WO2017024996A1 - Hydroxy amidine derivative, preparation method and use in medicine thereof - Google Patents

Hydroxy amidine derivative, preparation method and use in medicine thereof Download PDF

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Publication number
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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French (fr)
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/en
Publication of WO2017024996A1 publication Critical patent/WO2017024996A1/en

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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

Provided are a hydroxy amidine derivative, a preparation method and a use in medicine thereof. In particular, provided are the hydroxy amidine derivative as shown by general formula (I), the preparation method thereof and a pharmaceutical composition containing the derivative, and the use thereof for treating diseases having a pathological feature of an IDO-mediated tryptophan metabolic pathway, with these diseases comprising cancer, Alzheimer's disease, immunological diseases, depression, anxiety disorders, cataracts, psychological obstacles and AIDS, wherein the definition of each substituent in the general formula (I) is the same as that defined in the description.

Description

羟基脒类衍生物、其制备方法及其在医药上的应用Hydroxy hydrazine derivative, preparation method thereof and application thereof in medicine 技术领域Technical field
本发明属于医药领域，涉及羟基脒类衍生物、其制备方法及其在医药研究上的应用，本发明公开了其作为IDO抑制剂，用于治疗具有IDO介导的色氨酸代谢途径病理学特征的疾病，所述的疾病包括癌症、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病。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.
背景技术Background technique
肿瘤生物治疗是应用现代生物技术及其相关产品进行肿瘤防治的新疗法，因其安全、有效、不良反应低等特点，成为继手术、放疗、化疗之后肿瘤治疗的第四种模式(Clin Cancer Res,1997；3:2623-2629)，其通过调动宿主的天然防御机制，比如抑制IDO介导的肿瘤免疫逃逸机制，或给予天然产生的靶向性很强的物质来获得抗肿瘤的效应。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.
吲哚胺2，3-双加氧酶(Indoleamine-pyrrole-2,3-dioxygenase，IDO)是一种含铁血红素单体蛋白，由403个氨基酸残基组成，包括两个折叠的α-螺旋结构域，大结构域包含催化口袋，底物可在催化口袋内与IDO发生疏水等作用(Int J Biochem Cell Biol.2007；39(12):2167-72)。在哺乳动物中，有两种基因编码的非相关的含有血红素的酶可以催化色氨酸的氧化降解：IDO和色氨酸2,3-双加氧酶(TDO)。每种酶催化相同的反应：在犬尿氨酸路径的第一个限速步骤色氨酸分解代谢中促进吲哚环的2,3-双键的氧化分解。TDO的表达主要限于肝脏，似乎作为一个自我平衡或“管家”基因，无法被免疫系统的信号所诱导或调解(Nat Rev Immunol.2004；4(10):762-74)。IDO是催化色氨酸转化为甲酰犬尿氨酸的酶，广泛分布在人和其他哺乳动物(兔、鼠)除肝脏以外的组织中，是肝脏以外唯一可催化色氨酸分解代谢的限速酶，而色氨酸是细胞维持活化和增殖所必需的氨基酸，也是构成蛋白质不可缺少的重要成分(Adv Exp Med Biol.2003；527:455-63、Biochim Biophys Acta.2001；1527(3):167-75)。IDO与干扰素(interferon，IFN)、白细胞介素(interleukin，IL)、肿瘤坏死因子等多种细胞因子关系密切，它们在一定条件下可激活IDO(J Psychiatry Neurosci.2004；29(1):11–17、Med Hypotheses.2003；61(5-6):519-25)。而T-细胞的细胞周期中存在一个对色氨酸水平非常敏感的调节点，一方面，IDO使局部色氨酸耗竭，致使T-细胞停滞于G1期中期，从而抑制了T细胞的增殖；另一方面，IDO催化色氨酸代谢产生的主要产物犬尿素由氧自由基介导引起细胞内氧化剂和抗氧化剂改变而诱导T-细胞凋亡，这是存在于机体的固有的免疫抑制机制。目前大量研究表明IDO在白血病细胞中较高表达，使局部T细胞增殖受抑，抑制T-细胞介导的免疫反应，使T-细胞活化信号转导受阻，从而介导肿瘤细胞逃 逸免疫系统的攻击。已经发现大多数人类肿瘤组成性地表达IDO(J Exp Med.2002；196(4):459-68、Nat Med.2003；9(10):1269-74、Trends Mol Med.2004；10(1):15-8)。因此，IDO是一个具潜力的癌症免疫治疗的靶标。Indoleamine-pyrrole-2,3-dioxygenase (IDO) 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). In mammals, two genes encoding unrelated heme-containing enzymes catalyze the oxidative degradation of tryptophan: IDO and tryptophan 2,3-dioxygenase (TDO). Each enzyme catalyzes the same reaction: promoting the 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. It is widely distributed in tissues other than the liver of humans and other mammals (rabbits, mice) and is the only restriction outside the liver that catalyzes the catabolism of tryptophan. Leptin, which is an essential amino acid for cells to maintain activation and proliferation, is also an indispensable component of protein (Adv Exp Med Biol. 2003; 527: 455-63, Biochim Biophys Acta. 2001; 1527 (3) :167-75). IDO is closely related to various cytokines such as interferon (IFN), interleukin (IL), and tumor necrosis factor. They can activate IDO under certain conditions (J Psychiatry Neurosci. 2004;29(1): 11–17, Med Hypotheses. 2003; 61(5-6): 519-25). In the cell cycle of T-cells, there is a regulation point that is very sensitive to tryptophan levels. On the one hand, IDO depletes local tryptophan, causing T-cells to arrest in the middle of G1 phase, thereby inhibiting the proliferation of T cells; On the other hand, 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. A large number of studies have shown that 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.
公开的选择性抑制IDO的抑制剂专利申请包括WO2004094409、WO2006122150、WO2007075598、WO200409387、WO2008147283、WO2013174947、WO2008075991、WO2004093871、WO2005051321、WO2006056304、WO2010005958和WO2014066834等。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抑制剂作为药物在医药行业具有良好的应用前景，但是目前尚未找到很好的IDO抑制剂可作为上市药物，为了达到更好的肿瘤治疗效果的目的，更好的满足市场需求，发明人希望能开发出新一代的高效低毒的选择性IDO抑制剂。本发明将提供一种新型结构的选择性IDO抑制剂，并发现具有此类结构的化合物表现出优异的效果和作用，特别是优异的药代吸收活性。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.
发明内容Summary of the invention
本发明的目的在于提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：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:
Figure PCTCN2016093584-appb-000001
Figure PCTCN2016093584-appb-000001
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：among them:
Figure PCTCN2016093584-appb-000002
选自顺式异构体、反式异构体和顺反异构体的混合物；
Figure PCTCN2016093584-appb-000002
a mixture selected from the group consisting of a cis isomer, a trans isomer, and a cis and trans isomer;
环A选自环烷基或杂环基，其中所述的环烷基、或杂环基各自独立地任选被选自烷基、卤素、氨基、硝基、羟基、烷氧基、羟烷基、氰基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)R4、-C(O)OR4、-S(O)mR4、-S(O)mNR5R6、-NR5R6、-C(O)NR5R6、-NR5C(O)R6和-NR5S(O)mR6中的一个或多个取代基所取代；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. , cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 4 , -C(O)R 4 , -C(O)OR 4 , -S(O) m R 4 ,- One of S(O) m NR 5 R 6 , -NR 5 R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)R 6 and -NR 5 S(O) m R 6 or Substituted by a plurality of substituents;
R1相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)R4、-(CH2)xC(O)OR4、-C(NH)NR5R6、-C(S)NR5R6、-S(O)mR4、-S(O)mNR5R6、-(CH2)xNR5R6、-(CH2)xC(O)NR5R6、-(CH2)xNR5C(O)R6和-(CH2)xNR5S(O)mR6，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-S(O)mNR7R8、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个 取代基所取代；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. 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, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl ,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 ,- Substituting one or more substituents of NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 and -NR 7 S(O) m R 8 ;
R2相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基和杂芳基；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. Base and heteroaryl;
R3选自烷基、卤代烷基、环烷基、环烷基烷氧基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、环烷基、环烷基烷氧基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、卤素、卤代烷基、氨基、硝基、羟基、烷氧基、羟烷基、氰基、环烷基、环烷基烷基、杂环基、芳基、杂芳基、-C(O)NR7R8、-S(O)mR7、-C(O)OR7、-OR7、-OR4、-C(O)R4、-C(O)OR4、-S(O)mR4、-S(O)mNR5R6、-NR5R6、-C(O)NR5R6、-NR5C(O)R6和-NR5S(O)mR6中的一个或多个取代基所取代；其中所述的环烷基烷基任选被选自烷基、卤素、卤代烷基、氨基、羟基、烷氧基、羟烷基中的一个或多个取代基所取代；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 NR 5 R 6 , -NR 5 R 6 , -C(O) Substituting one or more substituents of NR 5 R 6 , —NR 5 C(O)R 6 and —NR 5 S(O) m R 6 ; wherein said cycloalkylalkyl group is optionally selected from Substituted by one or more substituents of an alkyl group, a halogen, a halogenated alkyl group, an amino group, a hydroxyl group, an alkoxy group, or a hydroxyalkyl group;
R4选自氢原子、烷基、卤代烷基、羟基、氨基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、-NR7R8、-NR7C(O)R8和-NR7S(O)mR8，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、卤素、氨基、硝基、氰基、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个取代基所取代；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 , -S(O) m R 7 , -NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 and -NR 7 S (O) substituted with one or more substituents in m R 8 ;
R5和R6相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、羟烷基、羟基、氨基、环烷基、杂环基、芳基、杂芳基、-(CH2)xR3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-S(O)mNR7R8、-NR7R8、-(CH2)xC(O)NR7R8、-(CH2)xNR7C(O)R8和-(CH2)xNR7S(O)mR8，其中所述的烷基、卤代烷基、氨基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、卤代烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个取代基所取代；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. , -(CH 2 ) x 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, 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 One of -S(O) m R 7 , -NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 and -NR 7 S(O) m R 8 or Substituted by a plurality of substituents;
R7和R8相同或不同，且各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、-S(O)mNR9C(O)OR10、-C(O)OR10、-S(O)mNR9R10、环烷基、环烷基烷基、杂环基、芳基和杂芳基，其中所述的烷基、氨基、环烷基、环烷基烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；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 group, a heterocyclic group, an aryl group, and a heteroaryl group;
R9和R10相同或不同，且各自独立地选自氢原子、烷基、、氨基、烷氧基或羟烷基；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;
m为0、1或2；m is 0, 1 or 2;
n为0、1、2、3、4或5；n is 0, 1, 2, 3, 4 or 5;
p为0、1、2、3、4或5；且 p is 0, 1, 2, 3, 4 or 5;
x为0、1、2或3。x is 0, 1, 2 or 3.
在本发明一个优选的实施方案中，通式(I)所示的化合物，其中环A选自环烷基或杂环基，优选为C3-8的环烷基、或含有1个N原子的3-8元的单环杂环基或7-10元的桥杂环基，更优选为环己基、环丁基、四氢吡咯、哌啶基、环己亚胺，最优选为哌啶基、环己基。In a preferred embodiment of the invention, 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.
在本发明一个优选的实施方案中，通式(I)所示的化合物，其中n为1。In a preferred embodiment of the invention, the compound of formula (I) wherein n is 1.
在本发明一个优选的实施方案中，通式(I)所示的化合物，其中p为1或2。In a preferred embodiment of the invention, the compound of formula (I) wherein p is 1 or 2.
在本发明一个优选的实施方案中，通式(I)所示的化合物，其中R1相同或不同，且各自独立地选自氢原子、烷基、氨基、羟基、芳基、杂芳基、-C(O)R4、-(CH2)xC(O)OR4、-S(O)mR4、-S(O)mNR5R6、-(CH2)xNR5R6、-(CH2)xC(O)NR5R6、-(CH2)xNR5C(O)R6和-(CH2)xNR5S(O)mR6；其中所述的烷基、氨基、芳基和杂芳基各自独立地任选被选自硝基、氰基、-R3、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个取代基所取代；R3～R8、x和m如通式(I)中所定义。In a preferred embodiment of the invention, 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 7 C(O)R 8 And one or more substituents in -NR 7 S(O) m R 8 are substituted; R 3 to R 8 , x and m are as defined in the formula (I).
在本发明一个优选的实施方案中，通式(I)所示的化合物，其中R2为卤素、卤代烷基或烯基。In a preferred embodiment of the invention, the compound of formula (I) wherein R 2 is halogen, haloalkyl or alkenyl.
在本发明一个优选的实施方案中，通式(I)所示的化合物，其中R4选自氢原子、烷基、卤代烷基、羟基、氨基、烷氧基、卤代烷氧基、环烷基、杂环基。In a preferred embodiment of the invention, 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.
在本发明一个优选的实施方案中，通式(I)所示的化合物，其为通式(II)所示的化合物：In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (II):
Figure PCTCN2016093584-appb-000003
Figure PCTCN2016093584-appb-000003
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：R1、R2和p如通式(I)中所定义。Wherein: R 1 , R 2 and p are as defined in the formula (I).
在本发明一个优选的实施方案中，通式(II)所示的化合物，其为通式(III)所示的化合物： In a preferred embodiment of the invention, the compound of the formula (II) is a compound of the formula (III):
Figure PCTCN2016093584-appb-000004
Figure PCTCN2016093584-appb-000004
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：R1、R2和p如通式(I)中所定义。Wherein: R 1 , R 2 and p are as defined in the formula (I).
在本发明一个优选的实施方案中，通式(I)所示的化合物，其为通式(IV)所示的化合物：In a preferred embodiment of the invention, the compound of formula (I) is a compound of formula (IV):
Figure PCTCN2016093584-appb-000005
Figure PCTCN2016093584-appb-000005
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：among them:
环B选自芳基或杂芳基；Ring B is selected from aryl or heteroaryl;
Ra选自氢原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8；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. Base, -R 3 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 and -NR 7 S(O) m R 8 ;
R2、R3、R7、R8、m、和p如通式(I)中所定义；且R 2 , R 3 , R 7 , R 8 , m, and p are as defined in the formula (I);
y为0、1、2、3、4或5。y is 0, 1, 2, 3, 4 or 5.
在本发明一个优选的实施方案中，通式(I)所示的化合物，其为通式(V)所示的化合物：In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (V):
Figure PCTCN2016093584-appb-000006
Figure PCTCN2016093584-appb-000006
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：among them:
G选自C或N；G is selected from C or N;
Ra选自氢原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8； 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. Base, -R 3 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 and -NR 7 S(O) m R 8 ;
R2、R3、R7、R8、m、和p如通式(I)中所定义；且R 2 , R 3 , R 7 , R 8 , m, and p are as defined in the formula (I);
y为0、1、2、3、4或5。y is 0, 1, 2, 3, 4 or 5.
在本发明一个优选的实施方案中通式(I)所示的化合物，其为通式(VI)所示的化合物：In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (VI):
Figure PCTCN2016093584-appb-000007
Figure PCTCN2016093584-appb-000007
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：among them:
Ra选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-R3、-OR4、-C(O)R4、-C(O)OR4、-S(O)mR4、-S(O)mNR5R6、-NR5R6、-(CH2)xC(O)NR5R6、-(CH2)xNR5C(O)R6和-(CH2)xNR5S(O)mR6，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个取代基所取代；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, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy Base, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -R 3 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) Substituting one or more substituents of m R 7 , -NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 and -NR 7 S(O) m R 8 ;
R2～R8、m、x和p如通式(I)中所定义；且R 2 to R 8 , m, x and p are as defined in the general formula (I);
y为0、1、2、3、4或5的整数。y is an integer of 0, 1, 2, 3, 4 or 5.
在本发明一个优选的实施方案中，通式(I)所示的化合物，其为通式(V-A)所示的化合物：In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (V-A):
Figure PCTCN2016093584-appb-000008
Figure PCTCN2016093584-appb-000008
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：among them:
Rb选自氢原子、烷基、卤代烷基、氨基、环烷基、杂环基、芳基和杂芳基，其中所述的其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立 地任选被选自烷基、卤素、氨基、硝基、羟基、烷氧基、羟烷基、氰基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)R4、-C(O)OR4、-S(O)mR4、-S(O)mNR5R6、-NR5R6、-C(O)NR5R6、-NR5C(O)R6和-NR5S(O)mR6中的一个或多个取代基所取代；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 , -NR 5 C(O)R 6 and -NR 5 S(O) m R 6 ;
R4～R6和m如通式(I)中所定义。R 4 to R 6 and m are as defined in the formula (I).
本发明还提供了一种制备通式(I)所示的化合物的方法，该方法包括：The present invention also provides a process for the preparation of a compound of the formula (I), the process comprising:
Figure PCTCN2016093584-appb-000009
Figure PCTCN2016093584-appb-000009
通式(I-A)化合物在室温条件下，与R1NCO反应或者在低温下碱性条件下与R1的卤化物反应，任选在酸性条件下脱保护，得到通式(I)化合物；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);
其中，R1、R2、A、p和n如通式(I)中所定义。Wherein R 1 , R 2 , A, p and n are as defined in the formula (I).
在本发明一个优选的实施方案中，一种通式(I-B)所示化合物：In a preferred embodiment of the invention, a compound of the formula (I-B):
Figure PCTCN2016093584-appb-000010
Figure PCTCN2016093584-appb-000010
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，可作为制备通式(I)所示化合物；Or a tautomer, a mesophile, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, can be prepared as the formula (I) Compound shown;
其中，R1和n如权利通式(I)中所定义。Wherein R 1 and n are as defined in the formula (I).
本发明还提供了一种制备通式(I)所示化合物的方法，该方法包括：The invention also provides a process for the preparation of a compound of the formula (I), which process comprises:
Figure PCTCN2016093584-appb-000011
Figure PCTCN2016093584-appb-000011
通式(I-B)化合物在室温条件下与苯胺的衍生物反应，得到通式(I)化合物；The compound of the formula (I-B) is reacted with a derivative of aniline at room temperature to give a compound of the formula (I);
其中，R1、R2、A、p和n如通式(I)中所定义。Wherein R 1 , R 2 , A, p and n are as defined in the formula (I).
通式(I)的典型化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，包括但不限于：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:
Figure PCTCN2016093584-appb-000012
Figure PCTCN2016093584-appb-000012
Figure PCTCN2016093584-appb-000013
Figure PCTCN2016093584-appb-000013
Figure PCTCN2016093584-appb-000014
Figure PCTCN2016093584-appb-000014
Figure PCTCN2016093584-appb-000015
Figure PCTCN2016093584-appb-000015
Figure PCTCN2016093584-appb-000016
Figure PCTCN2016093584-appb-000016
Figure PCTCN2016093584-appb-000017
Figure PCTCN2016093584-appb-000017
Figure PCTCN2016093584-appb-000018
Figure PCTCN2016093584-appb-000018
Figure PCTCN2016093584-appb-000019
Figure PCTCN2016093584-appb-000019
Figure PCTCN2016093584-appb-000020
Figure PCTCN2016093584-appb-000020
Figure PCTCN2016093584-appb-000021
Figure PCTCN2016093584-appb-000021
Figure PCTCN2016093584-appb-000022
Figure PCTCN2016093584-appb-000022
Figure PCTCN2016093584-appb-000023
Figure PCTCN2016093584-appb-000023
Figure PCTCN2016093584-appb-000024
Figure PCTCN2016093584-appb-000024
Figure PCTCN2016093584-appb-000025
Figure PCTCN2016093584-appb-000025
Figure PCTCN2016093584-appb-000026
Figure PCTCN2016093584-appb-000026
Figure PCTCN2016093584-appb-000027
Figure PCTCN2016093584-appb-000027
Figure PCTCN2016093584-appb-000028
Figure PCTCN2016093584-appb-000028
Figure PCTCN2016093584-appb-000029
Figure PCTCN2016093584-appb-000029
Figure PCTCN2016093584-appb-000030
Figure PCTCN2016093584-appb-000030
Figure PCTCN2016093584-appb-000031
Figure PCTCN2016093584-appb-000031
Figure PCTCN2016093584-appb-000032
Figure PCTCN2016093584-appb-000032
Figure PCTCN2016093584-appb-000033
Figure PCTCN2016093584-appb-000033
Figure PCTCN2016093584-appb-000034
Figure PCTCN2016093584-appb-000034
Figure PCTCN2016093584-appb-000035
Figure PCTCN2016093584-appb-000035
Figure PCTCN2016093584-appb-000036
Figure PCTCN2016093584-appb-000036
Figure PCTCN2016093584-appb-000037
Figure PCTCN2016093584-appb-000037
通式(V)的典型化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，包括但不限于：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:
Figure PCTCN2016093584-appb-000038
Figure PCTCN2016093584-appb-000038
本发明的另一方面涉及一种药物组合物，其含有治疗有效剂量的通式(I)、(II)、(III)、(IV)、(IV-A)和(VI)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。本发明还涉及一种制备上述组合物的方法，其包括将通式(I)、(II)、(III)、(IV)、(IV-A)和(VI)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与药学上可接受的载体、稀释剂或赋形剂相混合。Another aspect of the invention relates to 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 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.
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备用于预防和/或治疗预防具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物中的用途。IDO抑制剂可以用于心脏障碍的抑制以及治疗其他具有IDO介导的色氨酸代谢途径的病理学特征的疾病，这些疾病包括诸如AIDS等病毒的感染，诸如莱姆病和链球菌感染等细胞感染、神经退行性病症(例如阿尔茨海默病、亨廷顿病和拍金森病)、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍、艾滋病、癌症(包括T细胞白血病和结肠癌)、眼睛疾病状态(例 如白内障和与年龄相关的黄化)以及自身免疫性疾病，其中所述的癌症可以选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。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. Infection, 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. 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.
本发明还涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，其用于预防和/或治疗预防具有IDO介导的色氨酸代谢途径的病理学特征的疾病。这些疾病包括诸如AIDS等病毒的感染，诸如莱姆病和链球菌感染等细胞感染、神经退行性病症(例如阿尔茨海默病、亨廷顿病和拍金森病)、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍、艾滋病、癌症(包括T细胞白血病和结肠癌)、眼睛疾病状态(例如白内障和与年龄相关的黄化)以及自身免疫性疾病，其中所述的癌症可以选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。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.
本发明还涉及一种治疗预防和/或治疗预防具有IDO介导的色氨酸代谢途径的病理学特征的疾病的方法，其包括向患者施用治疗有效剂量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。这些疾病包括诸如AIDS等病毒的感染，诸如莱姆病和链球菌感染等细胞感染、神经退行性病症(例如阿尔茨海默病、亨廷顿病和拍金森病)、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍、艾滋病、癌症(包括T细胞白血病和结肠癌)、眼睛疾病状态(例如白内障和与年龄相关的黄化)以及自身免疫性疾病，其中所述的癌症可以选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。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.
本发明另一方面涉及一种治疗癌症的方法，该方法包括向患者施用治疗有效剂量的本发明的通式(I)所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐。该方法显示出突出的疗效和较少的副作用，其中所述的癌症可以选自乳腺癌、宫颈癌、结肠癌、肺癌、 胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌，优选为输卵管肿瘤、腹膜肿瘤、IV期黑色素瘤、骨髓瘤和乳腺癌，更优选为乳腺癌。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.
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。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. These 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. For example, water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。It is also possible to use 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.
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶；分散剂或湿润剂可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。The aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such 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 A condensation product of a partial ester such as polyethylene oxide sorbitan monooleate. 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. Flavoring agents such as sucrose, saccharin or aspartame.
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油悬浮液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。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.
通过加入水可使适用于制备水混悬也的可分散粉末和颗粒提供活性成分和用 于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。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.
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂和由脂肪酸和己糖醇酐衍生的酯或偏酯例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。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.
药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Among the 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. For example, 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. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。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. In addition, 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. In addition, fatty acids such as oleic acid can also be prepared as an injection.
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。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. Such materials include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行被、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。As is well known to those skilled in the art, 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.
发明的详细说明Detailed description of the invention
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Terms used in the specification and claims have the following meanings unless stated to the contrary.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链 基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The term "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, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-B Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-B Hexyl group, 2,2- Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are 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.
术语“亚烷基”是指烷基的一个氢原子进一步被取代，例如：“亚甲基”指-CH2-、“亚乙基”指-(CH2)2-、“亚丙基”指-(CH2)3-、“亚丁基”指-(CH2)4-等。术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "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. The term "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.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至8个碳原子，更优选包含4至7个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。The term "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.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。 优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "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 π 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. 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 monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2016093584-appb-000039
Figure PCTCN2016093584-appb-000039
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：The term "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 π-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 fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2016093584-appb-000040
Figure PCTCN2016093584-appb-000040
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：The term "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 π-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. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2016093584-appb-000041
Figure PCTCN2016093584-appb-000041
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。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.
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3 至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3是杂原子；最优选包含3至6个环原子，其中1～2是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、四氢吡喃基等，优选哌啶基、吡咯烷基、吡喃基、四氢吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。The term "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. 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. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine. Base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydropyranyl, etc., preferably piperidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl Or morpholinyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：The term "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:
Figure PCTCN2016093584-appb-000042
Figure PCTCN2016093584-appb-000042
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：The term "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 π-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. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:
Figure PCTCN2016093584-appb-000043
Figure PCTCN2016093584-appb-000043
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数 目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：The term "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 π-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. Non-limiting examples of bridge heterocyclic groups include:
Figure PCTCN2016093584-appb-000044
Figure PCTCN2016093584-appb-000044
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：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:
Figure PCTCN2016093584-appb-000045
Figure PCTCN2016093584-appb-000045
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。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.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "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 π-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:
Figure PCTCN2016093584-appb-000046
Figure PCTCN2016093584-appb-000046
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。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.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、四唑基、四氮唑基、噻吩基、吡唑基或嘧啶基、噻唑基；更有选咪唑 基、吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "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 thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2016093584-appb-000047
Figure PCTCN2016093584-appb-000047
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。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.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of 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.
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
术语“环烷基烷基”指被一个或多个环烷基取代的烷基，其中环烷基、烷基如上所定义。例如，本发明中的一个优选实施例为环丙基取代的烷基。The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl, alkyl is as defined above. For example, a preferred embodiment of the invention is a cyclopropyl substituted alkyl group.
术语“环烷基烷氧基”指被一个或多个环烷基取代的烷氧基，其中环烷基、烷氧基如上所定义。例如，本发明中的一个优选实施例为环丙基取代的烷氧基。The term "cycloalkylalkoxy" refers to an alkoxy group substituted by one or more cycloalkyl groups, wherein cycloalkyl, alkoxy is as defined above. For example, a preferred embodiment of the invention is a cyclopropyl substituted alkoxy group.
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
术语“羟基”指-OH基团。The term "hydroxy" refers to an -OH group.
术语“卤素”指氟、氯、溴或碘。The term "halogen" means fluoro, chloro, bromo or iodo.
术语“氨基”指-NH2。The term "amino" means -NH 2.
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO2。The term "nitro" refers to -NO 2 .
术语“氧代基”指＝O。The term "oxo" refers to =0.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“异氰酸基”指-NCO。The term "isocyanato" refers to -NCO.
术语“肟基”指＝N-OH。 The term "mercapto" refers to =N-OH.
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基如上所定义。The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl is as defined above.
术语“酰卤”指含有-C(O)-卤素的基团的化合物。The term "acyl halide" refers to a compound containing a -C(O)-halogen group.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "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. .
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"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.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"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.
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"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.
本发明化合物的合成方法Method for synthesizing the compound of the present invention
为了完成本发明的目的，本发明采用如下技术方案：In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:
本发明通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：a compound of the formula (I) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a drug thereof The preparation method of the salt used includes the following steps:
Figure PCTCN2016093584-appb-000048
Figure PCTCN2016093584-appb-000048
方案一Option One
在高温酸性条件下(提供酸性条件的试剂优选为乙酸)，通式(a)化合物被氧化剂氧化为通式(b)化合物，该氧化剂优选二氧化硒；通式(b)化合物在碱性条件下(提供碱性条件的试剂优选为碳酸钾)，与盐酸羟胺在室温下进行反应，得到通式(c)化合物；将得到的通式(c)化合物在酸性条件下与N-氯代丁二酰亚胺反应， 得到通式(d)化合物；得到的通式(d)化合物在室温条件下与苯胺的衍生物反应，得到的通式(I-A)化合物；得到的通式(I-A)化合物在室温条件下与R1NCO反应或者在低温下碱性条件下与R1的卤化物反应，得到通式(I)化合物。Under high temperature acidic conditions (the reagent providing acidic conditions is preferably acetic acid), 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.
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾或碳酸铯。The reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. And 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.
所用的氧化剂包括但不限于：二氧化硒、双氧水、高锰酸钾或二氧化锰。The oxidizing agents used include, but are not limited to, selenium dioxide, hydrogen peroxide, potassium permanganate or manganese dioxide.
提供酸性条件的试剂包括但不限于甲酸、乙酸、盐酸、硫酸或甲磺酸。Agents that provide acidic conditions include, but are not limited to, formic acid, acetic acid, hydrochloric acid, sulfuric acid, or methanesulfonic acid.
其中：among them:
R1、R2、A、p和n如通式(I)中所定义。R 1 , R 2 , A, p and n are as defined in the formula (I).
Figure PCTCN2016093584-appb-000049
Figure PCTCN2016093584-appb-000049
方案二Option II
在高温酸性条件下(提供酸性条件的试剂优选为乙酸)，通式(e)化合物被氧化剂氧化为通式(f)化合物，该氧化剂优选二氧化硒；通式(f)化合物在碱性条件下(提供碱性条件的试剂优选为碳酸钾)，与盐酸羟胺在室温下进行反应，得到通式(g)化合物；将得到的通式(g)化合物在酸性条件下与N-氯代丁二酰亚胺反应，得到通式(I-B)化合物；得到的通式(I-B)化合物在室温条件下与苯胺的衍生物反应，得到通式(I)化合物。Under high temperature acidic conditions (the reagent providing acidic conditions is preferably acetic acid), 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).
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾或碳酸铯。The reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. And 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.
所用的氧化剂包括但不限于：二氧化硒、双氧水、高锰酸钾或二氧化锰。The oxidizing agents used include, but are not limited to, selenium dioxide, hydrogen peroxide, potassium permanganate or manganese dioxide.
提供酸性条件的试剂包括但不限于甲酸、乙酸、盐酸、硫酸或甲磺酸。Agents that provide acidic conditions include, but are not limited to, formic acid, acetic acid, hydrochloric acid, sulfuric acid, or methanesulfonic acid.
其中：among them:
R1、R2、A、p和n如通式(I)中所定义。R 1 , R 2 , A, p and n are as defined in the formula (I).
方案三 third solution
Figure PCTCN2016093584-appb-000050
Figure PCTCN2016093584-appb-000050
在低温下(优选为0℃)，碱性条件下(优选为三乙胺),通式(Ⅲ-a)化合物与R1的卤化物反应，得到通式(Ⅲ)化合物。At a low temperature (preferably 0 ° C), 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).
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾或碳酸铯。The reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. And 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.
R1、R2、和p如通式(II)或(III)中所定义。R 1 , R 2 , and p are as defined in the formula (II) or (III).
具体实施方式detailed description
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。The invention is further described in the following examples, which are not intended to limit the scope of the invention.
实施例Example
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)，化学位移是以10-6(ppm)作为单位给出。The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). 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. Methylsilane (TMS), chemical shifts are given in units of 10 -6 (ppm).
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo,型号：Finnigan LCQ advantage MAX)。The measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。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).
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。The average value of 50 measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产物采用的规格是0.4mm～0.5mm硅胶板。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.
柱层析一般使用烟台黄海200～300目硅胶为载体。Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH & Co.KG，Acros Organnics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。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.
实施例中如无特殊说明，反应均在氩气氛或氮气氛下进行。In the examples, unless otherwise specified, the reactions were all carried out under an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。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.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。 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.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
微波反应使用CEM Discover-S 908860型微波反应器。The microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
实施例中如无特殊说明，反应中的溶液是指水溶液。In the examples, the solution in the reaction means an aqueous solution unless otherwise specified.
实施例中如无特殊说明，反应的温度为室温。In the examples, the temperature of the reaction was room temperature unless otherwise specified.
室温为最适宜的反应温度，温度范围是20℃～30℃。Room temperature is the most suitable reaction temperature, and the temperature range is from 20 ° C to 30 ° C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). 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.
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：正己烷、乙酸乙酯和二氯甲烷体系，D：石油醚和乙酸乙酯体系，E：乙酸乙酯，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。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.
实施例1Example 1
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-苯基哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-phenylpiperidine-1-carboxamide
Figure PCTCN2016093584-appb-000051
Figure PCTCN2016093584-appb-000051
第一步first step
4-(2-羰基乙酰基)哌啶-1-甲酸叔丁酯4-(2-carbonylacetyl)piperidine-1-carboxylic acid tert-butyl ester
将二氧化硒(1.37g，0.012mol)置于反应瓶中，加入15mL 1,4-二氧六环，乙酸(0.24g，0.004mL)，0.23mL水，升温至90℃，加入预制的3mL 4-乙酰基哌啶-1-甲酸叔丁酯1a(1.4g，0.006mmol，采用公知的方法“Bioorganic & Medicinal Chemistry Letters,2011,21(5),1299-1305”制备而得)的1,4-二氧六环溶液，于90℃反应16小时。反应结束后，加入水10mL，用饱和碳酸氢钠溶液调节pH为8，用乙酸乙酯萃取(15mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(2-羰基乙酰基)哌啶-1-甲酸 叔丁酯1b(1.4g，黄色油状物)，产物不经纯化直接进行下一步反应。Selenium dioxide (1.37 g, 0.012 mol) was placed in a reaction flask, 15 mL of 1,4-dioxane, acetic acid (0.24 g, 0.004 mL), 0.23 mL of water, and the temperature was raised to 90 ° C, and the pre-made 3 mL was added. 4-acetylpiperidine-1-carboxylic acid tert-butyl ester 1a (1.4 g, 0.006 mmol, prepared by a known method "Bioorganic & Medicinal Chemistry Letters, 2011, 21 (5), 1299-1305"), The 4-dioxane solution was reacted at 90 ° C for 16 hours. After the reaction was completed, 10 mL of water was added, and the mixture was adjusted to pH 8 with a saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate (15 mL × 3), and the organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate Filtration and concentration of the filtrate under reduced pressure afforded crude title product 4-(2-carbonylacetyl)piperidine-1-carboxylic acid tert-Butyl ester 1b (1.4 g, yellow oil).
第二步Second step
4-(2-(肟基)乙酰基)哌啶-1-甲酸叔丁酯4-(2-(indolyl)acetyl)piperidine-1-carboxylic acid tert-butyl ester
将粗品4-(2-羰基乙酰基)哌啶-1-甲酸叔丁酯1b(1.4g，0.0058mol)溶于20mL甲醇中，加入碳酸钾(1.20g，0.0087mol)，加入盐酸羟胺(0.323g，0.0046mol)，于25℃搅拌下反应2小时。反应结束后，加入30mL乙酸乙酯，过滤，滤液减压浓缩得粗品标题产物4-(2-(肟基)乙酰基)哌啶-1-甲酸叔丁酯1c(1.1g，深黄色油状物)，产物不经纯化直接进行下一步反应。The crude 4-(2-carbonylacetyl)piperidine-1-carboxylic acid tert-butyl ester 1b (1.4 g, 0.0058 mol) was dissolved in methanol (20 mL), potassium carbonate (1.20 g, <RTI ID=0.0> g, 0.0046 mol), and reacted under stirring at 25 ° C for 2 hours. After completion of the reaction, 30 mL of ethyl acetate was added, and the filtrate was evaporated. The product was directly subjected to the next reaction without purification.
MS m/z(LC-MS):255.1[M-1]MS m/z (LC-MS): 255.1 [M-1]
第三步third step
4-(2-氯-2-(肟基)乙酰基)哌啶-1-甲酸叔丁酯4-(2-Chloro-2-(indenyl)acetyl)piperidine-1-carboxylic acid tert-butyl ester
将粗品4-(2-(肟基)乙酰基)哌啶-1-甲酸叔丁酯1c(1.1g，4.29mmol)加入10mLN,N-二甲基甲酰胺中，加入N-氯代丁二酰亚胺(573.1mg，4.29mmol)，加入5滴氯化氢的乙醚溶液，于25℃下搅拌反应1小时。反应结束后，加入20mL水，用乙酸乙酯萃取(15mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(20mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4-(2-氯-2-(肟基)乙酰基)哌啶-1-甲酸叔丁酯1d(2.0g，淡黄色油状物)，产物不经纯化直接进行下一步反应。The crude 4-(2-(indolyl)acetyl)piperidine-1-carboxylic acid tert-butyl ester 1c (1.1 g, 4.29 mmol) was added to 10 mL of N,N-dimethylformamide, and N-chlorobutane was added. The imide (573.1 mg, 4.29 mmol) was added with 5 drops of a solution of hydrogen chloride in diethyl ether, and the mixture was stirred at 25 ° C for 1 hour. After the completion of the reaction, 20 mL of water was added, and the mixture was combined with ethyl acetate (15 mL × 3), and the organic phase was combined, the organic phase was washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate The crude title product 4-(2-chloro-2-(indolyl)acetyl)piperidine-1-carboxylic acid tert-butyl ester 1d (2.0 g, pale yellow oil). .
第四步the fourth step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酸叔丁酯4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxylic acid tert-butyl ester
将粗品4-(2-氯-2-(肟基)乙酰基)哌啶-1-甲酸叔丁酯1d(1.45g，5mmol)和3-溴-4-氟苯胺(1.90g，10mmol)加入10mL乙醇中，于25℃下搅拌反应16小时。反应结束后，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酸叔丁酯1e(800mg，黄色固体)，收率36.0％。Add the crude 4-(2-chloro-2-(indolyl)acetyl)piperidine-1-carboxylic acid tert-butyl ester 1d (1.45 g, 5 mmol) and 3-bromo-4-fluoroaniline (1.90 g, 10 mmol) The reaction was stirred at 25 ° C for 16 hours in 10 mL of ethanol. After completion of the reaction, the reaction mixture was evaporated to dryness crystalljjjjjjjj tert-Butyl 2-(indolyl)acetyl)piperidine-1-carboxylate 1e (800 mg, yellow solid), yield 36.0%.
第五步the fifth step
N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(piperidin-4-yl)acetamidine
将4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酸叔丁酯1e(700mg，1.57mL)置于反应瓶中，加入10mL 4M的氯化氢1,4-二氧六环，于25℃下搅拌反应1小时。反应结束后，将反应液减压浓缩，得到粗品标题产物N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒1f(500mg，黄色固体)，产物不经纯化直接进行下一步反应。4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxylic acid tert-butyl ester 1e (700 mg, 1.57 mL) was placed in a reaction flask Medium, 10 mL of 4 M hydrogen chloride 1,4-dioxane was added, and the reaction was stirred at 25 ° C for 1 hour. After completion of the reaction, the reaction mixture was evaporated to dryness crystals crystals crystals crystals 1f (500 mg, yellow solid).
MS m/z(LC-MS):346.0[M+1]MS m/z (LC-MS): 346.0 [M+1]
第六步Step 6
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-苯基哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-phenylpiperidine-1-carboxamide
将苯胺(15mg，0.16mmol)溶于10mL四氢呋喃中，加入氯甲酸对硝基苯酯(32 mg，0.158mmol)，三乙胺(0.1mL，0.72mmol)，于25℃下搅拌反应30分钟，加入粗品N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒1f(55mg，0.159mmol)，于25℃下反应1小时，反应结束后，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，用5mL二氯甲烷打浆，得到标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-苯基哌啶-1-甲酰胺1(15mg，淡褐色固体)，收率20％。Aniline (15 mg, 0.16 mmol) was dissolved in 10 mL of tetrahydrofuran and p-nitrophenyl chloroformate was added (32 Mg, 0.158 mmol), triethylamine (0.1 mL, 0.72 mmol), was stirred at 25 ° C for 30 min, then was added N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl 2-(piperidin-4-yl)acetamidine 1f (55 mg, 0.159 mmol), which was reacted at 25 ° C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified and purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Pyridine-1-carboxamide 1 (15 mg, light brown solid), yield 20%.
MS m/z(LC-MS):463.2[M+1]MS m/z (LC-MS): 463.2 [M+1]
1H NMR(400MHz,DMSO-d6):δ11.69(s,1H),8.52(s,1H),8.40(s,1H),7.45(d,2H),7.16-7.24(m,3H),6.98-7.00(dd,1H),6.92(t,1H),6.70-6.73(m,1H),4.17-4.20(m,2H),3.52-3.57(m,1H),2.84-2.90(m,2H),1.85-1.87(m,2H),1.42-1.50(m,2H). 1 H NMR (400MHz, DMSO- d 6): δ11.69 (s, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 7.45 (d, 2H), 7.16-7.24 (m, 3H) , 6.98-7.00 (dd, 1H), 6.92 (t, 1H), 6.70-6.73 (m, 1H), 4.17-4.20 (m, 2H), 3.52-3.57 (m, 1H), 2.84-2.90 (m, 2H), 1.85-1.87 (m, 2H), 1.42-1.50 (m, 2H).
实施例2Example 2
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-苯腈)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-benzonitrile)piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000052
Figure PCTCN2016093584-appb-000052
将N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒1f(30mg，0.208mmol)溶于2mL四氢呋喃中，加入4-异氰酸苯甲腈2a(30mg，0.20mmol，采用公知的方法“Chemical & Pharmaceutical Bulletin,2012,60(8),1046-1054”制备而得)，于25℃下搅拌反应2小时。反应结束后，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-苯腈)哌啶-1-甲酰胺2(16mg，白色固体)，产率36％。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"), and 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%.
MS m/z(ESI):488.2[M+1]MS m/z (ESI): 488.2 [M+1]
1H NMR(400MHz,DMSO-d6):δ11.67(s,1H),9.01(s,1H),8.38(s,1H),7.67(s,4H),7.17(t,1H),6.98(dd,1H),6.70-6.73(m,1H),4.17-4.20(m,2H),3.53-3.59(m,1H),2.89-2.95(m,2H),1.86-1.89(m,2H),1.46-1.52(m,2H). 1 H NMR (400MHz, DMSO- d 6): δ11.67 (s, 1H), 9.01 (s, 1H), 8.38 (s, 1H), 7.67 (s, 4H), 7.17 (t, 1H), 6.98 (dd, 1H), 6.70-6.73 (m, 1H), 4.17-4.20 (m, 2H), 3.53-3.59 (m, 1H), 2.89-2.95 (m, 2H), 1.86-1.89 (m, 2H) , 1.46-1.52 (m, 2H).
实施例3Example 3
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-甲基-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺 4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-methyl-1H-pyrazol-4-yl) Phenyl) piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000053
Figure PCTCN2016093584-appb-000053
第一步first step
4-(4-异氰酸基苯基)-1-甲基-1H-吡唑4-(4-Isocyanophenyl)-1-methyl-1H-pyrazole
将4-(1-甲基-1H-吡唑-4-基)苯胺3a(24mg，0.14mmol，采用专利申请“WO2010132015”公开的方法制备而得)溶于10mL二氯甲烷中，加入三乙胺(42mg，0.42mmol)，将反应体系降温至0℃，于0℃加入三光气(14mg，0.05mmol)，于0℃搅拌反应30分钟。反应结束后，得到粗品标题产物4-(4-异氰酸基苯基)-1-甲基-1H-吡唑3b(28mg，0.14mmol)，产物不经纯化直接进行下一步。4-(1-Methyl-1H-pyrazol-4-yl)aniline 3a (24 mg, 0.14 mmol, prepared by the method disclosed in the patent application "WO2010132015") dissolved in 10 mL of dichloromethane, added to the triethyl The amine (42 mg, 0.42 mmol) was cooled to 0 ° C. EtOAc (EtOAc, EtOAc) After the reaction, the title product was obtained (yield: 4-(4-isocyanophenyl)-1-methyl-1H-pyrazole 3b (28 mg, 0.14 mmol).
第二步Second step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-甲基-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-methyl-1H-pyrazol-4-yl) Phenyl) piperidine-1-carboxamide
将粗品4-(4-异氰酸基苯基)-1-甲基-1H-吡唑3b(28mg，0.14mmol)溶于10mL二氯甲烷中，加入N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒1f(40mg，0.12mmol)，于25℃搅拌反应1小时。反应结束后，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-甲基-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺3(15mg，白色固体)，产率24％。The crude 4-(4-isocyanatophenyl)-1-methyl-1H-pyrazole 3b (28 mg, 0.14 mmol) was dissolved in 10 mL dichloromethane and N-(3-bromo-4-fluoro Phenyl)-N'-hydroxy-2-carbonyl-2-(piperidin-4-yl)acetamidine 1f (40 mg, 0.12 mmol) was stirred at 25 ° C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced vacuo. -(decyl)acetyl)-N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidine-1-carboxamide 3 (15 mg, white solid) %.
MS m/z(LC-MS):543.3[M-1]MS m/z (LC-MS): 543.3 [M-1]
1H NMR(400MHz,CD3OD):δ7.89(s,1H),7.76(s,1H),7.46(d,2H),7.36(d,2H),7.06-7.00(m,2H),6.80-6.76(m,1H),4.25-4.21(m,2H),3.92(s,3H),3.69-3.63(m,1H),3.05-2.99(m,2H),1.96-1.93(m,2H),1.70-1.60(m,2H). 1 H NMR (400MHz, CD 3 OD): δ7.89 (s, 1H), 7.76 (s, 1H), 7.46 (d, 2H), 7.36 (d, 2H), 7.06-7.00 (m, 2H), 6.80-6.76(m,1H), 4.25-4.21(m,2H), 3.92(s,3H),3.69-3.63(m,1H),3.05-2.99(m,2H),1.96-1.93(m,2H) ), 1.70-1.60 (m, 2H).
实施例4Example 4
N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(1-氨磺酰基哌啶-4-基)乙脒N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-sulfamoylpiperidin-4-yl)acetamidine
Figure PCTCN2016093584-appb-000054
Figure PCTCN2016093584-appb-000054
Figure PCTCN2016093584-appb-000055
Figure PCTCN2016093584-appb-000055
第一步first step
(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-基)磺酰基氨基甲酸叔丁酯(4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidin-1-yl)sulfonylcarbamic acid tert-butyl ester
将N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒1f(50mg，0.145mmol)溶于10mL二氯甲烷中，加入三乙胺(44mg，0.44mmol)，将反应体系降温至0℃，滴加预制的1mL氯磺酰基氨基甲酸叔丁酯4a(22mg，0.1mmol，采用专利申请“WO2010149684”公开的方法制备而得)的二氯甲烷溶液，于0℃搅拌反应1小时。反应结束后，加入5mL水，用二氯甲烷萃取(10mL×3)，合并有机相，用饱和氯化钠溶液洗涤(5mL)，用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-基)磺酰基氨基甲酸叔丁酯4b(60mg，无色油状物)，产率78％。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. After the reaction was completed, 5 mL of water was added, and the mixture was combined with methylene chloride (10 mL × 3), and the organic phase was combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate The resulting residue was purified to give titled product (4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1 Tert-butyl sulfonyl carbamate 4b (60 mg, colorless oil), yield 78%.
MS m/z(LC-MS):469.3[M-56+1]MS m/z (LC-MS): 469.3 [M-56+1]
第二步Second step
N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(1-氨磺酰基哌啶-4-基)乙脒N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-sulfamoylpiperidin-4-yl)acetamidine
将(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-基)磺酰基氨基甲酸叔丁酯4b(60mg，0.11mmol)溶于2mL甲醇中，加入2mL 4M的氯化氢1,4-二氧六环，反应体系于25℃搅拌反应1小时。反应结束后，加入5mL甲醇后减压浓缩，重复两次，所得残余物用氨水调节pH为10，用乙酸乙酯萃取(10mL×2)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(1-氨磺酰基哌啶-4-基)乙脒4(10mg，淡黄色固体)，产率21％。(4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidin-1-yl)sulfonylcarbamic acid tert-butyl ester 4b (60 mg, 0.11) Methyl) was dissolved in 2 mL of methanol, 2 mL of 4 M hydrogen chloride 1,4-dioxane was added, and the reaction was stirred at 25 ° C for 1 hour. After the reaction was completed, 5 mL of methanol was added, and the mixture was concentrated under reduced pressure, and the mixture was evaporated to dryness, and the residue was adjusted to pH 10 with aqueous ammonia, and extracted with ethyl acetate (10 mL×2). Concentration by pressure, the residue obtained was purified by EtOAc EtOAc (EtOAc) Sulfonylpiperidin-4-yl)acetamidine 4 (10 mg, pale yellow solid), yield 21%.
MS m/z(LC-MS):425.3[M+1]MS m/z (LC-MS): 425.3 [M+1]
1H NMR(400MHz,CD3OD):δ7.06-6.99(m,2H),6.79-6.76(m,1H),3.71-3.68(m,2H),3.50-3.44(m,1H),2.74-2.68(m,2H),2.00-1.98(m,2H),1.78-1.71(m,2H). 1 H NMR (400MHz, CD 3 OD): δ7.06-6.99 (m, 2H), 6.79-6.76 (m, 1H), 3.71-3.68 (m, 2H), 3.50-3.44 (m, 1H), 2.74 -2.68 (m, 2H), 2.00-1.98 (m, 2H), 1.78-1.71 (m, 2H).
实施例5Example 5
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(3-(甲基磺酰基)苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(3-(methylsulfonyl)phenyl)piperidine-1-yl Amide
Figure PCTCN2016093584-appb-000056
Figure PCTCN2016093584-appb-000056
Figure PCTCN2016093584-appb-000057
Figure PCTCN2016093584-appb-000057
第一步first step
1-异氰酸基-3-(甲基磺酰基)苯1-isocyanato-3-(methylsulfonyl)benzene
将3-(甲基磺酰基)苯胺盐酸盐5a(488mg，2.35mmol，采用公知的方法“Helvetica Chimica Acta,1981,64(6),1849-53”制备而得)加入30mL二氯甲烷中，加入三光气(220mg，0.74mmol)，三乙胺(0.37mL，2.66mmol)，反应体系于25℃搅拌反应30分钟，再回流反应45分钟，再于25℃反应30分钟。得标题产物1-异氰酸基-3-(甲基磺酰基)苯5b的反应液，产物不经纯化直接进行下一步反应。3-(Methylsulfonyl)aniline hydrochloride 5a (488 mg, 2.35 mmol, prepared by the well-known method "Helvetica Chimica Acta, 1981, 64 (6), 1849-53") was added to 30 mL of dichloromethane. Triphosgene (220 mg, 0.74 mmol), triethylamine (0.37 mL, 2.66 mmol) was added, and the reaction was stirred at 25 ° C for 30 minutes, refluxed for 45 minutes, and further reacted at 25 ° C for 30 minutes. The reaction product of the title product 1-isocyanato-3-(methylsulfonyl)benzene 5b was obtained, and the product was subjected to the next reaction without purification.
第二步Second step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(3-(甲基磺酰基)苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(3-(methylsulfonyl)phenyl)piperidine-1-yl Amide
将上述1-异氰酸基-3-(甲基磺酰基)苯5b的反应液取1mL加入预制的2mLN-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒1f(26mg，0.0755)的四氢呋喃溶液中，于25℃搅拌反应12小时。反应结束后，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，后用5mL二氯甲烷打浆得标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(3-(甲基磺酰基)苯基)哌啶-1-甲酰胺5(9mg，白色固体)，产率22％。1 mL of the above reaction solution of 1-isocyanato-3-(methylsulfonyl)benzene 5b was added to a pre-made 2 mL of N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl- 2-(piperidin-4-yl)acetamidine 1f (26 mg, 0.0755) in tetrahydrofuran was stirred at 25 ° C for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. m. Phenyl)amino)-2-(indolyl)acetyl)-N-(3-(methylsulfonyl)phenyl)piperidine-1-carboxamide 5 (9 mg, white solid).
MS m/z(ESI):541.3[M+1]MS m/z (ESI): 541.3 [M+1]
1H NMR(400MHz,DMSO-d6):δ11.68(s,1H),8.95(s,1H),8.39(s,1H),8.09(t,1H),7.82(d,1H),7.51(t,1H),7.46-7.49(m,1H),7.18(t,1H),6.98(dd,1H),6.72(ddd,1H),4.19-4.22(m,2H),3.54-3.59(m,1H),2.89-2.95(m,2H),1.86-1.89(m,2H),1.43-1.51(m,2H). 1 H NMR (400MHz, DMSO- d 6): δ11.68 (s, 1H), 8.95 (s, 1H), 8.39 (s, 1H), 8.09 (t, 1H), 7.82 (d, 1H), 7.51 (t, 1H), 7.46-7.49 (m, 1H), 7.18 (t, 1H), 6.98 (dd, 1H), 6.72 (ddd, 1H), 4.19-4.22 (m, 2H), 3.54-3.59 (m , 1H), 2.89-2.95 (m, 2H), 1.86-1.89 (m, 2H), 1.43-1.51 (m, 2H).
实施例6Example 6
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(3-氰基苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(3-cyanophenyl)piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000058
Figure PCTCN2016093584-appb-000058
第一步 First step
3-异氰酸基苯甲腈3-isocyanatobenzonitrile
将三光气(187mg，0.63mmol)溶于20mL四氢呋喃中，加入3-氨基苯甲腈6a(223mg，1.887mmol)和三乙胺(0.52mL，0.0876mmol)，反应体系于25℃搅拌反应1小时。得标题产物3-异氰酸基苯甲腈6b的悬浊液，产物不经纯化直接进行下一步反应。The 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.
