WO2017024996A1 - Dérivé d'hydroxyamidine, son procédé de préparation et son utilisation en médecine - Google Patents

Dérivé d'hydroxyamidine, son procédé de préparation et son utilisation en médecine Download PDF

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WO2017024996A1
WO2017024996A1 PCT/CN2016/093584 CN2016093584W WO2017024996A1 WO 2017024996 A1 WO2017024996 A1 WO 2017024996A1 CN 2016093584 W CN2016093584 W CN 2016093584W WO 2017024996 A1 WO2017024996 A1 WO 2017024996A1
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group
mmol
reaction
amino
cancer
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PCT/CN2016/093584
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Chinese (zh)
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杨方龙
桂斌
胡齐悦
金芳芳
贺峰
孙飘扬
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201680003843.4A priority Critical patent/CN107001271B/zh
Publication of WO2017024996A1 publication Critical patent/WO2017024996A1/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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/14—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the field of medicine, relates to a hydroxy quinone derivative, a preparation method thereof and application thereof in medical research, and discloses the invention as an IDO inhibitor for treating pathology of an IDO-mediated tryptophan metabolism pathway.
  • a disease characterized by cancer, Alzheimer's disease, autoimmune disease, depression, anxiety, cataract, psychological disorder, and AIDS.
  • Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth model of tumor treatment after surgery, radiotherapy and chemotherapy (Clin Cancer Res). , 1997; 3: 2623-2629), which achieves anti-tumor effects by mobilizing the host's natural defense mechanisms, such as inhibiting IDO-mediated tumor immune escape mechanisms, or by administering naturally occurring highly targeted substances.
  • Indoleamine-pyrrole-2,3-dioxygenase is a heme-containing monomeric protein consisting of 403 amino acid residues, including two folded alpha- The helical domain, the large domain contains a catalytic pocket, and the substrate can be hydrophobic with the IDO in the catalytic pocket (Int J Biochem Cell Biol. 2007; 39(12): 2167-72).
  • IDO Indoleamine-pyrrole-2,3-dioxygenase
  • TDO tryptophan 2,3-dioxygenase
  • TDO oxidative decomposition of the 2,3-double bond of the anthracycline in the tryptophan catabolism in the first rate-limiting step of the kynurenine pathway.
  • the expression of TDO is primarily restricted to the liver and appears to be a self-balancing or "housekeeping" gene that cannot be induced or mediated by signals from the immune system (Nat Rev Immunol. 2004; 4(10): 762-74).
  • IDO is an enzyme that catalyzes the conversion of tryptophan to formyl kynurenine.
  • IDO interferon
  • IL interleukin
  • T-cells In the cell cycle of T-cells, there is a regulation point that is very sensitive to tryptophan levels.
  • IDO depletes local tryptophan, causing T-cells to arrest in the middle of G1 phase, thereby inhibiting the proliferation of T cells;
  • IDO catalyzes the main product produced by the metabolism of tryptophan.
  • Canine urea is induced by oxygen free radicals to induce changes in intracellular oxidants and antioxidants to induce T-cell apoptosis, which is an intrinsic immunosuppressive mechanism present in the body.
  • IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits T-cell-mediated immune responses, and blocks T-cell activation signal transduction, thereby mediating tumor cell escape. The attack of the immune system. Most human tumors have been found to constitutively express IDO (J Exp Med. 2002; 196(4): 459-68, Nat Med. 2003; 9(10): 1269-74, Trends Mol Med. 2004; 10(1) ): 15-8). Therefore, IDO is a potential target for cancer immunotherapy.
  • Inhibitors of the disclosed selective inhibitors of IDO include WO2004094409, WO2006122150, WO2007075598, WO200409387, WO2008147283, WO2013174947, WO2008075991, WO2004093871, WO2005051321, WO2006056304, WO2010005958 and WO2014066834, and the like.
  • IDO inhibitors have good application prospects in the pharmaceutical industry as a drug, but at present, no good IDO inhibitors have been found as listed drugs. In order to achieve better tumor treatment effects, the inventors hope to better meet market demand. A new generation of highly efficient and low toxicity selective IDO inhibitors can be developed.
  • the present invention will provide a novel structure of selective IDO inhibitors, and it has been found that compounds having such structures exhibit excellent effects and effects, particularly excellent pharmacogen absorption activities.
  • the object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture form, or a pharmaceutically acceptable salt thereof:
  • a mixture selected from the group consisting of a cis isomer, a trans isomer, and a cis and trans isomer;
  • Ring A is selected from cycloalkyl or heterocyclic groups wherein each of the cycloalkyl or heterocyclic groups is independently selected from the group consisting of alkyl, halo, amino, nitro, hydroxy, alkoxy, hydroxyalkane.
