 11、R 12各自独立地为氢、羟基或C 1-3烷基；s为0、1、2或3。
在另一优选例中，R 1为氢或-L 1-Y 1；其中L 1为(CR 11R 12) s，Y 1为羟基、氰基、羧基、卤素、C 1-3烷基、苯基、4至6元饱和单杂环、C 3-6环烷基、C 1-3烷氧基；所述苯基、4至6元饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NHC(O)C 1-3烷基或-NHS(O) 2NR aR b；R a、R b如说明书中所定义；
其中R 11、R 12各自独立地为氢、羟基或C 1-3烷基；s为0、1、2或3；
所述4至6元饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃；
所述C 3-6环烷基选自：环丙基、环丁基、环戊基、环己基。
在另一优选例中，R 1为氢或-L 1-Y 1；其中L 1为(CR 11R 12) s，Y 1为羟基、氰基、羧基、卤素、C 1-3烷氧基或C 1-3烷基；其中R 11、R 12各自独立地为氢或C 1-3烷基；s为0、1、2或3。
在另一优选例中，R 1为氢、甲基、乙基、正丙基、异丙基、正丁基或异丁基。
在另一优选例中，R 0为氢、氰基、羟基、羧基、羟甲基、羟乙基、卤素、C 1-3烷基、-O(CH 2) p-C 1-3烷氧基、-(CH 2) t-NH 2、-(CH 2) t-N(CH 3) 2、-(CH 2) q-NHS(O) 2NH 2、-NR cC(O)C 1-3烷基、吡啶-2(1H)-酮、1-甲基吡啶-2(1H)-酮或-L 0-Y 0；其中L 0为一个键、O、(CR 01R 02) r或C(O)NR c，Y 0为苯基、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环或苯并4至7元饱和或部分不饱和杂环；所述苯基、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环、苯并4至7元饱和或部分不饱和杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、脒基、4至7元饱和单杂环、5至6元单环杂芳基、-CH(CH 3)C(O)NH 2、-C(O)NH-苯基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基或-NHS(O) 2NR aR b；其中R a、R b、R c、R 01、R 02、p、t、q、r如说明书中所定义。
在另一优选例中，R 0为氰基、羟基、羧基、羟甲基、羟乙基、卤素、C 1-3烷基、-O(CH 2) p-C 1-3烷氧基、-CH 2-NH 2、-CH 2-N(CH 3) 2、-CH 2-NHS(O) 2NH 2、-NHC(O)C 1-3烷基、吡啶-2(1H)-酮、1-甲基吡啶-2(1H)-酮或-L 0-Y 0；其中L 0为一个键或O，Y 0为苯基、5至6元单环杂芳基、8至10元双环杂芳基、苯并5至6元饱和或部分不饱和杂环；所述苯基、5至6元单环杂芳基、8至10元双环杂芳基、苯并5至6元饱和或部分不饱和杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、脒基、4至6元饱和单杂环、5至6元单环杂芳基、-CH(CH 3)C(O)NH 2、-C(O)NH-苯基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基或-NHS(O) 2NR aR b；
其中R a、R b各自独立地为氢、环丙基、甲基、乙基、正丙基或异丙基，或者R a、R b与连接的N原子共同形成选自氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物和四氢吡喃的4至7元饱和单杂环；
R c为氢、甲基、乙基、正丙基或异丙基；
p为0、1、2或3。
在另一优选例中，R 0为氰基、羟基、羧基、羟甲基、羟乙基、卤素、C 1-3烷基、-O(CH 2) p-C 1-3烷氧基、-CH 2-NH 2、-CH 2-N(CH 3) 2、-CH 2-NHS(O) 2NH 2、-NHC(O)C 1-3烷基、吡啶-2(1H)-酮、1-甲基吡啶-2(1H)-酮或-L 0-Y 0；其中L 0为一个键或O；Y 0为苯基、5至6元单环杂芳基、8至10元双环杂芳基、苯并5至6元饱和或部分不饱和杂环；所述苯基、5至6元单环杂芳基、8至10元双环杂芳基、苯并5至6元饱和或部分不饱和杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、氟、氯、溴、甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、甲氧基、乙氧基、丙氧基、异丙氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、脒基、-CH(CH 3)C(O)NH 2、-C(O)NH-苯基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基或-NHS(O) 2NR aR b；
其中R a、R b各自独立地为氢、环丙基、甲基、乙基、正丙基或异丙基，或者R a、R b与连接的N原子共同形成选自氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌 啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物和四氢吡喃的4至7元饱和单杂环；
R c为氢、甲基、乙基、正丙基或异丙基；
p为0、1、2或3。
在另一优选例中，R 2、R 4各自独立地为氢、卤素、C 1-10烷基或C 1-10烷氧基。
在另一优选例中，R 2为氢或C 1-3烷基；R 4为氢、卤素、C 1-3烷基或C 1-3烷氧基。
在另一优选例中，R 2为氢或C 1-3烷基；R 4为氢、C 1-3烷基或C 1-3烷氧基。
在另一优选例中，R 2为氢；R 4为氢或甲氧基。
在另一优选例中，R 2、R 4为氢。
在另一优选例中，A环为苯环、C 3-6环烷基环、环己烯、9至10元双环杂芳基环、5-6元饱和或部分不饱和单杂环、7-10元螺环、7-10元螺杂环或7-10元桥环。
在另一优选例中，A环为苯环、C 3-6环烷基环、5-6元饱和或部分不饱和单杂环、7-10元螺环。
在另一优选例中，A环为C 3-8环烷基环(优选为C 3-6环烷基环)、4至7元饱和或部分不饱和单杂环或螺环。
在另一优选例中，A环为苯环、环己基环、哌啶环、四氢吡喃环或螺杂环。
在另一优选例中，A环为环己基环、螺[2,5]辛烷或喹啉环。
在另一优选例中，
Figure PCTCN2019121726-appb-000007
为式(A)、式(B)或式(C)所示结构：
Figure PCTCN2019121726-appb-000008
式(A)中，W 1为N或CR a3；W 2为一个键、O、NR a4或CR a5R a6；W 3为O、NR a7或CR a8R a9；W 4为CR a10R a11；W 5为O或CR a2R a12；
v为0、1或2；
R a0如上述中R 0所定义；
R a1、R a2、R a3、R a5、R a6、R a8、R a9、R a10、R a11、R a12各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、甲基、氰基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a、R b、R c、R 0、m如说明书中所定义；R a4、R a7各自独立地为氢或C 1-10烷基。
在另一优选例中，A环为苯环；R 0为卤素或-O(CH 2) p-C 1-3烷氧基。
在另一优选例中，
Figure PCTCN2019121726-appb-000009
为式(A)所示结构：
Figure PCTCN2019121726-appb-000010
其中W 1为CR a3；W 2为CH 2；W 3为CH 2；W 4为CHR a10；W 5为CHR a2；
v为1；
R a1、R a2、R a3、R a10各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、甲基、氰基、NH 2或-NHS(O) 2NH 2；
u为0或1；
R a0为-L 0-Y 0；其中L 0为一个键或O，Y 0为苯基、5至6元单环杂芳基、8至10元双环杂芳基、苯并5至6元饱和或部分不饱和杂环；所述苯基、5至6元单环杂芳基、8至10元双环杂芳基、苯并5至6元饱和或部分不饱和杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、氟、氯、溴、甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、甲氧基、乙氧基、丙氧基、异丙氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、脒基、-CH(CH 3)C(O)NH 2、-C(O)NH-苯基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基或-NHS(O) 2NR aR b；
其中R a、R b各自独立地为氢、环丙基、甲基、乙基、正丙基或异丙基，或者R a、R b与连接的N原子共同形成选自氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物和四氢吡喃的4至7元饱和单杂环；
R c为氢、甲基、乙基、正丙基或异丙基。
在另一优选例中，L为一个键、O、NH、-CH 2NH-、-NHC(O)NH-、-CH 2NHC(O)NH-、-C(O)NH-、-NHC(O)-或-CH 2CH(OH)-。
在另一优选例中，L为O、NR c或C(R dR e)；R c、R d、R e如说明书中所定义。
在另一优选例中，L为NR c；R c为氢、甲基或乙基。更优选L为NH。
在另一优选例中，L为NH或-C(O)NH-。
在另一优选例中，L为C(R dR e)；R d、R e如说明书中所定义。
在另一优选例中，n为0。
在另一优选例中，n为1、2或3，R 5、R 6各自独立地为氢、羟基，n为2或3时，R 5可相同，也可彼此不同，R 6可相同，也可彼此不同。在另一优选例中，式(A)中，W 1为CR a3；W 2为一个键或CR a5R a6；W 3为O或NR a7；W 4为CR a10R a11；W 5为O或CR a2R a12；v为0或1；R a0如上述中R 0所定义；R a1、R a2、R a3、R a5、R a6、R a10、R a11、R a12各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a、R b、R c如说明书中所定义；R a7为氢或C 1-10烷基。
在另一优选例中，式(A)中，W 1为CR a3；W 2为一个键或CR a5R a6；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a0如上述R 0所定义；R a1、R a2、R a3、R a5、R a6、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或 -NR cS(O) 2NR aR b；u为0、1或2；R a、R b、R c如说明书中所定义。
在另一优选例中，式(A)中，W 1为N或CR a3；W 2为一个键、O、NR a4或CR a5R a6；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a0如上述中R 0所定义；R a1、R a2、R a3、R a5、R a6、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a、R b、R c如说明书中所定义；R a4为氢或C 1-10烷基。
在另一优选例中，式(A)中，W 1为N或CR a3；W 2为一个键或CR a5R a6；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a0如上述中R 0所定义；R a1、R a2、R a3、R a5、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a6为氢；R a、R b、R c如说明书中所定义。
在另一优选例中，式(A)中，W 1为N或CR a3；W 2为一个键或CR a5R a6；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a0如上述中R 0所定义；R a1、R a3、R a5、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a2为氢或羟基；R a6为氢；R a、R b、R c如说明书中所定义。
在另一优选例中，式(A)中，W 1为CR a3；W 2为一个键、O或NR a4；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a0如上述中R 0所定义；R a1、R a2、R a3、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a、R b、R c如说明书中所定义；R a4为氢或C 1-10烷基。
在另一优选例中，式(I)化合物为式(Ⅱ)所示结构：
Figure PCTCN2019121726-appb-000011
式(Ⅱ)中，
R 1为氢或-L 1-Y 1；其中L 1为(CR 11R 12) s；Y 1为羟基、氰基、羧基、卤素、C 1-3烷基、苯基、4至7元饱和单杂环、C 3-6环烷基、C 1-3烷氧基；所述苯基、4至7元饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NHC(O)C 1-3烷基或-NHS(O) 2NR aR b；
R 2、R 4各自独立地为氢、氰基、羟基、羟甲基、羟乙基、羧基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基；
R 3为-L 3-Y 3；其中L 3为一个键；Y 3为5至6元单环杂芳基、苯基、6元饱和或部分不饱 和单杂环(优选为1,2,3,6-四氢吡啶或环己烯)或C 3-6环烷基；所述5至6元单环杂芳基、苯基、6元饱和或部分不饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、哌啶、哌嗪、吗啉、四氢吡喃、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基、-NR cS(O) 2NR aR b；
或者L 3为(CR 31R 32) t或NR 33；Y 3为R 34；R 34为式(a)、式(b)、式(c)或式(d)所示结构：
Figure PCTCN2019121726-appb-000012
式中R a’、R b’、R 35各自独立地为氢、C 3-6环烷基或C 1-8烷基；或者R 35为氢或C 1-8烷基，R a’、R b’与连接的N原子共同形成4至7元饱和单杂环；或者R a’为氢或C 1-8烷基，R 35、R b’与连接的氮和碳原子原子共同形成4至7元饱和单杂环；
R 36、R 37各自独立地为氢或C 1-8烷基，或者R 37为氢或C 1-8烷基；R 36与L 3中的C或N原子共同形成式(b1)所示的环：
Figure PCTCN2019121726-appb-000013
或者R 36为氢或C 1-8烷基；R 37与L 3中的C或N原子共同形成式(b2)所示的环：
Figure PCTCN2019121726-appb-000014
R 38为氢或C 1-8烷基；
其中L 31、L 32各自独立地为N或CH，y1、y2各自独立地为0、1、2或3；
R 31、R 32各自独立地为氢、羟基或C 1-8烷基；
R 33为氢或C 1-8烷基；
t为0、1、2或3；
W 1为N或CR a3；W 2为一个键、O、NR a4或CR a5R a6；W 3为O、NR a7或CR a8R a9；W 4为CR a10R a11；W 5为O或CR a2R a12；
v为0、1或2；
R a0为氢、氰基、羟基、羧基、羟甲基、羟乙基、C 1-3烷基、-O(CH 2) p-C 1-3烷氧基、-(CH 2) t-NH 2、-(CH 2) t-N(CH 3) 2、-(CH 2) q-NHS(O) 2NH 2、-NR cC(O)C 1-3烷基、吡啶-2(1H)-酮、1-甲基吡啶-2(1H)- 酮或-L 0-Y 0；其中L 0为一个键、O、(CR 01R 02) r或C(O)NR c；Y 0为苯基、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环或苯并4至7元饱和或部分不饱和杂环；所述苯基、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环、苯并4至7元饱和或部分不饱和杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、脒基、4至7元饱和单杂环、5至6元单环杂芳基、-CH(CH 3)C(O)NH 2、-C(O)NH-苯基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基或-NHS(O) 2NR aR b；
R a1、R a2、R a3、R a5、R a6、R a8、R a9、R a10、R a11、R a12各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、卤素、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；
R a4、R a7各自独立地为氢或C 1-10烷基；
p、q、t、r、s各自独立地为0、1、2或3；
R a、R b、R c各自独立地为氢、C 3-6环烷基或C 1-8烷基，或者R a、R b与连接的N原子共同形成4至7元饱和单杂环；
R 01、R 02各自独立地为氢、羟基或C 1-3烷基；
R 11、R 12各自独立地为氢、羟基或C 1-3烷基。
n为0、1、2或3。
在另一优选例中，式(Ⅱ)化合物为式(Ⅱ-1)或式(Ⅱ-2)所示结构：
Figure PCTCN2019121726-appb-000015
式中各基团如说明书中所定义。
在另一优选例中，L 1为CH 2、CH 2CH 2、CH 2C(CH 3) 2、CH 2CH(OH)。
在另一优选例中，R 2为氢或C 1-3烷基；R 4为氢、卤素、C 1-3烷基或C 1-3烷氧基。
在另一优选例中，R 2为氢；R 4为氢或甲氧基。
在另一优选例中，Y 3中所述的4至7元饱和或部分不饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2,3,6-四氢吡啶或环己烯。
在另一优选例中，Y 3中所述的4至7元饱和或部分不饱和单杂环选自以下结构：
Figure PCTCN2019121726-appb-000016
Figure PCTCN2019121726-appb-000017
Figure PCTCN2019121726-appb-000018
上述基团任选地被1、2或3个选自下组的取代基所取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、哌啶、哌嗪、吗啉、四氢吡喃、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基、-NR cS(O) 2NR aR b；R a、R b、R c如说明书中所定义。
在另一优选例中，Y 3中所述的5至6元单环杂芳基选自：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环或吡嗪环。
在另一优选例中，Y 3中所述的5至6元单环杂芳基选自以下结构：
Figure PCTCN2019121726-appb-000019
Figure PCTCN2019121726-appb-000020
上述基团任选地被1、2或3个选自下组的取代基所取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、哌啶、哌嗪、吗啉、四氢吡喃、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基、-NR cS(O) 2N R aR b；R a、R b、R c如说明书中所定义。
在另一优选例中，Y 3中所述的5至6元单环杂芳基选自以下结构：
Figure PCTCN2019121726-appb-000021
在另一优选例中，Y 1中所述的4至7元饱和或部分不饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃。
在另一优选例中，Y 1中所述的4至7元饱和或部分不饱和单杂环选自以下结构：
Figure PCTCN2019121726-appb-000022
Figure PCTCN2019121726-appb-000023
上述基团任选地被1、2或3个选自下组的取代基所取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NHC(O)C 1-3烷基或-NHS(O) 2NR aR b；R a、R b如说明书中所定义。
在另一优选例中，Y 1中所述的5至6元单环杂芳基选自：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环或吡嗪环。
在另一优选例中，Y 1中所述的5至6元单环杂芳基选自以下结构：
Figure PCTCN2019121726-appb-000024
Figure PCTCN2019121726-appb-000025
上述基团任选地被1、2或3个选自下组的取代基所取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NHC(O)C 1-3烷基或-NHS(O) 2NR aR b；R a、R b如说明书中所定义。
在另一优选例中，Y 0中所述的4至7元饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃。
在另一优选例中，Y 0中所述的4至7元饱和单杂环选自以下结构：
Figure PCTCN2019121726-appb-000026
Figure PCTCN2019121726-appb-000027
Figure PCTCN2019121726-appb-000028
上述基团任选地被1、2或3个选自下组的取代基所取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、脒基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩、N-烷环吡咯、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-恶二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪、-CH(CH 3)C(O)NH 2、-C(O)NH-苯基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基或-NHS(O) 2NR aR b；R a、R b、R c如说明书中所定义。
在另一优选例中，Y 0中所述的5至6元单环杂芳基选自：噻吩、N-烷环吡咯、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-恶二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪。
在另一优选例中，Y 0中所述的5至6元单环杂芳基选自以下结构：
Figure PCTCN2019121726-appb-000029
Figure PCTCN2019121726-appb-000030
上述基团任选地被1、2或3个选自下组的取代基所取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、脒基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩、N-烷环吡咯、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-恶二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪、-CH(CH 3)C(O)NH 2、-C(O)NH-苯基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基或-NHS(O) 2NR aR b；R a、R b、R c如说明书中所定义。
在另一优选例中，Y 0中所述8至10元双环杂芳基环为苯并5或6元芳杂环且含有1,2或3个选自N、S或O的杂原子，选自：苯并呋喃、苯并噻吩、吲哚、苯并咪唑、苯并噻唑、 嘌呤、异喹啉、喹啉、噌啉环、喹喔啉。
在另一优选例中，Y 0中所述苯并4至7元(或苯并5至6元)饱和或部分不饱和杂环含有1、2或3个选自N、S或O的杂原子，选自：异吲哚啉-1-酮、邻苯二甲酰亚胺、3,4-二氢喹啉-1(2H)-酮、4-羟基喹啉、2,4-喹啉唑二酮、1,3-苯并二氧环戊烷(胡椒环)、2-苯并唑啉酮(恶唑)。
在另一优选例中，Y 0中所述的8至10元双环杂芳基或苯并4至7元饱和或部分不饱和杂环(或苯并5至6元饱和或部分不饱和杂环)选自以下结构：
Figure PCTCN2019121726-appb-000031
Figure PCTCN2019121726-appb-000032