第二步Second step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-氰基苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-cyanophenyl)piperidine-1-carboxamide
将上述3-异氰酸基苯甲腈6b的悬浊液取1mL加入预制的2mL N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒1f(30mg，0.0876mmol)的四氢呋喃溶液中，于25℃搅拌反应2小时。反应结束后，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(3-氰基苯基)哌啶-1-甲酰胺6(26mg，白色固体)，产率61.0％。Add 1 mL of the above suspension of 3-isocyanatobenzonitrile 6b to pre-formed 2 mL of N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(piperidine) The reaction was stirred at 25 ° C for 2 hours in a solution of -4-yl)ethyl acetate (30 mg, 0.0876 mmol) in tetrahydrofuran. After completion of the reaction, the reaction mixture was concentrated under reduced vacuo. -(Indolyl)acetyl)-N-(3-cyanophenyl)piperidine-1-carboxamide 6 (26 mg, white solid), yield 61.0%.
MS m/z(ESI):488.2[M+1]MS m/z (ESI): 488.2 [M+1]
1H NMR(400MHz,DMSO-d6):δ11.69(s,1H),8.88(s,1H),8.41(s,1H),7.94(s,1H),7.75(d,1H),7.45(t,1H),7.38(d,1H),7.18(t,1H),6.98(dd,1H),6.69-6.73(m,1H),4.17-4.20(m,2H),3.53-3.59(m,1H),2.88-2.94(m,2H),1.86-1.89(m,2H),1.43-1.51(m,2H). 1 H NMR (400MHz, DMSO- d 6): δ11.69 (s, 1H), 8.88 (s, 1H), 8.41 (s, 1H), 7.94 (s, 1H), 7.75 (d, 1H), 7.45 (t,1H), 7.38(d,1H), 7.18(t,1H), 6.98(dd,1H),6.69-6.73(m,1H), 4.17-4.20(m,2H),3.53-3.59(m , 1H), 2.88-2.94 (m, 2H), 1.86-1.89 (m, 2H), 1.43-1.51 (m, 2H).
实施例7Example 7
N-苄基-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺N-benzyl-4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000059
Figure PCTCN2016093584-appb-000059
将(异氰酸基甲基)苯7a(20mg，0.15mmol，采用公知的方法“Bioorganic & Medicinal Chemistry,2013,21(11),2960-2967”制备而得)加入预制的2mL N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒1f(30mg，0.0876)的四氢呋喃溶液中，于25℃搅拌反应2小时。反应结束后，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，用5mL二氯甲烷打浆，得标题产物N-苄基-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺7(6mg，白色固体)，产率14％。(Isocyanatomethyl)benzene 7a (20 mg, 0.15 mmol, prepared by the well-known method "Bioorganic & Medicinal Chemistry, 2013, 21 (11), 2960-2967") was added to the pre-made 2 mL N-(3) A solution of -bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(piperidin-4-yl)acetamidine 1f (30 mg, 0.0876) in tetrahydrofuran was stirred at 25 ° C for 2 hours. After completion of the reaction, the reaction mixture was evaporated to dryness mjjjjjjjjj Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide 7 (6 mg, white solid), yield 14%.
MS m/z(ESI):477.4[M+1]MS m/z (ESI): 477.4 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.37(s,1H),7.15-7.32(m,6H),7.09(t,1H),6.98(dd,1H),6.69-6.73(m,1H),4.24(d,2H),4.05-4.08(m,2H),3.47-3.53(m,1H), 2.74-2.80(m,2H),1.78-1.80(m,2H),1.35-1.43(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.86 (s, 1H), 8.37 (s, 1H), 7.15-7.32 (m, 6H), 7.09 (t, 1H), 6.98 (dd, 1H), 6.69-6.73 (m, 1H), 4.24 (d, 2H), 4.05-4.08 (m, 2H), 3.47-3.53 (m, 1H), 2.74-2.80 (m, 2H), 1.78-1.80 (m, 2H) ), 1.35-1.43 (m, 2H).
实施例8Example 8
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(甲磺酰基)苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(methylsulfonyl)phenyl)piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000060
Figure PCTCN2016093584-appb-000060
将1-异氰酸基-4-(甲磺酰基)苯(20mg，0.15mmol，采用公知的方法“Bioorganic & Medicinal Chemistry Letters,2010,20(4),7397-7400”制备而得)加入预制的2mLN-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒1f(30mg，0.0876)的四氢呋喃溶液中，于25℃搅拌反应12小时。反应结束后，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，用5mL二氯甲烷打浆，得标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(甲磺酰基)苯基)哌啶-1-甲酰胺8(13mg，白色固体)，产率27.7％。Addition of 1-isocyanato-4-(methylsulfonyl)benzene (20 mg, 0.15 mmol, prepared by the known method "Bioorganic & Medicinal Chemistry Letters, 2010, 20(4), 7397-7400") to prefabrication 2 mL of N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(piperidin-4-yl)acetamidine 1f (30 mg, 0.0876) in tetrahydrofuran at 25 ° C The reaction was stirred for 12 hours. After completion of the reaction, the reaction mixture was evaporated to dryness mjjjjjjjjjjj Phenyl)amino)-2-(indolyl)acetyl)-N-(4-(methylsulfonyl)phenyl)piperidine-1-carboxamide 8 (13 mg, white solid).
MS m/z(ESI):541.4[M+1]MS m/z (ESI): 541.4 [M+1]
1H NMR(400MHz,DMSO-d6):δ11.68(s,1H),9.04(s,1H),8.39(s,1H),7.77(d,2H),7.71(d,2H),7.17(t,1H),6.98(dd,1H),6.71(ddd,1H),4.18-4.21(m,2H),3.53-3.59(m,1H),3.14(s,3H),2.90-2.96(m,2H),1.87-1.90(m,2H),1.44-1.52(m,2H). 1 H NMR (400MHz, DMSO- d 6): δ11.68 (s, 1H), 9.04 (s, 1H), 8.39 (s, 1H), 7.77 (d, 2H), 7.71 (d, 2H), 7.17 (t, 1H), 6.98 (dd, 1H), 6.71 (ddd, 1H), 4.18-4.21 (m, 2H), 3.53-3.59 (m, 1H), 3.14 (s, 3H), 2.90-2.96 (m , 2H), 1.87-1.90 (m, 2H), 1.44-1.52 (m, 2H).
实施例9Example 9
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-吗啉基苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-morpholinylphenyl)piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000061
Figure PCTCN2016093584-appb-000061
Figure PCTCN2016093584-appb-000062
Figure PCTCN2016093584-appb-000062
将4-吗啉基苯胺(22mg，0.123mmol)溶于5mL四氢呋喃中，加入氯甲酸对硝基苯酯(25mg，0.124mmol)，三乙胺(0.04mL，0.288mmol)，于25℃反应30分钟，加入N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒1f(40mg，0.116mmol)，于25℃搅拌反应4小时。反应结束后，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-吗啉基苯基)哌啶-1-甲酰胺9(45mg，白色固体)，产率70％。4-Morolinyl aniline (22 mg, 0.123 mmol) was dissolved in 5 mL of THF. EtOAc (EtOAc (EtOAc:EtOAc) In a minute, N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(piperidin-4-yl)acetamidine 1f (40 mg, 0.116 mmol) was added and stirred at 25 ° C Reaction for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced vacuo. -(decyl)acetyl)-N-(4-morpholinylphenyl)piperidine-1-carboxamide 9 (45 mg, white solid), yield 70%.
MS m/z(ESI):548.4[M+1]MS m/z (ESI): 548.4 [M+1]
1H NMR(400MHz,DMSO-d6):δ11.68(s,1H),8.39(s,1H),8.31(s,1H),7.29(d,2H),7.18(t,1H),6.99(dd,1H),6.84(d,2H),6.71(ddd,1H),4.15-4.18(m,2H),3.72(t,4H),3.50-3.56(m,1H),3.01(t,4H),2.81-2.87(m,2H),1.83-1.86(m,2H),1.41-1.49(m,2H). 1 H NMR (400MHz, DMSO- d 6): δ11.68 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 7.29 (d, 2H), 7.18 (t, 1H), 6.99 (dd, 1H), 6.84 (d, 2H), 6.71 (ddd, 1H), 4.15-4.18 (m, 2H), 3.72 (t, 4H), 3.50-3.56 (m, 1H), 3.01 (t, 4H) ), 2.81-2.87 (m, 2H), 1.83-1.86 (m, 2H), 1.41-1.49 (m, 2H).
实施例10Example 10
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(氨磺酰氨基)苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(sulfamoylamino)phenyl)piperidine-1-yl Amide
Figure PCTCN2016093584-appb-000063
Figure PCTCN2016093584-appb-000063
Figure PCTCN2016093584-appb-000064
Figure PCTCN2016093584-appb-000064
第一步first step
N-(4-硝基苯基)氨磺酰氨基甲酸叔丁基酯N-(4-nitrophenyl)sulfamoylcarbamic acid tert-butyl ester
将氯磺酰氨基甲酸叔丁酯4a(1.6mg，7.52mmol)溶于50mL二氯甲烷中，加入4-硝基苯胺(988mg，7.5mmol)，加入三乙胺(1.5mL，10.8mmol)，于25℃反应48小时。反应结束后，将反应物减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，再用15mL二氯甲烷打浆，得到标题产物N-(4-硝基苯基)氨磺酰氨基甲酸叔丁基酯10b(1.4g，白色固体)，产率62％。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.jjjjjjjjjjjjj Tert-butyl amidocarboxylate 10b (1.4 g, white solid), yield 62%.
第二步Second step
N-(4-氨基苯基)氨磺酰氨基甲酸叔丁酯N-(4-Aminophenyl)sulfamoylcarbamic acid tert-butyl ester
将N-(4-硝基苯基)氨磺酰氨基甲酸叔丁基酯10b(1.4g，4.41mmol)溶于40mL甲醇中，加入280mg 10％的钯碳，反应体系用氢气置换三次，于25℃反应3小时。反应结束后，过滤，滤液减压浓缩，得粗品标题产物N-(4-氨基苯基)氨磺酰氨基甲酸叔丁酯10c(1.4g，淡褐色固体)，产物不经纯化直接进行下一步反应。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,jjjjjjjjjjjjjjjjjj reaction.
第三步third step
N-(4-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺)苯基)氨磺酰氨基甲酸叔丁酯N-(4-(4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide)phenyl)sulfamoylamino Tert-butyl formate
将粗品N-(4-氨基苯基)氨磺酰氨基甲酸叔丁酯10c(44mg，0.153mmol)溶于5mL四氢呋喃中，加入4-硝基苯甲酸(31mg，0.153mmol，Adamas)，三乙胺(0.03mL，0.216mmol)，于25℃反应30分钟，加入N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒1f(50mg，0.145mmol)，于25℃搅拌反应1小时。反应结束后，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物N-(4-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺)苯基)氨磺酰氨基 甲酸叔丁酯10d(41mg，白色固体)，产率43％。The crude 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. After completion of the reaction, the reaction mixture was evaporated to dryness crystalljjjjjjjjjjj Amino)-2-(indenyl)acetyl)piperidine-1-carboxamide)phenyl)sulfamoylamino Tert-butyl formate 10d (41 mg, white solid), yield 43%.
MS m/z(LC-MS):655.0[M-1]MS m/z (LC-MS): 655.0 [M-1]
第四步the fourth step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(氨磺酰氨基)苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(sulfamoylamino)phenyl)piperidine-1-yl Amide
将N-(4-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺)苯基)氨磺酰氨基甲酸叔丁酯10d(41mg，0.0623mmol)置于反应瓶中，加入4mL 4M的氯化氢1,4-二氧六环溶液，于25℃反应1小时。反应结束后，将反应液减压浓缩，用饱和碳酸氢钠溶液调节pH＞7，用乙酸乙酯萃取(25mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(氨磺酰氨基)苯基)哌啶-1-甲酰胺10(25mg，白色固体)，产率71％。N-(4-(4-(2-(3-Butyl-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide)phenyl)sulfamoyl Tert-butyl carbamate 10d (41 mg, 0.0623 mmol) was placed in a reaction flask, and 4 mL of a 4 M solution of hydrogen chloride 1,4-dioxane was added thereto, and the mixture was reacted at 25 ° C for 1 hour. After the reaction was completed, the reaction mixture was evaporated. EtOAcjjjjjjjjjj The resulting residue was purified by EtOAc (EtOAc) elut elut (4-(Aminosulfonylamino)phenyl)piperidine-1-carboxamide 10 (25 mg, white solid), yield 71%.
MS m/z(LC-MS):557.3[M+1]MS m/z (LC-MS): 557.3 [M+1]
1H NMR(400MHz,DMSO-d6):δ11.68(s,1H),9.14(s,1H),8.42(s,1H),8.39(s,1H),7.33(d,2H),7.18(t,1H),7.04(d,2H),6.98(dd,1H),6.94(s,2H),6.72(ddd,1H),4.15-4.19(m,2H),3.51-3.56(m,1H),2.83-2.88(m,2H),1.84-1.86(m,2H),1.41-1.49(m,2H). 1 H NMR (400MHz, DMSO- d 6): δ11.68 (s, 1H), 9.14 (s, 1H), 8.42 (s, 1H), 8.39 (s, 1H), 7.33 (d, 2H), 7.18 (t, 1H), 7.04 (d, 2H), 6.98 (dd, 1H), 6.94 (s, 2H), 6.72 (ddd, 1H), 4.15-4.19 (m, 2H), 3.51-3.56 (m, 1H) ), 2.83-2.88 (m, 2H), 1.84-1.86 (m, 2H), 1.41-1.49 (m, 2H).
实施例11Example 11
N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-((1r,4r)-4-((氨磺酰氨基)甲基)环己基)乙脒N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-((1r,4r)-4-((sulfamoylamino)methyl)cyclohexyl)acetamidine
Figure PCTCN2016093584-appb-000065
Figure PCTCN2016093584-appb-000065
第一步first step
(((1r,4r)-4-(2-羰基乙酰基)环己基)甲基)氨基甲酸叔丁酯(((1r,4r)-4-(2-carbonylacetyl)cyclohexyl)methyl)carbamic acid tert-butyl ester
将(((1r,4r)-4-((Z)-2-(肟基)乙酰基)环己基)甲基)氨基甲酸叔丁酯11a(6.623g， 0.026mol，采用公知的方法“Bioorganic & Medicinal Chemistry,2003,11(7),1319-1341”制备而得)加入200mL 1,4-二氧六环和993μL水中，加入二氧化硒(5.756g，0.052mol)，993μL乙酸，于80℃搅拌反应17小时。反应结束后，加入300mL水，用二氯甲烷萃取(150mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题产物(((1r,4r)-4-(2-羰基乙酰基)环己基)甲基)氨基甲酸叔丁酯11b(3.71g，黄色固体)，产率53.1％。tert-Butyl ((1r,4r)-4-((Z)-2-(indenyl)acetyl)cyclohexyl)methyl)carbamate 11a (6.623 g, 0.026 mol, prepared by a known method "Bioorganic & Medicinal Chemistry, 2003, 11 (7), 1319-1341") was added to 200 mL of 1,4-dioxane and 993 μL of water, and selenium dioxide (5.756 g, 0.052 mol), 993 μL of acetic acid, and the reaction was stirred at 80 ° C for 17 hours. After completion of the reaction, 300 mL of water was added, and the mixture was extracted with dichloromethane (150 mL × 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product ((1r,4r)-4-(2-carbonylacetyl)cyclohexyl)methyl)carbamic acid tert-butyl ester 11b (3.71 g, yellow solid).
第二步Second step
(((1r,4r)-4-(2-(肟基)乙酰基)环己基)甲基)氨基甲酸叔丁酯(((1r,4r)-4-(2-(indolyl)acetyl)cyclohexyl)methyl)carbamic acid tert-butyl ester
将(((1r,4r)-4-(2-羰基乙酰基)环己基)甲基)氨基甲酸叔丁酯11b(2.4g，8.911mmol)加入10mL甲醇中，加入盐酸羟胺(619mg，8.911mmol)，碳酸钾(1.847g，13.366mmol)加入反应瓶中，于25℃搅拌反应1小时。反应结束后，加入200mL乙酸乙酯，过滤，滤液减压浓缩得粗品标题产物(((1r,4r)-4-(2-(肟基)乙酰基)环己基)甲基)氨基甲酸叔丁酯11c(2.132g，浅棕黄色固体)，产物不经纯化直接进行下一步反应。tert-Butyl ((1r,4r)-4-(2-carbonylacetyl)cyclohexyl)methyl)carbamate 11b (2.4g, 8.911mmol) was added to 10mL of methanol, then hydroxylamine hydrochloride (619mg, 8.911mmol) Potassium carbonate (1.847 g, 13.366 mmol) was placed in a reaction flask, and the reaction was stirred at 25 ° C for 1 hour. After completion of the reaction, 200 mL of ethyl acetate was added, and the mixture was filtered. Ester 11c (2.132 g, light brown solid), product was taken to the next step without purification.
MS m/z(LC-MS):283[M-1]MS m/z (LC-MS): 283 [M-1]
第三步third step
(((1r,4r)-4-(2-氯-2-(肟基)乙酰基)环己基)甲基)氨基甲酸叔丁酯(((1r,4r)-4-(2-Chloro-2-(indenyl)acetyl)cyclohexyl)methyl)carbamic acid tert-butyl ester
将粗品(((1r,4r)-4-(2-(肟基)乙酰基)环己基)甲基)氨基甲酸叔丁酯11c(2.1g，7.385mmol)加入80mL N,N-二甲基甲酰胺中，加入N-氯代丁二酰亚胺(986mg，7.385mmol)，于25℃搅拌反应2小时。反应结束后，加入200mL乙酸乙酯，有机相用水洗涤(100mL×3)，饱和氯化钠溶液洗涤(100mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物(((1r,4r)-4-(2-氯-2-(肟基)乙酰基)环己基)甲基)氨基甲酸叔丁酯11d(1.788g，黄色油状物)，产物不经纯化直接进行下一步反应。Add the crude ((1r,4r)-4-(2-(indolyl)acetyl)cyclohexyl)methyl)carbamic acid tert-butyl ester 11c (2.1 g, 7.385 mmol) to 80 mL of N,N-dimethyl N-chlorosuccinimide (986 mg, 7.385 mmol) was added to the formamide, and the reaction was stirred at 25 ° C for 2 hours. After the reaction was completed, 200 mL of ethyl acetate was added, and the organic phase was washed with water (100 mL×3), washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate ((1r,4r)-4-(2-Chloro-2-(indenyl)acetyl)cyclohexyl)methyl)carbamic acid tert-butyl ester 11d (1.788 g, yellow oil). The next step is to react.
第四步the fourth step
(((1r,4r)-4(-2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环己基)甲基)氨基甲酸叔丁酯((1r,4r)-4(-2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclohexyl)methyl)carbamic acid tert-butyl ester
将粗品(((1r,4r)-4-(2-氯-2-(肟基)乙酰基)环己基)甲基)氨基甲酸叔丁酯11d(1.788g，5.608mmol)和3-溴-4-氟苯胺(2.131g，11.217mol)加入80mL乙醇中，于25℃下搅拌反应17小时。反应结束后，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到标题产物(((1r,4r)-4(-2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环己基)甲基)氨基甲酸叔丁酯11e(543mg，黄色固体)，收率20.5％。The crude product ((1r,4r)-4-(2-chloro-2-(indolyl)acetyl)cyclohexyl)methyl)carbamic acid tert-butyl ester 11d (1.788 g, 5.608 mmol) and 3-bromo- 4-Fluoroaniline (2.131 g, 11.217 mol) was added to 80 mL of ethanol, and the reaction was stirred at 25 ° C for 17 hours. After completion of the reaction, the reaction mixture was evaporated to dryness crystalljjjjjjjjjjj -Fluorophenyl)amino)-2-(indolyl)acetyl)cyclohexyl)methyl)carbamic acid tert-butyl ester 11e (543 mg, yellow solid).
MS m/z(LC-MS):471.8[M-1]MS m/z (LC-MS): 471.8 [M-1]
第五步the fifth step
2-((1r,4r)-4-(氨基甲基)环己基)-N-(3-溴-4-氟苯基)-N'-羟基-2-羰基乙脒 2-((1r,4r)-4-(aminomethyl)cyclohexyl)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonylacetamidine
将(((1r,4r)-4(-2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环己基)甲基)氨基甲酸叔丁酯11e(140mg，0.296mL)置于反应瓶中，加入2mL甲醇，加入2.5mL 4M的氯化氢1,4-二氧六环，于25℃下搅拌反应30分钟。反应结束后，将反应液减压浓缩，得到粗品标题产物2-((1r,4r)-4-(氨基甲基)环己基)-N-(3-溴-4-氟苯基)-N'-羟基-2-羰基乙脒11f(130mg，黄色油状物)，产物不经纯化直接进行下一步反应。(((1r,4r)-4(-2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclohexyl)methyl)carbamic acid tert-butyl ester 11e (140 mg, 0.296 mL) was placed in a reaction flask, 2 mL of methanol was added, 2.5 mL of 4 M hydrogen chloride 1,4-dioxane was added, and the reaction was stirred at 25 ° C for 30 minutes. After completion of the reaction, the reaction mixture was evaporated to dryness crystals crystals crystals '-Hydroxy-2-carbonylacetam 11f (130 mg, yellow oil).
MS m/z(LC-MS):372[M+1]MS m/z (LC-MS): 372 [M+1]
第六步Step 6
N-(((1r,4r)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环己基)甲基)氨磺酰氨基甲酸叔丁酯N-(((1r,4r)-4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclohexyl)methyl)sulfamoylcarbamic acid Tert-butyl ester
将氯磺酰基异氰酸酯(42mg，0.296mmol)溶于2mL二氯甲烷中，降温至0℃，加入叔丁醇(22mg，0.296mmol)，于0℃搅拌反应15分钟后备用。将粗品2-((1r,4r)-4-(氨基甲基)环己基)-N-(3-溴-4-氟苯基)-N'-羟基-2-羰基乙脒11f(110mg，0.296mmol)，2mL二氯甲烷和三乙胺(124μL，0.886mmol)加入反应瓶中，加入上述备用液，于25℃搅拌反应1小时。反应结束后，加入50mL二氯甲烷，依次用饱和碳酸氢钠溶液(30mL×2)、水(30mL×2)、饱和氯化钠溶液(30mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物N-(((1r,4r)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环己基)甲基)氨磺酰氨基甲酸叔丁酯11g(132mg，黄色固体)，产物不经纯化直接进行下一步反应。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. The crude 2-((1r,4r)-4-(aminomethyl)cyclohexyl)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonylacetam 11f (110 mg, 0.296 mmol), 2 mL of dichloromethane and triethylamine (124 μL, 0.886 mmol) were placed in a reaction flask, and the above-mentioned stock solution was added thereto, and the reaction was stirred at 25 ° C for 1 hour. After completion of the reaction, 50 mL of dichloromethane was added, and the mixture was washed successively with a saturated sodium hydrogen carbonate solution (30 mL×2), water (30 mL×2), and a saturated sodium chloride solution (30 mL×2), and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure afforded crude title product N-(((1r,4r)-4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl) Cyclohexyl)methyl)sulfamoylcarbamic acid tert-butyl ester 11 g (132 mg, yellow solid).
MS m/z(LC-MS):551.0[M+1]MS m/z (LC-MS): 551.0 [M+1]
第七步Seventh step
N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-((1r,4r)-4-((氨磺酰氨基)甲基)环己基)乙脒N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-((1r,4r)-4-((sulfamoylamino)methyl)cyclohexyl)acetamidine
将粗品N-(((1r,4r)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环己基)甲基)氨磺酰氨基甲酸叔丁酯11g(132mg，0.239mmol)溶于2mL甲醇中，加入2mL 4M的氯化氢1,4-二氧六环溶液，反应体系于25℃搅拌反应3小时。反应结束后，将反应液减压浓缩，加入50mL二氯甲烷，依次用饱和碳酸氢钠溶液(50mL×3)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-((1r,4r)-4-((氨磺酰氨基)甲基)环己基)乙脒11(45mg，淡黄色固体)，收率41.7％The crude N-(((1r,4r)-4-(2-((3-bromo-4-fluorophenyl)amino))-2-(indolyl)acetyl)cyclohexyl)methyl)sulfonyl 11 g of tert-butyl carbamate (132 mg, 0.239 mmol) was dissolved in 2 mL of methanol, and 2 mL of 4M hydrogen chloride 1,4-dioxane solution was added, and the reaction was stirred at 25 ° C for 3 hours. After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Chromatography The residue obtained was purified to give the titled product N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-((1r,4r)-4-( (Aminosulfonylamino)methyl)cyclohexyl)ethyl hydrazine 11 (45 mg, pale yellow solid), yield 41.7%
MS m/z(LC-MS):451[M+1]MS m/z (LC-MS): 451 [M+1]
1H NMR(400MHz,DMSO-d6):δ11.60(s,1H),8.32(s,1H),7.18-7.14(m,1H),6.97-6.95(m,1H),6.71-6.67(m,1H),6.49-6.44(m,3H),3.28-3.22(m,1H),2.74-2.67(m,2H),1.88-1.85(m,4H),1.45-1.28(m,3H),0.98-0.87(m,2H). 1 H NMR (400MHz, DMSO- d 6): δ11.60 (s, 1H), 8.32 (s, 1H), 7.18-7.14 (m, 1H), 6.97-6.95 (m, 1H), 6.71-6.67 ( m,1H), 6.49-6.44 (m, 3H), 3.28-3.22 (m, 1H), 2.74-2.67 (m, 2H), 1.88-1.85 (m, 4H), 1.45-1.28 (m, 3H), 0.98-0.87 (m, 2H).
实施例12Example 12
2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)-N-苯基乙酰胺 2-(3-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)-N-phenylacetamide
Figure PCTCN2016093584-appb-000066
Figure PCTCN2016093584-appb-000066
第一步first step
2-(3-(甲氧基(甲基)氨基甲酰基)环丁亚基)乙酸乙酯Ethyl 2-(3-(methoxy(methyl)carbamoyl)cyclobutylidene)
将50mL四氢呋喃置于反应瓶中，冰浴冷却至0℃，分批小心加入氢化钠固体(60％,1.76g,0.044mol)，10分钟后加入磷酰基乙酸三乙酯(9.86g，0.044mol)的四氢呋喃溶液，并于0℃持续搅拌30分钟，然后加入预制的N-甲氧基-N-甲基-3-羰基环丁甲酰胺12a(6.28g，0.04mol，采用专利申请“WO2009114512”公开的方法制备而得)的四氢呋喃溶液，并逐步升至25℃反应30分钟，TLC监测反应的进行。反应结束后，加入10mL水淬灭反应，加入水和乙酸乙酯各200mL萃取分液，有机相用水，饱和氯化钠溶液洗涤(30×3mL)，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物2-(3-(甲氧基(甲基)氨基甲酰基)环丁亚基)乙酸乙酯12b(8.0g，黄色液体)，产率88.0％。50 mL of tetrahydrofuran was placed in a reaction flask, cooled to 0 ° C in an ice bath, and sodium hydride solid (60%, 1.76 g, 0.044 mol) was carefully added in portions, and after 10 minutes, triethylphosphorylacetate (9.86 g, 0.044 mol) was added. a solution of tetrahydrofuran and stirring at 0 ° C for 30 minutes, then adding pre-formed N-methoxy-N-methyl-3-carbonylcyclobutanamide 12a (6.28 g, 0.04 mol, using the patent application "WO2009114512" The tetrahydrofuran solution prepared by the disclosed method was gradually raised to 25 ° C for 30 minutes, and the reaction was monitored by TLC. After the reaction was completed, the reaction was quenched by the addition of 10 mL of water, and water and ethyl acetate (200 mL) were added to separate the mixture. The organic phase was washed with water and saturated sodium chloride solution (30×3 mL), and the organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced vacuo. 8.0 g, yellow liquid), yield 88.0%.
MS m/z(LC-MS):228.2[M+1]MS m/z (LC-MS): 228.2 [M+1]
第二步Second step
2-(3-(甲氧基(甲基)氨基甲酰基)环丁基)乙酸乙酯2-(3-(methoxy(methyl)carbamoyl)cyclobutyl)acetate
将2-(3-(甲氧基(甲基)氨基甲酰基)环丁亚基)乙酸乙酯12b(8.0g，0.035mol)溶于80mL乙酸乙酯中，加入10％钯碳(800mg)，氢气置换3次，并在氢气氛下持 续搅拌3天，TLC监测反应的进行。待反应结束后，过滤除去钯碳，滤液减压浓缩得粗品标题产物2-(3-(甲氧基(甲基)氨基甲酰基)环丁基)乙酸乙酯12c(7.4g，黄色液体)，产物不经纯化直接进行下一步反应，产率91.8％。2-(3-(Methoxy(methyl)carbamoyl)cyclobutylidene) Ethyl Acetate 12b (8.0 g, 0.035 mol) was dissolved in ethyl acetate (80 mL), 10% palladium carbon (800 mg), hydrogen Replace 3 times and hold under hydrogen atmosphere Stirring was continued for 3 days, and the reaction was monitored by TLC. After the completion of the reaction, the palladium carbon was removed by filtration, and the filtrate was evaporated to dryness crystals. The product was directly subjected to the next reaction without purification, yield 91.8%.
MS m/z(LC-MS):230.2[M+1]MS m/z (LC-MS): 230.2 [M+1]
第三步third step
2-(3-乙酰环丁基)乙酸乙酯2-(3-acetylcyclobutyl)acetate
将粗品2-(3-(甲氧基(甲基)氨基甲酰基)环丁基)乙酸乙酯12c(7.4g，32.3mmol)加入50mL四氢呋喃中，冰浴冷却至0℃，滴加1.0M甲基溴化镁溶液(65mL，64.6mmol)，并在0℃搅拌30分钟。反应结束后，加入100mL饱和氯化铵溶液淬灭反应，然后加入水以及乙酸乙酯各100mL，反应混合体系分液，有机相用水，饱和氯化钠溶液洗涤(50mL×3)，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到标题产物2-(3-乙酰环丁基)乙酸乙酯12d(4.5g，无色液体)，产率88.0％。The crude ethyl 2-(3-(methoxy(methyl)carbamoyl)cyclobutyl)acetate 12c (7.4 g, 32.3 mmol) was added to 50 mL of THF, cooled to 0 ° C, Methylmagnesium bromide solution (65 mL, 64.6 mmol) was stirred at 0 °C for 30 min. After the reaction is completed, the reaction is quenched by adding 100 mL of a saturated ammonium chloride solution, then 100 mL of water and ethyl acetate are added, and the reaction mixture is separated, and the organic phase is washed with water and a saturated sodium chloride solution (50 mL×3), and the organic phase is collected. The residue was dried over anhydrous sodium sulfate (MgSO4). , colorless liquid), yield 88.0%.
第四步the fourth step
2-(3-(2-羰基乙酰基)环丁基)乙酸乙酯2-(3-(2-carbonylacetyl)cyclobutyl)acetate
将2-(3-乙酰环丁基)乙酸乙酯12d(2.0g，10.85mmol)和二氧化硒(2.4g，21.7mmol)加入20mL二氧六环中，加热至80℃反应12小时。次日，过滤，滤液减压浓缩得粗品标题产物2-(3-(2-羰基乙酰基)环丁基)乙酸乙酯12e(2.0g，红色液体)产物不经纯化直接进行下一步反应，产率93.0％。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. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The yield was 93.0%.
第五步the fifth step
2-(3-(2-(肟基)乙酰基)环丁基)乙酸乙酯2-(3-(2-(indolyl)acetyl)cyclobutyl)acetate
将粗品2-(3-(2-羰基乙酰基)环丁基)乙酸乙酯12e(2.0g，10.1mmol)置于反应瓶中，加入20mL甲醇，分别加入碳酸钾(2.1g，15mmol)，盐酸羟胺(702mg，10.1mmol)，并在25℃下搅拌反应1小时。反应结束后，垫硅胶过滤，滤液减压浓缩得粗品标题产物2-(3-(2-(肟基)乙酰基)环丁基)乙酸乙酯12f(2.0g，红色液体)，产物不经纯化直接进行下一步反应，产率95.2％。The crude ethyl 2-(3-(2-carbonylacetyl)cyclobutyl)acetate 12e (2.0 g, 10.1 mmol) was placed in a reaction flask, and 20 mL of methanol was added, and potassium carbonate (2.1 g, 15 mmol) was added. Hydroxylamine hydrochloride (702 mg, 10.1 mmol) was stirred at 25 ° C for 1 hour. After completion of the reaction, the pad was filtered over silica gel, EtOAcjjjjjjjjjj Purification was carried out directly to the next reaction in a yield of 95.2%.
MS m/z(LC-MS):214.3[M+1]MS m/z (LC-MS): 214.3 [M+1]
第六步Step 6
2-(3-(2-氯-2-(肟基)乙酰基)环丁基)乙酸乙酯2-(3-(2-chloro-2-(indolyl)acetyl)cyclobutyl)acetate
将粗品2-(3-(2-(肟基)乙酰基)环丁基)乙酸乙酯12f(2.0g，9.38mmol)溶于20mL N,N-二甲基甲酰胺中，加入4滴氯化氢乙醚溶液，然后加入N-氯代琥珀酰亚胺(1.25g，9.38mmol)，并在25℃下搅拌反应1小时。反应结束后，加入水以及乙酸乙酯各50mL，分液，有机相用水，饱和氯化钠溶液洗涤(30mL×3)，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品标题产物2-(3-(2-氯-2-(肟基)乙酰基)环丁基)乙酸乙酯12g(2.0g，黄色液体)，产物不经纯化直接进行下一步反应，产率86.9％。 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). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, The title product ethyl 2-(3-(2-chloro-2-(indolyl)acetyl)cyclobutyl)acetate 12 g (2.0 g, m.). %.
第七步Seventh step
2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)乙酸乙酯Ethyl 2-(3-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)acetate
将粗品2-(3-(2-氯-2-(肟基)乙酰基)环丁基)乙酸乙酯12g(2.0g，8.07mmol)溶于20mL乙醇中，加入3-溴-4-氟苯胺12h(2.3g，12.1mmol)，并在25℃下搅拌反应3天。反应结束后，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到标题产物2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)乙酸乙酯12i(1.5g，黄色液体)，产率46.3％。The crude ethyl 2-(3-(2-chloro-2-(indolyl)acetyl)cyclobutyl)acetate 12 g (2.0 g, 8.07 mmol) was dissolved in 20 mL of ethanol and then 3-bromo-4-fluoro Aniline 12 h (2.3 g, 12.1 mmol) was stirred at 25 ° C for 3 days. After completion of the reaction, the reaction mixture was evaporated to dryness mjjjjjjjj Ethylamino-2-(indenyl)acetyl)cyclobutyl)acetate 12i (1.5 g, yellow liquid), yield 46.3%.
MS m/z(LC-MS):401.3[M+1]MS m/z (LC-MS): 401.3 [M+1]
第八步Eighth step
2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)乙酸2-(3-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)acetic acid
将2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)乙酸乙酯12i(1.5g，3.74mmol)溶于23mL四氢呋喃和水的混合溶液(V:V＝15:8)中，加入氢氧化锂一水合物(314mg，7.48mmol)，加热至50℃持续搅拌2小时。反应结束后，将反应液减压浓缩除去大部分有机溶剂，残余物加入水和二氯甲烷各100mL，分液，水相用6N盐酸调节pH至3～4，水相用二氯甲烷萃取(50mL×3)，收集的有机相用水，饱和氯化钠溶液洗涤(30×3mL)，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品标题产物2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)乙酸12j(900mg，黄色固体)，产物不经纯化直接进行下一步反应，产率64.7％。Ethyl 2-(3-(2-(3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)acetate 12i (1.5 g, 3.74 mmol) To a mixed solution of 23 mL of tetrahydrofuran and water (V: V = 15:8), lithium hydroxide monohydrate (314 mg, 7.48 mmol) was added, and the mixture was heated to 50 ° C and stirred for 2 hours. After completion of the reaction, the 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%.
MS m/z(LC-MS):373.3[M+1]MS m/z (LC-MS): 373.3 [M+1]
第九步Step 9
2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)-N-苯基乙酰胺2-(3-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)-N-phenylacetamide
将粗品2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)乙酸12j(30mg，0.08mmol)溶于10mL二氯甲烷中，氩气置换三次，在氩气氛下加入草酰氯(51mg，0.40mmol)，于0℃搅拌2小时，反应液减压浓缩，备用。在残余物中加入10mL二氯甲烷，苯胺(15mg，0.16mmol)，N,N-二异丙基乙胺(31mg，0.24mmol)，搅拌均匀，并在25℃条件下反应30分钟，TLC监测反应的进行。反应结束后，加入水和二氯甲烷各30mL，分液，有机相用水，饱和氯化钠溶液洗涤(30×3mL)，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残留物，得到标题产物2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)-N-苯基乙酰胺12(10mg，白色固体)，产率27.8％。The crude 2-(3-(2-(3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)acetic acid 12j (30 mg, 0.08 mmol) was dissolved in 10 mL In the methyl chloride, argon gas was replaced three times, and oxalyl chloride (51 mg, 0.40 mmol) was added under an argon atmosphere, and the mixture was stirred at 0 ° C for 2 hr. 10 mL of dichloromethane, aniline (15 mg, 0.16 mmol), N,N-diisopropylethylamine (31 mg, 0.24 mmol) was added to the residue, stirred well, and reacted at 25 ° C for 30 minutes, TLC monitoring The reaction proceeds. After the reaction, 30 mL of water and dichloromethane were added, and the organic layer was washed with water and saturated sodium chloride solution (30×3 mL). The residue obtained was purified by silica gel column chromatography elutd elut elut elut elut Cyclobutyl)-N-phenylacetamide 12 (10 mg, white solid), yield 27.8%.
MS m/z(LC-MS):448.3[M+1]MS m/z (LC-MS): 448.3 [M+1]
1H NMR(400MHz,DMSO-d6):δ11.58(s,1H),9.84(s,1H),8.31(s,1H),7.55-7.57(m,2H),7.25-7.29(m,2H),7.13-7.18(m,1H),6.97-7.01(m,2H),6.71(m,1H),3.84-3.89(m,1H),2.65-2.69(m,1H),2.37-2.39(m,2H),2.26-2.29(m,2H),1.93-2.01(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.58 (s, 1H), 9.84 (s, 1H), 8.31 (s, 1H), 7.55-7.57 (m, 2H), 7.25-7.29 (m, 2H), 7.13-7.18 (m, 1H), 6.97-7.01 (m, 2H), 6.71 (m, 1H), 3.84-3.89 (m, 1H), 2.65-2.69 (m, 1H), 2.37-2.39 ( m, 2H), 2.26-2.29 (m, 2H), 1.93-2.01 (m, 2H).
实施例13Example 13
2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)-N-(4-甲氧基苯基)乙酰胺 2-(3-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)-N-(4-methoxyphenyl)acetamide
Figure PCTCN2016093584-appb-000067
Figure PCTCN2016093584-appb-000067
将2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)乙酸12j(30mg，0.08mmol)溶于5mL二氯甲烷中，并用并于冷却至0℃，加入半滴N,N-二甲基甲酰胺，加入草酰氯(51mg，0.40mmol)，于0℃搅拌2小时，反应液浓缩至干，备用。将残余物溶于10mL的二氯甲烷，加入对甲氧基苯胺(19.8mg，0.16mmol)，N,N-二异丙基乙胺(31mg，0.24mmol)，搅拌均匀，并在25℃下反应5分钟，TLC监测反应的进行。反应结束后，将反应液浓缩至干，加入少量二氯甲烷溶解，用薄层色谱法分别以展开剂体系A和B纯化所得残余物，得标题产物2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)-N-(4-甲氧基苯基)乙酰胺13(6mg，黄色固体)，收率15.6％。2-(3-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)acetic acid 12j (30 mg, 0.08 mmol) was dissolved in 5 mL of dichloro In methane, the mixture was cooled to 0 ° C, and then a half drop of N,N-dimethylformamide was added, and oxalyl chloride (51 mg, 0.40 mmol) was added, and the mixture was stirred at 0 ° C for 2 hours, and the reaction mixture was concentrated to dryness. The residue was dissolved in 10 mL of dichloromethane, p-methoxyaniline (19.8 mg, 0.16 mmol), N,N-diisopropylethylamine (31 mg, 0.24 mmol), and stirred at 25 ° C The reaction was carried out for 5 minutes, and the progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was concentrated to dryness, and then evaporated to dryness. -Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)-N-(4-methoxyphenyl)acetamide 13 (6 mg, yellow solid), yield 15.6 %.
MS m/z(LC-MS):478.3[M+1]MS m/z (LC-MS): 478.3 [M+1]
1H NMR(400MHz,CD3OD):δ7.39-7.43(m,2H),6.97-7.03(m,2H),6.85-6.88(m,2H),6.74-6.77(m,1H),4.08-4.14(m,1H),3.77(s,3H),2.71-2.77(m,1H),2.38-2.42(m,2H),2.36-2.47(m,2H),2.01-2.07(m,2H). 1 H NMR (400MHz, CD 3 OD): δ7.39-7.43 (m, 2H), 6.97-7.03 (m, 2H), 6.85-6.88 (m, 2H), 6.74-6.77 (m, 1H), 4.08 -4.14(m,1H),3.77(s,3H),2.71-2.77(m,1H),2.38-2.42(m,2H),2.36-2.47(m,2H),2.01-2.07(m,2H) .
实施例14Example 14
2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)-N-(4-(1-甲基-1H-吡唑-4-基)苯基)乙酰胺2-(3-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)-N-(4-(1-methyl-1H-) Pyrazol-4-yl)phenyl)acetamide
Figure PCTCN2016093584-appb-000068
Figure PCTCN2016093584-appb-000068
将2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)乙酸12j(90mg，0.24mmol)溶于5mL二氯甲烷中，并用冰浴冷却至0℃，加入1滴N,N-二甲基甲酰胺，加入草酰氯(152mg，1.2mmol)，于0℃搅拌2小时，反应液减压浓缩，备用。将残余物溶于10mL的二氯甲烷，加入4-(1-甲基-1H-吡唑-4-基)苯胺3a(68mg，0.36 mmol，采用专利申请“WO2010132015”公开的方法制备而得)，N,N-二异丙基乙胺(93mg，0.72mmol)，搅拌均匀，并在25℃条件下反应过夜，TLC监测反应的进行。反应结束后，往反应液中加入饱和碳酸氢钠溶液和二氯甲烷各50mL，分液，有机相用水，饱和氯化钠溶液洗涤(30×3mL)，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法分别以展开剂体系A和B纯化所得残余物，得标题产物2-(3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)-N-(4-(1-甲基-1H-吡唑-4-基)苯基)乙酰胺14(3mg，白色固体)，收率2.4％。2-(3-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)acetic acid 12j (90 mg, 0.24 mmol) was dissolved in 5 mL of dichloro The mixture was cooled to 0 ° C with EtOAc (EtOAc) (EtOAc) The residue was dissolved in 10 mL of dichloromethane and 4-(1-methyl-1H-pyrazol-4-yl)aniline 3a (68 mg, 0.36 Ment, prepared by the method disclosed in the patent application "WO2010132015", N,N-diisopropylethylamine (93 mg, 0.72 mmol), stirred uniformly, and reacted at 25 ° C overnight, and the reaction was monitored by TLC. . After the reaction was completed, 50 mL of a saturated sodium hydrogencarbonate solution and dichloromethane were added to the reaction mixture, and the organic layer was washed with water and saturated sodium chloride solution (30×3 mL), and the organic phase was collected and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure. 2-(indolyl)acetyl)cyclobutyl)-N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetamide 14 (3 mg, white solid) 2.4%.
MS m/z(LC-MS):528.4[M+1]MS m/z (LC-MS): 528.4 [M+1]
1H NMR(400MHz,CD3OD):δ7.91(s,1H),7.78(s,1H),7.47-7.54(m,4H),6.97-7.04(m,2H),6.75-6.77(m,1H),3.94-3.98(m,1H),3.91(s,3H),2.75-2.79(m,1H),2.44-2.46(m,2H),2.37-2.40(m,2H),2.02-2.05(m,2H). 1 H NMR (400 MHz, CD 3 OD): δ 7.91 (s, 1H), 7.78 (s, 1H), 7.47-7.54 (m, 4H), 6.97-7.04 (m, 2H), 6.75-6.77 (m) , 1H), 3.94-3.98 (m, 1H), 3.91 (s, 3H), 2.75-2.79 (m, 1H), 2.44-2.46 (m, 2H), 2.37-2.40 (m, 2H), 2.02-2.05 (m, 2H).
实施例15Example 15
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酸3-吡啶酯154-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxylic acid 3-pyridyl ester 15
Figure PCTCN2016093584-appb-000069
Figure PCTCN2016093584-appb-000069
将4-硝基苯吡啶-3-基碳酸酯15a(181mg，0.697mmol，采用申请专利”EP1849773A1”公开的方法制备而得)溶于30mL四氢呋喃中，加入1f(200mg，0.58mmol)，三乙胺(0.243mL，1.743mmol)，25℃下搅拌反应1小时。反应结束后，反应液减压浓缩，采用高效液相色谱法制备得到标题产物15(64mg，淡黄色固体)，收率23.7％。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.
MS m/z(ESI):465.2[M+1]MS m/z (ESI): 465.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.43-8.40(m,3H),7.64-7.62(m,1H),7.46-7.43(m,1H),7.20-7.15(m,1H),7.00-6.99(m,1H),6.73-6.71(m,1H),4.26-4.06(m,2H),3.57-3.55(m,1H),3.16-2.99(m,2H),1.94-1.91(m,2H),1.60-1.53(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.70 (s, 1H), 8.43-8.40 (m, 3H), 7.64-7.62 (m, 1H), 7.46-7.43 (m, 1H), 7.20-7.15 (m, 1H), 7.00-6.99 (m, 1H), 6.73-6.71 (m, 1H), 4.26-4.06 (m, 2H), 3.57-3.55 (m, 1H), 3.16-2.99 (m, 2H) , 1.94-1.91 (m, 2H), 1.60-1.53 (m, 2H).
实施例16Example 16
N-(4-(1H-吡唑-4-基)苯基)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺 N-(4-(1H-pyrazol-4-yl)phenyl)-4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine 1-carboxamide
Figure PCTCN2016093584-appb-000070
Figure PCTCN2016093584-appb-000070
第一步first step
4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)苯胺4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)aniline
将1-(四氢-2H-吡喃-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑16a(1.9g，6.8mmol，采用公知的方法“Zeitschrift fuer Naturforschung,B:A Journal of Chemical Sciences,2014,69(1),83-97”制备而得)，4-溴苯胺(1.17g，6.8mmol)，[1,1'-双(二苯基磷)二茂铁]二氯化钯(249mg，0.34mmol)，碳酸钾(1.89g，13.7mmol)加入30mL二氧六环和6mL水中，氩气氛下，于100℃搅拌反应4小时。反应结束后，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得标题产物4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)苯胺16b(849mg，黄褐色固体)，产率51％。1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H Pyrazole 16a (1.9 g, 6.8 mmol, prepared by the well-known method "Zeitschrift fuer Naturforschung, B: A Journal of Chemical Sciences, 2014, 69(1), 83-97"), 4-bromoaniline (1.17) g, 6.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (249 mg, 0.34 mmol), potassium carbonate (1.89 g, 13.7 mmol) was added to 30 mL of dioxane and The reaction was stirred at 100 ° C for 4 hours in 6 mL of water under an argon atmosphere. After completion of the reaction, the mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjj -pyrazol-4-yl)aniline 16b (849 mg, tan solid), yield 51%.
第二步Second step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-(tetrahydro-2H-pyran-2-yl) )-1H-pyrazol-4-yl)phenyl)piperidine-1-carboxamide
将三光气(20mg，0.067mmol)溶于5mL四氢呋喃中，加入4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)苯胺16b(42mg，0.172mmol)，0.06mL三乙胺，于25℃反应30分钟，加入(N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒1f(50mg，0.45mmol)，于25℃反应1小时。反应结束后，将反应液减压浓缩，用薄层色谱法以洗脱剂体系A纯化所得残余物，得标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基) 乙酰基)-N-(4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺16c(74mg，白色固体)，收率83％。The triphosgene (20 mg, 0.067 mmol) was dissolved in 5 mL of tetrahydrofuran, and 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenylamine 16b (42 mg, 0.172) was added. Methyl), 0.06 mL of triethylamine, reacted at 25 ° C for 30 minutes, and added (N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(piperidin-4-yl) Ethyl hydrazone 1f (50 mg, 0.45 mmol) was reacted for 1 hour at 25 ° C. After the reaction was completed, the reaction mixture was concentrated under reduced vacuo. (2-((3-bromo-4-fluorophenyl)amino)-2-(indenyl)) Acetyl)-N-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-1-carboxamide 16c (74 mg, white Solid), yield 83%.
第三步third step
N-(4-(1H-吡唑-4-基)苯基)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺N-(4-(1H-pyrazol-4-yl)phenyl)-4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine 1-carboxamide
将4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺16c(74mg，0.12mmol)加入10mL甲醇中，加入对甲苯磺酸(27mg，0.156mol)，于25℃下搅拌反应12小时。反应结束后，加入0.1mL三乙胺，将反应液减压浓缩，用薄层色谱法以洗脱剂体系A纯化所得残余物，得到标题产物N-(4-(1H-吡唑-4-基)苯基)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺16(30mg，白色固体)，收率47％。4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-(tetrahydro-2H-pyran-2-) Addyl p-toluenesulfonic acid (27 mg, 0.156 mol) in 25 mL of methanol The reaction was stirred for 12 hours. After the reaction was completed, 0.1 mL of triethylamine was added, and the reaction mixture was concentrated under reduced vacuo. Phenyl)-4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide 16 (30 mg, white solid) The yield was 47%.
MS m/z(LC-MS):531.4[M+1]MS m/z (LC-MS): 531.4 [M+1]
1H NMR(400MHz,DMSO-d6)δ12.83(s,1H),11.68(s,1H),8.51(s,1H),8.39(s,1H),8.04(s,1H),7.88(s,1H),7.43-7.48(m,4H),7.18(t,1H),6.99(dd,1H),6.71-6.74(m,1H),4.18-4.21(m,2H),3.52-3.58(m,1H),2.88-2.91(m,2H),1.85-1.88(m,2H),1.43-1.52(m,2H).1H NMR (400MHz, DMSO-d 6) δ12.83 (s, 1H), 11.68 (s, 1H), 8.51 (s, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.88 (s , 1H), 7.43-7.48 (m, 4H), 7.18 (t, 1H), 6.99 (dd, 1H), 6.71-6.74 (m, 1H), 4.18-4.21 (m, 2H), 3.52-3.58 (m , 1H), 2.88-2.91 (m, 2H), 1.85-1.88 (m, 2H), 1.43-1.52 (m, 2H).
实施例17Example 17
N-(3-溴-4-氟苯基)-N'-羟基-2-((1r,4r)-4-(甲基磺酰氨基甲基)环己基)-2-羰基乙脒17N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-((1r,4r)-4-(methylsulfonylaminomethyl)cyclohexyl)-2-carbonylethyl hydrazine 17
Figure PCTCN2016093584-appb-000071
Figure PCTCN2016093584-appb-000071
将11f(79mg，0.212mmol)，1.5mL二氯甲烷和三乙胺(89μL，0.637mmol)加入反应瓶中，加入甲烷磺酰氯(24mg，0.212mmol)，于25℃搅拌反应1小时。反应结束后，加入50mL二氯甲烷，依次用饱和碳酸氢钠溶液(50mL×3)、水(50mL×3)、饱和氯化钠溶液(50mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物17(25mg，淡黄色固体)，收率26.3％。11f (79 mg, 0.212 mmol), 1.5 mL of dichloromethane and triethylamine (89 μL, 0.637 mmol) were added to the reaction flask, methanesulfonyl chloride (24 mg, 0.212 mmol) was added, and the reaction was stirred at 25 ° C for 1 hour. After completion of the reaction, 50 mL of dichloromethane was added, and the mixture was washed successively with a saturated sodium hydrogen carbonate solution (50 mL×3), water (50 mL×3), and a saturated sodium chloride solution (50 mL×2), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated.jjjjjjjjj
MS m/z(ESI):452.2[M+1]MS m/z (ESI): 452.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.32(s,1H),7.18-7.14(m,1H),6.99-6.95(m,2H),6.71-6.67(m,1H),3.28-3.22(m,1H),2.85(s,3H),2.81-2.78(m,2H),1.90-1.83(m,4H),1.39-1.33(m,3H),1.00-0.92(m,2H), 1 H NMR (400MHz, DMSO- d 6) δ11.60 (s, 1H), 8.32 (s, 1H), 7.18-7.14 (m, 1H), 6.99-6.95 (m, 2H), 6.71-6.67 (m , 1H), 3.28-3.22 (m, 1H), 2.85 (s, 3H), 2.81-2.78 (m, 2H), 1.90- 1.83 (m, 4H), 1.39-1.33 (m, 3H), 1.00-0.92 (m, 2H),
实施例18 Example 18
N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-((1r,4r)-4-(氨磺酰基氨基)环己基)乙脒18N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-((1r,4r)-4-(sulfamoylamino)cyclohexyl)acetamidine 18
Figure PCTCN2016093584-appb-000072
Figure PCTCN2016093584-appb-000072
采用实施例11的合成路线，将第一步原料替换为((1r,4r)-4-乙酰基环己基)氨基甲酸叔丁酯(采用专利申请“WO2012018668”公开的方法制备而得)，制得标题产物18(14mg，黄色固体)。Using the synthetic route of Example 11, the first step of the starting material was replaced with ((1r, 4r)-4-acetylcyclohexyl)carbamic acid tert-butyl ester (prepared by the method disclosed in the patent application "WO2012018668"). The title product 18 (14 mg, yellow solid) was obtained.