  • R 1 is the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • heteroaryl Base, heteroaryl, -OR 4 , -C(O)R 4 , -(CH 2 ) x C(O)OR 4 , -C(NH)NR 5 R 6 , -C(S)NR 5 R 6 , -S(O) m R 4 , -S(O) m NR 5 R 6 , -(CH 2 ) x NR 5 R 6 , -(CH 2 ) x C(O)NR 5 R 6 , -(CH 2 ) x NR 5 C(O)R 6 and -(CH 2 ) x NR 5 S(O) m R 6 wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and hetero group
  • the aryl groups are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy
  • R 2 is the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • R 3 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, cycloalkylalkoxy, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, cycloalkylane
  • the oxy, heterocyclic, aryl and heteroaryl are each independently selected from alkyl, halo, haloalkyl, amino, nitro, hydroxy, alkoxy, hydroxyalkyl, cyano, cycloalkyl , cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, -C(O)NR 7 R 8 , -S(O) m R 7 , -C(O)OR 7 , -OR 7 ,- OR 4 , -C(O)R 4 , -C(O)OR 4 , -S(O) m R 4 , -S(O) m
  • R 4 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -NR 7 R 8 , -NR 7 C (O) R 8 and -NR 7 S(O) m R 8 , wherein said alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from an alkane Base, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 3 , -OR 7 , -C(O) R 7 , -C(O)OR 7 ,
  • R 5 and R 6 are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • alkyl group, haloalkyl group, amino group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from the group consisting of alkyl, haloalkyl, halogen, hydroxy, amino, nitro , cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, -R 3 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -S(O) m NR 7 R 8 , -NR 7 R 8 , -(CH 2 ) x C(O)NR 7 R 8 , -(CH 2 ) x NR 7 C(O)R 8 and -(CH 2 ) x NR 7 S(O) m R 8 wherein the alkyl group, haloalkyl group, amino group, cycl
  • R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a carboxylate group, -S(O) m NR 9 C(O) OR 10 , -C(O)OR 10 , -S(O) m NR 9 R 10 , cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl group,
  • the amino group, cycloalkyl group, cycloalkylalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, Substituted by one or more substituents of an alkoxy group, a hydroxyalkyl group, a cycloalkyl
  • R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an amino group, an alkoxy group or a hydroxyalkyl group;
  • n 0, 1 or 2;
  • n 0, 1, 2, 3, 4 or 5;
  • p 0, 1, 2, 3, 4 or 5;
  • x 0, 1, 2 or 3.
  • the compound of the formula (I), wherein the ring A is selected from a cycloalkyl or heterocyclic group, preferably a C 3-8 cycloalkyl group, or contains 1 N atom a 3-8 membered monocyclic heterocyclic group or a 7-10 membered bridged heterocyclic group, more preferably a cyclohexyl group, a cyclobutyl group, a tetrahydropyrrole, a piperidinyl group or a cycloheximide, most preferably a piperidine.
  • Base cyclohexyl.
  • the compound of the formula (I) wherein R 1 is the same or different and each independently selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a hydroxyl group, an aryl group, a heteroaryl group, -C(O)R 4 , -(CH 2 ) x C(O)OR 4 , -S(O) m R 4 , -S(O) m NR 5 R 6 , -(CH 2 ) x NR 5 R 6 , -(CH 2 ) x C(O)NR 5 R 6 , -(CH 2 ) x NR 5 C(O)R 6 and -(CH 2 ) x NR 5 S(O) m R 6 ;
  • the alkyl, amino, aryl and heteroaryl groups are each independently selected from the group consisting of nitro, cyano, -R 3 , -C(O)NR 7 R 8 , -NR
  • the compound of formula (I) wherein R 2 is halogen, haloalkyl or alkenyl.
  • the compound of the formula (I), wherein R 4 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, Heterocyclic group.
  • the compound of the formula (I) is a compound of the formula (II):
  • R 1 , R 2 and p are as defined in the formula (I).
  • the compound of the formula (II) is a compound of the formula (III):
  • R 1 , R 2 and p are as defined in the formula (I).
  • the compound of formula (I) is a compound of formula (IV):
  • Ring B is selected from aryl or heteroaryl
  • R a is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group.
  • R 2 , R 3 , R 7 , R 8 , m, and p are as defined in the formula (I);
  • y is 0, 1, 2, 3, 4 or 5.
  • the compound of the formula (I) is a compound of the formula (V):
  • G is selected from C or N;
  • R a is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group.
  • R 2 , R 3 , R 7 , R 8 , m, and p are as defined in the formula (I);
  • y is 0, 1, 2, 3, 4 or 5.
