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WO2017198159A1 - Dérivé d'imidazole contenant un cycle de liaison - Google Patents

Dérivé d'imidazole contenant un cycle de liaison Download PDF

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Publication number
WO2017198159A1
WO2017198159A1 PCT/CN2017/084604 CN2017084604W WO2017198159A1 WO 2017198159 A1 WO2017198159 A1 WO 2017198159A1 CN 2017084604 W CN2017084604 W CN 2017084604W WO 2017198159 A1 WO2017198159 A1 WO 2017198159A1
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Prior art keywords
compound
group
alkyl
mmol
heteroaryl
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PCT/CN2017/084604
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English (en)
Chinese (zh)
Inventor
张贵民
王升兰
孙成宏
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鲁南制药集团股份有限公司
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Priority claimed from CN201610326530.4A external-priority patent/CN107383012B/zh
Priority claimed from CN201610510930.0A external-priority patent/CN107556316B/zh
Application filed by 鲁南制药集团股份有限公司 filed Critical 鲁南制药集团股份有限公司
Publication of WO2017198159A1 publication Critical patent/WO2017198159A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of medicines, in particular to an imidazole derivative containing a bridged ring, a preparation method thereof and use thereof.
  • Indoleamine 2,3-dioxygenase a monomeric enzyme containing heme, catalyzes the epoxidation of L-tryptophan to form kynurenine.
  • the high expression of indoleamine 2,3-dioxygenase results in local cell tryptophan depletion, which induces T cell arrest in the G1 phase, thereby inhibiting T cell proliferation.
  • indoleamine 2,3-dioxygenase-dependent tryptophan degradation leads to an increase in kynurenine levels and also induces oxygen free radical-mediated T cell apoptosis.
  • the up-regulation of dendritic cell guanamine 2,3-dioxygenase expression enhances local regulatory T cell (Treg)-mediated immunosuppression by degrading local tryptophan, promoting the body's tumor-specific antigen Peripheral immune tolerance.
  • Teg local regulatory T cell
  • Indoleamine 2,3-dioxygenase has become the most important small molecule regulatory target for anti-tumor immunotherapy.
  • indoleamine 2,3-dioxygenase is associated with many physiological processes in the human body.
  • Munn et al. revealed that the fetus was able to survive the pregnancy without being genotyped without being rejected because of placental
  • the somatic trophoblast cells synthesize indoleamine 2,3-dioxygenase, which inhibits the rejection of the fetus by maternal T cells through blood flow. They further implanted pregnant mice with a sustained-release capsule containing the indoleamine 2,3-dioxygenase inhibitor 1-methyltryptophan, and the embryo was repelled and aborted (Munn DH, Zhou M, Attwood) JT, et al.
  • Immune escape is one of the main biological mechanisms of tumorigenesis and metastasis, and has become an important factor affecting the therapeutic effect of cancer.
  • Indoleamine 2,3-dioxygenase as an immunomodulatory enzyme, can effectively inhibit T cell function, enhance Treg cell function, and induce NK cell dysfunction.
  • Tumor cells can use these organisms' inherent immune regulation mechanisms. Escape from the identification and killing of the immune system (Jia Yunwei, Wang Yu. Chinese Journal of Cancer Biotherapy, 2004, 21 (6): 693-7). In order to enable tumor patients to get the best benefit from treatment, it is imperative to rationally adjust the treatment strategy for tumor immune escape.
  • the indoleamine 2,3-dioxygenase inhibitor of the invention can effectively regulate the immune system of the patient, block the immune escape of the tumor cells, and has a good therapeutic effect on most spontaneous tumors. Based on the regulation of the immune system, the indoleamine 2,3-dioxygenase inhibitor of the present invention can treat tumors in addition to other diseases related to immunity such as chronic infection and AIDS.
  • Indoleamine 2,3-dioxygenase is also closely related to neurological diseases. It can lower the level of serotonin and cause mental illness such as depression and anxiety. It can also cause neurotoxic metabolism such as quinolinic acid in the brain. Accumulation of products, which is closely related to the occurrence of neurodegenerative diseases such as Alzheimer's disease. Indoleamine 2,3-dioxygenase affects brain function by at least two mechanisms: 1) by reducing the circulating tryptophan concentration by metabolizing tryptophan in the inflammatory response, thereby lowering serotonin levels , leading to depression; 2) catalyzing the metabolism of tryptophan in the kynurenine pathway to accumulate kynurenine and neurotoxic quinolinic acid. (Kong Linglei, Qu Chunxiang, Yang Qing. Chinese Journal of Pharmaceutical Chemistry, 2009, 19(2): 147-154).
  • the invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:
  • n takes 0 or 1 or 2 or 3;
  • n 3 takes 0 or 1 or 2;
  • R 0 is selected from the group consisting of OH, C(O)OH, amino, amide, aminoacyl, heteroaryl containing at least one N or O or S, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano , amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy substituted C1-6 alkoxy or containing at least one N or O or S Heteroaryl, substituted by halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy Carbonyl group, amino group substituted by C1-6 alkyl group, 2-8 membered heteroalkyl group, 3-12 membered heterocycloalkyl group, C1-6 alkoxy group, C3-12 cycloalkenyl group, aryl group, hetero
  • R 5-8 is a single bond linked to a benzene ring
  • R 00 , R 1 , R 2 , R 3 , R 4 , R 9 , and R 10 are each independently selected from H, NH 2 , halogen, CN, CX 3-s H s , OH, C(O)OH, C(O)H, alkenyl, alkynyl, sulfinylamino, sulfone, sulfoxide, nitro, alkanoyl, phosphate, ureido, carbonate , C1-6 alkyl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkoxy, C3-12 cycloalkenyl, C2-6 alkenyl, aryl, heteroaryl Base, amide group, aminoacyl group, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, hetero
  • R 5-8 forms a benzo structure with a benzene ring, and takes a C 3-12 cycloalkyl group, a C 3-12 cycloalkenyl group, a 3-12 membered heterocycloalkyl group, a 3-12 membered heterocycloalkenyl group, an aryl group, and a heteroaryl group.
  • Base by halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, 2-8 membered heteroalkyl, 3-12 membered heterocycloalkyl, C1-6 alkane An oxy, C3-12 cycloalkenyl substituted C3-12 cycloalkyl or C3-12 cycloalkenyl or 3-12 membered heterocycloalkyl or 3-12 membered heterocycloalkenyl or aryl or heteroaryl;
  • n 2 of R 5-8 is 0 or 1 or 2 or 3 or 4;
  • R 11 is a cycloalkane or a cyclic olefin having a bridged ring structure.
  • Each R is independently selected from the group consisting of H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, sulfonamido, sulfone, sulfoxide, nitro, Phosphate group, ureido group, carbonate group, C1-6 alkyl group, C3-12 cycloalkyl group, C3-12 cycloalkenyl group, C1-6 heteroalkyl group, C3-12 heterocycloalkyl group, aryl group, hetero Aryl, amide, aminoacyl, C1-6 alkyl or C1-6 substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl Alkoxy or aryl or heteroaryl, carbonyl substituted by halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, C3-12 cyclo
  • R is n 1 , n 1 is any integer between 0-14 (including the end value); s is 0 or 1 or 2; a is a double bond; the position of a is located on the ring r 1 Any position that is reasonable; the number of a is 0 or 1 or 2 or 3; when the number of a is 0, the valence bond of its corresponding position is a single bond; x and y are each independently selected from 0 or 1 or 2 or 3.
  • C 1 is linked to the alpha or beta position on ring r 1 .
  • R is selected from Wherein, A is selected from N, S, P, O; W is selected from C or S or P; the number of O is s, s is 0 or 1 or 2; and each of R 1 and R 3 is independently selected from hydrogen, Amino, nitro, carbonyl, fluorenyl, halogen, CN, CX 3-s H s , OH, C(O)OH, C(O)H, sulfonamido, sulfone, sulfoxide, nitro, Alkanoyl, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C2-6 alkenyl, 2-8 membered heteroalkyl, 3- 12-membered heterocycloalkyl, aryl, heteroaryl, amido, aminoacyl, halogen, oxo, hydroxy, carboxy, carbonyl, aldehyde,
  • the above R is selected from Where x is 0 or 1 or 2, y is 2 or 1 or 0; p is 1 or 2 or 3 or 4 or 5; q is 1 or 2 or 3 or 4; B is C or N or O or S, The number is 0 or 1 or 2, and its position is any one or two of the ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ positions on the ring; b is a double bond, and its number is 0 or 1 or 2; its position It is a reasonable position of the valence bond on the ring; when the number of b is 0, the valence key of the corresponding position is a single bond.
  • n 1 is any integer between 0 and 5 (inclusive); n 2 is 0 or 1 or 2 or 3.
  • R 11 is selected from Wherein R is simultaneously bonded to any two atoms of the ⁇ , ⁇ , ⁇ , and ⁇ positions on the ring r 1 to form a covalent bond ; n 1 is 0 or 1 or 2 or 3.
  • the above ring r 1 is selected from
  • the heteroaryl is selected from the group consisting of pyridine, pyrimidine, pyrazine, pyridazine, and triazine.