MS m/z(ESI):437.3[M+1]MS m/z (ESI): 437.3 [M+1]
1HNMR(400MHz,DMSO-d6)δ11.64(s,1H),8.33(s,1H),7.18-7.14(m,1H),6.96-6.94(m,1H),6.71-6.68(m,1H),6.52-6.47(m,3H),3.13-3.17(m,1H),3.03-3.01(m,1H),2.05-2.01(m,2H),1.89-1.86(m,2H),1.38-1.31(m,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.64 (s, 1H), 8.33 (s, 1H), 7.18-7.14 (m, 1H), 6.96-6.94 (m, 1H), 6.71-6.68 (m, 1H), 6.52-6.47 (m, 3H), 3.13-3.17 (m, 1H), 3.03-3.01 (m, 1H), 2.05-2.01 (m, 2H), 1.89-1.86 (m, 2H), 1.38- 1.31 (m, 4H).
实施例19Example 19
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(2-氰基吡啶-4-基)哌啶-1-甲酰胺194-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(2-cyanopyridin-4-yl)piperidine-1-carboxamide 19
Figure PCTCN2016093584-appb-000073
Figure PCTCN2016093584-appb-000073
将三光气(34mg，0.116mmol)溶于1.5mL四氢呋喃中，0℃加入4-氨基2-氰基吡啶19a(14mg，0.116mmol，采用专利申请“WO2001302639”公开的方法制备而得)，三乙胺(48μL，0.349mmol，于0℃反应30分钟，减压浓缩反应液得残余物淡黄色固体待用。将1f(40mg，0.116mmol)溶于1.5mL四氢呋喃中，25℃下加入上述残余物，于25℃反应2小时。反应结束后，加入2mL甲醇淬灭反应，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物19(8mg，白色固体)，收率14％。The triphosgene (34 mg, 0.116 mmol) was dissolved in 1.5 mL of tetrahydrofuran, and 4-amino 2-cyanopyridine 19a (14 mg, 0.116 mmol, prepared by the method disclosed in the patent application "WO2001302639") was added at 0 ° C. The amine (48 μL, 0.349 mmol) was reacted for 30 min at 0 ° C. The reaction mixture was evaporated.jjjjjjjjjjjjjjjjjj The reaction was carried out for 2 hours at 25 ° C. After the reaction was completed, the reaction was quenched with EtOAc EtOAc (EtOAc) ), the yield is 14%.
MS m/z(ESI):491.3[M+1]MS m/z (ESI): 491.3 [M+1]
1H NMR(400 MHz,DMSO-d6)δ11.69(s,1H),9.39(s,1H),8.46-8.45(m,1H),8.38(s,1H),8.04-8.03(m,1H),7.72-7.70(m,1H),7.19-7.14(m,1H),6.99-6.97(m,1H),6.73-6.69(m,1H),4.19-4.16(m,2H),3.59-3.53(m,1H),2.98-2.93(m,2H),1.90-1.87(m,2H),1.52-1.43(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H), 9.39 (s, 1H), 8.46-8.45 (m, 1H), 8.38 (s, 1H), 8.04-8.03 (m, 1H), 7.72-7.70 (m, 1H), 7.19-7.14 (m, 1H), 6.99-6.97 (m, 1H), 6.73-6.69 (m, 1H), 4.19-4.16 (m, 2H), 3.59- 3.53 (m, 1H), 2.98-2.93 (m, 2H), 1.90- 1.87 (m, 2H), 1.52-1.43 (m, 2H).
实施例20Example 20
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-环丙基-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺 4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-cyclopropyl-1H-pyrazol-4-yl) Phenyl) piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000074
Figure PCTCN2016093584-appb-000074
第一步first step
1-环丙基-4-(4-硝基苯基)-1H-吡唑1-cyclopropyl-4-(4-nitrophenyl)-1H-pyrazole
将4-(4-硝基苯)-1H-吡唑20a(1.0g，5.3mmol，采用公知的方法“Medicinal Chemistry Research,2013,22(11),5610-5616”制备而得)溶解于50mL 1,2-二氯乙烷中，加入环丙基硼酸(1.02g，11.9mmol)，乙酸铜(1.11g，5.57mmol)，联吡啶(869mg，5.57mmol)，碳酸钠(1.69g，15.9mmol)，反应体系于70℃反应3小时。反应结束后，冷却至室温，过滤除去不溶物，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题产物1-环丙基-4-(4-硝基苯基)-1H-吡唑20b(612mg，黄色固体)，产率52.1％。4-(4-Nitrophenyl)-1H-pyrazole 20a (1.0 g, 5.3 mmol, prepared by a known method "Medicinal Chemistry Research, 2013, 22 (11), 5610-5616") was dissolved in 50 mL To 1,2-dichloroethane, cyclopropylboronic acid (1.02 g, 11.9 mmol), copper acetate (1.11 g, 5.57 mmol), bipyridine (869 mg, 5.57 mmol), sodium carbonate (1.69 g, 15.9 mmol) were added. The reaction system was reacted at 70 ° C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, and the insoluble material was filtered. The filtrate was concentrated under reduced pressure. Phenyl)-1H-pyrazole 20b (612 mg, yellow solid), yield 521.
第二步Second step
4-(1-环丙基-1H-吡唑-4-基)苯胺4-(1-cyclopropyl-1H-pyrazol-4-yl)aniline
将1-环丙基-4-(4-硝基苯基)-1H-吡唑20b(1.6g，7.0mmol)加入30mL乙醇和10mL水中，加入铁粉(784mg，14.0mmol)和氯化铵(1.5g，28.0mmol)，回流反应2小时。反应结束后，将反应液减压浓缩除去乙醇，加入二氯甲烷50mL，过滤除去不溶物，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4-(1-环丙基-1H-吡唑-4-基)苯胺20c(1.33g，黄色固体)，产率95.6％。1-Cyclopropyl-4-(4-nitrophenyl)-1H-pyrazole 20b (1.6 g, 7.0 mmol) was added to 30 mL of ethanol and 10 mL of water, and iron powder (784 mg, 14.0 mmol) and ammonium chloride were added. (1.5 g, 28.0 mmol), refluxed for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness, and then evaporated to ethyl ether. (1-Cyclopropyl-1H-pyrazol-4-yl)aniline 20c (1.33 g, yellow solid), yield 95.6%.
第三步third step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-环丙基-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-cyclopropyl-1H-pyrazol-4-yl) Phenyl) piperidine-1-carboxamide
将三光气(18mg，0.06mmol)溶解于10mL四氢呋喃中，一次性加入4-(1-环丙基-1H-吡唑-4-基)苯胺20c(35mg，0.17mmol)，再加入三乙胺(53mg，0.32mmol)，室温下搅拌反应30分钟。向反应液中加入(N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌 啶-4-基)乙脒1f(50mg，0.145mmol)，室温下搅拌反应1小时。反应结束后，将反应液减压浓缩，用薄层色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-环丙基-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺20(30mg，白色固体)，产率36.5％。The triphosgene (18 mg, 0.06 mmol) was dissolved in 10 mL of tetrahydrofuran, and 4-(1-cyclopropyl-1H-pyrazol-4-yl)aniline 20c (35 mg, 0.17 mmol) was added in one portion, followed by triethylamine. (53 mg, 0.32 mmol), the reaction was stirred at room temperature for 30 minutes. Add (N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(piperidin) to the reaction solution Pyridin-4-yl)acetamidine 1f (50 mg, 0.145 mmol) was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced vacuo. 2-(indolyl)acetyl)-N-(4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)piperidine-1-carboxamide 20 (30 mg, white solid) The rate is 36.5%.
MS m/z(LC-MS):569.4[M+1]MS m/z (LC-MS): 569.4 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.52(s,1H),8.39(s,1H),8.12(s,1H),7.77(s,1H),7.44(s,4H),7.18(t,1H),6.99(dd,1H),6.71-6.74(m,1H),4.18-4.21(m,2H),3.69-3.74(m,1H),3.52-3.58(m,1H),2.85-2.91(m,2H),1.85-1.88(m,2H),1.43-1.51(m,2H),1.04-1.06(m,2H),0.96-0.99(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.63 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.12 (s, 1H), 7.77 (s, 1H), 7.44 ( s, 4H), 7.18 (t, 1H), 6.99 (dd, 1H), 6.71-6.74 (m, 1H), 4.18-4.21 (m, 2H), 3.69-3.74 (m, 1H), 3.52-3.58 ( m,1H), 2.85-2.91 (m, 2H), 1.85-1.88 (m, 2H), 1.43-1.51 (m, 2H), 1.04-1.06 (m, 2H), 0.96-0.99 (m, 2H).
实施例21Example 21
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-(二氟甲基)-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-(difluoromethyl)-1H-pyrazole- 4-yl)phenyl)piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000075
Figure PCTCN2016093584-appb-000075
第一步first step
1-(二氟甲基)-4-(4-硝基苯基)-1H-吡唑1-(difluoromethyl)-4-(4-nitrophenyl)-1H-pyrazole
将4-(4-硝基苯)-1H-吡唑20a(1.0g，5.28mmo)，18-冠-6醚(279mg，1.05mmol)溶解于40mL乙腈中，向反应液中加入二氟氯乙酸钠(0.967g，6.34mmol)，氩气氛下，反应液升温至回流，搅拌反应18小时。反应液冷却至室温，过滤，滤饼用乙酸乙酯洗涤，收集滤液，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物1-(二氟甲基)-4-(4-硝基苯基)-1H-吡唑21a(680mg，淡黄色固体)，产率54％。4-(4-Nitrophenyl)-1H-pyrazole 20a (1.0 g, 5.28 mmo), 18-crown-6 ether (279 mg, 1.05 mmol) was dissolved in 40 mL of acetonitrile, and difluorochloride was added to the reaction mixture. Sodium acetate (0.967 g, 6.34 mmol) was heated to reflux under an argon atmosphere, and the mixture was stirred for 18 hours. The reaction mixture was cooled to room temperature, filtered, and then filtered, filtered, evaporated, evaporated, evaporated. 4-(4-Nitrophenyl)-1H-pyrazole 21a (680 mg, pale yellow solid), yield 54%.
第二步 Second step
4-(1-(二氟甲基)-1H-吡唑-4-基)苯胺4-(1-(Difluoromethyl)-1H-pyrazol-4-yl)aniline
将1-(二氟甲基)-4-(4-硝基苯基)-1H-吡唑21a(3g，12.54mmol)溶解于130mL乙醇和水(V:V＝10:3)的混合溶剂中。向反应液中依次加入铁粉(1.4g，25.08mmol)，氯化铵(2.68g，50.17mmol)。反应液升温至80℃，搅拌反应2小时。反应结束后，将反应液冷却至室温，减压浓缩，残余物中加入乙酸乙酯及少量甲醇，垫硅藻土过滤，滤饼用乙酸乙酯洗涤，收集滤液，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4-(1-(二氟甲基)-1H-吡唑-4-基)苯胺21b(2.35g，淡黄色固体)，产率89.7％。1-(Difluoromethyl)-4-(4-nitrophenyl)-1H-pyrazole 21a (3 g, 12.54 mmol) was dissolved in a mixed solvent of 130 mL of ethanol and water (V:V=10:3) in. Iron powder (1.4 g, 25.08 mmol) and ammonium chloride (2.68 g, 50.17 mmol) were sequentially added to the reaction mixture. The reaction solution was heated to 80 ° C, and the reaction was stirred for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The residue obtained was purified by column chromatography eluting to afford the title product 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenylamine 21b (2.35 g, pale yellow solid). The rate is 89.7%.
第三步third step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-(二氟甲基)-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-(difluoromethyl)-1H-pyrazole- 4-yl)phenyl)piperidine-1-carboxamide
将三光气(207mg，0.7mmol)溶解于100mL四氢呋喃中，逐次加入4-(1-(二氟甲基)-1H-吡唑-4-基)苯胺21b(382mg，1.83mmol)和三乙胺(528mg，5.23mmol)，室温下搅拌反应30分钟。向反应液中加入(N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(哌啶-4-基)乙脒1f(600g，1.74mmol)，室温下搅拌反应1小时。反应结束后，加入20mL甲醇淬灭，减压浓缩，用薄层色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-(二氟甲基)-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺21(160mg，白色固体)，产率15.8％。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. After completion of the reaction, 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%.
MS m/z(LC-MS):579.4[M+1]MS m/z (LC-MS): 579.4 [M+1]
1H NMR(400MHz,DMSO-d6):δ11.69(s,1H),8.60(s,1H),8.39(s,1H),8.20(s,1H),7.67(t,1H),7.57(d,2H),7.50(d,2H),7.18(t,1H),7.00(dd,1H),6.71-6.74(m,1H),4.18-4.21(m,2H),3.53-3.58(m,1H),2.86-2.92(m,2H),1.86-1.89(m,2H),1.43-1.52(m,2H). 1 H NMR (400MHz, DMSO- d 6): δ11.69 (s, 1H), 8.60 (s, 1H), 8.39 (s, 1H), 8.20 (s, 1H), 7.67 (t, 1H), 7.57 (d, 2H), 7.50 (d, 2H), 7.18 (t, 1H), 7.00 (dd, 1H), 6.71-6.74 (m, 1H), 4.18-4.21 (m, 2H), 3.53-3.58 (m , 1H), 2.86-2.92 (m, 2H), 1.86-1.89 (m, 2H), 1.43-1.52 (m, 2H).
实施例22Example 22
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-4-氟-N-苯基哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-4-fluoro-N-phenylpiperidine-1-carboxamide
Figure PCTCN2016093584-appb-000076
Figure PCTCN2016093584-appb-000076
第一步first step
1-(叔丁氧羰基)-4-氟哌啶-4-甲酸22b 1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid 22b
将22a(2g，7.63mmol)溶于30mL乙醇中，加入9.5mL 2M的氢氧化钠溶液，60℃搅拌反应2小时。反应结束后，反应液减压浓缩，加入1M盐酸调节pH小于7，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品标题产物22b(1.78g，白色固体)，收率94％。22a (2 g, 7.63 mmol) was dissolved in 30 mL of ethanol, 9.5 mL of 2M sodium hydroxide solution was added, and the reaction was stirred at 60 ° C for 2 hours. After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Solid), yield 94%.
第二步Second step
tert-butyl 4-fluoro-4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate4-氟-4-(甲氧基(甲基)氨基甲酰基)哌啶-1-甲酸叔丁酯22cTert-butyl 4-fluoro-4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate 4-fluoro-4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester 22c
将粗品22b(1.78g，7.2mmol)溶于40mL二氯甲烷中，加入催化量N,N-二甲基甲酰胺以及0.9mL草酰氯，室温下搅拌反应0.5小时，反应液减压浓缩备用。残余物中加入40mL二氯甲烷，加入N,O-二甲基羟胺盐酸盐(0.843g，8.64mmol)以及3mL三乙胺，室温下搅拌反应1小时。反应结束后，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题产物22c(1.3g，无色液体)，收率62％。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 tolululululululululululululululululululululu
第三步third step
4-乙酰基-4-氟哌啶-1-甲酸叔丁酯22d4-acetyl-4-fluoropiperidine-1-carboxylic acid tert-butyl ester 22d
将22c(1.3g，4.48mmol)溶于15mL四氢呋喃中，冰浴，加入1.8mL 3M的甲基溴化镁溶液，0℃下搅拌反应1小时，补加0.45mL甲基溴化镁溶液，0℃下搅拌反应0.5小时。反应结束后，加入饱和氯化铵溶液淬灭反应，分液，水相用乙酸乙酯萃取三次，合并有机相。无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，制得标题产物22d(930mg，无色液体)，产率84％。22c (1.3g, 4.48mmol) was dissolved in 15mL of tetrahydrofuran, ice bath, 1.8mL 3M methylmagnesium bromide solution was added, stirred at 0 ° C for 1 hour, added 0.45mL methyl magnesium bromide solution, 0 The reaction was stirred at ° C for 0.5 hours. After completion of the reaction, the reaction was quenched by the addition of saturated aqueous ammonium chloride. The residue was dried over anhydrous sodium sulfate.
第四步the fourth step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-4-氟-N-苯基哌啶-1-甲酰胺224-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-4-fluoro-N-phenylpiperidine-1-carboxamide 22
采用实施例1的合成路线，将第一步原料4-乙酰基哌啶-1-甲酸叔丁酯替换为22d，经过数步反应制得标题产物22(40mg，白色固体)，收率48％。Using the synthetic route of Example 1, the first step starting material, 4-acetylpiperidine-1-carboxylic acid tert-butyl ester, was replaced by 22d, and the title product 22 (40 mg, white solid). .
MS m/z(LC-MS):481.3[M+1]MS m/z (LC-MS): 481.3 [M+1]
实施例23Example 23
2-((1r,3r)-3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)-N-(4-(1-甲基-1H-吡唑-4-基)乙酰胺232-((1r,3r)-3-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)-N-(4-(1) -methyl-1H-pyrazol-4-yl)acetamide 23
Figure PCTCN2016093584-appb-000077
Figure PCTCN2016093584-appb-000077
Figure PCTCN2016093584-appb-000078
Figure PCTCN2016093584-appb-000078
将12j(30mg，0.08mmol)溶于8mL二氯甲烷中，冷却至0℃，加入1滴N,N-二甲基甲酰胺，加入草酰氯(51mg，0.40mmol)，于0℃搅拌2小时，反应液浓缩至干，备用。将残余物溶于8mL的二氯甲烷，加入1-甲基-1H-吡唑-4-胺(16mg，0.16mmol)，N,N-二异丙基乙胺(31mg，0.24mmol)，搅拌均匀，并在25℃下反应5分钟。反应结束后，加入饱和碳酸氢钠溶液、水、饱和氯化钠溶液、二氯甲烷各30mL，分液，依次用水(30mL×3)、饱和氯化钠溶液(30mL×3)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所残余物，得到淡黄色固体，用高效液相色谱法制备分离所得固体，得到标题产物23(5mg，白色固体)，收率13.9％。12j (30mg, 0.08mmol) was dissolved in 8mL of dichloromethane, cooled to 0 ° C, 1 drop of N, N-dimethylformamide was added, oxalyl chloride (51mg, 0.40mmol) was added, and stirred at 0 ° C for 2 hours The reaction solution was concentrated to dryness and was taken. The residue was dissolved in 8 mL of dichloromethane, and then stirred, and then evaporated, and then, then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, It was homogeneous and reacted at 25 ° C for 5 minutes. After the reaction was completed, 30 mL of saturated sodium hydrogencarbonate solution, water, saturated sodium chloride solution and dichloromethane were added, and the mixture was separated, and washed successively with water (30 mL×3) and saturated sodium chloride solution (30 mL×3), organic phase. The organic layer was dried over anhydrous sodium sulfate, filtered, and then evaporated. 5 mg, white solid), yield 13.9%.
MS m/z(LC-MS):452.3[M+1]MS m/z (LC-MS): 452.3 [M+1]
1H NMR(400MHz,CD3OD)δ7.42-7.43(m,1H),6.98-7.04(m,2H),6.75-6.77(m,1H),6.44-6.46(m,1H),4.05-4.09(m,1H),3.78(s,3H),2.70-2.72(m,1H),2.43-2.58(m,4H),2.01-2.08(m,2H). 1 H NMR (400 MHz, CD 3 OD) δ 7.42-7.43 (m, 1H), 6.98-7.04 (m, 2H), 6.75-6.77 (m, 1H), 6.44-6.46 (m, 1H), 4.05- 4.09 (m, 1H), 3.78 (s, 3H), 2.70-2.72 (m, 1H), 2.43-2.58 (m, 4H), 2.01-2.08 (m, 2H).
实施例24Example 24
N-(3-溴-4-氟苯基)-2-(1-(3,4-二氟苯基)哌啶-4-基)-N'-羟基-2-羰基乙脒24N-(3-Bromo-4-fluorophenyl)-2-(1-(3,4-difluorophenyl)piperidin-4-yl)-N'-hydroxy-2-carbonylacetamidine 24
Figure PCTCN2016093584-appb-000079
Figure PCTCN2016093584-appb-000079
将1f(200mg，0.58mmol)溶解于20mL二氯甲烷中，加入3,4-二氟苯硼酸(270mg，2.32mmol)，乙酸铜(140mg，1.16mmol)，三乙胺(230mg，2.32mmol)，于25℃反应16小时。反应结束后，过滤除去不溶物，滤液减压浓缩，用高效液相色谱法纯化所得残余物，得标题产物24(3mg，黄色液体)，产率1.91％。1f (200 mg, 0.58 mmol) was dissolved in 20 mL of dichloromethane, 3,4-difluorophenylboronic acid (270 mg, 2.32 mmol), copper acetate (140 mg, 1.16 mmol), triethylamine (230 mg, 2.32 mmol) , reacted at 25 ° C for 16 hours. After the reaction was completed, the insoluble material was filtered, and the filtrate was evaporated to dryness.
MS m/z(LC-MS):456.3[M+1]MS m/z (LC-MS): 456.3 [M+1]
1H NMR(400MHz,CD3OD)δ6.99-7.10(m,3H),6.78-6.79(m,1H),6.75-6.76(m,2H),3.65-3.68(m,2H),3.48-3.54(m,1H),2.73-2.78(m,2H),1.98-2.04(m,2H),1.75-1.81(m,2H). 1 H NMR (400MHz, CD 3 OD) δ6.99-7.10 (m, 3H), 6.78-6.79 (m, 1H), 6.75-6.76 (m, 2H), 3.65-3.68 (m, 2H), 3.48- 3.54 (m, 1H), 2.73-2.78 (m, 2H), 1.98-2.04 (m, 2H), 1.75-1.81 (m, 2H).
实施例25Example 25
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环己亚胺-1-甲酸叔丁酯4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cycloheximide-1-carboxylic acid tert-butyl ester
Figure PCTCN2016093584-appb-000080
Figure PCTCN2016093584-appb-000080
Figure PCTCN2016093584-appb-000081
Figure PCTCN2016093584-appb-000081
第一步first step
4-(甲氧基(甲基)氨基甲酰基)环己亚胺-1-甲酸叔丁酯25b4-(methoxy(methyl)carbamoyl)cycloheximide-1-carboxylic acid tert-butyl ester 25b
将1-(叔丁氧羰基)环己亚胺-4-甲酸25a(360mg，1.48mmol，采用公知的方法“Angewandte Chemie,International Edition,2013,52(23),6072-6075”制备而得)加入反应瓶中，加入1-羟基苯并三唑(240mg，1.78mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(341mg，1.78mmol)，三乙胺(448mg，4.44mmol)，N,O-二甲基羟胺盐酸盐(216mg，2.22mmol)，加入10mL二氯甲烷，室温下反应16小时。反应结束后，加入30mL水，分液，水层用二氯甲烷萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得标题产物25b(356mg，无色油状物)，产率84.1％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") Add to the reaction flask and add 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). After the reaction was completed, 30 mL of water was added, and the mixture was separated, the aqueous layer was extracted with methylene chloride, 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
第二步Second step
4-乙酰基环己亚胺-1-甲酸叔丁酯25c4-acetylcycloheximide-1-carboxylic acid tert-butyl ester 25c
将25b(350mg，1.22mmol)加入反应瓶中，加入10mL四氢呋喃，冰水冷却，滴加溴化甲基镁(0.6mol，1.83mmol)，滴加完毕，0℃反应1小时。反应结束后，加入50mL水，乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤(50mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得标题产物25c(220mg，浅黄色油状物)，产率74.5％25b (350 mg, 1.22 mmol) was added to a reaction flask, 10 mL of tetrahydrofuran was added thereto, and the mixture was cooled with ice water, and methylmagnesium bromide (0.6 mol, 1.83 mmol) was added dropwise thereto, and the reaction was completed at 0 ° C for 1 hour. After the reaction was completed, 50 mL of water was added, and ethyl acetate was added, and the organic phase was washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified to afford titled product 25c (220 mg, pale yellow oil).
第三步third step
4-(2-羰基乙酰基)环己亚胺-1-甲酸叔丁酯25d4-(2-carbonylacetyl)cycloheximide-1-carboxylic acid tert-butyl ester 25d
将二氧化硒(203mg，1.82mol)置于反应瓶中，加入10mL 1,4-二氧六环，25c(220mg，0.91mmol)，于80℃反应6小时。反应结束后，过滤除去不溶物，加入水30 mL，乙酸乙酯萃取，用饱和氯化钠溶液洗涤，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物25d(300mg，红色油状物)，产物不经纯化直接进行下一步反应。 Selenium dioxide (203 mg, 1.82 mol) was placed in a reaction flask, and 10 mL of 1,4-dioxane, 25c (220 mg, 0.91 mmol) was added, and the mixture was reacted at 80 ° C for 6 hours. After the reaction was completed, the insoluble material was filtered, and then filtered, evaporated, evaporated, evaporated. 300 mg, red oil), the product was taken to the next step without purification.
第四步the fourth step
4-(2-(肟基)乙酰基)环己亚胺-1-甲酸叔丁酯25e4-(2-(indenyl)acetyl)cycloheximide-1-carboxylic acid tert-butyl ester 25e
将粗品25d(233mg，0.91mol)溶于20mL甲醇中，加入碳酸钾(189mg，1.37mmol)，于0℃搅拌反应10分钟，分批加入盐酸羟胺(32mg，0.46mmol)，于0℃下搅拌反应1小时。反应结束后，过滤除去不溶物，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题产物25e(120mg，棕色油状物)，产率48.7％。The crude product 25d (233mg, 0.91mol) was dissolved in 20mL of methanol, then added with potassium carbonate (189mg, 1.37mmol), and the reaction was stirred at 0 °C for 10 minutes, and hydroxylamine hydrochloride (32mg, 0.46mmol) was added in portions and stirred at 0 °C. Reaction for 1 hour. After the reaction was completed, the insoluble material was filtered, and the filtrate was evaporated. mjjjjjjjjjj
第五步the fifth step
4-(2-氯-2-(肟基)乙酰基)环己亚胺-1-甲酸叔丁酯25f4-(2-Chloro-2-(indenyl)acetyl)cycloheximide-1-carboxylic acid tert-butyl ester 25f
将25e(120mg，0.44mmol)加入5mL N,N-二甲基甲酰胺中，加入N-氯代丁二酰亚胺(62mg，0.47mmol)，于25℃下搅拌反应1.5小时。反应结束后，加入20mL水，用乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(50mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物25f(103mg，黄色油状物)，产物不经纯化直接进行下一步反应。25e (120 mg, 0.44 mmol) was added to 5 mL of N,N-dimethylformamide, and N-chlorosuccinimide (62 mg, 0.47 mmol) was added, and the reaction was stirred at 25 ° C for 1.5 hours. After the completion of the reaction, 20 mL of water was added, and the mixture was combined with ethyl acetate (20 mL × 3), and the organic phase was combined, and the organic phase was washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate The crude title product 25f (103 mg, yellow oil) was obtained.
第六步Step 6
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环己亚胺-1-甲酸叔丁酯254-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cycloheximide-1-carboxylic acid tert-butyl ester 25
将粗品25f(100mg，0.33mmol)和3-溴-4-氟苯胺(125mg，0.66mmol)加入5mL乙醇中，于25℃下搅拌反应16小时。反应结束后，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物25(32mg，白色固体)，收率21.2％。Crude 25f (100 mg, 0.33 mmol) and 3-bromo-4-fluoroaniline (125 mg, 0.66 mmol) were added to 5 mL of ethanol, and the reaction was stirred at 25 ° C for 16 hours. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjj
MS m/z(ESI):458.3[M+1]MS m/z (ESI): 458.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ7.27-7.00(m,2H),6.85-6.79(m,2H),3.74-3.60(m,2H),3.46-3.43(m,2H),3.27-3.20(m,1H),2.11-1.96(m,2H),1.72-1.66(m,4H),1.60(s,9H). 1 H NMR (400MHz, DMSO- d 6) δ7.27-7.00 (m, 2H), 6.85-6.79 (m, 2H), 3.74-3.60 (m, 2H), 3.46-3.43 (m, 2H), 3.27 -3.20 (m, 1H), 2.11-1.96 (m, 2H), 1.72-1.66 (m, 4H), 1.60 (s, 9H).
实施例26Example 26
N-(3-溴-4-氟苯基)-2-(3-(4-氰基苯氧基)环丁基)-N'-羟基-2-羰基乙脒N-(3-Bromo-4-fluorophenyl)-2-(3-(4-cyanophenoxy)cyclobutyl)-N'-hydroxy-2-carbonylacetamidine
Figure PCTCN2016093584-appb-000082
Figure PCTCN2016093584-appb-000082
第一步first step
3-羟基-N-甲氧基-N-甲基环丁烷-1-甲酰胺26a3-hydroxy-N-methoxy-N-methylcyclobutane-1-carboxamide 26a
将N-甲氧基-N-甲基-3-羰基环丁甲酰胺12a(2.0g，12.7mmol)溶于40mL甲醇中，加入硼氢化钠(0.97g，25.5mmol)，室温下反应1小时。反应结束后，加入少量水淬灭反应，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物26a(1.9g，无色油状物)，收率70％。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
第二步Second step
3-(4-氰基苯氧基)-N-甲氧基-N-甲基环丁烷-1-甲酰胺26b3-(4-cyanophenoxy)-N-methoxy-N-methylcyclobutane-1-carboxamide 26b
将26a(251mg，2.11mmol)溶于二氯甲烷中，加入对氰基苯酚(337mg，2.11mmol)，三苯基膦(663mg，2.53mmol)，冰浴，加入偶氮二甲酸二异丙酯(511mg，2.53mmol)，升至室温，搅拌反应1小时。反应结束后，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物26b(140mg，白色固体)，收率25.5％。26a (251 mg, 2.11 mmol) was dissolved in dichloromethane, p-cyanophenol (337 mg, 2.11 mmol), triphenylphosphine (663 mg, 2.53 mmol), ice bath, diisopropyl azodicarboxylate (511 mg, 2.53 mmol), allowed to warm to room temperature and stirred for 1 hour. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjjj
第三步third step
4-((3-乙酰基环丁基)甲基)苯甲腈26c4-((3-acetylcyclobutyl)methyl)benzonitrile 26c
将26b(140mg，0.538mmol)加入2mL四氢呋喃中，冰浴冷却至0℃，滴加3.0M甲基溴化镁溶液(0.4mL，1.076mmol)，25℃搅拌2小时，有白色固体析出。反应结束后，加入水，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到标题产物26c(60mg，白色固体)，产率52％。26b (140 mg, 0.538 mmol) was added to 2 mL of tetrahydrofuran, and the mixture was cooled to 0 ° C, and then a solution of 3.0 M methylmagnesium bromide (0.4 mL, 1.076 mmol) was added dropwise, and the mixture was stirred at 25 ° C for 2 hr. After the reaction was completed, water was added, and ethyl acetate was evaporated. EtOAcjjjjjjjjjjjjjjj 60 mg, white solid), yield 52%.
第四步the fourth step
N-(3-溴-4-氟苯基)-2-(3-(4-氰基苯氧基)环丁基)-N'-羟基-2-羰基乙脒26N-(3-Bromo-4-fluorophenyl)-2-(3-(4-cyanophenoxy)cyclobutyl)-N'-hydroxy-2-carbonylethyl hydrazine 26
采用实施例25第三到六步的合成路线，将原料25c替换为26c，经过数步反应制得标题产物26(15mg，黄色粘稠物)，收率15％。Using the synthesis route of the third to sixth steps of Example 25, the starting material 25c was replaced with 26c, and the title product 26 (15 mg, yellow viscous material) was obtained in several steps, yield 15%.
MS m/z(LC-MS):432.2[M+1]MS m/z (LC-MS): 432.2 [M+1]
实施例27Example 27
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酸苄酯27Benzyl 4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxylate 27
Figure PCTCN2016093584-appb-000083
Figure PCTCN2016093584-appb-000083
将1f(103mg，0.3mmol)溶于30mL四氢呋喃中，加入三乙胺(59mg，0.58mmol)，冰水冷却，滴加预制的10mL氯甲酸苄酯(54mg，0.32mmol)的四氢呋喃溶液，0℃下搅拌反应2小时。反应结束后，反应液加入20mL水，乙酸乙酯萃取(10mL×4)，饱和氯化钠溶液(50mL×1)洗涤，无水硫酸镁干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，制得标题产物27(21mg，白色固体)，收率15.2％。1f (103mg, 0.3mmol) was dissolved in 30mL of tetrahydrofuran, added triethylamine (59mg, 0.58mmol), cooled in ice water, and pre-prepared 10mL benzyl chloroformate (54mg, 0.32mmol) in tetrahydrofuran solution, 0 °C The reaction was stirred for 2 hours. After completion of the reaction, the reaction mixture was combined with EtOAc EtOAc EtOAc. The obtained residue was purified to silicagel elut elut elut elut elut elut elut elut elut elut elut
MS m/z(LC-MS):478.2[M+1]MS m/z (LC-MS): 478.2 [M+1]
实施例28Example 28
N-(3-溴-4-氟苯基)-N'-羟基-2-(1-(4-硝基苯基)哌啶-4-基)-2-羰基乙脒28N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-(1-(4-nitrophenyl)piperidin-4-yl)-2-carbonylethyl hydrazine 28
Figure PCTCN2016093584-appb-000084
Figure PCTCN2016093584-appb-000084
将对氟硝基苯28a(81.9mg，0.58mmol)溶于2mL N,N-二甲基甲酰胺中，加入1f(200mg，0.58mmol)，N,N-二异丙基乙胺(149.9mg，1.16mmol)，60℃搅拌反应1小时。反应结束后，反应液加入40mL水，乙酸乙酯萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物28(100mg，黄色固体)，收率37.1％。The p-fluoronitrobenzene 28a (81.9 mg, 0.58 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and 1f (200 mg, 0.58 mmol), N,N-diisopropylethylamine (149.9 mg) was added. , 1.16 mmol), and the reaction was stirred at 60 ° C for 1 hour. After the completion of the reaction, the reaction mixture was combined with EtOAc EtOAc EtOAc. The resulting residue was purified to silica crystal elut elut elut elut elut elut elut elut elut elut
MS m/z(LC-MS):465.3[M+1]MS m/z (LC-MS): 465.3 [M+1]
1HNMR(400MHz,CDCl3)δ8.12-8.15(m,2H),7.02-7.10(m,2H),6.83-6.85(m,3H),4.01-4.03(m,2H),3.62-3.64(m,1H),3.10-3.13(m,2H),2.01-2.04(m,2H),1.81-1.84(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 - 8.15 (m, 2H), 7.02 - 7.10 (m, 2H), 6.83 - 6.85 (m, 3H), 4.01-4.03 (m, 2H), 3.62-3.64 ( m, 1H), 3.10-3.13 (m, 2H), 2.01-2.04 (m, 2H), 1.81-1.84 (m, 2H).
实施例29Example 29
N-(3-溴-4-氟苯基)-N'-羟基-2-(1-(4-(1-甲基-1H-吡唑-4-基)-2-硝基苯基)哌啶-4-基)-2-羰基乙脒29 N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-(1-(4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl) Piperidin-4-yl)-2-carbonylethyl hydrazine 29
Figure PCTCN2016093584-appb-000085
Figure PCTCN2016093584-appb-000085
采用实施例28的合成路线，将原料替换为4-(4-氟-3-硝基苯)-1-甲基-1H-吡唑(采用专利申请“WO2013053983”公开的方法制备而得)，制得标题产物29(13mg，红色固体)，收率15.9％。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%.
MS m/z(LC-MS):545.3[M+1]MS m/z (LC-MS): 545.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.39(s,1H),8.20(s,1H),7.97-7.98(m,1H),7.91(s,1H),7.76-7.78(m,1H),7.34-7.36(m,1H),7.18-7.20(m,1H),6.99-7.00(m,1H),6.73-6.74(m,1H),3.85(s,3H),3.43-3.49(m,1H),3.21-3.24(m,2H),2.85-2.88(m,2H),1.89-1.99(m,2H),1.64-1.69(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 8.39 (s, 1H), 8.20 (s, 1H), 7.97-7.98 (m, 1H), 7.91 (s, 1H), 7.76-7.78(m,1H),7.34-7.36(m,1H),7.18-7.20(m,1H),6.99-7.00(m,1H),6.73-6.74(m,1H),3.85(s,3H ), 3.43-3.49 (m, 1H), 3.21-3.24 (m, 2H), 2.85-2.88 (m, 2H), 1.89-1.99 (m, 2H), 1.64-1.69 (m, 2H).
实施例30Example 30
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-乙基-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-ethyl-1H-pyrazol-4-yl) Phenyl) piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000086
Figure PCTCN2016093584-appb-000086
第一步first step
1-乙基-4-(4-硝基苯基)-1H-吡唑30a1-ethyl-4-(4-nitrophenyl)-1H-pyrazole 30a
将20a(100mg，0.53mmo)溶解于5mL N,N-二甲基甲酰胺中，加入60％氢化钠(25mg，0.63mmol)，25℃搅拌1小时，向反应液中加入碘乙烷(99mg，0.63mmol)，反应继续搅拌反应1小时。反应结束后，加入水，用乙酸乙酯萃取3次，合并有机相，水洗涤3次，饱和氯化钠溶液洗涤1次，无水硫酸钠干燥，过滤，滤液减 压浓缩，用薄层色谱法以洗脱剂体系B纯化所得残余物，得到标题产物30a(90mg，黄色油状物)，产率79％。20a (100 mg, 0.53 mmo) was dissolved in 5 mL of N,N-dimethylformamide, 60% sodium hydride (25 mg, 0.63 mmol) was added, and the mixture was stirred at 25 ° C for 1 hour, and ethyl iodide (99 mg) was added to the reaction mixture. , 0.63 mmol), the reaction was continued to stir for 1 hour. After the reaction was completed, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was combined, washed three times with water, and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, filtrate reduced The residue was purified by EtOAc (EtOAc) elute
第二步Second step
4-(1-乙基-1H-吡唑-4-基)苯胺30b4-(1-ethyl-1H-pyrazol-4-yl)aniline 30b
将30a(90mg，0.4mmol)加入12mL乙醇和3mL水中，加入铁粉(93mg，1.66mmol)和氯化铵(177mg，3.3mmol)，于75℃搅拌反应2小时。反应结束后，将反应液减压浓缩，加入乙酸乙酯，用水洗涤，饱和氯化钠溶液洗涤，无水硫酸钠干燥，得粗品标题产物30b(60mg，红棕色固体)，产率78％。30a (90 mg, 0.4 mmol) was added to 12 mL of ethanol and 3 mL of water, and iron powder (93 mg, 1.66 mmol) and ammonium chloride (177 mg, 3.3 mmol) were added, and the reaction was stirred at 75 ° C for 2 hours. After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated
第三步third step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-乙基-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺304-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-ethyl-1H-pyrazol-4-yl) Phenyl) piperidine-1-carboxamide 30
将三光气(32mg，0.174mmol)溶解于50mL四氢呋喃中，加入预制的1mL 30b(32mg，0.174mmol)的四氢呋喃溶液，加入三乙胺(18mg，0.06mmol)，室温下搅拌反应1分钟，加入1f(50mg，0.145mmol)，室温下搅拌反应1小时。反应结束后，将反应液减压浓缩，用薄层色谱法以洗脱剂体系A纯化所得残余物，得到标题产物30(35mg，白色固体)，产率43％。The triphosgene (32 mg, 0.174 mmol) was dissolved in 50 mL of tetrahydrofuran, and a solution of 1 mL of 30b (32 mg, 0.174 mmol) in tetrahydrofuran was added, and triethylamine (18 mg, 0.06 mmol) was added, and the reaction was stirred at room temperature for 1 minute, and 1f was added. (50 mg, 0.145 mmol), the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj
MS m/z(ESI):557.4[M+1]MS m/z (ESI): 557.4 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.52(s,1H),8.39(s,1H),8.07(s,1H),7.78(s,1H),7.44-7.46(m,4H),7.16-7.20(t,1H),6.98-7.00(m,1H),6.71-6.73(m,1H),4.10-4.21(m,4H),3.53-3.57(m,1H),2.85-2.91(m,2H),1.85-1.88(m,2H),1.38-1.48(m,5H). 1 H NMR (400MHz, DMSO- d 6) δ11.69 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 7.78 (s, 1H), 7.44- 7.46 (m, 4H), 7.16-7.20 (t, 1H), 6.98-7.00 (m, 1H), 6.71-6.73 (m, 1H), 4.10-4.21 (m, 4H), 3.53-3.57 (m, 1H) ), 2.85-2.91 (m, 2H), 1.85-1.88 (m, 2H), 1.38-1.48 (m, 5H).
实施例31Example 31
N-(6-(1H-四氮唑-1-基)吡啶-3-基)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺N-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl Piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000087
Figure PCTCN2016093584-appb-000087
Figure PCTCN2016093584-appb-000088
Figure PCTCN2016093584-appb-000088
第一步first step
5-硝基-2-(1H-四唑-1-基)哌啶31c5-nitro-2-(1H-tetrazol-1-yl)piperidine 31c
将1H-四氮唑31a(700mg，10mmol)溶于100mL乙腈中，加入2-氯-5-硝基吡啶31b(1.74g，11mmol)和碳酸钾(1.38g，10mmol)，90℃搅拌5小时。反应结束后，冷却至室温，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残留物，得到标题产物31c(0.60g，淡黄色固体)，产率31％。1H-tetrazole 31a (700 mg, 10 mmol) was dissolved in 100 mL of acetonitrile, 2-chloro-5-nitropyridine 31b (1.74 g, 11 mmol) and potassium carbonate (1.38 g, 10 mmol) were added and stirred at 90 ° C for 5 hours. . After completion of the reaction, the mixture was cooled to room temperature, filtered, and then evaporated tolulululululululululululululululululululululululululu
第二步Second step
6-(1H-四唑-1-基)吡啶-3-胺31d6-(1H-tetrazol-1-yl)pyridin-3-amine 31d
将31c(600mg，3.1mmol)溶解于20mL乙酸乙酯中，加入120mg 10％的钯碳，氢气置换三次，于25℃搅拌反应2小时。反应结束后，过滤，滤液减压浓缩，得粗品标题产物31d(460mg，淡黄色固体)，产品不经纯化直接进行下一步反应。31c (600 mg, 3.1 mmol) was dissolved in 20 mL of ethyl acetate, 120 mg of 10% palladium carbon was added, and the mixture was replaced with hydrogen three times, and the reaction was stirred at 25 ° C for 2 hours. After completion of the reaction, the mixture was filtered.
第三步third step
N-(6-(1H-四唑-1-基)吡啶-3-基)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺31N-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl Piperidine-1-carboxamide 31
将三光气(30mg，0.185mmol)溶解于10mL四氢呋喃中，加入粗品31d(30mg，0.185mmol)，再加入三乙胺(0.15mL，1.08mmol)，室温下搅拌反应30分钟。向反应液中加入1f(50mg，0.145mmol)，室温下搅拌反应1小时。反应结束后，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物31(25mg，白色固体)，收率32％。The triphosgene (30 mg, 0.185 mmol) was dissolved in 10 mL of tetrahydrofuran, and crude 31d (30 mg, 0.185 mmol) was added, and then triethylamine (0.15 mL, 1.08 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. 1f (50 mg, 0.145 mmol) was added to the reaction mixture, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was evaporated. mjjjjjjj
MS m/z(ESI):532.4[M+1]MS m/z (ESI): 532.4 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),10.09(s,1H),9.10(s,1H),8.72(d,1H),8.39(s,1H),8.24(dd,1H),7.96(s,1H),7.18(t,1H),6.98-7.00(m,1H),6.71-6.73(m,1H),4.20-4.24(m,2H),3.55-3.61(m,1H),2.93-2.99(m,2H),1.89-1.92(m,2H),1.46-1.54(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 10.09 (s, 1H), 9.10 (s, 1H), 8.72 (d, 1H), 8.39 (s, 1H), 8.24 ( Dd,1H), 7.96 (s, 1H), 7.18 (t, 1H), 6.98-7.00 (m, 1H), 6.71-6.73 (m, 1H), 4.20-4.24 (m, 2H), 3.55-3.61 ( m, 1H), 2.93-2.99 (m, 2H), 1.89-1.92 (m, 2H), 1.46-1.54 (m, 2H).
实施例32Example 32
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(2-甲基吡啶-4-基)苯基)哌啶-1-甲 酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(2-methylpyridin-4-yl)phenyl)piperidyl Pyridin-1- Amide
Figure PCTCN2016093584-appb-000089
Figure PCTCN2016093584-appb-000089
第一步first step
2-甲基-4-(4-硝基苯基)吡啶32c2-methyl-4-(4-nitrophenyl)pyridine 32c
将4-溴-2-甲基吡啶32a(260mg，1.5mmol)，4-硝基苯硼酸32b(250mg，1.5mmol)，[1,1'-双(二苯基磷)二茂铁]二氯化钯(55mg，0.075mmol)，碳酸钾(414mg，3mmol)加入10mL二氧六环和1mL水中，氩气氛下，于105℃搅拌反应4小时。反应结束后，冷却至室温，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系B纯化所得残余物，制得标题产物32c(260mg，白色固体)，产率81％。4-Bromo-2-methylpyridine 32a (260 mg, 1.5 mmol), 4-nitrophenylboronic acid 32b (250 mg, 1.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene] Palladium chloride (55 mg, 0.075 mmol), potassium carbonate (414 mg, 3 mmol) was added to 10 mL of dioxane and 1 mL of water, and the mixture was stirred at 105 ° C for 4 hours under an argon atmosphere. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness.
第二步Second step
4-(2-甲基吡啶-4-基)胺32d4-(2-methylpyridin-4-yl)amine 32d
将32c(260mg，1.2mmol)溶解于20mL乙酸乙酯中，加入52mg 10％钯碳，氢气置换三次，于25℃搅拌反应2小时。反应结束后，过滤，滤液减压浓缩，得粗品标题产物32d(220mg，淡黄色固体)，粗品不经纯化直接进行下一步反应。32c (260 mg, 1.2 mmol) was dissolved in 20 mL of ethyl acetate, and 52 mg of 10% palladium carbon was added thereto, and the mixture was replaced with hydrogen three times, and the reaction was stirred at 25 ° C for 2 hours. After completion of the reaction, the mixture was filtered. EtOAcjjjjjjjjjjj
第三步third step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(2-甲基吡啶-4-基)苯基)哌啶-1-甲酰胺324-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(2-methylpyridin-4-yl)phenyl)piperidyl Pyridine-1-carboxamide 32
将三光气(20mg，0.07mmol)溶解于10mL四氢呋喃中，加入粗品32d(32mg，0.174mmol)，再加入三乙胺(53mg，0.52mmol)，室温下搅拌反应1小时。向反应液中加入1f(53mg，0.52mmol)，室温下搅拌反应1小时。反应结束后，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物32(20mg，淡黄色固体)，收率25％。The triphosgene (20 mg, 0.07 mmol) was dissolved in 10 mL of tetrahydrofuran, and the crude product was added 32 d (32 mg, 0.174 mmol), and triethylamine (53 mg, 0.52 mmol) was added, and the reaction was stirred at room temperature for 1 hour. 1f (53 mg, 0.52 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was evaporated. mjjjjjjj
MS m/z(LC-MS):554.5[M+1] MS m/z (LC-MS): 554.5 [M+1]
实施例33Example 33
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-(4-甲基-1H-咪唑-1-基)吡啶-3-基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-(4-methyl-1H-imidazol-1-yl)pyridine -3-yl) piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000090
Figure PCTCN2016093584-appb-000090
第一步first step
2-(4-甲基-1H-咪唑-1-基)-5-硝基吡啶33c2-(4-methyl-1H-imidazol-1-yl)-5-nitropyridine 33c
将2-溴-5-硝基吡啶33a(500mg，2.46mmol)溶于5mL N,N-二甲基甲酰胺中，加入4-甲基-1H-咪唑33b(0.81g，9.86mmol)，碳酸钾(1.02g，7.39mmol)，室温下反应16小时。反应结束后，反应液倒入200mL水中，过滤，滤饼用水洗涤，加入乙酸乙酯溶解滤饼，无水硫酸钠干燥，过滤，减压浓缩，得粗品标题产物33c(478mg，白色固体)，产品不经纯化直接下一步反应。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.
第二步Second step
6-(4-甲基-1H-咪唑-1-基)吡啶-3-胺33d6-(4-methyl-1H-imidazol-1-yl)pyridin-3-amine 33d
将粗品33c(478mg，2.34mmol)溶解于20mL甲醇中，加入二氯化锡二水(1.8g，7.97mmol)，于70℃搅拌反应5小时。反应结束后，过滤，滤液减压浓缩，加入1N氢氧化钠的甲醇溶液至pH>7，减压浓缩，加入100mL二氯甲烷和甲醇(V:V＝10:1)的混合溶剂，过滤，滤饼用二氯甲烷和甲醇(V:V＝10:1)的混合溶剂洗涤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物33d(310mg，淡黄色固体)，产率76％。The crude product 33c (478 mg, 2.34 mmol) was dissolved in 20 mL of methanol, then dichlorodichloride dihydrate (1.8 g, 7.97 mmol) was added, and the reaction was stirred at 70 ° C for 5 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. <1> 1N sodium hydroxide in methanol to pH >7, concentrated under reduced pressure, and a mixture of 100 mL of dichloromethane and methanol (V:V = 10:1) was added and filtered. The filter cake was washed with a mixed solvent of dichloromethane and methanol (V: V = 10:1), and the filtrate was concentrated under reduced pressure. Yellow solid), yield 76%.
第三步third step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-(4-甲基-1H-咪唑-1-基)吡啶-3-基)哌啶-1-甲酰胺334-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-(4-methyl-1H-imidazol-1-yl)pyridine -3-yl) piperidine-1-carboxamide 33
将三光气(21mg，0.07mmol)溶解于10mL四氢呋喃中，加入预制的1mL 33d (30mg，0.172mmol)的四氢呋喃溶液，再加入三乙胺(0.1mL，0.72mmol)，室温下搅拌反应30分钟。向反应液中加入1f(50mg，0.145mmol)，室温下搅拌反应1小时。反应结束后，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物33(40mg，白黄色固体)，收率52％。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. mjjjlilililililililililililililili
MS m/z(LC-MS):544.5[M+1]MS m/z (LC-MS): 544.5 [M+1]
实施例34Example 34
N-(3-溴-4-氟苯基)-N’-羟基-2-羰基-2-(1-N-(四氢-2H-吡喃-4-基)氨基磺酰基)哌啶-4-基)乙脒34N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-N-(tetrahydro-2H-pyran-4-yl)aminosulfonyl)piperidine- 4-base) acetamidine 34
Figure PCTCN2016093584-appb-000091
Figure PCTCN2016093584-appb-000091
采用实施例4的合成路线，将第一步原料替换为(四氢-2H-吡喃-4-基)氨基磺酰氯，制得标题产物34(9mg，黄色固体)，收率15.2％。Using the synthetic route of Example 4, the first step of the material was replaced by (tetrahydro-2H-pyran-4-yl)aminosulfonyl chloride to give the title product 34 (9 mg, yellow solid), yield 15.2%.
MS m/z(ESI):507.4[M+1]MS m/z (ESI): 507.4 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.34(s,1H),7.35-7.33(m,1H),7.19-7.14(m,1H),6.98-6.86(m,1H),6.73-6.69(m,1H),3.82-3.79(m,2H),3.59-3.56(m,2H),3.40-3.37(m,2H),3.24-3.16(m,2H),2.70-2.65(m,2H),1.93-1.90(m,2H),1.78-1.75(m,2H),1.57-1.43(m,4H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 8.34 (s, 1H), 7.35-7.33 (m, 1H), 7.19-7.14 (m, 1H), 6.98-6.86 (m , 1H), 6.73-6.69 (m, 1H), 3.82-3.79 (m, 2H), 3.59-3.56 (m, 2H), 3.40-3.37 (m, 2H), 3.24 - 3.16 (m, 2H), 2.70 -2.65 (m, 2H), 1.93-1.90 (m, 2H), 1.78-1.75 (m, 2H), 1.57-1.43 (m, 4H).
实施例35Example 35
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-吗啉吡啶-3-基)哌啶-1-甲酰胺354-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-morpholinpyridin-3-yl)piperidine-1-carboxamide 35
Figure PCTCN2016093584-appb-000092
Figure PCTCN2016093584-appb-000092
采用实施例31的合成路线，将第一步原料替换为吗啉，制得标题产物35(27mg，白色固体)，收率34％。Using the synthetic route of Example 31, the first starting material was replaced with morpholine to give the title product 35 (27 mg, white solid).
MS m/z(ESI):549.5[M+1]MS m/z (ESI): 549.5 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.38(s,2H),8.16(s,1H),7.63(d,1H),7.18(t,1H),6.98-7.00(m,1H),6.77(d,1H),6.68-6.70(m,1H),4.14-4.18(m,2H),3.68-3.71(m,4H),3.50-3.56(m,1H),3.32(s,4H),2.83-2.89(m,2H),1.84-1.87(m,2H),1.41-1.50(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.67 (s, 1H), 8.38 (s, 2H), 8.16 (s, 1H), 7.63 (d, 1H), 7.18 (t, 1H), 6.98- 7.00 (m, 1H), 6.77 (d, 1H), 6.68-6.70 (m, 1H), 4.14 - 4.18 (m, 2H), 3.68-3.71 (m, 4H), 3.50-3.56 (m, 1H), 3.32(s,4H),2.83-2.89(m,2H),1.84-1.87(m,2H),1.41-1.50(m,2H).