  • the compound of the formula (I) is a compound of the formula (VI):
  • R a is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -R 3 , -OR 4 , -C(O)R 4 , -C(O)OR 4 , -S(O) m R 4 , -S(O) m NR 5 R 6 , -NR 5 R 6 , -( CH 2 ) x C(O)NR 5 R 6 , —(CH 2 ) x NR 5 C(O)R 6 and —(CH 2 ) x NR 5 S(O) m R 6 , wherein the alkyl group , haloalkyl, cycloalky
  • R 2 to R 8 , m, x and p are as defined in the general formula (I);
  • y is an integer of 0, 1, 2, 3, 4 or 5.
  • the compound of the formula (I) is a compound of the formula (V-A):
  • R b is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic ring described therein
  • the radical, aryl and heteroaryl are each independently selected from alkyl, halo, amino, nitro, hydroxy, alkoxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, Heteroaryl, -OR 4 , -C(O)R 4 , -C(O)OR 4 , -S(O) m R 4 , -S(O) m NR 5 R 6 , -NR 5 R 6 , Substituting one or more substituents of -C(O)NR 5 R 6 ,
  • R 4 to R 6 and m are as defined in the formula (I).
  • the present invention also provides a process for the preparation of a compound of the formula (I), the process comprising:
  • the compound of the formula (I) is reacted with R 1 NCO at room temperature or with a halide of R 1 under basic conditions at a low temperature, optionally deprotected under acidic conditions to give a compound of the formula (I);
  • R 1 , R 2 , A, p and n are as defined in the formula (I).
  • R 1 and n are as defined in the formula (I).
  • the invention also provides a process for the preparation of a compound of the formula (I), which process comprises:
  • R 1 , R 2 , A, p and n are as defined in the formula (I).
  • a typical compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof including but not limited to:
  • a typical compound of the formula (V) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof including but not limited to:
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formulae (I), (II), (III), (IV), (IV-A) and (VI) Or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable An acceptable carrier, diluent or excipient.
  • the present invention also relates to a process for the preparation of the above composition
  • a process for the preparation of the above composition comprising the compounds of the formula (I), (II), (III), (IV), (IV-A) and (VI) or their mutual compounds Isomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent Or the excipients are mixed.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the prevention and/or treatment of a disease having a pathological feature of an IDO-mediated tryptophan metabolism pathway.
  • IDO inhibitors can be used for the inhibition of cardiac disorders as well as for the treatment of other pathological features of IDO-mediated tryptophan metabolism pathways, including infections of viruses such as AIDS, such as Lyme disease and streptococcal infections.
  • neurodegenerative disorders eg Alzheimer's disease, Huntington's disease and Parkson's disease
  • autoimmune diseases depression, anxiety, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer) Eye disease state (example Such as cataract and age-related yellowing) and autoimmune diseases, wherein the cancer may be selected from breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cavity.
  • prostate cancer prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma , mastoid renal tumors, head and neck tumors, leukemia, lymphoma, myeloma and non-small cell lung cancer.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of a disease preventing the pathological features of the IDO-mediated tryptophan metabolism pathway.
  • These diseases include infections of viruses such as AIDS, cellular infections such as Lyme disease and streptococcal infection, neurodegenerative disorders (such as Alzheimer's disease, Huntington's disease and Parkson's disease), autoimmune diseases, depression, Anxiety disorders, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer), eye disease states (such as cataracts and age-related yellowing), and autoimmune diseases, wherein the cancer may be selected from the breast Cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, Peritoneal tumors, stage IV melanoma, solid tumors, gliomas, glioblastoma, hepatocellular carcinoma, papillary renal tumors, head and neck tumors, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
  • the present invention also relates to a method of treating a disease preventing and/or treating a pathological feature having an IDO-mediated tryptophan metabolism pathway, comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • These diseases include infections of viruses such as AIDS, cellular infections such as Lyme disease and streptococcal infection, neurodegenerative disorders (such as Alzheimer's disease, Huntington's disease and Parkson's disease), autoimmune diseases, depression, Anxiety disorders, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer), eye disease states (such as cataracts and age-related yellowing), and autoimmune diseases, wherein the cancer may be selected from the breast Cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, Peritoneal tumors, stage IV melanoma, solid tumors, gliomas, glioblastoma, hepatocellular carcinoma, papillary renal tumors, head and neck tumors, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
  • Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the method exhibits outstanding efficacy and fewer side effects, wherein the cancer can be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, Gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor , glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer, preferably fallopian tube tumor, peritoneal tumor, stage IV Melanoma, myeloma and breast cancer, more preferably breast cancer.