  • the C3-12 heterocyclic group is selected from the group consisting of furan, pyrrole, thiophene, pyridine, quinoline, indole, indole, benzimidazole, pyrroline, pyrrolidine, pyran, dioxane, dioxane Ring, pyrazole, imidazole, oxazole, thiazole, triazole, morpholine, piperidine, piperazine.
  • R 5-8 are each independently selected from the group consisting of: H, OH, C 1-6 alkyl, halo, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3- 12 cycloalkyl substituted C1-6 alkyl.
  • R 5-8 is selected from aryl, 3-8 membered heteroaryl containing at least one N or O or S, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-10 membered hetero a cyclic group wherein the aryl group, a 3-8 membered heteroaryl group containing at least one N or O or S, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, and a 3-10 membered heterocyclic group are each one or Multiple R 1 substitutions.
  • R 5-8 is selected from aryl, 5- or 6- or 7-membered heteroaryl containing at least one N or O or S, monocyclic C5-8 cycloalkyl, monocyclic C5-8 ring An alkenyl, five- or six-membered monocyclic heterocyclic group, or a (monocyclic C5-8 cycloalkyl) C1-6 alkyl group, wherein each of the above groups is optionally and independently substituted by one or more R 1 .
  • R 5-8 is selected from aryl or 5- or 6-membered heteroaryl containing at least one N or O or S, wherein each of the above groups is optionally substituted with one or two R 1 .
  • R 5-8 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyranyl, furyl, pyrrolyl, thienyl, pyridyl, quinolinyl, cyclopropane And cyclobutane, cyclopentyl, cyclohexane, cycloheptyl and the above groups are each optionally substituted by one or more R 1 and independently.
  • each R, R 1 -R 4 , R 5-8 , R 9 , R 10 are each independently selected from the group consisting of H, NH 2 , CN, methyl, ethyl, propyl, isopropyl, butyl.
  • the amino-substituted amino, amido, aminoacyl group may be selected from the group consisting of methylamino, ethylamino, propylamino, isopropylamino, 1-butylamino, isobutylamino, tert-butylamino, 1-pentylamino, 1-hexylamino, Ethylene oxide amino, cyclohexylamino, heterocyclic hydrochloride amino (azetidine dihydrochloride 3-amino), 2-cyclopentyloxyphenylamino, 2-(cyclopentyloxy) Amino, morpholin-4-amino, cyclopropenylamino, cyclobutadienyl-2-amino
  • the above carbonyl group is selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl.
  • the above acyl group is selected from the group consisting of formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, cyclopropylformyl, cyclopropylacetyl, cyclopropylpropanoyl, cyclic Butylformyl, cyclobutylacetyl, cyclobutylpropanoyl, cyclopentylformyl, cyclopentylacetyl, cyclopentylpropanoyl, cyclohexylcarbonyl, cyclohexylacetyl, cyclohexylpropanoyl.
  • the above alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2- Methyl butyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl , amylmethyl, pentylethyl, pentylpropyl, pentylbutyl, hexylmethyl, hexylethyl, hexylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropane Methyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl,
  • the alkoxy group is selected from the group consisting of N-morpholine methoxy, N-morpholine ethoxy, N-morpholinyloxypropyl, methoxy, ethoxy, propoxy, isopropoxy , butoxy, isobutoxy, tert-butoxy, pentyloxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclopropyl Oxyl, cyclopropylpropoxy, cyclobutylmethoxy, cyclobutylethoxy, cyclobutyloxy, cyclopentyloxy, cyclopentylethoxy, cyclopentyloxy, cyclohexyloxy Base, cyclohexyloxy, cyclohexyloxy.
  • the above alkylsulfone group is selected from the group consisting of: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, Tert-butylsulfonyl, pentylsulfone, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 2,2 - dimethyl propyl sulfone group, 1,2-dimethyl propyl sulfone group, 1-ethyl propyl sulfone group, hexyl sulfone group, amyl methyl sulfone group, pentyl ethyl sulfone group, pentyl ethyl
  • the alkanoyl group is selected from the group consisting of: formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, cyclopropylformyl, cyclopropylacetyl, cyclopropylpropionyl , cyclobutylformyl, cyclobutylacetyl, cyclobutylpropionyl, cyclopentylcarbonyl, cyclopentylacetyl, cyclopentylpropanoyl, cyclohexylcarbonyl, cyclohexylacetyl, cyclohexylpropanoyl.
  • the compound of formula I above is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • n takes 0 or 1 or 2 or 3;
  • C 1 and r 1 are linked to the ⁇ or ⁇ or ⁇ position
  • n 1 is 0 or 1 or 2 or 3;
  • n 2 takes 0 or 1 or 2 or 3;
  • n 3 takes 0 or 1 or 2;
  • the number of a is 0 or 1 or 2.
  • the above C 1 and r 1 rings are linked to the ⁇ position
  • the R and r 1 rings are linked to the ⁇ position
  • R 00 is H
  • substituents H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, heteroalkyl, alkenyl, alkynyl, heterocycloalkyl, sub Sulfonylamino, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenylaryl, heteroaryl, amide, aminoacyl, C1-6 alkyl or C3-12 cycloalkyl or C1-6 alkoxy substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl Or aryl or heteroaryl;
  • n is selected from an integer of 0-6;
  • L 00 is selected from the group consisting of H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, alkenyl, alkynyl, sulfonamido, nitro, phosphate, ureido , carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl C1-6 heteroalkyl, C3-12 heterocycloalkyl, aryl, heteroaryl, amide, ammonia
  • the above C 1 and r 1 rings are linked to the alpha position, and the R and r 1 rings are linked to the delta position, such as structural formula XXXIII.
  • the present invention provides a compound of the formula Y-I or a pharmaceutically acceptable salt thereof:
  • n takes 0 or 1 or 2 or 3;
  • r 1 is a bridged ring; C 1 and r 1 are linked to the ⁇ or ⁇ position;
  • n 0 takes 0 or 1 or 2;
  • n 3 takes 0 or 1 or 2;
  • a is a double bond; the position of a is at any position where the valence bond on r 1 is reasonable; the number of a is 0 or 1 or 2 or 3;
  • R is a substituent at any position where the valence bond on r 1 is reasonable; R is n 1 and n 1 is an integer between 0-14 (inclusive);
  • Each R is independently selected from the group consisting of the following single bond substituents: H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, sulfonamido, sulfone, sulfoxide, nitrate Base, phosphate group, ureido group, carbonate group, C1-6 alkyl group, C3-12 cycloalkyl group, C3-12 cycloalkenyl group, C1-6 heteroalkyl group, C3-12 heterocycloalkyl group, aryl group , heteroaryl, amide, aminoacyl, C1-6 alkyl or C1 substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl -6 alkoxy or aryl or heteroaryl, carbonyl substituted by halogen, cyano, amino, aryl, heteroaryl,
  • halogen is selected from the group consisting of F, Cl, Br, I;
  • R 1 to R 10 are each independently selected from the group consisting of H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, alkenyl, alkynyl, sulfinylamino, sulfone, sub Sulfone, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycloalkane Base, aryl, heteroaryl, amido, aminoacyl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl, C3-12 ring Alkenyl substituted C1-6 alkyl or C3-12 cycloalkyl or C1-6 alkoxy or aryl or heteroaryl, halogen, cyano, amino,
  • n 1 is 0, and R 1 to R 10 are each independently selected from the group consisting of H, NH 2 , halogen, CN, CF 3 , OH, sulfonamido, C 1-6 alkyl, C 3-12 cycloalkyl.
  • Each R is independently selected from any one or two of the following single bond substituents: H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, sulfene Amino group, sulfone group, sulfoxide group, nitro group, phosphate group, ureido group, carbonate group, C1-6 alkyl group, C3-12 cycloalkyl group, C3-12 cycloalkenyl group, C1-6 heteroalkyl group, C3-12 heterocycloalkyl, aryl, heteroaryl, amido, aminoacyl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 naphthenic A substituted C1-6 alkyl or C1-6 alkoxy or aryl or heteroaryl.
  • the heteroaryl group of formula Y-I is selected from the group consisting of pyridine, pyrimidine, pyrazine, pyridazine, triazine.
  • the C3-12 heterocyclic group of formula YI is selected from the group consisting of furan, pyrrole, thiophene, pyridine, quinoline, indole, indole, benzimidazole, pyrroline, pyrrolidine, pyran, dioxane , dioxane, pyrazole, imidazole, oxazole, thiazole, triazole, morpholine, piperidine, piperazine.
  • the number of substitutions or substituents not mentioned in the present invention is 0, and the default is the condition that the valence bond is reached by H.