实施例36 Example 36
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(1-苯基-1H-吡唑-4-基)哌啶-1-甲酰胺364-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(1-phenyl-1H-pyrazol-4-yl)piperidine- 1-formamide 36
Figure PCTCN2016093584-appb-000093
Figure PCTCN2016093584-appb-000093
采用实施例19的合成路线，将原料19a替换为1-苯基-1H-吡唑-4-胺，制得标题产物36(10mg，白色固体)，收率10％。Using the synthetic route of Example 19, the starting material 19a was replaced with 1-phenyl-1H-pyrazol-4-amine to give the title product 36 (10 mg, white solid).
MS m/z(LC-MS):529.4[M+1]MS m/z (LC-MS): 529.4 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.78(s,1H),8.39(s,1H),8.35(s,1H),7.74(d,2H),7.70(s,1H),7.47(t,2H),7.26(t,1H),7.17(t,1H),6.98-7.00(m,1H),6.70-6.72(m,1H),4.15-4.18(m,2H),3.52-3.58(m,1H),2.86-2.92(m,2H),1.85-1.88(m,2H),1.41-1.49(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 8.35 (s, 1H), 7.74 (d, 2H), 7.70 ( s, 1H), 7.47 (t, 2H), 7.26 (t, 1H), 7.17 (t, 1H), 6.98-7.00 (m, 1H), 6.70-6.72 (m, 1H), 4.15-4.18 (m, 2H), 3.52-3.58 (m, 1H), 2.86-2.92 (m, 2H), 1.85-1.88 (m, 2H), 1.41-1.49 (m, 2H).
实施例37Example 37
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-(2-羟乙基)-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-(2-hydroxyethyl)-1H-pyrazole 4-yl)phenyl)piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000094
Figure PCTCN2016093584-appb-000094
第一步first step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-(2-((四氢-2H-吡喃-2-基)氧基)乙基)-1H-吡唑-3-基)苯基)哌啶-1-甲酰胺37a4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-(2-((tetrahydro-2H-pyran))) -2-yl)oxy)ethyl)-1H-pyrazol-3-yl)phenyl)piperidine-1-carboxamide 37a
采用实施例30的合成路线，将第一步原料替换为(2-溴乙氧基)-叔丁基二甲基硅烷(采用专利申请“WO2012084683”公开的方法制备而得)，经过数步反应制得标题产物37a(70mg，白色固体)，收率64％。Using the synthetic route of Example 30, the first step of the starting material was replaced by (2-bromoethoxy)-tert-butyldimethylsilane (prepared by the method disclosed in the patent application "WO2012084683"), after several steps of reaction. The title product 37a (70 mg, white solid) was obtained.
第二步Second step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-(2-羟乙基)-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺37 4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-(2-hydroxyethyl)-1H-pyrazole 4-yl)phenyl)piperidine-1-carboxamide 37
将37a(70mg，0.1mmol)溶于10mL四氢呋喃中，加入四丁基氟化铵溶液(0.15mL，0.15mmol)，25℃搅拌反应1小时。反应结束后，减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物得到标题产物37(20mg，类白色固体)，收率34％。37a (70 mg, 0.1 mmol) was dissolved in 10 mL of tetrahydrofuran, tetrabutylammonium fluoride solution (0.15 mL, 0.15 mmol) was added, and the reaction was stirred at 25 ° C for 1 hour. After completion of the reaction, the residue was evaporated.
MS m/z(ESI):573.4[M+1]MS m/z (ESI): 573.4 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.56(s,1H),8.39(s,1H),8.04(s,1H),7.79(s,1H),7.42-7.47(m,4H),7.16-7.20(t,1H),6.98-7.00(m,1H),6.71-6.73(m,1H),4.93-4.96(m,1H),4.12-4.22(m,4H),3.73-3.77(m,2H),3.51-3.60(m,1H),2.85-2.91(m,2H),1.85-1.88(m,2H),1.46-1.48(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.72 (s, 1H), 8.56 (s, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.79 (s, 1H), 7.42- 7.47 (m, 4H), 7.16-7.20 (t, 1H), 6.98-7.00 (m, 1H), 6.71-6.73 (m, 1H), 4.93-4.96 (m, 1H), 4.12-4.22 (m, 4H) ), 3.73-3.77 (m, 2H), 3.51-3.60 (m, 1H), 2.85-2.91 (m, 2H), 1.85-1.88 (m, 2H), 1.46-1.48 (m, 2H).
实施例38Example 38
2-(1-(苯并[d]噻唑-2-基)哌啶-4-基)-N-(3-溴-4-氟苯基)-N'-羟基-2-羰基乙脒382-(1-(Benzo[d]thiazol-2-yl)piperidin-4-yl)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonylethyl hydrazine 38
Figure PCTCN2016093584-appb-000095
Figure PCTCN2016093584-appb-000095
采用实施例28的合成路线，将原料替换为2-氯苯并噻唑，制得标题产物38(16mg，黄色固体)，收率38.1％。Using the synthetic route of Example 28, the material was replaced with 2-chlorobenzothiazole to give the title product 38 (16 mg, yellow solid).
MS m/z(ESI):477.3[M+1]MS m/z (ESI): 477.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.76-7.75(m,1H),7.46-7.44(m,1H),7.29-7.25(m,2H),7.18-7.14(m,1H),7.08-7.04(m,1H),7.00-6.98(m,1H),6.71-6.69(m,1H),4.12-4.08(m,2H),3.64-3.61(m,1H),3.27-3.23(m,2H),2.02-1.99(m,2H),1.64-1.59(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ8.39 (s, 1H), 7.76-7.75 (m, 1H), 7.46-7.44 (m, 1H), 7.29-7.25 (m, 2H), 7.18-7.14 (m, 1H), 7.08-7.04 (m, 1H), 7.00-6.98 (m, 1H), 6.71-6.69 (m, 1H), 4.12-4.08 (m, 2H), 3.64-3.61 (m, 1H) , 3.27-3.23 (m, 2H), 2.02-1.99 (m, 2H), 1.64-1.59 (m, 2H).
实施例39Example 39
N-((3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)甲基)苯甲酰胺N-((3-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)methyl)benzamide
Figure PCTCN2016093584-appb-000096
Figure PCTCN2016093584-appb-000096
第一步first step
2-(3-乙酰基环丁基)乙酸39a2-(3-acetylcyclobutyl)acetic acid 39a
将原料12d(5g，0.027mol)加入50mL四氢呋喃、10mL甲醇、5mL水中，加入一水合氢氧化锂(2.28g，.054mol)，室温下搅拌反应16小时。反应结束后，反应液减压浓缩，加入水，用1M盐酸调节pH至3，乙酸乙酯萃取三次，合并有机相，饱和氯化钠溶液洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品标题产物39a(4.1g，淡黄色液体)，产品不经纯化直接下一步反应。Raw material 12d (5 g, 0.027 mol) was added to 50 mL of tetrahydrofuran, 10 mL of methanol, and 5 mL of water, and lithium hydroxide monohydrate (2.28 g, .054 mol) was added thereto, and the reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Water was added, and the mixture was adjusted to pH 3 with 1M hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate Concentration gave the title product 39a (4.1 g, pale yellow).
第二步Second step
((3-乙酰环丁基)甲基)氨基甲酸叔丁酯39b((3-acetylcyclobutyl)methyl)carbamic acid tert-butyl ester 39b
将粗品39a(4.1g，0.026mol)溶于50mL甲苯中，加入12.5mL叔丁醇，15.5mL三乙胺以及6.8mL叠氮磷酸二苯酯，90℃搅拌反应16小时。反应结束后，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，制得标题产物39b(2g，淡黄色液体)，产率34％。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
第三步third step
((3-(2-((3-溴-4-氟苯基)氨基)-2-肟基)乙酰基)环丁基)甲基)氨基甲酸叔丁酯39c((3-(2-(3-Butyl-4-fluorophenyl)amino)-2-indenyl)acetyl)cyclobutyl)methyl)carbamic acid tert-butyl ester 39c
采用实施例25的合成路线，将第一步原料替换为((3-乙酰环丁基)甲基)氨基甲酸叔丁酯39b，经过三步反应制得粗品标题产物39c(280mg，红褐色油状物)，产品不经纯化直接进行下一步反应。Using the synthetic route of Example 25, the first step starting material was replaced with ((3-acetylcyclobutyl)methyl)carbamic acid tert-butyl ester 39b. The title product 39c (280 mg, red brown oil The product was directly subjected to the next reaction without purification.
第四步the fourth step
2-(3-(氨甲基)环丁基)-N-(3-溴-4-氟苯基)-N'-羟基-2-羰基乙脒39d2-(3-(Aminomethyl)cyclobutyl)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonylacetamidine 39d
将粗品39c(100mg，0.22mmol)置于反应瓶中，加入10mL甲醇，加入1mL4M的氯化氢1,4-二氧六环，于25℃下搅拌反应1小时。反应结束后，将反应液减压浓缩，得到粗品标题产物39d(70mg，红褐色固体)，产物不经纯化直接进行下一步反应。The crude product 39c (100 mg, 0.22 mmol) was placed in a reaction flask, and 10 mL of methanol was added thereto, and 1 mL of 4 M hydrogen chloride 1,4-dioxane was added thereto, and the reaction was stirred at 25 ° C for 1 hour. After the reaction was completed, the reaction mixture was evaporated. mjjjjjjjj
第五步the fifth step
N-((3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环丁基)甲基)苯甲酰胺39N-((3-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cyclobutyl)methyl)benzamide 39
将粗品39d(70mg，0.2mmol)溶于10mL二氯甲烷中，加入三乙胺(62mg，0.6mmol)，滴加苯甲酰氯(14mg，0.1mmol)，25℃下搅拌反应1小时。反应结束后，反应液加入5mL水，二氯甲烷萃取(10mL×3)，合并有机相，饱和氯化钠溶液洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，制得标题产物39(10mg，黄色固体)，收率11％。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
MS m/z(LC-MS):448.3[M+1]MS m/z (LC-MS): 448.3 [M+1]
实施例40Example 40
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(甲基氨基甲酰基)苯基)哌啶-1-甲 酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(methylcarbamoyl)phenyl)piperidine-1- A Amide
Figure PCTCN2016093584-appb-000097
Figure PCTCN2016093584-appb-000097
第一步first step
4-氨基-N-甲基苯甲酰胺40b4-amino-N-methylbenzamide 40b
将原料40a(1.1g，7.07mmol)溶于10mL四氢呋喃中，加入14.1mL 2M甲胺四氢呋喃溶液，室温下搅拌反应1小时。反应结束后，反应液减压浓缩，用薄层色谱法以展开剂体系B纯化所得残余物，制得标题产物40b(672mg，淡黄色油状物)，产率63％。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. mjjjjlililililililililili
第二步Second step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(甲基氨基甲酰基)苯基)哌啶-1-甲酰胺404-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(methylcarbamoyl)phenyl)piperidine-1- Formamide 40
采用实施例19的合成路线，将原料替换为40b，制得标题产物40(25mg，黄色固体)，收率32.9％。Using the synthetic route of Example 19, the starting material was replaced by 40b to give the title product 40 (25 mg, yellow solid).
MS m/z(ESI):520.4[M+1]MS m/z (ESI): 520.4 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.76(s,1H),8.38(s,1H),8.23-8.22(m,1H),7.73-7.70(m,2H),7.54-7.51(m,2H),7.19-7.15(m,1H),6.99-6.97(m,1H),6.53-6.50(m,1H),4.20-4.17(m,2H),3.55-3.52(m,1H),2.93-2.87(m,3H),2.76-2.73(m,2H),1.88-1.85(m,2H),1.51-1.46(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.67 (s, 1H), 8.76 (s, 1H), 8.38 (s, 1H), 8.23-8.22 (m, 1H), 7.73-7.70 (m, 2H ), 7.54-7.51 (m, 2H), 7.19-7.15 (m, 1H), 6.99-6.97 (m, 1H), 6.53-6.50 (m, 1H), 4.20-4.17 (m, 2H), 3.55-3.52 (m, 1H), 2.93-2.87 (m, 3H), 2.76-2.73 (m, 2H), 1.88-1.85 (m, 2H), 1.51-1.46 (m, 2H).
实施例41Example 41
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(四氢-2H-吡喃-4-基)哌啶-1-甲酰胺414-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-1- Formamide 41
Figure PCTCN2016093584-appb-000098
Figure PCTCN2016093584-appb-000098
采用实施例19的合成路线，将原料替换为四氢-2H-吡喃-4-胺，制得标题产物41(44mg，黄色固体)，收率64％。 The title material 41 (44 mg, yellow solid) was obtained from the title compound (yield: 64%).
MS m/z(LC-MS):471.1[M+1]MS m/z (LC-MS): 471.1 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.36(s,1H),7.17(t,1H),6.96-6.98(m,1H),6.69-6.71(m,1H),6.26-6.28(m,1H),4.01-4.05(m,2H),3.81-3.84(m,2H),3.61-3.64(m,1H),3.46-3.48(m,1H),3.27-3.30(m,2H),2.70(t,2H),1.76-1.78(m,2H),1.65-1.68(m,2H),1.35-1.44(m,4H). 1 H NMR (400MHz, DMSO- d 6) δ11.65 (s, 1H), 8.36 (s, 1H), 7.17 (t, 1H), 6.96-6.98 (m, 1H), 6.69-6.71 (m, 1H ), 6.26-6.28 (m, 1H), 4.01-4.05 (m, 2H), 3.81-3.84 (m, 2H), 3.61-3.64 (m, 1H), 3.46-3.48 (m, 1H), 3.27-3.30 (m, 2H), 2.70 (t, 2H), 1.76-1.78 (m, 2H), 1.65-1.68 (m, 2H), 1.35-1.44 (m, 4H).
实施例42Example 42
(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(吡啶-2-基)哌啶-1-甲酰胺42(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(pyridin-2-yl)piperidine-1-carboxamide 42
Figure PCTCN2016093584-appb-000099
Figure PCTCN2016093584-appb-000099
采用实施例19的合成路线，将原料替换为2-氨基吡啶，制得标题产物42(5mg，黄色固体)，收率9.2％。The title material (42 mg, yellow solid) was obtained in the yield of 9.2%.
MS m/z(LC-MS):464.0[M+1]MS m/z (LC-MS): 464.0 [M+1]
实施例43Example 43
N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-((1r,3r)-3-((氨磺酰基氨基)甲基)环丁基)乙脒43N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-((1r,3r)-3-((sulfamoylamino)methyl)cyclobutyl)acetamidine 43
Figure PCTCN2016093584-appb-000100
Figure PCTCN2016093584-appb-000100
采用实施例4的合成路线，将原料1f替换为39d，制得标题产物43(2.1mg，白色固体)，收率6％。Using the synthetic route of Example 4, the starting material 1f was replaced with 39d to give the title product 43 (2.1 mg, white solid), yield 6%.
MS m/z(ESI):423.2[M+1]MS m/z (ESI): 423.2 [M+1]
实施例44Example 44
N-(3-溴-4-氟苯基)-N’-羟基-2-羰基-2-(1-氨基磺酰基环己亚胺-4-基)乙脒N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-aminosulfonylcycloheximide-4-yl)acetamidine
Figure PCTCN2016093584-appb-000101
Figure PCTCN2016093584-appb-000101
Figure PCTCN2016093584-appb-000102
Figure PCTCN2016093584-appb-000102
第一步first step
2-(环己亚胺-4-基)-N-(3-溴-4-氟苯基)-N'-羟基-2-羰基乙脒44a2-(cycloheximide-4-yl)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonylacetamone 44a
将25(28mg，0.061mmol)加入5mL 4N的盐酸1,4-二氧六环中，室温下反应2小时。反应结束后，减压浓缩，得粗品标题产物44a(30mg，黄色固体)，产品不经纯化直接进行下一步反应。25 (28 mg, 0.061 mmol) was added to 5 mL of 4N 1,4-dioxane hydrochloride and allowed to react at room temperature for 2 hours. After completion of the reaction, the residue was evaporated to dryness crystal crystal crystal crystal crystal
第二步Second step
(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)环己亚胺-1-基)磺酰基氨基甲酸叔丁酯44b(4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)cycloheximide-1-yl)sulfonylcarbamic acid tert-butyl ester 44b
将异氰酸氯磺酸酯(10mg，0.073mmol)溶于5mL二氯甲烷中，在0℃下，滴加预制的1mL叔丁醇(6mg，0.073mmol)的二氯甲烷溶液，搅拌反应30分钟得备用液a。在反应瓶中加入预制的2mL粗品44a(21mg，0.061mmol)的二氯甲烷溶液，滴加上述备用液a，室温搅拌反应1小时。反应结束后，加入水20mL，用二氯甲烷萃取，饱和氯化钠溶液洗涤，无水硫酸镁干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物44b(15mg，白色固体)，产率46.8％。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. After the completion of the reaction, 20 mL of water was added, and the mixture was extracted with methylene chloride, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product 44b (15 mg, white solid).
第三步third step
N-(3-溴-4-氟苯基)-N’-羟基-2-羰基-2-(1-氨基磺酰基环己亚胺-4-基)乙脒44N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-aminosulfonylcycloheximide-4-yl)acetam 44
将44b(15mg，0.03mmol)溶于5mL二氯甲烷中，加入5mL三氟乙酸，反应体系于25℃搅拌反应2小时。反应结束后，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物44(7mg，白色固体)，收率41.6％。44b (15 mg, 0.03 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the reaction was stirred at 25 ° C for 2 hours. After completion of the reaction, the residue was evaporated.jjjjjjjj
MS m/z(ESI):437.2[M+1]MS m/z (ESI): 437.2 [M+1]
1H NMR(400MHz,CD3OD)δ6.98-7.04(m,2H),6.75-6.78(m,1H),3.65-3.50(m,1H),3.44-3.48(m,1H),3.31-3.35(m,1H),3.15-3.31(m,1H),2.02-2.16(m,3H),1.62-1.81(m,3H). 1 H NMR (400MHz, CD 3 OD) δ6.98-7.04 (m, 2H), 6.75-6.78 (m, 1H), 3.65-3.50 (m, 1H), 3.44-3.48 (m, 1H), 3.31- 3.35 (m, 1H), 3.15-3.31 (m, 1H), 2.02-2.16 (m, 3H), 1.62-1.81 (m, 3H).
实施例45Example 45
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-((2-羟乙基)氨基)吡啶-3-基)哌啶-1-甲酰胺 4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-((2-hydroxyethyl)amino)pyridin-3-yl Piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000103
Figure PCTCN2016093584-appb-000103
第一步first step
N-(2-((叔丁基二甲基硅基)氧基)乙基)-5-硝基吡啶-2-胺45bN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-nitropyridin-2-amine 45b
将2-((5-硝基吡啶-2-基)氨基)乙醇45a(0.5g，2.732mmol，采用专利申请“WO2013013815”公开的方法制备而得)溶于10mL四氢呋喃中，加入咪唑(0.28g，4.098mmol)和叔丁基二甲基氯硅烷(0.49g，3.279mmol)，25℃下反应24小时。反应结束后，加入40mL水，用乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩得标题产物45b(590mg，黄色固体)，收率72.7％。产品不经纯化直接下一步反应。2-((5-Nitropyridin-2-yl)amino)ethanol 45a (0.5 g, 2.732 mmol, prepared by the method disclosed in the patent application "WO2013013815") was dissolved in 10 mL of tetrahydrofuran, and imidazole (0.28 g) was added. , 4.098 mmol) and tert-butyldimethylsilyl chloride (0.49 g, 3.279 mmol) were reacted at 25 ° C for 24 hours. After completion of the reaction, 40 mL of water was added, and the mixture was combined with ethyl acetate (EtOAc (EtOAc). (590 mg, yellow solid), yield 72.7%. The product was directly reacted without further purification.
第二步Second step
(2-((叔丁基二甲基硅基)氧基)乙基)-(5-硝基吡啶-2-基)氨基甲酸叔丁酯45c(2-((tert-Butyldimethylsilyl)oxy)ethyl)-(5-nitropyridin-2-yl)carbamic acid tert-butyl ester 45c
将粗品45b(0.5g，1.68mmol)溶于20mL乙腈中，加入4-二甲氨基吡啶(0.02g，0.168mmol)和二碳酸二叔丁酯(0.4g，1.85mmol)，25℃下反应16小时。反应结束后，反应液减压浓缩，硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得标题产物45c(600mg，无色油状物)，收率89％。The crude product 45b (0.5 g, 1.68 mmol) was dissolved in 20 mL of acetonitrile, and 4-dimethylaminopyridine (0.02 g, 0.168 mmol) and di-tert-butyl dicarbonate (0.4 g, 1.85 mmol) were added, and the reaction was carried out at 25 ° C. hour. After the reaction was completed, the reaction mixture was evaporated. mjjjjjjj
第三步third step
(5-氨基吡啶-2-基)(2-((叔丁基二甲基硅基)氧基)乙基)氨基甲酸叔丁酯45d (5-Aminopyridin-2-yl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamic acid tert-butyl ester 45d
将45c(50mg，0.126mmol)溶解于12mL甲醇和水(V:V＝5:1)的混合溶剂中。向反应液中依次加入铁粉(21mg，0.377mmol)，氯化铵(40mg，0.755mmol)。反应液升温至70℃，搅拌反应1小时。反应结束后，将反应液冷却至室温，减压浓缩，残余物中加入20mL乙酸乙酯和15mL水，分液，水相用乙酸乙酯萃取(20mL×2)，合并有机相，有机相用饱和氯化钠溶液洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物45d(45mg，黄色油状物)，产品不经纯化直接进行下一步反应。45c (50 mg, 0.126 mmol) was dissolved in a mixed solvent of 12 mL of methanol and water (V:V = 5:1). Iron powder (21 mg, 0.377 mmol) and ammonium chloride (40 mg, 0.755 mmol) were sequentially added to the reaction mixture. The reaction solution was heated to 70 ° C, and the reaction was stirred for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.
第四步the fourth step
(5-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺基)吡啶-2-基)(2-((叔丁基二甲基硅基)氧基)乙基)氨基甲酸叔丁酯45e(5-(4-(2-(4-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamido)pyridin-2-yl)(2 -((tert-Butyldimethylsilyl)oxy)ethyl)carbamic acid tert-butyl ester 45e
将三光气(14mg，0.0466mmol)溶于10mL四氢呋喃中，加入粗品45d(45mg，0.122mmol)，三乙胺(36mg，0.352mmol)，于25℃反应30分钟，加入1f(40mg，0.117mmol)，于25℃反应1小时。反应结束后，加入2mL甲醇淬灭反应，反应液减压浓缩，得到粗品标题产物45e(60mg，黄色油状物)，产品不经纯化直接进行下一步反应The triphosgene (14 mg, 0.0466 mmol) was dissolved in 10 mL of tetrahydrofuran, and the crude product was added 45d (45 mg, 0.122 mmol), triethylamine (36 mg, 0.352 mmol), and reacted at 25 ° C for 30 minutes, and added 1f (40 mg, 0.117 mmol) , reacted at 25 ° C for 1 hour. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc)
第五步the fifth step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-((2-羟乙基)氨基)吡啶-3-基)哌啶-1-甲酰胺454-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-((2-hydroxyethyl)amino)pyridin-3-yl Piperidine-1-carboxamide 45
将粗品45e(60mg，0.0813mmol)溶于2mL甲醇中，加入2mL 2M的盐酸溶液，25℃下搅拌反应18小时。反应结束后，用饱和碳酸氢钠溶液调节pH至7，乙酸乙酯萃取(30mL×3)，合并有机相，有机相用饱和氯化钠溶液30mL洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物得标题产物45(3mg，白色固体)，收率7.05％。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 EtOAcqqqqqqq
MS m/z(ESI):523.3[M+1]MS m/z (ESI): 523.3 [M+1]
1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.52-7.55(m,1H),7.30(t,1H),7.01(t,1H),6.73-6.77(m,1H),6.63(d,1H),5.34(t,2H),4.59(s,1H),4.18(d,2H),3.71(t,2H),3.63(s,1H),3.60(s,1H),3.00(t,2H),2.19(t,2H),1.95-2.05(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ7.91 (s, 1H), 7.52-7.55 (m, 1H), 7.30 (t, 1H), 7.01 (t, 1H), 6.73-6.77 (m, 1H), 6.63 (d, 1H), 5.34 (t, 2H), 4.59 (s, 1H), 4.18 (d, 2H), 3.71 (t, 2H), 3.63 (s, 1H), 3.60 (s, 1H), 3.00 (t, 2H), 2.19 (t, 2H), 1.95-2.05 (m, 4H).
实施例46Example 46
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(1-(甲磺酰基)-1H-吡唑-4-基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(1-(methylsulfonyl)-1H-pyrazol-4-yl) Piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000104
Figure PCTCN2016093584-appb-000104
Figure PCTCN2016093584-appb-000105
Figure PCTCN2016093584-appb-000105
第一步first step
4-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺基)-1H-吡唑-1-甲酸叔丁酯46b4-(4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide)-1H-pyrazole-1-carboxylic acid Tert-butyl ester 46b
0℃下，将三光气(129mg，0.436mmol)溶于3mL四氢呋喃中，加入4-氨基-1H-吡唑-1-甲酸叔丁酯46a(80mg，0.436mmol，采用申请专利““WO2014128465””公开的方法制备而得)，三乙胺(0.304mL，2.179mmol)，于0℃反应20分钟，反应液减压浓缩得残余物，加入3mL四氢呋喃，1f(150mg，0.436mmol)，加入三乙胺(0.304mL，2.179mmol)，于25℃反应1小时。反应结束后，2mL甲醇淬灭反应，将反应液减压浓缩，用硅胶色谱法以洗脱剂体系A纯化所得残余物，制得标题产物46b(182mg，黄色固体)，收率44％。At 0 ° C, 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. Prepared by the method disclosed, triethylamine (0.304 mL, 2.179 mmol), which was reacted at 0 ° C for 20 min. The reaction mixture was concentrated under reduced pressure to give a residue, 3 ml of tetrahydrofuran, 1f (150 mg, 0.436 mmol), Amine (0.304 mL, 2.179 mmol) was reacted at 25 ° C for 1 hour. After completion of the reaction, 2 mL of MeOH was evaporated. EtOAcjjjjjjjjjj
第二步Second step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(1H-吡唑-4-基)哌啶-1-甲酰胺46c4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(1H-pyrazol-4-yl)piperidine-1-carboxamide 46c
将46b(182mg，0.329mmol)溶于4mL二氯甲烷中，加入4mL三氟醋酸，25℃搅拌反应1小时。反应结束后，反应液减压浓缩，加入50mL乙酸乙酯和50mL碳酸氢钠溶液，分液，水相用乙酸乙酯萃取(50mL×2)，合并有机相，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得标题产物46c(143mg，黄色固体)，收率96％。46b (182 mg, 0.329 mmol) was dissolved in 4 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the mixture was stirred at 25 ° C for 1 hour. After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated, The residue was purified by EtOAc EtOAc (EtOAc)
第三步third step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(1-(甲磺酰基)-1H-吡唑-4-基)哌啶-1-甲酰胺464-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(1-(methylsulfonyl)-1H-pyrazol-4-yl) Piperidine-1-carboxamide 46
将46c(100mg，0.221mmol)溶于4mL二氯甲烷中，加入0.092mL三乙胺，冷却至0℃，滴加入甲烷磺酰氯(25mg，0.221mmol)，0℃搅拌反应1小时。反应结束后，加入2mL甲醇淬灭反应，反应液减压浓缩，用高效液相色谱法纯化所得残余物，得到标题产物46(7mg，白色固体)，收率6.0％。46c (100 mg, 0.221 mmol) was dissolved in 4 mL of dichloromethane, EtOAc (EtOAc), EtOAc (EtOAc) After completion of the reaction, the reaction was quenched with EtOAc (EtOAc)EtOAc.
MS m/z(ESI):531.2[M+1] MS m/z (ESI): 531.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),10.59(s,1H),8.98(s,1H),8.13(s,1H),8.02-7.91(m,2H),7.50(s,1H),7.34(s,1H),4.12-4.09(m,2H),3.44(s,3H),2.86-2.80(m,2H),2.66(s,1H),1.85-1.83(m,2H),1.51-1.48(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ10.86 (s, 1H), 10.59 (s, 1H), 8.98 (s, 1H), 8.13 (s, 1H), 8.02-7.91 (m, 2H), 7.50(s,1H), 7.34(s,1H),4.12-4.09(m,2H), 3.44(s,3H),2.86-2.80(m,2H),2.66(s,1H),1.85-1.83 ( m, 2H), 1.51-1.48 (m, 2H).
实施例47Example 47
N-(6-(((1-氨基环丙基)甲基)氨基)吡啶-3-基)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺N-(6-(((1-Aminocyclopropyl)methyl)amino)pyridin-3-yl)-4-(2-((3-bromo-4-fluorophenyl)amino)-2-( Mercapto)acetyl)piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000106
Figure PCTCN2016093584-appb-000106
第一步first step
4-甲基苯磺酸(1-((叔丁氧羰基)氨基)环丙基)甲基酯47b4-methylbenzenesulfonic acid (1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl ester 47b
将(1-羟甲基)环丙基)氨基甲酸叔丁酯47a(2g，10.68mmol)溶于50mL二氯甲烷中，加入4-二甲氨基吡啶(1.566g，12.818mmol)，加入对甲苯磺酰氯(2.24g，11.75mmol)，25℃搅拌反应3小时。反应结束后，加入150mL水，用二氯甲烷萃取(100mL×3)，合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗 品标题产物47b(3.5g，黄色固体)，产品不经纯化直接进行下一步反应。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.
第二步Second step
(1-((1,3-二羰基异吲哚啉-2-基)甲基)环丙基)氨基甲酸叔丁酯47c(1-((1,3-Dicarbonylisoindolin-2-yl)methyl)cyclopropyl)carbamic acid tert-butyl ester 47c
将粗品47b(3.5g，10.25mmol)溶于120mL N,N-二甲基甲酰胺中，加入18-冠-6(2.71g，10.25mmol)，加入邻苯二甲酰亚胺钾盐(2.848g，15.376mmol)，50℃搅拌反应18小时。反应结束后，加入100mL水，用乙酸乙酯萃取(100mL×3)，合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题产物47c(3.19g，黄色固体)，收率98.5％。The crude 47b (3.5 g, 10.25 mmol) was dissolved in 120 mL of N,N-dimethylformamide, 18-crown-6 (2.71 g, 10.25 mmol) was added, and potassium phthalimide was added (2.848). g, 15.376 mmol), and the reaction was stirred at 50 ° C for 18 hours. After completion of the reaction, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL×3), and the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to crystalljjjjjjjj
第三步third step
(1-(氨甲基)环丙基)氨基甲酸叔丁酯47d(1-(Aminomethyl)cyclopropyl)carbamic acid tert-butyl ester 47d
将47c(3.19g，10.1mmol)溶于60mL甲醇中，加入85％水合肼(773mg，13.125mmol)，回流搅拌反应18小时。反应结束后，反应液减压浓缩，加入500mL二氯甲烷，搅拌30分钟，过滤，滤液用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物47d(1.8g，黄色油状物)，产品不经纯化直接进行下一步反应。47c (3.19 g, 10.1 mmol) was dissolved in 60 mL of methanol, and 85% hydrazine hydrate (773 mg, 13.125 mmol) was added, and the reaction was stirred under reflux for 18 hours. After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated The product was directly subjected to the next reaction without purification.
第四步the fourth step
(1-(((5-硝基吡啶-2-基)氨基)甲基)环丙基)氨基甲酸叔丁酯47e(1-((5-Nitropyridin-2-yl)amino)methyl)cyclopropyl)carbamic acid tert-butyl ester 47e
将粗品47d(1.8g，9.644mmol)溶于60mL N,N-二甲基甲酰胺中，加入2-氯-5-硝基吡啶(1.685g，10.63mmol)，加入碳酸钾(4.001g，28.992mmol)，80℃搅拌反应18小时。反应结束后，加入300mL水，用乙酸乙酯萃取(200mL×3)，合并有机相，有机相依次用水(300mL×3)、饱和氯化钠溶液(300mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品标题产物47e(952mg，棕褐色固体)，产品不经纯化直接进行下一步反应。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. The organic phase was washed with water (300 mL×3), saturated sodium chloride solution (300 mL×2), dried over anhydrous sodium sulfate The filtrate was concentrated under reduced pressure to give the title compound 47e ( 952 mg, tan.
第五步the fifth step
((1-((叔丁氧羰基)氨基)环丙基)甲基)(5-硝基吡啶-2-基)氨基甲酸叔丁酯47f((1-((tert-Butoxycarbonyl)amino)cyclopropyl)methyl)(5-nitropyridin-2-yl)carbamic acid tert-butyl ester 47f
将47e(0.5g，1.68mmol)溶于20mL四氢呋喃中，加入三乙胺(0.542mL，3.892mmol)，4-二甲氨基吡啶(16mg，0.130mmol)和二碳酸二叔丁酯(0.566g，2.594mmol)，25℃下反应17小时。反应结束后，加入100mL水，用乙酸乙酯萃取(100mL×3)，合并有机相，减压浓缩，硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题产物47f(305mg，黄色油状物)，收率57.5％。47e (0.5 g, 1.68 mmol) was dissolved in 20 mL of tetrahydrofuran, triethylamine (0.542 mL, 3.892 mmol), 4-dimethylaminopyridine (16 mg, 0.130 mmol) and di-tert-butyl dicarbonate (0.566 g, 2.594 mmol), reacted at 25 ° C for 17 hours. After completion of the reaction, 100 mL of water was added, and ethyl acetate (100 mL × 3) was evaporated. Oil), yield 57.5%.
第六步Step 6
(5-氨基吡啶-2-基)((1-((叔丁基羰基)氨基)环丙基)甲基)氨基甲酸叔丁酯47g(5-Aminopyridin-2-yl)((1-((tert-Butylcarbonyl))amino)cyclopropyl)methyl)carbamic acid tert-butyl ester 47g
将47f(305mg，0.747mmol)溶解于25mL乙醇和水(V:V＝4:1)的混合溶剂中。向反应液中依次加入铁粉(167mg，2.987mmol)，氯化铵(920mg，5.974mmol)。反应液回流搅拌反应1小时。反应结束后，将反应液加入100mL水，用乙酸乙酯萃取(100mL×3)，合并有机相，，有机相用饱和氯化钠溶液洗涤(200mL×3)，无水硫酸镁干燥，过滤，滤液减压浓缩，得到粗品标题产物47g(280mg，棕黄色油 状物)，产品不经纯化直接下一步。47f (305 mg, 0.747 mmol) was dissolved in a mixed solvent of 25 mL of ethanol and water (V:V = 4:1). Iron powder (167 mg, 2.987 mmol) and ammonium chloride (920 mg, 5.974 mmol) were sequentially added to the reaction mixture. The reaction solution was stirred under reflux for 1 hour. After the reaction was completed, the reaction mixture was added to 100 mL of water, and the mixture was evaporated to ethyl acetate (100 mL×3), and the organic phase was combined and washed with saturated sodium chloride solution (200 mL×3), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude title product 47 g (280 mg, brown oil The product was taken directly to the next step without purification.
第七步Seventh step
(5-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺)吡啶-2-基)((1-((叔丁氧羰基)氨基)环丙基)甲基)氨基甲酸叔丁酯47h(5-(4-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide)pyridin-2-yl)((1 -((tert-Butoxycarbonyl)amino)cyclopropyl)methyl)carbamic acid tert-butyl ester 47h
0℃下，将三光气(73mg，0.245mmol)置于50mL单口瓶中，加入预制的3mL含有47g(92mg，0.245mmol)和三乙胺(0.171mL，1.224mmol)四氢呋喃溶液，于0℃反应30分钟，反应液减压浓缩得残余物，加入3mL四氢呋喃，1f(84mg，0.245mmol)，加入三乙胺(0.171mL，1.224mmol)，于25℃反应1小时。反应结束后，2mL甲醇淬灭反应，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，制得标题产物47h(60mg，黄色固体)，收率32.8％。At 0 ° C, 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. After 30 minutes, the reaction mixture was evaporated to dryness mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj After the completion of the reaction, 2 mL of MeOH was evaporated, and the residue was evaporated. mjjjjjjj
第八步Eighth step
N-(6-(((1-氨基环丙基)甲基)氨基)吡啶-3-基)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺47N-(6-(((1-Aminocyclopropyl)methyl)amino)pyridin-3-yl)-4-(2-((3-bromo-4-fluorophenyl)amino)-2-( Mercapto)acetyl)piperidine-1-carboxamide 47
将47h(60mg，0.08mmol)溶于2mL甲醇中，加入2mL 4M的氯化氢1,4-二氧六环溶液，25℃下搅拌反应4小时。反应结束后，加入50mL乙酸乙酯，用饱和碳酸氢钠溶液洗涤(30mL×3)，有机相减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物制得标题产物47(30mg，淡黄色固体)，收率68.2％。47h (60mg, 0.08mmol) was dissolved in 2mL of methanol, 2mL of 4M hydrogen chloride 1,4-dioxane solution was added, and the reaction was stirred at 25 ° C for 4 hours. After completion of the reaction, 50 mL of ethyl acetate was added, and the mixture was washed with a saturated sodium hydrogen carbonate solution (30 mL × 3), and the organic phase was concentrated under reduced pressure. , pale yellow solid), yield 68.2%.
MS m/z(ESI):548.3[M+1]MS m/z (ESI): 548.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(brs,2H),8.37(s,1H),8.28(s,1H),7.98-7.97(m,1H),7.46-7.43(m,1H),7.19-7.15(m,2H),6.99-6.97(m,1H),6.72-6.69(m,1H),6.54-6.53(m,1H),6.50-6.48(m,1H),4.17-4.13(m,2H),3.53-5.51(m,1H),3.43-3.42(m,2H),2.87-2.81(m,2H),1.85-1.82(m,2H),1.46-1.43(m,2H),0.79-0.73(m,4H). 1 H NMR (400MHz, DMSO- d 6) δ11.67 (brs, 2H), 8.37 (s, 1H), 8.28 (s, 1H), 7.98-7.97 (m, 1H), 7.46-7.43 (m, 1H ), 7.19-7.15 (m, 2H), 6.99-6.97 (m, 1H), 6.72-6.69 (m, 1H), 6.54-6.53 (m, 1H), 6.50-6.48 (m, 1H), 4.17-4.13 (m, 2H), 3.53-5.51 (m, 1H), 3.43-3.42 (m, 2H), 2.87-2.81 (m, 2H), 1.85-1.82 (m, 2H), 1.46-1.43 (m, 2H) , 0.79-0.73 (m, 4H).
实施例48Example 48
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-甲氧基哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-methoxypiperidine-1-carboxamide
Figure PCTCN2016093584-appb-000107
Figure PCTCN2016093584-appb-000107
第一步first step
甲氧基氨基甲酸4-氨基苯酯48b4-aminophenyl methoxy carbamate 48b
将甲氧基胺盐酸盐(456mg，5.46mmol)溶于16mL二氯甲烷和水(V:V＝3:5)的混合溶剂中，加入碳酸氢钠(767mg，9.13mmol)，冷却至0℃。0℃下，向其中滴 加预制的4mL的4-氨基氯甲酸苯酯48a(1g，4.96mmol)的二氯甲烷溶液，0℃下搅拌反应20min。反应结束后，过滤，滤饼水洗，将滤饼溶于乙醚中，无水硫酸钠干燥，加压浓缩，得粗品标题产物48b(700mg，白色固体)，产品不经纯化直接进行下一步反应。Methoxyamine hydrochloride (456 mg, 5.46 mmol) was dissolved in a mixed solvent of 16 mL of dichloromethane and water (V:V=3:5), and sodium hydrogencarbonate (767 mg, 9.13 mmol) was added and cooled to 0 °C. Drop at 0 °C A pre-formed 4 mL solution of phenyl 4-aminochloroformate 48a (1 g, 4.96 mmol) in dichloromethane was stirred and stirred at 0 ° C for 20 min. After the reaction was completed, the mixture was filtered, and the filtered cake was washed with diethyl ether, dried over anhydrous sodium sulfate, and concentrated under vacuo to give crude title product 48b (700 mg, white solid).
第二步Second step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-甲氧基哌啶-1-甲酰胺484-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-methoxypiperidine-1-carboxamide 48
将1f(306mg，0.889mmol)溶于四氢呋喃中，冷却至0℃，加入136b(198mg，0.933mmol)，再加入三氟醋酸(0.5mL，3.6mmol)，0℃下搅拌反应2小时。反应结束后，加入甲醇，减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物48(230mg，白色固体)，收率62％。1f (306 mg, 0.889 mmol) was dissolved in tetrahydrofuran, cooled to 0 ° C, 136b (198 mg, 0.933 mmol) was added, and then trifluoroacetic acid (0.5 mL, 3.6 mmol) was added, and the reaction was stirred at 0 ° C for 2 hours. After completion of the reaction, methanol was added, and the residue was evaporated. mjjjjjj
MS m/z(ESI):417.2[M+1]MS m/z (ESI): 417.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),9.70(s,1H),8.37(s,1H),7.17(t,1H),6.96-6.98(m,1H),6.71-6.72(m,1H),3.87-3.91(m,2H),3.52(s,3H),3.45-3.52(m,1H),2.72-2.78(m,2H),1.77-1.80(m,2H),1.33-1.42(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 9.70 (s, 1H), 8.37 (s, 1H), 7.17 (t, 1H), 6.96-6.98 (m, 1H), 6.71-6.72 (m, 1H), 3.87-3.91 (m, 2H), 3.52 (s, 3H), 3.45-3.52 (m, 1H), 2.72-2.78 (m, 2H), 1.77-1.80 (m, 2H) ), 1.33-1.42 (m, 2H).
实施例49Example 49
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺494-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide 49
Figure PCTCN2016093584-appb-000108
Figure PCTCN2016093584-appb-000108
将1f(400mg，1.16mmol)溶于30mL四氢呋喃溶液中，加入1mL三乙胺，滴加入三甲基硅基异氰酸酯(0.19ml，1.41mmol)，于25℃搅拌反应18小时。反应结束后，甲醇淬灭反应，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物49(170mg，淡黄色固体)，产率38％。1f (400 mg, 1.16 mmol) was dissolved in 30 mL of tetrahydrofuran solution, 1 mL of triethylamine was added, trimethylsilyl isocyanate (0.19 ml, 1.41 mmol) was added dropwise, and the reaction was stirred at 25 ° C for 18 hours. After the reaction was completed, the reaction mixture was evaporated. EtOAcjjjjjjjjjj
MS m/z(ESI):387.3[M+1]MS m/z (ESI): 387.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.37(s,1H),7.15-7.19(m,1H),6.96-6.98(m,1H),6.69-6.71(m,1H),5.94(s,2H),3.97-4.00(m,2H),3.44-3.50(m,1H),2.69-2.75(m,2H),1.74-1.77(m,2H),1.32-1.40(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.66 (s, 1H), 8.37 (s, 1H), 7.15-7.19 (m, 1H), 6.96-6.98 (m, 1H), 6.69-6.71 (m , 1H), 5.94 (s, 2H), 3.97-4.00 (m, 2H), 3.44 - 3.50 (m, 1H), 2.69-2.75 (m, 2H), 1.74-1.77 (m, 2H), 1.32-1.40 (m, 2H).
实施例50Example 50
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-甲基哌啶-1-甲酰胺50 4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-methylpiperidine-1-carboxamide 50
Figure PCTCN2016093584-appb-000109
Figure PCTCN2016093584-appb-000109
将乙酸(68mg，1.13mmol)和三乙胺(0.26mL，1.87mmol)溶于2mL甲苯中，加入叠氮磷酸二苯酯50a(312mg，1.13mmol)，100℃下密封搅拌反应1小时，冷却至室温后，冰浴，将反应液滴加入预制的15mL 1f(409mg，1.18mmol)的四氢呋喃溶液中，0℃下搅拌反应1小时。反应结束后，减压浓缩反应液，用薄层色谱法以洗脱剂体系A纯化所得残余物，得标题产物50(290mg，白色固体)，收率64％。Acetic acid (68 mg, 1.13 mmol) and triethylamine (0.26 mL, 1.87 mmol) were dissolved in 2 mL of toluene, diphenylphosphoryl azide 50a (312 mg, 1.13 mmol) was added, and the mixture was stirred and reacted at 100 ° C for 1 hour, cooled. After room temperature, the reaction mixture was poured into a pre-prepared 15 mL of 1f (409 mg, 1.18 mmol) in tetrahydrofuran, and the mixture was stirred at 0 ° C for 1 hour. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj
MS m/z(ESI):401.2[M+1]MS m/z (ESI): 401.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.37(s,1H),7.17(t,1H),6.96-6.98(m,1H),6.68-6.71(m,1H),6.41-6.43(m,1H),3.97-4.00(m,2H),3.44-3.49(m,1H),2.68-2.74(m,2H),2.55(d,3H),1.75-1.78(m,2H),1.31-1.40(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.66 (s, 1H), 8.37 (s, 1H), 7.17 (t, 1H), 6.96-6.98 (m, 1H), 6.68-6.71 (m, 1H ), 6.41-6.43 (m, 1H), 3.97-4.00 (m, 2H), 3.44-3.49 (m, 1H), 2.68-2.74 (m, 2H), 2.55 (d, 3H), 1.75-1.78 (m , 2H), 1.31-1.40 (m, 2H).
实施例51Example 51
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲脒514-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide 51
Figure PCTCN2016093584-appb-000110
Figure PCTCN2016093584-appb-000110
将1-吡唑甲脒盐酸盐51a(140mg，0.955mmol)溶于10mL N,N-二甲基甲酰胺中，加入1f(300mg，0.87mmol)，N,N-二异丙基乙胺(0.3mL，1.69mmol)，25℃搅拌反应60小时。反应结束后，反应液减压浓缩，用高效液相色谱法纯化所得残余物，得到标题产物51(133mg，灰褐色固体)，收率39.6％。1-pyrazolamide hydrochloride 51a (140 mg, 0.955 mmol) was dissolved in 10 mL of N,N-dimethylformamide and 1f (300 mg, 0.87 mmol), N,N-diisopropylethylamine (0.3 mL, 1.69 mmol), and the reaction was stirred at 25 ° C for 60 hours. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj
MS m/z(LC-MS):386.3[M+1]MS m/z (LC-MS): 386.3 [M+1]
实施例52Example 52
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-(甲磺酰基氨基)吡啶-3-基)哌啶-1-甲酰胺 4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-(methylsulfonylamino)pyridin-3-yl)piperidine- 1-carboxamide
Figure PCTCN2016093584-appb-000111
Figure PCTCN2016093584-appb-000111
第一步first step
(5-硝基吡啶-2-基)氨基甲酸叔丁酯52b(5-nitropyridin-2-yl)carbamic acid tert-butyl ester 52b
将5-硝基吡啶-2-胺52a(2g，0.014mol)溶于80mL二氯甲烷中，加入二羰基二叔丁酯(3.452g，0.016mol)，三乙胺(3.0mL，0.022mol)，4-二甲氨基吡啶(878mg，7.188mmol)加入反应瓶中，于25℃反应17小时。反应结束后，加入100mL二氯甲烷，用水洗涤，有机相减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物52b(793mg，黄色固体)，产率23.0％。5-Nipyridin-2-amine 52a (2 g, 0.014 mol) was dissolved in 80 mL of dichloromethane, di-di-di-di-butyl-di- butyl ester (3.452 g, 0.016 mol), triethylamine (3.0 mL, 0.022 mol) 4-Dimethylaminopyridine (878 mg, 7.188 mmol) was added to the reaction flask and reacted at 25 ° C for 17 hours. After completion of the reaction, 100 mL of dichloromethane was added, EtOAcjjjjjjjjjjjjjjjj .
第二步Second step
(5-氨基吡啶-2-基)氨基甲酸叔丁酯52c(5-Aminopyridin-2-yl)carbamic acid tert-butyl ester 52c
将52b(794mg，3.319mmol)溶于30mL甲醇和10mL水中，加入744mg的铁，氯化铵(1.422g，26.552mmol)，于70℃反应1小时。反应结束后，加入100mL 水，乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品标题产物52c(550mg，浅棕红色固体)，产品不经纯化直接进行下一步反应。52b (794 mg, 3.319 mmol) was dissolved in 30 mL of methanol and 10 mL of water, and 744 mg of iron, ammonium chloride (1.422 g, 26.552 mmol) was added and reacted at 70 ° C for 1 hour. After the reaction is over, add 100mL The mixture was extracted with EtOAc (EtOAc)EtOAc. The next step is to react.
第三步third step
(5-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺)吡啶-2-基)氨基甲酸叔丁酯52d(5-(4-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide)pyridin-2-yl)carbamic acid Butyl ester 52d
将4mL四氢呋喃加入反应瓶中，于0℃下，加入三光气(129mg，0.436mmol)，粗品52c(91mg，0.436mmol)，三乙胺(304μL，2.179mmol)，于0℃搅拌反应30分钟，减压浓缩备用，滴加入预制的4mL的1f(150mg，0.436mmol)的四氢呋喃溶液和三乙胺(304μL，2.179mmol)，于25℃搅拌反应2小时。反应结束后，加入2 mL甲醇淬灭反应，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物52d(154mg，黄色固体)，产率61.1％。4 mL of tetrahydrofuran was added to the reaction flask, and triphosgene (129 mg, 0.436 mmol), crude product 52c (91 mg, 0.436 mmol), triethylamine (304 μL, 2.179 mmol) was stirred at 0 ° C for 30 min. The mixture was concentrated under reduced pressure. EtOAc (EtOAc m.) 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
第四步the fourth step
N-(6-氨基吡啶-3-基)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺52eN-(6-Aminopyridin-3-yl)-4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide 52e
将粗品52d(154mg，3.319mmol)溶于10mL二氯甲烷中，加入10mL三氟乙酸，于25℃反应3小时。反应结束后，将反应液减压浓缩，加入100mL乙酸乙酯，有机相依次用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品标题产物52e(120mg，黄色油状物)，产品不经纯化直接进行下一步反应。The crude product 52d (154 mg, 3.319 mmol) was dissolved in dichloromethane (10 mL), and then 10% trifluoroacetic acid was reacted and reacted at 25 ° C for 3 hours. After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated Product 52e (120 mg, yellow oil), product was taken to the next step without purification.
第五步the fifth step
N-(5-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺)吡啶-2-基)氨磺酰氨基甲酸叔丁酯52fN-(5-(4-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide)pyridin-2-yl)Ammonia Tert-butyl sulfonylcarbamate 52f
将2mL四氢呋喃加入反应瓶中，0℃下，加入氯磺酰基异氰酸酯(42mg，0.300mmol)，加入叔丁醇(22mg，0.300mmol)，于0℃搅拌反应20分钟后备用。将预制的2ml粗品52e(120mg，0.250mmol)的四氢呋喃溶液，三乙胺(174μL，1.252mmol)加入反应瓶中，加入上述备用液，于25℃搅拌反应1小时。反应结束后，加入3mL甲醇淬灭反应，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物52f(135mg，黄色固体)，产率81.8％。2 mL of tetrahydrofuran was added to the reaction flask, and chlorosulfonyl isocyanate (42 mg, 0.300 mmol) was added at 0 ° C, tert-butanol (22 mg, 0.300 mmol) was added, and the mixture was stirred at 0 ° C for 20 minutes and then was taken. A solution of 2 ml of crude product 52e (120 mg, 0.250 mmol) in tetrahydrofuran, triethylamine (174 μL, 1.252 mmol) was added to the reaction flask, and the above-mentioned stock solution was added, and the reaction was stirred at 25 ° C for 1 hour. After the reaction was completed, the reaction was purified by EtOAc EtOAcjjjjjjj
第六步Step 6
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-(甲磺酰基氨基)吡啶-3-基)哌啶-1-甲酰胺524-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-(methylsulfonylamino)pyridin-3-yl)piperidine- 1-formamide 52
将52f(135mg，0.205mmol)置于反应瓶中，加入10mL二氯甲烷和10mL三氟乙酸，于25℃反应1小时。反应结束后，将反应液减压浓缩，高效液相色谱法纯化所得残余物，得到标题产物52(13mg，淡黄色固体)，产率11.4％。52f (135 mg, 0.205 mmol) was placed in a reaction flask, and 10 mL of dichloromethane and 10 mL of trifluoroacetic acid were added and reacted at 25 ° C for 1 hour. After the reaction was completed, the reaction mixture was evaporated. mjjjlilililililililili
MS m/z(ESI):558.2[M+1] MS m/z (ESI): 558.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.88(s,1H),7.30-7.27(m,1H),7.21-7.11(m,2H),8.89(s,1H),8.66(s,1H),8.29-8.27(m,1H),5.33-5.31(m,3H),4.16-4.13(m,2H),3.61(s,1H),2.85-2.79(m,2H),2.02-1.97(m,2H),1.81-1.78(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ8.11 (s, 1H), 7.88 (s, 1H), 7.30-7.27 (m, 1H), 7.21-7.11 (m, 2H), 8.89 (s, 1H ), 8.66 (s, 1H), 8.29-8.27 (m, 1H), 5.33-5.31 (m, 3H), 4.16-4.13 (m, 2H), 3.61 (s, 1H), 2.85-2.79 (m, 2H) ), 2.02-1.97 (m, 2H), 1.81-1.78 (m, 2H).
