CN107001271B - Hydroxyamidine derivatives, their preparation method and their application in medicine - Google Patents

Hydroxyamidine derivatives, their preparation method and their application in medicine Download PDF

Info

Publication number
CN107001271B
CN107001271B CN201680003843.4A CN201680003843A CN107001271B CN 107001271 B CN107001271 B CN 107001271B CN 201680003843 A CN201680003843 A CN 201680003843A CN 107001271 B CN107001271 B CN 107001271B
Authority
CN
China
Prior art keywords
alkyl
amino
reaction
added
bromo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201680003843.4A
Other languages
Chinese (zh)
Other versions
CN107001271A (en
Inventor
杨方龙
桂斌
胡齐悦
金芳芳
贺峰
孙飘扬
陶维康
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Original Assignee
Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Hengrui Medicine Co Ltd, Shanghai Hengrui Pharmaceutical Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Publication of CN107001271A publication Critical patent/CN107001271A/en
Application granted granted Critical
Publication of CN107001271B publication Critical patent/CN107001271B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Provides a hydroxy amidine derivative, a preparation method thereof and application thereof in medicines. In particular to a hydroxyamidine derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative and application thereof in treating diseases with IDO mediated tryptophan metabolic pathway pathological characteristics, wherein the diseases comprise cancer, Alzheimer disease, autoimmune diseases, depression, anxiety, cataract, psychological disorder and AIDS, and each substituent in the general formula (I) is defined as the specification.

Description

Hydroxyamidines analog derivative, preparation method and its application in medicine
Technical field
The invention belongs to field of medicaments, are related to hydroxyamidines analog derivative, preparation method and its answering on medical research With the invention discloses it as IDO inhibitor, for treating the tryptophan metabolic pathway pathological characteristics mediated with IDO Disease, the disease includes cancer, Alzheimer disease, autoimmune disease, depression, anxiety disorder, cataract, the heart Manage obstacle and AIDS.
Background technique
Tumor biotherapy is the new treatment that treatment and prevention of tumour is carried out using modern biotechnology and its Related product, Yin Qian Entirely, effectively, the features such as adverse reaction is low, become the 4th kind of mode (Clin of the oncotherapy after operation, radiotherapy, chemotherapy Cancer Res, 1997；3:2623-2629), by the natural immunology defense of transfer host, for example inhibit the swollen of IDO mediation Tumor Immune escaping mechanism, or the very strong substance of naturally-produced targeting is given to obtain antitumor effect.
Indoleamine 2,3-dioxygenase (Indoleamine-pyrrole-2,3-dioxygenase, IDO) is a kind of iron content Ferroheme monomeric protein is made of 403 amino acid residues, and the α-helixstructure domain folded including two, big structure domain includes With IDO the effects of hydrophobic (Int J Biochem Cell Biol.2007 can occur for catalytic pocket, substrate in catalytic pocket； 39 (12): 2167-72).In mammals, there are two types of the irrelevant enzymes containing ferroheme of gene coding can be catalyzed color The oxidative degradation of propylhomoserin: IDO and tryptophan 2,3- dioxygenase (TDO).The identical reaction of every kind of enzymatic: on kynurenin road Promote the oxygenolysis of 2, the 3- double bond of indole ring in first rate-limiting step tryptophan catabolism of diameter.The expression master of TDO It is limited to liver, it appears that as a homeostasis or " house keeper " gene, can not be induced or be reconciled by the signal of immune system (Nat Rev Immunol.2004；4 (10): 762-74).IDO is the enzyme for being catalyzed tryptophan transfer and turning to formylkynurenine, extensively It is general to be distributed in people and other mammals (rabbit, mouse) in the tissue in addition to liver, it is that tryptophan can be uniquely catalyzed other than liver The rate-limiting enzyme of catabolism, and tryptophan is amino acid necessary to cell maintains activation and is proliferated, and constitutes protein not Important component (the Adv Exp Med Biol.2003 that can lack；527:455-63, Biochim Biophys Acta.2001； 1527 (3): 167-75).IDO and interferon (interferon, IFN), interleukins (interleukin, IL), tumour are bad The cytokine profiles such as necrosis factor are in close relations, they can activate IDO (J Psychiatry under certain condition Neurosci.2004；29 (1): 11-17, Med Hypotheses.2003；61 (5-6): 519-25).And the cell of T- cell There are the horizontal very sensitive point of adjustment of a tryptophan in period, on the one hand, IDO makes local tryptophan depletion, causes T- Cells arrest is in the G1 interim phase, to inhibit the proliferation of T cell；On the other hand, IDO is catalyzed the main of tryptophan metabolism generation Product cynruin causes Cellular Oxidation agent and antioxidant to change and induces T- Apoptosis by Mediated by Free Radicals, this is to deposit It is the intrinsic immunosuppression mechanism of body.At present a large number of studies show that IDO higher expression in leukaemia cell, makes part T cell proliferation is suppressed, the immune response for inhibiting T- cell-mediated, so that the transduction of T- cell activation signal is obstructed, thus mediate tumor The attack of cell evasion immune system.It has been found that most of mankind's tumor groups express IDO (J Exp Med.2002 with becoming second nature； 196 (4): 459-68, Nat Med.2003；9 (10): 1269-74, Trends Mol Med.2004；10 (1): 15-8).Cause This, IDO is the target of the cancer immunotherapy of a tool potentiality.
The inhibitor patent application of disclosed selective depression IDO include WO2004094409, WO2006122150, WO2007075598、WO200409387、WO2008147283、WO2013174947、WO2008075991、WO2004093871、 WO2005051321, WO2006056304, WO2010005958 and WO2014066834 etc..
IDO inhibitor has a good application prospect as drug in pharmaceuticals industry, but not yet finds at present well IDO inhibitor can be used as marketed drug, in order to achieve the purpose that better oncotherapy effect, better meet the market demand, Inventor wishes to develop the selective IDO inhibitor of the high-efficiency low-toxicity of a new generation.The present invention will provide a kind of new structure Selective IDO inhibitor, and the compound for being found to have this class formation shows excellent effect and effect, especially excellent Medicine generation absorb activity.
Summary of the invention
The purpose of the present invention is to provide a kind of logical formula (I) compound represented or its tautomers, mesomer, outer Raceme, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer shape Formula or its pharmaceutical salt,
Wherein:
Mixture selected from cis-isomer, transisomer and cis-trans-isomer；
Ring A is selected from naphthenic base or heterocycle, wherein the naphthenic base or heterocycle are optionally selected from alkane each independently Base, halogen, amino, nitro, hydroxyl, alkoxy, hydroxyalkyl, cyano, naphthenic base, heterocycle, aryl, heteroaryl ,-OR4、-C (O)R4、-C(O)OR4、-S(O)mR4、-S(O)mNR5R6、-NR5R6、-C(O)NR5R6、-NR5C(O)R6With-NR5S(O)mR6In Replaced one or more substituent groups；
R1It is identical or different, and be each independently selected from hydrogen atom, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, Halogen, amino, nitro, hydroxyl, cyano, naphthenic base, heterocycle, aryl, heteroaryl ,-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)R6With-(CH2)xNR5S(O)mR6, wherein the alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and Heteroaryl is each independently optionally by selected from alkyl, halogenated alkyl, halogen, amino, nitro, cyano, hydroxyl, alkoxy, halogenated Alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl, heteroaryl ,-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-S (O)mNR7R8、-NR7R8、-C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8In one or more substituent groups replaced；
R2It is identical or different, and be each independently selected from hydrogen atom, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, Halogen, amino, nitro, hydroxyl, cyano, naphthenic base, heterocycle, aryl and heteroaryl；
R3Selected from alkyl, halogenated alkyl, naphthenic base, cycloalkyl alkoxy, heterocycle, aryl and heteroaryl, wherein described Alkyl, halogenated alkyl, naphthenic base, cycloalkyl alkoxy, heterocycle, aryl and heteroaryl each independently optionally by be selected from alkane Base, halogen, halogenated alkyl, amino, nitro, hydroxyl, alkoxy, hydroxyalkyl, cyano, naphthenic base, cycloalkyl-alkyl, heterocycle, Aryl, heteroaryl ,-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)R6With-NR5S(O)mR6In one or more substituent groups replaced；Its Described in cycloalkyl-alkyl optionally by one in alkyl, halogen, halogenated alkyl, amino, hydroxyl, alkoxy, hydroxyalkyl Replaced a or multiple substituent groups；
R4Selected from hydrogen atom, alkyl, halogenated alkyl, hydroxyl, amino, alkoxy, halogenated alkoxy, naphthenic base, heterocycle, Aryl, heteroaryl ,-NR7R8、-NR7C(O)R8With-NR7S(O)mR8, wherein the alkyl, halogenated alkyl, naphthenic base, heterocycle Base, aryl and heteroaryl are optionally selected from alkyl, halogen, amino, nitro, cyano, hydroxyl, hydroxyalkyl, alcoxyl each independently Base, naphthenic base, heterocycle, aryl, heteroaryl ,-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O) NR7R8、-NR7C(O)R8With-NR7S(O)mR8In one or more substituent groups replaced；
R5And R6It is identical or different, and it is each independently selected from hydrogen atom, alkyl, halogenated alkyl, alkoxy, hydroxyalkyl, hydroxyl Base, amino, naphthenic base, heterocycle, aryl, heteroaryl ,-(CH2)xR3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-S (O)mNR7R8、-NR7R8、-(CH2)xC(O)NR7R8、-(CH2)xNR7C(O)R8With-(CH2)xNR7S(O)mR8, wherein the alkane Base, halogenated alkyl, amino, naphthenic base, heterocycle, aryl and heteroaryl each independently optionally by selected from alkyl, halogenated alkyl, Halogen, hydroxyl, amino, nitro, cyano, alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl ,-R3、-OR7、-C (O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8One or more of take Replaced Dai Ji；
R7And R8It is identical or different, and be each independently selected from hydrogen atom, alkyl, alkoxy, hydroxyalkyl, hydroxyl, amino, Carboxylate ,-S (O)mNR9C(O)OR10、-C(O)OR10、-S(O)mNR9R10, naphthenic base, cycloalkyl-alkyl, heterocycle, aryl And heteroaryl, wherein alkyl, amino, naphthenic base, cycloalkyl-alkyl, heterocycle, aryl and the heteroaryl are each independently Optionally by selected from alkyl, halogen, hydroxyl, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, naphthenic base, heterocycle, Replaced one or more substituent groups in aryl and heteroaryl；
R9And R10It is identical or different, and be each independently selected from hydrogen atom, alkyl, amino, alkoxy or hydroxyalkyl；
M is 0,1 or 2；
N is 0,1,2,3,4 or 5；
P is 0,1,2,3,4 or 5；And
X is 0,1,2 or 3.
In a preferred embodiment of the present invention, lead to formula (I) compound represented, middle ring A be selected from naphthenic base or Heterocycle, preferably C3-8Naphthenic base or the 3-8 member containing 1 N atom monocyclic heterocycles base or 7-10 member bridge heterocycle, More preferably cyclohexyl, cyclobutyl, nafoxidine, piperidyl, cycloheximide, most preferably piperidyl, cyclohexyl.
In a preferred embodiment of the present invention, lead to formula (I) compound represented, wherein n is 1.
In a preferred embodiment of the present invention, lead to formula (I) compound represented, wherein p is 1 or 2.
In a preferred embodiment of the present invention, lead to formula (I) compound represented, wherein R1It is identical or different, and It is each independently selected from hydrogen atom, alkyl, amino, hydroxyl, aryl, heteroaryl ,-C (O) R4、-(CH2)xC(O)OR4、-S(O)mR4、-S(O)mNR5R6、-(CH2)xNR5R6、-(CH2)xC(O)NR5R6、-(CH2)xNR5C(O)R6With-(CH2)xNR5S(O)mR6；Its Described in alkyl, amino, aryl and heteroaryl each independently optionally by be selected from nitro, cyano ,-R3、-C(O)NR7R8、- NR7C(O)R8With-NR7S(O)mR8In one or more substituent groups replaced；R3~R8, x and m be as defined in logical formula (I).
In a preferred embodiment of the present invention, lead to formula (I) compound represented, wherein R2For halogen, alkyl halide Base or alkenyl.
In a preferred embodiment of the present invention, lead to formula (I) compound represented, wherein R4Selected from hydrogen atom, alkane Base, halogenated alkyl, hydroxyl, amino, alkoxy, halogenated alkoxy, naphthenic base, heterocycle.
In a preferred embodiment of the present invention, lead to formula (I) compound represented, to change shown in logical formula (II) Close object:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer shape Formula or its officinal salt,
Wherein: R1、R2With p as defined in logical formula (I).
In a preferred embodiment of the present invention, lead to formula (II) compound represented, for shown in logical formula (III) Compound:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer shape Formula or its officinal salt,
Wherein: R1、R2With p as defined in logical formula (I).
In a preferred embodiment of the present invention, lead to formula (I) compound represented, to change shown in logical formula (IV) Close object:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer shape Formula or its officinal salt,
Wherein:
Ring B is selected from aryl or heteroaryl；
RaSelected from hydrogen atom, alkyl, halogenated alkyl, halogen, amino, nitro, cyano, hydroxyl, alkoxy, haloalkoxy Base, hydroxyalkyl, naphthenic base, heterocycle, aryl, heteroaryl ,-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C (O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8；
R2、R3、R7、R8, m and p be as defined in logical formula (I)；And
Y is 0,1,2,3,4 or 5.
In a preferred embodiment of the present invention, lead to formula (I) compound represented, to change shown in logical formula (V) Close object:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer shape Formula or its officinal salt,
Wherein:
G is selected from C or N；
RaSelected from hydrogen atom, alkyl, halogenated alkyl, halogen, amino, nitro, cyano, hydroxyl, alkoxy, haloalkoxy Base, hydroxyalkyl, naphthenic base, heterocycle, aryl, heteroaryl ,-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C (O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8；
R2、R3、R7、R8, m and p be as defined in logical formula (I)；And
Y is 0,1,2,3,4 or 5.
Lead to formula (I) compound represented, in a preferred embodiment of the present invention to change shown in logical formula (VI) Close object:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer shape Formula or its officinal salt,
Wherein:
RaSelected from hydrogen atom, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyanogen Base, naphthenic base, heterocycle, aryl, heteroaryl ,-R3、-OR4、-C(O)R4、-C(O)OR4、-S(O)mR4、-S(O)mNR5R6、- NR5R6、-(CH2)xC(O)NR5R6、-(CH2)xNR5C(O)R6With-(CH2)xNR5S(O)mR6, wherein the alkyl, alkyl halide Base, naphthenic base, heterocycle, aryl and heteroaryl are optionally selected from alkyl, halogenated alkyl, halogen, amino, nitre each independently Base, cyano, hydroxyl, alkoxy, halogenated alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl, heteroaryl ,-R3、-OR7、-C(O) R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8In one or more replace Replaced base；
R2~R8, m, x and p be as defined in logical formula (I)；And
The integer that y is 0,1,2,3,4 or 5.
In a preferred embodiment of the present invention, lead to formula (I) compound represented, be shown in general formula (V-A) Compound:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer shape Formula or its officinal salt,
Wherein:
RbSelected from hydrogen atom, alkyl, halogenated alkyl, amino, naphthenic base, heterocycle, aryl and heteroaryl, wherein described Wherein alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are optionally selected from alkyl, halogen each independently Element, amino, nitro, hydroxyl, alkoxy, hydroxyalkyl, cyano, naphthenic base, heterocycle, aryl, heteroaryl ,-OR4、-C(O)R4、-C (O)OR4、-S(O)mR4、-S(O)mNR5R6、-NR5R6、-C(O)NR5R6、-NR5C(O)R6With-NR5S(O)mR6In one or more Replaced a substituent group；
R4~R6With m as defined in logical formula (I).
The present invention also provides a kind of methods for preparing logical formula (I) compound represented, this method comprises:
General formula (I-A) compound at room temperature, with R1NCO reaction or at low temperature under alkaline condition with R1Halogen Compound reaction, is optionally deprotected in acid condition, obtains logical formula (I) compound；
Wherein, R1、R2, A, p and n be as defined in logical formula (I).
In a preferred embodiment of the present invention, compound shown in a kind of general formula (I-B):
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer shape Formula or its officinal salt can be used as compound shown in the logical formula (I) of preparation；
Wherein, R1With n as right is led to defined in formula (I).
The present invention also provides a kind of methods for preparing compound shown in logical formula (I), this method comprises:
General formula (I-B) compound with the derivatives reaction of aniline, obtains logical formula (I) compound at room temperature；
Wherein, R1、R2, A, p and n be as defined in logical formula (I).
It is the typical compound or its tautomer of logical formula (I), mesomer, racemic modification, enantiomter, diastereomeric Or mixtures thereof isomers form or its officinal salt, including but not limited to:
It is the typical compound or its tautomer of logical formula (V), mesomer, racemic modification, enantiomter, diastereomeric Or mixtures thereof isomers form or its officinal salt, including but not limited to:
Another aspect of the present invention relates to a kind of pharmaceutical compositions, logical formula (I), (II) containing treatment effective dose, (III), (IV), (IV-A) and (VI) compound represented or its tautomer, mesomer, racemic modification, enantiomerism Body, diastereoisomer, or mixtures thereof form or pharmaceutical salt and one or more pharmaceutically acceptable carriers, Diluent or excipient.The invention further relates to a kind of methods for preparing above-mentioned composition comprising by logical formula (I), (II), (III), (IV), (IV-A) and (VI) compound represented or its tautomer, mesomer, racemic modification, enantiomerism Body, diastereoisomer, or mixtures thereof form or its pharmaceutical salt and pharmaceutically acceptable carrier, diluent or tax Shape agent mixes.
The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, Or mixtures thereof enantiomter, diastereoisomer form or its officinal salt, or prepared comprising its pharmaceutical composition For prevent and/or Prevention have IDO mediate tryptophan metabolic pathway pathological characteristics disease drug in Purposes.IDO inhibitor can be used for the inhibition of cardiac disorder and treat other with the IDO tryptophan metabolic pathway mediated The disease of pathological characteristics, these diseases include the infection of the virus such as AIDS, and Lyme disease and streptococcal infection etc. are thin Born of the same parents' infection, Neurodegenerative conditions (such as Alzheimer disease, Huntington disease and the gloomy disease of bat gold), autoimmune disease, suppression Strongly fragrant disease, anxiety disorder, cataract, mental handicape, AIDS, cancer (including T cell leukaemia and colon cancer), ocular disease state (such as cataract and age-related yellow) and autoimmune disease, wherein the cancer can be selected from mammary gland Cancer, cervical carcinoma, colon cancer, lung cancer, gastric cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney Cancer, oophoroma, bladder cancer, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phase melanoma, solid tumor, neuroglia The renal tumor of tumor, spongioblastoma, hepatocellular carcinoma, mastoid process, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small thin Born of the same parents' lung cancer.