  • n 1 is 0, R 1 to R 4 and R 10 are H, and the structural formula is as in the formula Y-III:
  • R 5 to R 9 are each independently selected from the group consisting of H, NH 2 , halogen, CN, CF 3 , OH, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 1-6 heteroalkyl , C3-12 heterocycloalkyl, aryl, heteroaryl, amido, aminoacyl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 a cycloalkyl, C3-12 cycloalkenyl substituted C1-6 alkyl or C3-12 cycloalkyl or C1-6 alkoxy or aryl or heteroaryl, halogen, cyano, amino, aryl, Heteroaryl, C1-6 alkyl, C3-12 cycloalkyl substituted carbonyl, amino substituted by C1-6 alkyl, C3-12 cycloalkyl, C3-12 cyclo
  • the present invention provides a compound of the formula S-I or a pharmaceutically acceptable salt thereof:
  • SR 1 is selected from the group consisting of CN, OH, C(O)OH, C(O)H, an amide group, an aminoacyl group, a heteroaryl group containing at least one N or O or S, and a halogen, a hydroxyl group, a carboxyl group, a carbonyl group, Aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl substituted C1-6 alkoxy or heteroaryl containing at least one N or O or S, by hydroxy, carboxy, carbonyl, Aldehyde, cyano, amino substituted C1-6 alkyl or C3-6 cycloalkyl or aryl or heteroaryl, halo, cyano, amino, aryl, heteroaryl, C1-6 alkyl, a C3-12 cycloalkyl-substituted carbonyl group, an amino group substituted with a C1-6 alkyl group, a C3-12 cycloal
  • n is selected from an integer of 0-6;
  • SR 2 , R 3 to R 8 , SR 9 , SR 10 , SR 11 , L 00 are each independently selected from H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, Alkenyl, alkynyl, sulfonamido, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkane , C3-12 heterocycloalkyl, aryl, heteroaryl, amido, aminoacyl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 a cycloalkyl-substituted C1-6 alkyl or C3-12 cycloalkyl or C3-12 cycloalkenyl or C1-6 alkoxy or aryl or hetero
  • SR 2 , SR 9 , SR 10 , SR 11 are each independently selected from H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, C1-6 alkyl, C3-12 Cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycloalkyl, aryl, heteroaryl, amide, aminoacyl, halogen, hydroxy, carboxy, carbonyl, aldehyde , cyano, amino, aryl, heteroaryl, C 3-12 cycloalkyl substituted C 1-6 alkyl or C 3-12 cycloalkyl or C 1-6 alkoxy or aryl or heteroaryl.
  • L 00 is independently selected from the group consisting of H, NH 2 , OH, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 1-6 heteroalkyl, C 3-12 heterocycloalkyl, aryl , heteroaryl, amido, aminoacyl, C1-6 alkyl or C3 substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl -12 cycloalkyl or C1-6 alkoxy or aryl or heteroaryl.
  • Each R is independently selected from any one or two of the following single bond substituents: H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, sulfene Amino, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycloalkyl , aryl, heteroaryl, amido, aminoacyl, C1-6 alkane substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl Or a C1-6 alkoxy group or an aryl or heteroaryl group.
  • R 1 in formula SI is selected from the group consisting of OH, C(O)OH, C(O)H, an amide group, a heteroaryl group containing at least one N or O or S, and a hydroxyl group, an amino group, an aryl group, Carboxyl-substituted C1-6 alkyl or C1-6 cycloalkyl or aryl or heteroaryl, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, aryl, heteroaryl Substituted amino, amide, aminoacyl.
  • SR 1 in formula SI is selected from the group consisting of OH, C(O)OH, C(O)H, an amide group, a heteroaryl group containing at least one N or O or S, and a hydroxyl group, an amino group, an aryl group. a carboxy-substituted C1-6 alkyl group or a C1-6 cycloalkyl group or an aryl or heteroaryl group, a C1-6 alkyl group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group, an aryl group, a heteroaryl group A substituted amino group or an amide group.
  • SR 1 in formula SI is selected from the group consisting of OH, C(O)OH, an amino group, a carboxyl group, a heteroaryl group containing at least one N or O or S, and a C1-6 alkane substituted with a hydroxyl group, an amino group, or a carboxyl group. base.
  • SR 1 in formula SI is selected from OH.
  • substituents H, OH, C(O)H, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycle Alkyl, aryl, heteroaryl, C1-6 alkyl or C 3 substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl -12 cycloalkyl or aryl or heteroaryl.
  • the heteroaryl group of formula S-I is selected from the group consisting of pyridine, pyrimidine, pyran, pyridazine, triazine, pyran.
  • the C3-12 heterocyclic group in formula SI is selected from the group consisting of furan, pyrrole, thiophene, pyridine, quinoline, indole, indole, benzimidazole, furan, pyrroline, dioxane, dioxane Ring, pyrazole, imidazole, oxazole, thiazole, piperidine, triazole, morpholine, piperidine, piperazine.
  • the number of substitutions or substituents not mentioned in the present invention is 0, and the default is the condition that the valence bond is reached by H.
  • L 0 is selected from the group consisting of H, NH 2 , C1-6 heteroalkyl, C 3-12 heterocycloalkyl, ureido, C 1-10 alkyl, C 3-12 cycloalkyl, aryl, heteroaryl, Halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl substituted C1-6 alkyl or aryl or heteroaryl; hetero atom taken O, N Or S.
  • the structure is as follows:
  • R 2 is independently selected from the group consisting of H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C ( O) H, sulfonamido, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycloalkyl, aryl, heteroaryl, amido, aminoacyl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 naphthenic a substituted C1-6 alkyl group or a C3-12 cycloalkyl group or a C1-6 alkoxy group or an aryl or heteroaryl group, which is halogen, cyano, amino, aryl,
  • SR 2 When SR 2 is taken with or without a substituted aryl, heteroaryl, C1-6 cycloalkyl group, SR 2 is a single bond or a side chain linked to the bare ring; the parallel link means two atoms are shared. And a covalent bond between the two atoms;
  • p is 1 or 2 or 3 or 4 or 5;
  • the hetero atom B is N or O or S, the number of which is 0 or 1 or 2, and its position is any of the ⁇ , ⁇ , ⁇ , ⁇ and ⁇ positions on the ring.
  • b is a double bond, the number of which takes 0 or 1 or 2, and its position is any position where the valence bond on the ring is reasonable.
  • A is N, and N is replaced by a L 00 , and the structural formula is as follows:
  • L 0 and L 00 are each independently selected from the following single bond substituents: H, OH, C(O)OH, C(O)H, carbonate group, C1-6 alkyl group, C3-12 cycloalkyl group, C3- 12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycloalkyl, aryl, heteroaryl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl , C 3-12 cycloalkyl substituted C 1-6 alkyl or C 1-6 alkoxy or aryl or heteroaryl;
  • L 00 is selected from H, NH 2 , halogen, CN, CF 3 , OH, C (O OH, C(O)H, C1-6 heteroalkyl, C3-12 heterocycloalkyl, C1-6 alkyl, C3-12 cycloalkyl, aryl, heteroaryl, amido, aminoacyl,
  • R 1 is a hydroxyl group
  • R 2 on the same carbon atom as R 1 is hydrogen
  • L 0 in the formula S-II is hydrogen
  • the structural formula is respectively S. -VI, formula S-VII, formula S-IX:
  • Each R is independently selected from any one or more of the following single bond substituents: H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, sulfene Amino, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, C1-6 heteroalkyl, C3-12 heterocycloalkyl , aryl, heteroaryl, amido, aminoacyl, C1-6 alkane substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl Or a C1-6 alkoxy group or an aryl or heteroaryl group.
  • A is N
  • L 0 is (R) y H x-1
  • the structural formula is formula S-VIII: x takes 1 or 2, and y takes 1 or 2.
  • L 1 and L 2 are independently selected from the group consisting of H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, C1-6 heteroalkyl, C3-12 heterocycloalkane.
  • Base sulfonamido, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkenyl, aryl, heteroaryl, amide , aminoacyl, C1-6 alkyl or C1-6 alkoxy or aryl substituted by halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl Or a heteroaryl group, a carbonyl group substituted by halogen, cyano, amino, aryl, heteroaryl, C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkyl, C3-12 cycloalkyl , C 3-12 cycloalkenyl, aryl, heteroaryl substituted amino, amide, aminoacyl;
  • R 12 is selected from aryl, heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-10 membered heterocyclic or C3-8 cycloalkyl C1-6 alkyl, wherein aryl, Heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-10 membered heterocyclyl and C3-8 cycloalkyl C1-6 alkyl are each optionally and independently employed by one or more L 1 Replace
  • L 1 and L 2 in the formula SX are each independently selected from the group consisting of: H, OH, C 1-6 alkyl, and are halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl. a C3-12 cycloalkyl substituted C1-6 alkyl group; m is 0 or 1 or 2; R 12 is Where b is a double bond, the position of b is a reasonable position of any valence bond on the ring, and the number of b is 0 or 1 or 2 or 3. When the number of b is 0, the valence bond of the corresponding position is a single bond.
  • Z is selected from N or O or S, the position of Z is a reasonable position of any valence bond on the ring; p is selected from 0 or 1 or 2 or 3; the position of L 1 is a reasonable position of any valence bond on the ring; R 12 As a substituent group, the substitution position is on an atom of a reasonable valence bond on the ring.