实施例53Example 53
N-(3-溴-4-氟苯基)-N’-羟基-2-羰基-2-(1-氨基磺酰基吡咯烷-4-基)乙脒53N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-aminosulfonylpyrrolidin-4-yl)acetamidine 53
Figure PCTCN2016093584-appb-000112
Figure PCTCN2016093584-appb-000112
采用实施例44的合成路线，将原料替换为3-乙酰基吡咯烷-1-氨基甲酸叔丁酯(采用专利申请“WO2012126901”公开的方法制备而得)，得到标题产物53(20mg，黄色固体)，收率41.6％。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%.
MS m/z(LC-MS):409.2[M+1]MS m/z (LC-MS): 409.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),8.40(s,1H),7.14-7.19(t,1H),7.00-7.02(m,1H),6.84(s,2H),6.72-6.74(m,1H),3.98-4.01(m,1H),3.41-3.43(m,1H),3.23-3.25(m,1H),3.15-3.19(m,2H),1.99-2.02(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.78 (s, 1H), 8.40 (s, 1H), 7.14-7.19 (t, 1H), 7.00-7.02 (m, 1H), 6.84 (s, 2H ), 6.72-6.74 (m, 1H), 3.98-4.01 (m, 1H), 3.41-3.43 (m, 1H), 3.23-3.25 (m, 1H), 3.15-3.19 (m, 2H), 1.99-2.02 (m, 2H).
实施例54Example 54
(S)-N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(1-氨磺酰基哌啶-3-基)乙脒54(S)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-sulfamoylpiperidin-3-yl)acetamidine 54
Figure PCTCN2016093584-appb-000113
Figure PCTCN2016093584-appb-000113
采用实施例44的合成路线，将原料替换为(S)-3-乙酰基哌啶-1-甲酸叔丁酯(采用专利申请“WO2011117254”公开的方法制备而得)，制得标题产物54(40mg，黄色固体)，收率70.2％。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%.
MS m/z(ESI):423.2[M+1]MS m/z (ESI): 423.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),8.38(s,1H),7.17-7.13(m,1H),7.02-7.00(m,1H),8.79(s,2H),8.74-8.70(m,1H),3.58-3.49(m,2H),3.39(s,2H),2.68-2.63(m,1H),1.95-1.93(m,1H),1.83-1.80(m,1H),1.56-1.52(m,1H),1.41-1.33(m,1H). 1 H NMR (400MHz, DMSO- d 6) δ11.77 (s, 1H), 8.38 (s, 1H), 7.17-7.13 (m, 1H), 7.02-7.00 (m, 1H), 8.79 (s, 2H ), 8.74-8.70 (m, 1H), 3.58-3.49 (m, 2H), 3.39 (s, 2H), 2.68-2.63 (m, 1H), 1.95-1.93 (m, 1H), 1.83-1.80 (m , 1H), 1.56-1.52 (m, 1H), 1.41-1.33 (m, 1H).
实施例55Example 55
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-羧酸甲酯55Methyl 4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxylate 55
Figure PCTCN2016093584-appb-000114
Figure PCTCN2016093584-appb-000114
Figure PCTCN2016093584-appb-000115
Figure PCTCN2016093584-appb-000115
将1f(103mg，0.3mmol)溶于10mL二氯甲烷中，加入三乙胺(60mg，0.6mmol)，冰水冷却，滴加氯甲酸甲酯(28mg，0.3mmol，溶于5mL二氯甲烷中)二氯甲烷溶液，0℃下搅拌反应1小时。反应结束后，反应液加入30mL水，二氯甲烷萃取(20mL×3)，饱和氯化钠溶液(50mL×1)洗涤，无水硫酸镁干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物55(75mg，白色固体)，收率62.5％。1f (103mg, 0.3mmol) was dissolved in 10mL of dichloromethane, triethylamine (60mg, 0.6mmol) was added, cooled in ice water, methyl chloroformate (28mg, 0.3mmol, dissolved in 5mL of dichloromethane) The dichloromethane solution was stirred at 0 ° C for 1 hour. After the reaction was completed, the reaction mixture was combined with EtOAc EtOAc EtOAc. The obtained residue was purified to silica gel elut elut elut elut elut elut elut elut elut
MS m/z(ESI):402.2[M+1]MS m/z (ESI): 402.2 [M+1]
1H NMR(400MHz,CDCl3)δ9.12(s,1H),7.00-7.07(m,2H),6.88(s,1H),6.79-6.81(m,1H),4.21-4.29(m,2H),3.75(s,3H),3.48-3.53(m,1H),2.88-2.94(m,2H),1.85-1.95(m,2H),1.65(s,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.12 (s, 1H), 7.00-7.07 (m, 2H), 6.88 (s, 1H), 6.79-6.81 (m, 1H), 4.21-4.29 (m, 2H) ), 3.75 (s, 3H), 3.48-3.53 (m, 1H), 2.88-2.94 (m, 2H), 1.85-1.95 (m, 2H), 1.65 (s, 2H).
实施例56Example 56
(1R,5S)-3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(1R,5S)-3-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-8-azabicyclo[3.2.1]octane-8 - tert-butyl formate
Figure PCTCN2016093584-appb-000116
Figure PCTCN2016093584-appb-000116
第一步first step
(1R,5S)-3-(1-羟乙基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯56b(1R,5S)-3-(1-hydroxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 56b
将原料(1R,5S)-3-甲酰基-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯56a(1g，4.18mmol，采用专利申请“WO2011059021”公开的方法制备而得)溶于15mL四氢呋喃中，冷却至0℃，加入1.7mL 3M的甲基溴化镁溶液，0℃下搅拌反应1小时。反应结束后，加入1M的盐酸溶液淬灭反应。分液，水相用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品标题产物56b(1.06g，无 色液体)，产物不经纯化直接下一步反应。Starting material (1R,5S)-3-formyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 56a (1 g, 4.18 mmol, prepared by the method disclosed in patent application "WO2011059021" It was dissolved in 15 mL of tetrahydrofuran, cooled to 0 ° C, and 1.7 mL of a 3 M solution of methylmagnesium bromide was added, and the reaction was stirred at 0 ° C for 1 hour. After completion of the reaction, the reaction was quenched by the addition of 1 M hydrochloric acid solution. The mixture was separated, EtOAc (EtOAc m. Color liquid), the product was directly reacted without further purification.
第二步Second step
(1R,5S)-3-乙酰基-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯56c(1R,5S)-3-acetyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 56c
将粗品56b(1.06g，4.18mmol)溶于30mL二氯甲烷中，加入戴斯-马丁氧化剂(1.8g，4.17mmol)，25℃下搅拌反应1.5小时。反应结束后，加入饱和碳酸氢钠溶液和饱和硫代硫酸钠溶液，搅拌5分钟。分液，水相用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物56c(807mg，无色液体)，收率77％。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
第三步third step
(1R,5S)-3-(2-羰基乙酰基)-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯56d(1R,5S)-3-(2-carbonylacetyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 56d
将二氧化硒(700mg，6.3mmol)置于反应瓶中，加入30mL 1,4-二氧六环，56c(800mg，3.19mmol)，于90℃反应12小时。反应结束后，过滤除去不溶物，滤液减压浓缩，将所得残余物溶于乙酸乙酯，过滤，滤液用水洗涤，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物56d(670mg，淡褐色油状物)，产物不经纯化直接进行下一步反应。Selenium dioxide (700 mg, 6.3 mmol) was placed in a reaction flask, and 30 mL of 1,4-dioxane, 56c (800 mg, 3.19 mmol) was added, and the mixture was reacted at 90 ° C for 12 hours. After the reaction was completed, the insoluble material was filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Product 56d (670 mg, mp.).
第四步the fourth step
(1R,5S)-3-(2-(肟基)乙酰基)-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯56e(1R,5S)-3-(2-(indolyl)acetyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 56e
将粗品56d(67mg，2.53mmol)溶于20mL甲醇中，加入碳酸钾(524mg，3.79mmol)，于0℃搅拌反应10分钟，分批加入预制的2.5mL盐酸羟胺(88mg，1.266mmol)的甲醇溶液，于0℃搅拌下反应0.5小时。反应结束后，，过滤除去不溶物，滤液减压浓缩，用薄层色谱法以展开剂体系B纯化所得残余物，得标题产物56e(166mg，淡褐色油状物)，产率23％。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.
第五步the fifth step
(1R,5S)-3-(2-氯-2-(肟基)乙酰基)-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯56f(1R,5S)-3-(2-chloro-2-(indolyl)acetyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 56f
将56e(2.52g，8.9mmol)加入30mL N,N-二甲基甲酰胺中，加入N-氯代丁二酰亚胺(1.25g，9.36mmol)，于25℃下搅拌反应1小时。反应结束后，加入水和乙酸乙酯分液，有机相用乙酸乙酯萃取(50mL×3)，合并有机相，有机相依次用水和饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物56f(3.167g，淡黄色油状物)，产物不经纯化直接进行下一步反应。56e (2.52 g, 8.9 mmol) was added to 30 mL of N,N-dimethylformamide, and N-chlorosuccinimide (1.25 g, 9.36 mmol) was added, and the reaction was stirred at 25 ° C for 1 hour. After the reaction was completed, water and ethyl acetate were added, and the organic phase was combined with ethyl acetate (50 mL×3), and the organic phase was combined. The organic phase was washed sequentially with water and saturated sodium chloride The filtrate was concentrated under reduced vacuo to give crystals crystals crystals crystals
第六步Step 6
(1R,5S)-3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯56(1R,5S)-3-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-8-azabicyclo[3.2.1]octane-8 - tert-butyl formate 56
将粗品56f(3.15g，9.9mmol)和3-溴-4-氟苯胺(3.8g，19.9mmol)加入30mL乙醇中，于25℃下搅拌反应12小时。反应结束后，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物56(1.8g，褐色粘稠物)，收率38％。 Crude 56f (3.15 g, 9.9 mmol) and 3-bromo-4-fluoroaniline (3.8 g, 19.9 mmol) were added to 30 mL of ethanol, and the reaction was stirred at 25 ° C for 12 hours. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjj
MS m/z(ESI):470.2[M+1]MS m/z (ESI): 470.2 [M+1]
1H NMR(400MHz,CDCl3)δ7.61(s,1H),7.08-7.10(m,1H),7.03(t,1H),6.83-6.86(m,2H),4.28-4.38(m,2H),3.85-3.91(m,1H),2.04-2.06(m,2H),1.89-1.92(m,2H),1.73-1.78(m,4H),1.50-1.54(m,9H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (s, 1H), 7.08-7.10 (m, 1H), 7.03 (t, 1H), 6.83-6.86 (m, 2H), 4.28-4.38 (m, 2H) ), 3.85-3.91 (m, 1H), 2.04-2.06 (m, 2H), 1.89-1.92 (m, 2H), 1.73-1.78 (m, 4H), 1.50-1.54 (m, 9H).
实施例57Example 57
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-氰基-3-异丙基苯基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-cyano-3-isopropylphenyl)piperidine-1 -formamide
Figure PCTCN2016093584-appb-000117
Figure PCTCN2016093584-appb-000117
第一步first step
4-氨基-2-异丙基苯甲腈57b4-amino-2-isopropylbenzonitrile 57b
将4-氨基-2-溴苯甲腈57a(150mg，0.76mmol)溶于20mL1,4-二氧六环中，加入[1,1'-双二苯基膦二茂铁]二氯化钯(56mg，0.076mmol)和0.25M二异丙基锌(6mL，1.5mmol)，氩气氛下，于100℃搅拌反应2小时。反应结束后，硅藻土过滤反应液，滤液减压浓缩，用薄层色谱法以展开剂体系B纯化所得残余物，得标题产物57b(80mg，褐色油状物)，收率66％。4-Amino-2-bromobenzonitrile 57a (150 mg, 0.76 mmol) was dissolved in 20 mL of 1,4-dioxane, and [1,1'-bisdiphenylphosphinoferrocene]palladium dichloride was added. (56 mg, 0.076 mmol) and 0.25 M diisopropyl zinc (6 mL, 1.5 mmol) were stirred at 100 ° C for 2 hours under argon. After the completion of the reaction, the reaction mixture was filtered. EtOAcjjjjjjj
第二步Second step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-氰基-3-异丙基苯基)哌啶-1-甲酰胺574-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-cyano-3-isopropylphenyl)piperidine-1 -formamide 57
将三光气(86mg，0.29mmol)溶于30mL四氢呋喃中，加入57b(49mg，0.305mmol)，三乙胺(88mg，0.87mmol)，于25℃反应30分钟，加入1f(100mg，0.29mmol)，于25℃搅拌反应1小时。反应结束后，加入甲醇，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物57(10mg，白色固体)，收率6.5％。The triphosgene (86 mg, 0.29 mmol) was dissolved in 30 mL of tetrahydrofuran, 57b (49 mg, 0.305 mmol), triethylamine (88 mg, 0.87 mmol) was added and reacted at 25 ° C for 30 minutes, and 1f (100 mg, 0.29 mmol) was added. The reaction was stirred at 25 ° C for 1 hour. After completion of the reaction, methanol was added, and the reaction mixture was evaporated. mjjjjjjjj
MS m/z(ESI):530.3[M+1]MS m/z (ESI): 530.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),9.00(s,1H),8.39(s,1H),756-7.62(m,3H),7.15-7.20(m,1H),6.98-7.00(m,1H),6.70-6.73(m,1H),4.19-4.22(m,2H),3.53-3.61(m,1H),3.15-3.18(m,1H),2.89-2.95(m,2H),1.87-1.90(m,2H),1.43-1.51(m,2H),0.93-0.94(d,6H). 1 H NMR (400MHz, DMSO- d 6) δ11.70 (s, 1H), 9.00 (s, 1H), 8.39 (s, 1H), 756-7.62 (m, 3H), 7.15-7.20 (m, 1H ), 6.98-7.00 (m, 1H), 6.70-6.73 (m, 1H), 4.19-4.22 (m, 2H), 3.53-3.61 (m, 1H), 3.15-3.18 (m, 1H), 2.89-2.95 (m, 2H), 1.87-1.90 (m, 2H), 1.43-1.51 (m, 2H), 0.93-0.94 (d, 6H).
实施例58Example 58
N-(3-溴-4-氟苯基)-N’-羟基-2-羰基-2-((1R,5S)-8-氨磺酰基-8-氮杂双环[3.2.1]辛烷-3-基)乙脒N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-((1R,5S)-8-sulfamoyl-8-azabicyclo[3.2.1]octane -3-yl) acetamidine
Figure PCTCN2016093584-appb-000118
Figure PCTCN2016093584-appb-000118
第一步first step
2-((1R,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-N-(3-溴-4-氟苯基)-N'-羟基-2-羰基乙脒58a2-((1R,5S)-8-Azabicyclo[3.2.1]octane-3-yl)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl B脒58a
将56(600mg，1.28mmol)溶于3mL二氯甲烷中，加入3mL三氟乙酸，反应体系于25℃搅拌反应1小时。反应结束后，减压浓缩，得到粗品标题产物58a(1.2g，黄褐色油状物)，产品不经纯化直接进行下一步反应。56 (600 mg, 1.28 mmol) was dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the reaction was stirred at 25 ° C for 1 hour. After completion of the reaction, the residue was evaporated to mjjjjjjjjj
第二步Second step
((1R,5S)-3-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-8-氮杂双环[3.2.1]辛烷-8-基)磺酰基氨基甲酸叔丁酯58b((1R,5S)-3-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-8-azabicyclo[3.2.1]octane- 8-yl) tert-butyl sulfonyl carbamate 58b
将氯磺酰基异氰酸酯(9.17mg，6.48mmol)溶于10mL二氯甲烷中，冷却至0℃，加入叔丁醇(480mg，6.47mmol)，0℃搅拌反应5分钟得备用液。将58a(1.2g，3.24mmol)，三乙胺(2.25mL，16.2mmol)和30mL二氯甲烷入反应瓶中，加入4mL备用液，0℃下搅拌1小时。反应结束后，加入甲醇淬灭反应，减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物58b(180mg，褐色固体)，产率10％。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.
第三步third step
N-(3-溴-4-氟苯基)-N’-羟基-2-羰基-2-((1R,5S)-8-氨磺酰基-8-氮杂双环[3.2.1]辛烷-3-基)乙脒58N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-((1R,5S)-8-sulfamoyl-8-azabicyclo[3.2.1]octane -3-base) 脒58
将58b(180mg，0.327mmol)溶于3mL二氯甲烷中，加入3mL三氟乙酸，反应体系于25℃搅拌反应1小时。反应结束后，减压浓缩用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物58(86mg，灰白色固体)，收率58％。58b (180 mg, 0.327 mmol) was dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the reaction was stirred at 25 ° C for 1 hour. After completion of the reaction, the residue obtained was purified byjjjjlilililililililililililililili
MS m/z(ESI):449.2[M+1]MS m/z (ESI): 449.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.38(s,1H),7.17(t,1H),6.95-6.97 (m,1H),6.83(s,2H),6.67-6.69(m,1H),4.12(s,2H),3.73-3.78(m,1H),2.13-2.15(m,2H),1.72-1.78(m,2H),1.62-1.66(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.71 (s, 1H), 8.38 (s, 1H), 7.17 (t, 1H), 6.95-6.97 (m, 1H), 6.83 (s, 2H), 6.67-6.69 (m, 1H), 4.12 (s, 2H), 3.73-3.78 (m, 1H), 2.13-2.15 (m, 2H), 1.72-1.78 (m, 2H), 1.62-1.66 (m, 2H) ).
实施例59Example 59
N-(3-溴-4-氟苯基)-2-(1-甲酰基哌啶-4-基)-N’-羟基-2-羰基乙脒59N-(3-Bromo-4-fluorophenyl)-2-(1-formylpiperidin-4-yl)-N'-hydroxy-2-carbonylethylhydrazine 59
Figure PCTCN2016093584-appb-000119
Figure PCTCN2016093584-appb-000119
将甲酸(88mg，1.91mmol)溶于乙酸酐(100mg，0.97mmol)中，60℃搅拌反应2小时，将上述反应液溶于1mL四氢呋喃中，冰浴下，加入到预制的30mL混合1f(300mg，0.87mmol)和1mL三乙胺的四氢呋喃溶液中，0℃搅拌反应1小时。反应结束后，加入甲醇，减压浓缩干反应液，用薄层色谱法以洗脱剂体系A纯化所得残余物，得到标题产物59(90mg，淡黄色固体)，收率25％。The formic acid (88 mg, 1.91 mmol) was dissolved in acetic anhydride (100 mg, 0.97 mmol), and the reaction was stirred at 60 ° C for 2 hours. The reaction solution was dissolved in 1 mL of tetrahydrofuran, and added to the pre-prepared 30 mL of 1f (300 mg). The reaction was stirred at 0 ° C for 1 hour in a solution of 1 mL of triethylamine in tetrahydrofuran. After completion of the reaction, methanol was added, and the residue was evaporated. mjjjjjjjj
MS m/z(ESI):372.2[M+1]MS m/z (ESI): 372.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.39(s,1H),7.99(s,1H),7.17(t,1H),6.97-6.98(m,1H),6.69-6.71(m,1H),4.20-4.23(m,1H),3.72-3.75(m,1H),3.57-3.61 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 8.39 (s, 1H), 7.99 (s, 1H), 7.17 (t, 1H), 6.97-6.98 (m, 1H), 6.69-6.71 (m, 1H), 4.20-4.23 (m, 1H), 3.72-3.75 (m, 1H), 3.57-3.61
(m,1H),3.10-3.13(m,1H),2.66-2.72(m,1H),1.86-1.90(m,2H),1.40-1.44(m,1H),1.28-1.32(m,1H).(m, 1H), 3.10-3.13 (m, 1H), 2.66-2.72 (m, 1H), 1.86-1.90 (m, 2H), 1.40-1.44 (m, 1H), 1.28-1.32 (m, 1H) .
实施例60Example 60
N-(3-溴-2,4-二氟苯基)-N’-羟基-2-羰基-2-(1-氨基磺酰基哌啶-4-基)乙脒N-(3-Bromo-2,4-difluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-aminosulfonylpiperidin-4-yl)acetamidine
Figure PCTCN2016093584-appb-000120
Figure PCTCN2016093584-appb-000120
第一步first step
4-(2-((3-溴-2,4-二氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酸叔丁酯60a4-(2-((3-Bromo-2,4-difluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxylic acid tert-butyl ester 60a
将粗品1d(400mg，1.376mmol)和3-溴-2,4-二氟苯胺(572mg，2.752mmol)加入10mL乙醇中，于25℃下搅拌反应16小时。反应结束后，将反应液减压浓缩， 用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物60a(210mg，黄色油状物)，收率33.0％。The crude 1d (400 mg, 1.376 mmol) and 3-bromo-2,4-difluoroaniline (572 mg, 2.752 mmol) were added to 10 mL of ethanol, and the reaction was stirred at 25 ° C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by EtOAc EtOAcjjjjjj
第二步Second step
N-(3-溴-2,4-二氟苯基)-N’-羟基-2-羰基-2-(1-氨基磺酰基哌啶-4-基)乙脒60N-(3-Bromo-2,4-difluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-aminosulfonylpiperidin-4-yl)acetam 60
采用实施例44的合成路线，将原料25换成60a，制得标题产物60(30mg，白色固体)，产率：37％。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).
MS m/z(ESI):441.2[M+1]MS m/z (ESI): 441.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),8.28(s,1H),7.07-7.16(m,2H),6.77(s,2H),3.52(d,2H),3.26-3.30(m,1H),2.53-2.58(m,2H),1.88(d,2H),1.47-1.57(m,2H) 1 H NMR (400MHz, DMSO- d 6) δ11.44 (s, 1H), 8.28 (s, 1H), 7.07-7.16 (m, 2H), 6.77 (s, 2H), 3.52 (d, 2H), 3.26-3.30 (m, 1H), 2.53-2.58 (m, 2H), 1.88 (d, 2H), 1.47-1.57 (m, 2H)
实施例61Example 61
N’-羟基-N-(3-碘苯基)-2-羰基-2-(1-氨基磺酰基哌啶-4-基)乙脒61N'-hydroxy-N-(3-iodophenyl)-2-carbonyl-2-(1-aminosulfonylpiperidin-4-yl)acetamidine 61
Figure PCTCN2016093584-appb-000121
Figure PCTCN2016093584-appb-000121
采用实施例60的合成路线，将原料3-溴-2,4-二氟苯胺替换为3-碘苯胺，制得标题产物61(45mg，白色固体)，收率27.6％。The title product 61 (45 mg, white solid) was obtained from the title compound (yield: 27.6%).
MS m/z(ESI):453.2[M+1]MS m/z (ESI): 453.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.35(s,1H),7.18(d,1H),7.06(s,1H),6.92-6.98(m,1H),6.78(s,2H),6.68(d,1H),3.53(d,2H),3.23-3.29(m,1H),2.57(t,2H),1.94(d,2H),1.55-1.58(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.70 (s, 1H), 8.35 (s, 1H), 7.18 (d, 1H), 7.06 (s, 1H), 6.92-6.98 (m, 1H), 6.78(s,2H), 6.68(d,1H), 3.53(d,2H),3.23-3.29(m,1H), 2.57(t,2H), 1.94(d,2H),1.55-1.58(m, 2H).
实施例62Example 62
N-(3-溴-2-氟苯基)-N’-羟基-2-羰基-2-(1-氨基磺酰基哌啶-4-基)乙脒62N-(3-Bromo-2-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-aminosulfonylpiperidin-4-yl)acetam 62
Figure PCTCN2016093584-appb-000122
Figure PCTCN2016093584-appb-000122
采用实施例60的合成路线，将原料3-溴-2,4-二氟苯胺替换为3-溴-2-氟苯胺，制得标题产物62(30mg，白色固体)，收率80.8％。The title product 62 (30 mg, white solid) was obtained from the title compound (yield: 80%).
MS m/z(ESI)423.2[M+1]MS m/z (ESI) 423.2 [M+1]
1H NMR(400MHz,CDCl3)δ11.50(s,1H),8.31(s,1H),7.23-7.27(m,1H),7.00(m,2H),6.77(m,2H),3.52(d,2H),3.26-3.30(m,1H),2.52-2.58(m,2H),1.89(d,2H),1.49-1.55(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ11.50 (s, 1H), 8.31 (s, 1H), 7.23-7.27 (m, 1H), 7.00 (m, 2H), 6.77 (m, 2H), 3.52 ( d, 2H), 3.26-3.30 (m, 1H), 2.52-2.58 (m, 2H), 1.89 (d, 2H), 1.49-1.55 (m, 2H).
实施例63Example 63
N-(5-溴-2-氟苯基)-N’-羟基-2-羰基-2-(1-氨基磺酰基哌啶-4-基)乙脒63 N-(5-Bromo-2-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-aminosulfonylpiperidin-4-yl)acetamidine 63
Figure PCTCN2016093584-appb-000123
Figure PCTCN2016093584-appb-000123
采用实施例60的合成路线，将原料3-溴-2,4-二氟苯胺替换为5-溴-2-氟苯胺，制得标题产物63(13mg，白色固体)，收率30.9％。The title product 63 (13 mg, white solid) was obtained from the title compound (yield: 30%).
MS m/z(ESI):423.2[M+1]MS m/z (ESI): 423.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),8.29(s,1H),7.20(d,1H),7.11-7.18(m,1H),7.05(t,1H),6.76(s,2H),3.52(d,2H),3.23-3.29(m,1H),2.52-2.58(m,2H),1.88(d,2H),1.50-1.55(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.57 (s, 1H), 8.29 (s, 1H), 7.20 (d, 1H), 7.11-7.18 (m, 1H), 7.05 (t, 1H), 6.76(s,2H), 3.52(d,2H),3.23-3.29(m,1H),2.52-2.58(m,2H),1.88(d,2H),1.50-1.55(m,2H).
实施例64Example 64
N-(3-溴苯基)-N’-羟基-2-羰基-2-(1-氨基磺酰基哌啶-4-基)乙脒64N-(3-Bromophenyl)-N'-hydroxy-2-carbonyl-2-(1-aminosulfonylpiperidin-4-yl)acetamidine 64
Figure PCTCN2016093584-appb-000124
Figure PCTCN2016093584-appb-000124
采用实施例60的合成路线，将原料3-溴-2,4-二氟苯胺替换为3-溴苯胺，制得标题产物64(26mg，白色固体)，收率29.4％。The title product, 64 (26 mg, white solid) was obtained from the title compound (yield: 29.4%).
MS m/z(ESI):405.2[M+1]MS m/z (ESI): 405.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.42(s,1H),7.05-7.15(m,1H),6.95-7.02(m,1H),6.87(s,1H),6.78(s,2H),6.66(d,1H),3.52(d,2H),3.26-3.31(m,1H),2.57(t,2H),1.94(d,2H),1.49-1.62(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.74 (s, 1H), 8.42 (s, 1H), 7.05-7.15 (m, 1H), 6.95-7.02 (m, 1H), 6.87 (s, 1H ), 6.78 (s, 2H), 6.66 (d, 1H), 3.52 (d, 2H), 3.26-3.31 (m, 1H), 2.57 (t, 2H), 1.94 (d, 2H), 1.49-1.62 ( m, 2H).
实施例65Example 65
N-(3-氯苯基)-N’-羟基-2-羰基-2-(1-氨基磺酰基哌啶-4-基)乙脒65N-(3-chlorophenyl)-N'-hydroxy-2-carbonyl-2-(1-aminosulfonylpiperidin-4-yl)acetamidine 65
Figure PCTCN2016093584-appb-000125
Figure PCTCN2016093584-appb-000125
采用实施例60的合成路线，将原料3-溴-2,4-二氟苯胺替换为3-氯苯胺，制得标题产物65(30mg，白色固体)，收率31.9％。The title product 65 (30 mg, white solid) was obtained from the title compound (yield: 31%).
MS m/z(ESI):361.2[M+1]MS m/z (ESI): 361.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.42(s,1H),7.16(t,1H),6.87(d,1H),6.73-6.77(m,3H),6.62(d,1H),3.53(d,2H),3.26-3.31(m,1H),2.57(t,2H),1.94(d,2H),1.53-1.59(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.74 (s, 1H), 8.42 (s, 1H), 7.16 (t, 1H), 6.87 (d, 1H), 6.73-6.77 (m, 3H), 6.62 (d, 1H), 3.53 (d, 2H), 3.26-3.31 (m, 1H), 2.57 (t, 2H), 1.94 (d, 2H), 1.53-1.59 (m, 2H).
实施例66Example 66
N-(4-氟-3-(三氟甲基)苯基)-N'-羟基-2-羰基-2-(1-氨磺酰基哌啶-4-基)乙脒66 N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-2-carbonyl-2-(1-sulfamoylpiperidin-4-yl)acetamene 66
Figure PCTCN2016093584-appb-000126
Figure PCTCN2016093584-appb-000126
采用实施例60的合成路线，将原料3-溴-2,4-二氟苯胺替换为4-氟-3-三氟甲基苯胺，制得标题产物66(30mg，白色固体)，收率32.3％。The title product 66 (30 mg, white solid) was obtained from the title compound (yield 32.3). %.
MS m/z(ESI):413.2[M+1]MS m/z (ESI): 413.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),8.55(s,1H),7.28(d,1H),6.95-7.01(m,2H),6.78(s,2H),3.53(d,2H),3.32-3.40(m,1H),2.57(t,2H),1.94(d,2H),1.53-1.59(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.78 (s, 1H), 8.55 (s, 1H), 7.28 (d, 1H), 6.95-7.01 (m, 2H), 6.78 (s, 2H), 3.53 (d, 2H), 3.32-3.40 (m, 1H), 2.57 (t, 2H), 1.94 (d, 2H), 1.53-1.59 (m, 2H).
实施例67Example 67
N-(3-氯-4-氟苯基)-N’-羟基-2-羰基-2-(1-氨基磺酰基哌啶-4-基)乙脒67N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-aminosulfonylpiperidin-4-yl)acetamidine 67
Figure PCTCN2016093584-appb-000127
Figure PCTCN2016093584-appb-000127
采用实施例60的合成路线，将原料3-溴-2,4-二氟苯胺替换为3-氯-4-氟苯胺，制得标题产物67(35mg，白色固体)，收率40.1％。The title product, 67 (35 mg, white solid) was obtained from the title compound (yield: 40.1%).
MS m/z(ESI):379.3[M+1]MS m/z (ESI): 379.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.39(s,1H),7.19(t,1H),6.85(dd,1H),6.77(s,2H),6.65-6.68(s,1H),3.52(d,2H),3.26-3.31(m,1H),2.57(t,2H),1.93(d,2H),1.53-1.59(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.69 (s, 1H), 8.39 (s, 1H), 7.19 (t, 1H), 6.85 (dd, 1H), 6.77 (s, 2H), 6.65- 6.68(s,1H), 3.52(d,2H), 3.26-3.31(m,1H), 2.57(t,2H), 1.93(d,2H),1.53-1.59(m,2H).
实施例68Example 68
N-(3-溴-5-氟苯基)-N’-羟基-2-羰基-2-(1-氨基磺酰基哌啶-4-基)乙脒68N-(3-Bromo-5-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-aminosulfonylpiperidin-4-yl)acetamidine 68
Figure PCTCN2016093584-appb-000128
Figure PCTCN2016093584-appb-000128
采用实施例60的合成路线，将原料3-溴-2,4-二氟苯胺替换为3-溴-5-氟苯胺，制得标题产物68(50mg，黄褐色固体)，收率15％。The title product 68 (50 mg, a tan solid) was obtained in the yield of 15%.
MS m/z(ESI):423.2[M+1]MS m/z (ESI): 423.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.64(s,1H),6.94(d,1H),6.78(s,1H),6.71(s,1H),6.48(d,1H),3.52-3.55(m,2H),2.54-2.60(m,1H),1.94-1.99(m,2H),1.23-1.30(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.98 (s, 1H), 8.64 (s, 1H), 6.94 (d, 1H), 6.78 (s, 1H), 6.71 (s, 1H), 6.48 ( d, 1H), 3.52-3.55 (m, 2H), 2.54-2.60 (m, 1H), 1.94-1.99 (m, 2H), 1.23-1.30 (m, 2H).
实施例69Example 69
N'-羟基-2-羰基-2-(1-氨磺酰基哌啶-4-基)-N-(3-(三氟甲基)苯基)乙脒69 N'-hydroxy-2-carbonyl-2-(1-sulfamoylpiperidin-4-yl)-N-(3-(trifluoromethyl)phenyl)acetamidine 69
Figure PCTCN2016093584-appb-000129
Figure PCTCN2016093584-appb-000129
采用实施例60的合成路线，将原料3-溴-2,4-二氟苯胺替换为3-(三氟甲基)苯胺，制得标题产物69(30mg，白色固体)，收率31.3％。The title product, 69 (30 mg, white solid) was obtained from the title compound (yield: 31.3%).
MS m/z(ESI):395.3[M+1]MS m/z (ESI): 395.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.82(s,1H),8.58(s,1H),7.37(t,1H),7.16(d,1H),6.99(s,1H),6.94(d,1H),6.78(d,2H),3.58(d,2H),3.26-3.31(m,1H),2.58(t,2H),1.95(d,2H),1.53-1.59(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.82 (s, 1H), 8.58 (s, 1H), 7.37 (t, 1H), 7.16 (d, 1H), 6.99 (s, 1H), 6.94 ( d,1H), 6.78(d,2H), 3.58(d,2H), 3.26-3.31(m,1H), 2.58(t,2H),1.95(d,2H),1.53-1.59(m,2H) .
实施例70Example 70
N-(3-氯-5-乙烯基苯基)-N’-羟基-2-羰基-2-(1-氨基磺酰基哌啶-4-基)乙脒N-(3-chloro-5-vinylphenyl)-N'-hydroxy-2-carbonyl-2-(1-aminosulfonylpiperidin-4-yl)acetamidine
Figure PCTCN2016093584-appb-000130
Figure PCTCN2016093584-appb-000130
第一步first step
1-氯-3-硝基-5-乙烯基苯70b1-chloro-3-nitro-5-vinylbenzene 70b
将70a(450mg，1.9mmol，采用专利申请“CN102146022”公开的方法制备而得)溶于18mL 1,4-二氧六环和水(V:V＝6:1)的混合溶剂中，依次加入乙烯基硼酸频哪醇酯(293mg，1.9mmoml)，[1,1'-双(二苯基磷)二茂铁]二氯化钯(139mg，0.19mmol)，碳酸钾(787mg，5.7mmol)，氩气氛下，80℃搅拌反应6小时。反应结束后，冷却至室温，向反应液加入30mL水，乙酸乙酯萃取(20mL×3)，合并有机相，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物70b(250mg，黄色油状物)，收率71.4％。70a (450 mg, 1.9 mmol, prepared by the method disclosed in the patent application "CN102146022") was dissolved in a mixed solvent of 18 mL of 1,4-dioxane and water (V:V=6:1), and sequentially added. Vinylboronic acid pinacol ester (293 mg, 1.9 mmoml), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (139 mg, 0.19 mmol), potassium carbonate (787 mg, 5.7 mmol) The reaction was stirred at 80 ° C for 6 hours under an argon atmosphere. After the completion of the reaction, the mixture was cooled to room temperature, and the mixture was evaporated to dryness. The resulting residue was purified to silica gel elut elut elut elut elut elut elut elut elut elut
第二步Second step
3-氯-5-乙烯基苯胺70c3-chloro-5-vinylaniline 70c
将70b(250mg，1.36mmol)溶解于12mL乙醇和水(V:V＝5:1)的混合溶剂中，向反应液中依次加入铁粉(152mg，2.7mmol)，氯化铵(294mg，5.44mmol)。反应液升温至80℃，搅拌反应1小时。反应结束后，将反应液冷却至室温，加入20mL 水，乙酸乙酯萃取(20mL×3)，合并有机相，饱和氯化钠水溶液50mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物70c(180mg，黄色油状物)，收率86.1％。70b (250mg, 1.36mmol) was dissolved in a mixed solvent of 12mL of ethanol and water (V:V=5:1), and iron powder (152mg, 2.7mmol), ammonium chloride (294mg, 5.44) was sequentially added to the reaction liquid. Mm). The reaction solution was heated to 80 ° C, and the reaction was stirred for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, and 20 mL was added. Water, ethyl acetate (20 mL × 3), EtOAc (EtOAc) The obtained residue was purified to silicagel elut elut elut elut elut elut elut elut elut
第三步third step
N-(3-溴苯基)-N’-羟基-2-羰基-2-(1-氨基磺酰基哌啶-4-基)乙脒70N-(3-bromophenyl)-N'-hydroxy-2-carbonyl-2-(1-aminosulfonylpiperidin-4-yl)acetam 70
采用实施例60的合成路线，将原料3-溴-2,4-二氟苯胺替换为70c，制得标题产物70(2mg，白色固体)，收率33.8％。The title product 70 (2 mg, white solid) was obtained in the yield of 33.8%.
MS m/z(ESI):387.3[M+1]MS m/z (ESI): 387.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),8.43(s,1H),7.04(s,1H),6.79(s,2H),6.99-6.60(m,3H),5.80-5.75(d,1H),5.30-5.27(d,1H),5.55-5.52(m,2H),3.17-3.16(m,1H),2.60-2.55(m,2H),1.97-1.94(m,2H),1.61-1.55(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.78 (s, 1H), 8.43 (s, 1H), 7.04 (s, 1H), 6.79 (s, 2H), 6.99-6.60 (m, 3H), 5.80-5.75(d,1H), 5.30-5.27(d,1H),5.55-5.52(m,2H),3.17-3.16(m,1H), 2.60-2.55(m,2H),1.97-1.94(m , 2H), 1.61-1.55 (m, 2H).
实施例71Example 71
N-苄基-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-硫代甲酰胺71N-benzyl-4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-thiocarboxamide 71
Figure PCTCN2016093584-appb-000131
Figure PCTCN2016093584-appb-000131
将异硫氰酸苄酯71a(43mg，0.291mmol，采用公知的方法“Beilstein Journal of Organic Chemistry,2012,8(6),61-70”制备而得)溶于2mL四氢呋喃，滴加入预制的1f(100mg，0.29mmol)的8mL四氢呋喃溶液中，25℃下搅拌反应1小时。反应结束后，浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物71(25mg，淡黄色固体)，收率17％。Benzyl isothiocyanate 71a (43 mg, 0.291 mmol, prepared by the well-known method "Beilstein Journal of Organic Chemistry, 2012, 8 (6), 61-70") was dissolved in 2 mL of tetrahydrofuran, and the pre-formed 1f was added dropwise. (100 mg, 0.29 mmol) in 8 mL of tetrahydrofuran solution, the reaction was stirred at 25 ° C for 1 hour. After completion of the reaction, the residue was evaporated to purified crystal crystal crystal crystal crystal crystal crystal
MS m/z(ESI):493.3[M+1]MS m/z (ESI): 493.3 [M+1]
1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.35(m,5H),7.07(s,1H),7.00(t,1H),6.78-6.83(m,2H),5.67(s,1H),4.87(d,1H),4.59(d,2H),3.55-3.65(m,1H),3.20(t,2H),1.95(d,2H),1.73-1.78(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.77 (s, 1H), 7.35 (m, 5H), 7.07 (s, 1H), 7.00 (t, 1H), 6.78-6.83 (m, 2H), 5.67 ( s, 1H), 4.87 (d, 1H), 4.59 (d, 2H), 3.55-3.65 (m, 1H), 3.20 (t, 2H), 1.95 (d, 2H), 1.73-1.78 (m, 2H) .
实施例72Example 72
N-(3-溴-4-氟苯基)-2-(1-(5-氰基噻唑-2-基)哌啶-4-基)-N’-羟基-2-羰基乙脒72 N-(3-Bromo-4-fluorophenyl)-2-(1-(5-cyanothiazol-2-yl)piperidin-4-yl)-N'-hydroxy-2-carbonylacetamidine 72
Figure PCTCN2016093584-appb-000132
Figure PCTCN2016093584-appb-000132
将2-氯-5-氰基噻唑72a(42mg，0.29mmol，采用专利申请“WO2002006276”公开的方法制备而得)溶于5mL N,N-二甲基甲酰胺中，加入1f(100mg，0.29mmol)，150℃搅拌反应1小时。反应结束后，冷却至室温，将反应液倒入水中，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物72(20mg，白色固体)，收率15.2％。2-Chloro-5-cyanothiazole 72a (42 mg, 0.29 mmol, prepared by the method disclosed in the patent application "WO2002006276") was dissolved in 5 mL of N,N-dimethylformamide, and 1f (100 mg, 0.29) was added. Methyl), the reaction was stirred at 150 ° C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, and the mixture was evaporated. The resulting residue was purified to silica crystal elut elut elut elut elut elut elut elut elut
MS m/z(LC-MS):452.3[M+1]MS m/z (LC-MS): 452.3 [M+1]
1H NMR(400MHz,CD3OD)δ11.71(s,1H),8.38(s,1H),8.02(s,1H),7.14-7.18(s,1H),6.98-7.00(m,1H),6.70-6.72(m,1H),3.99-4.03(d,2H),3.60-3.62(m,1H),3.26-3.29(d,2H),1.96-1.99(d,2H),1.57-1.61(m,2H). 1 H NMR (400 MHz, CD 3 OD) δ 11.71 (s, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.14-7.18 (s, 1H), 6.98-7.00 (m, 1H) , 6.70-6.72 (m, 1H), 3.99-4.03 (d, 2H), 3.60-3.62 (m, 1H), 3.26-3.29 (d, 2H), 1.96-1.99 (d, 2H), 1.57-1.61 ( m, 2H).
实施例73Example 73
N-(3-溴-4-氟苯基)-2-(1-(2-氟-4-(甲磺酰基)苯基)哌啶-4-基)-N’-羟基-2-羰基乙脒73N-(3-Bromo-4-fluorophenyl)-2-(1-(2-fluoro-4-(methylsulfonyl)phenyl)piperidin-4-yl)-N'-hydroxy-2-carbonyl脒73
Figure PCTCN2016093584-appb-000133
Figure PCTCN2016093584-appb-000133
采用实施例72的合成路线，将原料72a替换为1,2-二氟-4-甲基磺酰基苯，制得标题产物73(20mg，黄色固体)，收率13.3％。The starting material 72a was replaced with 1,2-difluoro-4-methylsulfonylbenzene using the procedure of Example 72 to give the title product (yield:
MS m/z(LC-MS):516.2[M+1]MS m/z (LC-MS): 516.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.39(s,1H),7.62-7.66(t,2H),7.15-7.24(m,2H),6.98-7.01(m,1H),6.71-6.73(d,1H),3.61-3.64(d,2H),3.48-3.53(m,1H),3.18(s,3H),2.88-2.94(t,2H),1.94-1.99(t,2H),1.68-1.73(t,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 8.39 (s, 1H), 7.62-7.66 (t, 2H), 7.15-7.24 (m, 2H), 6.98-7.01 (m , 1H), 6.71-6.73 (d, 1H), 3.61-3.64 (d, 2H), 3.48-3.53 (m, 1H), 3.18 (s, 3H), 2.88-2.94 (t, 2H), 1.94-1.99 (t, 2H), 1.68-1.73 (t, 2H).
实施例74Example 74
N-(3-溴-4-氟苯基)-2-(1-(4-氰基吡啶-2-基)哌啶-4-基)-N’-羟基-2-羰基乙脒74 N-(3-Bromo-4-fluorophenyl)-2-(1-(4-cyanopyridin-2-yl)piperidin-4-yl)-N'-hydroxy-2-carbonylethyl hydrazine 74
Figure PCTCN2016093584-appb-000134
Figure PCTCN2016093584-appb-000134
将2-氯-4-氰基吡啶74a(60mg，0.43mmol)溶于2mL N,N-二甲基甲酰胺中，加入1f(100mg，0.29mmol)，65℃搅拌反应3小时。反应结束后，冷却至室温，将反应液倒入20mL水中，乙酸乙酯萃取(15mL×3)，合并有机相，饱和氯化钠溶液20mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物74(15mg，浅黄色固体)，收率11.6％。2-Chloro-4-cyanopyridine 74a (60 mg, 0.43 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and 1f (100 mg, 0.29 mmol) was added, and the reaction was stirred at 65 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was poured into 20 mL of water, ethyl acetate (15 mL × 3), and the organic phase was combined, washed with 20 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate . The resulting residue was purified to silica crystal elut elut elut elut elut elut elut elut
MS m/z(LC-MS):446.3[M+1]MS m/z (LC-MS): 446.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.37(s,1H),8.27-8.29(m,1H),7.34(s,1H),7.16-7.18(m,1H),6.91-6.99(m,2H),6.69-6.71(m,1H),4.40-4.44(m,2H),3.61-3.64(m,1H),2.94-3.00(m,2H),1.87-1.91(m,2H),1.47-1.52(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.69 (s, 1H), 8.37 (s, 1H), 8.27-8.29 (m, 1H), 7.34 (s, 1H), 7.16-7.18 (m, 1H ), 6.91-6.99 (m, 2H), 6.69-6.71 (m, 1H), 4.40-4.44 (m, 2H), 3.61-3.64 (m, 1H), 2.94-3.00 (m, 2H), 1.87-1.91 (m, 2H), 1.47-1.52 (m, 2H).
实施例75Example 75
N-(3-溴-4-氟苯基)-2-(1-(5-氰基吡啶-2-基)哌啶-4-基)-N’-羟基-2-羰基乙脒75N-(3-Bromo-4-fluorophenyl)-2-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-N'-hydroxy-2-carbonylacetamidine 75
Figure PCTCN2016093584-appb-000135
Figure PCTCN2016093584-appb-000135
将6-氯-3-氰基吡啶75a(61mg，0.44mmol)溶于3mL N-甲基吡咯烷酮中，加入1f(100mg，0.29mmol)，N,N-二异丙基乙胺(170mg，1.32mmol)，25℃搅拌反应18小时。反应结束后，将反应液倒入30mL水中，乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠水溶液洗涤(30mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物75(55mg，白色固体)，收率42.3％。6-Chloro-3-cyanopyridine 75a (61 mg, 0.44 mmol) was dissolved in 3 mL of N-methylpyrrolidone, 1f (100 mg, 0.29 mmol), N,N-diisopropylethylamine (170 mg, 1.32) Methyl), the reaction was stirred at 25 ° C for 18 hours. After the reaction was completed, the reaction mixture was poured into water (30 mL), ethyl acetate (30 mL × 3). . The obtained residue was purified to silicagel elut elut elut elut elut elut elut elut
MS m/z(LC-MS):446.3[M+1]MS m/z (LC-MS): 446.3 [M+1]
实施例76Example 76
N-(3-溴-4-氟苯基)-N’-羟基-2-(1-(4-(甲磺酰基)苯基)哌啶-4-基)-2-羰基乙脒76 N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-(1-(4-(methylsulfonyl)phenyl)piperidin-4-yl)-2-carbonylacetylene 76
Figure PCTCN2016093584-appb-000136
Figure PCTCN2016093584-appb-000136
采用实施例72的合成路线，将原料72a替换为4-甲基磺酰基氟苯，制得标题产物76(10mg，白色固体)，收率13.8％。The starting material 72a was replaced with 4-methylsulfonylfluorobenzene using the procedure of Example 72 to give the title product 76 (10 mg, white solid).
MS m/z(LC-MS):498.3[M+1]MS m/z (LC-MS): 498.3 [M+1]
实施例77Example 77
N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(1-(吡啶-2-基)哌啶-4-基)乙脒77N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-(pyridin-2-yl)piperidin-4-yl)acetam 77
Figure PCTCN2016093584-appb-000137
Figure PCTCN2016093584-appb-000137
采用实施例72的合成路线，将原料72a替换为2-氯吡啶，制得标题产物77(4mg，棕色固体)，收率4％。Using the synthetic route of Example 72, the starting material 72a was replaced with 2-chloropyridine to give the title product 77 (4 mg, brown solid).
MS m/z(LC-MS):421.3[M+1]MS m/z (LC-MS): 421.3 [M+1]
实施例78Example 78
4-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-基)苯甲酸乙酯784-4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidin-1-yl)benzoic acid ethyl ester 78
Figure PCTCN2016093584-appb-000138
Figure PCTCN2016093584-appb-000138
采用实施例72的合成路线，将原料72a替换为4-氟苯甲酸乙酯，制得标题产物78(5mg，黄色固体)，收率10.2％。The starting material 72a was replaced with ethyl 4-fluorobenzoate to give the title product 78 (5 mg, yellow solid).
MS m/z(LC-MS):492.3[M+1]MS m/z (LC-MS): 492.3 [M+1]
1H NMR(400MHz,CD3OD)δ7.85-7.87(m,2H),6.96-7.05(m,4H),6.75-6.78(m,1H),4.27-4.32(m,2H),3.97-4.01(m,2H),3.59-3.65(m,1H),2.92-3.01(m,2H),1.96-1.98(m,2H),1.72-1.77(m,2H),1.29-1.38(m,3H). 1 H NMR (400MHz, CD 3 OD) δ7.85-7.87 (m, 2H), 6.96-7.05 (m, 4H), 6.75-6.78 (m, 1H), 4.27-4.32 (m, 2H), 3.97- 4.01 (m, 2H), 3.59-3.65 (m, 1H), 2.92-3.01 (m, 2H), 1.96-1.98 (m, 2H), 1.72-1.77 (m, 2H), 1.29-1.38 (m, 3H) ).
实施例79Example 79
N-(3-溴-4-氟苯基)-N'-羟基-2-羰基-2-(1-(嘧啶-4-基)哌啶-4-基)乙脒79N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-(pyrimidin-4-yl)piperidin-4-yl)acetamidine 79
Figure PCTCN2016093584-appb-000139
Figure PCTCN2016093584-appb-000139
采用实施例72的合成路线，将原料72a替换为4-氯嘧啶，制得标题产物79(20mg，白色固体)，收率16.3％。The starting material 72a was replaced with 4-chloropyrimidine using the synthetic route of Example 72 to give the title product 79 (20 mg, white solid).
MS m/z(LC-MS):422.3[M+1]MS m/z (LC-MS): 422.3 [M+1]
1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.19-8.21(m,1H),7.01-7.08(m,2H),6.84-6.89(m,2H),6.54-6.56(m,1H),4.45-4.48(m,2H),3.66-3.68(m,1H),3.03-3.10(m,2H),1.99-2.04(m,2H),1.69-1.73(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.61 (s, 1H), 8.19-8.21 (m, 1H), 7.01-7.08 (m, 2H), 6.84-6.89 (m, 2H), 6.54-6.56 (m) , 1H), 4.45-4.48 (m, 2H), 3.66-3.68 (m, 1H), 3.03-3.10 (m, 2H), 1.99-2.04 (m, 2H), 1.69-1.73 (m, 2H).
实施例80Example 80
4-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-基)苯甲酸4-(4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidin-1-yl)benzoic acid
Figure PCTCN2016093584-appb-000140
Figure PCTCN2016093584-appb-000140
第一步first step
4-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-基)苯甲酸叔丁酯80b4-(4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidin-1-yl)benzoic acid tert-butyl ester 80b
将4-氟-苯甲酸叔丁酯80a(410mg，2.09mmol)溶于20mL N,N-二甲基甲酰胺中，加入1f(650mg，1.74mmol)，N,N-二异丙基乙胺(561mg，4.35mmol)，95℃搅拌反应72小时。反应结束后，冷却至室温，将反应液倒入水中，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物80b(120mg，黄色固体)，产品不经纯化直接进行下一步反应。4-Fluoro-benzoic acid tert-butyl ester 80a (410 mg, 2.09 mmol) was dissolved in 20 mL of N,N-dimethylformamide, 1f (650 mg, 1.74 mmol), N,N-diisopropylethylamine (561 mg, 4.35 mmol), and the reaction was stirred at 95 ° C for 72 hours. After completion of the reaction, the mixture was cooled to room temperature, and the mixture was evaporated. EtOAcjjjjjjjjjjj ), the product was directly subjected to the next reaction without purification.
第二步Second step
4-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-基)苯甲酸804-(4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidin-1-yl)benzoic acid 80
将80b(120mg，0.23mmol)溶于6mL二氯甲烷中，加入0.5mL三氟醋酸，25℃搅拌反应18小时。反应结束后，减压浓缩反应液，用薄层色谱法以洗脱剂体系A纯化所得残余物，得到标题产物80(65mg，白色固体)，收率60.7％。80b (120 mg, 0.23 mmol) was dissolved in 6 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the reaction was stirred at 25 ° C for 18 hours. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj
MS m/z(LC-MS):464.2[M+1]MS m/z (LC-MS): 464.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),11.70(s,1H),8.40(s,1H),7.70-7.77(m,2H),7.14-7.19(m,1H),6.96-6.99(m,3H),6.69-6.72(m,1H),3.96-4.01(m,2H),3.53-3.59(m,1H),2.88-2.94(m,2H),1.88-1.91(m,2H),1.55-1.61(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ12.28 (s, 1H), 11.70 (s, 1H), 8.40 (s, 1H), 7.70-7.77 (m, 2H), 7.14-7.19 (m, 1H ), 6.96-6.99 (m, 3H), 6.69-6.72 (m, 1H), 3.96-4.01 (m, 2H), 3.53-3.59 (m, 1H), 2.88-2.94 (m, 2H), 1.88-1.91 (m, 2H), 1.55-1.61 (m, 2H).