The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, mappings Or mixtures thereof isomers, diastereoisomer form or its officinal salt, or comprising its pharmaceutical composition, be used for pre- The disease of the pathological characteristics for the tryptophan metabolic pathway that there is anti-and/or Prevention IDO to mediate.These diseases include such as The infection of the virus such as AIDS, the cell infections such as Lyme disease and streptococcal infection, Neurodegenerative conditions (such as alzheimer ' Silent disease, Huntington disease and clap the gloomy disease of gold), autoimmune disease, depression, anxiety disorder, cataract, mental handicape, AIDS, Cancer (including T cell leukaemia and colon cancer), ocular disease state (such as cataract and age-related yellow) and Autoimmune disease, wherein the cancer can be selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, gastric cancer, the carcinoma of the rectum, pancreas Gland cancer, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, bladder cancer, liver cancer, fallopian tube cneoplasms, ovary Tumor, peritoneal tumor, IV phase melanoma, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process are renal Tumor, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer.
The invention further relates to a kind of diseases for the tryptophan metabolic pathway that there is IDO to mediate for Prevention and/or Prevention The method of the disease of feature of science comprising to patient apply treatment effective dose logical formula (I) compound represented or its mutually Or mixtures thereof tautomeric, mesomer, racemic modification, enantiomter, diastereoisomer form or its is pharmaceutically acceptable Salt, or the pharmaceutical composition comprising it.These diseases include the infection of the virus such as AIDS, such as Lyme disease and streptococcus sense The cell infections such as dye, Neurodegenerative conditions (such as Alzheimer disease, Huntington disease and the gloomy disease of bat gold), autoimmune disease Disease, depression, anxiety disorder, cataract, mental handicape, AIDS, cancer (including T cell leukaemia and colon cancer), eyes disease Diseased state (such as cataract and age-related yellow) and autoimmune disease, wherein the cancer can be selected from Breast cancer, cervical carcinoma, colon cancer, lung cancer, gastric cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, bone Cancer, kidney, oophoroma, bladder cancer, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phase melanoma, solid tumor, mind Through glioma, spongioblastoma, hepatocellular carcinoma, the renal tumor of mastoid process, head and neck neoplasm, leukaemia, lymthoma, myeloma and Non-small cell lung cancer.
Another aspect of the present invention is related to a kind of method for the treatment of cancer, and this method includes applying treatment effective dose to patient Logical formula (I) of the invention described in compound or its tautomer, mesomer, racemic modification, enantiomter, non-right Reflect or mixtures thereof isomers form or its officinal salt.This method shows curative effect outstanding and less side effect, wherein The cancer can be selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, gastric cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, mouth Chamber cancer, prostate cancer, osteocarcinoma, kidney, oophoroma, bladder cancer, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phase are black The renal tumor of melanoma, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process, head and neck neoplasm, white blood Disease, lymthoma, myeloma and non-small cell lung cancer, preferably fallopian tube cneoplasms, peritoneal tumor, IV phase melanoma, myeloma And breast cancer, more preferably breast cancer.
Pharmaceutical composition containing active constituent, which can be, is suitable for oral form, such as tablet, dragee, pastille, water Or oil suspension, dispersible powder or particle, lotion, hard or soft capsule or syrup or elixir.It can be any according to this field Know that the method for preparing Pharmaceutical composition prepares Orally administered composition, such composition can containing it is one or more it is selected from the following at Point: sweetener, corrigent, colorant and preservative, to provide pleasing and palatable pharmaceutical formulation.Tablet contain active constituent and The suitable nontoxic pharmaceutical excipient for preparing tablet for mixing.These excipient can be inert excipient, such as carbon Sour calcium, sodium carbonate, lactose, calcium phosphate or sodium phosphate；Granulating agent and disintegrating agent, such as microcrystalline cellulose, cross-linked carboxymethyl fiber Plain sodium, cornstarch or alginic acid；Adhesive, such as starch, gelatin, polyvinylpyrrolidone or Arabic gum；And lubricant, example Such as magnesium stearate, stearic acid or talcum powder.These tablets can not be coated or can be by covering the taste of drug or in gastrointestinal tract Middle delay disintegration and absorption, thus the known technology for providing slow releasing function in a long time is coated.For example, water can be used Dissolubility taste masked substance, such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or extend time substance such as ethyl fibre Dimension element, acetylbutyrylcellulose.
Also available wherein active constituent mixes hard bright with inert solid diluent such as calcium carbonate, calcium phosphate or kaolin Glue capsule or in which active constituent and water-solubility carrier such as polyethylene glycol or oily solvent such as peanut oil, atoleine or olive The Perle of olive oil mixing provides oral preparation.
Water slurry contains active material and the suitable excipient for preparing water slurry for mixing.Such excipient is Suspending agent, such as sodium carboxy methyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, mosanom, polyvinylpyrrolidone And Arabic gum；Dispersing agent or wetting agent can be the contracting of naturally-produced phosphatide such as lecithin or alkylene oxide and fatty acid Close the condensation product of product such as Myrj 45 or ethylene oxide and long-chain fatty alcohol, such as 17 carbon ethylidene Oxygroup cetanol (heptadecaethyleneoxy cetanol) or ethylene oxide and the portion as derived from fatty acid and hexitol The condensation product of ester, such as polyoxyethylene sorbitol monoleate or ethylene oxide is divided to spread out with by fatty acid and hexitan The condensation product of raw partial ester, such as polyethylene oxide Sorbitan Monooleate.Aqueous suspension can also containing a kind of or Determination of Preservatives such as ethylparaben or nipalgin n-propyl, one or more colorants, one or more corrigents and one Kind or a variety of sweeteners, such as sucrose, saccharin or aspartame.
Oil suspension can by making active constituent be suspended in vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or It is formulated in mineral oil such as atoleine.Oil suspension can contain thickener, such as beeswax, hard paraffin or cetanol.It can Above-mentioned sweetener and corrigent is added, to provide palatable preparation.It can be by the way that antioxidant such as Butylated Hydroxyanisole or α-be added Give birth to these compositions of phenol preservation.
It can make to be suitable for preparing that water is suspended dispersible powder also and particle provides active constituent and is used for by the way that water is added Mixed dispersing agent or wetting agent, suspending agent or one or more preservatives.Suitable dispersing agent or wetting agent and suspending agent can Illustrate above-mentioned example.Other excipient such as sweetener, corrigent and colorant can also be added.By the way that antioxidant example is added As ascorbic acid saves these compositions.
Pharmaceutical composition of the invention is also possible to the form of oil in water emulsion.Oil mutually can be vegetable oil such as olive oil Or or mixtures thereof peanut oil or mineral oil such as atoleine.Suitable emulsifier can be naturally-produced phosphatide, such as Soybean lecithin and the ester as derived from fatty acid and hexitan or partial ester such as sorbitan monooleate and the partial ester and ring The condensation product of oxidative ethane, such as polyoxyethylene sorbitol monoleate.Emulsion can also contain sweetener, corrigent, prevent Rotten agent and antioxidant.Syrup and elixir can be prepared with Sweetening agents such as glycerol, propylene glycol, sorbierite or sucrose.Such preparation Moderator, preservative, colorant and antioxidant can be contained.
Pharmaceutical composition can be sterile injectable aqueous form.The acceptable solvent or solvent that can be used have water, Ringer's solution and isotonic sodium chlorrde solution.Aseptic injection preparation can be the aseptic injection water packet that wherein active constituent is dissolved in oily phase Oil microemulsion.Such as active constituent is dissolved in the mixture of soybean oil and lecithin.Then water and glycerol is added in oil solution Processing forms micro emulsion in mixture.Can be by a large amount of injections in part, it will be in injection or the blood flow of micro emulsion injection patient.Alternatively, Preferably solution and micro emulsion are given in the way of it can keep the compounds of this invention constant circulating concentration.To keep this constant density, Continuous intravenous delivery device can be used.The example of this device is the intravenous injection of Deltec CADD-PLUS.TM.5400 type Pump.
Pharmaceutical composition can be for intramuscular and the aseptic injection water of subcutaneous administration or the form of oil suspension.It can be by Know technology, the dispersing agent or wetting agent and suspending agent for being suitable for those described above prepare the suspension.Aseptic injection preparation can also be with It is the aseptic injectable solution or suspension prepared in the acceptable non-toxic diluent of parenteral or solvent, such as 1,3-BDO The solution of middle preparation.Furthermore, it is convenient to use sterile fixed oil as solvent or suspension media.For this purpose, usable include Any reconciliation fixing oil including synthetic glycerine list or diester.In addition, fatty acid such as oleic acid can also prepare injection.
The compounds of this invention can be given by the suppository form for rectally.It can be by by drug and at normal temperatures For solid but in the rectum it is liquid, thus can dissolves and discharge the suitable nonirritant excipient mixing of drug in the rectum To prepare these pharmaceutical compositions.Substance of this kind includes the poly- second of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, various molecular weight The mixture of the aliphatic ester of two pure and mild polyethylene glycol.
As it is well known to the skilled in the art, the dosage of drug depends on many factors, including but and non-limiting In following factor: the activity of particular compound used, the age of patient, the weight of patient, the health status of patient, patient row Quilt, the diet of patient, administration time, administration mode, the rate of excretion, the combination of drug etc.；In addition, optimal therapeutic modality is such as The type of the mode for the treatment of, the consumption per day of general formula compound (I) or pharmaceutical salt can be tested according to traditional therapeutic scheme Card.
Detailed description of the invention
Unless stated to the contrary, the term used in the specification and in the claims has following meanings.
Term " alkyl " refers to saturated aliphatic hydrocarbons group, is the linear chain or branched chain group comprising 1 to 20 carbon atom, excellent Select the alkyl containing 1 to 12 carbon atom, the alkyl of further preferably 1 to 6 carbon atom.Non-limiting example include methyl, Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- diformazan Base propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl third Base, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethyl butyrate Base, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl, n-heptyl, 2- methyl oneself Base, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 2,2- dimethyl Amyl, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2,3- dimethylhexanyl, 2,4- dimethyl oneself Base, 2,5- dimethylhexanyl, 2,2- dimethylhexanyl, 3,3- dimethylhexanyl, 4,4- dimethylhexanyl, 2- ethylhexyl, 3- Ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethylpentyl, n-nonyl, 2- methyl -2- ethyl Hexyl, 2- methyl -3- ethylhexyl, 2,2- diethyl amyl group, positive decyl, 3,3- diethylhexyl, 2,2- diethylhexyl, and Its various branched isomer etc..Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting embodiment include first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- Dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- ethyl -2- first Base propyl, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- diformazan Base butyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl etc..Alkyl can be with It is substitution or non-substituted, when substituted, substituent group can be substituted on any workable tie point, the substitution Base is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, Halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkanes Sulfenyl, heterocycle alkylthio group, oxo base, carboxyl or carboxylate.
Term " alkylidene " refers to that a hydrogen atom of alkyl is further substituted, such as: " methylene " refers to-CH2, it is " sub- Ethyl " refers to-(CH2)2, " propylidene " refer to-(CH2)3, " butylidene " refer to-(CH2)4Etc..Term " alkenyl " refers to by least by two A carbon atom and at least one carbon-to-carbon double bond composition alkyl as defined above, such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl etc..Alkenyl can be substituted or non-substituted, and when substituted, substituent group is preferably one or more A following group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, Nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkane sulphur Base.
Term " naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, cycloalkyl ring include 3 to 20 carbon atoms, preferably comprise 3 to 12 carbon atoms, more preferably include 3 to 8 carbon atoms, more preferably include 4 to 7 carbon originals Son.The non-limiting example of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, Cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc.；Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring.
Term " spiro cycloalkyl group " refers to the polycyclic moiety that a carbon atom (claiming spiro-atom) is shared between 5 to 20 yuan of monocycle, It can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more Preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spirocyclanes according to the number for sharing spiro-atom between ring and ring Base or more spiro cycloalkyl groups, preferably single spiro cycloalkyl group and double spiro cycloalkyl groups.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 Member/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl groups.The non-limiting example of spiro cycloalkyl group includes:
Term " cycloalkyl " refers to 5 to 20 yuan, each ring in system and the shared a pair adjoined of other rings in system The full carbon polycyclic moiety of carbon atom, wherein one or more rings can be containing one or more double bonds, but none ring has The pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.It can be divided into according to a group cyclic number double Ring, tricyclic, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl. The non-limiting example of cycloalkyl includes:
Term " bridge ring alkyl " refers to 5 to 20 yuan, and the full carbon that any two ring shares two carbon atoms being not directly connected is more Cyclic group, can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to a group cyclic number, it is excellent It is selected as bicyclic, tricyclic or Fourth Ring, is more selected as bicyclic or tricyclic.The non-limiting example of bridge ring alkyl includes:
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being connected to precursor structure Ring together is naphthenic base, and non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..Naphthenic base can be Optionally replacing or non-substituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkane Base, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, Aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl or carboxylate.
Term " heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, and it includes 3 to 20 rings Atom, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), but do not wrap The loop section of-O-O- ,-O-S- or-S-S- are included, remaining annular atom is carbon.3 to 12 annular atoms are preferably comprised, wherein 1~4 It is hetero atom；3 to 8 annular atoms are most preferably comprised, wherein 1~3 is hetero atom；3 to 6 annular atoms are most preferably comprised, wherein 1 ~2 be hetero atom.The non-limiting example of monocyclic heterocycles base includes pyrrolidinyl, imidazolidinyl, tetrahydrofuran base, thiophane Base, glyoxalidine base, dihydrofuryl, pyrazoline base, pyrrolin base, piperidyl, piperazinyl, morpholinyl, thiomorpholine Base, high piperazine base, pyranose, THP trtrahydropyranyl etc., preferably piperidyl, pyrrolidinyl, pyranose, THP trtrahydropyranyl or morpholine Base.Multiring heterocyclic includes the heterocycle of loop coil, condensed ring and bridged ring.
Term " spiro heterocyclic radical " refers to the multiring heterocyclic that an atom (claiming spiro-atom) is shared between 5 to 20 yuan of monocycle Group, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom For carbon.It can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Preferably 6 to 14 Member, more preferably 7 to 10 yuan.Spiro heterocyclic radical is divided into single spiro heterocyclic radical, double according to the number for sharing spiro-atom between ring and ring Spiro heterocyclic radical or more spiro heterocyclic radicals, preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 Member/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting example of spiro heterocyclic radical includes:
Term " condensed hetero ring base " refers to 5 to 20 yuan, each ring in system and the shared a pair adjoined of other rings in system The polycyclic heterocyclic group of atom, one or more rings can be containing one or more double bonds, but none ring is with completely total The pi-electron system of yoke, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe miscellaneous original of (wherein m is integer 0 to 2) Son, remaining annular atom are carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to a group cyclic number can be divided into it is bicyclic, Tricyclic, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero rings Base.The non-limiting example of condensed hetero ring base includes:
Term " bridge heterocycle " refers to 5 to 14 yuan, and any two ring shares the polycyclic heterocycle of two atoms being not directly connected Group, can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated, one of them or Multiple annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom are carbon.Preferably 6 To 14 yuan, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge heterocycle can be divided into according to a group cyclic number, Bicyclic or tricyclic is more selected as at preferably bicyclic, tricyclic or Fourth Ring.The non-limiting example of bridge heterocycle includes:
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein being connected to one with precursor structure The ring risen is heterocycle, and non-limiting example includes:
Deng.
Heterocycle can be it is optionally replacing or non-substituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo Base, carboxyl or carboxylate.
Term " aryl " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely shared The ring of adjacent carbon atoms pair) group, preferably 6 to 10 yuan, such as phenyl and naphthalene.More preferable phenyl.The aryl rings can be with It condenses on heteroaryl, heterocycle or cycloalkyl ring, wherein be aryl rings with the ring that precursor structure links together, it is unrestricted Property example includes:
Aryl can be substituted or non-substituted, and when substituted, substituent group is preferably one or more following groups, It is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, ring Alkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl or carboxylic acid Ester group.
Term " heteroaryl " refers to the heteroaromatic system comprising 1 to 4 hetero atom, 5 to 14 annular atoms, and wherein hetero atom selects From oxygen, sulphur and nitrogen.Heteroaryl is preferably 5 to 10 yuan, contains 1 to 3 hetero atom；It is more preferably 5- or 6-membered, contain 1 to 2 miscellaneous original Son；It is preferred that such as imidazole radicals, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrole radicals, tetrazole radical, pyridyl group, phonetic Piperidinyl, thiadiazoles, pyrazinyl etc., preferably imidazole radicals, tetrazole radical, tetrazole base, thienyl, pyrazolyl or pyrimidine radicals, thiazole Base；More select imidazole radicals, pyrazolyl or thiazolyl.The heteroaryl ring can be condensed on aryl, heterocycle or cycloalkyl ring, The ring wherein to link together with precursor structure is heteroaryl ring, and non-limiting example includes:
Heteroaryl can be it is optionally replacing or non-substituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl Or carboxylate.
Term " alkoxy " refers to-O- (alkyl) and-O- (non-substituted naphthenic base), and wherein alkyl is as defined above. The non-limiting example of alkoxy includes: methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, penta oxygen of ring Base, cyclohexyloxy.Alkoxy can be optionally replacing or non-substituted, and when substituted, substituent group is preferably one or more A following group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, Nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkane sulphur Base, carboxyl or carboxylate.
Term " halogenated alkyl " refers to the alkyl replaced by one or more halogens, and wherein alkyl is as defined above.
Term " halogenated alkoxy " refers to the alkoxy replaced by one or more halogens, and wherein alkoxy is as defined above.
Term " cycloalkyl-alkyl " refers to the alkyl replaced by one or more naphthenic base, wherein naphthenic base, alkyl institute as above Definition.For example, a preferred embodiment in the present invention is the alkyl that cyclopropyl replaces.
Term " cycloalkyl alkoxy " refers to the alkoxy replaced by one or more naphthenic base, wherein naphthenic base, alkoxy As defined above.For example, a preferred embodiment in the present invention is the alkoxy that cyclopropyl replaces.
Term " hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, and wherein alkyl is as defined above.
Term " hydroxyl " refers to-OH group.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " amino " refers to-NH2。
Term " cyano " refers to-CN.
Term " nitro " refers to-NO2。
Term " oxo base " refers to=O.
Term " carboxyl " refers to-C (O) OH.
Term " isocyanate group " refers to-NCO.
Term " oximido " refers to=N-OH.
Term " carboxylate " refers to-C (O) O (alkyl) or-C (O) O (naphthenic base), and wherein alkyl is as defined above.
Term " carboxylic acid halides " refers to the compound containing-C (O)-halogen group.
" optional " or " optionally " mean event or environment described later can with but need not occur, which includes The occasion that the event or environment occur or do not occur.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group " But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this Field technical staff, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take Generation.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key Fixed.
" pharmaceutical composition " indicate containing one or more compounds described herein or its physiologically/pharmaceutical salt or The mixture and other components such as physiology/pharmaceutical carrier and excipient of pro-drug and other chemical constituents.Medicine The purpose of compositions is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
" officinal salt " refers to the salt of the compounds of this invention, has safety when this kind of salt is used in the mammalian body and has Effect property, and there is due bioactivity.