上述基团任选地被1、2或3个选自下组的取代基所取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、脒基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩、N-烷环吡咯、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-恶二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪、-CH(CH 3)C(O)NH 2、-C(O)NH-苯基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基或-NHS(O) 2NR aR b；R a、R b、R c如说明书中所定义。
在另一优选例中，Y 0为选自下组的结构：
Figure PCTCN2019121726-appb-000033
Figure PCTCN2019121726-appb-000034
上述基团任选地被1、2或3个选自下组的取代基所取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、脒基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩、N-烷环吡咯、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-恶二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪、-CH(CH 3)C(O)NH 2、-C(O)NH-苯基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基或-NHS(O) 2NR aR b；R a、R b、R c如说明书中所定义。
在另一优选例中，式(Ⅱ)中，W 1为CR a3；W 2为一个键或CR a5R a6；W 3为O或NR a7；W 4为CR a10R a11；W 5为O或CR a2R a12；v为0或1；R a0如说明书中所定义；R a1、R a2、R a3、R a5、R a6、R a10、R a11、R a12各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a、R b、R c如说明书中所定义；R a7为氢或C 1-10烷基。
在另一优选例中，式(Ⅱ)中，W 1为CR a3；W 2为一个键或CR a5R a6；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a0如说明书中所定义；R a1、R a2、R a3、R a5、R a6、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a、R b、R c如说明书中所定义。
在另一优选例中，式(Ⅱ)中，W 1为N或CR a3；W 2为一个键、O、NR a4或CR a5R a6；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a0如说明书中所定义；R a1、R a2、R a3、R a5、R a6、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a、R b、R c如说明书中所定义；R a4为氢或C 1-10烷基。
在另一优选例中，式(Ⅱ)中，W 1为N或CR a3；W 2为一个键或CR a5R a6；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a0如说明书中所定义；R a1、R a2、R a3、R a5、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a6为氢；R a、R b、R c如说明书中所定义。
在另一优选例中，式(Ⅱ)中，W 1为N或CR a3；W 2为一个键或CR a5R a6；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a0如说明书中所定义；R a1、R a3、R a5、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a2为氢或羟基；R a6为氢；R a、R b、R c如说明书中所定义。
在另一优选例中，式(Ⅱ)中，W 1为CR a3；W 2为一个键、O或NR a4；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a0如说明书中所定义；R a1、R a2、R a3、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b； u为0、1或2；R a、R b、R c如说明书中所定义；R a4为氢或C 1-10烷基。
在另一优选例中，式(Ⅱ)中，W 1为CR a3；W 2为CH 2；W 3为CH 2；W 4为CHR a10；W 5为CHR a2；v为1；R a1、R a2、R a3、R a10各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、甲基、氰基、NH 2或-NHS(O) 2NH 2；u为0或1；R a0为-L 0-Y 0；其中L 0为一个键或O；Y 0为苯基、5至6元单环杂芳基、8至10元双环杂芳基、苯并5至6元饱和或部分不饱和杂环；所述苯基、5至6元单环杂芳基、8至10元双环杂芳基、苯并5至6元饱和或部分不饱和杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、氟、氯、溴、甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、二氟乙基、三氟乙基、甲氧基、乙氧基、丙氧基、异丙氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、脒基、-CH(CH 3)C(O)NH 2、-C(O)NH-苯基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基或-NHS(O) 2NR aR b；
其中R a、R b各自独立地为氢、环丙基、甲基、乙基、正丙基或异丙基，或者R a、R b与连接的N原子共同形成选自氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物和四氢吡喃的4至7元饱和单杂环；
R c为氢、甲基、乙基、正丙基或异丙基。
在另一优选例中，R a、R b与连接的N原子共同形成的4至7元饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃。
在另一优选例中，R 35、R b与连接的氮和碳原子原子共同形成的4至7元饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃。
在另一优选例中，R 5、R 6与相连的碳原子共同形成的3至7元饱和单杂环选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃。
在另一优选例中，式(I)化合物选自表A或表B的结构。
表A
Figure PCTCN2019121726-appb-000035
Figure PCTCN2019121726-appb-000036
Figure PCTCN2019121726-appb-000037
表B
Figure PCTCN2019121726-appb-000038
Figure PCTCN2019121726-appb-000039
Figure PCTCN2019121726-appb-000040
本发明第二方面提供了一种药物组合物，所述药物组合物包括本发明第一方面所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物；以及药学可接受的载体。
本发明第三方面提供了如本发明第一方面所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，或如本发明第二方面所述药物组合物在制备药物中的应用，所述药物用于抑制吲哚胺2,3-双加氧酶的活性或者用于抑制患者的免疫抑制。
在另一优选例中，所述药物用于治疗或预防患者的癌症或肿瘤、病毒感染、抑郁症、神经变性病症、创伤、年龄相关的白内障、器官移植排斥或自身免疫疾病；优选的，其中所述癌症或肿瘤选自肺癌、骨癌、胃癌、胰腺癌、皮肤癌、头颈癌、子宫癌、卵巢癌、睾丸癌、 子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、直肠癌、结肠癌、肛门区癌、乳腺癌、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、尿道癌、阴茎癌、前列腺癌、胰腺癌、脑癌、睾丸癌、淋巴癌、移行细胞癌、膀胱癌、肾癌或输尿管癌、肾细胞癌、肾盂癌、霍奇金病、非霍奇金淋巴瘤、软组织肉瘤、儿童实体瘤、淋巴细胞性淋巴瘤、中枢神经系统(CNS)肿瘤、原发性中枢神经系统淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、黑素瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、慢性或急性白血病和所述癌的组合。
在另一优选例中，所述的应用是指将治疗有效剂量的前述的式(Ⅰ)化合物、其立体异构体或其药学上可接受盐、或前述药物组合物与抗CTLA-4抗体、抗PD-1抗体、抗PD-L1抗体、抗病毒剂、化疗剂、免疫抑制剂、辐射、抗肿瘤疫苗、抗病毒疫苗、细胞因子疗法或酪氨酸激酶抑制剂进行联合用药；优选的，所述细胞因子优选IL-2、IL-3、IL-4或IL-5，所述化疗剂优选细胞毒性剂，所述抗PD-1抗体优选Keytruda抗体。
本发明第四方面提供了一种调节吲哚胺2,3-双加氧酶活性的方法，包括将治疗有效剂量的前述式(Ⅰ)化合物、或其药学上可接受盐，立体异构体或溶剂化物、或前述药物组合物与吲哚胺2,3-双加氧酶接触。优选的，所述调节优选为抑制作用。
本发明第五方面提供了一种抑制患者的免疫抑制的方法，所述方法包括将治疗有效剂量的前述式(Ⅰ)化合物、或其药学上可接受盐，立体异构体或溶剂化物，或前述药物组合物给予患者。
本发明第六方面提供一种治疗癌症的方法，该方法包括向患者施用治疗有效剂量的本发明的通式(I)所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐。
在另一优选例中，所述癌症或肿瘤选自肺癌、骨癌、胃癌、胰腺癌、皮肤癌、头颈癌、子宫癌、卵巢癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、直肠癌、结肠癌、肛门区癌、乳腺癌、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、尿道癌、阴茎癌、前列腺癌、胰腺癌、脑癌、睾丸癌、淋巴癌、移行细胞癌、膀胱癌、肾癌或输尿管癌、肾细胞癌、肾盂癌、霍奇金病、非霍奇金淋巴瘤、软组织肉瘤、儿童实体瘤、淋巴细胞性淋巴瘤、中枢神经系统(CNS)肿瘤、原发性中枢神经系统淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、黑素瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、慢性或急性白血病和所述癌的组合。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。
具体实施方式
本发明人经过长期而深入的研究，意外地发现了一类氨基取代的吡啶酮衍生物，这些化合物对Hela和HEK-293细胞具有很好的抑制活性，以及更低的毒性，能够用作IDO抑制剂，对IDO相关的疾病具有进一步应用潜力。
术语定义
如本文所用，“烷基”指直链和支链的饱和的脂族烃基，C 1-10烷基为包含1至10个碳原子的烷基，优选为C 1-6烷基，更优选为C 1-3烷基，定义类似；烷基的非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等更优选。
如本文所用，“环烷基”和“环烷基环”可互换使用，均指饱和或部分不饱和单环环状烃基，“C 3-8环烷基”是指包含3至8个碳原子的环烃基，优选为C 3-6环烷基，定义类似。环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环戊基、环己烯基。
如本文所用，“螺环”是指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环的数目将螺环分为双螺环或多螺环，优选为双螺环。更优选为4元/5元、5元/5元或5元/6元双螺环。例如：
Figure PCTCN2019121726-appb-000041
如本文所用，“螺杂环”指单环之间共用一个原子(称螺原子)的多环烃，其中一个或两个环原子选自氮、氧或S(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环的数目将螺杂环分为双螺杂环或多螺杂环，优选双螺杂环。更优选为4元/5元、5元/5元或5元/6元双螺杂环。例如：
Figure PCTCN2019121726-appb-000042
如本文所用，“桥环”是指共用两个或两个以上碳原子的多环基团，共用的碳原子称为桥头碳，两个桥头碳之间可以是碳链，也可以是一个键，称为桥。这些可以含有一个或多个双 键，但没有一个环具有完全共轭的π电子系统。优选为双环或三环桥环。例如：
Figure PCTCN2019121726-appb-000043
如本文所用，“桥杂环”指共用两个或两个以上原子的多环基团，其中一个或多个环原子选自氮、氧或S(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为双环或三环桥杂环。例如：
Figure PCTCN2019121726-appb-000044
如本文所用，“8至10元双环”是指含8至10个环原子的含两个环的桥环，双环可为饱和全碳双环或部分不饱和的全碳双环，8至10元双环的实例包括(但不限于)：
Figure PCTCN2019121726-appb-000045
如本文所用，“C 1-8烷氧基”指-O-(C 1-8烷基)，其中烷基的定义如上所述。优选C 1-6烷氧基，更优选C 1-3烷氧基。非限制性实施例包含甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、异丁氧基、戊氧基等。
如本文所用，“C 6-10芳基”和“C 6-10芳环”可互换使用，均指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，指含有6至10个碳原子的芳基；优选苯基和萘基，更优选苯基。
如本文所用，“一个键”指由其连接的两个基团通过一个共价键连接。
如本文所用，“卤素”指氟、氯、溴或碘。
如本文所用，“卤代”指基团中一个或多个(如1、2、3、4或5个)氢被卤素所取代。
例如，“卤代C 1-10烷基”指烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷基的定义如上所述。选为卤代C 1-6烷基，更优选为卤代C 1-3烷基。卤代C 1-8烷基的例子包括(但 不限于)一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。
又例如，“卤代C 1-10烷氧基”指烷氧基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷氧基的定义如上所述。优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基。包括(但不限于)三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。
如本文所用，“氨基”指NH 2，“氰基”指CN，“硝基”指NO 2，“苄基”指-CH 2-苯基，“氧代基”指＝O，“羧基”指-C(O)OH，“乙酰基”指-C(O)CH 3，“羟甲基”指-CH 2OH，“羟乙基”指-CH 2CH 2OH或-CHOHCH 3，“羟基”指-OH，“硫醇”指SH。
如本文所用，“杂芳基环”与“杂芳基”可互换使用，是指具有5到10个环原子，优选5或6元单环杂芳基或8至10元双环杂芳基；环阵列中共享6、10或14个π电子；且除碳原子外还具有1到5个杂原子的基团。“杂原子”是指氮、氧或硫。
如本文所用，“4至7元饱和或部分不饱和单杂环”是指4至7元单环中的1、2或3个碳原子被选自氮、氧或S(O) t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳；优选4至6元，更优选5至6元。4至7元饱和或部分不饱和单杂环的实例包括(但不限于)氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、吡咯啉、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶等。
如本文所用，“5至6元单环杂芳基环”和“5至6元单环杂芳基”可互换使用，均是指含5至6个环原子的单杂芳基环，例如包括(但不限于)：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环等。
如本文所用，“8至10元双环杂芳基环”和“8至10元双环杂芳基”可互换使用，均是指含8至10个环原子的双杂芳基环，例如包括(但不限于)：苯并呋喃、苯并噻吩、吲哚、异吲哚、喹啉、异喹啉、吲唑、苯并噻唑、苯并咪唑、喹唑啉、喹喔啉、噌啉、酞嗪、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶、1，2-苯并异噻唑、吲唑、1H-吡唑并[3,4-B]吡啶。
如本文所用，“苯并4至7元饱和或部分不饱和杂环”是指苯环和4至7元饱和或部分不饱和杂环并用一个碳碳双键，苯并4至7元饱和或部分不饱和杂环中的杂环部分的1、2或3个碳原子被选自氮、氧或S(O) t(其中t是整数0至2)的杂原子所取代，优选苯并5至6元饱和或部分不饱和杂环。苯并4至7元饱和或部分不饱和杂环的实例包括(但不限于)异吲哚啉-1-酮、邻苯二甲酰亚胺、3,4-二氢喹啉-1(2H)-酮、4-羟基喹啉、2,4-喹啉唑二酮、1,3-苯并二氧环戊烷(胡椒环)、2-苯并唑啉酮(恶唑)。
如本文所用，“取代的”指基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
如本文所用，本文任一基团可以是取代的或未取代的。上述基团为取代时，取代基优选为1至5个以下基团，独立地选自CN、卤素、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、C 1-8烷基取代的胺基、胺基、卤代C 1-8烷基取代的胺基、4至6元饱和单杂环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环。
本文以上所述的各类取代基团其自身也是可以被本文所描述的基团取代。
本文所述的4至6元(5至6元)饱和单杂环被取代时，取代基的位置可处在它们可能的化学位置，示例性的单杂环的代表性的取代情况如下所示：
Figure PCTCN2019121726-appb-000046
Figure PCTCN2019121726-appb-000047
其中“Sub”表示本文所述的各类取代基；
Figure PCTCN2019121726-appb-000048
表示与其他原子的连接。
除非另有定义，本发明中(R 0) m表示A环上的氢被m个R 0取代，每个R 0相同或不同，且 各自独立地为说明书中所定义的基团。
除非另有定义，本发明中当L 0为(CR 01R 02) r，r为2或3时，其中的两个或三个R 01或R 02可以相同或不同，为各自独立的种类，例如L 0可以为C(CH 3)(OH)-C(CH 2CH 3)(OH)，C(CH 3)(CH 3)-C(CH 3)(OH)或C(H)(CH 2CH 3)-C(OH)(CH 3)。当L 1为(CR 11R 12) s或L 3为(CR 31R 32) t时情况也如此。
当本发明所述的4至6元饱和单杂环为取代基时，其自身也可以为取代或被1、2或3个选自下组的取代基所取代：卤素、羟基、C 1-3烷基、O＝、NR a0R b0、羟甲基、羟乙基、羧基、-C(O)OC 1-3烷基、乙酰基、卤代C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩环、N-烷基吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环；其中R a0、R b0各自独立地为氢或C 1-3烷基。
如本文中所用，术语“部分不饱和”是指包括至少一个双键或三键的环部分。如本文中所定义，术语“部分不饱和”涵盖具有多个不饱和位点的环，但并包括芳基或杂芳基部分。
如本文中所用，术语“杂环”是指环中的1、2或3个碳原子被选自氮、氧或S(O) t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。本发明中相同符号所表示的含义除非本发明具有特别说明，应理解为均具有相同的含义。另外，本发明中的各术语(包括取代基简写、试剂名称缩写等)若未特别声明应理解为本领域通常的含义。
所述“药学上可接受的盐”包括药学可接受的酸加成盐和药学可接受的碱加成盐。
“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他副作用的，与无机酸或有机酸所形成的盐。
“药学可接受的碱加成盐”，包括但不限于无机碱的盐如钠盐，钾盐，钙盐和镁盐等。包括但不限于有机碱的盐，比如铵盐，三乙胺盐，赖氨酸盐，精氨酸盐等。
本发明中提及的“溶剂化物”是指本发明的化合物与溶剂形成的配合物。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。例如，一个与水形成的配合物称为“水合物”。式(I)化合物的溶剂化物属于本发明范围之内。
本发明的化合物结构中环己基上呈对位取代的一组取代基3-氨基吡啶酮和苯基(或杂芳基)所连接的环己基上的两个碳原子并不是手性中心，
Figure PCTCN2019121726-appb-000049
的化学键表示法仅为了表示与呈对位取代的一组取代基所连接的两个化学键相对于环己基基团呈反式或顺式结构，因此将这两个化学键
Figure PCTCN2019121726-appb-000050
彼此交换而表示的化合物同样落在本发明的保护范围内。本发明式(I)或式(Ⅱ)所示的化合物可以包含反式和顺式结构的混合物形式存在，或以顺式结构形式存在，或以反式结构形式存在。优选以顺式结构形式存在。本发明中环己基上呈对位取代的一组取代基3-氨基吡啶酮和苯基(或杂芳基)与所连接的环己基上的两个碳原子通过
Figure PCTCN2019121726-appb-000051
键表示的结构为包含反式和顺式结构的混合物，其保护范围包括反式或顺式结构。此外化合物结 构中环己基对位上连接的一对化学键均为
Figure PCTCN2019121726-appb-000052
或均为
Figure PCTCN2019121726-appb-000053
时，表示相同含义，均表示顺式结构。环己基对位上连接的一对化学键分别为
Figure PCTCN2019121726-appb-000054
或分别为
Figure PCTCN2019121726-appb-000055
时，表示相同含义，均表示反式结构。
本发明式(I)或式(Ⅱ)所示的化合物可以含有一个或多个手性中心，并以不同的光学活性形式存在。当化合物含有一个手性中心时，化合物包含对映异构体。本发明包括这两种异构体和异构体的混合物，如外消旋混合物。对映异构体可以通过本专业已知的方法拆分，例如结晶以及手性色谱等方法。当式(I)或式(Ⅱ)化合物含有多于一个手性中心时，可以存在非对映异构体。本发明包括拆分过的光学纯的特定异构体以及非对映异构体的混合物。非对映异构体可由本专业已知方法拆分，比如结晶以及制备色谱。
本发明包括上述化合物的前药。前药包括已知的氨基保护基和羧基保护基，在生理条件下被水解或经由酶反应释放得到母体化合物。具体的前药制备方法可参照(Saulnier，M.G.；Frennesson，D.B.；Deshpande，M.S.；Hansel，S.B and Vysa，D.M.Bioorg.Med.Chem Lett.1994，4，1985-1990；和Greenwald，R.B.；Choe，Y.H.；Conover，C.D.；Shum，K.；Wu，D.；Royzen，M.J.Med.Chem.2000，43，475.)。
通常，本发明化合物或其药学可接受的盐、或其溶剂化物、或其立体异构体、或前药可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。
本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。
如本文所用，“治疗有效量”是指将引起个体的生物学或医学响应，例如降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等的本发明化合物的量。
本发明的药物组合物中含有的本发明化合物或其药学上可接受的盐、或其溶剂化物、或其立体异构体的治疗有效量优选为0.1mg-5g/kg(体重)。
如本文所用，“药学可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，最好为哺乳动物，更优选为人，其适合将活性试剂输送到目标靶点而不终止试剂的活性。
如本文所用，“患者”是指一种动物，最好为哺乳动物，更好的为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。
如本文所用，“治疗”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症(例如癌 症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。