  • the cancer can be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, Gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • Soft gelatin capsules provide oral preparations.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols
  • the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • preservatives such as ethylparaben or n-propylparaben
  • coloring agents such as ethylparaben or n-propylparaben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation.
  • These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.
  • Dispersible powders and granules suitable for the preparation of water suspensions can be provided by the addition of water to provide active ingredients and A mixed dispersing or wetting agent, a suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate.
  • the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be prepared as an injection.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, and the patient's behavior.
  • the dosage, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt The type can be verified according to traditional treatment options.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain containing from 1 to 20 carbon atoms.
  • the group is preferably an alkyl group having 1 to 12 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • an alkane Base alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, hetero
  • alkylene means that one hydrogen atom of the alkyl group is further substituted, for example, "methylene” refers to -CH 2 -, "ethylene” refers to -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, "butylene” means -(CH 2 ) 4 - and the like.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms. More than one carbon atom, more preferably from 4 to 7 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms Preferably comprising from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, wherein from 1 to 3 are heteroatoms; most preferably from 3 to 6 ring atoms, wherein from 1 to 2 It is a hetero atom.
  • monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • Non-limiting examples of spiroheterocyclyl groups include:
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A ⁇ -electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the number of the constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridge heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl An oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, tetrazolyl, tetrazolyl, thienyl, pyrazolyl or Pyrimidinyl, thiazolyl; more selective imidazole Base, pyrazolyl or
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
  • cycloalkylalkyl refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl, alkyl is as defined above.
  • a preferred embodiment of the invention is a cyclopropyl substituted alkyl group.
  • cycloalkylalkoxy refers to an alkoxy group substituted by one or more cycloalkyl groups, wherein cycloalkyl, alkoxy is as defined above.
  • a preferred embodiment of the invention is a cyclopropyl substituted alkoxy group.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • hydroxy refers to an -OH group.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • isocyanato refers to -NCO.
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl is as defined above.
  • acyl halide refers to a compound containing a -C(O)-halogen group.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • the preparation method of the salt used includes the following steps:
  • the compound of formula (a) is oxidized by an oxidizing agent to a compound of the formula (b), which is preferably selenium dioxide; the compound of the formula (b) is in basic conditions.
  • the reagent (providing a basic condition is preferably potassium carbonate), and reacting with hydroxylamine hydrochloride at room temperature to obtain a compound of the formula (c); and the obtained compound of the formula (c) under acidic conditions with N-chlorobutyl
  • the diimide reaction gives the compound of the formula (d); the obtained compound of the formula (d) is reacted with a derivative of aniline at room temperature to obtain a compound of the formula (IA); the obtained compound of the formula (IA)
  • the compound of the formula (I) is obtained by reacting with R 1 NCO at room temperature or with a halide of R 1 under basic conditions at a low temperature.
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases.
  • organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases.
  • potassium acetate, sodium t-butoxide or potassium t-butoxide, and the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.
  • the oxidizing agents used include, but are not limited to, selenium dioxide, hydrogen peroxide, potassium permanganate or manganese dioxide.
  • Agents that provide acidic conditions include, but are not limited to, formic acid, acetic acid, hydrochloric acid, sulfuric acid, or methanesulfonic acid.
  • R 1 , R 2 , A, p and n are as defined in the formula (I).
  • the compound of the general formula (e) is oxidized by the oxidizing agent to a compound of the formula (f), which is preferably selenium dioxide; the compound of the formula (f) is in basic conditions.
  • the reagent (providing a basic condition is preferably potassium carbonate), and reacting with hydroxylamine hydrochloride at room temperature to obtain a compound of the formula (g); and the obtained compound of the formula (g) under acidic conditions with N-chlorobutyl
  • the diimide reaction gives a compound of the formula (IB); the obtained compound of the formula (IB) is reacted with a derivative of aniline at room temperature to give a compound of the formula (I).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases.
  • organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases.
  • potassium acetate, sodium t-butoxide or potassium t-butoxide, and the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.
  • the oxidizing agents used include, but are not limited to, selenium dioxide, hydrogen peroxide, potassium permanganate or manganese dioxide.
  • Agents that provide acidic conditions include, but are not limited to, formic acid, acetic acid, hydrochloric acid, sulfuric acid, or methanesulfonic acid.
  • R 1 , R 2 , A, p and n are as defined in the formula (I).
  • a compound of the formula (III-a) is reacted with a halide of R 1 under basic conditions (preferably triethylamine) to give a compound of the formula (III).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases.
  • organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases.
  • potassium acetate, sodium t-butoxide or potassium t-butoxide, and the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.
  • R 1 , R 2 , and p are as defined in the formula (II) or (III).
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • chemical shifts are given in units of 10 -6 (ppm).