The synthetic method of the compounds of this invention
In order to complete the purpose of the present invention, the present invention adopts the following technical scheme:
The present invention lead to formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, The preparation method of or mixtures thereof diastereoisomer form or its pharmaceutical salt, comprising the following steps:
Scheme one
Under the conditions of high-temperature acidic (reagent for providing acid condition is preferably acetic acid), general formula (a) compound is oxidized agent It is oxidized to general formula (b) compound, the preferred selenium dioxide of the oxidant；General formula (b) compound (provides alkaline item under alkaline condition The reagent of part is preferably potassium carbonate), it is reacted at room temperature with hydroxylamine hydrochloride, obtains general formula (c) compound；It is logical by what is obtained Formula (c) compound is reacted with N- chlorosuccinimide in acid condition, obtains general formula (d) compound；Obtained general formula (d) Compound is at room temperature with the derivatives reaction of aniline, obtained general formula (I-A) compound；Obtained general formula (I-A) is changed Close object at room temperature with R1NCO reaction or at low temperature under alkaline condition with R1Halide reaction, obtain logical formula (I) Compound.
The reagent for providing alkaline condition includes organic base and inorganic base, and the organic bases include but is not limited to three second Amine, n,N-diisopropylethylamine, n-BuLi, lithium diisopropylamine, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, it is described Inorganic base includes but is not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.
Oxidant used includes but is not limited to: selenium dioxide, hydrogen peroxide, potassium permanganate or manganese dioxide.
The reagent for providing acid condition includes but is not limited to formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid.
Wherein:
R1、R2, A, p and n be as defined in logical formula (I).
Scheme two
Under the conditions of high-temperature acidic (reagent for providing acid condition is preferably acetic acid), general formula (e) compound is oxidized agent It is oxidized to general formula (f) compound, the preferred selenium dioxide of the oxidant；General formula (f) compound (provides alkaline item under alkaline condition The reagent of part is preferably potassium carbonate), it is reacted at room temperature with hydroxylamine hydrochloride, obtains general formula (g) compound；It is logical by what is obtained Formula (g) compound is reacted with N- chlorosuccinimide in acid condition, obtains general formula (I-B) compound；Obtained general formula (I-B) compound obtains logical formula (I) compound at room temperature with the derivatives reaction of aniline.
The reagent for providing alkaline condition includes organic base and inorganic base, and the organic bases include but is not limited to three second Amine, n,N-diisopropylethylamine, n-BuLi, lithium diisopropylamine, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, it is described Inorganic base includes but is not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.
Oxidant used includes but is not limited to: selenium dioxide, hydrogen peroxide, potassium permanganate or manganese dioxide.
The reagent for providing acid condition includes but is not limited to formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid.
Wherein:
R1、R2, A, p and n be as defined in logical formula (I).
Scheme three
(preferably 0 DEG C) at low temperature, (preferably triethylamine), general formula (III-a) compound and R under alkaline condition1's Halide reaction obtains logical formula (III) compound.
The reagent for providing alkaline condition includes organic base and inorganic base, and the organic bases include but is not limited to three second Amine, n,N-diisopropylethylamine, n-BuLi, lithium diisopropylamine, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, it is described Inorganic base includes but is not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.
R1、R2And p is as defined in logical formula (II) or (III).
Specific embodiment
The present invention is further described with reference to embodiments, but these embodiments not limit the scope of the present invention.
Embodiment
The structure of compound is by nuclear magnetic resonance (NMR) or mass spectrum (MS) come what is determined.The measurement of NMR is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometer, measurement solvent are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), it is inside designated as tetramethylsilane (TMS), chemical shift is with 10-6(ppm) it is provided as unit.
The measurement of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ advantage MAX)。
The measurement of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 × 4.6mm chromatography Column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini 150 × 4.6mm of C18 chromatographic column).
Kinases average inhibition and IC50The measurement of value is with NovoStar microplate reader (German BMG company).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and thin-layered chromatography (TLC) makes The specification that silica gel plate uses is 0.15mm~0.2mm, thin-layer chromatography isolate and purify product use specification be 0.4mm~ 0.5mm silica gel plate.
Column chromatography is generally carrier using 200~300 mesh silica gel of the Yantai Huanghai Sea.
Known starting material of the invention can be used or be synthesized according to methods known in the art, or can purchase certainly ABCR GmbH&Co.KG, Acros Organnics, Aldrich Chemical Company, splendid remote chemical science and technology (Accela ChemBio Inc), up to the companies such as auspicious chemicals.
In embodiment unless otherwise specified, reaction carries out under argon atmospher or nitrogen atmosphere.
Argon atmospher or nitrogen atmosphere refer to that reaction flask connects the argon gas or nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.
Pressure hydration reaction uses Parr 3916EKX type hydrogenation instrument and clear indigo plant QL-500 type hydrogen generator or HC2-SS Type hydrogenates instrument.
Hydrogenation usually vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.
Microwave reaction uses 908860 type microwave reactor of CEM Discover-S.
In embodiment unless otherwise specified, the solution in reaction refers to aqueous solution.
In embodiment unless otherwise specified, the temperature of reaction is room temperature.
Room temperature is optimum reaction temperature, and temperature range is 20 DEG C~30 DEG C.
The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), reacts the system of used solvent Have: A: methylene chloride and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone, The volume ratio of solvent is different according to the polarity of compound and is adjusted.
The system of the solvent of the system and thin-layered chromatography of the eluant, eluent for the column chromatography that purifying compound uses includes: A: Methylene chloride and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane, ethyl acetate and dichloromethane system, D: Petroleum ether and ethyl acetate system, E: the volume ratio of ethyl acetate, solvent is different according to the polarity of compound and is adjusted, A small amount of triethylamine and acid or alkaline reagent etc. can be added to be adjusted.
Embodiment 1
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- Phenylpiperidine -1- formamide
The first step
4- (2- carbonyl acetyl group) piperidines -1- t-butyl formate
Selenium dioxide (1.37g, 0.012mol) is placed in a reaction flask, 15mL Isosorbide-5-Nitrae-dioxane, acetic acid is added (0.24g, 0.004mL), 0.23mL water are warming up to 90 DEG C, and prefabricated 3mL 4- Acetylpiperidin -1- t-butyl formate 1a is added (1.4g, 0.006mmol, using well known method " Bioorganic&Medicinal Chemistry Letters, 2011,21 (5), 1299-1305 " is prepared) Isosorbide-5-Nitrae-dioxane solution, in 90 DEG C react 16 hours.After reaction, water is added 10mL, adjusting pH with saturated sodium bicarbonate solution is 8, is extracted with ethyl acetate (15mL × 3), merges organic phase, with saturation chlorine Change sodium solution washing (20mL), anhydrous sodium sulfate dries, filters, and filtrate decompression concentration obtains crude title product 4- (2- carbonyl Acetyl group) piperidines -1- t-butyl formate 1b (1.4g, yellow oil), product directly progress next step reaction without further purification.
Second step
4- (2- (oximido) acetyl group) piperidines -1- t-butyl formate
Crude product 4- (2- carbonyl acetyl group) piperidines -1- t-butyl formate 1b (1.4g, 0.0058mol) is dissolved in 20mL methanol In, it is added potassium carbonate (1.20g, 0.0087mol), is added hydroxylamine hydrochloride (0.323g, 0.0046mol), it is anti-under 25 DEG C of stirrings It answers 2 hours.After reaction, 30mL ethyl acetate, filtering is added, filtrate decompression is concentrated to give crude title product 4- (2- (oxime Base) acetyl group) piperidines -1- t-butyl formate 1c (1.1g, buff grease), product directly carries out anti-in next step without further purification It answers.
MS m/z (LC-MS): 255.1 [M-1]
Third step
4- (2- chloro- 2- (oximido) acetyl group) piperidines -1- t-butyl formate
10mL N is added in crude product 4- (2- (oximido) acetyl group) piperidines -1- t-butyl formate 1c (1.1g, 4.29mmol), It in dinethylformamide, is added N- chlorosuccinimide (573.1mg, 4.29mmol), the ether that 5 drop hydrogen chloride are added is molten Liquid is stirred to react 1 hour at 25 DEG C.After reaction, 20mL water is added, (15mL × 3) are extracted with ethyl acetate, are associated with Machine phase, organic phase wash (20mL × 3) with saturated sodium chloride solution, and anhydrous sodium sulfate dries, filters, and filtrate decompression concentration obtains To crude title product 4- (2- chloro- 2- (oximido) acetyl group) piperidines -1- t-butyl formate 1d (2.0g, light yellow oil), Product directly carries out next step reaction without further purification.
4th step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- t-butyl formate
Crude product 4- (2- chloro- 2- (oximido) acetyl group) piperidines -1- t-butyl formate 1d (1.45g, 5mmol) and 3- is bromo- 4- fluoroaniline (1.90g, 10mmol) is added in 10mL ethyl alcohol, is stirred to react at 25 DEG C 16 hours.After reaction, it will react Liquid be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtaining title product 4-, (((3- is bromo- by 2- 4- fluorophenyl) amino) -2- (oximido) acetyl group) piperidines -1- t-butyl formate 1e (800mg, yellow solid), yield 36.0%.
5th step
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine
By 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- t-butyl formate 1e (700mg, 1.57mL) is placed in a reaction flask, and hydrogen chloride Isosorbide-5-Nitrae-dioxane of 10mL4M is added, and it is small to be stirred to react 1 at 25 DEG C When.After reaction, reaction solution is concentrated under reduced pressure, obtains crude title product N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl Base -2- (piperidin-4-yl) ethanamidine 1f (500mg, yellow solid), product directly carry out next step reaction without further purification.
MS m/z (LC-MS): 346.0 [M+1]
6th step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- Phenylpiperidine -1- formamide
Aniline (15mg, 0.16mmol) is dissolved in 10mL tetrahydrofuran, addition p-nitrophenyl chloroformate ester (32mg, 0.158mmol), triethylamine (0.1mL, 0.72mmol) is stirred to react 30 minutes at 25 DEG C, and crude product N- (the bromo- 4- fluorine of 3- is added Phenyl)-N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine 1f (55mg, 0.159mmol), reacts 1 hour, instead at 25 DEG C After answering, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, with 5mL dichloromethane Alkane mashing, obtains title product 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- Phenylpiperidine -1- first Amide 1 (15mg, hazel-color solid), yield 20%.
MS m/z (LC-MS): 463.2 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.69 (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)
Embodiment 2
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyanophenyl) piperidines -1- formamide
By N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine 1f (30mg, It 0.208mmol) is dissolved in 2mL tetrahydrofuran, 4- isocyanic acid benzonitrile 2a (30mg, 0.20mmol, using well known method is added " Chemical&Pharmaceutical Bulletin, 2012,60 (8), 1046-1054 " are prepared), it is stirred at 25 DEG C Reaction 2 hours.After reaction, reaction solution is concentrated under reduced pressure, it is remaining with solvent system A to purify gained with thin-layered chromatography Object obtains title product 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyanophenyl) piperidines -1- first Amide 2 (16mg, white solid), yield 36%.
MS m/z (ESI): 488.2 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.67 (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)
Embodiment 3
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- methyl-1 H- pyrazoles -4- base) Phenyl) piperidines -1- formamide
The first step
4- (4- isocyanatophenyl) -1- methyl-1 H- pyrazoles
By 4- (1- methyl-1 H- pyrazoles -4- base) aniline 3a (24mg, 0.14mmol, using patent application Method disclosed in " WO2010132015 " is prepared) it is dissolved in 10mL methylene chloride, addition triethylamine (42mg, 0.42mmol), reaction system is cooled to 0 DEG C, in 0 DEG C of addition triphosgene (14mg, 0.05mmol), is stirred to react 30 in 0 DEG C Minute.After reaction, obtain crude title product 4- (4- isocyanatophenyl) -1- methyl-1 H- pyrazoles 3b (28mg, 0.14mmol), product directly carries out in next step without further purification.
Second step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- methyl-1 H- pyrazoles -4- base) Phenyl) piperidines -1- formamide
Crude product 4- (4- isocyanatophenyl) -1- methyl-1 H- pyrazoles 3b (28mg, 0.14mmol) is dissolved in 10mL dichloro In methane, addition N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine 1f (40mg, 0.12mmol), it is stirred to react in 25 DEG C 1 hour.After reaction, reaction solution is concentrated under reduced pressure, with thin-layered chromatography to be unfolded Agent system A purifying gained residue, obtains title product 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) - N- (4- (1- methyl-1 H- pyrazoles -4- base) phenyl) piperidines -1- formamide 3 (15mg, white solid), yield 24%.
MS m/z (LC-MS): 543.3 [M-1]
1H NMR (400MHz, CD3OD): δ 7.89 (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)
Embodiment 4
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- sulfamoyl piperidin-4-yl) ethanamidine
The first step
(4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) sulfonylcarbamic acid uncle Butyl ester
By N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine 1f (50mg, It 0.145mmol) is dissolved in 10mL methylene chloride, is added triethylamine (44mg, 0.44mmol), reaction system is cooled to 0 DEG C, drop Add prefabricated 1mL chlorosulfonyl t-butyl carbamate 4a (22mg, 0.1mmol, using patent application " WO2010149684 " public affairs The method opened is prepared) dichloromethane solution, be stirred to react in 0 DEG C 1 hour.After reaction, 5mL water is added, with two Chloromethanes extracts (10mL × 3), merges organic phase, washs (5mL) with saturated sodium chloride solution, dry with anhydrous sodium sulfate, mistake Filter, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) the sulfonylcarbamic acid tert-butyl ester 4b (60mg, nothing Color grease), yield 78%.
MS m/z (LC-MS): 469.3 [M-56+1]
Second step
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- sulfamoyl piperidin-4-yl) ethanamidine
By (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) sulfonylcarbamic acid Tert-butyl ester 4b (60mg, 0.11mmol) is dissolved in 2mL methanol, is added hydrogen chloride Isosorbide-5-Nitrae-dioxane of 2mL4M, reaction system in 25 DEG C are stirred to react 1 hour.After reaction, it is concentrated under reduced pressure, is repeated twice, gained residue ammonium hydroxide after 5mL methanol being added Adjusting pH is 10, and (10mL × 2) are extracted with ethyl acetate, and organic phase is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, With thin-layered chromatography with solvent system A purify gained residue, obtain title product N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl Base -2- carbonyl -2- (1- sulfamoyl piperidin-4-yl) ethanamidine 4 (10mg, faint yellow solid), yield 21%.
MS m/z (LC-MS): 425.3 [M+1]
1H NMR (400MHz, CD3OD): δ 7.06-6.99 (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)
Embodiment 5
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (3- (methyl sulphonyl) phenyl) piperazine Pyridine -1- formamide
The first step
1- isocyanate group -3- (methyl sulphonyl) benzene
By 3- (methyl sulphonyl) anilinechloride 5a (488mg, 2.35mmol, using well known method " Helvetica Chimica Acta, 1981,64 (6), 1849-53 " are prepared) it is added in 30mL methylene chloride, addition triphosgene (220mg, 0.74mmol), triethylamine (0.37mL, 2.66mmol), reaction system are stirred to react 30 minutes in 25 DEG C, then back flow reaction 45 is divided Clock reacts 30 minutes then at 25 DEG C.The reaction solution of title product 1- isocyanate group -3- (methyl sulphonyl) benzene 5b is obtained, product is not It is purified directly to carry out next step reaction.
Second step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (3- (methyl sulphonyl) phenyl) piperazine Pyridine -1- formamide
Take 1mL that prefabricated 2mL N- (3- is added the reaction solution of above-mentioned 1- isocyanate group -3- (methyl sulphonyl) benzene 5b Bromo- 4- fluorophenyl)-N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine 1f (26mg, 0.0755) tetrahydrofuran solution in, It is stirred to react in 25 DEG C 12 hours.After reaction, reaction solution is concentrated under reduced pressure, it is pure with solvent system A with thin-layered chromatography Change gained residue, is beaten to obtain title product 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) with 5mL methylene chloride afterwards Acetyl group)-N- (3- (methyl sulphonyl) phenyl) piperidines -1- formamide 5 (9mg, white solid), yield 22%.
MS m/z (ESI): 541.3 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.68 (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).
Embodiment 6
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (3- cyano-phenyl) piperidines -1- formyl Amine
The first step
3- isocyanate group benzonitrile
Triphosgene (187mg, 0.63mmol) is dissolved in 20mL tetrahydrofuran, addition 3- anthranilo nitrile 6a (223mg, 1.887mmol) it is stirred to react in 25 DEG C 1 hour with triethylamine (0.52mL, 0.0876mmol), reaction system.Obtain title product The suspension of 3- isocyanate group benzonitrile 6b, product directly carry out next step reaction without further purification.
Second step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyano-phenyl) piperidines -1- formyl Amine
Take 1mL that prefabricated 2mL N- (the bromo- 4- fluorophenyl of 3-)-is added the suspension of above-mentioned 3- isocyanate group benzonitrile 6b In the tetrahydrofuran solution of N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine 1f (30mg, 0.0876mmol), stirred in 25 DEG C Mix reaction 2 hours.After reaction, reaction solution is concentrated under reduced pressure, it is remaining with solvent system A to purify gained with thin-layered chromatography Object obtains title product 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (3- cyano-phenyl) piperidines -1- Formamide 6 (26mg, white solid), yield 61.0%.
MS m/z (ESI): 488.2 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.69 (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)
Embodiment 7
N- benzyl -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamide
By (isocyanatometyl) benzene 7a (20mg, 0.15mmol, using well known method " Bioorganic& Medicinal Chemistry, 2013,21 (11), 2960-2967 " are prepared) prefabricated 2mL N- (the bromo- 4- fluorine of 3- is added Phenyl)-N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine 1f (30mg, 0.0876) tetrahydrofuran solution in, in 25 DEG C It is stirred to react 2 hours.After reaction, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained it is residual Excess is beaten with 5mL methylene chloride, obtains title product N- benzyl -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) second Acyl group) piperidines -1- formamide 7 (6mg, white solid), yield 14%.
MS m/z (ESI): 477.4 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.86 (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)
Embodiment 8
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (mesyl) phenyl) piperidines - 1- formamide
By 1- isocyanate group -4- (mesyl) benzene (20mg, 0.15mmol, using well known method " Bioorganic& Medicinal Chemistry Letters, 2010,20 (4), 7397-7400 " are prepared) prefabricated 2mL N- (3- is added Bromo- 4- fluorophenyl)-N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine 1f (30mg, 0.0876) tetrahydrofuran solution in, It is stirred to react in 25 DEG C 12 hours.After reaction, reaction solution is concentrated under reduced pressure, it is pure with solvent system A with thin-layered chromatography Change gained residue, is beaten with 5mL methylene chloride, obtains title product 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) Acetyl group)-N- (4- (mesyl) phenyl) piperidines -1- formamide 8 (13mg, white solid), yield 27.7%.
MS m/z (ESI): 541.4 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.68 (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)
Embodiment 9
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- morpholino phenyl) piperidines -1- first Amide
4- morpholinyl phenylamine (22mg, 0.123mmol) is dissolved in 5mL tetrahydrofuran, p-nitrophenyl chloroformate ester is added (25mg, 0.124mmol), triethylamine (0.04mL, 0.288mmol) react 30 minutes in 25 DEG C, and N- (the bromo- 4- fluorobenzene of 3- is added Base)-N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine 1f (40mg, 0.116mmol), it is stirred to react in 25 DEG C 4 hours.Instead After answering, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- morpholino phenyl) piperidines -1- formamide 9 (45mg, white solid), yield 70%.