制备方法
下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。
除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。
用于本发明的化合物的制备方法：
本发明式(I)表示的化合物可通过已知的方法制备，例如，通过下述方法、与之等同的方法或实施例中所述的方法。在下面的制备方法中，原料化合物可以是盐的形式，该盐可以是本发明式(I)表示的化合物所示例的任何药学上可接受的盐。
反应方案(Ia)
Figure PCTCN2019121726-appb-000056
具体地，式(Ⅳa)表示的化合物可通过式(Ⅱa)化合物与式(Ⅲa)化合物的铃木反应(又称Suzuki偶联反应)反应制备，(Ⅴa)表示的化合物再通过式(Ⅳa)化合物反应制备。
反应方案(Ib)
Figure PCTCN2019121726-appb-000057
具体地，式(Ⅲb)表示的化合物可通过式(Ⅱb)化合物与联硼酸频那醇酯的Suzuki偶联反应反应制备，(Ⅳb)表示的化合物再通过式(Ⅲb)化合物和R 3Br的Suzuki偶联反应制备，(Ⅴb)表示的化合物再通过式(Ⅳb)化合物反应制备。
反应方案(Ic)
Figure PCTCN2019121726-appb-000058
具体地，(Ⅳc)表示的化合物通过式(Ⅱc)化合物和式(Ⅲc)化合物的取代反应制备，(Ⅴc)表示的化合物再通过式(Ⅳc)化合物反应制备。
反应方案(Id)
Figure PCTCN2019121726-appb-000059
具体地，式(Ⅳd)表示的化合物可通过式(Ⅱd)化合物与式(Ⅲd)化合物的还原胺化制备，(Ⅴd)表示的化合物再通过式(Ⅳd)化合物反应制备。
反应方案(Ie)
Figure PCTCN2019121726-appb-000060
具体地，式(Ⅳe)表示的化合物可通过式(Ⅱe)化合物与式(Ⅲe)化合物的还原胺化制备。
反应方案(If)
Figure PCTCN2019121726-appb-000061
具体地，式(Ⅲf)表示的化合物可通过式(Ⅱf)化合物与含有R 1基团的化合物反应通过已知反应制备，例如，
(1)式(Ⅱf)化合物与化合物R 1X(X为卤素，例如F、Cl、Br、I)发生取代反应，
(2)式(Ⅱf)化合物与化合物R 1OH发生取代反应，
(3)式(Ⅱf)化合物与含有R 1基团的化合物发生酰胺化反应，
(4)式(Ⅱf)化合物与含有R 1基团的化合物发生磺酰胺化反应，
(5)式(Ⅱf)化合物与含有R 1基团化合物发生还原胺化反应或类似的方法。
在上述反应方案中用作起始原料的式(Ⅱa)、式(Ⅲa)、式(Ⅱb)、式(Ⅱc)、式(Ⅲc)、式(Ⅱd)、式(Ⅲd)、式(Ⅱe)或式(Ⅲe)表示的化合物是已知的或可使用已知方法或参考本说明书记载的方法制得。
在反应方案(If)中用作起始原料的式(Ⅱf)化合物可通过反应方案(Ia)、(Ib)、(Ic)或(Id)，或通过R 1为H的反应方案(Ie)，或其他已知方法制得。
用于本发明的具有氨基、羧基或羟基的化合物可使用根据需要已通过常用于该基团的保护基进行保护的化合物来制备，在通过上述反应方案的反应过程后，可进行已知的脱保护反 应。
上述化合物之外的式(I)表示的化合物可通过组合描述于本说明书中实施例或组合已知方法来制备。
与现有技术相比，本发明的主要优点在于具有更好的IDO抑制活性和更低的毒性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。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。除非另外说明，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。
如本文所用，DMB为2,4-二甲氧基苄基，THF为四氢呋喃，EA为乙酸乙酯，PE为石油醚，Ac 2O为乙酸酐，NBS为N-溴代琥珀酰亚胺，DCM为二氯甲烷，AIBN为偶氮二异丁腈，Pd(dppf)Cl 2为1,1'-双(二苯基磷)二茂铁]二氯化钯，TFA为三氟乙酸，TBSCl为叔丁基二甲基氯硅烷，NCS为N-氯代丁二酰亚胺，DHP为3,4-二氢-2H-吡喃，LiAlH 4为氢化铝锂，PMB为对甲氧基苄基，LiHMDS为二(三甲基硅基)氨基锂，Pd 2(dba) 3为三(二亚苄基丙酮)二钯，RuPhos为2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯,DMAP为4-二甲氨基吡啶，THP为四氢吡喃，n-BuLi为正丁基锂，TMsOTf为三氟甲磺酸三甲基硅酯，TEBAC为三乙基苄基氯化铵，HATU为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，DMF为二甲基甲酰胺，DMSO为二甲基亚砜，DIPEA为N,N-二异丙基乙胺，BINAP为(2R,3S)-2,2'-双二苯膦基-1,1'-联萘，PMB为对甲氧基苄氯DPPF为1,1'-双(二苯基膦)二茂铁，DIAD为偶氮二甲酸二异丙酯，TMSCN为三甲基氰硅烷，DIBAL-H为二异丁基氢化铝，DMP为酞酸二甲酯，BPO为过氧化苯甲酰，MTBE为甲基叔丁基醚，m-CPBA为间氯过氧苯甲酸，Xantphos为4,5-双二苯基膦-9,9-二甲基氧杂蒽，Boc 2O为二碳酸二叔丁酯，Fmoc为9-芴基甲氧基羰基，Dess-Martin为戴斯-马丁氧化剂。
如本文所用，室温是指约为20-25℃。
中间体1a的制备
Figure PCTCN2019121726-appb-000062
将化合物1a-1(2.5g,12.9mmol)溶于乙腈(20ml)，加入对甲氧基苄氯(1.75ml,12.9mmol)，碳酸钾(1.8g,13.0mmol)，反应液在95℃下回流4h，LC-MS跟踪至反应完全。将反应液冷却至室温后用硅藻土过滤，滤液浓缩经柱层析纯化得化合物1a(3.80g,收率95％)。
中间体2a的制备
Figure PCTCN2019121726-appb-000063
步骤1：将化合物2a-1(50g,0.23mol)溶于DMF(500ml)，在0℃下分批加入钠氢(18.4g,0.4mol)，反应液在室温下搅拌30min，逐滴加入对甲氧基苄氯(53.4g,0.34mol)，反应液在室温下搅拌过夜，LC-MS跟踪至反应完全。用水将反应淬灭，将反应液浓缩至100ml，用乙酸乙酯稀释，用水洗涤，干燥，浓缩，经柱层析纯化的化合物2a-2(26g,Y:38％)，MS m/z(ESI):339[M+H] +。
步骤2：用化合物1a和2a-2作为反应原料，制备方法同化合物3a步骤2的制备方法，得化合物2a-3。
步骤3：将化合物2a-3(2.0g,4.5mmol)溶于乙醇(10ml)，加入铁粉(1.0g,18mmol)，饱和氯化铵溶液(2ml)，反应液回流搅拌1h，LC-MS跟踪至反应完全。反应液冷却至室温后过滤，滤液浓缩至干得化合物2a粗品(1.6g)，直接用于下一步反应，MS m/z(ESI):417[M+H] +。
中间体3a的制备
Figure PCTCN2019121726-appb-000064
步骤1：将化合物3a-1(32.7g,150mmol)，碘乙烷(46.8g,300mmol)溶于DMF(250ml)，加入碳酸钾(41.4g,300mmol)，反应液在60℃下搅拌5h，LC-MS跟踪至反应完全。将反应液倒入冰水中，过滤，滤饼用水洗涤，烘干得化合物3a-2(31g,收率84％)，MSm/z(ESI):247[M+H] +。
步骤2：将化合物3a-2(30g,121.95mmol)，化合物3a-3(28g,134.15mmol)溶于1,4-二氧六环/水(500ml/100ml)，加入碳酸钠(39g,365.85mmol)，Pd(dppf)Cl 2(6.24mg,8.54mmol)，反应液在氮气保护下100℃搅拌5h，LC-MS跟踪至反应完全。将反应液过滤，浓缩，经柱层析纯化得化合物3a-4(21g,收率70％)，MS m/z(ESI):249[M+H] +。
步骤3：将化合物3a-4(21g,84.68mmol)溶于甲醇，加入Pd/C(5g,10％)，反应液在氢气氛围下室温搅拌48小时，LC-MS跟踪至反应完全。将反应液过滤，滤液浓缩至干得化合物3a粗品(16g)，直接用于下一步反应，MS m/z(ESI):219[M+H] +。
中间体4a的制备
Figure PCTCN2019121726-appb-000065
步骤1：将化合物4a-1(9.4g,50mmol)，溴代异丁烷(34g,250mmol)溶于DMP(120ml)，加入碳酸钾(20.7g,150mmol)，反应液在100℃下搅拌5h，LC-MS跟踪至反应完全。反应液冷却至室温后倒入水中，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，干燥，浓缩，经柱层析纯化后得化合物4a-2(5.6g,收率46％)，MS m/z(ESI):245[M+H] +。
步骤2：将化合物4a-2(2.44g,10mmol)，化合物4a-4(5.08g,20mmol)溶于1,4-二氧六环，加入醋酸钾(2.94g,30mmol)，Pd(dppf)Cl 2(732mg,1mmol)，反应液在氮气保护下85℃搅拌4h，LC-MS跟踪至反应完全。将反应液冷却至室温后倒入水中，用乙酸乙酯萃取，合并有机相，干燥，浓缩，经柱层析纯化得化合物4a-5(2.51g,收率86％)，MS m/z(ESI):293[M+H] +。
步骤3：将化合物4a-5(2.13g,7.32mmol)，化合物4a-6(1g,6.10mmol)溶于1,4-二氧六环/水(40ml/10ml)，加入碳酸钠(1.94g,18.29mmol),Pd(dppf)Cl 2(445mg,0.61mmol)，反应液在100℃下搅拌6h，LC-MS跟踪至反应完全。将反应液冷却至室温后过滤，滤液浓缩，经柱层析纯化得化合物4a(0.91g,收率60％)，MS m/z(ESI):250[M+H] +。
中间体5a的制备
Figure PCTCN2019121726-appb-000066
步骤1：将化合物1a-1(500mg,2.58mmol)溶于DMF(15ml)，在0℃下分批加入钠氢(257mg,6.45mmol)，反应液在室温下搅拌20min，加入化合物5a-1(896mg,5.15mmol)，反应液在室温下搅拌4h，LC-MS跟踪至反应完全。将反应液倒入水中，用甲基叔丁基醚萃取，合并有机相，水洗，干燥，浓缩至干得化合物5a-2粗品(270mg)，MS m/z(ESI):241[M+H] +。
步骤2：制备方法同中间体3a步骤2方法，得化合物5a。MS m/z(ESI):237[M+H] +。
中间体6a的制备
Figure PCTCN2019121726-appb-000067
步骤1：将化合物6a-1(2g,12.81mmol)，钠氢(564mg,14.09mmol)溶于DMF(25ml)，反应液在50℃下搅拌1h，加入碘代异丁烷(3.63g,19.22mmol)，反应液在50℃下搅拌过夜，LC-MS跟踪至反应完全。将反应液倒入水中，用乙酸乙酯萃取，有机相用水洗涤，干燥，浓缩，经柱层析纯化得化合物6a-2(311mg,收率11％)，MS m/z(ESI):213[M+H] +。
步骤2：将化合物6a-2(310mg,1.46mmol)，碘甲烷(622mg,4.38mmol)溶于四氢呋喃(10ml)，加入碳酸钾(1g,7.30mmol)，反应液在100℃下封管反应过夜，LC-MS跟踪至反应完全。将反应液冷却至室温后饱和氯化铵溶液洗涤，水相用乙酸乙酯萃取合并有机相，干燥，浓缩至干得化合物6a-3粗品(412mg)，直接用于下一步反应，MS m/z(ESI):227[M+H] +。
步骤3：将化合6a-3(412mg,1.82mmol)，NBS(357mg,2mmol)溶于乙腈(15ml)，反应液在60℃下搅拌过夜，LC-MS跟踪至反应完全。将反应液用饱和碳酸氢钠溶液洗涤，水相用乙酸乙酯萃取，合并有机相，干燥，浓缩至干得化合物6a粗品(582mg)，直接用于下一步反应，MS m/z(ESI):305[M+H] +。
中间体7a的制备
Figure PCTCN2019121726-appb-000068
制备方法同中间体5a步骤2，得化合物7a，MS m/z(ESI):205[M+H] +。
中间体8a的制备
Figure PCTCN2019121726-appb-000069
步骤1：将化合物8a-1(2.98g,17.13mmol)溶于四氯化碳(20ml)，加入NBS(2.73mg,15.33mmol)，BPO(5mg,0.02mmol)，反应液回流20min，LC-MS跟踪至反应完全。将反应液冷却至室温后过滤，滤饼用环己烷重结晶的化合物8a-2(0.91g,Y:21％)。
步骤2：将化合物8a-2(800mg,3.17mmol)溶于冰醋酸(15ml)，加入醋酸钾(436mg,4.44mmol)，反应液在150℃下搅拌15h，LC-MS跟踪至反应完全。将反应液冷却至室温，过滤，滤液浓缩，用饱和碳酸氢钠溶液将反应液pH值中和至8左右，用乙酸乙酯萃取，合并有机相，干燥，浓缩至干得化合物8a粗品(817mg)，直接用于下一步反应，MS m/z(ESI):233[M+H] +。
中间体9a的制备
Figure PCTCN2019121726-appb-000070
将化合物9a-1(875mg,7.1mmol)，9a-2(500mg,3.55mmol)，9a-3(700mg,3.55mmol)溶于二氯甲烷，反应液在室温下搅拌过夜，LC-MS跟踪至反应完全。加入乙酸乙酯，将反应液过滤，滤饼用乙酸乙酯洗涤，烘干得化合物9a粗品(2.1g)，直接用于下一步反应，MS m/z(ESI):424[M+H] +。
中间体10a的制备
Figure PCTCN2019121726-appb-000071
制备方法同中间体5a步骤2的制备方法，得化合物10a，MS m/z(ESI):354[M+H] +。
中间体11a的制备
Figure PCTCN2019121726-appb-000072
步骤1：将锂铝氢(0.604g,15.9mmol)溶于二氯甲烷(35ml)，在0℃下慢慢加入化合物10a(1.87g,5.30mmol)的二氯甲烷(15ml)，反应液自然升至室温后，继续搅拌4h，LC-MS跟踪至反应完全。向反应液中一次加入0.6ml水，0.6ml 15％氢氧化钠溶液，1.8ml水，过滤，滤液用乙酸乙酯萃取，合并有机相，干燥，浓缩得化合物11a-1粗品(1.53g)，MS m/z(ESI):326[M+H] +。
步骤2：将化合物11a-1(1.42g,4.37mmol)溶于二氯甲烷(25ml)，在0℃下慢慢加入Dess-Martin，反应液自然升至室温后继续搅拌过夜，LC-MS跟踪至反应完全。向反应液中加入饱和碳酸钠溶液，分液，有机相干燥，浓缩得化合物11a-2粗品(678mg)，MS m/z(ESI):324[M+H] +。
步骤3：向钠氢(240mg,10.0mmol)的四氢呋喃(15ml)溶液中加入氯化甲氧基甲基三苯基磷盐(2.05g,6.0mmol)，反应液在室温下搅拌30min，慢慢加入化合物11a-2(646mg,2.0mmol)的四氢呋喃(10ml)溶液，反应液在室温下搅拌过夜，LC-MS跟踪至反应完全。在冰水浴下慢慢向反应液中加入水，用乙酸乙酯萃取，合并有机相，干燥，浓缩，经柱层析纯化得化合物11a-3(486mg,Y:69％)，MS m/z(ESI):352[M+H] +。
步骤4：将化合物11a-3(451mg,1.28mmol)溶于四氢呋喃(8ml)，加入盐酸溶液(2M,8ml)，反应液在氮气保护下80℃搅拌2h，LC-MS跟踪至反应完全。向反应液中加入水，用乙酸乙酯萃取，合并有机相，干燥，浓缩经柱层析纯化得化合物11a-4(370mg,Y:85％)，MS m/z(ESI):338[M+H] +。
步骤5：将化合物11a-4(302mg,0.90mmol)溶于四氢呋喃(10ml)，在氮气保护下0℃加入11a-5(1ml)，反应液自然升至室温后继续搅拌过夜，LC-MS跟踪至反应完全。向反应液中加入饱和氯化铵溶液，用乙酸乙酯萃取，合并有机相，干燥，浓缩，经柱层析纯化得化合物11a(112mg,Y:29％)，MS m/z(ESI):422[M+H] +。
中间体化合物12a-a和化合物12a-b的制备
Figure PCTCN2019121726-appb-000073
将化合物5a-3(1g,5.0mmol)，8a-1(870mg,5.0mmol)，三氟乙酸(1.71g,15mmol)溶于乙酸乙酯(50ml)，反应液在40℃下搅拌2h，在该温度下分批加入醋酸硼氢化钠(3.18g,15mmol)，反应液继续搅拌30min，LC-MS跟踪至反应完全。将反应液用乙酸乙酯稀释，用饱和碳酸氢钠溶液，饱和食盐水洗涤，干燥，浓缩，经柱层析(制备柱：21.2x250mm C18柱,体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：48％-53％乙腈变化)纯化得化合物12a-a(600mg)，化合物12a-b(800mg)，收率77％，MS m/z(ESI):361[M+H] +。
中间体13a的制备
Figure PCTCN2019121726-appb-000074
步骤1：将化合物13a-1(3.636g,20.0mmol)，氯化氧磷(1.84g,12.0mmol)溶于乙醚(10ml)，逐滴加入苯乙烯(1.042g,10.0mmol)，锌铜试剂(3.868g,30mmol)的乙醚溶液(10ml)，反应液在40℃下搅拌3h后，在室温下搅拌过夜，LC-MS跟踪至反应完全。将反应液过滤，加入正己烷室温搅拌1h，用水，饱和碳酸氢钠溶液，饱和食盐水洗涤，干燥，浓缩得化合物13a-2粗品(1.303g)。
步骤2：将化合物13a-2(1.303g,6.06mmol)，锌粉(1.584g,24.23mmol)溶于冰醋酸，反应液在90℃下搅拌过夜，LC-MS跟踪至反应完全。将反应液冷却至室温后，加入水，MTBE，分液，有机相用水，饱和碳酸氢钠溶液，饱和食盐水洗涤，干燥，浓缩经柱层析纯化得化合物13a(400mg,Y:44％)，MS m/z(ESI):147[M+H] +。
中间体14a的制备
Figure PCTCN2019121726-appb-000075
制备方法同中间体13a制备方法得化合物14a，MS m/z(ESI):181[M+H] +。
中间体15a的制备
Figure PCTCN2019121726-appb-000076
制备方法同中间11a-2的制备方法得化合物15a，MS m/z(ESI):218[M+H] +。
中间体16a的制备
Figure PCTCN2019121726-appb-000077
步骤1：将化合物16a-1(1.05g,5mmol)溶于四氢呋喃(40ml)，加入硼烷-二甲硫醚(2M,8ml)，反应液在室温下搅拌过夜，LC-MS跟踪至反应完全。向反应液中慢慢加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，干燥，浓缩至干得化合物16a-2(800mg)。
步骤2：将化合物16a-2(800mg,4.1mmol)溶于二氯甲烷(30ml)，加入DMP(2.5g,8.2mmol)，反应液在30℃下搅拌3h，LC-MS跟踪至反应完全。用饱和碳酸氢钠溶液将反应液pH值调至8左右，用二氯甲烷萃取，合并有机相，干燥，浓缩，经柱层析纯化得化合物16a-3(420mg)。
步骤3：将化合物16a-3(420mg,2.16mmol)溶于1,4-二氧六环/水(12ml/4ml)，加入二氧化硒(1.2g,10.82mmol)，反应液在110℃下反应3h，LC-MS跟踪至反应完全。将反应液浓缩，经柱层析纯化得化合物16a(150mg)。
中间体17a的制备
Figure PCTCN2019121726-appb-000078
步骤1：将化合物17a-1(5g,44mmol)溶于二氯甲烷(100ml)，逐滴加入苄溴(8.5g,49.6mmol)，反应液在室温下搅拌3h，LC-MS跟踪至反应完全。将反应液过滤，滤饼用乙酸乙酯洗涤，烘干得化合物17a-2(12.01g)，MS m/z(ESI):222[M+H] +。
步骤2：将化合物17a-3(4.92g,40mmol)，碳酸钾(11.04g,80mmol)溶于乙醇(100ml)，逐滴加入化合物17a-2(11.32mg,40mmol)的水溶液(20ml)，反应液在100℃下搅拌2h，LC-MS跟踪至反应完全。将反应液冷却至室温后倒入水中，用乙酸乙酯萃取，合并有机相，干燥，浓缩，经柱层析纯化得化合物17a(5g,Y:60％)，MS m/z(ESI):206[M+H] +。
中间体18a的制备
Figure PCTCN2019121726-appb-000079
步骤1：将化合物18a-1(5.31g,30mmol)，18a-2(5.16g,60mmol)，叔丁醇钾(10g,90mmol)溶于四氢呋喃(100ml)，反应液在室温下搅拌6h，LC-MS跟踪至反应完全。加入饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取，合并有机相，干燥，浓缩，经柱层析纯化得化合物18a-3(3.5g,Y:37％)，MS m/z(ESI):318[M+H] +。
步骤2：将化合物18a-3(3.5g,11mmol)，氯化钠(12.86g,220mmol)，水(10ml)溶于 DMSO(100ml)，反应液在150℃下搅拌24h，LC-MS跟踪至反应完全。反应液冷却至室温后用乙酸乙酯萃取，有机相用饱和食盐水洗涤，干燥，浓缩，经柱层析纯化得化合物18a(1.2g,Y:42％)，MS m/z(ESI):260[M+H] +。
中间体19a的制备
Figure PCTCN2019121726-appb-000080
步骤1：制备方法同中间体5a步骤2方法，得化合物19a-3，MS m/z(ESI):243[M+H] +。
步骤2：将化合物19a-3(600mg,0.25mmol)溶于乙醇/水(6ml/6ml)，加入碳酸钾(3.4mg,0.025mmol)，反应液回流18h，LC-MS跟踪至反应完全。将反应液冷却至室温后，分液，有机相过滤得化合物19a-4(421mg,收率65％)，MS m/z(ESI):261[M+H] +。
步骤3：将化合物19a-4(400mg,1.54mmol)溶于甲醇(15ml)，加入钯炭(40mg)，反应液在氢气氛围下室温搅拌4h，LC-MS跟踪至反应完全。将反应液过滤，滤液浓缩的化合物19a-5粗品(417mg)，直接用于下一步反应，MS m/z(ESI):263[M+H] +。
步骤4：将化合物19a-5(417g,1.59mmol)溶于二氯甲烷(6ml)，加入三氟乙酸(6ml)，反应液在室温下搅拌过夜，LC-MS跟踪至反应完全。加入饱和碳酸氢钠溶液将反应液pH值调至8左右，用乙酸乙酯萃取，合并有机相，干燥，浓缩得化合物19a-6粗品(360mg)，直接用于下一步反应，MS m/z(ESI):219[M+H] +。
步骤5：将化合物19a-6(259mg,1.19mmol)溶于氯仿(10ml)，加入NBS(254mg,1.43mmol)，p-TsOCl(20mg,0.12mmol)，将反应液回流8h，LC-MS跟踪至反应完全。将反应液浓缩至干得化合物19a-7粗品(0.67g)，直接用于下一步反应，MS m/z(ESI):297[M+H] +。
步骤6：将化合物19a-7(0.67g,1.19mmol)溶于冰醋酸(8ml)，加入醋酸钾(0.58g,5.94mmol)，反应液在100℃下搅拌12h，LC-MS跟踪至反应完全。将反应液浓缩，加入饱和碳酸氢钠溶液将pH值调至8，用乙酸乙酯萃取，合并有机相，干燥，浓缩至干得化合物19a粗品(0.34g)，直接用于下一步反应，MS m/z(ESI):277[M+H] +。
中间体20a的制备
Figure PCTCN2019121726-appb-000081
步骤1：将化合物20a-1(4.34g,20mmol)溶于四氢呋喃(50ml)，在-78℃下逐滴加入正丁基锂(2.5M,8ml)，反应液在-78℃下搅拌1h，加入化合物20a-2(3.75g,24mmol)，反应液在-78℃下搅拌2h，LC-MS跟踪至反应完全。加入饱和氯化铵溶液淬灭反应，用乙酸乙酯萃取，合并有机相，干燥，浓缩，经柱层析纯化得化合物20a-3(4.5g,Y:76％)，MS m/z(ESI): 295[M+H] +。
步骤2：制备方法同中间体19a步骤4方法，得化合物20a，MS m/z(ESI):251[M+H] +。
中间体21a的制备
Figure PCTCN2019121726-appb-000082
步骤1：将化合物21a-1(2.13g,7.94mmol)溶于甲醇(15ml)，加入溴化氢溶液(15ml)，反应液在60℃下搅拌12h，LC-MS跟踪至反应完全。将反应液浓缩，用饱和碳酸氢钠溶液中和反应液，用二氯甲烷萃取，干燥，浓缩得化合物21a-2粗品(1.8g)，MS m/z(ESI):254[M+H] +。
步骤2：将化合物21a-2(1.8g,7.1mmol)，溴代异丁烷(1.95g,14.2mmol)溶于DMF(20ml)，加入碳酸钾(2.94g,21.3mmol)，反应液在100℃下搅拌12h，LC-MS跟踪至反应完全。将反应液浓缩，经柱层析纯化得化合物21a(1.2g,Y:54％)，MS m/z(ESI):310[M+H] +。
中间体22a的制备
Figure PCTCN2019121726-appb-000083
步骤1：将化合物22a-1(6.1g,20mmol)，叔丁醇钾(2.24g,20mmol)溶于四氢呋喃(50ml)，反应液在0℃下搅拌1h，加入化合物8a-1(1.74g,10mmol)，反应液在室温下搅拌12h，LC-MS跟踪至反应完全。加入饱和氯化铵溶液淬灭反应，用乙酸乙酯萃取，合并有机相，干燥，浓缩，经柱层析纯化得化合物22a-2(430mg,Y:21％)，MS m/z(ESI):203[M+H] +。