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for separation and purification of thin layer chromatography is 0.4mm. ⁇ 0.5mm silica gel plate.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Dare Chemicals.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution in the reaction means an aqueous solution unless otherwise specified.
  • the temperature of the reaction was room temperature unless otherwise specified.
  • Room temperature is the most suitable reaction temperature, and the temperature range is from 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane, acetic acid Ethyl ester and dichloromethane system, D: petroleum ether and ethyl acetate system, E: ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acid or alkali may be added. The reagents and the like are adjusted.
  • N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(piperidin-4-yl)acetamidine 1f (30 mg, 0.208 mmol) was dissolved in 2 mL of THF.
  • 4-isocyanic acid benzonitrile 2a (30 mg, 0.20 mmol, obtained by a known method "Chemical & Pharmaceutical Bulletin, 2012, 60 (8), 1046-1054"
  • the reaction was stirred at 25 ° C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced vacuo.
  • -(decyl)acetyl)-N-(4-benzonitrile)piperidine-1-carboxamide 2 (16 mg, white solid), yield 36%.
  • N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(piperidin-4-yl)acetamidine 1f (50 mg, 0.145 mmol) was dissolved in 10 mL dichloromethane. Triethylamine (44 mg, 0.44 mmol) was added, the reaction system was cooled to 0 ° C, and pre-prepared 1 mL of tert-butyl chlorosulfonyl carbamate 4a (22 mg, 0.1 mmol) was prepared by the method disclosed in the patent application "WO2010149684". The resulting dichloromethane solution was stirred at 0 ° C for 1 hour.
  • triphosgene (187 mg, 0.63 mmol) was dissolved in 20 mL of tetrahydrofuran, 3-aminobenzonitrile 6a (223 mg, 1.887 mmol) and triethylamine (0.52 mL, 0.0876 mmol) were added, and the reaction was stirred at 25 ° C for 1 hour. . A suspension of the title product 3-isocyanatobenzonitrile 6b was obtained, and the product was directly subjected to next reaction without purification.
  • tert-Butyl chlorosulfonylcarbamate 4a (1.6 mg, 7.52 mmol) was dissolved in 50 mL of dichloromethane, 4-nitroaniline (988 mg, 7.5 mmol) was added, and triethylamine (1.5 mL, 10.8 mmol) was added. The reaction was carried out at 25 ° C for 48 hours. After completion of the reaction, the reaction mixture was evaporated.jjjjjjjjjjjj Tert-butyl amidocarboxylate 10b (1.4 g, white solid), yield 62%.
  • N-(4-nitrophenyl)sulfamoylcarbamic acid tert-butyl ester 10b (1.4 g, 4.41 mmol) was dissolved in 40 mL of methanol, 280 mg of 10% palladium carbon was added, and the reaction system was replaced with hydrogen three times. The reaction was carried out at 25 ° C for 3 hours. After completion of the reaction, the mixture was filtered,jjjjjjjjjjjjjjjj reaction.
  • N-(4-aminophenyl)sulfamoylcarbamic acid tert-butyl ester 10c (44 mg, 0.153 mmol) was dissolved in 5 mL of tetrahydrofuran, and 4-nitrobenzoic acid (31 mg, 0.153 mmol, Adamas), triethyl Amine (0.03 mL, 0.216 mmol), reacted at 25 ° C for 30 min, then added N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(piperidin-4-yl) Ethyl 1f (50 mg, 0.145 mmol) was stirred at 25 ° C for 1 hour.
  • EtOAcjjjjjjjjjjjjjjjjjjjj The resulting residue was purified by EtOAc (EtOAc) elut elut (4-(Aminosulfonylamino)phenyl)piperidine-1-carboxamide 10 (25 mg, white solid), yield 71%.
  • the chlorosulfonyl isocyanate (42 mg, 0.296 mmol) was dissolved in 2 mL of dichloromethane, cooled to 0 ° C, tert-butanol (22 mg, 0.296 mmol) was added, and the mixture was stirred at 0 ° C for 15 minutes and then was taken.
  • 2-(3-Acetylcyclobutyl)acetate 12d (2.0 g, 10.85 mmol) and selenium dioxide (2.4 g, 21.7 mmol) were added to 20 mL of dioxane and heated to 80 ° C for 12 hours. The next day, the mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the crude 2-(3-(2-(indolyl)acetyl)cyclobutyl)acetate 12f (2.0 g, 9.38 mmol) was dissolved in 20 mL of N,N-dimethylformamide and 4 drops of hydrogen chloride were added. A solution of diethyl ether, then N-chlorosuccinimide (1.25 g, 9.38 mmol) was added, and the reaction was stirred at 25 ° C for 1 hour. After the reaction was completed, 50 mL of water and ethyl acetate were added, and the organic layer was washed with water and a saturated sodium chloride solution (30 mL ⁇ 3).