MS m/z (ESI): 548.4 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.68 (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)
Embodiment 10
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (sulfamoylamino group) phenyl) piperazine Pyridine -1- formamide
The first step
N- (4- nitrobenzophenone) sulfamoylamino group carboxylate
Chlorine sulfonamido t-butyl formate 4a (1.6mg, 7.52mmol) is dissolved in 50mL methylene chloride, 4- nitro is added Aniline (988mg, 7.5mmol) is added triethylamine (1.5mL, 10.8mmol), reacts 48 hours in 25 DEG C.After reaction, will Reactant is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, then beaten with 15mL methylene chloride Slurry, obtains title product N- (4- nitrobenzophenone) sulfamoylamino group carboxylate 10b (1.4g, white solid), yield 62%.
Second step
N- (4- aminophenyl) sulfamoylamino group t-butyl formate
N- (4- nitrobenzophenone) sulfamoylamino group carboxylate 10b (1.4g, 4.41mmol) is dissolved in 40mL methanol In, the palladium carbon of 280mg 10% is added, reaction system is replaced three times with hydrogen, reacted 3 hours in 25 DEG C.After reaction, mistake Filter, filtrate decompression concentration, obtains crude title product N- (4- aminophenyl) sulfamoylamino group t-butyl formate 10c (1.4g, light brown Color solid), product directly carries out next step reaction without further purification.
Third step
N- (4- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamide) phenyl) ammonia Sulfonamido t-butyl formate
Crude product N- (4- aminophenyl) sulfamoylamino group t-butyl formate 10c (44mg, 0.153mmol) is dissolved in 5mL tetra- In hydrogen furans, it is added 4- nitrobenzoic acid (31mg, 0.153mmol, Adamas), triethylamine (0.03mL, 0.216mmol), in 25 DEG C are reacted 30 minutes, addition N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine 1f (50mg, 0.145mmol), it is stirred to react in 25 DEG C 1 hour.After reaction, reaction solution is concentrated under reduced pressure, with thin-layered chromatography to be unfolded Agent system A purifying gained residue, obtains title product N- (4- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) second Acyl group) piperidines -1- formamide) phenyl) sulfamoylamino group t-butyl formate 10d (41mg, white solid), yield 43%.
MS m/z (LC-MS): 655.0 [M-1]
4th step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (sulfamoylamino group) phenyl) piperazine Pyridine -1- formamide
By N- (4- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamide) phenyl) Sulfamoylamino group t-butyl formate 10d (41mg, 0.0623mmol) is placed in a reaction flask, and the hydrogen chloride Isosorbide-5-Nitrae-two of 4mL4M is added Six ring solution of oxygen reacts 1 hour in 25 DEG C.After reaction, reaction solution is concentrated under reduced pressure, is adjusted with saturated sodium bicarbonate solution PH > 7 is extracted with ethyl acetate (25mL × 3), merges organic phase, and anhydrous sodium sulfate dries, filters, and filtrate decompression concentration is used Thin-layered chromatography purifies gained residue with solvent system A, obtains title product 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino)- 2- (oximido) acetyl group)-N- (4- (sulfamoylamino group) phenyl) piperidines -1- formamide 10 (25mg, white solid), yield 71%.
MS m/z (LC-MS): 557.3 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.68 (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)
Embodiment 11
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- ((1r, 4r) -4- ((sulfamoylamino group) methyl) hexamethylene Base) ethanamidine
The first step
(((1r, 4r) -4- (2- carbonyl acetyl group) cyclohexyl) methyl) t-butyl carbamate
By (((1r, 4r) -4- ((Z) -2- (oximido) acetyl group) cyclohexyl) methyl) t-butyl carbamate 11a (6.623g, 0.026mol, using well known method " Bioorganic&Medicinal Chemistry, 2003,11 (7), 1319-1341 " is prepared) it is added in 200mL Isosorbide-5-Nitrae-dioxane and 993 μ L water, addition selenium dioxide (5.756g, 0.052mol), 993 μ L acetic acid is stirred to react 17 hours in 80 DEG C.After reaction, 300mL water is added, is extracted with methylene chloride It takes (150mL × 3), merges organic phase, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with silica gel column chromatography to elute Agent system B purifying gained residue, obtains title product (((1r, 4r) -4- (2- carbonyl acetyl group) cyclohexyl) methyl) amino first Tert-butyl acrylate 11b (3.71g, yellow solid), yield 53.1%.
Second step
(((1r, 4r) -4- (2- (oximido) acetyl group) cyclohexyl) methyl) t-butyl carbamate
By (((1r, 4r) -4- (2- carbonyl acetyl group) cyclohexyl) methyl) t-butyl carbamate 11b (2.4g, It 8.911mmol) is added in 10mL methanol, is added hydroxylamine hydrochloride (619mg, 8.911mmol), potassium carbonate (1.847g, It 13.366mmol) is added in reaction flask, is stirred to react in 25 DEG C 1 hour.After reaction, 200mL ethyl acetate, mistake is added Filter, filtrate decompression are concentrated to give crude title product (((1r, 4r) -4- (2- (oximido) acetyl group) cyclohexyl) methyl) carbamic acid Tert-butyl ester 11c (2.132g, pale yellowish brown solid), product directly carry out next step reaction without further purification.
MS m/z (LC-MS): 283 [M-1]
Third step
(((1r, 4r) -4- (2- chloro- 2- (oximido) acetyl group) cyclohexyl) methyl) t-butyl carbamate
By crude product (((1r, 4r) -4- (2- (oximido) acetyl group) cyclohexyl) methyl) t-butyl carbamate 11c (2.1g, It 7.385mmol) is added in 80mL n,N-Dimethylformamide, is added N- chlorosuccinimide (986mg, 7.385mmol), It is stirred to react in 25 DEG C 2 hours.After reaction, 200mL ethyl acetate is added, (100mL × 3) are washed with water in organic phase, satisfy (100mL × 2) are washed with sodium chloride solution, anhydrous sodium sulfate dries, filters, and filtrate decompression concentration obtains crude title product (((1r, 4r) -4- (2- chloro- 2- (oximido) acetyl group) cyclohexyl) methyl) t-butyl carbamate 11d (1.788g, yellow oil Shape object), product directly carries out next step reaction without further purification.
4th step
(((1r, 4r) -4 (- 2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclohexyl) methyl) amino T-butyl formate
By crude product (((1r, 4r) -4- (2- chloro- 2- (oximido) acetyl group) cyclohexyl) methyl) t-butyl carbamate 11d The bromo- 4- fluoroaniline (2.131g, 11.217mol) of (1.788g, 5.608mmol) and 3- is added in 80mL ethyl alcohol, stirs at 25 DEG C Mix reaction 17 hours.After reaction, reaction solution is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained Residue obtains title product (((1r, 4r) -4 (- 2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) hexamethylene Base) methyl) t-butyl carbamate 11e (543mg, yellow solid), yield 20.5%.
MS m/z (LC-MS): 471.8 [M-1]
5th step
2- ((1r, 4r) -4- (amino methyl) cyclohexyl)-N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl ethanamidine
By (((1r, 4r) -4 (- 2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclohexyl) methyl) ammonia Base t-butyl formate 11e (140mg, 0.296mL) is placed in a reaction flask, and 2mL methanol is added, and the hydrogen chloride 1 of 2.5mL 4M is added, 4- dioxane is stirred to react 30 minutes at 25 DEG C.After reaction, reaction solution is concentrated under reduced pressure, obtains crude title production Object 2- ((1r, 4r) -4- (amino methyl) cyclohexyl)-N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl ethanamidine 11f (130mg, yellow oil), product directly carry out next step reaction without further purification.
MS m/z (LC-MS): 372 [M+1]
6th step
N- (((1r, 4r) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclohexyl) methyl) ammonia Sulfonamido t-butyl formate
Chloro sulfonyl isocyanate (42mg, 0.296mmol) is dissolved in 2mL methylene chloride, is cooled to 0 DEG C, uncle is added Butanol (22mg, 0.296mmol), it is spare after being stirred to react 15 minutes in 0 DEG C.By crude product 2- ((1r, 4r) -4- (amino methyl) Cyclohexyl)-N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl ethanamidine 11f (110mg, 0.296mmol), 2mL methylene chloride It is added in reaction flask with triethylamine (124 μ L, 0.886mmol), above-mentioned reserve liquid is added, is stirred to react in 25 DEG C 1 hour.Reaction After, 50mL methylene chloride is added, successively with saturated sodium bicarbonate solution (30mL × 2), water (30mL × 2), saturation chlorination Sodium solution (30mL × 2) washing, organic phase are dried, filtered with anhydrous sodium sulfate, and filtrate decompression concentration obtains crude title product N- (((1r, 4r) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclohexyl) methyl) sulfamoylamino group T-butyl formate 11g (132mg, yellow solid), product directly carry out next step reaction without further purification.
MS m/z (LC-MS): 551.0 [M+1]
7th step
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- ((1r, 4r) -4- ((sulfamoylamino group) methyl) hexamethylene Base) ethanamidine
By crude product N- (((1r, 4r) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclohexyl) first Base) sulfamoylamino group t-butyl formate 11g (132mg, 0.239mmol) is dissolved in 2mL methanol, the hydrogen chloride 1 of 2mL 4M is added, 4- dioxane solution, reaction system are stirred to react 3 hours in 25 DEG C.After reaction, reaction solution is concentrated under reduced pressure, is added 50mL methylene chloride is successively washed with saturated sodium bicarbonate solution (50mL × 3), and organic phase is dried, filtered with anhydrous sodium sulfate, Filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product N- (the bromo- 4- fluorine of 3- Phenyl) and-N '-hydroxyl -2- carbonyl -2- ((1r, 4r) -4- ((sulfamoylamino group) methyl) cyclohexyl) ethanamidine 11 (45mg, it is faint yellow Solid), yield 41.7%
MS m/z (LC-MS): 451 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.60 (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)
Embodiment 12
2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-phenyl acetanilide,Phenacetylaniline
The first step
2- (3- (methoxyl group (methyl) carbamoyl) ring Ding Yaji) ethyl acetate
50mL tetrahydrofuran is placed in a reaction flask, ice bath is cooled to 0 DEG C, be carefully added into batches sodium hydride solid (60%, 1.76g, 0.044mol), the tetrahydrofuran solution of phosphonoacetate (9.86g, 0.044mol) is added after ten minutes, and In 0 DEG C persistently stir 30 minutes, be then added prefabricated N- methoxy-. N-methyl -3- carbonyl ring fourth formamide 12a (6.28g, 0.04mol is prepared using method disclosed in patent application " WO2009114512 ") tetrahydrofuran solution, and gradually rise It is reacted 30 minutes to 25 DEG C, the progress of TLC monitoring reaction.After reaction, 10mL water quenching reaction is added, water and acetic acid is added Each 200mL of ethyl ester extracts liquid separation, organic phase water, and saturated sodium chloride solution washs (30 × 3mL), collects organic phase, anhydrous sulphur Sour sodium dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title Product 2- (3- (methoxyl group (methyl) carbamoyl) ring Ding Yaji) ethyl acetate 12b (8.0g, yellow liquid), yield 88.0%.
MS m/z (LC-MS): 228.2 [M+1]
Second step
2- (3- (methoxyl group (methyl) carbamoyl) cyclobutyl) ethyl acetate
2- (3- (methoxyl group (methyl) carbamoyl) ring Ding Yaji) ethyl acetate 12b (8.0g, 0.035mol) is molten It in 80mL ethyl acetate, is added 10% palladium carbon (800mg), hydrogen is replaced 3 times, and is persistently stirred 3 days under a hydrogen atmosphere, TLC The progress of monitoring reaction.To after reaction, be filtered to remove palladium carbon, filtrate decompression is concentrated to give crude title product 2- (3- (methoxy Base (methyl) carbamoyl) cyclobutyl) ethyl acetate 12c (7.4g, yellow liquid), product directly carries out next without further purification Step reaction, yield 91.8%.
MS m/z (LC-MS): 230.2 [M+1]
Third step
2- (3- acetyl cyclobutyl) ethyl acetate
By crude product 2- (3- (methoxyl group (methyl) carbamoyl) cyclobutyl) ethyl acetate 12c (7.4g, 32.3mmol) It is added in 50mL tetrahydrofuran, ice bath is cooled to 0 DEG C, is added dropwise 1.0M methyl magnesium bromide solution (65mL, 64.6mmol), and 0 DEG C stirring 30 minutes.After reaction, 100mL saturated ammonium chloride solution quenching reaction is added, water and acetic acid second is then added Each 100mL of ester, reaction mixture liquid separation, organic phase water, saturated sodium chloride solution wash (50mL × 3), collect organic phase, Anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain To title product 2- (3- acetyl cyclobutyl) ethyl acetate 12d (4.5g, colourless liquid), yield 88.0%.
4th step
2- (3- (2- carbonyl acetyl group) cyclobutyl) ethyl acetate
By 2- (3- acetyl cyclobutyl) ethyl acetate 12d (2.0g, 10.85mmol) and selenium dioxide (2.4g, It 21.7mmol) is added in 20mL dioxane, is heated to 80 DEG C and reacts 12 hours.Next day, filtering, filtrate decompression are concentrated to give crude product Title product 2- (3- (2- carbonyl acetyl group) cyclobutyl) ethyl acetate 12e (2.0g, red liquid) product is direct without further purification Carry out next step reaction, yield 93.0%.
5th step
2- (3- (2- (oximido) acetyl group) cyclobutyl) ethyl acetate
Crude product 2- (3- (2- carbonyl acetyl group) cyclobutyl) ethyl acetate 12e (2.0g, 10.1mmol) is placed in reaction flask In, 20mL methanol is added, is separately added into potassium carbonate (2.1g, 15mmol), hydroxylamine hydrochloride (702mg, 10.1mmol), and at 25 DEG C Under be stirred to react 1 hour.After reaction, the filtering of pad silica gel, filtrate decompression are concentrated to give crude title product 2- (3- (2- (oxime Base) acetyl group) cyclobutyl) ethyl acetate 12f (2.0g, red liquid), product directly progress next step reaction without further purification, production Rate 95.2%.
MS m/z (LC-MS): 214.3 [M+1]
6th step
2- (3- (2- chloro- 2- (oximido) acetyl group) cyclobutyl) ethyl acetate
Crude product 2- (3- (2- (oximido) acetyl group) cyclobutyl) ethyl acetate 12f (2.0g, 9.38mmol) is dissolved in 20mL In n,N-Dimethylformamide, be added 4 drop ether solution of hydrogen chloride, then be added N-chlorosuccinimide (1.25g, 9.38mmol), and at 25 DEG C it is stirred to react 1 hour.After reaction, water and each 50mL of ethyl acetate, liquid separation is added has Machine mutually uses water, and saturated sodium chloride solution washs (30mL × 3), collects organic phase, and anhydrous sodium sulfate dries, filters, filtrate decompression It is concentrated to give crude title product 2- (3- (2- chloro- 2- (oximido) acetyl group) cyclobutyl) ethyl acetate 12g (2.0g, yellow liquid Body), product directly carries out next step reaction, yield 86.9% without further purification.
7th step
2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) ethyl acetate
Crude product 2- (3- (2- chloro- 2- (oximido) acetyl group) cyclobutyl) ethyl acetate 12g (2.0g, 8.07mmol) is dissolved in In 20mL ethyl alcohol, the bromo- 4- fluoroaniline 12h (2.3g, 12.1mmol) of 3- is added, and be stirred to react at 25 DEG C 3 days.Reaction terminates Afterwards, reaction solution is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) ethyl acetate 12i (1.5g, yellow liquid), Yield 46.3%.
MS m/z (LC-MS): 401.3 [M+1]
8th step
2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) acetic acid
By 2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) ethyl acetate 12i (1.5g, 3.74mmol) is dissolved in the mixed solution (V: V=15: 8) of 23mL tetrahydrofuran and water, and lithium hydroxide one is added and is hydrated Object (314mg, 7.48mmol) is heated to 50 DEG C and persistently stirs 2 hours.After reaction, reaction solution is concentrated under reduced pressure and is removed greatly Water and each 100mL of methylene chloride, liquid separation, water phase 6N salt acid for adjusting pH to 3~4, water phase is added in part organic solvent, residue It is extracted with dichloromethane (50mL × 3), the organic phase water of collection, saturated sodium chloride solution washs (30 × 3mL), collects organic Phase, anhydrous sodium sulfate dry, filter, and filtrate decompression is concentrated to give crude title product 2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) ammonia Base) -2- (oximido) acetyl group) cyclobutyl) acetic acid 12j (900mg, yellow solid), product without further purification directly carry out in next step Reaction, yield 64.7%.
MS m/z (LC-MS): 373.3 [M+1]
9th step
2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-phenyl acetanilide,Phenacetylaniline
By crude product 2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) acetic acid 12j (30mg, 0.08mmol) is dissolved in 10mL methylene chloride, argon gas replace three times, under an argon be added oxalyl chloride (51mg, 0.40mmol), it is stirred 2 hours in 0 DEG C, reaction solution is concentrated under reduced pressure, spare.10mL methylene chloride, aniline are added in residue (15mg, 0.16mmol), n,N-diisopropylethylamine (31mg, 0.24mmol), stirs evenly, and reacts 30 under the conditions of 25 DEG C Minute, the progress of TLC monitoring reaction.After reaction, water and each 30mL of methylene chloride, liquid separation, organic phase water, saturation is added Sodium chloride solution washs (30 × 3mL), collects organic phase, and anhydrous sodium sulfate dries, filters, and silicagel column is used in filtrate decompression concentration Chromatography purifies gained residue with eluant, eluent system A, obtains title product 2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino)- 2- (oximido) acetyl group) cyclobutyl)-phenyl acetanilide,Phenacetylaniline 12 (10mg, white solid), yield 27.8%.
MS m/z (LC-MS): 448.3 [M+1]
1H NMR (400MHz, DMSO-d6): 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)
Embodiment 13
2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-N- (4- methoxyphenyl) Acetamide
By 2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) acetic acid 12j (30mg, It 0.08mmol) is dissolved in 5mL methylene chloride, and with and in be cooled to 0 DEG C, half drop n,N-Dimethylformamide is added, grass is added Acyl chlorides (51mg, 0.40mmol) stirs 2 hours in 0 DEG C, and reaction solution is concentrated to dryness, spare.Residue is dissolved in the dichloro of 10mL Methane is added P-nethoxyaniline (19.8mg, 0.16mmol), n,N-diisopropylethylamine (31mg, 0.24mmol), and stirring is equal It is even, and reacted 5 minutes at 25 DEG C, the progress of TLC monitoring reaction.After reaction, reaction solution is concentrated to dryness, is added a small amount of Methylene chloride dissolution, with thin-layered chromatography respectively with solvent system A and B purify obtained by residue, obtain title product 2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-N- (4- methoxyphenyl) acetamide 13 (6mg, Yellow solid), yield 15.6%.