步骤2：将化合物22a-2(430mg,2.13mmol)，盐酸溶液(2N,10.6ml)溶于四氢呋喃(15ml)，反应液在60℃下搅拌2h，LC-MS跟踪至反应完全。反应液冷却至室温后用二氯甲烷萃取，合并有机相，干燥，浓缩得化合物22a粗品(380mg)。
中间体23a的制备
Figure PCTCN2019121726-appb-000084
将化合物23a-1(216mg,1mmol)溶于乙醇，加入醋酸铵(385mg,5mmol)，氰基硼氢化钠(125mg,2mmol)，反应液在微波120℃下反应20min，LC-MS跟踪至反应完全。将反应液浓缩，加入饱和碳酸钠溶液，用乙酸乙酯萃取，合并有机相，干燥，浓缩至干得化合物23a粗品(231mg)，直接用于下一步反应，MS m/z(ESI):217[M+H] +。
中间体24a的制备
Figure PCTCN2019121726-appb-000085
步骤1：将化合物24a-1(5g,26.31mmol)，次氯酸钠溶液(200ml)溶于乙腈，反应液在室温下搅拌过夜，LC-MS跟踪至反应完全。反应液用乙腈萃取，合并有机相，干燥，浓缩至干得化合物24a-2粗品(2.03g)，直接用于下一步反应，MS m/z(ESI):238[M+H] +。
步骤2：将化合物24a-2(200mg,0.84mmol)，氯化亚砜(10ml)，DMF(2ml)溶于二氯甲烷，反应液在50℃下搅拌1h，将溶剂浓缩，在0-10℃下加入二氯甲烷(20ml)，二甲胺盐酸盐(140mg,1.68mmol)，三乙胺(1ml)，反应液在室温下搅拌过夜，LC-MS跟踪至反应完全。将反应液浓缩，加入乙酸乙酯，用饱和碳酸氢钠溶液洗涤，干燥，浓缩得化合物24a粗品(274mg)，MS m/z(ESI)：265[M+H] +。
中间体25a的制备
Figure PCTCN2019121726-appb-000086
将化合物25a-1(6.48g,32.3mmol)，化合物25a-2(2.5g,26.9mmol)，三乙胺(81.5g,80.6mmol)溶于DMF(55ml),加入HATU(15.3g,40.3mmol)，反应液在室温下搅拌2h，LC-MS跟踪至反应完全。反应液倒入水中，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，干燥，浓缩经柱层析纯化得化合物25a(4.5g,收率70％)，MS m/z(ESI):241[M+H] +。
中间体26a的制备
Figure PCTCN2019121726-appb-000087
将化合物26a-1(2.0g,11.50mmol)溶于乙腈(60ml)，加入化合物26a-2(1.43mg,13.80mmol)，硫酸钠(164mg,1.16mmol)，反应液在室温下搅拌45h，LC-MS跟踪至反应完全。向反应液中加入饱和碳酸氢钠溶液中和反应液，用乙酸乙酯萃取，合并有机相，干燥，浓缩，经柱层析纯化得化合物26a(2.07g,收率80％)，MS m/z(ESI):224[M+H] +。
中间体27a的制备
Figure PCTCN2019121726-appb-000088
步骤1：将钠丝(4.15g,0.18mmol)置于甲醇中(50ml)，回流30min，将反应液浓缩，加入乙醇(50ml)，甲苯(50ml)，化合物27a-1(8.0g,72mmol)，然后逐滴加入化合物27a-2(36g,360mmol)将反应液温度维持在40-45℃，滴加完毕，反应液在45℃下搅拌18h，LC-MS跟踪至反应完全。向反应液中加入水，分液，有机相干燥，浓缩得化合物27a-3粗品(17g)直接用于下一步反应，MS m/z(ESI):165[M+H] +。
步骤2：将化合物27a-3(17g,102.41mmol)溶于甲醇(150ml)，加入氯化铁(16.6g,102.41mmol)，反应液在室温下搅拌18h，LC-MS跟踪至反应完全。将反应液浓缩，过滤，滤液浓 缩经柱层析纯化得化合物27a-4(4.3g,收率26％)，MS m/z(ESI):165[M+H] +。
步骤3：在0℃下向硝酸溶液(65％,4ml)中逐滴加入化合物27a-4(797mg,4.8mmol)，反应液在0℃下搅拌2h后升至室温搅拌10min，LC-MS跟踪至反应完全。将反应液倒入冰水中，过滤，滤饼用水洗涤，烘干得化合物27a-5(412mg,收率41％)，MS m/z(ESI):210[M+H] +。
步骤4：将化合物27a-5(412mg,1.97mmol)溶于甲醇(20ml)，加入钯炭(40mg)，反应液在氢气氛围下室温搅拌5h，LC-MS跟踪至反应完全。将反应液过滤，滤液浓缩得化合物27a粗品(271mg)，直接用于下一步反应，MS m/z(ESI):180[M+H] +。
中间体28a的制备
Figure PCTCN2019121726-appb-000089
将化合物28a-1(200mg,0.813mmol)溶于二氯甲烷(20ml)，加入m-CPBA(422mg,2.44mmol)，反应液在室温下搅拌过夜，LC-MS跟踪至反应完全。将反应液浓缩，经柱层析纯化得化合物28a(180mg,收率84％)，MS m/z(ESI):263[M+H] +。
下表中的中间体化合物29a参考中间体3a的方法制备，不同的是将步骤1中的化合物3a-1换成5-溴-4-甲氧基-3-硝基吡啶-2(1H)-酮，将碘乙烷换成溴代异丁烷。
化合物30a、31a、35a参考中间体3a的方法制备，不同的是将步骤1中的碘乙烷分别换成2-碘丙烷、溴代异丁烷和碘甲烷。
化合物34a、39a、40a、41a、42a、43a、44a、47a、48a、49a参考中间体3a的方法制备，不同的是将步骤1中的碘乙烷换成溴代异丁烷，将步骤2中的化合物3a-3分别换成34a-1、39a-1、40a-1、41a-1、42a-1、43a-1、44a-1、47a-1、48a-1、49a-1。
化合物38a参考中间体3a的方法制备，不同的是将步骤1中的碘乙烷换成碘甲烷，将步骤2中的化合物3a-3换成47a-1。
化合物45a参考中间体3a的方法制备，不同的是将步骤1中的碘乙烷换成溴代异丁烷，将化合物3a-1换成5-溴-4-甲基-3-硝基吡啶-2(1H)-酮。
化合物46a参考中间体3a的方法制备，不同的是将步骤1中的化合物3a-1换成5-溴-6-甲基-3-硝基吡啶-2(1H)-酮。
Figure PCTCN2019121726-appb-000090
Figure PCTCN2019121726-appb-000091
Figure PCTCN2019121726-appb-000092
Figure PCTCN2019121726-appb-000093
下表中的中间体化合物50a参考化合物19a-6的方法制备，不同的是将步骤2省略。
化合物51a-53a、62a、65a参考化合物19a-6的方法制备，不同的是将步骤1中的化合物19a-1分别换成4-溴-2-甲氧基吡啶、5-溴-2-甲氧基吡啶、3-溴-5-甲氧基吡啶、1-(5-溴吡啶-2-基)乙-1-酮和5-溴-2-异丙氧基吡啶，并省略步骤2。
化合物54a、56a、57a、58a、60a、61a、64a参考化合物19a-6的方法制备，不同的是将步骤1中的化合物19a-1分别换成6-溴烟腈、5-溴-6-甲氧基-2-氰基吡啶、5-溴-6-甲基-2-氰基吡啶、5-溴-4-甲氧基-2-氰基吡啶、5-溴-3-甲基-2-氰基吡啶、5-溴-3-甲氧基-2-氰基吡啶、5-溴-3-氟-2-氰基吡啶。
化合物59a的制备
Figure PCTCN2019121726-appb-000094
步骤1：在0℃下，向NH 3/EtOH(5mL,10mmol,2M)溶液中加入5-溴吡啶-2-磺酰氯(500mg,0.19mmol)搅拌1小时，反应液浓缩，用二氯甲烷(5mL)重新溶解，水洗，盐水洗，无水硫酸钠干燥，滤液经过减压浓缩得到固体粗产物5-溴吡啶-2-磺酰胺(450mg，97％)。MS(ESI)237[M+H] +。
步骤2-4：参照化合物66a的方法制备得到化合物59a。MS(ESI)255[M+H] +。
化合物63a的制备
Figure PCTCN2019121726-appb-000095
步骤1：将4-溴吡啶酸(1000mg，4.95mmol)和DMF(3ml)溶解于二氯甲烷(20ml)，草酰氯(5ml)慢慢滴加入，在40℃下搅拌2h。反应完全，加压蒸干溶剂得到固体粗产物(1051mg)并直接用于下一步反应。
步骤2：将4-溴-吡啶甲酰氯(1051mg，4.80mmol)溶解于二氯甲烷(10ml)中，将溶液室温下滴加到混有三乙胺(3ml)，二甲氨溶液(5ml，5.0mmol)和二氯甲烷(25ml)的混合体系中，室温搅拌2h。反应完全，减压蒸干溶剂，通过柱层析(DCM:MeOH＝0-30％)得到产物(1033mg)两步收率：91.6％。MS(ESI)229.0[M+H] +。
步骤3-5：参照化合物77a-3的方法制备得到化合物63a。MS(ESI)247.1[M+H] +。
化合物66a的制备
Figure PCTCN2019121726-appb-000096
步骤1：化合物66a-1(666mg,3.0mmol),4,4,5,5-四甲基-2-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)-1,3,2-二氧杂硼烷(798mg,3.0mmol),碳酸钠(318mg,3.0mmol)在二氧六环20ml和水6ml的混合溶剂中氩气保护下加入1,1'-双(二苯基膦)二茂铁]二氯化钯(109mg,0.015mmol),反应液加热到100度反应5小时，LC-MS检测反应完全。反应液减压浓缩干，用硅胶柱分离纯化得到产品66a-2(900mg,棕色固体)。MS(ESI)281[M+H] +。
步骤2：化合物66a-2(900mg,3.21mmol)溶解在40ml的乙酸乙酯里,加入300mg Pd/C,混合物在氢气保护下室温反应4h，LC-MS检测反应完全.减压浓缩,用硅胶柱分离纯化得到产品66a-3(800mg,Y:62.06％)。MS(ESI)283[M+H] +。
步骤3：化合物66a-3(800mg,2.82mmol)溶于四氢呋喃20ml中，4M的盐酸30ml加入，混合物在室温下搅拌4小时，浓缩至干得到产品66a(770mg,Y:100％)。MS(ESI)239[M+H] +。
化合物70a的制备
Figure PCTCN2019121726-appb-000097
步骤1：将5-溴嘧啶-2-羧酸(950mg，4.68mmol)和DMF(1ml)溶解于氯化亚砜(5ml)中，在40℃下搅拌1h，减压蒸干溶剂并加入二氯甲烷(25ml)溶解，将溶液在0-10℃下滴加到混有三乙胺(5ml)，盐酸二甲氨基(572mg，7.02mmol)和二氯甲烷(25ml)的混合体系中，在0-10℃下搅拌1h，慢慢升至室温并搅拌2h。反应完全，减压蒸干溶剂，通过柱层析(PE:EA＝40-80％)得到粗品产物(1207mg)，直接用于下一步反应。MS(ESI)229.9[M+H] +。
步骤2-4：参照化合物77a-3的方法制备得到化合物70a。MS(ESI)248.1[M+H]+。
化合物73a的制备
Figure PCTCN2019121726-appb-000098
步骤1：0℃下，向氢化钠(61mg,1.5mmol,60％wt)和四氢呋喃(3mL)的混合溶液中滴加5-溴-1H-吡唑并[3,4-B]吡啶(198mg,1mmol)和四氢呋喃(2mL)，搅拌30分钟，然后加入碘甲烷(187mg，1.3mmol)。反应液在室温下搅拌过夜，用饱和氯化铵水溶液淬灭，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，柱层析(乙酸乙酯：石油醚＝10-50％),提纯得到固体产物5-溴-1-甲基-1H-吡唑并[3,4-b]吡啶(150mg，70％)。MS(ESI)212[M+H] +。
步骤2-4：参照化合物66a的方法制备得到化合物73a。MS(ESI)230[M+H]+。
化合物76a的制备
Figure PCTCN2019121726-appb-000099
步骤1：将4,4,5,5-四甲基-2-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)-1,3,2-二氧杂硼烷(1064mg,4.00mmol)，2-溴苯并噻唑(864mg,4.00mmol)，无水碳酸钠(848mg,8.00mmol)，1,1'-双(二苯基膦)二茂铁]二氯化钯(42mg,0.04mmol)加入到二氧六环(50mL)和水(10mL)的混合物溶液中，然后在氮气下，100℃反应2小时。待反应完全后，用乙酸乙酯萃取，合并有机相，用饱和氯化钠水溶液洗涤，用无水硫酸钠干燥，过滤，减压浓缩，过硅胶柱层析(石油醚：乙酸乙酯＝5：1)得到化合物76a-1(650mg，60％)。
步骤2：将化合物76a-1(600mg,2.20mmol)溶解在甲醇(50mL)中，加入10％钯碳(100mg)，置换氢气，在氢气氛围下加班反应过夜。反应完全后，硅藻土过滤除去钯碳，甲醇洗一次，过滤液浓缩得到化合物76a-2(600mg，100％)直接进入下步反应。
步骤3：将化合物76a-2(600mg,2.18mmol)溶解在四氢呋喃(10mL)中，加入5mL浓盐酸，在室温下反应三个小时。减压浓缩。得到白色固体盐酸盐化合物76a(500mg，100％)。
化合物77a的制备
Figure PCTCN2019121726-appb-000100
步骤1：将4,4,5,5-四甲基-2-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)-1,3,2-二氧杂硼烷(14.0g，52.5mmol)，4-溴-1,2-二甲氧基苯(10.8g，50.0mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(2.2g，3.0mmol)和碳酸钠(15.9g，300mmol)加入到1，4-二氧六环(200mL)和水(50mL)的混合溶液中，并将此混合液在100℃搅拌16小时，待原料反应完全，将反应液冷却，过滤，滤液经过减压蒸干，柱层析(乙酸乙酯：石油醚＝0-25％)提纯得到固体产物化合物77a-1(10.4g，75％)。MS(ESI)277[M+H] +。
步骤2：将钯碳(10％，2.0g)加入到77a-1(10.4g，37.68mmol)的甲醇(250mL)溶液中，并将反应液在室温的氢气下搅拌18小时，过滤，除去不溶物质，滤液经过减压蒸干得到粗产物77a-2(10.5g，100％)。MS(ESI)279[M+H] +。
步骤3：将化合物77a-2(10.5g，37.70mmol)加入到二氯甲烷(10mL)和三氟乙酸(50 mL)的混合溶液中，并加热到60℃搅拌3小时，待原料反应完毕，将反应液减压蒸干，用乙酸乙酯稀释，用饱和碳酸氢钠水溶液调节pH＝8，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过减压浓缩得到粗产物77a-3(6.6g，75％)。MS(ESI)235[M+H] +。
步骤4：将化合物77a-3(2.34g，10.0mmol)和溴化铜(2.23g，10.0mmol)加入到乙酸乙酯(100mL)中，并加热到40℃搅拌4小时，待原料反应完毕，将反应液冷却到室温并过滤，滤液经过减压浓缩得到粗产物77a-4(3.12g，100％)。MS(ESI)313[M+H] +。
步骤5：将化合物77a-4(3.12g，10.0mmol)和醋酸钾(1.84g，20.0mmol)加入到醋酸(30mL)中，并加热到110℃搅拌18小时，待原料反应完毕，用饱和碳酸氢钠水溶液调节pH＝8，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过减压浓缩得到粗产物77a(2.45g，83％)。MS(ESI)293[M+H] +。
化合物67a至69a、74a、75a、79a、81a至89a参照化合物66a或76a的制备方法进行制备，不同的是将步骤1中的化合物66a-1或2-溴苯并噻唑分别换成4-溴噻吩-2-甲酰胺、2-溴噻唑-4-甲酰胺、2-溴噻唑-5-甲酰胺、3溴喹啉、4-溴喹啉、5-溴-1,2,3-三甲氧基苯、5-溴异吲哚-1,3-二酮、6-溴异喹啉、6-溴喹啉、7-溴喹唑啉-4(3H)-酮、7-溴喹唑啉-2,4(1H，3H)-二酮、5-溴异吲哚-1-酮、6-溴-3,4-二氢异喹啉-1(2H)-酮、4-溴-1H-吡唑、4-(4-溴苯基)-1-甲基-1H-吡唑。
化合物71a、72a参照化合物70a的方法制备。
化合物78a参照化合物77a的方法制备。
化合物80a参照化合物79a的方法制备。
化合物90a的制备
Figure PCTCN2019121726-appb-000101
步骤1：将6-氟-4-羟基喹啉(815mg，5mmol)和4-羟基环己烷甲酸乙酯(860mg，5mmol)溶解于THF(20ml)中，室温下加入PPh 3和DIAD，搅拌过夜反应。将反应液倒入水中，用EA萃取，合并有机相，干燥，浓缩，经柱层析纯化得化合物90a-1。
步骤2：化合物90a-1(600mg，2mmol)的THF(20ml)溶液，在0℃下慢慢加入锂铝氢(160mg，4mmol)，反应液自然升至室温后继续搅拌10min。向反应液中加入水和氢氧化钾溶液，过滤，滤液用EA萃取，合并有机相，干燥，浓缩经柱层析纯化得化合物90a-2。
步骤3：在化合物90a-2(500mg，2mmol)的DCM(20ml)溶液中加入DMP(1.2g，4mmol),室温反应3h，用碳酸氢钠溶液调节pH至8左右，EA萃取，合并有机相，干燥，浓缩经柱层析纯化得得化合物90a。
化合物91a的制备
Figure PCTCN2019121726-appb-000102
步骤1：将2-氨基-4-溴苄腈(2000mg，10.15mmol)和碳酸钾(2104mg，15.23mmol)溶解于DMSO(10ml)中搅拌，加入30％H 2O 2(10ml)室温搅拌30min。反应完全，加入水(30ml)，用EA萃取，干燥，浓缩，经柱层析纯化得化合物91a-1。MS(ESI)215[M+H] +。
步骤2-3：参照化合物77a的方法的步骤1-2制备得到化合物91a。MS(ESI)277[M+H] +。
化合物94a的制备
Figure PCTCN2019121726-appb-000103
步骤1：将2-氨基-5-溴吡啶(5.16g,30mmol)和DIPEA(15.5g,120mmol)溶于DCM(150ml)溶液中，加入乙酰氯(3.51g,45mmol)，室温搅拌反应8h，纯化得到化合物94a-1(4.28g,Y:67％)。MS(ESI)215[M+H] +。
步骤2：将化合物94a-1(4.28g,20mmol)溶于DMF(30ml)，在0℃下加入NaH(1.2g,30mmol)，室温下反应30min。再加入碘甲烷(8.52g,60mmol)，在室温下反应2h。在反应液加入水(60ml)，用乙酸乙酯萃取，合并有机相，干燥，浓缩，经柱层析纯化得化合物94a-2(3.62g,Y:79％)，MS m/z(ESI):229[M+H] +。
步骤3：参考化合物19a-3的制备方法，得到化合物94a-3。MS m/z(ESI):289[M+H] +。
步骤4-5：参考化合物19a方法的步骤3-4，得到化合物94a。MS(ESI)247[M+H] +。
化合物95a的制备
Figure PCTCN2019121726-appb-000104
步骤1：参考化合物19a-3的制备方法，得到化合物95a-1。
步骤2：将化合物95a-1(1.5g,6.2mmol)溶于甲醇(20ml)和水(10ml)的混合溶液中，加入氢氧化钾(700mg，12.4mmol)，反应液在100℃下搅拌过夜后，LC-MS跟踪至反应完全。将反应液浓缩，经pre-HPLC纯化得化合物95a-2。
步骤3：将化合物95a-2(783mg,3mmol)，环丙基氨(171mg,3mmol)溶于DMF(15ml)，加入TEA(606mg,6mmol)和HATU(1.7g,4.5mmol)，反应液在室温下搅拌2h，LC-MS跟踪至反应完全。反应液倒入水中，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，干燥，浓缩经柱层析纯化得化合物95a-3。MS m/z(ESI):301[M+H] +。
步骤4-5：参考化合物19a方法的步骤3-4，得到化合物95a。MS(ESI)259[M+H] +。
化合物96a的制备
Figure PCTCN2019121726-appb-000105
步骤1-2：参考化合物19a制备方法的步骤1和3，得到化合物96a-2。
步骤3：参考化合物94a制备方法的步骤1，得到化合物96a-3。
步骤4：参考化合物19a制备方法的步骤4，得到化合物96a。MS(ESI)233[M+H] +。
化合物92a和化合物98a参照化合物59a的方法制备。
化合物93a以28a-1为原料，参照化合物19a的方法步骤5-6制备化合物93a的制备。
化合物97a和化合物100a以95a-2为原料，参照化合物95a的方法制备。
化合物99a的制备
Figure PCTCN2019121726-appb-000106
步骤1：6,7-二氢-5H-吡咯[3,4-b]吡啶盐酸盐(1g,5.3mmol)和1,4-环己二酮单乙二醇缩酮(2g,2.5mmol)溶于二氯甲烷(15ml)和甲醇(50ml)中，加入醋酸(21ml)和氰基硼氢化钠(668mg,10.6mmol)，混合物在室温下搅拌过夜。加入碳酸氢钠溶液调节pH至8左右， 纯化得到化合物99a-1。
步骤2：参考化合物19a方法的步骤4，得到化合物99a。MS(ESI)217[M+H] +。
Figure PCTCN2019121726-appb-000107
Figure PCTCN2019121726-appb-000108
中间体37a的制备
Figure PCTCN2019121726-appb-000109
将化合物37a-1(1.015g,5mmol)，三乙胺(11.4ml,10mmol)溶于二氯甲烷(10ml)，在0℃下逐滴加入化合物37a-2(453mg,5mmol)的二氯甲烷溶液，反应液在0℃下搅拌30min后，在室温下继续搅拌1h，LC-MS跟踪至反应完全。反应液浓缩，经柱层析纯化得化合物37a(1.1g)，MS m/z(ESI):257[M+H] +。
实施例13/14：3-[[(4S)-2-羟基-4-苯基-环己基]氨基]-5-(1-甲基吡唑-4-基)-1H-吡啶-2-酮(P-13)和3-[[(4R)-2-羟基-4-苯基-环己基]氨基]-5-(1-甲基吡唑-4-基)-1H-吡啶-2-酮(P-14)的制备
Figure PCTCN2019121726-appb-000110
步骤1：将化合物7a(616mg,3.02mmol)，化合物8a(700mg,3.02mmol)，三氟乙酸(4ml)溶于1,4-二氧六环，反应液在50℃下搅拌1.5h，加入醋酸硼氢化钠(2.56g,12.07mmol)，反应液在35-40℃搅拌2h，LC-MS跟踪至反应完全。加入饱和碳酸氢钠溶液将pH调至8左右，用乙酸乙酯萃取，干燥，浓缩，经柱层析纯化得化合物13-1(321mg,Y:25％)，MS m/z(ESI):421[M+H] +。
步骤2：制备方法同实施例28步骤2方法，得化合物13-2。MS m/z(ESI):407[M+H] +。
步骤3：将化合物13-2(150mg,0.37mmol)溶于四氢呋喃(5ml)，加入氢氧化锂溶液(4M,3ml)，反应液在室温下搅拌1h，LC-MS跟踪至反应完全。用盐酸(2M)将反应液pH值中和至8左右，用乙酸乙酯萃取，合并有机相，干燥，浓缩，经pre-HPLC(制备柱：21.2x250mm C18柱,体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：48％-53％乙腈变化)纯化得化合物P-13(21mg,Y:16％)，化合物P-14(6mg,Y:4％)，MS m/z(ESI):365[M+H] +。
化合物P-16参考实施例13/14步骤1和步骤3的制备方法，不同之处在于用化合物77a替代化合物8a，用化合物31a代替化合物7a。
化合物P-19参考实施例13/14步骤1和步骤3的制备方法，不同之处在于用化合物78a替代化合物8a，用化合物31a代替化合物7a。
化合物P-20参考实施例13/14步骤1和步骤3的制备方法，不同之处在于用化合物19a替代化合物8a，用化合物4a代替化合物7a。
Figure PCTCN2019121726-appb-000111
实施例28：5-(1-甲基-1H-吡唑-4-基)-3-(((1S，4S)-4-苯基环己基)氨基)吡啶-2(1H)-酮(P-28)的制备
Figure PCTCN2019121726-appb-000112
步骤1：将化合物12a-a(361mg,1.0mmol)，7a-2(228mg,1.1mmol)溶于1,4-二氧六环(40ml)，加入Pd(dppf)Cl 2(74mg,0.1mmol)，饱和碳酸钠溶液(6ml)，反应液在氮气保护下80℃搅拌1h，LC-MS跟踪至反应完全。将反应液用硅藻土过滤，滤液浓缩得化合物28-1粗品(500mg)，直接用于下一步反应，MS m/z(ESI):363[M+H] +。
步骤2：将化合物28-1(220mg,0.61mmol)溶于DMF(10ml)，加入对甲苯磺酸(524mg,3.05mmol)，氯化锂(128mg,3.04mmol)，反应液在130℃下搅拌1h，LC-MS跟踪至反应完全。将反应液倒入水中，用乙酸乙酯萃取，合并有机相，干燥，浓缩，经pre-HPLC纯化得化合物P-28(158.10mg,Y:60％)，MS(ESI)349.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),7.93(s,1H),7.66(s,1H),7.33–7.08(m,5H),6.81(s,1H),6.44(d,J＝1.8Hz,1H),5.19(d,J＝7.9Hz,1H),3.78(s,3H),3.71(s,1H),2.59(t,J＝10.7Hz,1H),1.89(d,J＝11.8Hz,2H),1.76–1.49(m,6H).