实施例81Example 81
N-(3-溴-4-氟苯基)-N’-羟基-2-羰基-2-(1-苯基哌啶-4-基)-乙脒N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-phenylpiperidin-4-yl)-acetamidine
Figure PCTCN2016093584-appb-000141
Figure PCTCN2016093584-appb-000141
第一步first step
2-(1-(4-氨基苯基)哌啶-4-基)-N-(3-溴-4-氟苯基)-N’-羟基-2-羰基乙脒81a2-(1-(4-Aminophenyl)piperidin-4-yl)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonylethenyl 81a
将28(220mg，0.47mmol)溶于30mL 1,4-二氧六环和10mL水中，加入连二亚硫酸钠(823mg，4.7mmol)，碳酸钾(324.3mg，2.35mmol)，25℃搅拌反应1小时。反应结束后，反应液加入20mL水，乙酸乙酯萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤(20mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物81a(130mg，白色固体)，收率63.5％。28 (220 mg, 0.47 mmol) was dissolved in 30 mL of 1,4-dioxane and 10 mL of water, sodium dithionite (823 mg, 4.7 mmol), potassium carbonate (324.3 mg, 2.35 mmol), and the reaction was stirred at 25 ° C for 1 hour. . After the completion of the reaction, the reaction mixture was combined with EtOAc EtOAc EtOAc. The obtained residue was purified to silica gel elut elut elut elut elut elut elut elut elut
第二步Second step
N-(3-溴-4-氟苯基)-N’-羟基-2-羰基-2-(1-苯基哌啶-4-基)-乙脒81N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-phenylpiperidin-4-yl)-acetamidine 81
将81a(20mg，0.46mmol)溶于4mL N,N-二甲基甲酰胺中，加热至70℃，滴加入预制的1mL亚硝酸叔丁酯(10mg，0.92mmol)的N,N-二甲基甲酰胺溶液，滴加完毕立即处理反应。反应液加入50mL水，乙酸乙酯萃取(40mL×1)，依次用水(30mL×3)、饱和氯化钠溶液(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用薄层层析法以展开剂体系A纯化所得残余物，得到标题产物81(5mg，黄色固体)，收率26.3％。81a (20mg, 0.46mmol) was dissolved in 4mL N,N-dimethylformamide, heated to 70 ° C, and pre-formed 1mL of t-butyl nitrite (10mg, 0.92mmol) of N, N-dimethyl The base carboxamide solution was treated immediately after the addition. The reaction mixture was poured into 50 mL of EtOAc (EtOAc)EtOAc. The resulting residue was purified by EtOAcjjjjjjjj
MS m/z(LC-MS):420.3[M+1]MS m/z (LC-MS): 420.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.38(s,1H),7.17-7.22(m,3H),6.94-6.98(m,3H),6.72-6.76(m,2H),3.75-3.78(m,2H),3.42-3.49(m,1H),2.69-2.75(m,2H),1.89-2.01(m,2H),1.61-1.67(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 8.38 (s, 1H), 7.17-7.22 (m, 3H), 6.94-6.98 (m, 3H), 6.72-6.76 (m , 2H), 3.75-3.78 (m, 2H), 3.42-3.49 (m, 1H), 2.69-2.75 (m, 2H), 1.89-2.01 (m, 2H), 1.61-1.67 (m, 2H).
实施例82Example 82
N-(3-溴-4-氟苯基)-N’-羟基-2-(1-(2-甲氧基苯基)哌啶-4-基)-2-羰基乙脒 N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-(1-(2-methoxyphenyl)piperidin-4-yl)-2-carbonylacetamidine
Figure PCTCN2016093584-appb-000142
Figure PCTCN2016093584-appb-000142
第一步first step
N-(3-溴-4-氟苯基)-N'-羟基-2-(1-(2-甲氧基-4-硝基苯)哌啶-4-基)-2-羰基乙脒82bN-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-(1-(2-methoxy-4-nitrophenyl)piperidin-4-yl)-2-carbonylacetyl 82b
将2-甲氧基-4-氟硝基苯82a(206mg，1.21mmol)溶于13mL N,N-二甲基甲酰胺中，加入1f(378mg，1.1mmol)，N,N-二异丙基乙胺(213mg，1.65mmol)，100℃搅拌反应12小时。反应结束后，反应液加入50mL水和50mL乙酸乙酯，分液，有机相用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩。用薄层色谱法以展开剂体系B纯化所得残余物，得到标题产物82b(200mg，黄色固体)，收率40.4％。2-Methoxy-4-fluoronitrobenzene 82a (206 mg, 1.21 mmol) was dissolved in 13 mL of N,N-dimethylformamide, 1f (378 mg, 1.1 mmol), N,N-diisopropyl Ethylethylamine (213 mg, 1.65 mmol) was stirred at 100 ° C for 12 hours. After the reaction was completed, the reaction mixture was combined with 50 ml of water and 50 ml of ethyl acetate, and the organic layer was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate The resulting residue was purified by EtOAc EtOAcjjjjj
第二步Second step
2-(1-(4-氨基-2-甲氧基苯基)哌啶-4-基)-N-(3-溴-4-氟苯基)-N'-羟基-2-羰基乙脒82c2-(1-(4-Amino-2-methoxyphenyl)piperidin-4-yl)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-carbonylacetamidine 82c
将82b(150mg，0.3mmol)溶于8mL 1,4-二氧六环和4mL水中，加入连二亚硫酸钠(261mg，1.5mmol)，碳酸钾(81mg，0.6mmol)，25℃搅拌反应0.5小时。反应结束后，反应液加入50mL水，50mL乙酸乙酯，分液，有机相依次用水和饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物82c(40mg，灰色固体)，收率28.6％。82b (150 mg, 0.3 mmol) was dissolved in 8 mL of 1,4-dioxane and 4 mL of water, and sodium dithionite (261 mg, 1.5 mmol), potassium carbonate (81 mg, 0.6 mmol) was added, and the mixture was stirred at 25 ° C for 0.5 hour. After the reaction was completed, the reaction mixture was combined with EtOAc EtOAc EtOAc. The resulting residue was purified by EtOAc EtOAcjjjjj
第三步third step
N-(3-溴-4-氟苯基)-N’-羟基-2-(1-(2-甲氧基苯基)哌啶-4-基)-2-羰基乙脒82N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-(1-(2-methoxyphenyl)piperidin-4-yl)-2-carbonylacetylene 82
将82c(40mg，0.086mmol)溶于4mL N,N-二甲基甲酰胺中，加热至70℃，滴加入预制的1mL亚硝酸叔丁酯(18mg，0.172mmol)的N,N-二甲基甲酰胺溶液，滴加完毕立即处理反应。反应液加入50mL水，50mL乙酸乙酯，分液，有机相依次用水和饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用薄层层析法以展开剂体系A纯化所得残余物，得到标题产物82(4mg，白色固体)， 收率10.5％。82c (40mg, 0.086mmol) was dissolved in 4mL N,N-dimethylformamide, heated to 70 ° C, and pre-formed 1mL of t-butyl nitrite (18mg, 0.172mmol) N, N-dimethyl The base carboxamide solution was treated immediately after the addition. The reaction mixture was combined with 50 mL of EtOAc EtOAc. The resulting residue was purified using EtOAc (EtOAc) The yield was 10.5%.
MS m/z(LC-MS):450.3[M+1]MS m/z (LC-MS): 450.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.14(s,1H),7.58-7.61(m,2H),7.32-7.39(m,5H),4.28(s,3H),3.91-3.97(m,2H),3.27-3.28(m,1H),3.08-3.13(m,2H),2.39-2.41(m,2H),2.27-2.29(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.14 (s, 1H), 8.14 (s, 1H), 7.58-7.61 (m, 2H), 7.32-7.39 (m, 5H), 4.28 (s, 3H ), 3.91-3.97 (m, 2H), 3.27-3.28 (m, 1H), 3.08-3.13 (m, 2H), 2.39-2.41 (m, 2H), 2.27-2.29 (m, 2H).
实施例83Example 83
N-(3-溴-4-氟苯基)-N’-羟基-2-(1-(5-硝基噻唑-2-基)哌啶-4-基)-2-羰基乙脒83N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-(1-(5-nitrothiazol-2-yl)piperidin-4-yl)-2-carbonylacetamidine 83
Figure PCTCN2016093584-appb-000143
Figure PCTCN2016093584-appb-000143
将2-溴-5-硝基噻唑83a(1.0g，4.78mmol)溶于15mL N,N-二甲基甲酰胺中，加入1f(1.65g，4.78mmol)，N,N-二异丙基乙胺(1.54g，12mmol)，80℃搅拌反应2小时。反应结束后，冷却至室温，将反应液倒入水中，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物83(300mg，黄色固体)，收率13.6％。2-Bromo-5-nitrothiazole 83a (1.0 g, 4.78 mmol) was dissolved in 15 mL of N,N-dimethylformamide, 1f (1.65 g, 4.78 mmol), N,N-diisopropyl Ethylamine (1.54 g, 12 mmol) was stirred at 80 ° C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, and the mixture was evaporated. The obtained residue was purified to silica crystal elut elut elut elut elut elut elut elut
MS m/z(LC-MS):472.2[M+1]MS m/z (LC-MS): 472.2 [M+1]
实施例84Example 84
N-(3-溴-4-氟苯基)-N’-羟基-2-羰基-2-(1-(4-吡啶-2-基)噻唑-2-基)哌啶-4-基)乙脒84N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-(4-pyridin-2-yl)thiazol-2-yl)piperidin-4-yl)脒84
Figure PCTCN2016093584-appb-000144
Figure PCTCN2016093584-appb-000144
将2-溴-4-(吡啶-2-基)噻唑84a(48mg，0.2mmol，采用专利申请“WO2012170845”公开的方法制备而得)溶于5mL N,N-二甲基甲酰胺中，加入1f (68mg，0.2mmol)，N,N-二异丙基乙胺(52mg，0.4mmol)，100℃搅拌反应5小时。反应结束后，冷却至室温，将反应液倒入50mL水中，50mL乙酸乙酯萃取，有机相水洗涤(30mL×3)，饱和氯化钠水溶液洗涤(30mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物84(5mg，黄色固体)，收率4.5％。2-Bromo-4-(pyridin-2-yl)thiazole 84a (48 mg, 0.2 mmol, prepared by the method disclosed in the patent application "WO2012170845") was dissolved in 5 mL of N,N-dimethylformamide and added 1f (68 mg, 0.2 mmol), N,N-diisopropylethylamine (52 mg, 0.4 mmol). After the reaction was completed, the mixture was cooled to room temperature, and the mixture was poured into 50 mL of water, EtOAc (50 mL), EtOAc (EtOAc) Filtration and concentration of the filtrate under reduced pressure. The resulting residue was purified to silica crystal elut elut elut elut elut elut elut elut
MS m/z(LC-MS):504.3[M+1]MS m/z (LC-MS): 504.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.55-8.56(m,1H),8.39(s,1H),7.92-7.94(m,1H),7.83-7.85(m,1H),7.47(s,1H),7.28-7.30(m,1H),7.15-7.19(m,1H),6.99-7.01(m,1H),6.71-6.74(m,1H),4.04-4.07(m,2H),3.57-3.63(m,1H),3.13-3.19(m,2H),1.96-2.01(m,2H),1.62-1.65(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.72 (s, 1H), 8.55-8.56 (m, 1H), 8.39 (s, 1H), 7.92-7.94 (m, 1H), 7.83-7.85 (m , 1H), 7.47 (s, 1H), 7.28-7.30 (m, 1H), 7.15-7.19 (m, 1H), 6.99-7.01 (m, 1H), 6.71-6.74 (m, 1H), 4.04-4.07 (m, 2H), 3.57-3.63 (m, 1H), 3.13-3.19 (m, 2H), 1.96-2.01 (m, 2H), 1.62-1.65 (m, 2H).
实施例85Example 85
N-(3-溴-4-氟苯基)-2-(1-(5-溴噻唑-2-基)哌啶-4-基)-N’-羟基--2-羰基乙脒85N-(3-Bromo-4-fluorophenyl)-2-(1-(5-bromothiazol-2-yl)piperidin-4-yl)-N'-hydroxy--2-carbonylacetamidine 85
Figure PCTCN2016093584-appb-000145
Figure PCTCN2016093584-appb-000145
采用实施例84的合成路线，将原料84a替换为2,5-二溴噻唑，制得标题产物85(5mg，淡黄色固体)，收率10％。Using the synthetic route of Example 84, the starting material 84a was replaced with 2,5-dibromothiazole to give the title product 85 (5 mg, pale yellow solid).
MS m/z(LC-MS):507.1[M+1]MS m/z (LC-MS): 507.1 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.37(s,1H),7.14-7.20(m,2H),6.98-7.00(m,1H),6.69-6.72(m,1H),3.86-2.89(m,2H),3.54-3.60(m,1H),3.07-3.13(m,2H),1.91-1.94(m,2H),1.51-1.61(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.70 (s, 1H), 8.37 (s, 1H), 7.14-7.20 (m, 2H), 6.98-7.00 (m, 1H), 6.69-6.72 (m , 1H), 3.86-2.89 (m, 2H), 3.54-3.60 (m, 1H), 3.07-3.13 (m, 2H), 1.91-1.94 (m, 2H), 1.51-1.61 (m, 2H).
实施例86Example 86
N-(3-溴-4-氟苯基)-2-(1-(4-氰基噻唑-2-基)哌啶-4-基)-N’-羟基-2-羰基乙脒86N-(3-Bromo-4-fluorophenyl)-2-(1-(4-cyanothiazol-2-yl)piperidin-4-yl)-N'-hydroxy-2-carbonylacetylene 86
Figure PCTCN2016093584-appb-000146
Figure PCTCN2016093584-appb-000146
采用实施例84的合成路线，将原料84a替换为2-溴-4-氰基噻唑，制得标题产物86(13mg，淡黄色固体)，收率25％。The starting material 84a was replaced with 2-bromo-4-cyanothiazole using the procedure of Example 84 to give the title product 86 (13 mg, pale yellow solid).
MS m/z(LC-MS):452.2[M+1]MS m/z (LC-MS): 452.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.38(s,1H),7.96(m,1H),7.14-7.19(m,1H),6.98-7.00(m,1H),6.70-6.72(m,1H),3.93-3.96(m,2H),3.55-3.61(m,1H),3.15-3.21(m,2H),1.94-1.96(m,2H),1.58-1.60(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.71 (s, 1H), 8.38 (s, 1H), 7.96 (m, 1H), 7.14-7.19 (m, 1H), 6.98-7.00 (m, 1H ), 6.70-6.72 (m, 1H), 3.93-3.96 (m, 2H), 3.55-3.61 (m, 1H), 3.15-3.21 (m, 2H), 1.94-1.96 (m, 2H), 1.58-1.60 (m, 2H).
实施例87 Example 87
N-(3-溴-4-氟苯基)-N’-羟基-2-羰基-2-(1-(噻唑-2-基)哌啶-4-基)-乙脒87N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-(thiazol-2-yl)piperidin-4-yl)-acetamidine 87
Figure PCTCN2016093584-appb-000147
Figure PCTCN2016093584-appb-000147
采用实施例84的合成路线，将原料84a替换为2-溴噻唑，制得标题产物87(10mg，淡黄色固体)，收率8％。Using the synthetic route of Example 84, the starting material 84a was replaced with 2-bromothiazole to give the title product 87 (10 mg, pale yellow solid).
MS m/z(LC-MS):427.3[M+1]MS m/z (LC-MS): 427.3 [M+1]
实施例88Example 88
2-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-基)噻唑-5-羧酸甲酯88Methyl 2-(4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidin-1-yl)thiazole-5-carboxylate 88
Figure PCTCN2016093584-appb-000148
Figure PCTCN2016093584-appb-000148
采用实施例84的合成路线，将原料84a替换为2-溴噻唑-5-羧酸甲酯(采用公知的方法“Journal of Organic Chemistry,2011,76(16),6972-6978”制备而得)，制得标题产物88(20mg，白色固体)，收率41.7％。Using the synthetic route of Example 84, the starting material 84a was replaced with methyl 2-bromothiazole-5-carboxylate (prepared by a known method "Journal of Organic Chemistry, 2011, 76(16), 6972-6978"). The title product 88 (20 mg, white solid) was obtained.
MS m/z(LC-MS):485.2[M+1]MS m/z (LC-MS): 485.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.38(s,1H),7.85-7.86(m,1H),7.14-7.18(m,1H),6.98-7.00(m,1H),6.71-6.73(m,1H),4.02-4.05(m,2H),3.74(s,3H)，3.58-3.64(m,1H),3.21-3.27(m,2H),1.95-1.98(m,2H),1.53-1.63(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.71 (s, 1H), 8.38 (s, 1H), 7.85-7.86 (m, 1H), 7.14-7.18 (m, 1H), 6.98-7.00 (m , 1H), 6.71-6.73 (m, 1H), 4.02-4.05 (m, 2H), 3.74 (s, 3H), 3.58-3.64 (m, 1H), 3.21-3.27 (m, 2H), 1.95-1.98 (m, 2H), 1.53-1.63 (m, 2H).
实施例89Example 89
N-(3-溴-4-氟苯基)-N’-羟基-2-羰基-2-(1-(4-(三氟甲基)噻唑-2-基)哌啶-4-基)乙脒89N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-4-yl)乙脒89
Figure PCTCN2016093584-appb-000149
Figure PCTCN2016093584-appb-000149
采用实施例84的合成路线，将原料84a替换为2-溴-4-三氟甲基噻唑，制得标题产物89(100 mg，白色固体)，收率20.4％。Using the synthetic route of Example 84, the starting material 84a was replaced with 2-bromo-4-trifluoromethylthiazole to afford the title product 89 (100 mg, white solid).
MS m/z(LC-MS):495.2[M+1]MS m/z (LC-MS): 495.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.38(s,1H),7.54(s,1H),7.14-7.19(m,1H),6.99-7.00(m,1H),6.70-6.72(m,1H),3.93-3.96(m,2H),3.54-3.60(m,1H),3.13-3.19(m,2H),1.94-1.97(m,2H),1.54-1.64(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.71 (s, 1H), 8.38 (s, 1H), 7.54 (s, 1H), 7.14-7.19 (m, 1H), 6.99-7.00 (m, 1H ), 6.70-6.72 (m, 1H), 3.93-3.96 (m, 2H), 3.54-3.60 (m, 1H), 3.13-3.19 (m, 2H), 1.94-1.97 (m, 2H), 1.54-1.64 (m, 2H).
实施例90 Example 90
2-(1-(5-氨基-1,3,4-噻二唑-2-基)哌啶-4-基)-N-(3-溴-4-氟苯基)-N'-羟基-2-羰基乙脒902-(1-(5-Amino-1,3,4-thiadiazol-2-yl)piperidin-4-yl)-N-(3-bromo-4-fluorophenyl)-N'-hydroxyl -2-carbonylethyl hydrazine 90
Figure PCTCN2016093584-appb-000150
Figure PCTCN2016093584-appb-000150
采用实施例84的合成路线，将原料84a替换为2-氨基-5-溴-1,3,4-噻二唑(采用专利申请“WO2013163244”公开的方法制备而得)，制得标题产物90(45mg，粉红色固体)，收率69.8％。Using the synthetic route of Example 84, the starting material 84a was replaced with 2-amino-5-bromo-1,3,4-thiadiazole (prepared by the method disclosed in the patent application "WO2013163244") to obtain the title product 90. (45 mg, pink solid), yield 69.8%.
MS m/z(LC-MS):443.2[M+1]MS m/z (LC-MS): 443.2 [M+1]
实施例91Example 91
2-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-基)-N-甲基噻唑-5-甲酰胺2-(4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidin-1-yl)-N-methylthiazole-5-carboxamide
Figure PCTCN2016093584-appb-000151
Figure PCTCN2016093584-appb-000151
第一步first step
2-溴-N-甲基噻唑-5-甲酰胺91b2-bromo-N-methylthiazole-5-carboxamide 91b
将2-溴噻唑-5-羧酸91a(206mg，1.0mmol)溶于5mL N,N-二甲基甲酰胺中，加入2M的甲胺(2mL，4mmol)，N,N-二异丙基乙胺(516mg，4mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(456mg，1.2mmol)，25℃搅拌反应16小时。反应结束后，减压浓缩反应液，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物91b(45mg，白色固体)，收率20.3％。2-Bromothiazole-5-carboxylic acid 91a (206 mg, 1.0 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and 2M methylamine (2mL, 4mmol), N,N-diisopropyl Ethylamine (516 mg, 4 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (456 mg, 1.2 mmol), stirred at 25 ° C The reaction was continued for 16 hours. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj
第二步Second step
2-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-基)-N-甲基噻唑-5-甲酰胺912-(4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidin-1-yl)-N-methylthiazole-5-carboxamide 91
将91b(45mg，0.2mmol)溶于5mL二甲基亚砜中，加入1f(69mg，0.2mmol)，N,N-二异丙基乙胺(52mg，0.4mmol)，90℃搅拌反应12小时。反应结束后，冷却至室温，将反应液倒入30mL水中，30mL乙酸乙酯萃取，有机相水洗涤(30mL×3)，饱和氯化钠水溶液洗涤(30mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩。用薄 层色谱法以展开剂体系A纯化所得残余物，得到标题产物91(8mg，棕色固体)，收率8.1％。91b (45mg, 0.2mmol) was dissolved in 5mL of dimethyl sulfoxide, 1f (69mg, 0.2mmol), N,N-diisopropylethylamine (52mg, 0.4mmol) was added, and the reaction was stirred at 90 ° C for 12 hours. . After the reaction was completed, it was cooled to room temperature, and the reaction mixture was poured into water (30 mL), EtOAc (30 mL, EtOAc) Filtration and concentration of the filtrate under reduced pressure. Thin The resulting residue was purified with EtOAc EtOAcjjjjj
MS m/z(LC-MS):484.2[M+1]MS m/z (LC-MS): 484.2 [M+1]
1H NMR(400MHz,DMSO-d6):δ11.69(s,1H),8.37(s,1H),8.14-8.15(m,1H),7.72(s,1H),7.13-7.17(m,1H),6.97-6.99(m,1H),6.69-6.72(m,1H),3.96-3.99(m,2H),3.56-3.60(m,1H),3.12-3.17(m,2H),2.69-2.70(m,3H),1.54-1.60(m,2H),1.22-1.32(m,2H). 1 H NMR (400MHz, DMSO- d 6): δ11.69 (s, 1H), 8.37 (s, 1H), 8.14-8.15 (m, 1H), 7.72 (s, 1H), 7.13-7.17 (m, 1H), 6.97-6.99 (m, 1H), 6.69-6.72 (m, 1H), 3.96-3.99 (m, 2H), 3.56-3.60 (m, 1H), 3.12-3.17 (m, 2H), 2.69- 2.70 (m, 3H), 1.54-1.60 (m, 2H), 1.22-1.32 (m, 2H).
实施例92Example 92
2-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-基)-N-甲基噻唑-4-甲酰胺922-(4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidin-1-yl)-N-methylthiazole-4-carboxamide 92
Figure PCTCN2016093584-appb-000152
Figure PCTCN2016093584-appb-000152
采用实施例91的合成路线，将原料91a替换为2-溴-噻唑-4-羧酸，制得标题产物92(10mg，棕色固体)，收率10.1％。The starting material 91a was replaced with 2-bromo-thiazole-4-carboxylic acid using the synthetic route of Example 91 to give the title product 92 (10 mg, brown solid).
MS m/z(LC-MS):484.2[M+1]MS m/z (LC-MS): 484.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.38(s,1H),8.02-8.03(m,1H),7.36(s,1H),7.14-7.19(m,1H),6.98-7.00(m,1H),6.71-6.74(m,1H),4.01-4.04(m,2H),3.55-3.61(m,1H),3.09-3.17(m,2H),2.73-2.74(m,3H),1.93-1.96(m,2H),1.55-1.64(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.71 (s, 1H), 8.38 (s, 1H), 8.02-8.03 (m, 1H), 7.36 (s, 1H), 7.14-7.19 (m, 1H ), 6.98-7.00 (m, 1H), 6.71-6.74 (m, 1H), 4.01-4.04 (m, 2H), 3.55-3.61 (m, 1H), 3.09-3.17 (m, 2H), 2.73-2.74 (m, 3H), 1.93-1.96 (m, 2H), 1.55-1.64 (m, 2H).
实施例93Example 93
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(1-(2-羟乙基)-1H-吡唑-4-基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(1-(2-hydroxyethyl)-1H-pyrazole-4- Piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000153
Figure PCTCN2016093584-appb-000153
Figure PCTCN2016093584-appb-000154
Figure PCTCN2016093584-appb-000154
第一步first step
4-硝基-1-(2-((四氢-2H-吡喃-2-基)氧基)乙基)-1H-吡唑93b4-nitro-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole 93b
将2-(4-硝基-1H-吡唑-1-基)-1-乙醇93a(1.878g，11.9mmol，采用专利申请“WO2013017479”公开的方法制备而得)溶于70mL二氯甲烷中，加入3,4-二氢吡喃(1.65mL，18.0mmol)，对甲苯磺酸吡啶盐(604mg，2.4mmol)，25℃搅拌反应18小时。反应结束后，减压浓缩干反应液，60℃搅拌反应18小时。反应结束后，过滤，滤液减压浓缩，得到粗品标题产物93b(2.92g，无色油状物)，产品不经纯化直接进行下一步反应。2-(4-Nitro-1H-pyrazol-1-yl)-1-ethanol 93a (1.878 g, 11.9 mmol, prepared by the method disclosed in the patent application "WO2013017479") was dissolved in 70 mL of dichloromethane 3,4-Dihydropyran (1.65 mL, 18.0 mmol), p-toluenesulfonic acid pyridinium salt (604 mg, 2.4 mmol) was added, and the reaction was stirred at 25 ° C for 18 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the mixture was stirred at 60 ° C for 18 hours. After completion of the reaction, the mixture was filtered and evaporated.
第二步Second step
1-(2-((四氢-2H-吡喃-2-基)氧基)乙基-1H-吡唑-4-胺93c1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl-1H-pyrazole-4-amine 93c
将粗品93b(2.92g，12.1mmol)溶于40mL甲醇中，加入590mg 10％钯碳，氢气置换三次，25℃搅拌反应3小时。反应结束后，硅藻土过滤，滤液减压浓缩得粗品标题产物93c(2.6g，红褐色油状物)，产品不经纯化直接下一步反应。The crude product 93b (2.92 g, 12.1 mmol) was dissolved in 40 mL of methanol, 590 mg of 10% palladium carbon was added, and the mixture was replaced by hydrogen three times, and the reaction was stirred at 25 ° C for 3 hours. After completion of the reaction, the celite was filtered, and the filtrate was evaporated.
第三步third step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(1-(2-((四氢-2H-吡喃-2-基)氧基)乙基)-1H-吡唑-4-基)哌啶-1-甲酰胺93d4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(1-(2-((tetrahydro-2H-pyran-2-) Ethyl)ethyl)-1H-pyrazol-4-yl)piperidine-1-carboxamide 93d
将三光气(350mg，1.18mmol)溶于20mL四氢呋喃中，加入预制的20mL粗品93c(368mg，1.74mmol)的四氢呋喃溶液，三乙胺(1.5mL，10.8mmol)于25℃反应30分钟，加入预制的20mL 1f(500mg，1.45mmol)的四氢呋喃溶液，于25℃反应1小时。反应结束后，加入甲醇淬灭反应，反应液减压浓缩，用薄层色谱法以洗脱剂体系A纯化所得残余物，得到标题产物93d(430mg，黄褐色固体)，收率51％。The triphosgene (350 mg, 1.18 mmol) was dissolved in 20 mL of tetrahydrofuran, and a pre-formed 20 mL of crude 93c (368 mg, 1.74 mmol) in tetrahydrofuran solution, triethylamine (1.5 mL, 10.8 mmol) was reacted at 25 ° C for 30 min. A solution of 20 mL of 1f (500 mg, 1.45 mmol) in tetrahydrofuran was reacted at 25 ° C for 1 hour. After completion of the reaction, the reaction mixture was evaporated to dryness crystals crystals crystals crystals
第四步the fourth step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(1-(2-羟乙基)-1H-吡唑-4-基)哌啶-1-甲酰胺934-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(1-(2-hydroxyethyl)-1H-pyrazole-4- Piperidin-1-carboxamide 93
将93d(430mg，0.739mmol)溶于30mL甲醇中，加入一水合对甲苯磺酸(141mg，0.738mmol)，25℃搅拌反应18小时。反应结束后，加入饱和碳酸氢钠溶液， 减压浓缩，用薄层色谱法以洗脱剂体系A纯化所得残余物得到标题产物93(135mg，白色固体)，收率36.7％。93d (430 mg, 0.739 mmol) was dissolved in 30 mL of methanol, p-toluenesulfonic acid monohydrate (141 mg, 0.738 mmol) was added, and the reaction was stirred at 25 ° C for 18 hours. After the reaction is over, a saturated sodium bicarbonate solution is added. The residue was purified by EtOAc (EtOAc) elut elut
MS m/z(ESI):497.2[M+1]MS m/z (ESI): 497.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.51(s,1H),8.37(s,1H),7.70(s,1H),7.35(s,1H),7.17(t,1H),6.97-6.99(m,1H),6.69-6.73(m,1H),4.83(t,1H),4.05-4.13(m,2H),4.02-4.04(m,2H),3.65-3.69(m,2H),3.49-3.52(m,1H),2.81-2.86(m,2H),1.81-1.84(m,2H),1.37-1.46(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.66 (s, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 7.70 (s, 1H), 7.35 (s, 1H), 7.17 ( t,1H), 6.97-6.99 (m, 1H), 6.69-6.73 (m, 1H), 4.83 (t, 1H), 4.05-4.13 (m, 2H), 4.02-4.04 (m, 2H), 3.65- 3.69 (m, 2H), 3.49-3.52 (m, 1H), 2.81-2.86 (m, 2H), 1.81-1.84 (m, 2H), 1.37-1.46 (m, 2H).
实施例94Example 94
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(1-(2-甲氧乙基)-1H-吡唑-4-基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(1-(2-methoxyethyl)-1H-pyrazole-4 -yl) piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000155
Figure PCTCN2016093584-appb-000155
第一步first step
1-(2-甲氧基乙基)-4硝基-1H-吡唑94b1-(2-methoxyethyl)-4nitro-1H-pyrazole 94b
将4-硝基-1H-吡唑94a(2g，17.7mmol)溶于20mL乙腈中，依次加入溴乙醇甲醚(2.7g，19.4mmol)，碳酸钾(3.66g，26.5mmol)，60℃搅拌反应18小时。反应结束后，过滤，滤饼用乙酸乙酯和二氯甲烷洗涤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物94b(3g，淡黄色油状物)，收率100％。4-Nitro-1H-pyrazole 94a (2 g, 17.7 mmol) was dissolved in 20 mL of acetonitrile, followed by bromoethanol methyl ether (2.7 g, 19.4 mmol), potassium carbonate (3.66 g, 26.5 mmol), stirred at 60 ° C Reaction for 18 hours. After completion of the reaction, the mixture was filtered,jjjjjjjjjjjjjjjjj ), the yield is 100%.
第二步Second step
1-(2-甲氧基乙基)-1H-吡唑-4-胺94c1-(2-methoxyethyl)-1H-pyrazole-4-amine 94c
将94b(3.0g，17.5mmol)溶于20mL甲醇中，加入600mg 10％钯碳，氢气置换三次，25℃搅拌反应2小时。反应结束后，硅藻土过滤，滤液减压浓缩得粗品标题产物94c(2.1g，紫色油状物)，产品不经纯化直接下一步反应。94b (3.0 g, 17.5 mmol) was dissolved in 20 mL of methanol, 600 mg of 10% palladium carbon was added, and hydrogen was replaced three times, and the reaction was stirred at 25 ° C for 2 hours. After completion of the reaction, the celite was filtered, and the filtrate was evaporated.
第三步third step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(1-(2-甲氧乙基)-1H-吡唑-4-基)哌啶-1-甲酰胺944-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(1-(2-methoxyethyl)-1H-pyrazole-4 -yl) piperidine-1-carboxamide 94
将三光气(43mg，0.145mmol)溶于20mL四氢呋喃中，加入粗品94c(43mg， 0.305mmol)的四氢呋喃溶液，三乙胺(88mg，0.87mmol)于25℃反应30分钟，加入预制的5mL 1f(100mg，0.29mmol)的四氢呋喃溶液，于25℃反应1小时。反应结束后，加入甲醇淬灭反应，反应液减压浓缩，用薄层色谱法以洗脱剂体系A纯化所得残余物得到标题产物94(142mg，白色固体)，收率28％。The triphosgene (43 mg, 0.145 mmol) was dissolved in 20 mL of tetrahydrofuran, and crude 94c (43 mg, A solution of 0.305 mmol) in tetrahydrofuran, triethylamine (88 mg, 0.87 mmol) was reacted at 25 ° C for 30 minutes, and a pre-formed 5 mL of 1f (100 mg, 0.29 mmol) in tetrahydrofuran was added and reacted at 25 ° C for 1 hour. After completion of the reaction, the reaction was quenched with EtOAc (EtOAc).
MS m/z(ESI):511.3[M+1]MS m/z (ESI): 511.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.51(s,1H),8.38(s,1H),7.68(s,1H),7.36(s,1H),7.15-7.19(d,1H),6.97-6.99(m,1H),6.70-6.72(m,1H),4.10-4.17(m,4H),3.61-3.63(m,2H),3.51-3.53(m,1H),3.22(s,3H),2.81-2.87(m,2H),1.82-1.84(m,2H),1.38-1.44(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.67 (s, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 7.68 (s, 1H), 7.36 (s, 1H), 7.15- 7.19 (d, 1H), 6.97-6.99 (m, 1H), 6.70-6.72 (m, 1H), 4.10-4.17 (m, 4H), 3.61-3.63 (m, 2H), 3.51-3.53 (m, 1H) ), 3.22 (s, 3H), 2.81-2.87 (m, 2H), 1.82-1.84 (m, 2H), 1.38-1.44 (m, 2H).
实施例95Example 95
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(5-氟-1-(2-羟乙基)-1H-吡唑-4-基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(5-fluoro-1-(2-hydroxyethyl)-1H-pyridyl Zol-4-yl)piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000156
Figure PCTCN2016093584-appb-000156
第一步first step
(1-(2-((四氢-2H-吡喃-2-基)氧基)乙基)-1H-吡唑-4-基)氨基甲酸叔丁酯95a (1-(2-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)carbamic acid tert-butyl ester 95a
将93c(3.5g，16.6mmol)溶于100mL二氯甲烷中，加入3.45mL三乙胺，4-二甲氨基吡啶(202mg，1.65mmol)和二碳酸二叔丁酯(4.34g，19.9mmol)，25℃搅拌反应16小时。反应结束后，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题产物95a(4.62g，棕褐色油状物)，收率90％。93c (3.5 g, 16.6 mmol) was dissolved in 100 mL of dichloromethane, 3.45 mL of triethylamine, 4-dimethylaminopyridine (202 mg, 1.65 mmol) and di-tert-butyl dicarbonate (4.34 g, 19.9 mmol). The reaction was stirred at 25 ° C for 16 hours. After the reaction was completed, the reaction mixture was evaporated. mjjjjjjj
第二步Second step
N-[(叔丁氧基)羰基]-N-{1-[2-(吡喃-2-基氧基)乙基]-1H-吡唑-4-基}氨基甲酸叔丁酯95bN-[(tert-Butoxy)carbonyl]-N-{1-[2-(pyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}carbamic acid tert-butyl ester 95b
将95a(4.62g，14.8mmol)溶于70mL四氢呋喃中，冰浴冷却，加入氢化钠(713mg，17.8mmol)，0℃搅拌反应0.5小时，再加入二碳酸二叔丁酯(4.53g，20.8mmol)，0℃搅拌反应5分钟，25℃搅拌反应0.5小时。反应结束后，加入氢氧化钠水溶液淬灭反应，乙酸乙酯萃取3次，合并有机相，饱和氯化钠溶液洗涤1次，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题产物95b(5.3g，淡红褐色液体)，收率87％。95a (4.62g, 14.8mmol) was dissolved in 70mL of tetrahydrofuran, cooled in an ice bath, sodium hydride (713mg, 17.8mmol) was added, the reaction was stirred at 0 ° C for 0.5 h, then di-tert-butyl dicarbonate (4.53 g, 20.8 mmol) was added. The reaction was stirred at 0 ° C for 5 minutes, and the reaction was stirred at 25 ° C for 0.5 hour. After the reaction was completed, the reaction was quenched with aqueous sodium hydroxide and extracted with EtOAc EtOAc. The residue obtained was purified by EtOAc EtOAc (EtOAc)
第三步third step
N-[(叔丁氧基)羰基]-N-{5-氟-1-[2-(吡喃-2-基氧基)乙基]-1H-吡唑-4-基}氨基甲酸叔丁酯95cN-[(tert-Butoxy)carbonyl]-N-{5-fluoro-1-[2-(pyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}carbamic acid Butyl ester 95c
将95b(3g，7.29mmol)溶于80mL四氢呋喃，冷却至-78℃，滴加2M的二异丙基氨基锂(4.4mL，8.8mmol)，-78℃搅拌反应1小时，再滴加预制的30mL N-氟代双苯磺酰胺(3.45g，10.9mmol)的四氢呋喃溶液，-78℃搅拌反应1小时。反应结束后，加入氢氧化钠溶液淬灭反应，乙酸乙酯萃取3次，合并有机相，饱和氯化钠溶液洗涤1次，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题产物95c(2.3g，黄色液体)，收率73％。95b (3g, 7.29mmol) was dissolved in 80mL of tetrahydrofuran, cooled to -78 ° C, 2M lithium diisopropylamide (4.4mL, 8.8mmol) was added dropwise, the reaction was stirred at -78 ° C for 1 hour, and pre-prepared A solution of 30 mL of N-fluorobisbenzenesulfonamide (3.45 g, 10.9 mmol) in tetrahydrofuran was stirred at -78 °C for 1 hour. After the completion of the reaction, the reaction was quenched by the addition of sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by EtOAc EtOAc (EtOAc)
第四步the fourth step
N-[(叔丁氧基)羰基]-N-[5-氟-1-(2-羟乙基)-1H-吡唑-4-基]氨基甲酸叔丁酯95dN-[(tert-Butoxy)carbonyl]-N-[5-fluoro-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]carbamic acid tert-butyl ester 95d
将95c(1.025g，2.39mmol)溶于30mL甲醇中，加入一水合对甲苯磺酸(227mg，1.19mmol)，25℃搅拌反应18小时。反应结束后，加入1mL三乙胺，减压浓缩，得到粗品标题产物95d(1.2g，黄色油状物)，产品不经纯化直接下一步反应。95c (1.025 g, 2.39 mmol) was dissolved in 30 mL of methanol, p-toluenesulfonic acid monohydrate (227 mg, 1.19 mmol) was added, and the reaction was stirred at 25 ° C for 18 hours. After completion of the reaction, 1 mL of triethylamine was added, and the residue was evaporated.
第五步the fifth step
乙酸2-(4-{二[(叔丁氧基)羰基]氨基}-5-氟-1H-吡唑-1-基)乙基酯95e2-(4-{bis[(tert-butoxy)carbonyl]amino}-5-fluoro-1H-pyrazol-1-yl)ethyl acetate 95e
将粗品95d(1.2g，3.47mmol)溶于30mL二氯甲烷中，冷却至0℃，加入0.75mL三乙胺，滴加入乙酰氯(0.25mL，3.5mmol)，0℃搅拌反应1小时。反应结束后，加入碳酸氢钠溶液淬灭反应，分液，有机相依次用水、饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物95e(960mg，黄色油状物)，产品不经纯化直接下一步反应。The crude product 95d (1.2 g, 3.47 mmol) was dissolved in dichloromethane (30 mL), cooled to 0 ° C, 0.75 mL of triethylamine was added, acetyl chloride (0.25 mL, 3.5 mmol) was added dropwise, and the reaction was stirred at 0 ° C for 1 hour. After the reaction was completed, the reaction was quenched with sodium hydrogen carbonate solution, and the mixture was evaporated. EtOAcjjjjjjjjjjj Oily), the product is directly reacted without further purification.
第六步 Step 6
乙酸2-(4-氨基-5-氟-1H-吡唑-1-基)乙基酯95f2-(4-Amino-5-fluoro-1H-pyrazol-1-yl)ethyl acetate 95f
将粗品95e(960mg，2.48mmol)溶于20mL二氯甲烷中，加入20mL三氟醋酸，25℃搅拌反应1小时。反应结束后，反应液减压浓缩，加入二氯甲烷，饱和碳酸氢钠溶液洗涤2次，饱和氯化钠溶液洗涤1次，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系B纯化所得残余物，得标题产物95f(90mg，褐色粘稠物)，收率19％。The crude product 95e (960 mg, 2.48 mmol) was dissolved in dichloromethane (20 mL), 20 mL of trifluoroacetic acid was added, and the mixture was stirred at 25 ° C for 1 hour. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, dichloromethane (dichloromethane), washed twice with saturated sodium hydrogen carbonate solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The residue obtained was purified by EtOAc EtOAc (EtOAc)
第七步Seventh step
乙酸2-(4-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺)-5-氟-1H-吡唑-1-基)乙基酯95g2-(4-(4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide)-5-fluoro-1H -pyrazol-1-yl)ethyl ester 95g
将三光气(139mg，0.468mmol)溶于10mL四氢呋喃中，加入95f(88mg，0.47mmol)，三乙胺(0.78mL，5.6mmol)，于25℃反应30分钟，将上述反应液加入预制的15mL的1f(100mg，0.29mmol)的四氢呋喃液中，于25℃搅拌反应1小时。反应结束后，加入甲醇，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物95g(50mg，褐色固体)，收率19％。The triphosgene (139 mg, 0.468 mmol) was dissolved in 10 mL of tetrahydrofuran, 95f (88 mg, 0.47 mmol), triethylamine (0.78 mL, 5.6 mmol) was added, and the reaction mixture was reacted at 25 ° C for 30 minutes, and the reaction mixture was added to pre-formed 15 mL. The reaction was stirred at 25 ° C for 1 hour in 1f (100 mg, 0.29 mmol) of tetrahydrofuran. After the reaction was completed, methanol was added, and the reaction mixture was evaporated. mjjjjjjj
第八步Eighth step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(5-氟-1-(2-羟乙基)-1H-吡唑-4-基)哌啶-1-甲酰胺954-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(5-fluoro-1-(2-hydroxyethyl)-1H-pyridyl Zol-4-yl)piperidine-1-carboxamide 95
将95g(50mg，0.0897mmol)溶于10mL甲醇中，加入碳酸钾(25mg，0.181mmol)，25℃搅拌反应1小时。反应结束后，反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物95(10mg，白色固体)，收率21.6％。95 g (50 mg, 0.0897 mmol) was dissolved in 10 mL of methanol, potassium carbonate (25 mg, 0.181 mmol) was added, and the mixture was stirred at 25 ° C for 1 hour. After completion of the reaction, the reaction mixture was evaporated.jjjjjjjjj
MS m/z(ESI):515.3[M+1]MS m/z (ESI): 515.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.38(s,1H),8.01(s,1H),7.32(s,1H),7.17(t,1H),6.98-6.99(m,1H),6.70-6.73(m,1H),4.08-4.12(m,2H),3.98(t,2H),3.67(t,2H),3.49-3.52(m,1H),2.81-2.87(m,2H),1.81-1.84(m,2H),1.38-1.46(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 8.38 (s, 1H), 8.01 (s, 1H), 7.32 (s, 1H), 7.17 (t, 1H), 6.98- 6.99 (m, 1H), 6.70-6.73 (m, 1H), 4.08-4.12 (m, 2H), 3.98 (t, 2H), 3.67 (t, 2H), 3.49-3.52 (m, 1H), 2.81 2.87 (m, 2H), 1.81-1.84 (m, 2H), 1.38-1.46 (m, 2H).
实施例96Example 96
(R)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-(2,3-二羟基丙基)-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺(R)-4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-(2,3-dihydroxypropyl) -1H-pyrazol-4-yl)phenyl)piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000157
Figure PCTCN2016093584-appb-000157
Figure PCTCN2016093584-appb-000158
Figure PCTCN2016093584-appb-000158
第一步first step
(R)-1-(2,2-二甲基-1,3-二氧戊环-4-基)甲基)-4-(4-硝基苯基)-1H-吡唑98a(R)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-(4-nitrophenyl)-1H-pyrazole 98a
将4-(4-硝基苯)-1H-吡唑1g(500mg，2.64mmol，采用公知的方法“Medicinal Chemistry Research,2013,22(11),5610-5616”制备而得)溶解于20ml N,N-二甲基甲酰胺中，加入碳酸铯(1.29g，3.95mmol)，(S)-(-)-4-氯甲基-2,2-二甲基-1,3-二氧戊环(478mg，3.7mmol)，于100℃反应18小时。反应结束后，加入乙酸乙酯，垫硅藻土过滤，滤饼用乙酸乙酯洗涤，收集滤液，滤液用水洗涤三次，饱和氯化钠溶液洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物96a(710mg，淡黄色液体)，产品不经纯化直接下一步反应。1-(4-Nitrophenyl)-1H-pyrazole 1 g (500 mg, 2.64 mmol, prepared by a known method "Medicinal Chemistry Research, 2013, 22 (11), 5610-5616") was dissolved in 20 ml of N , N-dimethylformamide, cesium carbonate (1.29 g, 3.95 mmol), (S)-(-)-4-chloromethyl-2,2-dimethyl-1,3-dioxol The ring (478 mg, 3.7 mmol) was reacted at 100 ° C for 18 hours. After completion of the reaction, ethyl acetate was added, and the mixture was filtered over Celite, and filtered, and the filtrate was washed with ethyl acetate. The filtrate was collected, and the filtrate was washed three times with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and filtered. Concentration gave the crude title product 96a (710 mg, pale yellow).
第二步Second step
(R)-4-(1-(2,2-二甲基-1,3-二氧戊环-4-基)甲基)-1H-吡唑-4-基)苯胺96b(R)-4-(1-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)aniline 96b
将粗品96a(710mg，2.31mmol)溶解于30mL乙醇和水(V:V＝5:1)的混合溶剂中。向反应液中依次加入铁粉(306mg，5.46mmol)，氯化铵(584mg，10.9mmol)。反应液升温至80℃，搅拌反应2小时。反应结束后，将反应液冷却至室温，减压浓缩，残余物中加入乙酸乙酯及少量甲醇，垫硅藻土过滤，滤饼用乙酸乙酯洗涤，收集滤液，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物96b(550mg，褐色液体)，产率87％。The crude product 96a (710 mg, 2.31 mmol) was dissolved in a mixed solvent of 30 mL of ethanol and water (V:V=5:1). Iron powder (306 mg, 5.46 mmol) and ammonium chloride (584 mg, 10.9 mmol) were sequentially added to the reaction mixture. The reaction solution was heated to 80 ° C, and the reaction was stirred for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Column chromatography The residue obtained was purified with EtOAc EtOAc (EtOAc)
第三步third step
(R)-4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-((2,2-二甲基-1,3-二氧戊环-4-基)甲基)-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺96c(R)-4-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-((2,2-dimethyl)) -1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)phenyl)piperidine-1-carboxamide 96c
将三光气(34mg，0.114mmol)溶于10mL四氢呋喃中，加入预制的10mL 96b(82mg，0.3mmol中)的四氢呋喃溶液，0.2mL三乙胺，于25℃反应30分钟，加入预制的10mL 1f(100mg，0.29mmol)的四氢呋喃溶液，于25℃反应1小时。反应结束后，将反应液减压浓缩，用薄层色谱法以洗脱剂体系A纯化所得残余物，得标题产物96c(110mg，淡黄褐色固体)，收率59％。The triphosgene (34 mg, 0.114 mmol) was dissolved in 10 mL of tetrahydrofuran, and a pre-formed 10 mL 96b (82 mg, 0.3 mmol) of tetrahydrofuran solution, 0.2 mL of triethylamine was reacted at 25 ° C for 30 minutes, and pre-formed 10 mL of 1f ( A solution of 100 mg, 0.29 mmol) in tetrahydrofuran was reacted at 25 ° C for 1 hour. After completion of the reaction, the reaction mixture was evaporated. mjjjjjlililililililililililili
第四步 the fourth step
(R)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-(2,3-二羟基丙基)-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺96(R)-4-(2-((3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-(2,3-dihydroxypropyl) -1H-pyrazol-4-yl)phenyl)piperidine-1-carboxamide 96
将96c(110mg，0.193mmol)溶于15ml甲醇中，加入甲烷磺酸(25mg，0.26mmol)，于25℃反应18小时。反应结束后，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物96(40mg，淡黄褐色固体)，产率39％。96c (110 mg, 0.193 mmol) was dissolved in 15 ml of methanol, methanesulfonic acid (25 mg, 0.26 mmol) was added and the mixture was reacted at 25 ° C for 18 hours. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjj
MS m/z(ESI):603.4[M+1]MS m/z (ESI): 603.4 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.52(s,1H),8.39(s,1H),8.00(s,1H),7.79(s,1H),7.44-7.46(m,4H),7.18(t,1H),6.98-7.00(m,1H),6.73-6.74(m,1H),5.00(d,1H),4.75(t,1H),4.18-4.24(m,3H),3.95-4.00(m,1H),3.81-3.84(m,1H),3.54-3.56(m,1H),3.30-3.38(m,2H),2.85-2.91(m,2H),1.85-1.89(m,2H),1.45-1.49(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.69 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 7.44- 7.46 (m, 4H), 7.18 (t, 1H), 6.98-7.00 (m, 1H), 6.73-6.74 (m, 1H), 5.00 (d, 1H), 4.75 (t, 1H), 4.18-4.24 ( m, 3H), 3.95-4.00 (m, 1H), 3.81-3.84 (m, 1H), 3.54-3.56 (m, 1H), 3.30-3.38 (m, 2H), 2.85-2.91 (m, 2H), 1.85-1.89 (m, 2H), 1.45-1.49 (m, 2H).
实施例97Example 97
(S)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-(1-(2,3-二羟基丙基)-1H-吡唑-4-基)苯基)哌啶-1-甲酰胺97(S)-4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-(1-(2,3-dihydroxypropyl) -1H-pyrazol-4-yl)phenyl)piperidine-1-carboxamide 97
Figure PCTCN2016093584-appb-000159
Figure PCTCN2016093584-appb-000159
采用实施例96的合成路线，将原料(S)-(-)-4-氯甲基-2,2-二甲基-1,3-二氧戊环替换为(R)-(-)-4-氯甲基-2,2-二甲基-1,3-二氧戊环(采用公知的方法“Pharma Chemica,2011,3(4),219-226”，制得标题产物97(45mg，黄褐色固体)，收率48％。Using the synthetic route of Example 96, the starting material (S)-(-)-4-chloromethyl-2,2-dimethyl-1,3-dioxolan was replaced by (R)-(-)- 4-Chloromethyl-2,2-dimethyl-1,3-dioxolane (using a known method "Pharma Chemica, 2011, 3(4), 219-226", the title product 97 (45 mg) was obtained. , tan solid), yield 48%.
MS m/z(ESI):603.4[M+1]MS m/z (ESI): 603.4 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.52(s,1H),8.39(s,1H),8.00(s,1H),7.79(s,1H),7.44-7.46(m,4H),7.18(t,1H),6.98-7.00(m,1H),6.73-6.74(m,1H),5.00(d,1H),4.75(t,1H),4.18-4.24(m,3H),3.95-4.00(m,1H),3.81-3.84(m,1H),3.54-3.56(m,1H),3.30-3.38(m,2H),2.85-2.91(m,2H),1.85-1.89(m,2H),1.45-1.49(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.69 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 7.44- 7.46 (m, 4H), 7.18 (t, 1H), 6.98-7.00 (m, 1H), 6.73-6.74 (m, 1H), 5.00 (d, 1H), 4.75 (t, 1H), 4.18-4.24 ( m, 3H), 3.95-4.00 (m, 1H), 3.81-3.84 (m, 1H), 3.54-3.56 (m, 1H), 3.30-3.38 (m, 2H), 2.85-2.91 (m, 2H), 1.85-1.89 (m, 2H), 1.45-1.49 (m, 2H).
实施例98Example 98
N-(4-(1-((1-氨基环丙基)甲基)-1H-吡唑-4-基)苯基)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺 N-(4-(1-((1-aminocyclopropyl)methyl)-1H-pyrazol-4-yl)phenyl)-4-(2-((3-bromo-4-fluorophenyl) Amino)-2-(indolyl)acetyl)piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000160
Figure PCTCN2016093584-appb-000160
第一步first step
甲磺酸(1-((叔丁氧羰基)氨基)环丙基)甲基酯98bMethanesulfonic acid (1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl ester 98b
将(1-羟甲基)环丙基)氨基甲酸叔丁酯98a(3.74g，20mmol)溶于40mL二氯甲烷中，加入三乙胺(3g，30mmol)，冰浴，滴加入甲烷磺酰氯(2.75g，24mmol)，0℃搅拌反应2小时。反应结束后，加入50mL饱和碳酸氢钠溶液，分液，有机相用饱和氯化钠溶液50mL洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物98b(4.8g，淡黄色固体)，产品不经纯化直接下一步。(1-Hydroxymethyl)cyclopropyl)carbamic acid tert-butyl ester 98a (3.74 g, 20 mmol) was dissolved in 40 mL of dichloromethane, triethylamine (3 g, 30 mmol) was added, and iced, and methanesulfonyl chloride was added dropwise. (2.75 g, 24 mmol), the reaction was stirred at 0 ° C for 2 hours. After the reaction was completed, 50 mL of a saturated sodium hydrogencarbonate solution was added, and the organic layer was washed with 50 mL of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to give crude title product 98b (4.8 g, Yellow solid), the product was taken directly to the next step without purification.