MS m/z (LC-MS): 478.3 [M+1]
1H NMR (400MHz, CD3OD): δ 7.39-7.43 (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)
Embodiment 14
2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-N- (4- (1- methyl-1 H- Pyrazoles -4- base) phenyl) acetamide
By 2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) acetic acid 12j (90mg, It 0.24mmol) is dissolved in 5mL methylene chloride, and is cooled with an ice bath to 0 DEG C, 1 drop n,N-Dimethylformamide is added, oxalyl is added Chlorine (152mg, 1.2mmol) stirs 2 hours in 0 DEG C, and reaction solution is concentrated under reduced pressure, spare.Residue is dissolved in the dichloromethane of 10mL 4- (1- methyl-1 H- pyrazoles -4- base) aniline 3a (68mg, 0.36mmol, using patent application " WO2010132015 " is added in alkane Disclosed method is prepared), n,N-diisopropylethylamine (93mg, 0.72mmol) stirs evenly, and anti-under the conditions of 25 DEG C It should stay overnight, the progress of TLC monitoring reaction.After reaction, saturated sodium bicarbonate solution and methylene chloride are added into reaction solution Each 50mL, liquid separation, organic phase water, saturated sodium chloride solution wash (30 × 3mL), collect organic phase, and anhydrous sodium sulfate is dry, Filtering, filtrate decompression concentration, with thin-layered chromatography respectively with solvent system A and B purify obtained by residue, obtain title product 2- (3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-N- (4- (1- methyl-1 H- pyrazoles -4- base) Phenyl) acetamide 14 (3mg, white solid), yield 2.4%.
MS m/z (LC-MS): 528.4 [M+1]
1H NMR (400MHz, CD3OD): 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)
Embodiment 15
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formic acid 3- pyridine ester 15
By 4- nitrobenzene pyridin-3-yl carbonic ester 15a (181mg, 0.697mmol, using applying for a patent " Method disclosed in EP1849773A1 " is prepared) it is dissolved in 30mL tetrahydrofuran, it is added 1f (200mg, 0.58mmol), three second Amine (0.243mL, 1.743mmol) is stirred to react 1 hour at 25 DEG C.After reaction, reaction solution is concentrated under reduced pressure, using efficient Title product 15 (64mg, faint yellow solid), yield 23.7% is prepared in liquid chromatography.
MS m/z (ESI): 465.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.70 (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)
Embodiment 16
N- (4- (1H- pyrazoles -4- base) phenyl) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperazine Pyridine -1- formamide
The first step
4- (1- (tetrahydro -2H- pyrans -2- base) -1H- pyrazoles -4- base) aniline
By 1- (tetrahydro -2H- pyrans -2- base) -4- (4,4,5,5- tetramethyls -1,3,2- dioxy boron pentane -2- base) -1H- Pyrazoles 16a (1.9g, 6.8mmol, using well known method " Zeitschrift fuer Naturforschung, B:A Journal of Chemical Sciences, 2014,69 (1), 83-97 " are prepared), 4- bromaniline (1.17g, 6.8mmol), [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride (249mg, 0.34mmol), potassium carbonate (1.89g, It 13.7mmol) is added in 30mL dioxane and 6mL water, under argon atmospher, is stirred to react in 100 DEG C 4 hours.After reaction, Filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 4- (1- (tetrahydro -2H- pyrans -2- base) -1H- pyrazoles -4- base) aniline 16b (849mg, Tan solid), yield 51%.
Second step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (tetrahydro -2H- pyrans -2- Base) -1H- pyrazoles -4- base) phenyl) piperidines -1- formamide
Triphosgene (20mg, 0.067mmol) is dissolved in 5mL tetrahydrofuran, 4- (1- (tetrahydro -2H- pyrans -2- is added Base) -1H- pyrazoles -4- base) aniline 16b (42mg, 0.172mmol), 0.06mL triethylamine, in 25 DEG C react 30 minutes, be added (N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine 1f (50mg, 0.45mmol), it is anti-in 25 DEG C It answers 1 hour.After reaction, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with eluant, eluent system A purify gained residue, Obtain title product 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (tetrahydro -2H- pyrans -2- Base) -1H- pyrazoles -4- base) phenyl) piperidines -1- formamide 16c (74mg, white solid), yield 83%.
Third step
N- (4- (1H- pyrazoles -4- base) phenyl) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperazine Pyridine -1- formamide
By 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (tetrahydro -2H- pyrans -2- Base) -1H- pyrazoles -4- base) phenyl) and piperidines -1- formamide 16c (74mg, 0.12mmol) be added 10mL methanol in, be added to first Benzene sulfonic acid (27mg, 0.156mol) is stirred to react 12 hours at 25 DEG C.After reaction, 0.1mL triethylamine is added, it will be anti- Answer liquid to be concentrated under reduced pressure, with thin-layered chromatography with eluant, eluent system A purify gained residue, obtain title product N- (4- (1H- pyrrole Azoles -4- base) phenyl) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamide 16 (30mg, White solid), yield 47%.
MS m/z (LC-MS): 531.4 [M+1]
1H NMR (400MHz, DMSO-d6) δ 12.83 (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).
Embodiment 17
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- ((1r, 4r) -4- (sulfonyloxy methyl amino methyl) cyclohexyl) -2- carbonyl Base ethanamidine 17
By 11f (79mg, 0.212mmol), reaction flask is added in 1.5mL methylene chloride and triethylamine (89 μ L, 0.637mmol) In, it is added methane sulfonyl chloride (24mg, 0.212mmol), is stirred to react in 25 DEG C 1 hour.After reaction, 50mL dichloro is added Methane is successively washed with saturated sodium bicarbonate solution (50mL × 3), water (50mL × 3), saturated sodium chloride solution (50mL × 2), Organic phase is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by it is residual Excess obtains title product 17 (25mg, faint yellow solid), yield 26.3%.
MS m/z (ESI): 452.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.60 (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),
Embodiment 18
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- ((1r, 4r) -4- (sulphamoylamino) cyclohexyl) second Amidine 18
Using the synthetic route of embodiment 11, first step raw material is replaced with into ((1r, 4r) -4- acetyl butylcyclohexyl) amino T-butyl formate (is prepared) using method disclosed in patent application " WO2012018668 ", be made title product 18 (14mg, Yellow solid).
MS m/z (ESI): 437.3 [M+1]
1HNMR (400MHz, DMSO-d6) 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)
Embodiment 19
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (2- cyanopyridine -4- base) piperidines -1- Formamide 19
Triphosgene (34mg, 0.116mmol) is dissolved in 1.5mL tetrahydrofuran, 0 DEG C of addition 4- amino 2- cyanopyridine 19a (14mg, 0.116mmol are prepared using method disclosed in patent application " WO2001302639 "), triethylamine (48 μ L, 0.349mmol reacts 30 minutes in 0 DEG C, and it is stand-by that reduced pressure reaction solution obtains residue faint yellow solid.By 1f (40mg, It 0.116mmol) is dissolved in 1.5mL tetrahydrofuran, above-mentioned residue is added at 25 DEG C, reacted 2 hours in 25 DEG C.Reaction terminates Afterwards, be added 2mL methanol quenching reaction, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained remnants Object obtains title product 19 (8mg, white solid), yield 14%.
MS m/z (ESI): 491.3 [M+1]
1H NMR (400MHz, DMSO-d6) 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)
Embodiment 20
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- cyclopropyl -1H- pyrazoles -4- Base) phenyl) piperidines -1- formamide
The first step
1- cyclopropyl -4- (4- nitrobenzophenone) -1H- pyrazoles
By 4- (4- nitrobenzene) -1H- pyrazoles 20a (1.0g, 5.3mmol, using well known method " Medicinal Chemistry Research, 2013,22 (11), 5610-5616 " are prepared) it is dissolved in 50mL 1, in 2- dichloroethanes, It is added cyclopropylboronic acid (1.02g, 11.9mmol), copper acetate (111g, 5.57mmol), bipyridyl (869mg, 5.57mmol), Sodium carbonate (1.69g, 15.9mmol), reaction system are reacted 3 hours in 70 DEG C.After reaction, it is cooled to room temperature, is filtered to remove Insoluble matter, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 1- ring Propyl -4- (4- nitrobenzophenone) -1H- pyrazoles 20b (612mg, yellow solid), yield 52.1%.
Second step
4- (1- cyclopropyl -1H- pyrazoles -4- base) aniline
30mL ethyl alcohol and 10mL is added in 1- cyclopropyl -4- (4- nitrobenzophenone) -1H- pyrazoles 20b (1.6g, 7.0mmol) In water, addition iron powder (784mg, 14.0mmol) and ammonium chloride (1.5g, 28.0mmol), back flow reaction 2 hours.Reaction terminates Afterwards, reaction solution is concentrated under reduced pressure and removes ethyl alcohol, methylene chloride 50mL is added, be filtered to remove insoluble matter, silicon is used in filtrate decompression concentration Rubber column gel column chromatography purifies gained residue with eluant, eluent system B, obtains title product 4- (1- cyclopropyl -1H- pyrazoles -4- base) benzene Amine 20c (1.33g, yellow solid), yield 95.6%.
Third step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- cyclopropyl -1H- pyrazoles -4- Base) phenyl) piperidines -1- formamide
Triphosgene (18mg, 0.06mmol) is dissolved in 10mL tetrahydrofuran, 4- (1- cyclopropyl -1H- is added at one time Pyrazoles -4- base) aniline 20c (35mg, 0.17mmol), triethylamine (53mg, 0.32mmol) is added, is stirred to react 30 at room temperature Minute.(N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine 1f is added into reaction solution (50mg, 0.145mmol) is stirred to react 1 hour at room temperature.After reaction, reaction solution is concentrated under reduced pressure, uses thin-layered chromatography Gained residue is purified with eluant, eluent system A, obtains title product 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) second Acyl group)-N- (4- (1- cyclopropyl -1H- pyrazoles -4- base) phenyl) piperidines -1- formamide 20 (30mg, white solid), yield 36.5%.
MS m/z (LC-MS): 569.4 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.63 (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)
Embodiment 21
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (difluoromethyl) -1H- pyrrole Azoles -4- base) phenyl) piperidines -1- formamide
The first step
1- (difluoromethyl) -4- (4- nitrobenzophenone) -1H- pyrazoles
By 4- (4- nitrobenzene) -1H- pyrazoles 20a (1.0g, 5.28mmo), 6 ether of 18- crown- (279mg, 1.05mmol) dissolution In 40mL acetonitrile, difluoro sodium chloroacetate (0.967g, 6.34mmol) is added into reaction solution, under argon atmospher, reaction solution heating To reflux, it is stirred to react 18 hours.Reaction solution is cooled to room temperature, and filtering, filter cake is washed with ethyl acetate, collects filtrate, filtrate Be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 1- (difluoromethyl)- 4- (4- nitrobenzophenone) -1H- pyrazoles 21a (680mg, faint yellow solid), yield 54%.
Second step
4- (1- (difluoromethyl) -1H- pyrazoles -4- base) aniline
1- (difluoromethyl) -4- (4- nitrobenzophenone) -1H- pyrazoles 21a (3g, 12.54mmol) is dissolved in 130mL ethyl alcohol With the in the mixed solvent of water (V: V=10: 3).Iron powder (1.4g, 25.08mmol), ammonium chloride are sequentially added into reaction solution (2.68g, 50.17mmol).Reaction solution is warming up to 80 DEG C, is stirred to react 2 hours.After reaction, reaction solution is cooled to room Temperature is concentrated under reduced pressure, and ethyl acetate and a small amount of methanol, pad diatomite filtering are added in residue, and filter cake is washed with ethyl acetate, received Collect filtrate, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 4- (1- (difluoromethyl) -1H- pyrazoles -4- base) aniline 21b (2.35g, faint yellow solid), yield 89.7%.
Third step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (difluoromethyl) -1H- pyrrole Azoles -4- base) phenyl) piperidines -1- formamide
Triphosgene (207mg, 0.7mmol) is dissolved in 100mL tetrahydrofuran, 4- (1- (difluoromethyl)-is gradually added 1H- pyrazoles -4- base) aniline 21b (382mg, 1.83mmol) and triethylamine (528mg, 5.23mmol), it is stirred to react 30 at room temperature Minute.(N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (piperidin-4-yl) ethanamidine 1f is added into reaction solution (600g, 1.74mmol) is stirred to react 1 hour at room temperature.After reaction, 20mL methanol is added to be quenched, is concentrated under reduced pressure, use is thin Layer chromatography purifies gained residue with eluant, eluent system A, obtains title product 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (difluoromethyl) -1H- pyrazoles -4- base) phenyl) piperidines -1- formamide 21 (160mg, white Solid), yield 15.8%.
MS m/z (LC-MS): 579.4 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.69 (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)
Embodiment 22
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) fluoro- N- Phenylpiperidine -1- formamide of -4-
The first step
1- (tertbutyloxycarbonyl) -4- fluorine resources -4- formic acid 22b
22a (2g, 7.63mmol) is dissolved in 30mL ethyl alcohol, the sodium hydroxide solution of 9.5mL 2M, 60 DEG C of stirrings are added Reaction 2 hours.After reaction, reaction solution is concentrated under reduced pressure, and 1M salt acid for adjusting pH is added less than 7, and ethyl acetate extracts three times, closes And organic phase, anhydrous sodium sulfate dry, filter, filtrate decompression is concentrated to give crude title product 22b (1.78g, white solid), is received Rate 94%.
Second step
tert-butyl 4-fluoro-4-(methoxy(methyl)carbamoyl)piperidine-1- carboxylate
The fluoro- 4- of 4- (methoxyl group (methyl) carbamoyl) piperidines -1- t-butyl formate 22c
Crude product 22b (1.78g, 7.2mmol) is dissolved in 40mL methylene chloride, catalytic amount n,N-Dimethylformamide is added And 0.9mL oxalyl chloride, it is stirred to react at room temperature 0.5 hour, reaction solution is concentrated under reduced pressure spare.40mL dichloro is added in residue Methane is added N, O- dimethyl hydroxylamine hydrochloride (0.843g, 8.64mmol) and 3mL triethylamine, it is small to be stirred to react 1 at room temperature When.After reaction, reaction solution be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title Product 22c (1.3g, colourless liquid), yield 62%.
Third step
4- acetyl group -4- fluorine resources -1- t-butyl formate 22d
22c (1.3g, 4.48mmol) is dissolved in 15mL tetrahydrofuran, ice bath, the methyl-magnesium-bromide of 1.8mL 3M is added Solution is stirred to react 1 hour at 0 DEG C, adds 0.45mL methyl magnesium bromide solution, be stirred to react at 0 DEG C 0.5 hour.Reaction knot Saturated ammonium chloride solution quenching reaction, liquid separation is added in Shu Hou, and water phase is extracted with ethyl acetate three times, merges organic phase.Anhydrous sulphur Sour sodium dries, filters, filtrate decompression concentration, purify gained residue with silica gel column chromatography with eluant, eluent system B, obtained title Product 22d (930mg, colourless liquid), yield 84%.
4th step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) fluoro- N- Phenylpiperidine -1- formamide 22 of -4-
Using the synthetic route of embodiment 1, first step raw material 4- Acetylpiperidin -1- t-butyl formate is replaced with into 22d, It is reacted by number step and title product 22 (40mg, white solid), yield 48% is made.
MS m/z (LC-MS): 481.3 [M+1]
Embodiment 23
2- ((1r, 3r) -3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-N- (4- (1- Methyl-1 H- pyrazoles -4- base) acetamide 23
12j (30mg, 0.08mmol) is dissolved in 8mL methylene chloride, is cooled to 0 DEG C, 1 drop N, N- dimethyl formyl is added Amine is added oxalyl chloride (51mg, 0.40mmol), stirs 2 hours in 0 DEG C, reaction solution is concentrated to dryness, spare.Residue is dissolved in The methylene chloride of 8mL is added 1- methyl-1 H- pyrazoles -4- amine (16mg, 0.16mmol), n,N-diisopropylethylamine (31mg, 0.24mmol), it stirs evenly, and is reacted 5 minutes at 25 DEG C.After reaction, saturated sodium bicarbonate solution is added, water, satisfies With sodium chloride solution, each 30mL of methylene chloride, liquid separation is successively washed with water (30mL × 3), saturated sodium chloride solution (30mL × 3) Wash, organic phase is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify it is residual Excess obtains faint yellow solid, with high performance liquid chromatography preparative separation obtained solid, obtains title product 23 (5mg, white Solid), yield 13.9%.
MS m/z (LC-MS): 452.3 [M+1]
1H NMR (400MHz, CD3OD) 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)
Embodiment 24
N- (the bromo- 4- fluorophenyl of 3-) -2- (1- (3,4- difluorophenyl) piperidin-4-yl)-N '-hydroxyl -2- carbonyl ethanamidine 24
1f (200mg, 0.58mmol) is dissolved in 20mL methylene chloride, addition 3,4- difluoro phenyl boric acid (270mg, 2.32mmol), copper acetate (140mg, 1.16mmol), triethylamine (230mg, 2.32mmol) react 16 hours in 25 DEG C.Reaction After, be filtered to remove insoluble matter, filtrate decompression concentration, with high performance liquid chromatography purify obtained by residue, obtain title product 24 (3mg, yellow liquids), yield 1.91%.
MS m/z (LC-MS): 456.3 [M+1]
1H NMR (400MHz, CD3OD) δ 6.99-7.10 (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).
Embodiment 25
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cycloheximide -1- t-butyl formate
The first step
4- (methoxyl group (methyl) carbamoyl) cycloheximide -1- t-butyl formate 25b
By 1- (tertbutyloxycarbonyl) cycloheximide -4- formic acid 25a (360mg, 1.48mmol, using well known method " Angewandte Chemie, International Edition, 2013,52 (23), 6072-6075 " are prepared) it is added It in reaction flask, is added I-hydroxybenzotriazole (240mg, 1.78mmol), 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne two is sub- Amine hydrochlorate (341mg, 1.78mmol), triethylamine (448mg, 4.44mmol), N, O- dimethyl hydroxylamine hydrochloride (216mg, 2.22mmol), 10mL methylene chloride is added, reacts 16 hours at room temperature.After reaction, 30mL water, liquid separation is added, water layer is used Methylene chloride extraction, saturated sodium chloride solution washing, anhydrous sodium sulfate dry, filter, and silica gel column chromatography is used in filtrate decompression concentration Method purifies gained residue with eluant, eluent system A, obtains title product 25b (356mg, colorless oil), yield 84.1%
Second step
4- acetyl group cycloheximide -1- t-butyl formate 25c
25b (350mg, 1.22mmol) is added in reaction flask, 10mL tetrahydrofuran is added, ice water is cooling, and bromination is added dropwise Methyl magnesium (0.6mol, 1.83mmol), is added dropwise, and 0 DEG C is reacted 1 hour.After reaction, 50mL water, ethyl acetate is added Extraction, organic phase wash (50mL × 3) with saturated sodium chloride solution, and anhydrous sodium sulfate dries, filters, and filtrate decompression concentration is used Silica gel column chromatography purifies gained residue with eluant, eluent system A, obtains title product 25c (220mg, light yellow oil), produces Rate 74.5%
Third step
4- (2- carbonyl acetyl group) cycloheximide -1- t-butyl formate 25d
Selenium dioxide (203mg, 1.82mol) is placed in a reaction flask, 10mL Isosorbide-5-Nitrae-dioxane, 25c is added (220mg, 0.91mmol) reacts 6 hours in 80 DEG C.After reaction, it is filtered to remove insoluble matter, water 30mL, acetic acid second is added Ester extraction, is washed with saturated sodium chloride solution, merges organic phase, and anhydrous sodium sulfate dries, filters, and filtrate decompression concentration obtains Crude title product 25d (300mg, red oil), product directly carry out next step reaction without further purification.