  • R 12 in formula S-VIII is selected from phenyl, C3-8 membered heteroaryl containing at least one N or O or S, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3 a 10-membered heterocyclic group wherein the phenyl group has a C3-8 membered heteroaryl group containing at least one N or O or S, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, and a 3-10 membered heterocyclic group. Each is replaced by one or more L 1 .
  • R 12 in formula SX is phenyl, five- or six- or seven-membered heteroaryl containing at least one N or O or S, monocyclic C5-8 cycloalkyl, monocyclic C5-8 a cycloalkenyl, five- or six-membered monocyclic heterocyclic group, or a (monocyclic C5-8 cycloalkyl) C1-6 alkyl group, wherein each of the above groups is optionally and independently selected by one or more L 1 Replace.
  • R 12 in formula SX is phenyl or a five or six membered heteroaryl group containing at least one N or O or S, wherein each of the above groups is optionally substituted with one or two L 1 .
  • R 12 in formula SX is selected from the group consisting of a benzene ring, a pyridine ring, a pyrimidine ring, a pyran ring, a furan ring, a pyrrole ring, a thiophene ring, a pyridine ring, a quinoline ring, a ring.
  • Propane, cyclobutane, cyclopentyl, cyclohexane, cycloheptyl and the above groups are each optionally substituted by one or more L 1 and independently.
  • R 12 is a benzene ring having a substituent such as the formula S-IX:
  • L 3 to L 7 are selected from the group consisting of H, NH 2 , halogen, CN, CF 3 , OH, C(O)OH, C(O)H, C1-6 heteroalkyl, C3-12 heterocycloalkyl, Sulfonylamino, nitro, phosphate, ureido, carbonate, C1-6 alkyl, C3-12 cycloalkyl, aryl, heteroaryl, amide, aminoacyl, halogen, hydroxy, Carboxyl, carbonyl, aldehyde, cyano, amino, aryl, heteroaryl, C3-12 cycloalkyl substituted C1-6 alkyl or C1-6 alkoxy or aryl or heteroaryl, by halogen, Cyano, amino, aryl, heteroaryl, C1-6 alkyl, C3-12 cycloalkyl substituted carbonyl, C1-6 alkyl, C3-12 cycloalkyl, C3-12 cycloalkeny
  • SR 2 , R3 to R8, SR 9 , SR 10 and R 11 are all hydrogen, as in the formula S-XII:
  • m is selected from 0 or 1 or 2;
  • L 1 and L 2 are each independently selected from: H, OH, aryl, heteroaryl, halogen, hydroxy, carboxy, carbonyl, aldehyde, cyano, amino, aryl, a heteroaryl group, a C3-12 cycloalkyl-substituted aryl group or a heteroaryl group or a cycloalkyl group;
  • L 3 to L 7 are each independently selected from the group consisting of: H, OH, C 1-6 alkyl, heteroaryl, by halogen, Hydroxy, carboxyl, carbonyl, aldehyde, cyano, amino, C1-6 alkyl, aryl, heteroaryl, C3-12 cycloalkyl substituted aryl or heteroaryl or alkyl.
  • each substituent in the formula TM-IX has the same definitions as the formula I and the formula IX, and the specific steps are as follows:
  • the chloride is at least one selected from the group consisting of phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene chloride, thionyl chloride, trimethylchlorosilane, ⁇ , ⁇ , ⁇ -trichlorotoluene;
  • the base is an organic base, and in some embodiments is selected as N,N-diisopropylethylamine (DIPEA), diethylamine (DEA) or triethylamine (TEA).
  • DIPEA N,N-diisopropylethylamine
  • DEA diethylamine
  • TAA triethylamine
  • the base is selected from the group consisting of alkyl lithium, cycloalkyl lithium or aryl lithium; further selected from the group consisting of methyl lithium, ethyl lithium, propyl lithium, isopropyl lithium, n-Butyllithium, sec-butyllithium, tert-butyllithium, pentyllithium, hexyllithium, cyclohexyllithium, tert-octyllithium, n-icosyllithium, phenyllithium, methylphenyllithium, butyl Phenyllithium, naphthyllithium, butylcyclohexyllithium; further selected from n-butyllithium, t-butyllithium or hexyllithium; the solvent of the base is at least one selected from the group consisting of hexane, petroleum ether, benzene, toluene or xylene ;
  • R 4 is H;
  • the strong base is selected from the group consisting of lithium metal alkyl compounds, aromatic alkali metal compounds, aromatic alkyl alkali metal compounds, amine lithium compounds, alkali metal hydrides, alkali metal salts of fatty alcohols; further selected from NaH , Ph 3 CNa, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium t-butoxide; alkyl butyl lithium, phenyl lithium; lithium diisopropylamide (LDA), lithium hexamethyldisilazide LiHMDS);
  • LDA lithium diisopropylamide
  • M5 is ringed in the presence of an acid, deprotected to obtain M6;
  • the acid is selected from the group consisting of alkyd, aromatic acid, enoic acid, saturated fatty acid, phenol; further selected from the group consisting of acetic acid, propionic acid, butyric acid, glycolic acid, lactic acid, benzoic acid, phenylacetic acid, acrylic acid, oleic acid, citric acid, Oxalic acid, malonic acid, succinic acid;
  • M6 is reduced with a reducing agent to obtain the target compound XI;
  • the reducing agent is preferably at least one of NaBH 4 , KBH 4 , NaBH 4 /LiCl;
  • the method provided by the present invention is only one way to achieve a synthetic TM-IX compound, wherein the M6, M5, M4, M3, and M2 are independent and are not limited to the method of the present invention.
  • the present invention provides a method for synthesizing the above compound of formula II, the steps are as follows:
  • Compound Z-5 is reduced with a reducing agent to obtain the target compound II;
  • the reducing agent is selected from the group consisting of NaBH 4 , KBH 4 or NaBH 4 /LiCl.
  • the acid is selected from the group consisting of alkyd, aromatic acid, enoic acid, saturated fatty acid, phenol; further said acid is selected from the group consisting of acetic acid, propionic acid, butyric acid, glycolic acid, lactic acid, benzoic acid, phenylacetic acid, acrylic acid , oleic acid, citric acid, oxalic acid, malonic acid, succinic acid;
  • the ring-forming reaction is carried out under heating; preferably, the reaction heating temperature is 50 to 95 °C.
  • the present invention provides a method for synthesizing the above compound of formula II, the steps are as follows:
  • the number of a is 1, and the position is in the meta position of ⁇ .
  • the present invention provides a method for synthesizing the above compound Z-5.
  • the C 1 and r 1 rings are linked to the ⁇ position, and the synthesis step of the compound Z-4 is as follows:
  • the organic base is selected from the group consisting of lithium metal alkyl compounds, aromatic alkali metal compounds, aromatic alkyl alkali metal compounds, amine lithium compounds, alkali metal hydrides, alkali metal salts of fatty alcohols; further selected from NaH, Ph 3 CNa, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium t-butoxide, butyl lithium, phenyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS).
  • LiHMDS lithium hexamethyldisilazide
  • the present invention provides a method for synthesizing the above compound of formula I, wherein the C 1 and r 1 rings in the compound Z-4 are linked to the ⁇ position, and the synthesis step of the compound Z-4 is as follows:
  • the strong base is selected from the group consisting of tC 4 H 9 OK, NaH, Ph 3 CNa, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium t-butoxide; lithium metal alkyl compound, butyl lithium, phenyl Lithium; an amine lithium compound, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS).
  • LDA lithium diisopropylamide
  • LiHMDS lithium hexamethyldisilazide
  • the invention provides a method for synthesizing compound Z-3, and the synthetic steps of compound Z-3 are as follows:
  • the invention provides a method for synthesizing the compound M3, and the synthetic steps of the compound M3 are as follows:
  • the invention provides a method for synthesizing the compound M3, and the synthesis steps are as follows:
  • the chloride is at least one selected from the group consisting of phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosgene, thionyl chloride, trimethylchlorosilane, and ⁇ , ⁇ , ⁇ -trichlorotoluene. .
  • the invention provides a method for synthesizing compound Z-2, wherein the synthesis step of compound Z-2 when n 3 is 0 is as follows:
  • Compound Z-2-x compound 1a is reacted with the compound Z-2-1, said R a is selected from H, boric acid, alkenyl boronic acid group or boronate group; said ligand is selected from R b PPh 3 , AsPh 3 , n-Bu 3 P, (MeO) 3 P, Ph 2 P(CH 2 ) 2 PPh 2 , Ph 2 P(CH 2 ) 3 PPh 2 ; the X is selected from Cl, Br, I, a triflate group;
  • the base is selected from the group consisting of potassium carbonate, cesium carbonate, sodium t-butoxide, potassium acetate, potassium phosphate, cesium hydroxide, cesium carbonate;
  • the reaction temperature is preferably from 70 to 95 °C.