实施例30：1-苄基-5-(1-甲基-1H-吡唑-4-基)-3-(((1S，4S)-4-苯基环己基)氨基)吡啶-2(1H)-酮(P-30)的制备
Figure PCTCN2019121726-appb-000113
将化合物P-28(110mg,0.316mmol)，氯化苄(40mg,0.316mmol)，碳酸钾(87mg,0.632mmol)溶于乙腈，反应液在80℃下搅拌过夜，LC-MS跟踪至反应完全。将反应液浓缩，将反应液过滤，滤液浓缩，经pre-HPLC纯化得化合物P-30(28mg,Y:20％)，MSm/z(ESI):439.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.66(s,1H),7.40–7.07(m,11H),6.45(d,J＝1.9Hz,1H),5.32(d,J＝7.9Hz,1H),5.10(s,2H),3.79(s,3H),3.71(s,1H),2.60(d,J＝3.9Hz,1H),1.71(ddd,J＝50.4,43.0,12.1Hz,8H)。
实施例43 5-(4-((2-氧代-5-(1H-吡唑-4-基)-1,2-二氢吡啶-3-基)氨基)环己基)-2-氰基吡啶(P-43)的制备
Figure PCTCN2019121726-appb-000114
步骤1：参照中间体化合物12a-a和化合物12a-b的制备方法中的反应条件进行制备，得到化合物43a-1。MS m/z(ESI):387.2[M+H]+。
步骤2-3：参照实施例28中的反应条件进行制备，得到化合物P-43。MS m/z(ESI):361.2[M+H] +。
实施例57和58 5-(1H-吡唑-4-基)-3-(((1R，4R)-4-(吡啶-3-基)环己基)氨基) 吡啶-2(1H)-酮(P-57)和5-(1H-吡唑-4-基)-3-(((1S，4S)-4-(吡啶-3-基)环己基)氨基)吡啶-2(1H)-酮(P-58)的制备
Figure PCTCN2019121726-appb-000115
参考中间体化合物12a-a和12a-b的制备方法中的反应条件和分离纯化条件，得化合物57-a和58-a。分别以化合物57-a和58-a为原料，参考实施例28的制备方法中的反应条件进行制备，得到化合物P-57(MS(ESI):336.2[M+H] +)和P-58(MS(ESI):336.2[M+H] +)。
化合物P-31参考实施例28的制备方法，不同之处在于用化合物12a-b替代化合物12a-a。
化合物P-33参考实施例13/14步骤1的制备方法，不同之处在于用化合物38a替代化合物7a，用化合物8a-1代替化合物8a。分离条件与实施例13/14步骤3中相同。
化合物P-35参考实施例13/14步骤1的制备方法，不同之处在于用化合物38a替代化合物7a，用化合物8a-1代替化合物8a。分离条件与实施例13/14步骤3中相同。
化合物P-36参考实施例28的制备方法，不同之处在于用化合物1a-1替代化合物7a-2。
化合物P-37参考实施例28的制备方法，不同之处在于用化合物1a-1替代化合物7a-2，用化合物12a-b替代化合物12a-a。
化合物P-39参考实施例28的制备方法，不同之处在于用4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-咪唑替代化合物7a-2。
化合物P-40参考实施例28的制备方法，不同之处在于用4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-咪唑替代化合物7a-2，用化合物12a-b替代化合物12a-a。
化合物P-41参考实施例28的制备方法，不同之处在于用3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑替代化合物7a-2。
化合物P-42参考实施例28的制备方法，不同之处在于用3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑替代化合物7a-2，用化合物12a-b替代化合物12a-a。
化合物P-44参考实施例30的制备方法，不同之处在于用碘甲烷替代氯化苄。
化合物P-46参考实施例28的制备方法，不同之处在于用2-环丙基-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷替代化合物7a-2。
化合物P-49参考实施例43的制备方法，不同之处在于用化合物74a替代化合物50a，用化合物3a-3替换化合物化合物1a-1。
化合物P-50参考实施例28的制备方法，不同之处在于用4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-2H-1,2,3-三唑替代化合物7a-2。
化合物P-51参考实施例43的制备方法，不同之处在于用化合物75a替代化合物50a，用化合物3a-3替换化合物化合物1a-1。
化合物P-52参考实施例43的制备方法，不同之处在于用化合物8a-1替换化合物50a，用1-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡咯替代化合物1a-1。
化合物P-55和P-56参考实施例57和58的制备方法，不同之处在于用化合物88a替换4-(吡啶-3-基)环己-1-酮。
化合物P-59参考实施例13/14的步骤1和步骤2的制备方法，不同之处在于用中间体5a替代化合物7a，用化合物8a-1替代化合物8a。
化合物P-60参考实施例43的制备方法，不同之处在于用化合物8a-1替换化合物50a，用1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑替代化合物1a-1。
化合物P-61参考实施例28的制备方法，不同之处在于用4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)哌啶替代化合物7a-2。
化合物P-62参考实施例28的制备方法，不同之处在于用4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异恶唑替代化合物7a-2。
化合物P-63参考实施例28的制备方法，不同之处在于用4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异噻唑替代化合物7a-2。
化合物P-64参考实施例28的制备方法，不同之处在于用5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)噻唑替代化合物7a-2。
化合物P-67参考实施例28的制备方法，不同之处在于用化合物5a-2替代7a-2。
化合物P-68和P-69参考实施例57和58的制备方法，不同之处在于用化合物8a-1替换4-(吡啶-3-基)环己-1-酮，用1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑替换化合物1a-1。
化合物P-70参考实施例28的制备方法，不同之处在于用2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)乙-1-醇替代化合物7a-2。
化合物P-74参考实施例13/14步骤1和2的制备方法，不同之处在于用4-(4-甲氧基苯基)环己-1-酮替代化合物8a。
化合物P-77和P-78参考实施例57和58的制备方法，不同之处在于用化合物89a替换4-(吡啶-3-基)环己-1-酮，用化合物3a-3替换化合物1a-1。
化合物P-79参考实施例13/14步骤1和2的制备方法，不同之处在于用化合物14a替代 化合物8a。
化合物P-80至P-84、P-86、P-90、P-91、P-93、P-98、P-100、P-102、P-111、P-113、P-114、P-119至P-122、P-126、P-138、P-140、P-142、P-143、P-180、P-181、P-92参考实施例30的制备方法，不同之处在于分别用邻氯苄溴、2-溴丙烷、溴代异丁烷、4-氯苄溴、4-氰基苄溴、4-甲氧基苄溴、2-氯-1-环己基乙醇、4-溴甲基哌啶、4-溴甲基四氢吡喃、溴甲基环丙烷、3-溴甲基氧杂环丁烷、3,5-二甲氧基苄溴、1-溴代异戊烷、2-溴乙基甲基醚、1-溴-2,2-二甲基丙烷、1-氯丙烷、溴乙烷、溴甲基环己烷、1-氯-2-甲基-2-丙醇、4-(溴甲基)-1-甲基哌啶、1-溴-2-氟乙烷、1-溴-2-氟-2-甲基丙烷、溴丁烷、溴乙腈、4-(溴甲基)-1-甲基-1H-吡唑溴、溴代环丙烷、3-(溴甲基)氮杂环丁烷替代氯化苄。
化合物P-85参考实施例13/14步骤1和2制备方法，不同之处在于用化合物17a替代化合物8a。
化合物P-87和P-88参考实施例13/14步骤1制备方法，不同之处在于用4-(4-甲氧基苯基)环己-1-酮替代化合物8a，用化合物35a替代化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-94参考实施例13/14步骤1和2的制备方法，不同之处在于用4-(4-氯苯基)环己-1-酮替代化合物8a。分离条件与实施例13/14步骤3中相同。
化合物P-101参考实施例13步骤1制备方法，不同之处在于用1-苯基-4-酮替代化合物8a，用化合物31a替代化合物7a。
化合物P-103参考实施例30的制备方法，不同之处在于用化合物P-46替代P-28，用碘甲烷替代氯化苄。
化合物P-104参考实施例30的制备方法，不同之处在于用化合物P-46替代化合物P-28。
化合物P-105参考实施例30的制备方法，不同之处在于用化合物P-74替代化合物P-28。
化合物P-108参考实施例30的制备方法，不同之处在于用化合物P-77替代P-28，用溴代异丁烷替代氯化苄。
化合物P-112参考实施例13步骤1的制备方法，不同之处在于用化合物39a替代化合物7a，用化合物8a-1代替化合物8a。分离条件与实施例13/14步骤3中相同。
化合物P-116参考实施例13步骤1和2的制备方法，不同之处在于用4-(4-(三氟甲基)苯基)环己-1-酮替代化合物8a。分离条件与实施例13/14步骤3中相同。
化合物P-117参考实施例13步骤1的制备方法，不同之处在于用4-(4-氧环己基)苄腈替代化合物8a，用化合物31a替代化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-118参考实施例30的制备方法，不同之处在于用化合物P-228替代P-28，用溴代异丁烷替代氯化苄。
化合物P-123参考实施例13步骤1的制备方法，不同之处在于用4-(苯并[d][1,3]二氧杂环戊烯-5-基)环己-1-酮替代化合物8a，用化合物35a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-124参考实施例13步骤1的制备方法，不同之处在于用4-(3-甲氧基苯基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-125参考实施例13步骤1的制备方法，不同之处在于用4-(4-(二甲基氨基)苯基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-127参考实施例13步骤1的制备方法，不同之处在于用4-(对甲苯基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-129参考实施例13步骤1的制备方法，不同之处在于用4-(4-甲氧基苯基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-130参考实施例13步骤1的制备方法，不同之处在于用4-(苯并[d][1,3]二氧杂环戊烯-5-基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-131参考实施例13步骤1的制备方法，不同之处在于用4-(3,4-二甲氧基苯基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-132参考实施例13步骤1的制备方法，不同之处在于用4-(6-甲氧基吡啶-3-基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-133参考实施例13步骤1的制备方法，不同之处在于用4-(吡啶-4-基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-134参考实施例30的制备方法，不同之处在于用化合物P-64替代P-28，用溴代异丁烷替代氯化苄。
化合物P-136参考实施例13步骤1的制备方法，不同之处在于用化合物8a-1替代化合物8a，用化合物41a替代化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-137参考实施例30的制备方法，不同之处在于用化合物P-63替代P-28，用溴代异丁烷替代氯化苄。
化合物P-144参考实施例13步骤1的制备方法，不同之处在于用4-(4-(二甲基氨基)苯基)环己-1-酮替代化合物8a，用化合物3a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-146参考实施例13步骤1的制备方法，不同之处在于用4-(5-甲氧基吡啶-3-基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-147参考实施例13步骤1的制备方法，不同之处在于用4-(3-甲氧基苯基)环己-1-酮替代化合物8a，用化合物3a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-149参考实施例13步骤1的制备方法，不同之处在于用4-(5-甲氧基吡啶-3- 基)环己-1-酮替代化合物8a，用化合物3a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-150参考实施例13步骤1的制备方法，不同之处在于用化合物8a-1替代化合物8a，用化合物42a替代化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-151参考实施例13步骤1的制备方法，不同之处在于用化合物8a-1替代化合物8a，用化合物43a替代化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-152参考实施例13步骤1的制备方法，不同之处在于用4-(4-甲氧基苯基)环己-1-酮替代化合物8a，用化合物3a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-153参考实施例13步骤1的制备方法，不同之处在于用4-(苯并[d][1,3]二氧杂环戊烯-5-基)环己-1-酮替代化合物8a，用化合物3a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-156参考实施例13步骤1的制备方法，不同之处在于用化合物8a-1替代化合物8a，用化合物34a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-157参考实施例13步骤1的制备方法，不同之处在于用4-(4-异丙氧基苯基)环己-1-酮替代化合物8a，用化合物3a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-160参考实施例13步骤1的制备方法，不同之处在于用4-(嘧啶-5-基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-161参考实施例13步骤1的制备方法，不同之处在于用化合物8a-1替代化合物8a，用化合物44a替代化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-162参考实施例13步骤1的制备方法，不同之处在于用4-(3,4-二甲氧基苯基)环己-1-酮替代化合物8a，用化合物3a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-164参考实施例13步骤1的制备方法，不同之处在于用4-(2-甲氧基苯基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-167参考实施例13步骤1的制备方法，不同之处在于用4-(2-异丙氧基吡啶-4-基)环己-1-酮替代化合物8a，用化合物3a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-168参考实施例13步骤1的制备方法，不同之处在于用4-(2-甲氧基吡啶-4-基)环己-1-酮替代化合物8a，用化合物3a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-171参考实施例13步骤1的制备方法，不同之处在于用4-(2-甲氧基嘧啶-5-基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-172参考实施例13步骤1的制备方法，不同之处在于用4-(2-甲氧基吡啶-4- 基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-174参考实施例13步骤1的制备方法，不同之处在于用94a替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-176参考实施例13步骤1的制备方法，不同之处在于用化合物28a-1替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
实施例177：1-异丁基-5-(1-甲基-1H-吡唑-4-基)-3-(((1S，4S)-4-(3,4,5-三甲氧基苯基)环己基)氨基)吡啶-2(1H)-酮(P-177)的制备
Figure PCTCN2019121726-appb-000116
步骤1：将化合物7a(200mg，0.98mmol)，化合物79a(259mg，0.98mmol)和TFA(1ml)溶解在1,4-二氧六环(10ml)中，在50℃下搅拌1h，在0-10℃下加入三乙酰氧基硼氢化钠(623mg，2.43mmol)，继续室温搅拌过夜。当反应结束，将反应液过滤除去不溶解的物质，将溶液减压蒸干，通过柱纯化制备得到白色的固体产物P-177-1(50mg)。三步收率：11.3％。MS(ESI)453.2[M+H] +。
步骤2：将化合物P-177-1(23mg，0.051mmol)和氢溴酸水溶液(40％，2ml)溶液于甲醇5(ml),室温下搅拌过夜。反应结束，减压蒸干溶剂的到固体P-177-2(20mg),未做进一步纯化，粗品直接用于下一步反应。MS(ESI)439.3[M+H] +。
步骤3：将化合物P-177-2(20mg，0.046mmol)，溴代异丙烷(19mg，0.137mmol)无水碳酸钾(32mg，0.23mmol)溶解在DMF(5ml)中，在100℃下搅拌过夜。当反应结束，将反应液过滤除去不溶解的物质，将溶液减压蒸干，通过高效液相制备(制备条件:制备柱：21.2x250mm C18柱体系：10mM NH 4HCO 3H 2O波长：254/214nm梯度：50％-55％乙腈变化)得到白色的固体产物P-177(1.71mg，纯度83.11％)。两步收率：7.6％。MS(ESI)495.3[M+H] +。
化合物P-179参考实施例13步骤1的制备方法，不同之处在于用化合物8a-1替代化合物8a，用化合物45a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-182参考实施例13步骤1的制备方法，不同之处在于用化合物20a替代化合物8a，用化合物31a替代化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-183参考实施例13步骤1的制备方法，不同之处在于用4-(4-(甲基磺酰基)苯基)环己-1-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-185参考实施例13步骤1的制备方法，不同之处在于用化合物8a-1替代化合物8a，用化合物46a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-187参考实施例13步骤1的制备方法，不同之处在于用4-(吡啶-2-基)环己-1- 酮替代化合物8a，用化合物31a替代化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-186、P-188参考实施例13步骤1的制备方法，不同之处在于用化合物18a替代化合物8a，用化合物31a替代化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-189参考实施例13步骤1的制备方法，不同之处在于用4-(吡啶-3-基)环己-1-酮替代化合物8a，用化合物31a替代化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-190参考实施例13步骤1制备方法，不同之处在于用6-苯基-2H-吡喃-3(4H)-酮替代化合物8a，用化合物31a替代化合物7a。
化合物P-192参考实施例13步骤1的制备方法，不同之处在于用4-(3,4-二甲氧基苯基)环己-1-酮替代化合物8a，用化合物29a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-193参考实施例13步骤1的制备方法，不同之处在于用28a-1替代化合物8a，用化合物3a代替化合物7a。分离条件与实施例13/14步骤3中相同。
实施例194：3-(((1S，4S)-4-(6-氨基吡啶-3-基)环己基)氨基)-1-异丁基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮(P-194)的制备
Figure PCTCN2019121726-appb-000117
步骤1：将化合物31a(800mg，3.25mmol)，化合物96a(1132mg，4.87mmol)和TFA(1ml)溶解在THF(20ml)中，在50℃下搅拌1h。室温下加入三乙酰氧基硼氢化钠(2066mg，9.75mmol)，继续室温搅拌过夜。当反应结束，将反应液过滤除去不溶解的物质，将溶液减压蒸干，通过柱纯化制备得到白色的固体产物P-194(655mg)。1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.74(d,J＝2.2Hz,1H),7.66(s,1H),7.22(dd,J＝8.4,2.3Hz,1H),7.10(d,J＝1.9Hz,1H),6.51–6.26(m,2H),5.63(s,1H),5.27(d,J＝8.1Hz,1H),3.79(s,3H),3.71(d,J＝7.4Hz,2H),3.68–3.64(m,1H),2.15–2.04(m,1H),1.96(d,J＝8.0Hz,1H),1.86(d,J＝12.6Hz,2H),1.57(s,6H),1.32(s,1H),0.84(d,J＝6.7Hz,6H)。
化合物P-195参考实施例13步骤1制备方法，不同之处在于用6-(3,4-二甲氧基苯基)二氢-2H-吡喃-3(4H)-酮替代化合物8a，用化合物31a替代化合物7a。