4th step
4- (2- (oximido) acetyl group) cycloheximide -1- t-butyl formate 25e
Crude product 25d (233mg, 0.91mol) is dissolved in 20mL methanol, is added potassium carbonate (189mg, 1.37mmol), in 0 It DEG C is stirred to react 10 minutes, hydroxylamine hydrochloride (32mg, 0.46mmol) is added portionwise, is stirred to react at 0 DEG C 1 hour.Reaction knot Shu Hou, is filtered to remove insoluble matter, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain Title product 25e (120mg, brown oil), yield 48.7%.
5th step
4- (2- chloro- 2- (oximido) acetyl group) cycloheximide -1- t-butyl formate 25f
25e (120mg, 0.44mmol) is added in 5mL n,N-Dimethylformamide, N- chlorosuccinimide is added (62mg, 0.47mmol) is stirred to react 1.5 hours at 25 DEG C.After reaction, 20mL water is added, is extracted with ethyl acetate (20mL × 3) merge organic phase, and organic phase washs (50mL × 3) with saturated sodium chloride solution, and anhydrous sodium sulfate dries, filters, Filtrate decompression concentration, obtains crude title product 25f (103mg, yellow oil), and product directly carries out in next step without further purification Reaction.
6th step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cycloheximide -1- t-butyl formate 25
5mL ethyl alcohol is added in the bromo- 4- fluoroaniline (125mg, 0.66mmol) of crude product 25f (100mg, 0.33mmol) and 3- In, it is stirred to react at 25 DEG C 16 hours.After reaction, reaction solution is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent System B purifying gained residue, obtains title product 25 (32mg, white solid), yield 21.2%.
MS m/z (ESI): 458.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 7.27-7.00 (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).
Embodiment 26
N- (the bromo- 4- fluorophenyl of 3-) -2- (3- (4- cyano-benzene oxygen) cyclobutyl)-N '-hydroxyl -2- carbonyl ethanamidine
The first step
3- hydroxy-n-methoxy-. N-methyl cyclobutane -1- formamide 26a
N- methoxy-. N-methyl -3- carbonyl ring fourth formamide 12a (2.0g, 12.7mmol) is dissolved in 40mL methanol, is added Enter sodium borohydride (0.97g, 25.5mmol), reacts 1 hour at room temperature.After reaction, a small amount of water quenching reaction is added, depressurizes Concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 26a (1.9g, colorless oil Object), yield 70%.
Second step
3- (4- cyano-benzene oxygen)-N- methoxy-. N-methyl cyclobutane -1- formamide 26b
26a (251mg, 2.11mmol) is dissolved in methylene chloride, is added 4-hydroxybenzonitrile (337mg, 2.11mmol), three Phenylphosphine (663mg, 2.53mmol), ice bath are added diisopropyl azodiformate (511mg, 2.53mmol), are warmed to room temperature, It is stirred to react 1 hour.After reaction, reaction solution be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by it is residual Excess obtains title product 26b (140mg, white solid), yield 25.5%.
Third step
4- ((3- acetyl tetramethylcyclobutyl) methyl) benzonitrile 26c
26b (140mg, 0.538mmol) is added in 2mL tetrahydrofuran, ice bath is cooled to 0 DEG C, and 3.0M methyl bromide is added dropwise Change magnesium solution (0.4mL, 1.076mmol), 25 DEG C are stirred 2 hours, there is white solid precipitation.After reaction, water, acetic acid is added Ethyl ester extraction, merges organic phase, and anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent body It is B purifying gained residue, obtains title product 26c (60mg, white solid), yield 52%.
4th step
N- (the bromo- 4- fluorophenyl of 3-) -2- (3- (4- cyano-benzene oxygen) cyclobutyl)-N '-hydroxyl -2- carbonyl ethanamidine 26
Using the synthetic route of 25 third of embodiment to six steps, raw material 25c is replaced with into 26c, is made by number step reaction Title product 26 (15mg, clear yellow viscous object), yield 15%.
MS m/z (LC-MS): 432.2 [M+1]
Embodiment 27
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- benzyl formate 27
1f (103mg, 0.3mmol) is dissolved in 30mL tetrahydrofuran, is added triethylamine (59mg, 0.58mmol), ice water It is cooling, the tetrahydrofuran solution of prefabricated 10mL benzyl chloroformate (54mg, 0.32mmol) is added dropwise, it is small to be stirred to react 2 at 0 DEG C When.After reaction, 20mL water is added in reaction solution, and ethyl acetate extracts (10mL × 4), saturated sodium chloride solution (50mL × 1) Washing, anhydrous magnesium sulfate dry, filter, filtrate decompression concentration.It is remaining that gained purified with eluant, eluent system A with silica gel column chromatography Title product 27 (21mg, white solid), yield 15.2% is made in object.
MS m/z (LC-MS): 478.2 [M+1]
Embodiment 28
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- (1- (4- nitrobenzophenone) piperidin-4-yl) -2- carbonyl ethanamidine 28
P-fluoronitrobenzene 28a (81.9mg, 0.58mmol) is dissolved in 2mL n,N-Dimethylformamide, 1f is added (200mg, 0.58mmol), n,N-diisopropylethylamine (149.9mg, 1.16mmol), 60 DEG C are stirred to react 1 hour.Reaction knot 40mL water is added in Shu Hou, reaction solution, and ethyl acetate extracts (15mL × 3), merges organic phase, saturated sodium chloride solution washing (20mL × 2), anhydrous sodium sulfate dries, filters, filtrate decompression concentration.Institute is purified with eluant, eluent system B with silica gel column chromatography Residue is obtained, title product 28 (100mg, yellow solid), yield 37.1% are obtained.
MS m/z (LC-MS): 465.3 [M+1]
1HNMR (400MHz, CDCl3) 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).
Embodiment 29
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- (1- (4- (1- methyl-1 H- pyrazoles -4- base) -2- nitrobenzophenone) piperazine Pyridine -4- base) -2- carbonyl ethanamidine 29
Using the synthetic route of embodiment 28, raw material is replaced with into 4- (the fluoro- 3- nitrobenzene of 4-) -1- methyl-1 H- pyrazoles (being prepared using method disclosed in patent application " WO2013053983 "), is made title product 29 (13mg, red solid), Yield 15.9%.
MS m/z (LC-MS): 545.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 30
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- ethyl -1H- pyrazoles -4- base) Phenyl) piperidines -1- formamide
The first step
1- ethyl -4- (4- nitrobenzophenone) -1H- pyrazoles 30a
20a (100mg, 0.53mmo) is dissolved in 5mL n,N-Dimethylformamide, 60% sodium hydride of addition (25mg, 0.63mmol), it stirs 1 hour for 25 DEG C, iodoethane (99mg, 0.63mmol) is added into reaction solution, reaction continues to be stirred to react 1 Hour.After reaction, water is added, is extracted with ethyl acetate 3 times, merging organic phase, water washing 3 times, saturated sodium chloride solution Washing 1 time, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with thin-layered chromatography with eluant, eluent system B purify obtained by it is residual Excess obtains title product 30a (90mg, yellow oil), yield 79%.
Second step
4- (1- ethyl -1H- pyrazoles -4- base) aniline 30b
30a (90mg, 0.4mmol) is added in 12mL ethyl alcohol and 3mL water, iron powder (93mg, 1.66mmol) and chlorine is added Change ammonium (177mg, 3.3mmol), is stirred to react in 75 DEG C 2 hours.After reaction, reaction solution is concentrated under reduced pressure, acetic acid is added Ethyl ester is washed with water, and saturated sodium chloride solution washing, anhydrous sodium sulfate is dry, obtains crude title product 30b (60mg, rufous Solid), yield 78%.
Third step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- ethyl -1H- pyrazoles -4- base) Phenyl) piperidines -1- formamide 30
Triphosgene (32mg, 0.174mmol) is dissolved in 50mL tetrahydrofuran, be added prefabricated 1mL30b (32mg, Tetrahydrofuran solution 0.174mmol) is added triethylamine (18mg, 0.06mmol), is stirred to react at room temperature 1 minute, and 1f is added (50mg, 0.145mmol) is stirred to react 1 hour at room temperature.After reaction, reaction solution is concentrated under reduced pressure, uses thin-layered chromatography Gained residue is purified with eluant, eluent system A, obtains title product 30 (35mg, white solid), yield 43%.
MS m/z (ESI): 557.4 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.69 (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).
Embodiment 31
N- (6- (1H- tetrazole -1- base) pyridin-3-yl) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) second Acyl group) piperidines -1- formamide
The first step
5- nitro -2- (1H-TETRAZOLE -1- base) piperidines 31c
1H- tetrazole 31a (700mg, 10mmol) is dissolved in 100mL acetonitrile, 2- chloro-5-nitropyridine 31b is added (1.74g, 11mmol) and potassium carbonate (1.38g, 10mmol), 90 DEG C are stirred 5 hours.After reaction, it is cooled to room temperature, mistake Filter, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 31c (0.60g, faint yellow solid), yield 31%.
Second step
6- (1H-TETRAZOLE -1- base) pyridine -3- amine 31d
31c (600mg, 3.1mmol) is dissolved in 20mL ethyl acetate, the palladium carbon of 120mg 10% is added, hydrogen is set It changes three times, is stirred to react in 25 DEG C 2 hours.After reaction, it filters, filtrate decompression concentration obtains crude title product 31d (460mg, faint yellow solid), product directly carry out next step reaction without further purification.
Third step
N- (6- (1H-TETRAZOLE -1- base) pyridin-3-yl) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl Base) piperidines -1- formamide 31
Triphosgene (30mg, 0.185mmol) is dissolved in 10mL tetrahydrofuran, addition crude product 31d (30mg, 0.185mmol), triethylamine (0.15mL, 1.08mmol) is added, is stirred to react at room temperature 30 minutes.It is added into reaction solution 1f (50mg, 0.145mmol) is stirred to react 1 hour at room temperature.After reaction, reaction solution is concentrated under reduced pressure, uses thin-layer chromatography Method purifies gained residue with solvent system A, obtains title product 31 (25mg, white solid), yield 32%.
MS m/z (ESI): 532.4 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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).
Embodiment 32
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (2- picoline -4- base) benzene Base) piperidines -1- formamide
The first step
2- methyl -4- (4- nitrobenzophenone) pyridine 32c
By 4- bromine-2-methylpyridine 32a (260mg, 1.5mmol), 4- nitrobenzene boronic acid 32b (250mg, 1.5mmol), 10mL is added in [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride (55mg, 0.075mmol), potassium carbonate (414mg, 3mmol) In dioxane and 1mL water, under argon atmospher, it is stirred to react in 105 DEG C 4 hours.After reaction, it is cooled to room temperature, filters, filter Liquid is concentrated under reduced pressure, and purify gained residue with thin-layered chromatography with solvent system B, be made title product 32c (260mg, it is white Solid), yield 81%.
Second step
4- (2- picoline -4- base) amine 32d
32c (260mg, 1.2mmol) is dissolved in 20mL ethyl acetate, 10% palladium carbon of 52mg, hydrogen displacement three is added It is secondary, it is stirred to react in 25 DEG C 2 hours.After reaction, filter, filtrate decompression concentration, obtain crude title product 32d (220mg, Faint yellow solid), crude product directly carries out next step reaction without further purification.
Third step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (2- picoline -4- base) benzene Base) piperidines -1- formamide 32
Triphosgene (20mg, 0.07mmol) is dissolved in 10mL tetrahydrofuran, addition crude product 32d (32mg, 0.174mmol), triethylamine (53mg, 0.52mmol) is added, is stirred to react at room temperature 1 hour.1f is added into reaction solution (53mg, 0.52mmol) is stirred to react 1 hour at room temperature.After reaction, reaction solution is concentrated under reduced pressure, uses thin-layered chromatography Gained residue is purified with solvent system A, obtains title product 32 (20mg, faint yellow solid), yield 25%.
MS m/z (LC-MS): 554.5 [M+1]
Embodiment 33
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- (4- methyl-1 H-imidazole-1-group) Pyridin-3-yl) piperidines -1- formamide
The first step
2- (4- methyl-1 H-imidazole-1-group) -5- nitropyridine 33c
The bromo- 5- nitropyridine 33a (500mg, 2.46mmol) of 2- is dissolved in 5mL n,N-Dimethylformamide, 4- is added Methyl-1 H- imidazoles 33b (0.81g, 9.86mmol), potassium carbonate (1.02g, 7.39mmol) react 16 hours at room temperature.Reaction After, reaction solution pours into 200mL water, and filtering, filter cake is washed with water, and ethyl acetate dissolving filter cake, anhydrous sodium sulfate is added It dries, filters, is concentrated under reduced pressure, obtains crude title product 33c (478mg, white solid), product is directly anti-in next step without further purification It answers.
Second step
6- (4- methyl-1 H-imidazole-1-group) pyridine -3- amine 33d
Crude product 33c (478mg, 2.34mmol) is dissolved in 20mL methanol, addition two water of stannous chloride (1.8g, 7.97mmol), it is stirred to react in 70 DEG C 5 hours.After reaction, it filters, the first of 1N sodium hydroxide is added in filtrate decompression concentration Alcoholic solution is concentrated under reduced pressure to pH > 7, the mixed solvent of 100mL methylene chloride and methanol (V: V=10: 1), filtering, filter cake is added It is washed with the mixed solvent of methylene chloride and methanol (V: V=10: 1), filtrate decompression concentration, with thin-layered chromatography with solvent body It is A purifying gained residue, obtains title product 33d (310mg, faint yellow solid), yield 76%.
Third step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- (4- methyl-1 H-imidazole-1-group) Pyridin-3-yl) piperidines -1- formamide 33
Triphosgene (21mg, 0.07mmol) is dissolved in 10mL tetrahydrofuran, be added prefabricated 1mL 33d (30mg, Tetrahydrofuran solution 0.172mmol) adds triethylamine (0.1mL, 0.72mmol), is stirred to react at room temperature 30 minutes.To 1f (50mg, 0.145mmol) is added in reaction solution, is stirred to react at room temperature 1 hour.After reaction, reaction solution is depressurized dense Contracting, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 33 (40mg, white yellow solid), receipts Rate 52%.
MS m/z (LC-MS): 544.5 [M+1]
Embodiment 34
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1-N- (tetrahydro -2H- pyrans -4- base) aminosulfonyl Base) piperidin-4-yl) ethanamidine 34
Using the synthetic route of embodiment 4, first step raw material is replaced with into (tetrahydro -2H- pyrans -4- base) aminosulfonyl Title product 34 (9mg, yellow solid), yield 15.2% is made in chlorine.
MS m/z (ESI): 507.4 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 35
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- morpholine pyridin-3-yl) piperidines -1- Formamide 35
Using the synthetic route of embodiment 31, first step raw material is replaced with into morpholine, be made title product 35 (27mg, it is white Color solid), yield 34%.
MS m/z (ESI): 549.5 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.67 (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)
Embodiment 36
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (1- phenyl -1H- pyrazoles -4- base) piperazine Pyridine -1- formamide 36
Using the synthetic route of embodiment 19, raw material 19a is replaced with into 1- phenyl -1H- pyrazoles -4- amine, title is made and produces Object 36 (10mg, white solid), yield 10%.
MS m/z (LC-MS): 529.4 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 37
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (2- ethoxy) -1H- pyrrole Azoles -4- base) phenyl) piperidines -1- formamide
The first step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (2- ((tetrahydro -2H- pyrans - 2- yl) oxygroup) ethyl) -1H- pyrazole-3-yl) phenyl) piperidines -1- formamide 37a
Using the synthetic route of embodiment 30, first step raw material is replaced with into (2- bromine oxethyl)-tert-butyldimethyl silyl Alkane (is prepared) using method disclosed in patent application " WO2012084683 ", reacts by number step and title product 37a is made (70mg, white solid), yield 64%.
Second step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (2- ethoxy) -1H- pyrrole Azoles -4- base) phenyl) piperidines -1- formamide 37
37a (70mg, 0.1mmol) is dissolved in 10mL tetrahydrofuran, addition tetrabutyl ammonium fluoride solution (0.15mL, 0.15mmol), it is stirred to react 1 hour for 25 DEG C.After reaction, it is concentrated under reduced pressure, is purified with thin-layered chromatography with solvent system A Gained residue obtains title product 37 (20mg, off-white powder), yield 34%.
MS m/z (ESI): 573.4 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.72 (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)
Embodiment 38
2- (1- (benzo [d] thiazol-2-yl) piperidin-4-yl)-N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl second Amidine 38
Using the synthetic route of embodiment 28, raw material is replaced with into 2- chloro benzothiazole, be made title product 38 (16mg, Yellow solid), yield 38.1%.
MS m/z (ESI): 477.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 8.39 (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)
Embodiment 39
N- ((3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) methyl) benzamide
The first step
2- (3- acetyl tetramethylcyclobutyl) acetic acid 39a
By in raw material 12d (5g, 0.027mol) addition 50mL tetrahydrofuran, 10mL methanol, 5mL water, a hydronium(ion) is added Lithia (2.28g .054mol) is stirred to react 16 hours at room temperature.After reaction, reaction solution is concentrated under reduced pressure, and water is added, With 1M salt acid for adjusting pH to 3, ethyl acetate is extracted three times, merges organic phase, saturated sodium chloride solution washed once, anhydrous slufuric acid Sodium dries, filters, and filtrate decompression concentration obtains crude title product 39a (4.1g, weak yellow liquid), product is direct without further purification It reacts in next step.
Second step
((3- acetyl cyclobutyl) methyl) t-butyl carbamate 39b
Crude product 39a (4.1g, 0.026mol) is dissolved in 50mL toluene, the 12.5mL tert-butyl alcohol, 15.5mL triethylamine is added And 6.8mL diphenyl phosphate azide, 90 DEG C are stirred to react 16 hours.After reaction, reaction solution is concentrated under reduced pressure, and uses silicagel column Chromatography purifies gained residue with eluant, eluent system B, is made title product 39b (2g, weak yellow liquid), yield 34%.
Third step
((3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- oximido) acetyl group) cyclobutyl) methyl) t-butyl carbamate 39c
Using the synthetic route of embodiment 25, first step raw material is replaced with into ((3- acetyl cyclobutyl) methyl) carbamic acid Crude title product 39c (280mg, brown-red oil) is made by three-step reaction in tert-butyl ester 39b, and product is straight without further purification Row is tapped into react in next step.