  • the present invention also provides a method for synthesizing the compound Z-2, wherein the synthesis step of the compound Z-2 when n 3 is 1 or 2 is as follows:
  • the present invention provides the above compounds The synthesis method, wherein each substituent of the formula TM-X 0 is selected as the formula 1 and the formula X (wherein R 3 is selected as Boc-), the specific steps are as follows:
  • the base is selected from the group consisting of alkyl lithium, cycloalkyl lithium or aryl lithium;
  • the solvent of the base is at least one selected from the group consisting of hexane, petroleum ether, benzene, toluene or xylene;
  • R 4 take H; strong base selected tC 4 H 9 OK, NaH, KH, Ph 3 CNa, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium t-butoxide, metallic lithium alkyl compound, an amine compound of lithium;
  • the lithium metal alkyl compound is butyl lithium or phenyl lithium; preferably the amine lithium compound is diisopropylamino lithium (LDA) or hexamethyldisilazide lithium (LiHMDS);
  • the acid is selected from the group consisting of alkyd, aromatic acid, enoic acid, saturated fatty acid, phenol;
  • acetic acid propionic acid, butyric acid, glycolic acid, lactic acid, benzoic acid, phenylacetic acid, acrylic acid, oleic acid, citric acid, oxalic acid, malonic acid, succinic acid;
  • the reducing agent is NaBH 4 , KBH 4 , NaBH 4 /LiCl.
  • the present invention provides the above compounds a method for synthesizing, wherein each substituent of the formula TM-X 1 is selected as in Formula 1 and Formula X (R 3 in the formula X); the synthesis step is as follows: the compound TM-X 0 is reduced with a reducing agent to obtain a target compound TM-X 1 ;
  • the acid is preferably at least one selected from the group consisting of hydrochloric acid, hydrobromic acid, and sulfuric acid.
  • the invention provides a compound
  • the synthetic method, the steps are as follows:
  • the reducing agent is NaBH 4 , KBH 4 , NaBH 4 /LiCl.
  • Compound 1 is reacted with triphosgene (triphosgene) under basic conditions to obtain compound 1;
  • the base is selected from trialkylamine; specifically, at least one selected from the group consisting of trimethylamine, triethylamine, and tripropylamine;
  • the solvent selected for each step of the above or below of the present invention is a conventional solvent in the art, and the selection principle is to dissolve the reactant but not participate in the reaction, extract the product or separate the corresponding product in the crystal and the impurity.
  • the numbers M1 and M11 used in the present invention are numbers for convenience of describing the general formula, and they may be modified into other numbers in the specific embodiment, such as 1, 2, 3, etc., for convenience of description, without affecting the structural formula.
  • the essence of the reaction equation is the expression of the general formula and the general reaction equation. Those skilled in the art will be able to determine that the substituents of each of the intermediates in all of the above synthetic routes are based on the structure of the target compound.
  • the solvent selected for each step of the above or below of the present invention is a conventional solvent in the art, and the selection principle is to dissolve the reactant but not participate in the reaction, extract the product or separate the corresponding product in the crystal and the impurity.
  • the termination of the reaction may be carried out by adding a substance which can react with an excess of the reactants. If any of the examples can be quenched with water or with saturated ammonium chloride.
  • the purification of the product in each step of the reaction is selected from the group consisting of extraction, crystallization, solvent removal, column chromatography; the operations are all conventional techniques in the art, and the prior art Personnel can handle it on a case-by-case basis.
  • the general formula of the present invention and the synthetic method of the general formula can be derived from specific compounds which are not limited to these specific substances, and can be obtained by those skilled in the art without the need of creative labor under the guidance of the general formula and the synthetic method of the general formula of the present invention. All are within the scope of the invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound, i.e., I, II, YI, YII, SI to S-XII, and the like, and a compound thereof, and a specific substance thereof, or a pharmaceutically acceptable salt thereof, and One or more pharmaceutically acceptable pharmaceutical excipients.
  • the application provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions include, but are not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal administration dosage forms.
  • the composition may be in the form of a liquid, solid, semi-solid, gel or aerosol.
  • the pharmaceutical composition may be an oral tablet, a capsule, a pill, a powder, a sustained release preparation, a solution and a suspension, a sterile solution, suspension or emulsion for parenteral injection.
  • the pharmaceutical composition is in a unit dosage form suitable for single administration of precise dosages.
  • the amount of the compound ranges from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day. In other embodiments, the amount of the compound ranges from about 0.5 mg/kg body weight/day to about 50 mg/kg body weight/day. In some embodiments, the amount of the compound is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound is from about 0.005 g/day to about 5 g/day.
  • the amount of the compound is from about 0.01 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound is from about 0.1 g/day to about 1 g/day. In other embodiments, a dose level below the lower limit of the above range may already be sufficient. In other embodiments, dose levels above the upper limit of the above range may be required. In some embodiments, the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses more than once a day.
  • the compound is administered twice daily. In other embodiments, the compound is administered three times a day. In other embodiments, the compound is administered four times a day. In other embodiments, the compound is administered more than four times a day.
  • the individual to which the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human.
  • the present invention provides the use of all of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof for the preparation of a medicament for treating a tryptophan mediated by indoleamine 2,3-dioxygenase A pathological feature of the acid metabolism pathway.
  • the mediation is, for example, the down-regulation of the expression of the indoleamine 2,3-dioxygenase.
  • the present invention provides the use of all of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof for the preparation of a guanamine 2,3-dioxygenase inhibitor.
  • the present invention provides all of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, as a guanamine 2,3-dioxygenase inhibitor; or a therapeutic thereof having a guanamine 2,3- A disease characterized by the pathology of a dioxygenase-mediated tryptophan metabolism pathway.
  • the mediation is, for example, the down-regulation of the expression of the indoleamine 2,3-dioxygenase.
  • the present invention provides a method for inhibiting indoleamine 2,3-dioxygenase by using all of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof.
  • the method includes a method of inhibiting indoleamine 2,3-dioxygenase in vivo and in vitro. Also provided are methods of treating all of the above compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for treating pathological features of the indoleamine 2,3-dioxygenase-mediated tryptophan metabolic pathway.
  • Pathological features of the indoleamine 2,3-dioxygenase-mediated tryptophan metabolism pathway of the present invention include cancer, infectious diseases, neurodegenerative diseases, depression, anxiety or age-related Cataract
  • the cancer is selected from the group consisting of lung cancer, liver cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, renal cancer, head and neck cancer, lymphoma, melanoma or leukemia;
  • the neurodegenerative disease refers to Alzheimer's syndrome
  • the infectious disease refers to an infection caused by bacteria, fungi, viruses or parasites.
  • the activity test results show that the compound obtained by the present invention has excellent enzyme inhibitory activity.
  • compound S-1 is significantly more active than compound S-20 in comparison to its structurally similar compound S-20.
  • Indoleamine 2,3-dioxygenase inhibitor can significantly reduce the side effects of drugs when used in tumor treatment, and significantly improve the quality of life of mice. It can not only improve the quality of life of patients, but also greatly improve patients. Medication compliance and drug effectiveness.
  • the cyclophosphamide and each compound in the present invention were compared before and after administration, and the results showed that each compound in the present invention can significantly promote the growth of the body weight, the amount and the model of the animal compared with the cyclophosphamide. There was no significant difference in the group comparison.
  • the compound of the invention can significantly improve the learning and memory damage of the animal, improve the learning acquisition ability and the spatial memory ability, and has positive therapeutic significance for neurodegenerative diseases such as Alzheimer's syndrome.
  • the compound of the present invention can promote the action of DC-stimulated T cell proliferation, and can be used for the treatment of tumor diseases, autoimmune diseases, transplant rejection, and infectious diseases.
  • Absolute bioavailability measurement results show that each compound in the present invention has high bioavailability, and has obvious advantages compared with compound S-21 and compound 1505, and compound 103 is bioavailable compared with its structural analog 1505. The degree is significantly higher than compound 1505.
  • the indoleamine 2,3-dioxygenase inhibitor of the present invention is used in the preparation of a medicament for treating a pathological characteristic disease having a tryptophan 2,3-dioxygenase-mediated tryptophan metabolic pathway
  • the compound of the present invention is a guanamine 2,3-dioxygenase inhibitor, which inhibits the immunity of the body by inhibiting the proliferation inhibition of T cells by inhibiting the activity of the indoleamine 2,3-dioxygenase. Function, thus completing the monitoring and killing effect of the human immune system on tumor cells. Based on this special mechanism of action, this compound does not adversely affect the growth of normal cells of the human body while inhibiting the growth of tumor cells, thus significantly reducing the side effects of the drug. Moreover, it has a significant therapeutic effect on autoimmune diseases, transplant rejection, and infectious diseases associated with T cell proliferation.
  • Alzheimer's and other neurodegenerative diseases are effective, which can significantly improve the learning and memory impairment of animals, and significantly improve the ability of learning and spatial memory.
  • the manufacturer's instructions for use of the kit can be utilized, or the reaction can be carried out and purified according to methods well known in the art or as described in the present application.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
  • the group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • CH 2 O is equivalent to OCH 2 .
  • alkyl as used herein includes an optionally substituted alkyl group.
  • compound is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes.
  • the compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compounds of the present application containing asymmetrically substituted carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent.
  • the compounds of the present application also include tautomeric forms.
  • the tautomeric form is derived from the exchange of a single bond with an adjacent double bond and accompanied by a proton transfer.
  • the compounds of the present application also include atoms of all isotopes, whether in the intermediate or the final compound.