  • reaction solution was concentrated under reduced pressure to remove a portion of organic solvent, and the residue was taken from water and dichloromethane (100 mL), and the aqueous phase was adjusted to pH 3-4 with 6 N hydrochloric acid and the aqueous phase was extracted with dichloromethane ( 50mL ⁇ 3), the collected organic phase was washed with water and saturated sodium chloride solution (30 ⁇ 3mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product 2-(3-(2) -((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)acetic acid 12j (900 mg, yellow solid). 64.7%.
  • 4-Nitrophenylpyridin-3-yl carbonate 15a (181 mg, 0.697 mmol, prepared by the method disclosed in the patent EP 1 849 773 A1) was dissolved in 30 mL of tetrahydrofuran, and 1f (200 mg, 0.58 mmol), triethyl The amine (0.243 mL, 1.743 mmol) was stirred at 25 ° C for 1 hour. After completion of the reaction, the reaction mixture was evaporated.
  • Triphosgene (207 mg, 0.7 mmol) was dissolved in 100 mL of tetrahydrofuran, and 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)aniline 21b (382 mg, 1.83 mmol) and triethylamine were added sequentially. (528 mg, 5.23 mmol), and the reaction was stirred at room temperature for 30 minutes.
  • (N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(piperidin-4-yl)acetamidine 1f (600 g, 1.74 mmol) was added to the mixture. The reaction was stirred for 1 hour.
  • EtOAc (EtOAc m.) 4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)piperidine-1 Formamide 21 (160 mg, white solid), yield 15.8%.
  • the crude product 22b (1.78 g, 7.2 mmol) was dissolved in 40 mL of dichloromethane, and a catalytic amount of N,N-dimethylformamide and 0.9 mL of oxalyl chloride was added thereto, and the reaction was stirred at room temperature for 0.5 hour, and the reaction mixture was concentrated under reduced pressure. 40 mL of dichloromethane was added to the residue, and N,O-dimethylhydroxylamine hydrochloride (0.843 g, 8.64 mmol) and 3 mL of triethylamine were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated tolulululululululululululululululululululu
  • 1-(tert-Butoxycarbonyl)cycloheximide-4-carboxylic acid 25a 360 mg, 1.48 mmol, prepared by a known method "Angewandte Chemie, International Edition, 2013, 52(23), 6072-6075"
  • 1-hydroxybenzotriazole 240 mg, 1.78 mmol
  • 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (341 mg, 1.78 mmol).
  • Triethylamine (448 mg, 4.44 mmol), N,O-dimethylhydroxylamine hydrochloride (216 mg, 2.22 mmol).
  • N-Methoxy-N-methyl-3-carbonylcyclobutancarboxamide 12a (2.0 g, 12.7 mmol) was dissolved in 40 mL of methanol, sodium borohydride (0.97 g, 25.5 mmol) was added and reacted for 1 hour at room temperature. . After the reaction was completed, the reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal
  • Example 28 Using the synthetic route of Example 28, the starting material was replaced with 4-(4-fluoro-3-nitrophenyl)-1-methyl-1H-pyrazole (prepared by the method disclosed in the patent application "WO2013053983”), The title product 29 (13 mg, red solid) was obtained in a yield of 15.9%.
  • 2-Bromo-5-nitropyridine 33a (500 mg, 2.46 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and 4-methyl-1H-imidazole 33b (0.81 g, 9.86 mmol) was added. Potassium (1.02 g, 7.39 mmol) was reacted at room temperature for 16 hours. After the completion of the reaction, the reaction mixture was poured into EtOAc EtOAc EtOAc. The product was directly reacted without further purification.