4th step
2- (3- (aminomethyl) cyclobutyl)-N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl ethanamidine 39d
Crude product 39c (100mg, 0.22mmol) is placed in a reaction flask, 10mL methanol is added, the hydrogen chloride of 1mL4M is added Isosorbide-5-Nitrae-dioxane is stirred to react 1 hour at 25 DEG C.After reaction, reaction solution is concentrated under reduced pressure, obtains crude title production Object 39d (70mg, red brown solid), product directly carry out next step reaction without further purification.
5th step
N- ((3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) methyl) benzamide 39
Crude product 39d (70mg, 0.2mmol) is dissolved in 10mL methylene chloride, is added triethylamine (62mg, 0.6mmol), drop Add chlorobenzoyl chloride (14mg, 0.1mmol), is stirred to react at 25 DEG C 1 hour.After reaction, 5mL water, dichloro is added in reaction solution Methane extracts (10mL × 3), merges organic phase, and saturated sodium chloride solution washed once, and anhydrous sodium sulfate dries, filters, filtrate It is concentrated under reduced pressure, gained residue purify with solvent system A with thin-layered chromatography, (10mg, yellow are solid for obtained title product 39 Body), yield 11%.
MS m/z (LC-MS): 448.3 [M+1]
Embodiment 40
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (methylcarbamoyl) phenyl) Piperidines -1- formamide
The first step
4- Amino-N-methyl benzamide 40b
Raw material 40a (1.1g, 7.07mmol) is dissolved in 10mL tetrahydrofuran, 14.1mL 2M methylamine tetrahydrofuran is added Solution is stirred to react 1 hour at room temperature.After reaction, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system B Purifying gained residue, is made title product 40b (672mg, light yellow oil), yield 63%.
Second step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (methylcarbamoyl) phenyl) Piperidines -1- formamide 40
Using the synthetic route of embodiment 19, raw material is replaced with into 40b, title product 40 (25mg, yellow solid) is made, Yield 32.9%.
MS m/z (ESI): 520.4 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.67 (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)
Embodiment 41
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (tetrahydro -2H- pyrans -4- base) piperidines - 1- formamide 41
Using the synthetic route of embodiment 19, raw material is replaced with into tetrahydro -2H- pyrans -4- amine, title product 41 is made (44mg, yellow solid), yield 64%.
MS m/z (LC-MS): 471.1 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.65 (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)
Embodiment 42
(2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (pyridine -2- base) piperidines -1- formamide 42
Using the synthetic route of embodiment 19, raw material is replaced with into 2-aminopyridine, title product 42 (5mg, yellow is made Solid), yield 9.2%.
MS m/z (LC-MS): 464.0 [M+1]
Embodiment 43
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- ((1r, 3r) -3- ((sulphamoylamino) methyl) ring Butyl) ethanamidine 43
Using the synthetic route of embodiment 4, raw material 1f is replaced with into 39d, title product 43 is made, and (2.1mg, white are solid Body), yield 6%.
MS m/z (ESI): 423.2 [M+1]
Embodiment 44
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- amino-sulfonyl cycloheximide -4- base) ethanamidine
The first step
2- (cycloheximide -4- base)-N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl ethanamidine 44a
25 (28mg, 0.061mmol) are added in hydrochloric acid Isosorbide-5-Nitrae-dioxane of 5mL 4N, are reacted 2 hours at room temperature.Instead It after answering, is concentrated under reduced pressure, obtains crude title product 44a (30mg, yellow solid), product directly carries out in next step without further purification Reaction.
Second step
(4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) cycloheximide -1- base) sulfuryl amino first Tert-butyl acrylate 44b
Isocyanic acid chlorosulfonic acid ester (10mg, 0.073mmol) is dissolved in 5mL methylene chloride, at 0 DEG C, is added dropwise prefabricated The dichloromethane solution of the 1mL tert-butyl alcohol (6mg, 0.073mmol) is stirred to react 30 minutes to obtain reserve liquid a.It is added in reaction flask The dichloromethane solution of prefabricated 2mL crude product 44a (21mg, 0.061mmol), is added dropwise above-mentioned reserve liquid a, reaction 1 is stirred at room temperature Hour.After reaction, water 20mL is added, is extracted with dichloromethane, saturated sodium chloride solution washing, anhydrous magnesium sulfate is dry, Filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 44b (15mg, white solid), yield 46.8%.
Third step
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- amino-sulfonyl cycloheximide -4- base) ethanamidine 44
44b (15mg, 0.03mmol) is dissolved in 5mL methylene chloride, 5mL trifluoroacetic acid is added, reaction system is in 25 DEG C It is stirred to react 2 hours.After reaction, be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, Obtain title product 44 (7mg, white solid), yield 41.6%.
MS m/z (ESI): 437.2 [M+1]
1H NMR (400MHz, CD3OD) δ 6.98-7.04 (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).
Embodiment 45
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- ((2- ethoxy) amino) pyridine - 3- yl) piperidines -1- formamide
The first step
N- (2- ((t-Butyldimethylsilyl) oxygroup) ethyl) -5- nitropyridine -2- amine 45b
By 2- ((5- nitropyridine -2- base) amino) ethyl alcohol 45a (0.5g, 2.732mmol, using patent application Method disclosed in " WO2013013815 " is prepared) it is dissolved in 10mL tetrahydrofuran, it is added imidazoles (0.28g, 4.098mmol) With tert-butyl chloro-silicane (0.49g, 3.279mmol), react 24 hours at 25 DEG C.After reaction, 40mL water is added, It is extracted with ethyl acetate (80mL × 3), merges organic phase, organic phase washed once with saturated sodium chloride solution, anhydrous sodium sulfate It dries, filters, filtrate decompression is concentrated to give title product 45b (590mg, yellow solid), yield 72.7%.Product is straight without further purification It connects and reacts in next step.
Second step
(2- ((t-Butyldimethylsilyl) oxygroup) ethyl)-(5- nitropyridine -2- base) t-butyl carbamate 45c
Crude product 45b (0.5g, 1.68mmol) is dissolved in 20mL acetonitrile, addition 4-dimethylaminopyridine (0.02g, 0.168mmol) and di-tert-butyl dicarbonate (0.4g, 1.85mmol), it reacts 16 hours at 25 DEG C.After reaction, reaction solution It is concentrated under reduced pressure, silica gel column chromatography purifies gained residue with eluant, eluent system A, obtains title product 45c (600mg, colorless oil Object), yield 89%.
Third step
(5- aminopyridine -2- base) (2- ((t-Butyldimethylsilyl) oxygroup) ethyl) t-butyl carbamate 45d
45c (50mg, 0.126mmol) is dissolved in the in the mixed solvent of 12mL first alcohol and water (V: V=5: 1).To reaction It is sequentially added in liquid iron powder (21mg, 0.377mmol), ammonium chloride (40mg, 0.755mmol).Reaction solution is warming up to 70 DEG C, stirring Reaction 1 hour.After reaction, reaction solution is cooled to room temperature, is concentrated under reduced pressure, be added in residue 20mL ethyl acetate and 15mL water, liquid separation, water phase are extracted with ethyl acetate (20mL × 2), merge organic phase, and organic phase is washed with saturated sodium chloride solution Once, anhydrous sodium sulfate dries, filters, and filtrate decompression concentration is obtained crude title product 45d (45mg, yellow oil), produced Product directly carry out next step reaction without further purification.
4th step
(5- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamido) pyridine -2- Base) (2- ((t-Butyldimethylsilyl) oxygroup) ethyl) t-butyl carbamate 45e
Triphosgene (14mg, 0.0466mmol) is dissolved in 10mL tetrahydrofuran, addition crude product 45d (45mg, 0.122mmol), triethylamine (36mg, 0.352mmol) reacts 30 minutes in 25 DEG C, is added 1f (40mg, 0.117mmol), in 25 DEG C are reacted 1 hour.After reaction, 2mL methanol quenching reaction is added, reaction solution is concentrated under reduced pressure, and obtains crude title product 45e (60mg, yellow oil), product directly carry out next step reaction without further purification
5th step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- ((2- ethoxy) amino) pyridine - 3- yl) piperidines -1- formamide 45
Crude product 45e (60mg, 0.0813mmol) is dissolved in 2mL methanol, the hydrochloric acid solution of 2mL 2M is added, is stirred at 25 DEG C Mix reaction 18 hours.After reaction, pH to 7 is adjusted with saturated sodium bicarbonate solution, ethyl acetate extracts (30mL × 3), closes And organic phase, organic phase washed once with saturated sodium chloride solution 30mL, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, With thin-layered chromatography with solvent system A purify gained residue obtain title product 45 (3mg, white solid), yield 7.05%.
MS m/z (ESI): 523.3 [M+1]
1H NMR (400MHz, CDCl3) δ 7.91 (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)
Embodiment 46
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (1- (mesyl) -1H- pyrazoles -4- Base) piperidines -1- formamide
The first step
4- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamido) -1H- pyrrole Azoles -1- t-butyl formate 46b
At 0 DEG C, triphosgene (129mg, 0.436mmol) is dissolved in 3mL tetrahydrofuran, 4- amino -1H- pyrazoles-is added 1- t-butyl formate 46a (80mg, 0.436mmol, using apply for a patent method disclosed in " " WO2014128465 " " preparation and ), triethylamine (0.304mL, 2.179mmol) reacts 20 minutes in 0 DEG C, and residue is concentrated under reduced pressure to obtain in reaction solution, and 3mL is added Tetrahydrofuran, 1f (150mg, 0.436mmol) are added triethylamine (0.304mL, 2.179mmol), react 1 hour in 25 DEG C.Instead After answering, reaction solution is concentrated under reduced pressure 2mL methanol quenching reaction, with silica gel chromatography with eluant, eluent system A purify gained it is residual Excess is made title product 46b (182mg, yellow solid), yield 44%.
Second step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (1H- pyrazoles -4- base) piperidines -1- first Amide 46c
46b (182mg, 0.329mmol) is dissolved in 4mL methylene chloride, 4mL trifluoracetic acid is added, 25 DEG C are stirred to react 1 Hour.After reaction, reaction solution is concentrated under reduced pressure, and 50mL ethyl acetate and 50mL sodium bicarbonate solution, liquid separation is added, and water phase is used Ethyl acetate extracts (50mL × 2), merges organic phase, is concentrated under reduced pressure, purify with silica gel column chromatography with eluant, eluent system A obtained by Residue obtains title product 46c (143mg, yellow solid), yield 96%.
Third step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (1- (mesyl) -1H- pyrazoles -4- Base) piperidines -1- formamide 46
46c (100mg, 0.221mmol) is dissolved in 4mL methylene chloride, 0.092mL triethylamine is added, is cooled to 0 DEG C, It is added dropwise to methane sulfonyl chloride (25mg, 0.221mmol), 0 DEG C is stirred to react 1 hour.After reaction, 2mL methanol is added to be quenched Reaction, reaction solution be concentrated under reduced pressure, with high performance liquid chromatography purify gained residue, obtain title product 46 (7mg, white admittedly Body), yield 6.0%.
MS m/z (ESI): 531.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 10.86 (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)
Embodiment 47
N- (6- (((1- amino cyclopropyl) methyl) amino) pyridin-3-yl) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) - 2- (oximido) acetyl group) piperidines -1- formamide
The first step
4- toluenesulfonic acid (1- ((tertbutyloxycarbonyl) amino) cyclopropyl) methyl ester 47b
By (1- methylol) cyclopropyl) t-butyl carbamate 47a (2g, 10.68mmol) is dissolved in 50mL methylene chloride, It is added 4-dimethylaminopyridine (1.566g, 12.818mmol), is added paratoluensulfonyl chloride (2.24g, 11.75mmol), 25 DEG C It is stirred to react 3 hours.After reaction, 150mL water is added, is extracted with dichloromethane (100mL × 3), merges organic phase, it is organic It is mutually dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration obtains crude title product 47b (3.5g, yellow solid), product Next step reaction is directly carried out without further purification.
Second step
(1- ((1,3- dicarbapentaborane isoindoline -2- base) methyl) cyclopropyl) t-butyl carbamate 47c
Crude product 47b (3.5g, 10.25mmol) is dissolved in 120mL n,N-Dimethylformamide, 18- crown- 6 is added (2.71g, 10.25mmol) is added potassium phthalimide (2.848g, 15.376mmol), and 50 DEG C to be stirred to react 18 small When.After reaction, 100mL water is added, is extracted with ethyl acetate (100mL × 3), merges organic phase, the anhydrous sulphur of organic phase Sour sodium dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title produce Object 47c (3.19g, yellow solid), yield 98.5%.
Third step
(1- (aminomethyl) cyclopropyl) t-butyl carbamate 47d
47c (3.19g, 10.1mmol) is dissolved in 60mL methanol, is added 85% hydrazine hydrate (773mg, 13.125mmol), Return stirring reacts 18 hours.After reaction, reaction solution is concentrated under reduced pressure, and 500mL methylene chloride is added, and stirs 30 minutes, mistake Filter, filtrate are dried, filtered with anhydrous sodium sulfate, and filtrate decompression concentration obtains crude title product 47d (1.8g, yellow oily Object), product directly carries out next step reaction without further purification.
4th step
(1- (((5- nitropyridine -2- base) amino) methyl) cyclopropyl) t-butyl carbamate 47e
Crude product 47d (1.8g, 9.644mmol) is dissolved in 60mL n,N-Dimethylformamide, the chloro- 5- nitro of 2- is added Pyridine (1.685g, 10.63mmol) is added potassium carbonate (4.001g, 28.992mmol), and 80 DEG C are stirred to react 18 hours.Reaction After, 300mL water is added, is extracted with ethyl acetate (200mL × 3), merging organic phase, organic phase washed with water (300mL × 3), saturated sodium chloride solution (300mL × 2) is washed, and anhydrous sodium sulfate dries, filters, and filtrate decompression is concentrated to get crude title Product 47e (952mg, sepia solid), product directly carry out next step reaction without further purification.
5th step
((1- ((tertbutyloxycarbonyl) amino) cyclopropyl) methyl) (5- nitropyridine -2- base) t-butyl carbamate 47f
47e (0.5g, 1.68mmol) is dissolved in 20mL tetrahydrofuran, is added triethylamine (0.542mL, 3.892mmol), 4-dimethylaminopyridine (16mg, 0.130mmol) and di-tert-butyl dicarbonate (0.566g, 2.594mmol) react 17 at 25 DEG C Hour.After reaction, 100mL water is added, is extracted with ethyl acetate (100mL × 3), merges organic phase, is concentrated under reduced pressure, silica gel Column chromatography purifies gained residue with eluant, eluent system B, obtains title product 47f (305mg, yellow oil), yield 57.5%.
6th step
(5- aminopyridine -2- base) ((1- ((tert-butyl carbonyl) amino) cyclopropyl) methyl) t-butyl carbamate 47g
47f (305mg, 0.747mmol) is dissolved in the in the mixed solvent of 25mL second alcohol and water (V: V=4: 1).To reaction It is sequentially added in liquid iron powder (167mg, 2.987mmol), ammonium chloride (920mg, 5.974mmol).Reaction solution return stirring reaction 1 Hour.After reaction, 100mL water is added in reaction solution, is extracted with ethyl acetate (100mL × 3), merge organic phase, it is organic (200mL × 3) mutually are washed with saturated sodium chloride solution, anhydrous magnesium sulfate dries, filters, and filtrate decompression concentration obtains crude product mark Inscribe product 47g (280mg, pale tan oil), product without further purification directly in next step.
7th step
(5- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamide) pyridine -2- Base) ((1- ((tertbutyloxycarbonyl) amino) cyclopropyl) methyl) t-butyl carbamate 47h
At 0 DEG C, triphosgene (73mg, 0.245mmol) is placed in 50mL single port bottle, prefabricated 3mL is added and contains 47g (92mg, 0.245mmol) and triethylamine (0.171mL, 1.224mmol) tetrahydrofuran solution reacts 30 minutes in 0 DEG C, reaction Liquid is concentrated under reduced pressure to obtain residue, is added 3mL tetrahydrofuran, 1f (84mg, 0.245mmol), be added triethylamine (0.171mL, 1.224mmol), it is reacted 1 hour in 25 DEG C.After reaction, 2mL methanol quenching reaction, reaction solution is concentrated under reduced pressure, and uses thin layer Chromatography purifies gained residue with solvent system A, is made title product 47h (60mg, yellow solid), yield 32.8%.
8th step
N- (6- (((1- amino cyclopropyl) methyl) amino) pyridin-3-yl) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) - 2- (oximido) acetyl group) piperidines -1- formamide 47
47h (60mg, 0.08mmol) is dissolved in 2mL methanol, hydrogen chloride Isosorbide-5-Nitrae-dioxane solution of 2mL4M is added, It is stirred to react at 25 DEG C 4 hours.After reaction, 50mL ethyl acetate is added, washed with saturated sodium bicarbonate solution (30mL × 3), organic phase is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify the obtained title product of gained residue 47 (30mg, Faint yellow solid), yield 68.2%.
MS m/z (ESI): 548.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.67 (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)
Embodiment 48
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- methoxy piperide -1- formamide
The first step
Methoxy carbamate 4- amino phenyl ester 48b
Methoxy amine hydrochlorate (456mg, 5.46mmol) is dissolved in the mixing of 16mL methylene chloride and water (V: V=3: 5) In solvent, it is added sodium bicarbonate (767mg, 9.13mmol), is cooled to 0 DEG C.At 0 DEG C, the 4- ammonia of prefabricated 4mL is added dropwise thereto The dichloromethane solution of base phenyl chloroformate 48a (1g, 4.96mmol) is stirred to react 20min at 0 DEG C.After reaction, mistake Filter, filter cake washing, filter cake is dissolved in ether, and anhydrous sodium sulfate is dry, pressurization concentration, obtain crude title product 48b (700mg, White solid), product directly carries out next step reaction without further purification.
Second step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- methoxy piperide -1- formamide 48
1f (306mg, 0.889mmol) is dissolved in tetrahydrofuran, is cooled to 0 DEG C, be added 136b (198mg, 0.933mmol), it adds trifluoracetic acid (0.5mL, 3.6mmol), is stirred to react at 0 DEG C 2 hours.After reaction, first is added Alcohol, be concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 48 (230mg, white consolidate Body), yield 62%.
MS m/z (ESI): 417.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 49
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamide 49
1f (400mg, 1.16mmol) is dissolved in 30mL tetrahydrofuran solution, 1mL triethylamine is added, is added dropwise to trimethyl Silicon substrate isocyanates (0.19ml, 1.41mmol) is stirred to react 18 hours in 25 DEG C.After reaction, methanol quenching reaction, will Reaction solution be concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 49 (170mg, it is light Yellow solid), yield 38%.
MS m/z (ESI): 387.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.66 (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)
Embodiment 50
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- methyl piperidine -1- formamide 50
Acetic acid (68mg, 1.13mmol) and triethylamine (0.26mL, 1.87mmol) are dissolved in 2mL toluene, nitrine is added Diphenyl phosphate 50a (312mg, 1.13mmol) is sealed at 100 DEG C and is stirred to react 1 hour, after being cooled to room temperature, and ice bath will be anti- It answers drop to be added in the tetrahydrofuran solution of prefabricated 15mL 1f (409mg, 118mmol), is stirred to react at 0 DEG C 1 hour.Instead After answering, be concentrated under reduced pressure reaction solution, with thin-layered chromatography with eluant, eluent system A purify obtained by residue, obtain title product 50 (290mg, white solid), yield 64%.