  • the atoms of an isotope include the same number of atoms but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the compound of the present application includes a compound in which part or all of hydrogen (H) is replaced by hydrazine (T) and/or hydrazine (D); and some or all of 12 C is replaced by 13 C and/or 14 C Compounds; and alternative compounds between other isotopes (such as N, O, P, S), such as 14 N and 15 N; 18 O and 17 O; 31 P and 32 P; 35 S and 36 S, and the like.
  • the compounds described herein may have one or more stereoisomeric centers, and each isomeric center may exist in the R or S configuration or a combination thereof.
  • a compound described herein can have one or more double bonds, and each double bond can exist in an E (trans) or Z (cis) configuration, or a combination thereof.
  • a particular stereoisomer, regioisomer, diastereomer, enantiomer or epimer should be understood to include all possible isomers, such as stereoisomers. Isomers, structural isomers, diastereomers, enantiomers or epimers, and mixtures thereof.
  • the compounds described herein include all stereoisomers, structural isomers, diastereomers, enantiomers or epimeric forms, and corresponding mixtures thereof, which are different in configuration.
  • optionally substituted alkyl means “unsubstituted alkyl” (alkyl substituted without a substituent) or “substituted alkyl” (alkyl substituted with a substituent) .
  • C 1 -C n as used herein includes C 1 -C 2 , C 1 -C 3 , ... C 1 -C n .
  • the "C 1 -C 4 " group means having from 1 to 4 carbon atoms in the moiety, ie the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbons atom.
  • C 1 -C 4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms, that is, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and n-butyl Base, isobutyl, sec-butyl and tert-butyl.
  • a numerical range, for example, "1-10” refers to each integer in a given range, for example "1-10 carbon atoms” means that the group may have 1 carbon atom, 2 carbon atoms, 3 Carbon atom, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to an optionally substituted straight or optionally substituted branched aliphatic hydrocarbon.
  • the "alkyl” herein may preferably have from 1 to about 20 carbon atoms, for example from 1 to about 10 carbon atoms, from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms, or from 1 to about 4.
  • Alkyl embodiments herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-1 -butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl 1-yl-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2 - dimethyl-l-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, positive Butyl, isopentyl, neopentyl, tert-amyl and hexyl, as well as longer alkyl groups such as
  • alkyl When a group as defined herein, such as “alkyl” appears numerical range, for example, “C 1 -C 6 alkyl” or “C 1 - 6 alkyl” refers to by a carbon atom, 2 carbon atoms, 3 An alkyl group consisting of a carbon atom, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkyl group herein also contains an unspecified number range.
  • alkyl includes alkyl groups bonded to other groups, such as alkyl groups in alkoxy groups, alkyl groups in alkylthio groups, hydroxyalkyl groups, haloalkyl groups, cyanoalkyl groups, alkylamino groups (such as “alkyl” in monoalkylamino, dialkylamino) and the like.
  • alkylamino as used herein, alone or in combination, means alkylamino (-HN-alkyl (ie, monoalkylamino) or -N-(alkyl) 2 (ie, dialkylamino).
  • alkyl is as described above.
  • alkoxy refers to an alkyl ether group (O-alkyl), non-limiting examples of which include methoxy, ethoxy, n-propoxy, isopropyl Oxyl, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy groups.
  • the alkenyl group has, but is not limited to, from 2 to about 18 carbon atoms, for example, from 2 to about 10 carbon atoms, or from 2 to about 8 carbon atoms, from 2 to about 6 carbon atoms, from 2 to about 4 carbon atom.
  • the double bond in these groups may be in the cis or trans conformation and should be understood to encompass both isomers.
  • C 2 -C 6 alkenyl or “C 2 - 6 alkenyl” means 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbons
  • An alkenyl group consisting of an atom or 6 carbon atoms, and the alkenyl group herein also covers the case where the numerical range is not specified.
  • halo or "halogen-substituted” as used herein, alone or in combination, means that one or more hydrogen atoms of an optionally substituted group (eg, alkyl, alkenyl, and alkynyl) are replaced with fluorine, chlorine. , bromine, iodine atoms or a combination thereof.
  • two or more hydrogen atoms eg, difluoromethyl, trifluoromethyl
  • two are replaced with halogen atoms that are not identical to each other.
  • a plurality of hydrogen atoms for example, 1-chloro-1-fluoro-1-iodoethyl).
  • Non-limiting examples of haloalkyl groups are fluoromethyl and bromoethyl.
  • a non-limiting example of a haloalkenyl group is a bromovinyl group.
  • a non-limiting example of a haloalkynyl group is a chloroethynyl group.
  • aryl/aryl refers to an optionally substituted aromatic hydrocarbon radical having from 6 to about 20, such as from 6 to 12 or from 6 to 10 ring-forming carbon atoms. It may be a fused aromatic ring or a non-fused aromatic ring.
  • the fused aromatic ring contains 2-4 aromatic ring fused rings, and the other independent rings may be an alicyclic ring, a heterocyclic ring, an aromatic ring, an aromatic heterocyclic ring or any combination thereof.
  • the aryl group herein includes a monocyclic, bicyclic, tricyclic or more cyclic aryl group.
  • Non-limiting examples of monocyclic aryl groups include 6 to about 12, 6 to about 10 or 6 to about 8 monocyclic aryl groups of a ring-forming carbon atom, such as phenyl; fused ring aryl groups include bicyclic rings, A tricyclic or more cyclic aryl group such as a naphthyl group, a phenanthryl group, an anthracenyl group or a fluorenyl group; and a non-fused bisaryl group including a biphenyl group.
  • heteroaryl refers to an optionally substituted monovalent heteroaryl group containing from about 5 to about 20, such as from 5 to 12 or from 5 to 10 backbones, wherein one or A plurality of (eg, 1-4, 1-3, 1-2) ring-forming atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. Atom, but not limited to this. The ring of the group does not contain two adjacent O or S atoms.
  • Heteroaryl groups include monocyclic heteroaryl or polycyclic heteroaryl (eg bicyclic heteroaryl, tricyclic heteroaryl, etc.).
  • heteroaryl includes an optionally substituted monovalent fused or non-fused heteroaryl having at least one hetero atom.
  • heteroaryl also includes fused and non-fused heteroaryl groups containing from 5 to about 12 backbone-forming ring atoms, and fused and non-fused, containing from 5 to about 10 backbone-forming ring atoms. Heteroaryl. It can be bonded to a heteroaryl group through a carbon atom or a hetero atom.
  • an imidazole can pass through any of its carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazole-5-
  • the base or its nitrogen atom is attached to the parent molecule.
  • a heteroaryl group can be further substituted by any or all of its carbon atoms and/or any or all of the heteroatoms.
  • the fused heteroaryl group may contain 2-4 aromatic heterocyclic fused fused rings, and the other independent rings may be an alicyclic ring, a heterocyclic ring, an aromatic ring, an aromatic heterocyclic ring or any combination thereof.
  • Non-limiting examples of monocyclic heteroaryl groups include from 5 to about 12, from 5 to about 10, from 5 to about 7 or 6 monocyclic heteroaryl groups which are backbone-ringed, for example, non-limiting examples thereof Included is pyridyl; fused ring heteroaryl includes benzimidazolyl, quinolinyl, acridinyl, and non-fused biheteroaryl includes bipyridinyl.
  • heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, imidazole, triazole, tetrazole, thiazole, isothiazole, 1,2,4-thiadiene Oxazole, pyrrole, pyrazole, oxazole, isoxazole, oxadiazole, benzofuran, benzothiophene, benzothiazole, hydrazine, carbazole, quinoline, isoquinoline, indole, carbazole, benzo Imidazole, pyrrolopyridine, pyrrolopyrimidine, pyrazolopyridine, pyrazolopyrimidine and the like.
  • heterocycle refers to a non-aromatic heterocycle, including heterocycloalkyl (saturated heterocyclyl) and heterocycloalkenyl (unsaturated heterocyclyl).
  • heterocycloalkyl saturated heterocyclyl
  • heterocycloalkenyl unsaturated heterocyclyl
  • One or more (e.g., 1-4, 1-3, 1-2) ring-forming atoms are heteroatoms such as oxygen, nitrogen or sulfur atoms.
  • the heterocyclic group may include a monocyclic heterocyclic group (heterocyclic group having one ring) or a polycyclic heterocyclic group (for example, a bicyclic heterocyclic group (heterocyclic group having two rings), a tricyclic heterocyclic group, or the like).
  • the bicyclic heterocyclic group may be a spiro ring or a bridged ring.
  • Heterocyclyl groups can have from 3 to about 20, such as from 3 to about 10, from 3 to about 8, from 5 to about 8, or from 5 to about 6, ring-forming atoms.
  • heterocyclic groups include azinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl ( Homopiperidinyl), oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3- 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, Dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl (3) -azabicyclo[3.1.0]hexyl
  • the term also encompasses all cyclic forms of saccharides including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Examples include, but are not limited to, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, isoxazolidine, isothiazolidine, pyrazolidine, morpholine, thio? Porphyrin, piperazine, piperidinyl and the like.