化合物P-196参考实施例13步骤1的制备方法，不同之处在于用化合物20a替代化合物8a，用化合物3a替代化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-198参考实施例13步骤1的制备方法，不同之处在于用6-(4-氧代环己基)苯并[d]恶唑-2(3H)-酮替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-199和P-200参考实施例13步骤1的制备方法，不同之处在于用化合物19a-6替代化合物8a，用化合物31a替代化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-202参考实施例13步骤1的制备方法，不同之处在于用95a替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-203参考实施例13步骤1的制备方法，不同之处在于用97a替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-204参考实施例13步骤1的制备方法，不同之处在于用4-(3,4-二甲氧基苯基)环己-1-酮替代化合物8a，用化合物29a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-205参考实施例13步骤1的制备方法，不同之处在于用98a替代化合物8a，用化合物31a代替化合物7a。分离条件与实施例13/14步骤3中相同。
化合物P-208参考实施例294的制备方法，不同之处在于用化合物70a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮，用化合物31a代替化合物4a。
化合物P-209参考实施例294的制备方法，不同之处在于用化合物100a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮，用化合物31a代替化合物4a。
化合物P-250参考实施例13步骤1的制备方法，不同之处在于用19a-6替代8a，4a替代7a。分离条件与实施例13/14步骤3中相同。
Figure PCTCN2019121726-appb-000118
Figure PCTCN2019121726-appb-000119
Figure PCTCN2019121726-appb-000120
Figure PCTCN2019121726-appb-000121
Figure PCTCN2019121726-appb-000122
Figure PCTCN2019121726-appb-000123
Figure PCTCN2019121726-appb-000124
Figure PCTCN2019121726-appb-000125
Figure PCTCN2019121726-appb-000126
Figure PCTCN2019121726-appb-000127
Figure PCTCN2019121726-appb-000128
Figure PCTCN2019121726-appb-000129
Figure PCTCN2019121726-appb-000130
Figure PCTCN2019121726-appb-000131
Figure PCTCN2019121726-appb-000132
Figure PCTCN2019121726-appb-000133
Figure PCTCN2019121726-appb-000134
Figure PCTCN2019121726-appb-000135
Figure PCTCN2019121726-appb-000136
实施例219：3-(((1S，4S)-4-(氨基甲基)-4-(3,4-二甲氧基苯基)环己基)氨基)-1-异丁基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮(P-219)的制备
Figure PCTCN2019121726-appb-000137
将化合物P-188(216mg,0.44mmol)，氯化镍(861mg,6.63mmol)溶于甲醇，在0℃下加入硼氢化钠(252mg,6.63mmol)，反应液在室温下搅拌过夜，LC-MS跟踪至反应完全。将反应液浓缩，经pre-HPLC纯化得化合物P-219(78mg,Y:40％)，MS m/z(ESI):494.2[M+H] +。
实施例220：3-(((1R，4R)-4-(氨基甲基)-4-(3,4-二甲氧基苯基)环己基)氨基)-1-异丁基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮(P-220)的制备
Figure PCTCN2019121726-appb-000138
参考实施例219的类似方法制备，MS m/z(ESI):494.2[M+H] +。
实施例221：3-(((1S，4S)-4-(氨基甲基)-4-(3,4-二甲氧基苯基)环己基)氨基)-1-异丁基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮(P-221)的制备
Figure PCTCN2019121726-appb-000139
将化合物P-219(35mg,0.071mmo)溶于1,4-二氧六环，加入化合物221-1(40mg,0.4mmol)，反应液在120℃下搅拌过夜，LC-MS跟踪至反应完全。将反应液浓缩，经pre-HPLC纯化得化合物P-221(3mg,Y:7.5％)，MS m/z(ESI):573.3[M+H] +。
实施例222：3-(((1R，4R)-4-(氨基甲基)-4-(3,4-二甲氧基苯基)环己基)氨基)-1-异丁基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮(P-222)的制备
Figure PCTCN2019121726-appb-000140
参考实施例221的类似方法制备，不同的是以化合物P-220为原料。MS m/z(ESI):573.3[M+H] +。
实施例224：2-(5-(1-甲基-1H-吡唑-3-基)-2-氧代-3-(((1s，4s)-4-苯基环己基)氨基)吡啶-1(2H)-基)乙酸(P-224)的制备
Figure PCTCN2019121726-appb-000141
步骤1：将化合物P-28(200mg,0.57mmol)溶于DMF(20ml)，加入溴乙酸乙酯(143mg,0.86mmol)，碳酸钾(158mg,1.14mmol)，碘化钾(10mg,0.06mmol)，反应液在120℃搅拌4h，LC-MS跟踪至反应完全。将反应液浓缩，经pre-HPLC纯化得化合物224-1(50mg,收率20％)，MSm/z(ESI):435[M+H] +。
步骤2：将化合物224-1(248mg,0.57mmol)溶于1,4-二氧六环(10ml)，加入一水合氢氧化锂(239mg,5.7mmol)，水(10ml)，反应液在室温下搅拌过夜，LC-MS跟踪至反应完全。将反应液浓缩，经pre-HPLC纯化得化合物P-224(10mg,收率4％)，MS m/z(ESI):407.3[M+H] +。 1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.61(d,J＝0.6Hz,1H),7.19(dddd,J＝12.7,7.3,6.7,1.8Hz,6H),6.44(d,J＝2.0Hz,1H),5.24(d,J＝7.8Hz,1H),4.49(s,2H),3.80(d,J＝7.2Hz,3H),3.71(s,1H),2.60(s,1H),1.71(ddd,J＝51.9,34.2,12.6Hz,8H).
实施例225：((1s，4s)-4-((5-(1-甲基-1H-吡唑-4-基)-2-氧代-1,2-二氢吡啶-3-基)氨基)环己基)苯甲酸(P-225)的制备
Figure PCTCN2019121726-appb-000142
将化合物P-117(343.2mg,0.80mmol)溶于乙醇(3ml)，加入氢氧化钾75％乙醇溶液(6M，0.8ml)，反应液在室温下搅拌过夜后，回流1h，LC-MS跟踪至反应完全。向反应液中加入12M盐酸溶液将反应液pH调至2左右，将反应液浓缩，经pre-HPLC纯化得化合物P-225(10.5mg,Y:3％)，MS m/z(ESI):449.3[M+H] +。
实施例226：5-((4-((1-异丁基-5-(1-甲基-1H-吡唑-4-基)-2-氧代-1,2-二氢吡啶-3-基)氨基)环己基)烟酸(P-226)的制备
Figure PCTCN2019121726-appb-000143
参考实施例225的条件制备，MS m/z(ESI):450.2[M+H] +。
实施例227：3-(甲基((1S，4S)-4-苯基环己基)氨基)-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮(P-227)的制备
Figure PCTCN2019121726-appb-000144
步骤1：将化合物12a-a(60mg,0.17mmol)溶于1,4-二氧六环(18ml)，加入甲醛(0.6ml)，三氟乙酸(6ml)，反应液在室温下搅拌2h，加入醋酸硼氢化钠(106mg,0.5mmol)，反应液在室温下继续搅拌3h，LC-MS跟踪至反应完全。向反应液中加入饱和碳酸氢钠溶液，二氯甲烷，分液，有机相干燥，浓缩，经柱层析纯化得化合物227-1(86mg)，MS m/z(ESI):375[M+H] +。
步骤2：制备方法同实施例28步骤1方法，MS m/z(ESI):377[M+H] +。
步骤3：制备方法同实施例28步骤2方法，MS m/z(ESI):363[M+H] +。
实施例228：5-(((1S，4S)-4-苯基环己基)氨基)-[3,3'-联吡啶]-6(1H)-酮(P-228)的制备
Figure PCTCN2019121726-appb-000145
步骤1：将化合物12a-a(140mg,0.39mmol)，化合物4a-4(198mg,0.78mmol)溶于1,4-二氧六环，加入四三苯基膦钯(23mg,0.05mmol)，碳酸钾(108mg,2mmol)，反应液在120℃下微波反应1h，LC-MS跟踪至反应完全。将反应液浓缩，粗品经柱层析纯化得化合物228-1(112mg,收率：70％)，MS m/z(ESI):409[M+H] +。
步骤2：将化合物228-1(360mg,0.88mmol)，化合物228-2(166mg,1.06mmol)溶于1,4-二氧六环/水(4ml/1ml)，加入四三苯基膦钯(105mg,0.09mmol)，乙酸钾(346mg,3.53mmol)，反应液在微波下120℃反应30min，LC-MS跟踪至反应完全。将反应液过滤，滤液浓缩经柱层析纯化得化合物228-3(267mg,Y:84％)，MS m/z(ESI):360[M+H] +。
步骤3：制备方法同实施例28步骤2方法，MS m/z(ESI):346[M+H] +。
实施例229：5-((4-苯基环己基)氨基)-[3,4'-联吡啶]-6(1H)-酮(P-229)的制备
Figure PCTCN2019121726-appb-000146
参考实施例228的条件制备，MS m/z(ESI):346.2[M+H] +。
实施例243：3-(((1R，4R)-4-羟基-4-(6-甲氧基吡啶-3-基)环己基)氨基)-1-异丁基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮(P-243)的制备
Figure PCTCN2019121726-appb-000147
步骤1：参考实施例13/14步骤1的条件制备，MS m/z(ESI):343.2[M+H] +。
步骤2：将化合物243-3(376mg,2mmol)溶于四氢呋喃(40ml)，在-78℃下逐滴加入正丁基锂溶液(1M,2ml)，反应液在-78℃下搅拌1h，加入化合物243-2(342mg,1mmol)四氢呋喃溶液，反应液在-78℃下搅拌2h，LC-MS跟踪至反应完全。加水淬灭反应，用乙酸乙酯萃取，合并有机相，干燥，浓缩，经pre-HPLC(制备柱：21.2x250mm C18柱,体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：48％-53％乙腈变化)纯化得化合物P-243(19mg,Y:4％)，MS m/z(ESI):452.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.21(s,1H),7.93(s,1H),7.73(d,J＝8.7Hz,1H),7.66(s,1H),7.08(s,1H),6.74(d,J＝8.7Hz,1H),6.43(s,1H),5.23(d,J＝7.9Hz,1H),4.93(s,1H),3.79(s,6H),3.69(d,J＝7.1Hz,2H),3.60(d,J＝4.3Hz,1H),2.13–1.87(m,5H),1.67–1.47(m,4H),0.82(d,J＝6.4Hz,6H).
实施例244/245：3-((R)-羟基-((1R，4R)-4-苯基环己基)甲基)-1-异丁基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮(P-244)和3-((S)-羟基-((1S，4R)-4-苯基环己基)甲基)-1-异丁基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮(P-245)的制备
Figure PCTCN2019121726-appb-000148
制备方法同实施例243步骤2方法，分离条件(制备柱：21.2x250mm C18柱,体系：10mMNH 4HCO 3H 2O，波长：254/214nm，梯度：48％-53％乙腈变化)。MS m/z(ESI):420.3[M+H] +。 1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.78(d,J＝2.6Hz,1H),7.67(s,1H),7.62(d,J＝2.5Hz,1H),7.30–7.19(m,4H),7.14(d,J＝7.0Hz,1H),4.94–4.84(m,2H),3.79(s,3H),3.76–3.64(m,2H),2.10–2.02(m,1H),1.96(dd,J＝14.7,7.2Hz,3H),1.80(s,2H),1.58(s,1H),1.42(s,4H),0.81(t,J＝6.8Hz,6H).
实施例246：3-((4-(3,4-二甲氧基苯基)-4-(羟基甲基)环己基)氨基)-1-异丁基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮(P-246)的制备
Figure PCTCN2019121726-appb-000149
步骤1：将化合物P-186(210mg,0.43mmol)溶于二氯甲烷(15ml)，在-78℃下逐滴加入DIBAL-H(1M，1.27ml)，反应液在-78℃下搅拌6h，LC-MS跟踪至反应完全。加水淬灭反应，用乙酸乙酯萃取，合并有机相，干燥，浓缩至干得化合物246-1粗品(140mg)，MS m/z(ESI):493[M+H] +。
步骤2：制备方法同实施例257步骤3方法，MS m/z(ESI):495.3[M+H] +。
实施例247 1-异丁基-3-(((1S，4S)-4-(5-(5-甲基-1,2,4-恶二唑-3-基)吡啶-3-基)环己基)氨基)-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮(P-247)的制备
Figure PCTCN2019121726-appb-000150
步骤1：制备方法同实施例13步骤1方法，MS m/z(ESI):431[M+H] +。
步骤2：将化合物247-2(828mg,1.8mmol)溶于乙醇/水(50ml/10ml)，加入盐酸羟胺(373mg,5.4mmol)，碳酸氢钠(900mg,10.8mmol)，反应液在氮气保护下回流4小时，LC-MS跟踪至反应完全。将反应液浓缩，加入水，用乙酸乙酯萃取，合并有机相，干燥，浓缩至干得化合物247-3粗品(900mg)，直接用于下一步反应。MS m/z(ESI):464[M+H] +。
步骤3：将化合物247-3(900mg,2.0mmol)溶于二氯甲烷(100ml)，加入乙酰氯(468mg,6.0mmol)，DIPEA(1032mg,8.0mmol)，反应液在氮气保护下室温搅拌2h，LC-MS跟踪至反应完全。加入二氯甲烷稀释反应液，用水和饱和食盐水洗涤，干燥，浓缩，经柱层析纯化得化合物247-4(800mg,收率83％)，MS m/z(ESI):506[M+H] +。
步骤4：将化合物247-4(800mg,1.58mmol)溶于甲苯，反应液在氮气保护下回流过夜，LC-MS跟踪至反应完全。将反应液浓缩，经pre-HPLC(制备柱：21.2x250mm C18柱,体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：48％-53％乙腈变化)纯化得化合物P-247(17.48mg,收率3％)，MS m/z(ESI):488[M+H] +。
实施例248：1-异丁基-3-(((1R，4R)-4-(5-甲基-1,2,4-恶二唑-3-基)环己基)氨基)-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮(P-248)的制备
Figure PCTCN2019121726-appb-000151
参考实施例247的条件制备，其区别在于用4-氧代环己烷甲腈替换实施例247步骤1中的247-1化合物，分离条件(制备柱：21.2x250mm C18柱,体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：48％-53％乙腈变化)。MS m/z(ESI):411.2[M+H] +。
实施例249：1-异丁基-5-(1-甲基-1H-吡唑-4-基)-3-(((1S，4S)-4-(6-(吗啉-4-羰基)吡啶-3-基)环己基)氨基)吡啶-2(1H)-酮(P-249)的制备
Figure PCTCN2019121726-appb-000152
步骤1：参考实施例13/14步骤1方法中的条件制备，经pre-HPLC(制备柱：21.2x250mmC18柱,体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：48％-53％乙腈变化)。纯化得化合物249-1，MS m/z(ESI):431[M+H] +。
步骤2：参考实施例225中的条件制备，得化合物249-2。MS m/z(ESI):450[M+H] +。
步骤3：将化合物249-2(50mg,0.10mmol)，化合物249-3(26mg,0.3mmol),DIPEA(25mg,0.20mmol)溶于二氯甲烷(13ml)，加入HATU(57mg,0.15mmol)，反应液室温下搅拌4h，LC-MS跟踪至反应完全。反应液用二氯甲烷稀释后用饱和食盐水洗涤，干燥，浓缩经pre-HPLC纯化得化合物P-249(1.02mg,Y:2％)，MS(ESI)519.3[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.47(d,J＝1.9Hz,1H),7.94(s,1H),7.79(dd,J＝8.2,2.4Hz,1H),7.66(d,J＝0.8Hz,1H),7.53(d,J＝8.1Hz,1H),7.11(d,J＝2.0Hz,1H),6.44(d,J＝2.0Hz,1H),5.32(d,J＝8.1Hz,1H),3.79(s,3H),3.71(d,J＝7.4Hz,2H),3.61(s,2H),3.52(s,2H),3.44(s,2H),3.27(s,1H),2.67–2.60(m,1H),2.32–2.26(m,1H),2.14–2.05(m,1H),1.89(s,2H),1.69(s,6H),0.83(t,J＝5.9Hz,6H).
实施例257：5-((1S，4S)-4-(羟甲基)-4–((1-异丁基-5-(1-甲基-1H-吡唑-4-基)-2-氧代-1,2-二氢吡啶-3-基)氨基)环己基)-N，N-二甲基吡啶酰胺(P-257)的制备
Figure PCTCN2019121726-appb-000153
步骤1：将化合物28a-1(200mg,0.82mmol)，化合物31a(221mg,0.90mmol)溶于冰醋酸，反应液在0℃下搅拌30min，加入TMSCN(123mg,1.23mmol)，反应液在室温下搅拌过夜，LC-MS跟踪至反应完全。将反应液倒入冰的氨水中，用二氯甲烷/甲醇(10/1,v/v)萃取，合并有机相，干燥，浓缩，经柱层析(制备柱：21.2x250mm C18柱,体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：48％-53％乙腈变化)。纯化得化合物257-1(150mg,收率36％)，MS m/z(ESI):502[M+H] +。
步骤2：将化合物257-1(100mg,0.2mmol)溶于二氯甲烷(10ml)，在氮气保护下，-78℃加入1.5M DIBAL-H(0.4ml,0.6mmol)，反应液在-78℃搅拌3h，LC-MS跟踪至反应完全。将反应液浓缩得化合物257-2粗品(120mg)，MS m/z(ESI):505[M+H] +。
步骤3：将化合物257-2(120mg,0.24mmol)溶于甲醇，加入硼氢化钠(18mg,0.48mmol)，反应液在室温下搅拌30min，LC-MS跟踪至反应完全。将反应液浓缩经pre-HPLC纯化得化合物P-257(0.52mg)，MS m/z(ESI):507.3[M+H] +。
实施例281：5-((1S，4S)-4-((1-异丁基-5-(异噻唑-4-基)-2-氧代-1,2-二氢吡啶-3-基)氨基)环己基)噻吩-2-甲酰胺(P-281)的制备
Figure PCTCN2019121726-appb-000154
步骤1：化合物66a(239mg,1.00mmol)和化合物4a(249mg,1.00mmol)溶于二氯甲烷20ml中，加入2ml醋酸和氰基硼氢化钠(63mg,1.00mmol)，混合物在室温下搅拌4小时，用硅胶柱分离纯化得到化合物P-281-1(170mg,棕色固体)。MS(ESI)472[M+H] +。
步骤2：化合物P-281-1(47mg,0.10mmol)溶于浓氨水20ml中，封管加热100度搅拌4小时，浓缩至干，Prep-HPLC制备得到顺式结构的化合物P-281(15mg，Y:37％)，制备柱：21.2X250mm C18柱,体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：48％-53％乙腈变化。MS(ESI)457.3[M+H]+。1H NMR(400MHz,DMSO)δ9.12(s,1H),8.90(s,1H),7.81(s,1H),7.54(d,J＝1.5Hz,1H),7.45(s,1H),7.22(s,1H),6.88(s,1H),6.63(s,1H),5.27(d,J＝8.0Hz,1H),3.75(d,J＝7.4Hz,2H),3.69(s,1H),2.97(s,1H),2.10(dt,J＝13.7,6.8Hz,1H),1.92(d,J＝10.3Hz,4H),1.73–1.68(m,4H),0.89(d,J＝6.7Hz,6H).