第二步Second step
(1-((4碘-1H-吡唑-1-基)甲基)环丙基)氨基甲酸叔丁酯98c(1-((4-Iodo-1H-pyrazol-1-yl)methyl)cyclopropyl)carbamic acid tert-butyl ester 98c
将粗品98b(4.53g，17mmol)溶于40mL二甲基乙酰胺中，加入碳酸铯(11.1g，34.2mmol)，加入4-碘-1H-吡唑(2.2g，11.4mmol)，氩气氛下，70℃搅拌反应16小时。反应结束后，反应液减压浓缩，残余物加入100mL水，乙酸乙酯萃取(100mL×3)，合并有机相，有机相用饱和氯化钠溶液100mL洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题产物98c(3g，类白色固体)，收率73％。Crude 98b (4.53 g, 17 mmol) was dissolved in 40 mL of dimethylacetamide, cesium carbonate (11.1 g, 34.2 mmol) was added, and 4-iodo-1H-pyrazole (2.2 g, 11.4 mmol) was added under argon atmosphere. The reaction was stirred at 70 ° C for 16 hours. After the reaction, the reaction mixture was concentrated under reduced pressure. EtOAc m. The filtrate was concentrated under reduced pressure. EtOAc m.
第三步third step
(1-((4-(4-硝基苯基)-1H-吡唑-1-基)甲基)环丙基)氨基甲酸叔丁酯98e(1-((4-(4-Nitrophenyl)-1H-pyrazol-1-yl)methyl)cyclopropyl)carbamic acid tert-butyl ester 98e
将98c(600mg，1.65mmol)，4-硝基苯硼酸98d(276mg，1.65mmol)，[1,1'- 双(二苯基磷)二茂铁]二氯化钯(121mg，0.16mmol)，碳酸钾(456mg，3.3mmol)加入30mL二氧六环和6mL水中，氩气氛下，于100℃搅拌反应16小时。反应结束后，加入乙酸乙酯和无水硫酸钠，硅藻土过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得标题产物98e(320mg，淡褐色固体)，产率54％。98c (600mg, 1.65mmol), 4-nitrophenylboronic acid 98d (276mg, 1.65mmol), [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride (121 mg, 0.16 mmol), potassium carbonate (456 mg, 3.3 mmol) was added to 30 mL of dioxane and 6 mL of water, and the reaction was stirred at 100 ° C under an argon atmosphere. hour. After completion of the reaction, ethyl acetate and anhydrous sodium sulfate were added, EtOAc (EtOAc m. ), the yield was 54%.
第四步the fourth step
(1-((4-(4-氨基苯基)-1H-吡唑-1-基)甲基)环丙基)氨基甲酸叔丁酯98f(1-((4-(4-Aminophenyl)-1H-pyrazol-1-yl)methyl)cyclopropyl)carbamic acid tert-butyl ester 98f
将98e(320mg，0.89mmol)溶解于25mL乙醇和水(V:V＝5:1)的混合溶剂中。向反应液中依次加入铁粉(100mg，1.78mmol)，氯化铵(191mg，3.57mmol)。反应液升温至80℃，搅拌反应3小时。反应结束后，将反应液冷却至室温，减压浓缩，残余物中加入乙酸乙酯，垫硅藻土过滤，滤饼用乙酸乙酯洗涤，收集滤液，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物98f(160mg，褐色液体)，产率54％。98e (320 mg, 0.89 mmol) was dissolved in a mixed solvent of 25 mL of ethanol and water (V:V=5:1). Iron powder (100 mg, 1.78 mmol) and ammonium chloride (191 mg, 3.57 mmol) were sequentially added to the reaction mixture. The reaction solution was heated to 80 ° C and stirred for 3 hours. After the reaction was completed, the reaction mixture was cooled to EtOAc. EtOAc m. The resulting residue was purified with EtOAc EtOAc (EtOAc)
第五步the fifth step
(1-((4-(4-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺)苯基)-1H-吡唑-1-基)甲基)环丙基)氨基甲酸叔丁酯98g(1-((4-(4-(4-(4-(4-(4-(4-(4-phenyl-4-phenylphenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide)phenyl) -1H-pyrazol-1-yl)methyl)cyclopropyl)carbamic acid tert-butyl ester 98g
将三光气(34mg，0.114mmol)溶于10mL四氢呋喃中，加入预制的的10mL 98f(100mg，0.3mmol)四氢呋喃溶液，0.12mL三乙胺，于25℃反应30分钟，加入预制的10mL 1f(100mg，0.29mmol)的四氢呋喃溶液，于25℃反应1小时。反应结束后，甲醇淬灭反应，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物98g(70mg，白色固体)，收率34％。The triphosgene (34 mg, 0.114 mmol) was dissolved in 10 mL of tetrahydrofuran, and a pre-formed 10 mL 98f (100 mg, 0.3 mmol) tetrahydrofuran solution, 0.12 mL of triethylamine, was reacted at 25 ° C for 30 minutes, and pre-made 10 mL 1f (100 mg) was added. A solution of 0.29 mmol) in tetrahydrofuran was reacted at 25 ° C for 1 hour. After the completion of the reaction, the reaction mixture was evaporated. EtOAcjjjjjjjjjj
第六步Step 6
N-(4-(1-((1-氨基环丙基)甲基)-1H-吡唑-4-基)苯基)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基哌啶-1-甲酰胺98N-(4-(1-((1-aminocyclopropyl)methyl)-1H-pyrazol-4-yl)phenyl)-4-(2-((3-bromo-4-fluorophenyl) Amino)-2-(indenyl)acetylpiperidine-1-carboxamide 98
将98g(70mg，0.112mmol)溶于15mL 4M的氯化氢1,4-二氧六环溶液，于25℃反应1小时。反应结束后，将反应液减压浓缩，高效液相色谱法制得标题产物98(40mg，白色固体)，收率63.5％。98 g (70 mg, 0.112 mmol) was dissolved in 15 mL of 4M hydrogen chloride 1,4-dioxane solution and reacted at 25 ° C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced vacuo.
MS m/z(ESI):598.4[M+1]MS m/z (ESI): 598.4 [M+1]
1H NMR(400MHz,CD3OD)δ7.98(s,1H),7.91(s,1H),7..49-7.52(m,2H),7.37-7.40(m,2H),7.01-7.07(m,2H),6.78-6.81(m,1H),4.41(s,2H),4.22-4.26(m,2H),3.64-3.70(m,1H),3.00-3.06(m,2H),1.94-1.97(m,2H),1.64-1.69(m,2H),1.15-1.21(m,2H),1.08-1.19(m,2H). 1 H NMR (400 MHz, CD 3 OD) δ 7.98 (s, 1H), 7.91 (s, 1H), 7..49-7.52 (m, 2H), 7.37-7.40 (m, 2H), 7.01-7.07 (m, 2H), 6.78-6.81 (m, 1H), 4.41 (s, 2H), 4.22-4.26 (m, 2H), 3.64-3.70 (m, 1H), 3.00-3.06 (m, 2H), 1.94 -1.97 (m, 2H), 1.64-1.69 (m, 2H), 1.15-1.21 (m, 2H), 1.08-1.19 (m, 2H).
实施例99Example 99
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-氰基-5-甲氧基吡啶-3-基)哌啶-1-甲酰胺99 4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-cyano-5-methoxypyridin-3-yl)piperidin Pyridine-1-carboxamide 99
Figure PCTCN2016093584-appb-000161
Figure PCTCN2016093584-appb-000161
将三光气(181mg，0.114mmol)溶于20mL四氢呋喃中，加入预制的20mL 2-氰基-3-甲氧基-5-氨基吡啶99a(136mg，0.91mmol，采用申请专利WO2003062241”公开的方法制备而得)的四氢呋喃溶液，三乙胺(264mg，2.6mmol)，于25℃反应30分钟，加入预制的1f(100mg，0.29mmol)的20mL四氢呋喃溶液，于25℃反应1小时。反应结束后，甲醇淬灭反应，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，制得标题产物99(200mg，白色固体)，收率44％。The triphosgene (181 mg, 0.114 mmol) was dissolved in 20 mL of tetrahydrofuran, and pre-formed 20 mL of 2-cyano-3-methoxy-5-aminopyridine 99a (136 mg, 0.91 mmol, prepared by the method disclosed in WO2003062241) was prepared. A tetrahydrofuran solution, triethylamine (264 mg, 2.6 mmol) was reacted at 25 ° C for 30 minutes, and a pre-prepared 1f (100 mg, 0.29 mmol) in 20 mL of tetrahydrofuran was added and reacted at 25 ° C for 1 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc.
MS m/z(ESI):519.3[M+1]MS m/z (ESI): 519.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),9.27(s,1H),8.40(s,2H),7.93(s,1H),7.15-7.19(t,1H),6.98-7.00(m,1H),6.70-6.71(m,1H),4.18-4.22(m,2H),3.91(s,3H),3.50-3.51(m,1H),2.94-2.98(m,2H),1.88-1.91(m,2H),1.48-1.50(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.69 (s, 1H), 9.27 (s, 1H), 8.40 (s, 2H), 7.93 (s, 1H), 7.15-7.19 (t, 1H), 6.98-7.00 (m, 1H), 6.70-6.71 (m, 1H), 4.18-4.22 (m, 2H), 3.91 (s, 3H), 3.50-3.51 (m, 1H), 2.94-2.98 (m, 2H) ), 1.88-1.91 (m, 2H), 1.48-1.50 (m, 2H).
实施例100Example 100
4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-氟苄基)哌啶-1-甲酰胺1004-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-fluorobenzyl)piperidine-1-carboxamide 100
Figure PCTCN2016093584-appb-000162
Figure PCTCN2016093584-appb-000162
采用实施例99的合成路线，将原料99a替换为4-氟苄胺，得标题产物100(50mg，白色固体)，收率34.9％。The starting material 99a was replaced with 4-fluorobenzylamine using the procedure of Example 99 to give the title product 100 (50 mg, white solid).
MS m/z(ESI):495.2[M+1]MS m/z (ESI): 495.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.36(s,1H),7.26-7.28(m,2H)7.10-7.17(m,4H),6.98-7.10(m,1H),6.71-6.72(m,1H),4.20-4.21(s,2H),4.03-4.07(m,2H),3.46-3.52(m,1H),2.74-2.80(m,2H),1.77-1.80(m,2H),1.34-1.43(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.65 (s, 1H), 8.36 (s, 1H), 7.26-7.28 (m, 2H) 7.10-7.17 (m, 4H), 6.98-7.10 (m, 1H), 6.71-6.72 (m, 1H), 4.20-4.21 (s, 2H), 4.03-4.07 (m, 2H), 3.46-3.52 (m, 1H), 2.74-2.80 (m, 2H), 1.77- 1.80 (m, 2H), 1.34-1.43 (m, 2H).
实施例101Example 101
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-氰基-5-甲基吡啶-3-基)哌啶-1-甲酰胺101 4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-cyano-5-methylpyridin-3-yl)piperidine 1-carboxamide 101
Figure PCTCN2016093584-appb-000163
Figure PCTCN2016093584-appb-000163
采用实施例99的合成路线，将原料99a替换为2-氰基-3-甲-5-氨基吡啶(采用专利申请“WO2015155626”公开的方法制备而得)，制得标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-氰基-5-甲基吡啶-3-基)哌啶-1-甲酰胺101(13mg，白色固体)，收率10％。Using the synthetic route of Example 99, the starting material 99a was replaced with 2-cyano-3-methyl-5-aminopyridine (prepared by the method disclosed in the patent application "WO2015155626") to give the title product 4-(2- ((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-cyano-5-methylpyridin-3-yl)piperidine-1-carboxamide 101 (13 mg, white solid), yield 10%.
MS m/z(ESI):503.3[M+1]MS m/z (ESI): 503.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),9.18(s,1H),8.62(s,1H),8.40(s,1H),8.02(s,1H),7.15-7.20(m,1H),6.99-6.70(m,1H),6.71-6.73(m,1H),4.18-4.21(m,2H),3.55-3.60(m,1H),2.92-2.99(m,2H),2.30(s,3H),1.88-1.91(m,2H),1.44-1.52(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.69 (s, 1H), 9.18 (s, 1H), 8.62 (s, 1H), 8.40 (s, 1H), 8.02 (s, 1H), 7.15- 7.20 (m, 1H), 6.99-6.70 (m, 1H), 6.71-6.73 (m, 1H), 4.18-4.21 (m, 2H), 3.55-3.60 (m, 1H), 2.92-2.99 (m, 2H) ), 2.30 (s, 3H), 1.88-1.91 (m, 2H), 1.44-1.52 (m, 2H).
实施例102Example 102
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-氰基-3-甲氧基苯基)哌啶-1-甲酰胺1024-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-cyano-3-methoxyphenyl)piperidine-1 -formamide 102
Figure PCTCN2016093584-appb-000164
Figure PCTCN2016093584-appb-000164
采用实施例99合成路线，将原料99a替换为替换为4-氨基-2-甲氧基苯腈，制得标题产物102(70mg，白色固体)，收率46％。The title product 102 (70 mg, white solid) was obtained in a yield of 46%.
MS m/z(ESI):518.2[M+1]MS m/z (ESI): 518.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),9.01(s,1H),8.39(s,1H),7.53(d,1H),7.45(s,1H),7.23(d,1H),7.17(t,1H),6.98-7.00(m,1H),6.71-6.73(m,1H),4.17-4.20(m,2H),3.53-3.59(m,1H),2.90-2.96(m,2H),1.87-1.90(m,2H),1.43-1.51(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 9.01 (s, 1H), 8.39 (s, 1H), 7.53 (d, 1H), 7.45 (s, 1H), 7.23 ( d, 1H), 7.17 (t, 1H), 6.98-7.00 (m, 1H), 6.71-6.73 (m, 1H), 4.17-4.20 (m, 2H), 3.53-3.59 (m, 1H), 2.90- 2.96 (m, 2H), 1.87-1.90 (m, 2H), 1.43-1.51 (m, 2H).
实施例103Example 103
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-甲氧基苄基)哌啶-1-甲酰胺1034-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-methoxybenzyl)piperidine-1-carboxamide 103
Figure PCTCN2016093584-appb-000165
Figure PCTCN2016093584-appb-000165
采用实施例99合成路线，将原料99a替换为4-甲氧基苄胺，制得标题产物103(60mg，白色固体)，收率40.5％。The title product 103 (60 mg, white solid) was obtained in the yield of 40.5%.
MS m/z(ESI):507.3[M+1] MS m/z (ESI): 507.3 [M+1]
1H NMR(400MHz,CDCl3)δ9.07(s,1H),7.24(d,2H),7.04-7.06(m,1H),6.97-7.00(m,1H),6.87(d,2H),6.80(s,1H),4.69-4.75(m,1H),4.37(d,2H),4.05(d,2H),3.81(s,3H),3.50(s,2H),2.92(t,2H),1.93(d,2H),1.57-1.69(m,2H) 1 H NMR (400MHz, CDCl 3 ) δ9.07 (s, 1H), 7.24 (d, 2H), 7.04-7.06 (m, 1H), 6.97-7.00 (m, 1H), 6.87 (d, 2H), 6.80(s,1H),4.69-4.75(m,1H), 4.37(d,2H),4.05(d,2H),3.81(s,3H),3.50(s,2H),2.92(t,2H) , 1.93 (d, 2H), 1.57-1.69 (m, 2H)
实施例104Example 104
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-苯乙基哌啶-1-甲酰胺1044-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-phenethylpiperidine-1-carboxamide 104
Figure PCTCN2016093584-appb-000166
Figure PCTCN2016093584-appb-000166
采用实施例99的合成路线，将原料99a替换为苯乙胺，制得标题产物104(35mg，白色固体)，收率24.6％。The title material 104 (35 mg, white solid) was obtained in the yield of 24.6%.
MS m/z(ESI):491.3[M+1]MS m/z (ESI): 491.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.37(s,1H),7.26-7.28(m,5H),7.10-7.17(m,2H),6.98-7.10(m,1H),6.71-6.72(m,1H),4.20-4.21(s,2H),4.03-4.07(m,3H),2.74-2.80(m,4H),1.77-1.80(m,2H),1.34-1.43(m,2H) 1 H NMR (400MHz, DMSO- d 6) δ11.66 (s, 1H), 8.37 (s, 1H), 7.26-7.28 (m, 5H), 7.10-7.17 (m, 2H), 6.98-7.10 (m , 1H), 6.71-6.72 (m, 1H), 4.20-4.21 (s, 2H), 4.03-4.07 (m, 3H), 2.74-2.80 (m, 4H), 1.77-1.80 (m, 2H), 1.34 -1.43(m,2H)
实施例105Example 105
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(5-氰基吡啶-3-基)哌啶-1-甲酰胺1054-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(5-cyanopyridin-3-yl)piperidine-1-carboxamide 105
Figure PCTCN2016093584-appb-000167
Figure PCTCN2016093584-appb-000167
采用实施例99合成路线，将原料99a替换为5-氨基-3-氰基吡啶，制得标题产物105(130mg，白色固体)，收率45.8％。The title product 105 (130 mg, white solid) was obtained in a yield of 45.8%.
MS m/z(ESI):489.3[M+1]MS m/z (ESI): 489.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),9.09(s,1H),8.88(s,1H),8.57(s,1H),8.39(s,1H),8.33(s,1H),7.17(t,1H),6.98-7.00(m,1H),6.71-6.73(m,1H),4.18-4.20(m,2H),3.55-3.60(m,1H),2.92-2.98(m,2H),1.88-1.91(m,2H),1.45-1.54(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 9.09 (s, 1H), 8.88 (s, 1H), 8.57 (s, 1H), 8.39 (s, 1H), 8.33 ( s, 1H), 7.17 (t, 1H), 6.98-7.00 (m, 1H), 6.71-6.73 (m, 1H), 4.18-4.20 (m, 2H), 3.55-3.60 (m, 1H), 2.92 2.98 (m, 2H), 1.88-1.91 (m, 2H), 1.45-1.54 (m, 2H).
实施例106Example 106
4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(2-氟-4-甲磺酰基)哌啶-1-甲酰胺106 4-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(2-fluoro-4-methylsulfonyl)piperidine-1-carboxamide 106
Figure PCTCN2016093584-appb-000168
Figure PCTCN2016093584-appb-000168
采用实施例99成路线，将原料99a替换为2-氟-4-甲磺酰基苯胺，制得标题产物106(100mg，淡黄色固体)，收率62％。The title product 106 (100 mg, pale yellow solid) was obtained in a yield of 62%.
MS m/z(ESI):559.2[M+1]MS m/z (ESI): 559.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.76(s,1H),8.39(s,1H),7.78(t,1H),7.73(d,1H),7.68(d,1H),7.18(d,1H),6.98-7.00(m,1H),6.70-6.73(m,1H),4.18-4.20(d,2H),3.53-3.59(m,1H),2.91-2.97(m,2H),1.86-1.89(m,2H),1.45-1.54(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 8.76 (s, 1H), 8.39 (s, 1H), 7.78 (t, 1H), 7.73 (d, 1H), 7.68 ( d, 1H), 7.18 (d, 1H), 6.98-7.00 (m, 1H), 6.70-6.73 (m, 1H), 4.18-4.20 (d, 2H), 3.53-3.59 (m, 1H), 2.91 2.97 (m, 2H), 1.86-1.89 (m, 2H), 1.45-1.54 (m, 2H).
实施例107Example 107
4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(5-氰基吡啶-3-基)哌啶-1-甲酰胺1074-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(5-cyanopyridin-3-yl)piperidine-1-carboxamide 107
Figure PCTCN2016093584-appb-000169
Figure PCTCN2016093584-appb-000169
采用实施例99合成路线，将原料99a替换为5-氨基-3-氰基吡啶，制得标题产物107(60mg，淡黄色固体)，收率42％。The title product 107 (60 mg, pale yellow solid) was obtained in a yield of 42%.
MS m/z(ESI):489.2[M+1]MS m/z (ESI): 489.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),9.09(s,1H),8.88(s,1H),8.57(s,1H),8.39(s,1H),8.33(s,1H),7.17(m,1H),6.98-7.00(m,1H),6.71-6.74(m,1H),4.17-4.21(m,2H),3.54-3.60(m,1H),2.92-2.98(m,2H),1.88-1.91(m,2H),1.44-1.53(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 9.09 (s, 1H), 8.88 (s, 1H), 8.57 (s, 1H), 8.39 (s, 1H), 8.33 ( s, 1H), 7.17 (m, 1H), 6.98-7.00 (m, 1H), 6.71-6.74 (m, 1H), 4.17-4.21 (m, 2H), 3.54-3.60 (m, 1H), 2.92 2.98 (m, 2H), 1.88-1.91 (m, 2H), 1.44-1.53 (m, 2H).
实施例108Example 108
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(吡啶-3-基)哌啶-1-甲酰胺1084-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(pyridin-3-yl)piperidine-1-carboxamide 108
Figure PCTCN2016093584-appb-000170
Figure PCTCN2016093584-appb-000170
采用实施例99合成路线，将原料99a替换为3-氨基吡啶，制得标题产物108(50mg，淡黄褐色固体)，收率37％。The title material 108 (50 mg, pale yellow brown solid) was obtained in the yield of 37%.
MS m/z(ESI):464.3[M+1]MS m/z (ESI): 464.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.74(s,1H),8.65(s,1H),8.38(s,1H),8.15(s,1H),7.89(d,1H),7.27-7.28(m,1H),7.17(t,1H),6.99(m,1H),6.70-6.73(m, 1H),4.17-4.21(m,2H),3.55-3.56(m,1H),2.88-2.94(m,2H),1.86-1.89(m,2H),1.45-1.49(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 8.74 (s, 1H), 8.65 (s, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 7.89 ( d, 1H), 7.27-7.28 (m, 1H), 7.17 (t, 1H), 6.99 (m, 1H), 6.70-6.73 (m, 1H), 4.17-4.21 (m, 2H), 3.55-3.56 ( m, 1H), 2.88-2.94 (m, 2H), 1.86-1.89 (m, 2H), 1.45-1.49 (m, 2H).
实施例109Example 109
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(3-氰基苄基)哌啶-1-甲酰胺1094-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(3-cyanobenzyl)piperidine-1-carboxamide 109
Figure PCTCN2016093584-appb-000171
Figure PCTCN2016093584-appb-000171
采用实施例99的合成路线，将原料99a替换为3-氰基苄胺，制得标题产物109(23mg，白色固体)，收率15.7％。The starting material 99a was replaced with 3-cyanobenzylamine using the procedure of Example 99 to give the title product 109 (23 mg, white solid).
MS m/z(ESI):502.3[M+1]MS m/z (ESI): 502.3 [M+1]
1H NMR(400MHz,CDCl3)δ7.55-7.59(m,4H),7.43-7.46(m,1H),6.98-7.05(m,1H),6.78-6.84(m,1H),4.82-4.90(s,1H),4.42-4.49(m,3H),3.98-4.04(m,1H),3.50(s,1H),2.84-2.96(m,2H),2.03-2.18(m,2H),1.80-1.95(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.55-7.59 (m, 4H), 7.43-7.46 (m, 1H), 6.98-7.05 (m, 1H), 6.78-6.84 (m, 1H), 4.82-4.90 (s, 1H), 4.42-4.49 (m, 3H), 3.98-4.04 (m, 1H), 3.50 (s, 1H), 2.84-2.96 (m, 2H), 2.03-2.18 (m, 2H), 1.80 -1.95 (m, 2H).
实施例110Example 110
4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(3-氰基-4-甲氧基苄基)哌啶-1-甲酰胺1104-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(3-cyano-4-methoxybenzyl)piperidin-1- Formamide 110
Figure PCTCN2016093584-appb-000172
Figure PCTCN2016093584-appb-000172
采用实施例99的合成路线，将原料99a替换为5-(氨甲基)-2-甲氧基苯腈(采用专利申请“WO2001030745”公开的方法制备而得)，得到标题产物110(45mg，灰白色固体)，收率29％。Using the synthetic route of Example 99, the starting material 99a was replaced with 5-(aminomethyl)-2-methoxybenzonitrile (prepared by the method disclosed in the patent application "WO2001030745") to give the title product 110 (45 mg, Off-white solid), yield 29%.
MS m/z(ESI):532.4[M+1]MS m/z (ESI): 532.4 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.37(s,1H),7.54-7.55(m,2H),7.15-7.20(m,2H),7.09-7.11(m,1H),6.98-6.99(m,1H),6.70-6.72(m,1H),4.18(s,2H),4.02-4.05(m,2H),3.89(s,3H),3.49-3.51(m,1H),2.74-2.77(m,2H),1.78-1.81(m,2H),1.35-1.39(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.66 (s, 1H), 8.37 (s, 1H), 7.54-7.55 (m, 2H), 7.15-7.20 (m, 2H), 7.09-7.11 (m , 1H), 6.98-6.99 (m, 1H), 6.70-6.72 (m, 1H), 4.18 (s, 2H), 4.02-4.05 (m, 2H), 3.89 (s, 3H), 3.49-3.51 (m , 1H), 2.74-2.77 (m, 2H), 1.78-1.81 (m, 2H), 1.35-1.39 (m, 2H).
实施例111Example 111
(S)-4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(1-苯乙基)哌啶-1-甲酰胺111(S)-4-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(1-phenylethyl)piperidine-1-carboxamide 111
Figure PCTCN2016093584-appb-000173
Figure PCTCN2016093584-appb-000173
采用实施例99合成路线，将原料99a替换为(S)-1-苯乙胺，制得标题产物111(55mg，白色固体)，收率38.7％。The title product 111 (55 mg, white solid) was obtained (yield: 38.7%).
MS m/z(ESI):491.3[M+1]MS m/z (ESI): 491.3 [M+1]
1H NMR(400MHz,CDCl3)δ9.65(s,1H),8.65(s,1H),7.32-7.36(m,4H),6.96-7.04(m,2H),6.63-6.79(m,2H),4.99-5.06(m,1H),4.75(d,1H),4.00-4.06(m,2H),3.94-3.99(m,1H),2.91(t,2H),1.87-1.94(m,2H),1.63-1.70(m,2H),1.50(d,3H). 1 H NMR (400MHz, CDCl 3 ) δ 9.65 (s, 1H), 8.65 (s, 1H), 7.32-7.36 (m, 4H), 6.96-7.04 (m, 2H), 6.63-6.79 (m, 2H) ), 4.99-5.06 (m, 1H), 4.75 (d, 1H), 4.00-4.06 (m, 2H), 3.94-3.99 (m, 1H), 2.91 (t, 2H), 1.87-1.94 (m, 2H) ), 1.63-1.70 (m, 2H), 1.50 (d, 3H).
实施例112Example 112
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-氟苯乙基)哌啶-1-甲酰胺1124-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-fluorophenethyl)piperidine-1-carboxamide 112
Figure PCTCN2016093584-appb-000174
Figure PCTCN2016093584-appb-000174
采用实施例99的合成路线，将原料99a替换为4-氟苯乙胺，制得标题产物112(62mg，淡黄色固体)，收率42％。The title material 112 (62 mg, pale yellow solid) was obtained in a yield of 42%.
MS m/z(ESI):509.3[M+1]MS m/z (ESI): 509.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.36(s,1H),7.17-7.23(m,3H),7.07-7.11(m,2H),6.98-6.99(m,1H),6.71-6.73(m,1H),6.57-6.59(m,1H),3.98-4.00(m,2H),3.45-3.51(m,1H),3.19-3.23(m,2H),2.69-2.75(m,4H),1.74-1.77(m,2H),1.31-1.39(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.65 (s, 1H), 8.36 (s, 1H), 7.17-7.23 (m, 3H), 7.07-7.11 (m, 2H), 6.98-6.99 (m , 1H), 6.71-6.73 (m, 1H), 6.57-6.59 (m, 1H), 3.98-4.00 (m, 2H), 3.45-3.51 (m, 1H), 3.19-3.23 (m, 2H), 2.69 -2.75 (m, 4H), 1.74-1.77 (m, 2H), 1.31-1.39 (m, 2H).
实施例113Example 113
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-氨基甲酰基苄基)哌啶-1-甲酰胺1134-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-carbamoylbenzyl)piperidine-1-carboxamide 113
Figure PCTCN2016093584-appb-000175
Figure PCTCN2016093584-appb-000175
采用实施例99的合成路线，将原料99a替换为4-(氨甲基)苯甲酰胺(采用专利申请“WO2003097579”公开的方法制备而得)，得到标题产物113(10mg，白色固体)，收率6.6％。Using the synthetic route of Example 99, the starting material 99a was replaced with 4-(aminomethyl)benzamide (prepared by the method disclosed in the patent application "WO2003097579") to give the title product 113 (10 mg, white solid). The rate is 6.6%.
MS m/z(ESI):520.3[M+1]MS m/z (ESI): 520.3 [M+1]
1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.80(s,1H),7.68(d,1H),7.50(t,1H),7.42(t,1H),7.04-7.07(m,1H),7.01(t,1H),6.82-6.98(m,1H),5.35(s,1H),4.87-4.93(m,1H),4.50(d,2H),4.04(d,2H),3.46(t,1H),2.94(t,2H),2.23(t,1H),2.01-2.06(m,1H),1.87-1.94(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.00 (s, 1H), 7.80 (s, 1H), 7.68 (d, 1H), 7.50 (t, 1H), 7.42 (t, 1H), 7.04-7.07 ( m,1H),7.01(t,1H),6.82-6.98(m,1H),5.35(s,1H),4.87-4.93(m,1H),4.50(d,2H),4.04(d,2H) , 3.46(t,1H), 2.94(t,2H), 2.23(t,1H), 2.01-2.06(m,1H),1.87-1.94(m,2H).
实施例114Example 114
(R)-4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(1-苯乙基)哌啶-1-甲酰胺114(R)-4-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(1-phenylethyl)piperidine-1-carboxamide 114
Figure PCTCN2016093584-appb-000176
Figure PCTCN2016093584-appb-000176
采用实施例99的合成路线，将原料99a替换为(R)-1-苯乙胺，制得标题产物114(69mg，淡黄色固体)，收率48％。The title material 114 (69 mg, pale yellow solid) was obtained from the title compound (yield: 48%).
MS m/z(ESI):491.3[M+1]MS m/z (ESI): 491.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.38(s,1H),7.25-7.28(m,5H),7.10-7.17(m,2H),6.98-7.10(m,1H),6.71-6.72(m,1H),4.83-4.85(m,1H),3.68-3.70(m,4H),2.53-2.55(m,1H),2.03-2.05(m,2H),1.78-1.81(m,2H),1.64(s,3H) 1 H NMR (400MHz, DMSO- d 6) δ11.67 (s, 1H), 8.38 (s, 1H), 7.25-7.28 (m, 5H), 7.10-7.17 (m, 2H), 6.98-7.10 (m , 1H), 6.71-6.72 (m, 1H), 4.83-4.85 (m, 1H), 3.68-3.70 (m, 4H), 2.53-2.55 (m, 1H), 2.03-2.05 (m, 2H), 1.78 -1.81(m,2H),1.64(s,3H)
实施例115Example 115
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(2-氰基吡啶-4-基)甲基)哌啶-1-甲酰胺1154-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(2-cyanopyridin-4-yl)methyl)piperidine-1 -formamide 115
Figure PCTCN2016093584-appb-000177
Figure PCTCN2016093584-appb-000177
采用实施例99的合成路线，将原料99a替换为4-氨甲基-2-氰基吡啶(采用公知的方法“Bioorganic & Medicinal Chemistry,2005,13(12),4022-4036”制备而得)，制得标题产物115(40mg，淡褐色固体)，收率27％。Using the synthetic route of Example 99, the starting material 99a was replaced with 4-aminomethyl-2-cyanopyridine (prepared by the known method "Bioorganic & Medicinal Chemistry, 2005, 13(12), 4022-4036") The title product 115 (40 mg, light brown solid) was obtained, yield 27%.
MS m/z(ESI):503.3[M+1]MS m/z (ESI): 503.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.66-8.69(m,1H),8.38(s,1H),7.87(m,1H),7.57-7.59(m,1H),7.26-7.28(m,1H),7.17(t,1H),6.97-6.99(m,1H),6.70-6.72(m,1H),4.30(d,2H),4.03-4.07(m,2H),3.48-3.51(m,1H),2.79-2.85(m,2H),1.77-1.83(m,2H),1.39-1.45(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.67 (s, 1H), 8.66-8.69 (m, 1H), 8.38 (s, 1H), 7.87 (m, 1H), 7.57-7.59 (m, 1H ), 7.26-7.28 (m, 1H), 7.17 (t, 1H), 6.97-6.99 (m, 1H), 6.70-6.72 (m, 1H), 4.30 (d, 2H), 4.03-4.07 (m, 2H) ), 3.48-3.51 (m, 1H), 2.79-2.85 (m, 2H), 1.77-1.83 (m, 2H), 1.39-1.45 (m, 2H).
实施例116Example 116
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-甲基吡啶-3-基)哌啶-1-甲酰胺1164-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-methylpyridin-3-yl)piperidine-1-carboxamide 116
Figure PCTCN2016093584-appb-000178
Figure PCTCN2016093584-appb-000178
采用实施例99的合成路线，将原料99a替换为3-氨基-6-甲基吡啶，制得标题产物116(45mg，淡黄色固体)，收率32.4％。The starting material 99a was replaced with 3-amino-6-methylpyridine using the procedure of Example 99 to give the title product 116 (45 mg, pale yellow solid).
MS m/z(ESI):478.2[M+1]MS m/z (ESI): 478.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.60(s,1H),8.48-8.47(m,1H),8.38(s,1H),7.76-7.73(m,1H),7.19-7.15(m,1H),7.11-7.10(m,1H),6.99-6.98(m,1H),6.72-6.70(m,1H),4.19-4.16(m,2H),3.57-3.51(m,1H),2.91-2.86(m,2H),2.37(s,3H),1.88-1.85(m,2H),1.51-1.42(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.67 (s, 1H), 8.60 (s, 1H), 8.48-8.47 (m, 1H), 8.38 (s, 1H), 7.76-7.73 (m, 1H ), 7.19-7.15 (m, 1H), 7.11-7.10 (m, 1H), 6.99-6.98 (m, 1H), 6.72-6.70 (m, 1H), 4.19-4.16 (m, 2H), 3.57-3.51 (m, 1H), 2.91-2.86 (m, 2H), 2.37 (s, 3H), 1.88-1.85 (m, 2H), 1.51-1.42 (m, 2H).
实施例117Example 117
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(3-甲氧基苄基)哌啶-1-甲酰胺1174-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(3-methoxybenzyl)piperidine-1-carboxamide 117
Figure PCTCN2016093584-appb-000179
Figure PCTCN2016093584-appb-000179
采用实施例99的合成路线，将原料99a替换为3-甲氧基苄胺，制得标题产物4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(3-甲氧基苄基)哌啶-1-甲酰胺117(30mg，白色固体)，收率20.4％。Using the synthetic route of Example 99, the starting material 99a was replaced with 3-methoxybenzylamine to give the title product 4-(2-((3-bromo-4-fluorophenyl)amino)-2-(fluorenyl). Acetyl)-N-(3-methoxybenzyl)piperidine-1-carboxamide 117 (30 mg, white solid), yield 20.4%.
MS m/z(ESI):507.3[M+1]MS m/z (ESI): 507.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.38(s,1H),7.17-7.21(m,2H),7.08-7.10(m,1H),6.97-6.98(m,1H),6.72-6.83(m,4H),4.22(s,2H),4.05-4.09(m,2H),3.73(s,3H),3.49-3.51(m,1H),2.75-2.81(m,2H),1.78-1.81(m,2H),1.38-1.40(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.67 (s, 1H), 8.38 (s, 1H), 7.17-7.21 (m, 2H), 7.08-7.10 (m, 1H), 6.97-6.98 (m , 1H), 6.72-6.83 (m, 4H), 4.22 (s, 2H), 4.05-4.09 (m, 2H), 3.73 (s, 3H), 3.49-3.51 (m, 1H), 2.75-2.81 (m , 2H), 1.78-1.81 (m, 2H), 1.38-1.40 (m, 2H).
实施例118Example 118
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(吡啶-2-基甲基)哌啶-1-甲酰胺1184-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(pyridin-2-ylmethyl)piperidine-1-carboxamide 118
Figure PCTCN2016093584-appb-000180
Figure PCTCN2016093584-appb-000180
采用实施例99的合成路线，将原料99a替换为2-吡啶甲胺，制得标题产物118(15mg，浅黄色固体)，收率11％。The title material 118 (15 mg, pale yellow solid) was obtained in the yield of 11%.
MS m/z(ESI):478.3[M+1]MS m/z (ESI): 478.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.48(s,1H),8.38(s,1H),7.72-7.76(m,1H),7.18-7.26(m,4H),6.98-6.99(m,1H),6.71-6.73(m,1H),4.33(s,2H),4.06-4.10(m,2H),3.51-3.57(m,1H),2.77-2.84(m,2H),1.79-1.82(m,2H),1.40-1.43(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 7.72-7.76 (m, 1H), 7.18-7.26 (m, 4H ), 6.98-6.99 (m, 1H), 6.71-6.73 (m, 1H), 4.33 (s, 2H), 4.06-4.10 (m, 2H), 3.51-3.57 (m, 1H), 2.77-2.84 (m) , 2H), 1.79-1.82 (m, 2H), 1.40-1.43 (m, 2H).
实施例119Example 119
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(环己基甲基)哌啶-1-甲酰胺119 4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(cyclohexylmethyl)piperidine-1-carboxamide 119
Figure PCTCN2016093584-appb-000181
Figure PCTCN2016093584-appb-000181
采用实施例99的合成路线，将原料99a替换为环己基甲胺，制得标题产物119(25mg，白色固体)，收率16.8％。The title material 119 (25 mg, white solid) was obtained in the yield of 16.8%.
MS m/z(ESI):483.3[M+1]MS m/z (ESI): 483.3 [M+1]
1H NMR(400MHz,CDCl3)δ7.08-7.15(m,1H),7.00(t,1H),6.55-6.67(m,1H),5.52-5.60(m,1H),5.30-5.35(m,1H),4.52(s,1H),4.32-4.36(m,1H),3.95-4.05(m,3H),3.83-3.87(m,1H),3.50(s,3H),3.09(t,2H),2.91(t,2H),2.82(s,1H),2.45-2.50(t,1H),2.20-2.29(m,1H),1.71-1.90(m,3H),1.58-1.68(m,4H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.08-7.15 (m, 1H), 7.00 (t, 1H), 6.55-6.67 (m, 1H), 5.52 - 5.60 (m, 1H), 5.30 - 5.35 (m) , 1H), 4.52 (s, 1H), 4.32-4.36 (m, 1H), 3.95-4.05 (m, 3H), 3.83-3.87 (m, 1H), 3.50 (s, 3H), 3.09 (t, 2H) ), 2.91 (t, 2H), 2.82 (s, 1H), 2.45-2.50 (t, 1H), 2.20-2.29 (m, 1H), 1.71-1.90 (m, 3H), 1.58-1.68 (m, 4H) ).
实施例120Example 120
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-甲氧基苯乙基)哌啶-1-甲酰胺1204-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-methoxyphenethyl)piperidine-1-carboxamide 120
Figure PCTCN2016093584-appb-000182
Figure PCTCN2016093584-appb-000182
采用实施例99的合成路线，将原料99a替换为4-甲氧基苯乙胺，制得标题产物120(45mg，白色固体)，收率29.8％。The title material 120 (45 mg, white solid) was obtained in the yield of 29.8%.
MS m/z(ESI):521.3[M+1]MS m/z (ESI): 521.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.40(s,1H),7.13-7.17(t,1H),7.08-7.10(d,2H),6.97-6.98(m,1H),6.85-6.86(d,2H),6.71-6.83(m,1H),6.57-6.58(m,1H),3.98-4.01(m,2H),3.47-3.49(m,1H),3.15-3.18(m,2H),2.62-2.74(m,4H),1.74-1.77(m,2H),1.34-1.36(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.67 (s, 1H), 8.40 (s, 1H), 7.13-7.17 (t, 1H), 7.08-7.10 (d, 2H), 6.97-6.98 (m , 1H), 6.85-6.86 (d, 2H), 6.71-6.83 (m, 1H), 6.57-6.58 (m, 1H), 3.98-4.01 (m, 2H), 3.47-3.49 (m, 1H), 3.15 -3.18 (m, 2H), 2.62-2.74 (m, 4H), 1.74-1.77 (m, 2H), 1.34-1.36 (m, 2H).
实施例121Example 121
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-甲基磺酰基)苄基)哌啶-1-甲酰胺1214-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-methylsulfonyl)benzyl)piperidine-1-carboxamide 121
Figure PCTCN2016093584-appb-000183
Figure PCTCN2016093584-appb-000183
采用实施例99的合成路线，将原料99a替换为4-甲磺酰基苄胺，制得标题产物121(35mg，白色固体)，收率21.7％。The starting material 99a was replaced with 4-methanesulfonylbenzylamine using the procedure of Example 99 to give the title product 121 (35 mg, white solid).
MS m/z(ESI):555.3[M+1] MS m/z (ESI): 555.3 [M+1]
实施例122Example 122
4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(2-甲氧基苄基)哌啶-1-甲酰胺1224-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(2-methoxybenzyl)piperidine-1-carboxamide 122
Figure PCTCN2016093584-appb-000184
Figure PCTCN2016093584-appb-000184
采用实施例99的合成路线，将原料99a替换为2-甲氧基苄胺，制得标题产物122(40mg，淡黄色固体)，收率27％。The title material 122 (40 mg, pale yellow solid) was obtained in the yield of 27%.
MS m/z(ESI):507.3[M+1]MS m/z (ESI): 507.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.37(s,1H),7.15-7.19(m,3H),6.88-6.98(m,4H),6.71-6.72(m,1H),4.22(s,2H),4.06-4.10(m,2H),3.75(s,3H),3.49-3.51(m,1H),2.76-2.81(m,2H),1.78-1.81(m,2H),1.39-1.43(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.66 (s, 1H), 8.37 (s, 1H), 7.15-7.19 (m, 3H), 6.88-6.98 (m, 4H), 6.71-6.72 (m , 1H), 4.22 (s, 2H), 4.06-4.10 (m, 2H), 3.75 (s, 3H), 3.49-3.51 (m, 1H), 2.76-2.81 (m, 2H), 1.78-1.81 (m , 2H), 1.39-1.43 (m, 2H).
实施例123Example 123
4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(吡啶-4-基甲基)哌啶-1-甲酰胺1234-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(pyridin-4-ylmethyl)piperidine-1-carboxamide 123
Figure PCTCN2016093584-appb-000185
Figure PCTCN2016093584-appb-000185
采用实施例99的合成路线，将原料99a替换为4-甲基氨基吡啶，制得标题产物123(33mg，淡黄色固体)，收率23.9％。The title material 123 (33 mg, pale yellow solid) was obtained in the yield of 23.9%.
MS m/z(ESI):478.3[M+1]MS m/z (ESI): 478.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.48(s,1H),8.35-8.42(m,2H),7.82-7.85(m,2H),7.18-7.26(m,2H),6.98-6.99(m,1H),6.71-6.73(m,1H),4.33(s,2H),4.06-4.10(m,2H),3.51-3.57(m,1H),2.77-2.84(m,2H),1.79-1.82(m,2H),1.40-1.43(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 8.48 (s, 1H), 8.35-8.42 (m, 2H), 7.82-7.85 (m, 2H), 7.18-7.26 (m , 2H), 6.98-6.99 (m, 1H), 6.71-6.73 (m, 1H), 4.33 (s, 2H), 4.06-4.10 (m, 2H), 3.51-3.57 (m, 1H), 2.77-2.84 (m, 2H), 1.79-1.82 (m, 2H), 1.40-1.43 (m, 2H).
实施例124Example 124
4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(吡啶-3-基甲基)哌啶-1-甲酰胺1244-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(pyridin-3-ylmethyl)piperidine-1-carboxamide 124
Figure PCTCN2016093584-appb-000186
Figure PCTCN2016093584-appb-000186
采用实施例99的合成路线，将原料99a替换为3-甲基氨基吡啶，制得标题产物124(25mg，淡黄色固体)，收率18％。The starting material 99a was replaced with 3-methylaminopyridine using the procedure of Example 99 to give the title product 124 (25 mg, pale yellow solid).
MS m/z(ESI):478.3[M+1] MS m/z (ESI): 478.3 [M+1]
实施例125Example 125
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-(1-环丙基-1H-吡唑-4-基)吡啶-3-基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-(1-cyclopropyl-1H-pyrazol-4-yl) Pyridin-3-yl)piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000187
Figure PCTCN2016093584-appb-000187
第一步first step
6-(1-环丙基-1H-吡唑-4-基)吡啶-3-胺125b6-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-amine 125b
将1-环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑125a(304mg，1.3mmol，采用专利申请“CN103122000”公开的方法制备而得)，6-溴-3-氨基吡啶(150mg，0.867mmol)，[1,1'-双(二苯基磷)二茂铁]二氯化钯(28mg，0.043mmol)，碳酸钾(180mg，1.3mmol)加入16mL二氧六环和2mL水中，氩气氛下，于85℃搅拌反应18小时。反应结束后，反应液中加入100mL水，用乙酸乙酯萃取(60mL×3)，合并有机相，浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得标题产物125b(154mg，黄褐色固体)，产率89％。1-Cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 125a (304 mg, 1.3 mmol, Prepared by the method disclosed in the patent application "CN103122000", 6-bromo-3-aminopyridine (150 mg, 0.867 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (28 mg, 0.043 mmol), potassium carbonate (180 mg, 1.3 mmol) was added to 16 mL of dioxane and 2 mL of water, and the mixture was stirred at 85 ° C for 18 hours under an argon atmosphere. After completion of the reaction, 100 mL of water was added to the reaction mixture, and the mixture was evaporated. , tan solid), yield 89%.
第二步Second step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-(1-环丙基-1H-吡唑-4-基)吡啶-3-基)哌啶-1-甲酰胺1254-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-(1-cyclopropyl-1H-pyrazol-4-yl) Pyridin-3-yl)piperidine-1-carboxamide 125
将三光气(172mg，0.579mmol)溶于50mL四氢呋喃中，加入125b(290mg，1.448mmol)，0.6mL三乙胺，于0℃反应30分钟，加入1f(498mg，1.448mmol)，于25℃反应1小时。反应结束后，加入10mL甲醇，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物125(135mg，白色固体)，收率16.3％。The triphosgene (172 mg, 0.579 mmol) was dissolved in 50 mL of tetrahydrofuran, 125b (290 mg, 1.448 mmol), 0.6 mL of triethylamine was added, and the mixture was reacted at 0 ° C for 30 minutes, and 1f (498 mg, 1.448 mmol) was added and reacted at 25 ° C. 1 hour. After the reaction was completed, 10 mL of methanol was added, and the reaction mixture was evaporated to dryness.
MS m/z(ESI):570.4[M+1]MS m/z (ESI): 570.4 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.70(s,1H),8.55(s,1H),8.38(s,1H),8.24(s,1H),7.88(s,1H),7.86-7.83(m,1H),7.54-7.52(m,1H),7.19-7.15(m,1H),7.00-6.98(m,1H),6.73-6.70(m,1H),4.21-4.17(m,2H),3.77-3.72(m,1H),3.58-3.52(m,1H),2.93-2.87(m,2H),1.89-1.86(m,2H),1.51-1.43(m,2H),1.10-1.06(m,2H), 0.99-0.94(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 8.70 (s, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 8.24 (s, 1H), 7.88 ( s, 1H), 7.86-7.83 (m, 1H), 7.54-7.52 (m, 1H), 7.19-7.15 (m, 1H), 7.00-6.98 (m, 1H), 6.73-6.70 (m, 1H), 4.21-4.17(m,2H),3.77-3.72(m,1H),3.58-3.52(m,1H),2.93-2.87(m,2H),1.89-1.86(m,2H),1.51-1.43(m , 2H), 1.10.10.06 (m, 2H), 0.99-0.94 (m, 2H).
实施例126Example 126
4-((4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺基)甲基)苯甲酸4-((4-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamido)methyl)benzoic acid
Figure PCTCN2016093584-appb-000188
Figure PCTCN2016093584-appb-000188
第一步first step
4-((4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺基)甲基)苯甲酸乙酯126bEthyl 4-((4-(2-(3-bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamido)methyl)benzoate 126b
将三光气(34mg，0.116mmol)溶于20mL四氢呋喃中，加入4-氨甲基苯甲酸乙酯126a(54mg，0.307mmol)，三乙胺(0.12mL，0.86mmol)，于25℃反应30分钟，加入1f(100mg，0.29mmol)，于25℃搅拌反应1小时。反应结束后，加入甲醇，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物126b(40mg，白色固体)，收率25％。The triphosgene (34 mg, 0.116 mmol) was dissolved in 20 mL of tetrahydrofuran, ethyl 4-aminomethylbenzoate 126a (54 mg, 0.307 mmol), triethylamine (0.12 mL, 0.86 mmol), and reacted at 25 ° C for 30 min. 1f (100 mg, 0.29 mmol) was added, and the reaction was stirred at 25 ° C for 1 hour. After completion of the reaction, methanol was added, and the reaction mixture was evaporated. mjjjjjjjj
第二步Second step
4-((4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺基)甲基)苯甲酸1264-((4-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamido)methyl)benzoic acid 126
将126b(20mg，0.0364mmol)溶于1mL乙醇中，加入1mL的氢氧化钠(3mg，0.0728mmol)溶液，25℃搅拌反应16小时。反应结束后，用1M盐酸调节pH至5，乙酸乙酯萃取(20mL×3)，合并有机相，饱和氯化钠溶液洗涤1次，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物126(5mg，白色固体)，收率26％。126b (20 mg, 0.0364 mmol) was dissolved in 1 mL of ethanol, and 1 mL of a solution of sodium hydroxide (3 mg, 0.0728 mmol) was added, and the reaction was stirred at 25 ° C for 16 hours. After the completion of the reaction, the pH was adjusted to 5 with 1M hydrochloric acid, ethyl acetate (20 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The resulting residue was purified with EtOAc EtOAcjjjjj
MS m/z(ESI):521.3[M+1]MS m/z (ESI): 521.3 [M+1]
1H NMR(400MHz,CD3OD)δ7.96(d,2H),7.38(d,2H),6.95-7.04(m,2H),6.74-6.76(m,1H),4.42(s,2H),4.10(d,2H),3.62(t,1H),2.94(t,2H),1.89-1.98(m,2H), 1.53-1.62(m,2H). 1 H NMR (400MHz, CD 3 OD) δ7.96 (d, 2H), 7.38 (d, 2H), 6.95-7.04 (m, 2H), 6.74-6.76 (m, 1H), 4.42 (s, 2H) , 4.10 (d, 2H), 3.62 (t, 1H), 2.94 (t, 2H), 1.89-1.98 (m, 2H), 1.53-1.62 (m, 2H).
实施例127Example 127
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-(2-羟乙氧基)吡啶-3-基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-(2-hydroxyethoxy)pyridin-3-yl)piperidin Pyridin-1-carboxamide
Figure PCTCN2016093584-appb-000189
Figure PCTCN2016093584-appb-000189
第一步first step
2-(2-((叔丁基二甲基硅基)氧基)乙氧基)-5-硝基吡啶127b2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-nitropyridine 127b
将2-(5-硝基-2-吡啶氧基)乙醇127a(0.5g，2.732mmol，采用专利申请“WO2008084873”公开的方法制备而得)溶于10mL四氢呋喃中，加入咪唑(0.28g，4.098mmol)和叔丁基二甲基氯硅烷(0.49g，3.279mmol)，25℃下反应24小时。反应结束后，加入40mL水，用乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系B纯化所得残余物得标题产物127b(350mg，黄色油状物)，收率43％。2-(5-Nitro-2-pyridyloxy)ethanol 127a (0.5 g, 2.732 mmol, prepared by the method disclosed in the patent application "WO2008084873") was dissolved in 10 mL of tetrahydrofuran, and imidazole (0.28 g, 4.098) was added. Methyl) and tert-butyldimethylsilyl chloride (0.49 g, 3.279 mmol) were reacted at 25 ° C for 24 hours. After completion of the reaction, 40 mL of water was added, and the mixture was evaporated. The resulting residue was purified to silica crystal elut elut elut elut elut elut elut elut
第二步Second step
6-(2-((叔丁基二甲基硅基)氧基)乙氧基)吡啶-3-胺127c6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-amine 127c
将127b(360mg，1.204mmol)溶解于20mL乙醇和水(V:V＝5:1)的混合溶剂中。 向反应液中依次加入铁粉(202mg，3.612mmol)，氯化铵(384mg，7.224mmol)。反应液升温至70℃，搅拌反应1小时。反应结束后，将反应液冷却至室温，减压浓缩，残余物中加入50mL乙酸乙酯和40mL水，分液，水相用乙酸乙酯萃取(50mL×2)，合并有机相，有机相用饱和氯化钠溶液洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物127c(330mg，黄绿色固体)，产品不经纯化直接进行下一步反应。127b (360 mg, 1.204 mmol) was dissolved in a mixed solvent of 20 mL of ethanol and water (V:V=5:1). Iron powder (202 mg, 3.612 mmol) and ammonium chloride (384 mg, 7.224 mmol) were sequentially added to the reaction mixture. The reaction solution was heated to 70 ° C, and the reaction was stirred for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The mixture was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and filtered, and then evaporated to give the crude product 127c (330 mg, yellow green solid).