  • Heterocyclyl also includes heterocycles having one or more aromatic rings fused (ie, having a common bond), such as 2,3-dihydrobenzofuran, 1,3-benzodioxolane, benzo -1,4-dioxane, phthalimide, naphthalimide.
  • the heterocyclic group having one or more aromatic condensations may be bonded to other groups through an aromatic ring or a non-aromatic ring moiety.
  • Other groups may be bonded to the heterocycle via a heteroatom or a carbon atom (ie, the heterocycle is attached or further substituted with the parent molecule).
  • Carbocyclyl refers to a non-aromatic carbocyclic ring, including cycloalkyl and cycloalkenyl.
  • the cycloalkyl group may be a monocyclic cycloalkyl group or a polycyclic cycloalkyl group (for example, having 2, 3 or 4 rings; such as a bicyclic cycloalkyl group), which may be a spiro ring or a bridged ring.
  • the cycloalkyl group may have from 3 to 20 carbon atoms, for example from 3 to about 15 ring-forming carbon atoms or from 3 to about 10 ring-forming carbon atoms or from 3 to 6 ring-forming carbon atoms, and may have 0, 1, 2 Or 3 double keys and / or 0, 1 or 2 triple keys.
  • a cycloalkyl group having 3-8 or 3-6 ring-forming carbon atoms e.g., a saturated monocyclic cycloalkyl group.
  • the cycloalkyl group also includes a ring having one or more aromatic rings fused (i.e., having a common bond), for example, a benzo derivative substituted pentane, pentene, hexane, or the like.
  • One or more aromatic fused cycloalkyl groups may be attached to the other groups through an aromatic ring or a moiety other than the aromatic ring.
  • the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclopentenyl group, a cyclohexadienyl group, a cycloheptatrienyl group, an adamantyl group and the like.
  • substituted means that one or more hydrogens are replaced by a specified group on a particular atom, if the specified original The normal valence of the subunit is not exceeded in the existing case, and the result is a stable compound after the substitution.
  • the terms "subject,” “patient,” or “individual” refer to an individual, including a mammal, and a non-mammal, having a disease, disorder, condition, or the like.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domesticated Animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs.
  • non-human mammals include, but are not limited to, birds and fish.
  • the mammal is a human.
  • treatment includes alleviating, alleviating or ameliorating the symptoms of a disease or condition, inhibiting a disease or condition, such as preventing the progression of a disease or condition, alleviating a disease or condition, improving the disease or condition, and alleviating the disease. Or the symptoms caused by the condition, or the symptoms of the disease or condition, the prevention of other symptoms, the improvement or prevention of the underlying metabolic causes of the symptoms, and the term includes the purpose of prevention.
  • the term also includes obtaining a therapeutic effect and/or a preventive effect.
  • the therapeutic effect refers to curing or ameliorating the underlying disease to be treated.
  • the healing or amelioration of one or more physiological symptoms associated with a underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, an improvement in the patient's condition is observed.
  • the composition can be administered to a patient at risk of developing a particular disease, or even if a diagnosis of the disease has not been made, the composition is administered to a patient who develops one or more physiological symptoms of the disease.
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one active substance that is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent after administration ( The amount of the compound as in the present application). The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical and rectal administration topical and rectal administration.
  • the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable biological reactions. Or interacting with any of the components contained in the composition in a poor manner.
  • pharmaceutical composition refers to a mixture of a compound of the present application and at least one pharmaceutically acceptable substance.
  • pharmaceutically acceptable substances include, but are not limited to, carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • carrier refers to a relatively non-toxic material that facilitates the introduction of a compound of the present application into a cell or tissue.
  • pharmaceutically acceptable salt refers to a salt which retains the biological effectiveness of the free acid and free base of the specified compound and which has no adverse effects biologically or otherwise.
  • the compounds of the present application also include pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt refers to a form in which a base group in a parent compound is converted into a salt.
  • Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of base groups such as amine (amino) groups.
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound, i.e., the basic group in the parent compound is reacted with from 1 to 4 equivalents of acid in a solvent system. Suitable salts include the Remingtong's Pharmaceutical Scicences, 17 th ed ., Mack Publishing Company, Easton, Pa., In 1985, p.1418, and Journal of Pharmaceutical Science, 66,2 (1977 ).
  • the salt in the present application refers to an acid salt formed with an organic acid/inorganic acid, and a basic salt formed with an organic base/inorganic base.
  • the basic functional group of the compound of the formula is pyridine or imidazole (but not limited to pyridine or imidazole)
  • the acidic functional group is a carboxy group.
  • Zwitterions internal salts are formed when the acid is, but not limited to, the carboxylic acid, and the internal salt is also included in the salt of the present application.
  • the crude product of compound 3 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL).
  • the extract was extracted with methylene chloride (30 mL).
  • the crude product was purified by pre-HPLC to give the object compound XSD1-064 (25 mg, the total yield of the three-step reaction was 25%).
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by Pre-HPLC to give the title compound XSD1-066 (28 mg, 19% yield of the two-step reaction).
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by Pre-HPLC to give the title compound XSD1-067 (6 mg, 5% yield of the two-step reaction).
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to yield the title compound XSD 1- 068 (42 mg, mp.
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-069 (50 mg, yield 37%).
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the title compound XSD 1-070 (100 mg, y.
  • the crude compound was dissolved in 5 mL of methanol, and NaBH 4 (200 mg, 5 mmol) was added to the mixture, and the reaction was stirred for 1 hour.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). (30 mL ⁇ 3), the combined extracts were washed with brine, dried over anhydrous sodium sulfate
  • the crude product was purified by pre-HPLC to give the title compound XSD1-071 (64.68 mg).
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-072 (10 mg, yield 8%).
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1- s (60 mg, yield 48%).
  • the compound 4 (240 mg, 1.0 mmol) was dissolved in a mixture of 2.2 mL of methanol and 0.5 mL of water, and hydrazine hydroxide octahydrate (160 mg, 0.5 mmol) was added, and the mixture was reacted overnight at room temperature under nitrogen atmosphere.
  • the aqueous phase was adjusted to pH 2 with EtOAc (EtOAc) (EtOAc)
  • EtOAc EtOAc
  • the compound 7 (140 mg, 0.35 mmol) was dissolved in 6 mL of anhydrous tetrahydrofuran, and then cooled to 0 ° C, then sodium hydrogen was added, and the mixture was stirred at room temperature for 30 min, and the solution of compound 7a in anhydrous tetrahydrofuran was added and the mixture was stirred at room temperature for 18 h. After quenching with saturated aqueous ammonium chloride, ethyl acetate (50 mL, EtOAc) was evaporated.
  • the crude compound 2 was dissolved in 3 mL of dichloromethane, and trifluoroacetic acid (0.6 mL) was added under ice-cooling, and the reaction was stirred for 18 hours.
  • the reaction mixture was adjusted to basic with saturated sodium hydrogen carbonate solution (10 mL), chloroform: isopropyl alcohol
  • the extract was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated.
  • the crude product was used directly in the next reaction.
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the title compound XSD1-085 (15 mg, 12% yield of the two-step reaction).
  • the crude compound 2 was dissolved in 3 mL of N,N'-dimethylformamide, and compound 1a (180 mg, 1.2 mmol), O-(7-nitrobenzotriazole)-N,N,N',N' Tetramethyluronium hexafluorophosphate (171 mg, 0.45 mmol) and diisopropylethylamine (400 mg, 3.0 mmol) were reacted overnight at room temperature under nitrogen atmosphere, quenched with water, ethyl acetate (50mL ⁇ 5) The combined extracts were washed with brine, dried over anhydrous sodium sulfate The crude product was purified by pre-HPLC to give the title compound XSD 1- 087 (16 mg, 14% yield of the two-step reaction).
  • the crude compound was dissolved in 3 mL of methanol, and NaBH4 (55 mg, 1.375 mmol) was added, and the mixture was stirred for 18 hours.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). (30 mL ⁇ 3), the combined extracts were washed with brine, dried over anhydrous sodium sulfate
  • the crude product was purified by pre-HPLC to give the title compound XSD1 - 8-8 (21 mg, 17% yield of the two-step reaction).
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the title compound XSD1-089 (24 mg, 20% yield of the two-step reaction).
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-090 (60 mg, yield 40.8%).
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-091 (15 mg, yield 10%).
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-092 (10 mg, yield 10%).
  • the crude compound 3 was dissolved in 1 mL of 1,4-dioxane, and a solution of HCl in 1,4-dioxane (2 mL, 4 mol/L) was added under ice-cooling, and stirred at room temperature for 2 h. The crude product was used directly in the next reaction.
  • the crude compound was dissolved in 3 mL of methanol, and NaBH 4 (51.4 mg, 1.286 mmol) was added under ice-cooling, and the reaction was stirred for 18 hours.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL).
  • the mixture was extracted with chloroform (30 mL ⁇ 3).
  • the crude product was purified by pre-HPLC to give the title compound XSD1-094 (60 mg, yield 40.8%).