实施例294：3-(((1S，4S)-4-(苯并[d]噻唑-2-基)环己基)氨基)-1-异丁基-5-(异噻唑-4-基)吡啶-2(1H)-酮(P-294)的制备
Figure PCTCN2019121726-appb-000155
将4-(苯并[d]噻唑-2-基)环己-1-酮(221mg，1.00mmol)，化合物4a(249mg，1.00mmol)和无水醋酸(0.2mL)加入到二氧六环(20mL)中，搅拌加热到50℃。分批加入醋酸硼氢化钠(800mg,4.00mmol)，反应三个小时，加入水淬灭反应，乙酸乙酯萃取，浓缩有机层，得到粗产物，经反相柱制备分离得到顺式结构化合物P-294(3mg，1％)(制备柱：21.2X250mmC18柱；体系：10mM NH 4HCO 3H 2O；波长：254/214nm；梯度：48％-53％乙腈变化)。MS(ESI)465.1[M+H] +；1H NMR(400MHz,MeOD)δ8.96(s,1H),8.78(s,1H),8.45(s,1H),7.70(d,J＝7.9Hz,1H),7.52(s,1H),7.43(d,J＝7.8Hz,1H),7.32(d,J＝2.1Hz,1H),6.69(d,J＝2.1Hz,1H),4.42(s,2H),3.90(d,J＝7.5Hz,2H),3.84(s,1H),2.79(s,1H),2.30–2.14(m,1H),2.08(d,J＝7.6Hz,2H),1.96–1.66(m,6H),0.96(d,J＝6.7Hz,6H).
实施例297：2-氨基-4-((1S，4S)-4-((1-异丁基-5-(异噻唑-4-基)-2-氧代-1,2-二氢吡啶-3-基)氨基)环己基)苯甲酰胺(P-297)的制备
Figure PCTCN2019121726-appb-000156
将化合物91a(249mg，0.9mmol)，化合物4a(150mg，0.6mmol)和TFA(2.5mL)加入到DCM(15mL)中，室温搅拌反应3h。在0-10℃下加入醋酸硼氢化钠(381mg,1.8mmol)，室温反应过夜。经反相柱制备分离得到顺式结构化合物P-297(制备柱：21.2X250mm C18柱；体系：10mM NH 4HCO 3H 2O；波长：254/214nm；梯度：48％-53％乙腈变化)。1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.90(s,1H),8.30(s,1H),7.60(s,1H),7.44(dd,J＝15.0,5.1Hz,2H),6.63(d,J＝2.0Hz,1H),6.52(d,J＝4.5Hz,1H),6.33(d,J＝8.2Hz,2H),5.33(d,J＝8.0Hz,1H),3.76(d,J＝7.3Hz,2H),2.82(d,J＝7.3Hz,1H),2.12(dd,J＝13.7,6.7Hz,1H),1.93(dd,J＝28.2,9.8Hz,2H),1.77–1.43(m,6H),0.85(d,J＝6.7Hz,6H)；MS：466.2[M+H]+。
实施例302：5-((1s，4s)-4-((1-异丁基-5-(异噻唑-4-基)-2-氧代-1,2-二氢吡啶-3-基)氨基)环己基)吡啶甲酰亚胺(P-302)的制备
Figure PCTCN2019121726-appb-000157
步骤1：将化合物4a(498mg，2.0mmol)和化合物19a-6(436mg，2.0mmol)加入到二氧六环(15mL)和三氟乙酸(3mL)的混合溶液中，然后在0℃搅拌10分钟，将三乙酰氧基硼氢化钠(1260mg，6.0mmol)加入到反应液中并在0℃搅拌30分钟，升到室温下再搅拌1小时，待原料反应完毕，用饱和碳酸氢钠水溶液调节pH＝8，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过减压浓缩并通过高效液相制备(柱子：Waters-SunFire Prep 19*250mm；流动相：A:乙腈，B:水+0.045％甲酸；波长：214/254；梯度：27-57)得到固体产物P-302-1(241mg，27％)。MS(ESI)452[M+H] +； 1H NMR(400MHz,DMSO)δ9.18(s,1H),8.95(s,1H),8.54(d,J＝1.5Hz,1H),8.06(s,1H),7.99(d,J＝8.1Hz,1H),7.87(dd,J＝8.1,1.9Hz,1H),7.59(s,1H),7.51(d,J＝1.8Hz,1H),6.69(d,J＝1.6Hz,1H),5.44(d,J＝8.0Hz,1H),3.80(d,J＝7.4Hz,3H),2.82(d,J＝4.7Hz,1H),2.17(dt,J＝13.7,6.8Hz,1H),1.96(d,J＝10.3Hz,2H),1.83–1.63(m,6H),0.89(d,J＝6.7Hz,6H).
步骤2：将化合物P-302-1(50mg，0.11mmol)和三乙胺(336mg，3.33mmol)加入到 二氯甲烷(15mL)溶液中，然后在室温下缓慢滴加三氟乙酸酐(466mg，0.22mmol)，滴加完毕，反应液在室温搅拌5小时，待原料反应完毕，反应液用饱和碳酸氢钠水溶液调节pH＝8，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过减压浓缩干得到粗产物P-302-2(56mg，95％)。MS(ESI)530[M+H] +。
步骤3：将双甲基硅基氨基锂(1M的四氢呋喃溶液,0.74ml，0.74mmol)加入到0℃的化合物P-302-2(56mg，0.11mmol)的四氢呋喃溶液中，反应液在0℃搅拌1小时，然后升到室温在搅拌1小时，待原料反应完全，将反应液倒入冰水中，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过减压浓缩，再通过高效液相制备(柱子：Waters-SunFire Prep 19*250mm；流动相：A:乙腈，B:水+0.045％甲酸；波长：214/254；梯度：27-57)分离得到化合物P-302(24mg，50％)，白色固体产物。MS:451[M+H] +；H NMR(400MHz,dmso)δ9.59(s,2H),9.14(s,1H),8.91(s,1H),8.71(s,1H),8.32(s,1H),8.18(d,J＝8.1Hz,1H),8.04(d,J＝8.0Hz,1H),7.48(d,J＝1.9Hz,1H),6.65(s,1H),5.41(d,J＝8.0Hz,1H),3.76(d,J＝7.5Hz,3H),2.86(s,1H),2.18–2.09(m,1H),1.91(s,2H),1.73(d,J＝5.2Hz,6H),0.86(d,J＝6.7Hz,6H).
实施例306：3-((4-(3,4-二甲氧基苯基)-2-羟基环己基)氨基)-1-乙基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮(P-306)的制备
Figure PCTCN2019121726-appb-000158
步骤1：将化合物77a(2.45g，8.39mmol)和化合物3a(1.41g，6.45mmol)加入到二氧六环(30mL)和三氟乙酸(5mL)的混合溶液中，然后在0℃搅拌15分钟，将三乙酰氧基硼氢化钠(4.10g，19.36mmol)加入到反应液中并在0℃搅拌30分钟，升到室温下再搅拌1小时，待原料反应完毕，用饱和碳酸氢钠水溶液调节pH＝8，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过减压浓缩并通过高效液相制备(柱子：Waters-SunFire Prep 19*250mm；流动相：A:乙腈，B:水+0.045％甲酸；波长：214/254；梯度：27-57％乙腈)得到固体产物P-306-1(1.7g，41％)。MS(ESI)495[M+H] +。
步骤2：将化合物P-306-1(1.7g，3.44mmol)加入到四氢呋喃(25mL)溶液中，然后在边搅拌边滴加氢氧化锂(4M,60mL,240mmol),滴加完毕，在室温搅拌6小时，待原料反应完毕，将反应液用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过减压浓缩并通过高效液相制备(柱子：21.2X250mm C18柱；体系：10mM NH 4HCO 3H 2O；波长：254/214nm；梯度：30-35％乙腈)得到顺式结构P-306(1.15g，74％)。MS:453[M+H] +； 1H NMR(400MHz,dmso)δ7.94(s,1H),7.66(s,1H),7.18(d,J＝1.9Hz,1H),6.84(d,J＝8.3Hz,1H),6.77(d,J＝1.7Hz,1H),6.70(dd,J＝8.2,1.7Hz,1H),6.45(d,J＝1.7Hz,1H),5.28(d,J＝4.9Hz,1H),4.99(s,1H),3.90(tdd,J＝15.7,11.1,5.5Hz,3H),3.79(s,3H),3.71(s,3H),3.68(s, 3H),3.56(d,J＝20.2Hz,1H),2.56(dd,J＝25.4,13.7Hz,1H),2.05(d,J＝10.8Hz,1H),1.81(d,J＝14.1Hz,1H),1.66–1.29(m,4H),1.23(t,J＝7.1Hz,3H).
化合物P-258参考实施例30的制备方法，不同之处在于用2-溴乙醇替代氯化苄。
化合物P-259和P-197参考实施例249类似的方法制备。
化合物P-260参考实施例294的制备方法和分离条件，不同之处在于用化合物85a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-261参考实施例294的制备方法和分离条件，不同之处在于用化合物63a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-262参考实施例294的制备方法和分离条件，不同之处在于用化合物84a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-263参考实施例294的制备方法和分离条件，不同之处在于用化合物19a-6替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮，用化合物49a替代化合物4a。
化合物P-264参考实施例294的制备方法和分离条件，不同之处在于用化合物19a-6替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮，用化合物48a替代化合物4a。
化合物P-265参考实施例281的制备方法和分离条件，不同之处在于用化合物67a替代化合物66a。
化合物P-266参考实施例294的制备方法和分离条件，不同之处在于用化合物86a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-267参考实施例294的制备方法和分离条件，不同之处在于用化合物87a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-268参考实施例294的制备方法和分离条件，不同之处在于用4-(2-甲氧基吡啶-4-基)环己-1-酮替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-269参考实施例294的制备方法和分离条件，不同之处在于用4-(喹啉-6-基)环己-1-酮替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-270参考实施例294的制备方法和分离条件，不同之处在于用4-(1H-吡咯并[2,3-b]吡啶-3-基)环己-1-酮替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-271参考实施例294的制备方法和分离条件，不同之处在于用4-(苯并[d][1,3]二氧杂环戊烯-5-基)环己-1-酮替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-272参考实施例297的制备方法和分离条件，不同之处在于用92a替代化合物91a。
化合物P-273参考实施例281的制备方法和分离条件，不同之处在于用化合物68a替代化合物66a。
化合物P-274参考实施例281的制备方法和分离条件，不同之处在于用化合物69a替代化合物66a。
化合物P-275参考实施例294的制备方法和分离条件，不同之处在于用4-(4-氧环己基) 苯甲酰胺替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-276参考实施例294的制备方法和分离条件，不同之处在于用化合物72a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮，用化合物31a代替化合物4a。
化合物P-277参考实施例294的制备方法和分离条件，不同之处在于用化合物63a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮，用化合物31a代替化合物4a。
化合物P-278参考实施例294的制备方法和分离条件，不同之处在于用化合物71a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮，用化合物31a代替化合物4a。
化合物P-279参考实施例294的制备方法和分离条件，不同之处在于用化合物19a-6替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮，用化合物47a代替化合物4a。
化合物P-280参考实施例294的制备方法和分离条件，不同之处在于用化合物19a-6替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮，用化合物43a代替化合物4a。
化合物P-282参考实施例294的制备方法和分离条件，不同之处在于用化合物99a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-283参考实施例294的制备方法和分离条件，不同之处在于用化合物19a-6替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮，用化合物34a代替化合物4a。
化合物P-285参考实施例294的制备方法和分离条件，不同之处在于用化合物62a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-286参考实施例294的制备方法和分离条件，不同之处在于用4-(6-甲氧基吡啶-3-基)环己-1-酮替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-287参考实施例294的制备方法和分离条件，不同之处在于用化合物61a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-288参考实施例294的制备方法和分离条件，不同之处在于用化合物60a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-289参考实施例294的制备方法和分离条件，不同之处在于用化合物82a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-290参考实施例294的制备方法和分离条件，不同之处在于用化合物81a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-291参考实施例294的制备方法和分离条件，不同之处在于用化合物73a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-292参考实施例294的制备方法和分离条件，不同之处在于用化合物59a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-293参考实施例294的制备方法和分离条件，不同之处在于用4-(6-氟喹啉-4-基)环己-1-酮替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮，用化合物31a替代化合物4a。
化合物P-296参考实施例294的制备方法和分离条件，不同之处在于用化合物58a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-298参考实施例294的制备方法和分离条件，不同之处在于用化合物57a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-300参考实施例281步骤1的制备方法和分离条件，不同之处在于用化合物90a替代化合物66a。
化合物P-301参考实施例294的制备方法和分离条件，不同之处在于用化合物56a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-304参考实施例294的制备方法，不同之处在于用化合物54a替代化合物4-(苯并[d]噻唑-2-基)环己-1-酮。
化合物P-305参考实施例306的制备方法和分离条件，不同之处在于用化合物93a替代化合物77a，用化合物31a替代化合物3a。
Figure PCTCN2019121726-appb-000159
Figure PCTCN2019121726-appb-000160
Figure PCTCN2019121726-appb-000161
Figure PCTCN2019121726-appb-000162
Figure PCTCN2019121726-appb-000163
Figure PCTCN2019121726-appb-000164
Figure PCTCN2019121726-appb-000165
实施例307：5-(4-((1-异丁基-5-(1-甲基-1H-吡唑-4-yl)-2-氧代-1,2-二氢吡啶-3-基)氨基)-3-甲基环己基)-2-吡啶甲酰胺(P-307)的制备
Figure PCTCN2019121726-appb-000166
步骤1：将5-(4-羰基环己基)吡啶-2-甲酸甲酯(800mg，3.43mmol)加入到四氢呋喃(30mL)中，在-78℃慢慢滴加双三甲基硅基胺基锂(1M in THF，4.12mL，4.12mmol)并搅拌1小时，然后在-78℃将碘甲烷(488mg，3.43mmol)加入到反应液中，并将反应液升到室温 搅拌18小时，待原料反应完全，将反应液中加入饱和氯化铵水溶液，然后用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过减压浓缩干，再通过HPLC制备得到白色固体产物5-(3-甲基-4-羰基环己基)吡啶-2-甲酸甲酯(47mg，6％)，MS(ESI)：248.1[M+H] +。
步骤2：将5-(3-甲基-4-羰基环己基)吡啶-2-甲酸甲酯(47mg，0.19mmol)和3-氨基-1-异丁基-5-(1-甲基-1H-吡唑-4-基)吡啶酮(31a)加入到1，4-二氧六环(5mL)和三氟乙酸(0.5mL)的混合溶液中，反应液在50℃搅拌0.5小时，然后将反应液冷却到室温，将三乙酰氧基硼氢化钠(121mg，0.57mmol)加入到反应液中并搅拌0.5小时，待原料反应完全，用饱和碳酸氢钠水溶液将反应液的pH调至8左右，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过减压浓缩干得到油状产物5-(4-((1-异丁基-5-(1-甲基-1H-吡唑-4-yl)-2-氧代-1,2-二氢吡啶-3-基)氨基)-3-甲基环己基)-2-吡啶甲酸甲酯(91mg，>100％)，MS(ESI)：478.2[M+H] +。
步骤3：将5-(4-((1-异丁基-5-(1-甲基-1H-吡唑-4-yl)-2-氧代-1,2-二氢吡啶-3-基)氨基)-3-甲基环己基)-2-吡啶甲酸甲酯(91mg，0.19mmol)加入到7M氨气(甲醇溶液，8mL)中，然后将反应液在55℃搅拌18小时，反应完毕，将反应液减压蒸干，通过高效液相制备(制备柱：21.2x250mm C18柱,体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：48％-53％乙腈变化)得到白色固体产物5-(4-((1-异丁基-5-(1-甲基-1H-吡唑-4-yl)-2-氧代-1,2-二氢吡啶-3-基)氨基)-3-甲基环己基)-2-吡啶甲酰胺(7.18mg，8％)，MS(ESI)：463.3[M+H] +； 1H NMR(400MHz,dmso)δ8.49(s,1H),8.02(s,1H),7.95(d,J＝5.6Hz,2H),7.83(d,J＝7.4Hz,1H),7.67(s,1H),7.54(s,1H),7.10(s,1H),6.51(s,1H),5.23(d,J＝8.9Hz,1H),3.79(s,3H),3.76–3.58(m,3H),2.80(s,1H),2.17–2.06(m,1H),1.96(d,J＝14.1Hz,2H),1.62(dd,J＝29.5,14.3Hz,3H),1.47(dd,J＝23.7,11.8Hz,2H),0.90(d,J＝6.6Hz,3H),0.84(d,J＝6.6Hz,6H)。
实施例308：5-((1s,4s)-4-((1-异丁基-5-(3-亚甲基-2-氧代吡咯烷-1-基)-2-氧代-1,2-二氢吡啶-3-基)氨基)环己基)吡啶-2-甲酰胺(P-308)的制备
Figure PCTCN2019121726-appb-000167
步骤1：将5-溴-2-甲氧基-3-硝基吡啶(11.6g，50mmol)，2-吡咯烷酮(5.1g，60mmol)，反-(1R,2R)-N,N'-二甲基1,2-环己烷二胺(0.71g，5mmol)，CuI(0.95g，5mmol)和碳酸钾(13.8g，100mmol)的1，4-二氧六环(150mL)溶液加热至回流并搅拌24小时，然后将反应液 过滤除去不溶物，滤液经过减压浓缩并通过柱层析纯化得到黄色固体产物1-(6-甲氧基-5-硝基吡啶-3-基)吡咯烷-2-酮(8.1g，68％)，MS(ESI)：238.1[M+H] +。
步骤2：将氢溴酸(70mL)加入到1-(6-甲氧基-5-硝基吡啶-3-基)吡咯烷-2-酮(8.1g，34.18mmol)的甲醇(70mL)溶液中，然后将反应液加热至70℃并搅拌3小时，待原料反应完全，将反应液经过减压浓缩得到油状的粗产物1-(6-羟基-5-硝基吡啶-3-基)吡咯烷-2-酮(21g，>100％)，MS(ESI)：224.1[M+H] +。
步骤3：将1-(6-羟基-5-硝基吡啶-3-基)吡咯烷-2-酮(18.8g，84.30mmol)，溴代异丁烷(34.4g，252.91mmol)和碳酸钾(58.2g，421.52mmol)的N,N-二甲基甲酰胺(200mL)溶液加热至100℃并搅拌6小时，然后将反应液倒入水(800mL)中，用乙酸乙酯(200mL×3)萃取，合并有机相，用饱和食盐水洗涤(200mL×4)，无水硫酸钠干燥，过滤，滤液经过减压浓缩并通过柱层析纯化得到油状的产物1-异丁基-3-硝基-5-(2-氧代吡咯烷-1-基)吡啶-2(1H)-酮(3.1g，33％)，MS(ESI)：280.1[M+H] +。
步骤4：将1-异丁基-3-硝基-5-(2-氧代吡咯烷-1-基)吡啶-2(1H)-酮(2.79g，10mmol)的四氢呋喃(10mL)溶液缓慢滴入氢化钠(60％，1.12mg，28mmol)的四氢呋喃(50mL)溶液中，然后继续滴加草酸二乙酯(2.92g，20mmol)，滴加完毕，反应液加热至回流搅拌18小时，待原料反应完毕，将反应液降至室温，将乙酸(1mL)加入并在室温搅拌1小时，反应液用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过减压浓缩并通过柱层析纯化得到油状的产物2-(1-(1-异丁基-5-硝基-6-氧代-1,6-二氢吡啶-3-基)-2-氧代吡咯烷-3-基)-2-氧代乙酸乙酯(210mg，6％)，MS(ESI)：380.2[M+H] +。
步骤5：将2-(1-(1-异丁基-5-硝基-6-氧代-1,6-二氢吡啶-3-基)-2-氧代吡咯烷-3-基)-2-氧代乙酸乙酯(150mg，0.40mmol)和二乙胺(87mg，1.19mmol)的四氢呋喃(10mL)和水(4mL)的混合溶液降温至0℃，然后缓慢滴加甲醛水溶液(36.5％，130mg，1.58mmol)，滴加完毕，反应液在室温搅拌4小时，待原料反应完毕，反应液用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过减压浓缩干得到粗产物1-异丁基-5-(3-亚甲基-2-氧代吡咯烷-1-基)-3-硝基吡啶酮(160mg，>100％)，MS(ESI)：292.1[M+H] +。
步骤6：将1-异丁基-5-(3-亚甲基-2-氧代吡咯烷-1-基)-3-硝基吡啶酮(160mg，0.55mmol)的四氢呋喃(8mL)和水(2mL)的混合溶液中加入铁粉(308mg，5.50mmol)和氯化铵(291mg，5.50mmol)。反应液回流搅拌1小时，待原料反应完毕，将反应液过滤除去不溶物，滤液用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过减压浓缩干得到粗产物3-氨基-1-异丁基-5-(3-亚甲基-2-吡咯烷酮-1-基)-2-吡啶酮(141mg，98％)，MS(ESI)：262.2[M+H] +。
步骤7：将3-氨基-1-异丁基-5-(3-亚甲基-2-吡咯烷酮-1-基)-2-吡啶酮(94mg，0.36mmol)和5-(4-环己酮)-2-吡啶甲酰胺(158mg，0.72mmol)加入到1，4-二氧六环(5mL)和三氟乙酸(0.5mL)的混合溶液中，反应液在室温搅拌1小时，然后将三乙酰氧基硼氢化钠(230mg，1.08mmol)加入到反应液中并搅拌1小时，待原料反应完全，用饱和碳酸氢钠水溶液将反应液的pH调至8左右，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经 过减压浓缩干，通过高效液相(制备柱：21.2x250mm C18柱,体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：48％-53％乙腈变化)制备得到白色固体产物P-308(6.75mg，>4％)，MS(ESI)：464.3[M+H] +。 1H NMR(400MHz,dmso)δ8.49(d,J＝1.6Hz,1H),8.02(s,1H),7.94(d,J＝8.1Hz,1H),7.83(dd,J＝8.1,2.0Hz,1H),7.55(s,1H),7.16(d,J＝2.3Hz,1H),6.79(d,J＝2.2Hz,1H),5.78(s,1H),5.37(d,J＝7.4Hz,2H),3.71(dd,J＝11.4,5.0Hz,4H),3.60(s,1H),2.87–2.69(m,3H),2.05(dd,J＝13.7,6.9Hz,1H),1.90(d,J＝9.9Hz,2H),1.66(d,J＝20.8Hz,6H),0.84(d,J＝6.7Hz,6H)。
测试例1 Hela细胞的抑制活性测试
96孔板培养Hela细胞，然后加入50ng/ml IFNγ，10μg/ml L-Try和不同浓度的化合物培养48hrs，取上清转入另一96孔板中，加入5μl 6.1N的三氯乙酸，50℃放置30mins，离心取上清，加入等体积的2％(w/v)对-二甲氨基苯甲醛的乙酸溶液显色，最后用酶标仪读取480nm吸光度，使用XLfit软件计算化合物IC50值。
表1 本发明示例化合物对Hela细胞的抑制活性
化合物编号 Hela/μM 化合物编号 Hela/μM
    P-13 0.285
P-14 0.024    
P-16 0.005 P-19 0.024
P-20 0.016 P-30 0.139
P-80 0.181 P-81 0.063
P-82 0.049 P-83 0.186
P-86 0.223 P-87 0.259
P-98 0.066 P-104 0.215
P-105 0.079    
P-111 0.210 P-112 0.182
P-113 0.128 P-114 0.101
P-117 0.078 P-118 0.047
P-119 0.085 P-120 0.168
P-124 0.083 P-125 0.085
P-127 0.024 P-129 0.043
P-130 0.044 P-131 0.018
P-132 0.037 P-134 0.109
P-136 0.086 P-137 0.021
P-138 0.321 P-140 0.109