第三步third step
4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-(2-((叔丁基二甲基硅基)氧基)乙氧基)吡啶)-3-基)哌啶-1-甲酰胺127d4-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-(2-((tert-butyldimethylsilyl)oxy)oxyl) Ethoxy)pyridine)-3-yl)piperidine-1-carboxamide 127d
将三光气(17mg，0.058mmol)溶于10mL四氢呋喃中，加入粗品127c(41mg，0.153mmol)，0.06mL三乙胺，于25℃反应30分钟，加入1f(50mg，0.146mmol)，于25℃反应1小时。反应结束后，加入2mL甲醇淬灭反应，反应液减压浓缩。残余物中加入50mL乙酸乙酯和30mL水，分液，水相用乙酸乙酯萃取(40mL×2)，合并有机相，有机相用饱和氯化钠溶液洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物127d(60mg，黄色油状物)，产品不经纯化直接进行下一步反应The triphosgene (17 mg, 0.058 mmol) was dissolved in 10 mL of tetrahydrofuran, and crude 127c (41 mg, 0.153 mmol), 0.06 mL of triethylamine was added and reacted at 25 ° C for 30 minutes, and 1f (50 mg, 0.146 mmol) was added at 25 ° C. Reaction for 1 hour. After completion of the reaction, the reaction was quenched by the addition of 2 mL of methanol. 50 mL of ethyl acetate and 30 mL of water were added to the residue, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (40 mL × 2). The organic phase was combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude title product 127d (yield:
第四步the fourth step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-(2-羟乙氧基)吡啶-3-基)哌啶-1-甲酰胺1274-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-(2-hydroxyethoxy)pyridin-3-yl)piperidin Pyridine-1-carboxamide 127
将粗品127d(60mg，0.0942mmol)溶于5mL甲醇中，加入1mL浓度为2M的盐酸溶液，25℃下搅拌反应18小时。反应结束后，反应液用碳酸氢钠饱和溶液调节pH至7，乙酸乙酯萃取(30mL×3)，合并有机相，有机相用饱和氯化钠溶液30mL洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物得标题产物127(12mg，白色固体)，收率24％。The crude product 127d (60 mg, 0.0942 mmol) was dissolved in 5 mL of methanol, 1 mL of a 2M hydrochloric acid solution was added, and the reaction was stirred at 25 ° C for 18 hours. After completion of the reaction, the reaction mixture was adjusted to pH 7 with a saturated aqueous solution of sodium hydrogen carbonate, ethyl acetate (30 mL×3), and the organic phase was combined, and the organic phase was washed once with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. EtOAc m.
MS m/z(ESI):524.3[M+1]MS m/z (ESI): 524.3 [M+1]
1H NMR(400MHz,CD3OD)δ8.07(d,2H),7.70(dd,1H),6.98-7.05(m,2H),6.75-6.80(m,2H),4.30(t,2H),4.20(d,2H),3.86(t,2H),3.60-3.70(m,1H),3.35(s,1H),3.01(t,2H),1.93(d,2H),1.60-1.67(m,2H). 1 H NMR (400MHz, CD 3 OD) δ8.07 (d, 2H), 7.70 (dd, 1H), 6.98-7.05 (m, 2H), 6.75-6.80 (m, 2H), 4.30 (t, 2H) , 4.20 (d, 2H), 3.86 (t, 2H), 3.60-3.70 (m, 1H), 3.35 (s, 1H), 3.01 (t, 2H), 1.93 (d, 2H), 1.60-1.67 (m , 2H).
实施例128Example 128
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-氰基-3-甲氧基苄基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-cyano-3-methoxybenzyl)piperidine-1 -formamide
Figure PCTCN2016093584-appb-000190
Figure PCTCN2016093584-appb-000190
Figure PCTCN2016093584-appb-000191
Figure PCTCN2016093584-appb-000191
第一步first step
4-(叠氮甲基)-2-甲氧基苯腈128b4-(azidomethyl)-2-methoxybenzonitrile 128b
将4-氯甲基-2-甲氧基苯腈128a(400mg，2.2mmol)溶于10mL N,N-二甲基甲酰胺中，滴加预制的2mL叠氮化钠(170mg，2.62mmol)溶液，25℃下搅拌反应2小时。反应结束后，加入乙酸乙酯，水洗涤2次，饱和氯化钠溶液洗涤1次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物128b(400mg，无色油状物)，产品不经纯化直接下一步。4-Chloromethyl-2-methoxybenzonitrile 128a (400 mg, 2.2 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and pre-prepared 2 mL sodium azide (170 mg, 2.62 mmol) was added dropwise. The solution was stirred at 25 ° C for 2 hours. After the completion of the reaction, ethyl acetate was added, and the mixture was washed with EtOAc EtOAc (EtOAc m. The product was taken directly to the next step without purification.
第二步Second step
4-(氨甲基)-2-甲氧基苯腈128c4-(Aminomethyl)-2-methoxybenzonitrile 128c
将粗品128b(400mg，2.12mmol)溶于20mL四氢呋喃中，加入3mL水，三苯基膦(669mg，2.55mmol)，45℃下搅拌反应18小时。反应结束后，加入乙酸乙酯，饱和氯化钠溶液洗涤1次，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物128c(130mg，白色固体)，收率31.8％。The crude product 128b (400 mg, 2.12 mmol) was dissolved in 20 mL of tetrahydrofurane, and 3 mL of water, triphenylphosphine (669 mg, 2.55 mmol) was added, and the reaction was stirred at 45 ° C for 18 hours. After completion of the reaction, ethyl acetate and a saturated sodium chloride solution were added, and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. (130 mg, white solid), yield 31.8%.
第三步third step
4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(4-氰基-3-甲氧苄基)哌啶-1-甲酰胺1284-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(4-cyano-3-methoxybenzyl)piperidine-1-yl Amide 128
将三光气(43mg，0.15mmol)溶于20mL四氢呋喃中，加入预制的5mL 128c(49mg，0.305mmol)和三乙胺(88mg，0.87mmol)的四氢呋喃溶液，于25℃反应30分钟，加入1f(100mg，0.29mmol)，于25℃反应1小时。反应结束后，加入甲醇淬灭反应，反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物得到标题产物128(60mg，灰白色固体)，收率38.9％。The triphosgene (43 mg, 0.15 mmol) was dissolved in 20 mL of tetrahydrofuran, and a solution of 5 mL of 128c (49 mg, 0.305 mmol) and triethylamine (88 mg, 0.87 mmol) in tetrahydrofuran was added and reacted at 25 ° C for 30 minutes, and 1f ( 100 mg, 0.29 mmol), reacted at 25 ° C for 1 hour. After completion of the reaction, the reaction was quenched with EtOAc (EtOAc)EtOAc.
MS m/z(ESI):532.3[M+1]MS m/z (ESI): 532.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.37(s,1H),7.64-7.66(d,1H),717-7.22(m,2H),7.10(s,1H),6.96-6.98(m,2H),6.69-6.71(m,1H),4.30(s,2H),4.05-4.08(m,2H),3.88(s,3H),3.49-3.51(m,1H),2.79-2.81(m,2H),1.79-1.82(m,2H),1.39-1.42(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.67 (s, 1H), 8.37 (s, 1H), 7.64-7.66 (d, 1H), 717-7.22 (m, 2H), 7.10 (s, 1H ), 6.96-6.98 (m, 2H), 6.69-6.71 (m, 1H), 4.30 (s, 2H), 4.05-4.08 (m, 2H), 3.88 (s, 3H), 3.49-3.51 (m, 1H) ), 2.79-2.81 (m, 2H), 1.79-1.82 (m, 2H), 1.39-1.42 (m, 2H).
实施例129Example 129
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-(1-二氟甲基)-1H-吡唑-4-基)吡啶-3-基)哌啶-1-甲酰胺4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-(1-difluoromethyl)-1H-pyrazole-4 -yl)pyridin-3-yl)piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000192
Figure PCTCN2016093584-appb-000192
第一步first step
6-(1-(二氟甲基)-1H-吡唑-4-基)吡啶-3-胺129b6-(1-(Difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-amine 129b
将1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑129a(150mg，0.615mmol，采用专利申请“WO2014159224”公开的方法制备而得)，6-溴-3-氨基吡啶(106mg，0.615mmol)，[1,1'-双(二苯基磷)二茂铁]二氯化钯(45mg，0.062mmol)，碳酸钾(255mg，1.845mmol)加入10mL二氧六环和2mL水中，氩气氛下，于85℃搅拌反应3小时。反应结束后，反应液中加入50mL水，用乙酸乙酯萃取(80mL×3)，合并有机相，有机相用50mL饱和氯化钠水溶液洗涤1次，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得标题产物129b(150mg，棕色油状物)。1-(Difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 129a (150 mg, 0.615 mmol, prepared by the method disclosed in the patent application "WO2014159224", 6-bromo-3-aminopyridine (106 mg, 0.615 mmol), [1,1'-bis(diphenylphosphino)ferrocene] Palladium chloride (45 mg, 0.062 mmol), potassium carbonate (255 mg, 1.845 mmol) was added to 10 mL of dioxane and 2 mL of water, and the mixture was stirred at 85 ° C for 3 hours under an argon atmosphere. After completion of the reaction, 50 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (EtOAc (EtOAc) The residue was purified with EtOAc EtOAcjjjjjj
第二步Second step
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(6-(1-二氟甲基)-1H-吡唑-4-基)吡啶-3-基)哌啶-1-甲酰胺1294-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(6-(1-difluoromethyl)-1H-pyrazole-4 -yl)pyridin-3-yl)piperidine-1-carboxamide 129
将三光气(40mg，0.135mmol)溶于10mL四氢呋喃中，加入129b(34mg，0.161mmol)，0.3mL三乙胺，于25℃反应30分钟，加入1f(50mg，0.145mmol)，于25℃反应1小时。反应结束后，加入甲醇，将反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得标题产物129(9mg，黄色固体)，收率10.7％。The triphosgene (40 mg, 0.135 mmol) was dissolved in 10 mL of tetrahydrofuran, 129b (34 mg, 0.161 mmol), 0.3 mL of triethylamine was added, and the reaction was carried out at 25 ° C for 30 minutes, and 1f (50 mg, 0.145 mmol) was added and reacted at 25 ° C. 1 hour. After the reaction was completed, methanol was added, and the mixture was evaporated. mjjjjjjjjjj
MS m/z(ESI):580.3[M+1]MS m/z (ESI): 580.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.79(s,1H),8.70(s,1H),8.64(s,1H),8.39(s,1H),8.28(s,1H),7.92(d,1H),7.84(t,1H),7.70(d,1H),7.16(t,1H),6.98-7.00(m,1H),6.71-6.73(m,1H),4.19-4.22(m,2H),3.53-3.59(m,1H),2.89-2.95 (m,2H),1.87-1.90(m,2H),1.45-1.53(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (s, 1H), 8.79 (s, 1H), 8.70 (s, 1H), 8.64 (s, 1H), 8.39 (s, 1H), 8.28 ( s, 1H), 7.92 (d, 1H), 7.84 (t, 1H), 7.70 (d, 1H), 7.16 (t, 1H), 6.98-7.00 (m, 1H), 6.71-6.73 (m, 1H) , 4.19-4.22 (m, 2H), 3.53-3.59 (m, 1H), 2.89-2.95 (m, 2H), 1.87-1.90 (m, 2H), 1.45-1.53 (m, 2H).
实施例130Example 130
N-(6-((1-氨基环丙基)甲氧基)吡啶-3-基)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺N-(6-((1-Aminocyclopropyl)methoxy)pyridin-3-yl)-4-(2-((3-bromo-4-fluorophenyl)amino)-2-(fluorenyl) Acetyl) piperidine-1-carboxamide
Figure PCTCN2016093584-appb-000193
Figure PCTCN2016093584-appb-000193
第一步first step
(1-(((5-硝基吡啶-2-基)氧基)甲基)环丙基)氨基叔丁酯130b(1-((5-Nitropyridin-2-yl)oxy)methyl)cyclopropyl)amino-tert-butyl ester 130b
将(1-(羟甲基)环丙基)氨基甲酸叔丁酯(0.709g，3.784mmol)溶于20mL N,N-二甲基甲酰胺中，冰浴，加入60％氢化钠(0.15g，3.784mmol)，25℃下反应0.5小时，加入2-氯-5-硝基吡啶130a(0.5g，3.154mmol)，25℃下反应2.5小时。反应结束后，加入60mL水，用乙酸乙酯萃取(50mL×3)，合并有机相，有机相减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得标题产物130b(455mg，黄色固体)，收率46.6％。tert-Butyl (1-(hydroxymethyl)cyclopropyl)carbamate (0.709 g, 3.784 mmol) was dissolved in 20 mL of N,N-dimethylformamide, ice bath and 60% sodium hydride (0.15 g) , 3.784 mmol), and reacted at 25 ° C for 0.5 hour, 2-chloro-5-nitropyridine 130a (0.5 g, 3.154 mmol) was added, and the reaction was carried out at 25 ° C for 2.5 hours. After the reaction was completed, 60 mL of water was added, and ethyl acetate (50 mL × 3) was evaporated, and the organic phase was combined. 455 mg, yellow solid), yield 46.6%.
第二步Second step
(1-(((5-氨基吡啶-2-基)氧基)甲基)环丙基)氨基甲酸叔丁酯130c(1-((5-Aminopyridin-2-yl)oxy)methyl)cyclopropyl)carbamic acid tert-butyl ester 130c
将130b(455mg，1.471mmol)溶解于25mL乙醇和水(V:V＝4:1)的混合溶剂中。向反应液中依次加入铁粉(329mg，5.884mmol)，氯化铵(1.812g，11.768mmol)。反应液升温至70℃，搅拌反应1.5小时。反应结束后，将反应液加入50mL水， 用乙酸乙酯萃取(30mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(100mL×2)，减压浓缩，得到粗品标题产物130c(410mg)，产品不经纯化直接下一步。130b (455 mg, 1.471 mmol) was dissolved in a mixed solvent of 25 mL of ethanol and water (V:V = 4:1). Iron powder (329 mg, 5.884 mmol) and ammonium chloride (1.812 g, 11.768 mmol) were sequentially added to the reaction mixture. The reaction solution was heated to 70 ° C and stirred for 1.5 hours. After the reaction was completed, the reaction solution was added to 50 mL of water. The organic phase was combined with EtOAc (3 mL, EtOAc). .
第三步third step
(1-(((5-4-(2-(3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺)吡啶-2-基)氧基)甲基)环丙基)氨基甲酸叔丁酯130d(1-((5-4-(2-(3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidine-1-carboxamide)pyridin-2-yl) Oxy)methyl)cyclopropyl)carbamic acid tert-butyl ester 130d
0℃下，将三光气(86mg，0.29mmol)溶于5mL四氢呋喃中，加入预制的1mL粗品130c(81mg，0.290mmol)和三乙胺(0.163mL，1.162mmol)混合的四氢呋喃溶液，0℃反应30分钟，25℃加入1f(100mg，0.29mmol)和5mL四氢呋喃，于25℃反应2小时。反应结束后，加入5mL甲醇淬灭反应，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物得标题产物得到标题产物130d(122mg，黄色油状物)，收率64.9％。At 0 ° C, triphosgene (86 mg, 0.29 mmol) was dissolved in 5 mL of tetrahydrofuran, and a solution of 1 mL of crude 130c (81 mg, 0.290 mmol) and triethylamine (0.163 mL, 1.162 mmol) in tetrahydrofuran was added and the mixture was reacted at 0 °C. After 30 minutes, 1f (100 mg, 0.29 mmol) and 5 mL of tetrahydrofuran were added at 25 ° C, and the mixture was reacted at 25 ° C for 2 hours. After the completion of the reaction, the reaction mixture was evaporated to EtOAc (mjjjjjjjjj %.
第四步the fourth step
N-(6-((1-氨基环丙基)甲氧基)吡啶-3-基)-4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-甲酰胺130N-(6-((1-Aminocyclopropyl)methoxy)pyridin-3-yl)-4-(2-((3-bromo-4-fluorophenyl)amino)-2-(fluorenyl) Acetyl) piperidine-1-carboxamide 130
将130d(122mg，0.188mmol)溶于3mL甲醇中，加入3mL浓度为4M的氯化氢1,4-二氧六环溶液，25℃下搅拌反应2小时。反应结束后，反应液减压浓缩。残余物加入100mL乙酸乙酯，和100mL碳酸氢钠饱和溶液，乙酸乙酯萃取(100mL×3)，合并有机相，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物制得标题产物130(50mg，白色固体)，收率48.5％。130 d (122 mg, 0.188 mmol) was dissolved in 3 mL of methanol, and 3 mL of a 4 M hydrogen chloride 1,4-dioxane solution was added thereto, and the reaction was stirred at 25 ° C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was added to 100 mL of ethyl acetate, and EtOAc (EtOAc m. The title product 130 (50 mg, white solid) was obtained.
MS m/z(ESI):549.3[M+1]MS m/z (ESI): 549.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(brs,2H),8.50(s,1H),8.38(s,1H),8.13-8.12(m,1H),7.76-7.73(m,1H),7.19-7.15(m,1H),6.99-6.97(m,1H),6.77-6.72(m,3H),4.18-4.15(m,2H),4.08(s,2H),3.57-3.51(m,1H),2.90-2.84(m,2H),1.87-1.84(m,2H),1.50-1.41(m,2H),0.57-0.50(m,4H). 1 H NMR (400MHz, DMSO- d 6) δ11.68 (brs, 2H), 8.50 (s, 1H), 8.38 (s, 1H), 8.13-8.12 (m, 1H), 7.76-7.73 (m, 1H ), 7.19-7.15 (m, 1H), 6.99-6.97 (m, 1H), 6.77-6.72 (m, 3H), 4.18-4.15 (m, 2H), 4.08 (s, 2H), 3.57-3.51 (m , 1H), 2.90-2.84 (m, 2H), 1.87-1.84 (m, 2H), 1.50-1.41 (m, 2H), 0.57-0.50 (m, 4H).
实施例131Example 131
2-(1-(4-(1H-四氮唑-1-基)苯基)哌啶-4-基)-N-(3-溴-4-氟苯基)-N'-羟基-2-羰基乙脒1312-(1-(4-(1H-tetrazol-1-yl)phenyl)piperidin-4-yl)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2 -carbonyl acetam 131
Figure PCTCN2016093584-appb-000194
Figure PCTCN2016093584-appb-000194
将原料81a(43.3mg，0.1mmol)溶于1mL乙酸中，加入0.1mL原甲酸三乙酯， 25℃反应0.5小时，加入叠氮化钠(9.75mg，0.15mmol)，氩气氛下，80℃反应3小时。反应结束后，加入20mL水，饱和碳酸氢钠溶液调节pH至8，二氯甲烷萃取(20mL×3)，合并有机相，饱和氯化钠溶液洗涤(20mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩。薄层色谱法以洗脱剂体系A纯化所残余物制得标题产物131(12mg，浅棕色固体)，收率24.6％。The starting material 81a (43.3 mg, 0.1 mmol) was dissolved in 1 mL of acetic acid, and 0.1 mL of triethyl orthoformate was added. The reaction was carried out at 25 ° C for 0.5 hour, sodium azide (9.75 mg, 0.15 mmol) was added, and the mixture was reacted at 80 ° C for 3 hours under an argon atmosphere. After the reaction was completed, 20 mL of water was added, and the mixture was adjusted to pH 8 with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with dichloromethane (20 mL×3). The organic phase was combined and washed with saturated sodium chloride solution (20 mL×1), dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure. The title product 131 (12 mg, light brown solid) was obtained from EtOAc.
MS m/z(LC-MS):488.3[M+1]MS m/z (LC-MS): 488.3 [M+1]
1H NMR(400MHz,CDCl3)δ8.68(s,1H),7.53-7.55(m,2H),7.02-7.06(m,3H),6.87-7.00(m,2H),3.85-3.88(m,2H),3.51-3.54(m,1H),2.93-2.96(m,2H),2.01-2.04(m,2H),1.86-1.89(m,2H).1H NMR (400MHz, CDCl 3 ) δ 8.68 (s, 1H), 7.53-7.55 (m, 2H), 7.02-7.06 (m, 3H), 6.87-7.00 (m, 2H), 3.85-3.88 (m, 2H), 3.51-3.54 (m, 1H), 2.93-2.96 (m, 2H), 2.01-2.04 (m, 2H), 1.86-1.89 (m, 2H).
实施例132Example 132
4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)-N-(3,4-二氰基苄基)哌啶-1-甲酰胺1324-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)-N-(3,4-dicyanobenzyl)piperidine-1-carboxamide 132
Figure PCTCN2016093584-appb-000195
Figure PCTCN2016093584-appb-000195
采用实施例128的合成路线，将原料4-氯甲基-2-甲氧基苯腈替换为3,4-二氰基苄溴(采用公知的方法“Chem.Eur.T,2012,18,1727-1736”制备而得)，制得标题产物132(50mg，淡黄褐色固体)，收率33％。Using the synthetic route of Example 128, the starting material 4-chloromethyl-2-methoxybenzonitrile was replaced with 3,4-dicyanobenzyl bromide (using the well-known method "Chem. Eur. T, 2012, 18, 1727-1736 "Prepared" to give the title product 132 (50 mg, pale brown solid).
MS m/z(ESI):527.3[M+1]MS m/z (ESI): 527.3 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.37(s,1H),8.09(d,1H),7.97(s,1H),7.75(dd,1H),7.27(t,1H),7.17(t,1H),6.96-6.99(m,1H),6.72-6.73(m,1H),4.33(d,2H),4.02-4.05(m,2H),3.49-3.51(m,1H),2.78-2.83(m,2H),1.80-1.82(m,2H),1.38-1.44(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.66 (s, 1H), 8.37 (s, 1H), 8.09 (d, 1H), 7.97 (s, 1H), 7.75 (dd, 1H), 7.27 ( t,1H),7.17(t,1H),6.96-6.99(m,1H),6.72-6.73(m,1H),4.33(d,2H),4.02-4.05(m,2H), 3.49-3.51 ( m, 1H), 2.78-2.83 (m, 2H), 1.80-1.82 (m, 2H), 1.38-1.44 (m, 2H).
实施例133Example 133
2-(4-(2-((3-溴-4-氟苯基)氨基)-2-(肟基)乙酰基)哌啶-1-基)噻唑-5-甲酸1332-(4-(2-((3-Bromo-4-fluorophenyl)amino)-2-(indolyl)acetyl)piperidin-1-yl)thiazole-5-carboxylic acid 133
Figure PCTCN2016093584-appb-000196
Figure PCTCN2016093584-appb-000196
采用实施例84的合成路线，将原料2-溴-4-(吡啶-2-基)噻唑替换为2-溴噻唑-5-甲酸，制得标题产物133(10mg，白色固体)，收率7.4％。The title product 133 (10 mg, white solid) was obtained from y. %.
MS m/z(LC-MS):471.2[M+1]MS m/z (LC-MS): 471.2 [M+1]
1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),8.37(s,1H),7.57(s,1H),7.14-7.19(m,1H),6.98-7.00(m,1H),6.70-6.73(m,1H),3.98-4.01(m,2H),3.56-3.62(m,1H),3.12-3.18(m,2H),1.92-1.99(m,2H),1.54-1.62(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ11.80 (s, 1H), 8.37 (s, 1H), 7.57 (s, 1H), 7.14-7.19 (m, 1H), 6.98-7.00 (m, 1H ), 6.70-6.73 (m, 1H), 3.98-4.01 (m, 2H), 3.56-3.62 (m, 1H), 3.12-3.18 (m, 2H), 1.92-1.99 (m, 2H), 1.54-1.62 (m, 2H).
实施例134Example 134
N-(3-溴-4-氟苯基)-N’-羟基-2-羰基-2-(1-(4-(氨基磺酰基)苯基)哌啶-4-基)乙脒134N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-2-carbonyl-2-(1-(4-(aminosulfonyl)phenyl)piperidin-4-yl)acetamidine 134
Figure PCTCN2016093584-appb-000197
Figure PCTCN2016093584-appb-000197
采用实施例72的合成路线，将原料72a替换为4-氨基磺酰基氟苯，制得标题产物134(5mg，黄色固体)，收率5％。The starting material 72a was replaced with 4-aminosulfonylfluorobenzene using the procedure of Example 72 to give the title product 134 (5 mg, yellow solid).
MS m/z(LC-MS):499.3[M+1]MS m/z (LC-MS): 499.3 [M+1]
生物学评价Biological evaluation
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。The invention is further described below in conjunction with the test examples, but these examples are not intended to limit the scope of the invention.
测试例1、本发明化合物对人源IDO1蛋白酶抑制活性的测定Test Example 1. Determination of Protease Inhibitory Activity of Human IDO1 by the Compound of the Present Invention
体外人源IDO1蛋白酶活性通过以下的方法进行测试。The human IDO1 protease activity in vitro was tested by the following method.
该方法用来测定本发明中的化合物对人源IDO1蛋白酶活性的抑制作用。This method is used to determine the inhibitory effect of the compounds of the invention on the activity of human IDO1 protease.
一、实验材料及仪器First, experimental materials and instruments
1、酶标仪(Synergy HT,BIOTEK)1. Microplate reader (Synergy HT, BIOTEK)
2、色氨酸(T0254-5G,Sigma-Aldrich)2. Tryptophan (T0254-5G, Sigma-Aldrich)
3、过氧化氢酶来源于牛肝脏(C1345-1G,Sigma-Aldrich)3. Catalase is derived from bovine liver (C1345-1G, Sigma-Aldrich)
4、亚甲蓝(M9140-25G,Sigma-Aldrich)4, methylene blue (M9140-25G, Sigma-Aldrich)
5、L-抗坏血酸钠(A7631-25G,Sigma-Aldrich)5. L-ascorbate (A7631-25G, Sigma-Aldrich)
6、4-(二甲基氨基)苯甲醛(D2004-25G,Sigma-Aldrich)6, 4-(dimethylamino)benzaldehyde (D2004-25G, Sigma-Aldrich)
7、三氯乙酸(T9159-100G,Sigma-Aldrich)7. Trichloroacetic acid (T9159-100G, Sigma-Aldrich)
8、人源IDO1基因(SC126221,Origene)8, human IDO1 gene (SC126221, Origene)
二、实验步骤Second, the experimental steps
IDO1蛋白酶的自制Homemade IDO1 protease
将人源IDO1基因通过基因克隆技术转入到PET-30(a)质粒(Millipore，货号69909)中，然后转入感受态的大肠杆菌rosseta；在液态LB(Luria-Bertani)培养基[根据《分子克隆实验指南》(J.萨姆布鲁克D.W.拉塞尔著)配制每升培养基]中放大培养，收集菌体，超声破碎，通过挂镍柱，洗脱得到纯化的IDO1蛋白酶。The human IDO1 gene was transferred into the PET-30(a) plasmid (Millipore, Cat. No. 69909) by gene cloning technology, and then transferred into competent E. coli rosseta; in liquid LB (Luria-Bertani) medium [according to The molecular cloning experimental guide (J. Sambrook DW Russell) was prepared in a medium-amplified medium, and the cells were collected, sonicated, and the purified IDO1 protease was eluted by hanging a nickel column.
化合物测试实验：Compound test experiment:
用50mM的KPB将24μl的酶(IDO1)100倍稀释至2400μl，得到浓度为2.6ng/μl的酶溶液，在96孔反应板(AXYGEN，PCR-96-FLT-C)(以下简称反应板)每孔加入24μl酶溶液。空白对照孔加入24μl KPB[KPB缓冲液的配制(50mM)： 用分析天平称取KH2PO4 6.805g放入1000ml的烧杯，用量筒加入去离子水至900ml，用1M的KOH调整PH至6.5，将其导入1L的量筒内，补水至1L即可。4℃储存]。在反应板加入1μl的化合物或DMSO到对应的反应孔中。准备A液：取200μl 500mM L-抗坏血酸钠加1050μl KPB，混匀。B液：100μl 10mM色氨的酸加100μl 100000unit/ml的过氧化氢酶，加5μl 10mM的亚甲蓝，最后加1050μlKPB，混匀。取1200μl A液与1200μl B液，混匀。然后将此混合液以每孔24μl加入反应板中。将反应板放入恒温孵育箱内，37℃，孵育1h。在反应板中，每孔加入10μl 30％(W/V)三氯乙酸，在孵育箱内65℃孵育15分钟。将反应板在离心机上4700RPM离心，室温，5分钟。用排枪从反应板中转移40μl上清液到对应96孔测试板(Corning，#3599)中。每孔加入40μl 2％(W/V)的4-(二甲基氨基)苯甲醛/冰醋酸溶液，混匀1。在室温孵育2分钟后，在Synergy HT(BIOTEK)上读取480nm处的吸光值。24 μl of the enzyme (IDO1) was diluted 100-fold to 2400 μl with 50 mM KPB to obtain an enzyme solution having a concentration of 2.6 ng/μl in a 96-well reaction plate (AXYGEN, PCR-96-FLT-C) (hereinafter referred to as a reaction plate). 24 μl of the enzyme solution was added to each well. Add 24 μl of KPB to the blank control well [KPB buffer preparation (50 mM): Weigh KH 2 PO 4 6.805 g into an 1000 ml beaker with an analytical balance, add deionized water to 900 ml with a measuring cylinder, and adjust the pH to 6.5 with 1 M KOH. Put it into a 1L measuring cylinder and replenish it to 1L. Store at 4 ° C]. 1 μl of the compound or DMSO was added to the reaction well to the corresponding reaction well. Prepare solution A: Take 200 μl of 500 mM L-ascorbate plus 1050 μl of KPB and mix. Solution B: 100 μl of 10 mM tryptophan acid plus 100 μl of 100000 unit/ml catalase, add 5 μl of 10 mM methylene blue, and finally add 1050 μl of KPB and mix. Take 1200 μl of A solution and 1200 μl of B solution and mix. This mixture was then added to the reaction plate at 24 μl per well. The reaction plate was placed in a constant temperature incubator and incubated at 37 ° C for 1 h. In the reaction plate, 10 μl of 30% (w/v) trichloroacetic acid was added to each well, and incubated at 65 ° C for 15 minutes in an incubator. The plate was centrifuged at 4700 RPM on a centrifuge at room temperature for 5 minutes. 40 μl of the supernatant was transferred from the reaction plate with a lance to a corresponding 96-well test plate (Corning, #3599). 40 μl of 2% (w/v) 4-(dimethylamino)benzaldehyde/glacial acetic acid solution was added to each well and mixed. After incubation for 2 minutes at room temperature, the absorbance at 480 nm was read on Synergy HT (BIOTEK).
本发明中化合物对人源IDO1蛋白酶抑制活性通过以上的试验进行测定，测得的IC50值见表1。The protease inhibitory activity of the compound of the present invention against human IDO1 was measured by the above test, and the IC 50 values measured are shown in Table 1.
表1本发明中化合物对人源IDO1蛋白酶活性抑制IC50 Table 1 Inhibition of human IDO1 protease activity IC 50 by the compound of the present invention
Figure PCTCN2016093584-appb-000198
Figure PCTCN2016093584-appb-000198
Figure PCTCN2016093584-appb-000199
Figure PCTCN2016093584-appb-000199
Figure PCTCN2016093584-appb-000200
Figure PCTCN2016093584-appb-000200
结论：本发明化合物对人源IDO1蛋白酶活性具有明显的抑制作用。Conclusion: The compounds of the present invention have a significant inhibitory effect on the activity of human IDO1 protease.
测试例2、本发明化合物对HeLa细胞内IDO蛋白酶抑制活性的测定Test Example 2: Determination of IDO protease inhibitory activity in HeLa cells by the compound of the present invention
HeLa细胞内IDO蛋白酶活性通过以下的方法进行测试。The IDO protease activity in HeLa cells was tested by the following method.
该方法用来测定本发明中的化合物对HeLa细胞内IDO蛋白酶活性的抑制作用。(注：HeLa细胞株在干扰素伽马(INF-γ)的诱导下表达吲哚胺2,3-双加氧酶(IDO))This method was used to determine the inhibitory effect of the compounds of the present invention on IDO protease activity in HeLa cells. (Note: HeLa cell line expresses indoleamine 2,3-dioxygenase (IDO) under the induction of interferon gamma (INF-γ))
一、实验材料及仪器First, experimental materials and instruments
1、酶标仪(Synergy HT,BIOTEK)1. Microplate reader (Synergy HT, BIOTEK)
2、色氨酸(T0254-5G,Sigma-Aldrich)2. Tryptophan (T0254-5G, Sigma-Aldrich)
3、4-(二甲基氨基)苯甲醛(D2004-25G,Sigma-Aldrich)3, 4-(dimethylamino)benzaldehyde (D2004-25G, Sigma-Aldrich)
4、三氯乙酸(T9159-100G,Sigma-Aldrich)4. Trichloroacetic acid (T9159-100G, Sigma-Aldrich)
5、HeLa细胞株(CCL-2,ATCC)5. HeLa cell line (CCL-2, ATCC)
二、实验步骤Second, the experimental steps
用新鲜细胞培养基制取HeLa细胞悬液，以10000个细胞/孔，加入100μl细胞悬液到96孔细胞培养板中，5％二氧化碳，37℃培养24小时。去除上清，先每孔加入90μl无血清DMEM高糖培养基；然后每孔分别加入10μl梯度稀释的化合物(稀释液为含INF-γ和色氨酸及20％FBS的培养基，其终浓度依次为：100000，10000，1000，100，10，1nM)，5％二氧化碳，37℃培养48小时，取96孔细胞培 养板中上清80μl至96孔圆底板中，每孔加入16μl 30％(W/V)三氯乙酸，在孵育箱内65℃孵育25分钟。将反应板在离心机上4700RPM离心，5分钟。用排枪从反应板中转移50μl上清液到96孔平底透明板中，然后每孔加入50μl 2％(W/V)的4-(二甲基氨基)苯甲醛/冰醋酸溶液，在振荡器上混匀1分钟。在室温孵育2分钟后，在Synergy HT Reader上读取480nm处的吸光值。A HeLa cell suspension was prepared from fresh cell culture medium, and 100 μl of the cell suspension was added to a 96-well cell culture plate at 10,000 cells/well, and 5% carbon dioxide was cultured at 37 ° C for 24 hours. Remove the supernatant, first add 90 μl of serum-free DMEM high glucose medium to each well; then add 10 μl of the gradient dilution compound to each well (the dilution is medium containing INF-γ and tryptophan and 20% FBS, the final concentration In order: 100000, 10000, 1000, 100, 10, 1 nM), 5% carbon dioxide, cultured at 37 ° C for 48 hours, 96-well cell culture The supernatant was plated from 80 μl to 96-well round bottom plate, and 16 μl of 30% (w/v) trichloroacetic acid was added to each well, and incubated at 65 ° C for 25 minutes in an incubator. The plate was centrifuged at 4700 RPM on a centrifuge for 5 minutes. Transfer 50 μl of the supernatant from the reaction plate to a 96-well flat-bottom transparent plate with a lance, then add 50 μl of 2% (w/v) 4-(dimethylamino)benzaldehyde/glacial acetic acid solution to each well. Mix on for 1 minute. After incubation for 2 minutes at room temperature, the absorbance at 480 nm was read on a Synergy HT Reader.
本发明中化合物对HeLa细胞内IDO蛋白酶抑制活性通过以上的试验进行测定，测得的IC50值见表2。The IDO protease inhibitory activity of the compound of the present invention in HeLa cells was measured by the above test, and the IC 50 values measured are shown in Table 2.
表2本发明中化合物对HeLa细胞内IDO蛋白酶活性抑制IC50 Table 2 compounds of this invention inhibit the protease activity IC 50 within the pair of HeLa cells IDO
Figure PCTCN2016093584-appb-000201
Figure PCTCN2016093584-appb-000201
Figure PCTCN2016093584-appb-000202
Figure PCTCN2016093584-appb-000202
Figure PCTCN2016093584-appb-000203
Figure PCTCN2016093584-appb-000203
结论：本发明化合物对HeLa细胞内IDO蛋白酶活性具有明显的抑制作用。Conclusion: The compounds of the present invention have a significant inhibitory effect on IDO protease activity in HeLa cells.
药代动力学评价Pharmacokinetic evaluation
测试例3、本发明实施例化合物的药代动力学测试Test Example 3, Pharmacokinetic Testing of Compounds of the Inventive Examples
1、摘要1. Summary
以SD大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予实施例2、3、4、20、21、30、50、105、106、107和125化合物后不同时刻血浆中的药物浓度。研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。SD rats were used as test animals, and the rats were given intragastric administration of the compounds of Examples 2, 3, 4, 20, 21, 30, 50, 105, 106, 107 and 125 by LC/MS/MS. The concentration of the drug in the plasma. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
2、试验方案2, the test plan
2.1试验药品2.1 test drugs
实施例2、3、4、20、21、30、50、105、106、107和125化合物Examples 2, 3, 4, 20, 21, 30, 50, 105, 106, 107 and 125 compounds
2.2试验动物2.2 Test animals
健康成年SD大鼠44只，雌雄各半，购自上海西普尔-必凯实验动物有限公司，动物生产许可证号：SCXK(沪)2008-0016。There were 44 healthy adult SD rats, male and female, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.
2.3药物配制2.3 drug preparation
称取适量药物，加入0.3ml二甲基乙酰胺使溶解后，加入10％2-羟丙基-β-环糊精至终体积，超声制成0.3mg/ml混悬液。其中实施例50超声制成0.2mg/mL混悬液。An appropriate amount of the drug was weighed, and after dissolving by adding 0.3 ml of dimethylacetamide, 10% 2-hydroxypropyl-β-cyclodextrin was added to a final volume, and a 0.3 mg/ml suspension was prepared by ultrasonication. Example 50 was ultrasonically prepared to make a 0.2 mg/mL suspension.
2.4给药2.4 administration
SD大鼠44只，雌雄各半，平均分成11组；禁食一夜后分别灌胃给药，灌胃给药体积10ml/kg。Forty-four SD rats, male and female, were divided into 11 groups. After fasting overnight, they were intragastrically administered, and the intragastric administration volume was 10 ml/kg.
3、操作3, operation
灌胃给药组于给药前及给药后0.5,1.0,2.0,4.0,6.0,8.0,11.0,24.0h采血0.2ml，置于肝素化试管中，3500rpm离心10min分离血浆，于-20℃保存。In the gavage administration group, 0.2 ml of blood was collected before administration and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 h after administration, placed in heparinized tubes, and centrifuged at 3500 rpm for 10 min to separate plasma at -20 ° C. save.
用LC/MS/MS法测定不同化合物灌胃给药后大鼠血浆中的待测化合物含量。The content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method.
4、药代动力学参数结果4, pharmacokinetic parameters results
本发明实施例2、3、4、20、21、30、50、105、106、107、和125化合物的药代动力学参数如下： The pharmacokinetic parameters of the compounds of Examples 2, 3, 4, 20, 21, 30, 50, 105, 106, 107, and 125 of the present invention are as follows:
Figure PCTCN2016093584-appb-000204
Figure PCTCN2016093584-appb-000204
结论：本发明化合物的药代吸收良好，具有明显的药代吸收效果。 Conclusion: The compound of the present invention has good absorption of the drug and has obvious pharmacological absorption effect.

Claims (21)

  1. 一种通式(I)所示的化合物：A compound of the formula (I):
    Figure PCTCN2016093584-appb-100001
    Figure PCTCN2016093584-appb-100001
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中：among them:
    Figure PCTCN2016093584-appb-100002
    选自顺式异构体、反式异构体和顺反异构体的混合物；
    Figure PCTCN2016093584-appb-100002
    a mixture selected from the group consisting of a cis isomer, a trans isomer, and a cis and trans isomer;
    环A选自环烷基或杂环基，其中所述的环烷基或杂环基各自独立地任选被选自烷基、卤素、氨基、硝基、羟基、烷氧基、羟烷基、氰基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)R4、-C(O)OR4、-S(O)mR4、-S(O)mNR5R6、-NR5R6、-C(O)NR5R6、-NR5C(O)R6和-NR5S(O)mR6中的一个或多个取代基所取代；Ring A is selected from cycloalkyl or heterocyclic groups, wherein each of said cycloalkyl or heterocyclic groups is, independently, optionally selected from alkyl, halo, amino, nitro, hydroxy, alkoxy, hydroxyalkyl , cyano, cycloalkyl, heterocyclic, 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 , -C(O)NR 5 R 6 , -NR 5 C(O)R 6 and -NR 5 S(O) m R 6 one or more Substituted by a substituent;
    R1相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)R4、-(CH2)xC(O)OR4、-C(NH)NR5R6、-C(S)NR5R6、-S(O)mR4、-S(O)mNR5R6、-(CH2)xNR5R6、-(CH2)xC(O)NR5R6、-(CH2)xNR5C(O)R6和-(CH2)xNR5S(O)mR6，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-S(O)mNR7R8、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个取代基所取代；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. 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, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl ,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 ,- Substituting one or more substituents of NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 and -NR 7 S(O) m R 8 ;
    R2相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基和杂芳基；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. Base and heteroaryl;
    R3选自烷基、卤代烷基、环烷基、环烷基烷氧基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、环烷基、环烷基烷氧基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、卤素、卤代烷基、氨基、硝基、羟基、烷氧基、羟烷基、氰基、环烷基、环烷基烷基、杂环基、芳基、杂芳基、-C(O)NR7R8、-S(O)mR7、-C(O)OR7和-OR7中的一个或多个取代基所取代；其中所述的环烷基烷基任选被选自烷基、卤素、卤代烷基、氨基、羟基、烷氧基、羟烷基中的一个或多个取代基所取代；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 and -OR 7 Substituted by one or more substituents; wherein the cycloalkylalkyl group is optionally selected from one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, amino, hydroxy, alkoxy, hydroxyalkyl Replaced
    R4选自氢原子、烷基、卤代烷基、羟基、氨基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、-NR7R8、-NR7C(O)R8和-NR7S(O)mR8，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、卤 素、氨基、硝基、氰基、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个取代基所取代；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 , -S(O) m R 7 , -NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 and -NR 7 S (O) substituted with one or more substituents in m R 8 ;
    R5和R6相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、羟烷基、羟基、氨基、环烷基、杂环基、芳基、杂芳基、-(CH2)xR3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-S(O)mNR7R8、-NR7R8、-(CH2)xC(O)NR7R8、-(CH2)xNR7C(O)R8和-(CH2)xNR7S(O)mR8，其中所述的烷基、卤代烷基、氨基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、卤代烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8中的一个或多个取代基所取代；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. , -(CH 2 ) x 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, 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 One of -S(O) m R 7 , -NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 and -NR 7 S(O) m R 8 or Substituted by a plurality of substituents;
    R7和R8相同或不同，且各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、-S(O)mNR9C(O)OR10、-C(O)OR10、-S(O)mNR9R10、环烷基、环烷基烷基、杂环基、芳基和杂芳基，其中所述的烷基、氨基、环烷基、环烷基烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；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 group, a heterocyclic group, an aryl group, and a heteroaryl group;
    R9和R10相同或不同，且各自独立地选自氢原子、烷基、氨基、烷氧基或羟烷基；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;
    m为0、1或2；m is 0, 1 or 2;
    n为0、1、2、3、4或5；n is 0, 1, 2, 3, 4 or 5;
    p为0、1、2、3、4或5；且p is 0, 1, 2, 3, 4 or 5;
    x为0、1、2或3。x is 0, 1, 2 or 3.
  2. 根据权利要求1所述的通式(I)所示的化合物，其中：A选自环烷基或杂环基。The compound of the formula (I) according to claim 1, wherein A is selected from a cycloalkyl group or a heterocyclic group.
  3. 根据权利要求1～2中任一项所述的通式(I)所示的化合物，其中n为1。The compound of the formula (I) according to any one of claims 1 to 2, wherein n is 1.
  4. 根据权利要求1～3中任一项所述的通式(I)所示的化合物，其中p为1、2或3。The compound of the formula (I) according to any one of claims 1 to 3, wherein p is 1, 2 or 3.
  5. 根据权利要求1～4中任一项所述的通式(I)所示的化合物，其中R1相同或不同，且各自独立地选自氢原子、烷基、氨基、羟基、芳基、杂芳基、-C(O)R4、-(CH2)xC(O)OR4、-S(O)mR4、-S(O)mNR5R6、-(CH2)xNR5R6、-(CH2)xC(O)NR5R6、-(CH2)xNR5C(O)R6和-(CH2)xNR5S(O)mR6，其中所述的烷基、氨基、芳基和杂芳基各自独立地任选被选自硝基、氰基、-R3、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8 中的一个或多个取代基所取代；R3～R8、x和m如权利要求1中所定义。The compound of the formula (I) according to any one of claims 1 to 4, wherein R 1 is the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a hydroxyl group, an aryl group, and a hetero group. Aryl, -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 Wherein said alkyl, amino, aryl and heteroaryl are each independently selected from the group consisting of nitro, cyano, -R 3 , -C(O)NR 7 R 8 , -NR 7 C(O Substituting one or more substituents of R 8 and -NR 7 S(O) m R 8 ; R 3 to R 8 , x and m are as defined in claim 1.
  6. 根据权利要求1～5中任一项所述的通式(I)，其中R2为卤素、卤代烷基或烯基。The general formula (I) according to any one of claims 1 to 5, wherein R 2 is a halogen, a halogenated alkyl group or an alkenyl group.
  7. 根据权利要求1所述的通式(I)所示的化合物，其为通式(II)所示的化合物：The compound of the formula (I) according to claim 1, which is a compound of the formula (II):
    Figure PCTCN2016093584-appb-100003
    Figure PCTCN2016093584-appb-100003
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中：R1、R2、和p如权利要求1中所定义。Wherein: R 1 , R 2 , and p are as defined in claim 1.
  8. 根据权利要求7所述的通式(II)所示的化合物，其为通式(III)所示的化合物：The compound of the formula (II) according to claim 7, which is a compound of the formula (III):
    Figure PCTCN2016093584-appb-100004
    Figure PCTCN2016093584-appb-100004
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中：R1、R2和p如权利要求1中所定义。Wherein: R 1 , R 2 and p are as defined in claim 1.
  9. 根据权利要求1所述的通式(I)所示的化合物，其为通式(IV)所示的化合物：The compound of the formula (I) according to claim 1, which is a compound of the formula (IV):
    Figure PCTCN2016093584-appb-100005
    Figure PCTCN2016093584-appb-100005
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中：among them:
    环B选自芳基或杂芳基；Ring B is selected from aryl or heteroaryl;
    Ra选自氢原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8；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. Base, -R 3 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 and -NR 7 S(O) m R 8 ;
    R2、R3、R7、R8、m、和p如权利要求1中所定义；且 R 2 , R 3 , R 7 , R 8 , m, and p are as defined in claim 1;
    y为0、1、2、3、4或5。y is 0, 1, 2, 3, 4 or 5.
  10. 根据权利要求1所述的通式(I)所示的化合物，其为通式(V)所示的化合物：The compound of the formula (I) according to claim 1, which is a compound represented by the formula (V):
    Figure PCTCN2016093584-appb-100006
    Figure PCTCN2016093584-appb-100006
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中：among them:
    G选自C或N；G is selected from C or N;
    Ra选自氢原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8和-NR7S(O)mR8；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. Base, -R 3 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 7 R 8 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 and -NR 7 S(O) m R 8 ;
    R2、R3、R7、R8、m、和p如权利要求1中所定义；且R 2 , R 3 , R 7 , R 8 , m, and p are as defined in claim 1;
    y为0、1、2、3、4或5。y is 0, 1, 2, 3, 4 or 5.
  11. 根据权利要求10所述的通式(V)所示的化合物，其为通式(V-A)所示的化合物：The compound of the formula (V) according to claim 10 which is a compound represented by the formula (V-A):
    Figure PCTCN2016093584-appb-100007
    Figure PCTCN2016093584-appb-100007
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中：among them:
    Rb选自氢原子、烷基、卤代烷基、氨基、环烷基、杂环基、芳基和杂芳基，其中所述的其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、卤素、氨基、硝基、羟基、烷氧基、羟烷基、氰基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)R4、-C(O)OR4、-S(O)mR4、-S(O)mNR5R6、-NR5R6、-C(O)NR5R6、-NR5C(O)R6和-NR5S(O)mR6中的一个或多个取代基所取代；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 , -NR 5 C(O)R 6 and -NR 5 S(O) m R 6 ;
    R4～R6和m如权利要求1中所定义。R 4 to R 6 and m are as defined in claim 1.
  12. 根据权利要求1～11中任一项所述的通式(I)所示的化合物，其选自： The compound of the formula (I) according to any one of claims 1 to 11, which is selected from the group consisting of:
    Figure PCTCN2016093584-appb-100008
    Figure PCTCN2016093584-appb-100008
    Figure PCTCN2016093584-appb-100009
    Figure PCTCN2016093584-appb-100009
    Figure PCTCN2016093584-appb-100010
    Figure PCTCN2016093584-appb-100010
    Figure PCTCN2016093584-appb-100011
    Figure PCTCN2016093584-appb-100011
    Figure PCTCN2016093584-appb-100012
    Figure PCTCN2016093584-appb-100012
    Figure PCTCN2016093584-appb-100013
    Figure PCTCN2016093584-appb-100013
  13. 一种制备根据权利要求1所述的通式(I)化合物的方法，该方法包括：A method of preparing a compound of formula (I) according to claim 1 comprising:
    Figure PCTCN2016093584-appb-100014
    Figure PCTCN2016093584-appb-100014
    通式(I-A)化合物在室温条件下，与R1-NCO反应或者在低温下碱性条件下与R1的卤化物反应，任选在酸性条件下脱保护，得到通式(I)化合物；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);
    其中：among them:
    R1、R2、A、p和n如权利要求1中所定义。R 1 , R 2 , A, p and n are as defined in claim 1.
  14. 一种制备根据权利要求1所述的通式(I)化合物的方法，该方法包括： A method of preparing a compound of formula (I) according to claim 1 comprising:
    Figure PCTCN2016093584-appb-100015
    Figure PCTCN2016093584-appb-100015
    通式(I-B)化合物在室温条件下与苯胺的衍生物反应，得到通式(I)化合物；The compound of the formula (I-B) is reacted with a derivative of aniline at room temperature to give a compound of the formula (I);
    其中，R1、R2、A、p和n如权利要求1中所定义。Wherein R 1 , R 2 , A, p and n are as defined in claim 1.
  15. 一种通式(I-B)所示化合物：A compound of the formula (I-B):
    Figure PCTCN2016093584-appb-100016
    Figure PCTCN2016093584-appb-100016
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中，R1和n如权利要求1中所定义。Wherein R 1 and n are as defined in claim 1.
  16. 根据权利要求15中所述的通式(I-B)所示的化合物，其选自：A compound of the formula (I-B) according to claim 15 which is selected from the group consisting of:
    Figure PCTCN2016093584-appb-100017
    Figure PCTCN2016093584-appb-100017
  17. 一种药物组合物，其含有治疗有效量的根据权利要求1～12中任一项所述的通式(I)所示的化合物，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 12, together with one or more pharmaceutically acceptable carriers, diluents Or an excipient.
  18. 根据权利要求1～12中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐或根据权利要求17所述的药物组合物在制备用于预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物中的用途。The compound of the formula (I) according to any one of claims 1 to 12, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof A compound or a mixture thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 for the preparation of a medicament for preventing and/or treating a disease having a pathological characteristic of an IDO-mediated tryptophan metabolism pathway Use in.
  19. 根据权利要求18所述的用途，其中所述具有IDO介导的色氨酸代谢途径病理学特征的疾病选自癌症、骨髓增生异常综合征、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病，其中所述的癌症优选选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳 突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。The use according to claim 18, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolism pathway is selected from the group consisting of cancer, myelodysplastic syndrome, Alzheimer's disease, autoimmune disease, depression , anxiety, cataract, psychological disorder and AIDS, wherein the cancer is preferably selected from the group consisting of 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 tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, milk Renal tumors, head and neck tumors, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
  20. 一种治疗预防和/或治疗预防具有IDO介导的色氨酸代谢途径的病理学特征的疾病的方法，其包括向患者施用治疗有效剂量的根据权利要求1～12任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐或根据权利要求17所述的药物组合物，其中所述具有IDO介导的色氨酸代谢途径病理学特征的疾病选自癌症、骨髓增生异常综合征、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病。A method of treating a disease preventing and/or treating a disease having a pathological feature of an IDO-mediated tryptophan metabolism pathway, comprising administering to a patient a therapeutically effective dose of the agent according to any one of claims 1 to 12 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 The pharmaceutical composition according to claim 17, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, myelodysplastic syndrome, Alzheimer's disease, autoimmune disease, depression Symptoms, anxiety disorders, cataracts, psychological disorders and AIDS.
  21. 一种治疗预防和/或治疗预防具有IDO介导的色氨酸代谢途径的病理学特征的疾病的方法，其包括向患者施用治疗有效剂量的根据权利要求1～12任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐或根据权利要求17所述的药物组合物，其中所述具有IDO介导的色氨酸代谢途径病理学特征的疾病选自癌症，其中所述的癌症选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。 A method of treating a disease preventing and/or treating a disease having a pathological feature of an IDO-mediated tryptophan metabolism pathway, comprising administering to a patient a therapeutically effective dose of the agent according to any one of claims 1 to 12 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 The pharmaceutical composition according to claim 17, wherein the disease having the pathological characteristics of the IDO-mediated tryptophan metabolic pathway is selected from the group consisting of cancer, wherein the cancer is 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.
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CN116444454B (en) * 2023-06-16 2023-09-12 中国医学科学院医药生物技术研究所 N-hydroxy amidine derivative, preparation method and application thereof, and tumor immunotherapy medicament
CN116987281A (en) * 2023-08-08 2023-11-03 中原工学院 Double-function Cu (I) -MOF (metal organic framework) material, preparation method and application of self-driven photocatalytic reaction
CN116987281B (en) * 2023-08-08 2024-04-16 中原工学院 Double-function Cu (I) -MOF (metal organic framework) material, preparation method and application of self-driven photocatalytic reaction

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