  • the crude compound 4 was dissolved in 3 mL of dichloromethane, triethylamine (305.2 mg, 3.02 mmol) was then weighed and cooled to zero. The crude compound 3 was added dropwise to the reaction system. The reaction was carried out at room temperature overnight. The reaction solution was dried under reduced pressure and the crude material was applied to the next step.
  • the crude compound 5 was dissolved in 2 mL of 1,4-dioxane, stirred in an ice water bath to zero temperature, and a solution of HCl in 1,4-dioxane (10 mL, 4 mol/L) was added. The reaction was carried out at room temperature overnight. The reaction mixture was evaporated to dryness crystall
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD 1- s (20 mg, yield 15.4%).
  • the crude compound 2 was dissolved in 3 mL of methanol, and NaBH 4 (55 mg, 1.375 mmol) was added to the ice bath. The reaction was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The extract was extracted with methylene chloride (30 mL). The crude product was purified by pre-HPLC to give the object compound XSD1-097 (30 mg, yield: 21.8%).
  • the crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL ⁇ 3). The crude product was purified by pre-HPLC to give the object compound XSD1-117 (24 mg, yield 26.4%).
  • the crude compound 7 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added, and the mixture was stirred at room temperature for 2 h.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL)
  • the extract was extracted with dichloromethane (30 mL ⁇ 3).
  • the crude product was purified by pre-HPLC to give the object compound XSD1-124 (11 mg, yield 10.4%).
  • the crude compound 7 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added, and the mixture was stirred at room temperature for 2 h.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL)
  • the extract was extracted with dichloromethane (30 mL ⁇ 3).
  • the crude product was purified by pre-HPLC to give the object compound XSD1-125 (11 mg, yield: 14.8%).
  • the crude compound 2 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL)
  • the extract was extracted with dichloromethane (30 mL ⁇ 3).
  • the crude product was purified by pre-HPLC to give the object compound XSD1-126 (4.1 mg, yield: 8.9%).
  • the crude compound 2 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL)
  • the extract was extracted with dichloromethane (30 mL ⁇ 3).
  • the crude product was purified by pre-HPLC to give the object compound XSD 1-133 (20 mg, yield 19.9%).
  • the crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL ⁇ 3). The crude product was purified by pre-HPLC to give the object compound XSD 1-141 (20.5 mg, yield 15.1%).
  • the crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL ⁇ 3). The crude product was purified by pre-HPLC to give the object compound XSD1-142 (10 mg, yield 9.8%).
  • the crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL ⁇ 3). The crude product was purified by pre-HPLC to give the object compound XSD 1-144 (10 mg, yield 9.3%).
  • the crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL ⁇ 3). The crude product was purified by pre-HPLC to give the object compound XSD 1- s (4 mg, yield: 2.9%).
  • the crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL ⁇ 3). The crude product was purified by pre-HPLC to give the object compound XSD1-146 (8 mg, yield 7.6%).
  • the crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL ⁇ 3). The crude product was purified by pre-HPLC to give the object compound XSD 1-147 (10 mg, yield 9.3%).
  • the crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL ⁇ 3). The crude product was purified by pre-HPLC to give the object compound XSD 1-148 (20 mg, yield: 17.5%).
  • the crude compound 9 was dissolved in 3 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) The extract was extracted with dichloromethane (30 mL ⁇ 3). The crude product was purified by pre-HPLC to give the object compound XSD 1-149 (10 mg, yield 9.8%).
  • the crude compound was dissolved in 3 mL of methanol, and NaBH4 (55 mg, 1.375 mmol) was added, and the mixture was stirred for 18 hours.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). (30 mL ⁇ 3), the combined extracts were washed with brine, dried over anhydrous sodium sulfate
  • the crude product was purified by pre-HPLC to give the object compound XSD 1-150 (4 mg, 16% yield of the two-step reaction).
  • the crude compound 3 was dissolved in 10 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hr.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL)
  • the extract was extracted with dichloromethane (30 mL ⁇ 3).
  • the crude product was purified by pre-HPLC to give the object compound XSD 1-151 (2.6 mg, yield 7.2%).
  • the crude compound 3 was dissolved in 10 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hr.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL)
  • the extract was extracted with dichloromethane (30 mL ⁇ 3).
  • the crude product was purified by pre-HPLC to give the object compound XSD1-153 (3.7mg, yield 8.2%).
  • the crude compound 3 was dissolved in 10 mL of methanol, and sodium borohydride (89.6 mg, 2.24 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hr.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL)
  • the extract was extracted with dichloromethane (30 mL ⁇ 3).
  • the crude product was purified by pre-HPLC to give the object compound XSD1-153 (2.9mg, yield 7.5%).

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Abstract

L'invention concerne un dérivé d'imidazole contenant un cycle de liaison, et une composition associée. Le dérivé d'imidazole et la composition associée peuvent être utilisés pour la préparation de médicaments destinés au traitement de pathologies caractéristiques qui sont conditionnées par l'indoléamine 2,3-dioxygénase et qui sont liées au domaine du métabolisme du tryptophane. L'invention concerne également un procédé de préparation du dérivé et d'un intermédiaire correspondant.
PCT/CN2017/084604 2016-05-16 2017-05-16 Dérivé d'imidazole contenant un cycle de liaison WO2017198159A1 (fr)

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CN201610326530.4 2016-05-16
CN201610326530.4A CN107383012B (zh) 2016-05-16 2016-05-16 含二环的咪唑醇衍生物
CN201610510930.0A CN107556316B (zh) 2016-06-30 2016-06-30 含桥环的咪唑衍生物
CN201610510930.0 2016-06-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113372270A (zh) * 2021-06-24 2021-09-10 江西国药有限责任公司 一种仑伐替尼及其制备方法

Citations (7)

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Publication number Priority date Publication date Assignee Title
WO2012142237A1 (fr) * 2011-04-15 2012-10-18 Newlink Geneticks Corporation Dérivés d'imidazole fusionnés pouvant être employés en tant qu'inhibiteurs d'ido
CR20130565A (es) * 2013-11-04 2014-05-26 Newlink Genetics Corp Fusionados derivados de imidazol útil como ido inhibidores
WO2014159248A1 (fr) * 2013-03-14 2014-10-02 Newlink Genetics Corporation Composés tricycliques utilisés en tant qu'inhibiteurs de l'immunosuppression dont la médiation est assurée par la métabolisation du tryptophane
WO2016037026A1 (fr) * 2014-09-05 2016-03-10 Merck Patent Gmbh Composés diaza et triaza tricycliques à substitution cyclohexyl-éthyle utilisés comme antagonistes de l'indoleamine-2,3-dioxygénase (ido) pour le traitement du cancer
WO2016059412A1 (fr) * 2014-10-15 2016-04-21 Redx Pharma Plc Dérivés de 6,7-(hétérocycle fusionné)-5h-pyrrolo[1,2-c]imidazole et leur utilisation en tant que modulateurs de l'indoléamine 2,3-dioxygénase (ido) et/ou de la tryptophane 2,3-dioxygénase (td02)
WO2016131380A1 (fr) * 2015-02-16 2016-08-25 Shanghai De Novo Pharmatech Co.,Ltd. Composés à cycles condensés, composition pharmaceutique et utilisations associées
WO2016165613A1 (fr) * 2015-04-12 2016-10-20 Hangzhou Innogate Pharma Co., Ltd. Hétérocycles utiles comme inhibiteurs d'ido et de tdo

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012142237A1 (fr) * 2011-04-15 2012-10-18 Newlink Geneticks Corporation Dérivés d'imidazole fusionnés pouvant être employés en tant qu'inhibiteurs d'ido
WO2014159248A1 (fr) * 2013-03-14 2014-10-02 Newlink Genetics Corporation Composés tricycliques utilisés en tant qu'inhibiteurs de l'immunosuppression dont la médiation est assurée par la métabolisation du tryptophane
CR20130565A (es) * 2013-11-04 2014-05-26 Newlink Genetics Corp Fusionados derivados de imidazol útil como ido inhibidores
WO2016037026A1 (fr) * 2014-09-05 2016-03-10 Merck Patent Gmbh Composés diaza et triaza tricycliques à substitution cyclohexyl-éthyle utilisés comme antagonistes de l'indoleamine-2,3-dioxygénase (ido) pour le traitement du cancer
WO2016059412A1 (fr) * 2014-10-15 2016-04-21 Redx Pharma Plc Dérivés de 6,7-(hétérocycle fusionné)-5h-pyrrolo[1,2-c]imidazole et leur utilisation en tant que modulateurs de l'indoléamine 2,3-dioxygénase (ido) et/ou de la tryptophane 2,3-dioxygénase (td02)
WO2016131380A1 (fr) * 2015-02-16 2016-08-25 Shanghai De Novo Pharmatech Co.,Ltd. Composés à cycles condensés, composition pharmaceutique et utilisations associées
WO2016165613A1 (fr) * 2015-04-12 2016-10-20 Hangzhou Innogate Pharma Co., Ltd. Hétérocycles utiles comme inhibiteurs d'ido et de tdo

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113372270A (zh) * 2021-06-24 2021-09-10 江西国药有限责任公司 一种仑伐替尼及其制备方法

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