P-142 0.082 P-144 0.099
P-146 0.060 P-147 0.086
P-150 0.057 P-151 0.035
P-152 0.035 P-153 0.050
P-156 0.052 P-157 0.087
P-159 0.086 P-161 0.063
P-162 0.026 P-167 0.062
P-168 0.030 P-170 0.037
P-172 0.031 P-174 0.092
P-176 0.026 P-181 0.357
P-182 0.026 P-183 0.108
P-185 0.196 P-186 0.085
P-189 0.094 P-192 0.009
P-214 0.148 P-193 0.105
P-194 0.135 P-197 0.014
P-198 0.262 P-200 0.013
P-202 0.119 P-203 0.010
P-205 0.133 P-208 0.145
P-209 0.125 P-250 0.003
P-259 0.007 P-260 0.102
P-261 0.088 P-263 0.009
P-264 0.006 P-266 0.139
P-267 0.053 P-268 0.007
P-269 0.012 P-270 0.032
P-271 0.014 P-272 0.054
P-273 0.098 P-275 0.017
P-278 0.094 P-279 0.011
P-280 0.012 P-281 0.083
P-282 0.132 P-283 0.008
P-285 0.040 P-286 0.014
P-287 0.009 P-288 0.010
P-289 0.026 P-291 0.028
P-292 0.091 P-293 0.101
P-294 0.046 P-296 0.070
P-297 0.012 P-298 0.009
P-299 0.085 P-300 0.142
P-301 0.080 P-303 0.070
P-304 0.064 P-305 0.084
P-306 0.013 P-307 0.007
P-308 0.011    
测试例2 HEK293-hIDO1细胞的抑制活性测试
将构建的稳转细胞系HEK293-hIDO1加入96孔板后，加入20μg/ml L-Try和不同浓度的化合物，培养48hrs后取上清加入另一96孔板中，再加入5μl 6.1N的三氯乙酸，50℃放置30mins，离心取上清，加入等体积的2％(w/v)对-二甲氨基苯甲醛的乙酸溶液显色，最后用酶标仪读取480nm吸光度，使用XLfit软件计算化合物IC50值。
表2 本发明示例化合物对HEK-293细胞的抑制活性
化合物编号 HEK-293/μM 化合物编号 HEK-293/μM
P-14 0.066 P-15 0.022
P-16 <0.005 P-19 0.043
P-20 0.055 P-30 0.634
P-80 0.308 P-81 0.325
P-82 0.159 P-117 0.279
P-118 0.136 P-124 0.134
P-125 0.123 P-127 0.215
P-129 0.067 P-130 0.098
P-131 0.023 P-132 0.043
P-136 0.229 P-137 0.152
P-146 0.163 P-151 0.068
P-152 0.113 P-153 0.138
P-156 0.167 P-159 0.242
P-162 0.052 P-167 0.143
P-168 0.078 P-172 0.049
P-174 0.147 P-176 0.051
P-182 0.088 P-186 0.039
P-192 0.016 P-193 0.193
P-197 0.018 P-200 0.019
P-202 0.222 P-203 0.013
P-305 0.237 P-306 0.049
P-250 0.006 P-259 0.082
P-263 0.043 P-264 0.020
P-268 0.042 P-269 0.065
P-270 0.235 P-271 0.062
P-272 0.179 P-275 0.104
P-279 0.040 P-280 0.061
P-283 0.037 P-285 0.256
P-286 0.035 P-287 0.023
P-288 0.024 P-289 0.153
P-291 0.136 P-292 0.220
P-294 0.194 P-297 0.015
P-298 0.016 P-307 0.009
P-308 0.058    
从表1和2可以看出，本发明示例化合物对Hela和HEK-293细胞具有较好的抑制活性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (27)

  1. 一种式(I)所示的化合物，或其药学上可接受的盐、立体异构体或溶剂化物：
    Figure PCTCN2019121726-appb-100001
    式中，
    A环为C 6-10芳环(优选为苯环)、C 3-8环烷基环(优选为C 3-6环烷基环)、8至10元双环杂芳基环、4至7元饱和或部分不饱和单杂环、螺环、螺杂环、桥环或桥杂环；
    R 0为氢、氰基、羟基、羧基、羟甲基、羟乙基、卤素、C 1-10烷基、-O(CH 2) p-C 1-10烷氧基、-(CH 2) t-NR aR b、-(CH 2) q-NR cS(O) 2NR aR b、-NR cC(O)C 1-10烷基、吡啶-2(1H)-酮、1-甲基吡啶-2(1H)-酮或-L 0-Y 0；其中L 0为一个键、O、(CR 01R 02) r、C(O)NR c、或NR 03，Y 0为C 6-10芳基、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环或苯并4至7元饱和或部分不饱和杂环；所述C 6-10芳基、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环、苯并4至7元饱和或部分不饱和杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、脒基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基、-CH(CH 3)C(O)NR aR b、-C(O)N(R c)-C 6-10芳基、-S(O) 2C 1-10烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-10烷基或-NR cS(O) 2NR aR b；
    m为1、2或3；
    L为一个键、O、NR c、C(R dR e)、-CH 2NR c-、-NHC(O)NH-、-CH 2NHC(O)NH-、-C(O)NH-、-NHC(O)-或-CH 2CH(OH)-；
    R 1为氢或-L 1-Y 1；其中L 1为(CR 11R 12) s；Y 1为羟基、氰基、羧基、卤素、C 1-10烷基、C 6-10芳基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基、C 3-8环烷基、C 1-10烷氧基；所述C 6-10芳基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基环、-S(O) 2C 1-10烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-10烷基或-NR cS(O) 2N R aR b；
    R 3为-L 3-Y 3；其中L 3为一个键、(CR 31R 32) t、O或NR 33；Y 3为氢、R 34、5至6元单环杂芳基、C 6-10芳基、4至7元饱和或部分不饱和单杂环或C 3-8环烷基；所述5至6元单环杂芳基、C 6-10芳基、4至7元饱和或部分不饱和单杂环为未取代的或被1、2或3个选自下组的取 代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基环、-S(O) 2C 1-10烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-10烷基或-NR cS(O) 2N R aR b；
    p、q、t、r、s各自独立地为0、1、2或3；
    R a、R b、R c各自独立地为氢、C 3-6环烷基或C 1-8烷基，或者R a、R b与连接的N原子共同形成4至7元饱和单杂环；
    R d、R e各自独立地为氢、羟基或C 1-8烷基；
    R 01、R 02各自独立地为氢、羟基或C 1-8烷基；
    R 03为氢或C 1-8烷基；
    R 11、R 12各自独立地为氢、羟基或C 1-8烷基；
    R 31、R 32各自独立地为氢、羟基或C 1-8烷基；
    R 33为氢或C 1-8烷基；
    R 34为式(a)、式(b)、式(c)或式(d)所示结构：
    Figure PCTCN2019121726-appb-100002
    式中R a’、R b’、R 35各自独立地为氢、C 3-6环烷基或C 1-8烷基；或者R 35为氢或C 1-8烷基，R a’、R b’与连接的N原子共同形成4至7元饱和单杂环；或者R a’为氢或C 1-8烷基，R 35、R b’与连接的氮和碳原子原子共同形成4至7元饱和单杂环；
    R 36、R 37各自独立地为氢或C 1-8烷基；或者R 37为氢或C 1-8烷基，R 36与L 3中的C或N原子共同形成式(b1)所示的环：
    Figure PCTCN2019121726-appb-100003
    或者R 36为氢或C 1-8烷基，R 37与L 3中的C或N原子共同形成式(b2)所示的环：
    Figure PCTCN2019121726-appb-100004
    R 38为氢或C 1-8烷基；
    其中L 31、L 32各自独立地为N或CH，y1、y2各自独立地为0、1、2或3；
    R 2、R 4各自独立地为氢、氰基、羟基、羟甲基、羟乙基、羧基、卤素、C 1-10烷基、卤代 C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基；
    R 5、R 6各自独立地为氢、羟基、C 1-10烷基或氧代基；或R 5、R 6与相连的碳原子共同形成3至7元饱和单杂环或3至7元饱和单环；
    n为0、1、2或3。
  2. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，R 3为-L 3-Y 3；其中L 3为一个键，Y 3为5元或6元单环杂芳基、C 6-10芳基、4至7元饱和或部分不饱和单杂环或C 3-8环烷基；所述5元或6元单环杂芳基、C 6-10芳基、4至7元饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基环、-S(O) 2C 1-10烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-10烷基或-NR cS(O) 2N R aR b。
  3. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，R 3为-L 3-Y 3；其中L 3为一个键，Y 3为5至6元单环杂芳基、苯基、6元饱和或部分不饱和单杂环或C 3-6环烷基；所述5至6元单环杂芳基、苯基、6元饱和或部分不饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、哌啶、哌嗪、吗啉、四氢吡喃、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基、-NR cS(O) 2N R aR b。
  4. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，R 3为-L 3-Y 3；其中L 3为(CR 31R 32) t或NR 33；Y 3为R 34。
  5. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，R 1为氢或-L 1-Y 1；其中L 1为(CR 11R 12) s，Y 1为羟基、氰基、羧基、卤素、C 1-10烷基、C 6-10芳基、4至7元饱和单杂环、C 3-8环烷基、C 1-10烷氧基；所述C 6-10芳基、4至7元饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基环、-S(O) 2C 1-10烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-10烷基或-NR cS(O) 2N R aR b；
    其中R 11、R 12各自独立地为氢、羟基或C 1-8烷基；s为0、1、2或3。
  6. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，R 1为氢或-L 1-Y 1；其中L 1为(CR 11R 12) s，Y 1为羟基、氰基、羧基、卤素、C 1-3烷基、苯基、4至7元饱和单杂环、C 3-6环烷基、C 1-3烷氧基；所述苯基、4至7元饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NHC(O)C 1-3烷基或-NHS(O) 2NR aR b。
    其中R 11、R 12各自独立地为氢、羟基或C 1-3烷基；s为0、1、2或3。
  7. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，R 0为氢、氰基、羟基、羧基、羟甲基、羟乙基、C 1-3烷基、-O(CH 2) p-C 1-3烷氧基、-(CH 2) t-NH 2、-(CH 2) t-N(CH 3) 2、-(CH 2) q-NHS(O) 2NH 2、-NR cC(O)C 1-3烷基、吡啶-2(1H)-酮、1-甲基吡啶-2(1H)-酮或-L 0-Y 0；其中L 0为一个键、O、(CR 01R 02) r或C(O)NR c，Y 0为苯基、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环或苯并4至7元饱和或部分不饱和杂环；所述苯基、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环、苯并4至7元饱和或部分不饱和杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、脒基、4至7元饱和单杂环、5至6元单环杂芳基、-CH(CH 3)C(O)NH 2、-C(O)NH-苯基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NHC(O)C 1-3烷基或-NHS(O) 2NR aR b。
  8. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，R 2、R 4各自独立地为氢、卤素、C 1-10烷基或C 1-10烷氧基。
  9. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，A环为苯环、环己基环、哌啶环、四氢吡喃环或螺杂环。
  10. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，
    Figure PCTCN2019121726-appb-100005
    为式(A)、式(B)或式(C)所示结构：
    Figure PCTCN2019121726-appb-100006
    式中，W 1为N或CR a3；W 2为一个键、O、NR a4或CR a5R a6；W 3为O、NR a7或CR a8R a9；W 4为CR a10R a11；W 5为O或CR a2R a12；
    v为0、1或2；
    R a0为氢、氰基、羟基、羧基、羟甲基、羟乙基、卤素、C 1-10烷基、-O(CH 2) p-C 1-10烷氧基、-(CH 2) t-NR aR b、-(CH 2) q-NR cS(O) 2NR aR b、-NR cC(O)C 1-10烷基、吡啶-2(1H)-酮、1-甲基吡啶-2(1H)-酮或-L 0-Y 0；其中L 0为一个键、O、(CR 01R 02) r、C(O)NR c、或NR 03；Y 0为C 6-10芳基、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环或苯并4至7元饱和或部分不饱和杂环；所述C 6-10芳基、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环、苯并4至7元饱和或部分不饱和杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、脒基、4至7元饱和或部分不饱和单杂环、5至6元单环杂芳基、-CH(CH 3)C(O)NR aR b、-C(O)N(R c)-C 6-10芳基、-S(O) 2C 1-10烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-10烷基或-NR cS(O) 2N R aR b；
    R a1、R a2、R a3、R a5、R a6、R a8、R a9、R a10、R a11、R a12各自独立地为氢或-(CH 2) u-L a；其中 L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a4、R a7各自独立地为氢或C 1-10烷基。
  11. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，A环为苯环；R 0为卤素或-O(CH 2) p-C 1-3烷氧基。
  12. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，L为O、NR c或C(R dR e)；n为0、1、2或3。
  13. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，L为NR c；n为0、1、2或3。
  14. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，L为C(R dR e)；n为0或1。
  15. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，式(I)化合物为式(Ⅱ)所示结构：
    Figure PCTCN2019121726-appb-100007
    式中，
    R 1为氢或-L 1-Y 1；其中L 1为(CR 11R 12) s；Y 1为羟基、氰基、羧基、卤素、C 1-3烷基、苯基、4至7元饱和单杂环、C 3-6环烷基、C 1-3烷氧基；所述苯基、4至7元饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NHC(O)C 1-3烷基或-NHS(O) 2NR aR b；
    R 2、R 4各自独立地为氢、氰基、羟基、羟甲基、羟乙基、羧基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基；
    R 3为-L 3-Y 3；其中L 3为一个键；Y 3为5至6元单环杂芳基、苯基、6元饱和或部分不饱和单杂环(优选为1,2,3,6-四氢吡啶或环己烯)或C 3-6环烷基；所述5至6元单环杂芳基、苯基、6元饱和或部分不饱和单杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、哌啶、哌嗪、吗啉、四氢吡喃、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NR cC(O)C 1-3烷基、-NR cS(O) 2NR aR b；
    或者L 3为(CR 31R 32) t或NR 33；Y 3为R 34；R 34为式(a)、式(b)、式(c)或式(d)所示结构：
    Figure PCTCN2019121726-appb-100008
    式中R a’、R b’、R 35各自独立地为氢、C 3-6环烷基或C 1-8烷基；或者R 35为氢或C 1-8烷基，R a’、R b’与连接的N原子共同形成4至7元饱和单杂环；或者R a’为氢或C 1-8烷基，R 35、R b’与连接的氮和碳原子原子共同形成4至7元饱和单杂环；
    R 36、R 37各自独立地为氢或C 1-8烷基，或者R 37为氢或C 1-8烷基；R 36与L 3中的C或N原子共同形成式(b1)所示的环：
    Figure PCTCN2019121726-appb-100009
    或者R 36为氢或C 1-8烷基；R 37与L 3中的C或N原子共同形成式(b2)所示的环：
    Figure PCTCN2019121726-appb-100010
    R 38为氢或C 1-8烷基；
    其中L 31、L 32各自独立地为N或CH，y1、y2各自独立地为0、1、2或3；
    R 31、R 32各自独立地为氢、羟基或C 1-8烷基；
    R 33为氢或C 1-8烷基；
    t为0、1、2或3；
    W 1为N或CR a3；W 2为一个键、O、NR a4或CR a5R a6；W 3为O、NR a7或CR a8R a9；W 4为CR a10R a11；W 5为O或CR a2R a12；
    v为0、1或2；
    R a0为氢、氰基、羟基、羧基、羟甲基、羟乙基、C 1-3烷基、-O(CH 2) p-C 1-3烷氧基、-(CH 2) t-NH 2、-(CH 2) t-N(CH 3) 2、-(CH 2) q-NHS(O) 2NH 2、-NR cC(O)C 1-3烷基、吡啶-2(1H)-酮、1-甲基吡啶-2(1H)-酮或-L 0-Y 0；其中L 0为一个键、O、(CR 01R 02) r或C(O)NR c，Y 0为苯基、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环或苯并4至7元饱和或部分不饱和杂环；所述苯基、5至6元单环杂芳基、8至10元双环杂芳基、4至7元饱和单杂环、苯并4至7元饱和或部分不饱和杂环为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、羟乙基、羧基、氧代基、卤素、C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、脒基、4至7元饱和单杂环、5至6元单环杂芳基、-CH(CH 3)C(O)NH 2、-C(O)NH-苯基、-S(O) 2C 1-3烷基、-S(O) 2NR aR b、-C(O)NR aR b、-NR aR b、-NHC(O)C 1-3烷基或-NHS(O) 2NR aR b；
    R a1、R a2、R a3、R a5、R a6、R a8、R a9、R a10、R a11、R a12各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；
    R a4、R a7各自独立地为氢或C 1-10烷基；
    p、q、t、r、s各自独立地为0、1、2或3；
    R a、R b、R c各自独立地为氢、C 3-6环烷基或C 1-8烷基，或者R a、R b与连接的N原子共同形成4至7元饱和单杂环；
    R 01、R 02各自独立地为氢、羟基或C 1-3烷基；
    R 11、R 12各自独立地为氢、羟基或C 1-3烷基。
    n为0、1、2或3。
  16. 如权利要求15所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，W 1为CR a3；W 2为一个键或CR a5R a6；W 3为O或NR a7；W 4为CR a10R a11；W 5为O或CR a2R a12；v为0或1；R a1、R a2、R a3、R a5、R a6、R a10、R a11、R a12各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a7为氢或C 1-10烷基。
  17. 如权利要求15所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，W 1为CR a3；W 2为一个键或CR a5R a6；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a1、R a2、R a3、R a5、R a6、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2。
  18. 如权利要求15所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，W 1为N或CR a3；W 2为一个键、O、NR a4或CR a5R a6；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a1、R a2、R a3、R a5、R a6、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a4为氢或C 1-10烷基。
  19. 如权利要求15所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，W 1为N或CR a3；W 2为一个键或CR a5R a6；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a1、R a2、R a3、R a5、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a6为氢。
  20. 如权利要求15所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，W 1为N或CR a3；W 2为一个键或CR a5R a6；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a1、R a3、R a5、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a2为氢或羟基；R a6为氢。
  21. 如权利要求15所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，W 1为CR a3；W 2为一个键、O或NR a4；W 3为CR a8R a9；W 4为CR a10R a11；W 5为CHR a2；v为0或1；R a1、R a2、R a3、R a8、R a9、R a10、R a11各自独立地为氢或-(CH 2) u-L a；其中L a为羟基、氰基、甲基、NH 2或-NR cS(O) 2NR aR b；u为0、1或2；R a4为氢或C 1-10烷基。
  22. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，式(I)化合物选自表A或表B的结构。
  23. 一种药物组合物，所述药物组合物包括权利要求1至22中任一项所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物；以及药学可接受的载体。
  24. 如权利要求1至22中任一项所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，或如权利要求23所述药物组合物在制备药物中的应用，所述药物用于抑制吲哚胺2,3-双加氧酶的活性或者用于抑制患者的免疫抑制。
  25. 一种调节吲哚胺2,3-双加氧酶活性的方法，包括将治疗有效剂量的权利要求1所述化合物、或其药学上可接受的盐、立体异构体或溶剂化物，或权利要求23所述药物组合物与吲哚胺2,3-双加氧酶接触。优选的，所述调节优选为抑制作用。
  26. 一种抑制患者的免疫抑制的方法，所述方法包括将治疗有效剂量的权利要求1所述化合物、或其药学上可接受的盐、立体异构体或溶剂化物，或权利要求23所述药物组合物给予患者。
  27. 一种治疗癌症的方法，该方法包括向患者施用治疗有效剂量的权利要求1所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其药学上可接受盐。
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