  • Triphosgene (21mg, 0.07mmol) was dissolved in 10mL of tetrahydrofuran, and pre-made 1mL 33d was added. (30 mg, 0.172 mmol) in tetrahydrofuran solution, triethylamine (0.1 mL, 0.72 mmol) was added and the mixture was stirred at room temperature for 30 min. 1f (50 mg, 0.145 mmol) was added to the reaction mixture, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated. mjjjlililililililililililili
  • the crude product 39a (4.1 g, 0.026 mol) was dissolved in 50 mL of toluene, and 12.5 mL of t-butanol, 15.5 mL of triethylamine and 6.8 mL of diphenylphosphoryl azide were added, and the reaction was stirred at 90 ° C for 16 hours. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjj
  • the crude product 39d (70 mg, 0.2 mmol) was dissolved in 10 mL of dichloromethane, triethylamine (62 mg, 0.6 mmol) was added, benzoyl chloride (14 mg, 0.1 mmol) was added dropwise, and the reaction was stirred at 25 ° C for 1 hour. After the reaction was completed, the reaction solution was added with 5 mL of water and extracted with dichloromethane (10 mL ⁇ 3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to purified crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal
  • the raw material 40a (1.1 g, 7.07 mmol) was dissolved in 10 mL of tetrahydrofuran, and 14.1 mL of a 2M methylamine tetrahydrofuran solution was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was evaporated. mjjjjlilililililililili
  • the isocyanate chlorosulfonate (10 mg, 0.073 mmol) was dissolved in 5 mL of dichloromethane, and a pre-prepared 1 mL of t-butanol (6 mg, 0.073 mmol) in dichloromethane was added dropwise at 0 ° C, and the reaction was stirred 30
  • the spare solution a is obtained in minutes.
  • a pre-formed 2 mL of a crude solution of 44a (21 mg, 0.061 mmol) in dichloromethane was added to the reaction mixture, and the above-mentioned stock solution a was added dropwise, and the mixture was stirred at room temperature for 1 hour.
  • the crude product 45e (60 mg, 0.0813 mmol) was dissolved in 2 mL of methanol, 2 mL of 2M hydrochloric acid solution was added, and the reaction was stirred at 25 ° C for 18 hours. After completion of the reaction, the pH was adjusted to 7 with a saturated aqueous solution of sodium hydrogen carbonate, ethyl acetate (30 mL ⁇ 3), and the organic phase was combined. The organic phase was washed once with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, filtrate The residue was purified by EtOAcqqqqqqqqqqq
  • triphosgene (129 mg, 0.436 mmol) was dissolved in 3 mL of tetrahydrofuran, and 4-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester 46a (80 mg, 0.436 mmol, using the patent ""WO2014128465”" was used.
  • 4-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester 46a 80 mg, 0.436 mmol, using the patent ""WO2014128465”” was used.
  • triethylamine (0.304 mL, 2.179 mmol
  • tert-Butyl (1-hydroxymethyl)cyclopropyl)carbamate 47a (2 g, 10.68 mmol) was dissolved in 50 mL dichloromethane, then 4-dimethylaminopyridine (1.566 g, 12.818 mmol) Sulfonyl chloride (2.24 g, 11.75 mmol) was stirred at 25 ° C for 3 hours. After completion of the reaction, 150 mL of water was added, and the mixture was extracted with dichloromethane (100 mL ⁇ 3). The title product 47b (3.5 g, yellow solid) was taken to the next step without purification.
  • the crude product 47d (1.8 g, 9.644 mmol) was dissolved in 60 mL of N,N-dimethylformamide, 2-chloro-5-nitropyridine (1.685 g, 10.63 mmol) was added, and potassium carbonate (4.001 g, 28.992) was added. Methyl), the reaction was stirred at 80 ° C for 18 hours. After the reaction was completed, 300 mL of water was added, and the mixture was extracted with ethyl acetate (200 mL ⁇ 3), and the organic phase was combined.
  • triphosgene (73 mg, 0.245 mmol) was placed in a 50 mL single-mouth flask, and a pre-formed 3 mL solution containing 47 g (92 mg, 0.245 mmol) and triethylamine (0.171 mL, 1.224 mmol) in tetrahydrofuran was added and reacted at 0 ° C.
  • the reaction mixture was evaporated to dryness mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Example 44 Using the synthetic route of Example 44, the starting material was replaced with tert-butyl 3-acetylpyrrolidine-1-carbamate (prepared by the method disclosed in the patent application "WO2012126901”) to give the title product 53 (20 mg, yellow solid) ), the yield was 41.6%.
  • Example 44 Using the synthetic route of Example 44, the starting material was replaced with (S)-3-acetylpiperidine-1-carboxylic acid tert-butyl ester (prepared by the method disclosed in the patent application "WO2011117254") to obtain the title product 54 ( 40 mg, yellow solid), yield 70.2%.
  • the crude product 56b (1.06 g, 4.18 mmol) was dissolved in dichloromethane (30 mL). After completion of the reaction, a saturated sodium hydrogencarbonate solution and a saturated sodium thiosulfate solution were added and stirred for 5 minutes. The organic layer was combined and dried over anhydrous sodium sulfate. The resulting residue was purified to silica gel elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut
  • the crude product 56d (67 mg, 2.53 mmol) was dissolved in 20 mL of methanol, and then potassium carbonate (524 mg, 3.79 mmol) was added, and the reaction was stirred at 0 ° C for 10 minutes, and the pre-formed 2.5 mL of hydroxylamine hydrochloride (88 mg, 1.266 mmol) of methanol was added in portions. The solution was reacted for 0.5 hour while stirring at 0 °C. After the reaction was completed, the insoluble material was filtered, and the filtrate was evaporated to dryness.
  • Chlorosulfonyl isocyanate (9.17 mg, 6.48 mmol) was dissolved in 10 mL of dichloromethane, cooled to 0 ° C, tert-butanol (480 mg, 6.47 mmol) was added, and the mixture was stirred at 0 ° C for 5 minutes to obtain a stock solution.
  • 58a (1.2 g, 3.24 mmol)
  • triethylamine (2.25 mL, 16.2 mmol) and 30 mL dichloromethane were placed in a reaction flask, and 4 mL of a stock solution was added and stirred at 0 ° C for 1 hour. After completion of the reaction, the reaction mixture was evaporated.
  • Example 44 Using the synthetic route of Example 44, the starting material 25 was changed to 60a to give the title product 60 (30 mg, white solid).

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Abstract

La présente invention concerne un dérivé d'hydroxyamidine, son procédé de préparation et son utilisation en médecine. En particulier, l'invention concerne le dérivé d'hydroxyamidine tel que représenté par la formule générale (I), son procédé de préparation et une composition pharmaceutique contenant ledit dérivé, et son utilisation pour le traitement de maladies ayant une caractéristique pathologique d'une voie métabolique du tryptophane médiée par l'IDO, ces maladies comprenant le cancer, la maladie d'Alzheimer, des maladies immunitaires, la dépression, des troubles de l'anxiété, des cataractes, des obstacles psychologiques et le SIDA, la définition de chaque substituant dans la formule générale (I) étant la même que celle définie dans la description.
PCT/CN2016/093584 2015-08-07 2016-08-05 Dérivé d'hydroxyamidine, son procédé de préparation et son utilisation en médecine WO2017024996A1 (fr)

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WO2019057123A1 (fr) 2017-09-20 2019-03-28 杭州英创医药科技有限公司 Composé polycyclique agissant en tant qu'inhibiteur de l'ido et/ou en tant qu'inhibiteur double de l'ido-hdac
EP4052705A1 (fr) 2021-03-05 2022-09-07 Universität Basel Vizerektorat Forschung Compositions pour le traitement des maladies ou des pathologies associées à l'ebv
WO2022184930A2 (fr) 2021-03-05 2022-09-09 Universität Basel Compositions pour le traitement de maladies ou d'états associés à ebv
CN116444454A (zh) * 2023-06-16 2023-07-18 中国医学科学院医药生物技术研究所 N-羟基脒衍生物及制备方法和应用、肿瘤免疫治疗药物
CN116987281A (zh) * 2023-08-08 2023-11-03 中原工学院 双功能铜金属有机框架料Cu(I)-MOF、制备方法及自驱动光催化反应的应用

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CN106967005A (zh) * 2017-04-07 2017-07-21 钟燕 一种能抑制ido的化合物、其制备方法及其用途
WO2018184585A1 (fr) * 2017-04-07 2018-10-11 上海肇钰医药科技有限公司 Composé pour l'inhibition de l'ido, son procédé de fabrication et son utilisation
CN106967005B (zh) * 2017-04-07 2019-07-16 上海肇钰医药科技有限公司 一种能抑制ido的化合物、其制备方法及其用途
WO2019057123A1 (fr) 2017-09-20 2019-03-28 杭州英创医药科技有限公司 Composé polycyclique agissant en tant qu'inhibiteur de l'ido et/ou en tant qu'inhibiteur double de l'ido-hdac
EP4052705A1 (fr) 2021-03-05 2022-09-07 Universität Basel Vizerektorat Forschung Compositions pour le traitement des maladies ou des pathologies associées à l'ebv
WO2022184930A2 (fr) 2021-03-05 2022-09-09 Universität Basel Compositions pour le traitement de maladies ou d'états associés à ebv
CN116444454A (zh) * 2023-06-16 2023-07-18 中国医学科学院医药生物技术研究所 N-羟基脒衍生物及制备方法和应用、肿瘤免疫治疗药物
CN116444454B (zh) * 2023-06-16 2023-09-12 中国医学科学院医药生物技术研究所 N-羟基脒衍生物及制备方法和应用、肿瘤免疫治疗药物
CN116987281A (zh) * 2023-08-08 2023-11-03 中原工学院 双功能铜金属有机框架料Cu(I)-MOF、制备方法及自驱动光催化反应的应用
CN116987281B (zh) * 2023-08-08 2024-04-16 中原工学院 双功能铜金属有机框架料Cu(I)-MOF、制备方法及自驱动光催化反应的应用

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