MS m/z (ESI): 401.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.66 (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)
Embodiment 51
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- carbonamidine 51
1- pyrazoles amitraz hydrochloride 51a (140mg, 0.955mmol) is dissolved in 10mL n,N-Dimethylformamide, is added Enter 1f (300mg, 0.87mmol), n,N-diisopropylethylamine (0.3mL, 1.69mmol), 25 DEG C are stirred to react 60 hours.Reaction After, reaction solution is concentrated under reduced pressure, and purify gained residue with high performance liquid chromatography, obtain title product 51 (133mg, it is grey Brown solid), yield 39.6%.
MS m/z (LC-MS): 386.3 [M+1]
Embodiment 52
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- (methane sulfonylamino) pyridine -3- Base) piperidines -1- formamide
The first step
(5- nitropyridine -2- base) t-butyl carbamate 52b
5- nitropyridine -2- amine 52a (2g, 0.014mol) is dissolved in 80mL methylene chloride, the tertiary fourth of dicarbapentaborane two is added Ester (3.452g, 0.016mol), triethylamine (3.0mL, 0.022mol), 4-dimethylaminopyridine (878mg, 7.188mmol) add Enter in reaction flask, is reacted 17 hours in 25 DEG C.After reaction, 100mL methylene chloride is added, is washed with water, organic phase decompression Concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtaining title product 52b, (793mg, yellow are solid Body), yield 23.0%.
Second step
(5- aminopyridine -2- base) t-butyl carbamate 52c
52b (794mg, 3.319mmol) is dissolved in 30mL methanol and 10mL water, the iron of 744mg, ammonium chloride is added (1.422g, 26.552mmol) reacts 1 hour in 70 DEG C.After reaction, 100mL water is added, ethyl acetate extraction is organic It is mutually washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and filtrate decompression concentration obtains crude title product 52c (550mg, light brown red solid), product directly carry out next step reaction without further purification.
Third step
(5- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamide) pyridine -2- Base) t-butyl carbamate 52d
4mL tetrahydrofuran is added in reaction flask, at 0 DEG C, is added triphosgene (129mg, 0.436mmol), crude product 52c (91mg, 0.436mmol), triethylamine (304 μ L, 2.179mmol), is stirred to react 30 minutes in 0 DEG C, and spare, drop is concentrated under reduced pressure The tetrahydrofuran solution and triethylamine (304 μ L, 2.179mmol) of the 1f (150mg, 0.436mmol) of prefabricated 4mL is added, in 25 DEG C are stirred to react 2 hours.After reaction, 2mL methanol quenching reaction is added, reaction solution is concentrated under reduced pressure, thin-layer chromatography is used Method purifies gained residue with solvent system A, obtains title product 52d (154mg, yellow solid), yield 61.1%.
4th step
N- (6- aminopyridine -3- base) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- Formamide 52e
Crude product 52d (154mg, 3.319mmol) is dissolved in 10mL methylene chloride, 10mL trifluoroacetic acid is added, in 25 DEG C Reaction 3 hours.After reaction, reaction solution is concentrated under reduced pressure, 100mL ethyl acetate is added, organic phase successively uses unsaturated carbonate Hydrogen sodium solution and saturated sodium chloride solution washing, anhydrous sodium sulfate dry, filter, and filtrate decompression concentration obtains crude title product 52e (120mg, yellow oil), product directly carry out next step reaction without further purification.
5th step
N- (5- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamide) pyridine -2- Base) sulfamoylamino group t-butyl formate 52f
2mL tetrahydrofuran is added in reaction flask, at 0 DEG C, is added chloro sulfonyl isocyanate (42mg, 0.300mmol), It is added the tert-butyl alcohol (22mg, 0.300mmol), is stirred to react in 0 DEG C spare after twenty minutes.By prefabricated 2ml crude product 52e The tetrahydrofuran solution of (120mg, 0.250mmol), triethylamine (174 μ L, 1.252mmol) are added in reaction flask, are added above-mentioned Reserve liquid is stirred to react 1 hour in 25 DEG C.After reaction, 3mL methanol quenching reaction is added, with thin-layered chromatography to be unfolded Agent system A purifying gained residue, obtains title product 52f (135mg, yellow solid), yield 81.8%.
6th step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- (methane sulfonylamino) pyridine -3- Base) piperidines -1- formamide 52
52f (135mg, 0.205mmol) is placed in a reaction flask, 10mL methylene chloride and 10mL trifluoroacetic acid is added, in 25 DEG C are reacted 1 hour.After reaction, reaction solution is concentrated under reduced pressure, high performance liquid chromatography purifying gained residue is marked It inscribes product 52 (13mg, faint yellow solid), yield 11.4%.
MS m/z (ESI): 558.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 8.11 (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)
Embodiment 53
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- amino-sulfonyl pyrrolidines -4- base) ethanamidine 53
Using the synthetic route of embodiment 44, raw material is replaced with into 3- acetyl-pyrrolidine -1- t-butyl carbamate and (is adopted The method disclosed in patent application " WO2012126901 " is prepared), it obtains title product 53 (20mg, yellow solid), receives Rate 41.6%.
MS m/z (LC-MS): 409.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.78 (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)
Embodiment 54
(S)-N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- sulfamoyl piperidines -3- base) ethanamidine 54
Using the synthetic route of embodiment 44, raw material is replaced with into (S) -3- Acetylpiperidin -1- t-butyl formate and (is used Method disclosed in patent application " WO2011117254 " is prepared), title product 54 (40mg, yellow solid), yield is made 70.2%.
MS m/z (ESI): 423.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.77 (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)
Embodiment 55
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- carboxylate methyl ester 55
1f (103mg, 0.3mmol) is dissolved in 10mL methylene chloride, is added triethylamine (60mg, 0.6mmol), ice water is cold But, methylchloroformate (28mg, 0.3mmol are dissolved in 5mL methylene chloride) dichloromethane solution is added dropwise, is stirred to react 1 at 0 DEG C Hour.After reaction, 30mL water is added in reaction solution, and methylene chloride extracts (20mL × 3), saturated sodium chloride solution (50mL × 1) it washs, anhydrous magnesium sulfate dries, filters, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system A purify gained it is residual Excess obtains title product 55 (75mg, white solid), yield 62.5%.
MS m/z (ESI): 402.2 [M+1]
1H NMR (400MHz, CDCl3) 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)
Embodiment 56
(1R, 5S) -3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) -8- azabicyclo [3.2.1] Octane -8- t-butyl formate
The first step
(1R, 5S) -3- (1- ethoxy) -8- azabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester 56b
By raw material (1R, 5S) -3- formoxyl -8- azabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester 56a (1g, 4.18mmol is prepared using method disclosed in patent application " WO2011059021 ") it is dissolved in 15mL tetrahydrofuran, it is cooling To 0 DEG C, the methyl magnesium bromide solution of 1.7mL 3M is added, is stirred to react 1 hour at 0 DEG C.After reaction, the hydrochloric acid of 1M is added Solution quenching reaction.Liquid separation, water phase are extracted with ethyl acetate three times, merge organic phase, anhydrous sodium sulfate dries, filters, filtrate It is concentrated under reduced pressure, obtains crude title product 56b (1.06g, colourless liquid), product directly reacts in next step without further purification.
Second step
(1R, 5S) -3- acetyl group -8- azabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester 56c
Crude product 56b (1.06g, 4.18mmol) is dissolved in 30mL methylene chloride, addition Dai Si-Martin's oxidant (1.8g, 4.17mmol), it is stirred to react 1.5 hours at 25 DEG C.After reaction, saturated sodium bicarbonate solution and saturation thiosulfuric acid is added Sodium solution stirs 5 minutes.Liquid separation, water phase are extracted with dichloromethane three times, merge organic phase, and anhydrous sodium sulfate dries, filters, Filtrate decompression concentration.Silica gel column chromatography purifies gained residue with eluant, eluent system A, obtains title product 56c (807mg, nothing Color liquid), yield 77%.
Third step
(1R, 5S) -3- (2- carbonyl acetyl group) -8- azabicyclo [3.2.1] octane -8- t-butyl formate 56d
Selenium dioxide (700mg, 6.3mmol) is placed in a reaction flask, 30mL Isosorbide-5-Nitrae-dioxane, 56c is added (800mg, 3.19mmol) reacts 12 hours in 90 DEG C.After reaction, insoluble matter, filtrate decompression concentration, by institute are filtered to remove It obtains residue and is dissolved in ethyl acetate, filter, filtrate water washing merges organic phase, and anhydrous sodium sulfate dries, filters, and filtrate subtracts Pressure concentration, obtains crude title product 56d (670mg, pale brown oil object), and product directly carries out anti-in next step without further purification It answers.
4th step
(1R, 5S) -3- (2- (oximido) acetyl group) -8- azabicyclo [3.2.1] octane -8- t-butyl formate 56e
Crude product 56d (67mg, 2.53mmol) is dissolved in 20mL methanol, is added potassium carbonate (524mg, 3.79mmol), in 0 It DEG C is stirred to react 10 minutes, the methanol solution of prefabricated 2.5mL hydroxylamine hydrochloride (88mg, 1.266mmol) is added portionwise, in 0 DEG C Stirring lower reaction 0.5 hour.After reaction, insoluble matter, filtrate decompression concentration, with thin-layered chromatography to be unfolded are filtered to remove Agent system B purifying gained residue, obtains title product 56e (166mg, pale brown oil object), yield 23%.
5th step
(1R, 5S) -3- (2- chloro- 2- (oximido) acetyl group) -8- azabicyclo [3.2.1] octane -8- t-butyl formate 56f
56e (2.52g, 8.9mmol) is added in 30mL n,N-Dimethylformamide, N- chlorosuccinimide is added (1.25g, 9.36mmol) is stirred to react 1 hour at 25 DEG C.After reaction, water and ethyl acetate liquid separation, organic phase is added It is extracted with ethyl acetate (50mL × 3), merges organic phase, organic phase washed with water and saturated sodium chloride solution washing, anhydrous sulphur Sour sodium dries, filters, filtrate decompression concentration, obtain crude title product 56f (3.167g, light yellow oil), product without Purifying directly carries out next step reaction.
6th step
(1R, 5S) -3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) -8- azabicyclo [3.2.1] Octane -8- t-butyl formate 56
The bromo- 4- fluoroaniline (3.8g, 19.9mmol) of crude product 56f (3.15g, 9.9mmol) and 3- is added in 30mL ethyl alcohol, It is stirred to react at 25 DEG C 12 hours.After reaction, reaction solution is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purifying gained residue, obtains title product 56 (1.8g, brown viscous object), yield 38%.
MS m/z (ESI): 470.2 [M+1]
1H NMR (400MHz, CDCl3) 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)
Embodiment 57
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyano -3- isopropyl phenyl) piperazine Pyridine -1- formamide
The first step
4- amino -2- cumene formonitrile HCN 57b
4- amino -2- bromobenzylcyanide 57a (150mg, 0.76mmol) is dissolved in 20mL1, in 4- dioxane, be added [1, 1 '-bis- Diphenyl phosphino ferrocenes] palladium chloride (56mg, 0.076mmol) and 0.25M diisopropyl zinc (6mL, 1.5mmol), argon Under atmosphere, it is stirred to react in 100 DEG C 2 hours.After reaction, diatomite filtering reacting liquid, filtrate decompression concentration, with thin layer color Spectrometry purifies gained residue with solvent system B, obtains title product 57b (80mg, brown oil), yield 66%.
Second step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyano -3- isopropyl phenyl) piperazine Pyridine -1- formamide 57
Triphosgene (86mg, 0.29mmol) is dissolved in 30mL tetrahydrofuran, is added 57b (49mg, 0.305mmol), three Ethamine (88mg, 0.87mmol) reacts 30 minutes in 25 DEG C, is added 1f (100mg, 0.29mmol), it is small to be stirred to react 1 in 25 DEG C When.After reaction, be added methanol, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained remnants Object obtains title product 57 (10mg, white solid), yield 6.5%.
MS m/z (ESI): 530.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.70 (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)
Embodiment 58
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- ((1R, 5S) -8- sulfamoyl -8- azabicyclo [3.2.1] octane -3- base) ethanamidine
The first step
2- ((1R, 5S) -8- azabicyclo [3.2.1] octane -3- base)-N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl Base ethanamidine 58a
56 (600mg, 1.28mmol) are dissolved in 3mL methylene chloride, 3mL trifluoroacetic acid are added, reaction system is in 25 DEG C It is stirred to react 1 hour.After reaction, it is concentrated under reduced pressure, obtains crude title product 58a (1.2g, tan solid), product Next step reaction is directly carried out without further purification.
Second step
((1R, 5S) -3- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) -8- azabicyclo [3.2.1] Octane -8- base) sulfonylcarbamic acid tert-butyl ester 58b
Chloro sulfonyl isocyanate (9.17mg, 6.48mmol) is dissolved in 10mL methylene chloride, is cooled to 0 DEG C, is added The tert-butyl alcohol (480mg, 6.47mmol), 0 DEG C is stirred to react 5 minutes to obtain reserve liquid.By 58a (1.2g, 3.24mmol), triethylamine (2.25mL, 16.2mmol) and 30mL methylene chloride enter in reaction flask, and 4mL reserve liquid is added, stirs 1 hour at 0 DEG C.Reaction knot Shu Hou, be added methanol quenching reaction, be concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, marked It inscribes product 58b (180mg, brown solid), yield 10%.
Third step
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- ((1R, 5S) -8- sulfamoyl -8- azabicyclo [3.2.1] octane -3- base) ethanamidine 58
58b (180mg, 0.327mmol) is dissolved in 3mL methylene chloride, 3mL trifluoroacetic acid is added, reaction system is in 25 It DEG C is stirred to react 1 hour.After reaction, reduced pressure thin-layered chromatography purifies gained residue with solvent system A, obtains To title product 58 (86mg, pale solid), yield 58%.
MS m/z (ESI): 449.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.71 (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)
Embodiment 59
N- (the bromo- 4- fluorophenyl of 3-) -2- (1- formyl piperidine -4- base)-N '-hydroxyl -2- carbonyl ethanamidine 59
Formic acid (88mg, 1.91mmol) is dissolved in acetic anhydride (100mg, 0.97mmol), 60 DEG C are stirred to react 2 hours, Above-mentioned reaction solution is dissolved in 1mL tetrahydrofuran, under ice bath, be added to prefabricated 30mL mixing 1f (300mg, 0.87mmol) and In the tetrahydrofuran solution of 1mL triethylamine, 0 DEG C is stirred to react 1 hour.After reaction, methanol is added, dry reaction is concentrated under reduced pressure Liquid, with thin-layered chromatography with eluant, eluent system A purify gained residue, obtain title product 59 (90mg, faint yellow solid), receive Rate 25%.
MS m/z (ESI): 372.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 60
N- (bromo- 2, the 4- difluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- amino-sulfonyl piperidin-4-yl) ethanamidine
The first step
4- (2- ((bromo- 2, the 4- difluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- t-butyl formate 60a
10mL is added in bromo- 2, the 4- difluoroaniline (572mg, 2.752mmol) of crude product 1d (400mg, 1.376mmol) and 3- In ethyl alcohol, it is stirred to react at 25 DEG C 16 hours.After reaction, reaction solution is concentrated under reduced pressure, with thin-layered chromatography to be unfolded Agent system A purifying gained residue, obtains title product 60a (210mg, yellow oil), yield 33.0%.
Second step
N- (bromo- 2, the 4- difluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- amino-sulfonyl piperidin-4-yl) ethanamidine 60
Using the synthetic route of embodiment 44, raw material 25 is changed into 60a, title product 60 (30mg, white solid) is made, Yield: 37%.
MS m/z (ESI): 441.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.44 (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)
Embodiment 61
N '-hydroxy-n-(3- iodophenyl) -2- carbonyl -2- (1- amino-sulfonyl piperidin-4-yl) ethanamidine 61
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroaniline of raw material 3- is replaced with into 3- Iodoaniline, title is made Product 61 (45mg, white solid), yield 27.6%.
MS m/z (ESI): 453.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.70 (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)
Embodiment 62
N- (the bromo- 2- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- amino-sulfonyl piperidin-4-yl) ethanamidine 62
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroaniline of raw material 3- is replaced with into the bromo- 2- fluoroaniline of 3-, is made It obtains title product 62 (30mg, white solid), yield 80.8%.
MS m/z(ESI)423.2[M+1]
1H NMR (400MHz, CDCl3) δ 11.50 (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)
Embodiment 63
N- (the bromo- 2- fluorophenyl of 5-)-N '-hydroxyl -2- carbonyl -2- (1- amino-sulfonyl piperidin-4-yl) ethanamidine 63
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroaniline of raw material 3- is replaced with into the bromo- 2- fluoroaniline of 5-, is made It obtains title product 63 (13mg, white solid), yield 30.9%.
MS m/z (ESI): 423.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.57 (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)
Embodiment 64
N- (3- bromophenyl)-N '-hydroxyl -2- carbonyl -2- (1- amino-sulfonyl piperidin-4-yl) ethanamidine 64
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroaniline of raw material 3- is replaced with into 3- bromaniline, title is made Product 64 (26mg, white solid), yield 29.4%.
MS m/z (ESI): 405.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.74 (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)
Embodiment 65
N- (3- chlorphenyl)-N '-hydroxyl -2- carbonyl -2- (1- amino-sulfonyl piperidin-4-yl) ethanamidine 65
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroaniline of raw material 3- is replaced with into 3- chloroaniline, title is made Product 65 (30mg, white solid), yield 31.9%.
MS m/z (ESI): 361.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.74 (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)
Embodiment 66
N- (4- fluoro- 3- (trifluoromethyl) phenyl)-N '-hydroxyl -2- carbonyl -2- (1- sulfamoyl piperidin-4-yl) ethanamidine 66
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroaniline of raw material 3- is replaced with into the fluoro- 3- trifluoromethylbenzene of 4- Title product 66 (30mg, white solid), yield 32.3% is made in amine.
MS m/z (ESI): 413.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.78 (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).
Embodiment 67
N- (the chloro- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- amino-sulfonyl piperidin-4-yl) ethanamidine 67
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroaniline of raw material 3- is replaced with into the chloro- 4- fluoroaniline of 3-, is made It obtains title product 67 (35mg, white solid), yield 40.1%.
MS m/z (ESI): 379.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.69 (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)
Embodiment 68
N- (the bromo- 5- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- amino-sulfonyl piperidin-4-yl) ethanamidine 68
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroaniline of raw material 3- is replaced with into the bromo- 5- fluoroaniline of 3-, is made It obtains title product 68 (50mg, Tan solid), yield 15%.
MS m/z (ESI): 423.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.98 (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)
Embodiment 69
N '-hydroxyl -2- carbonyl -2- (1- sulfamoyl piperidin-4-yl)-N- (3- (trifluoromethyl) phenyl) ethanamidine 69
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroaniline of raw material 3- is replaced with into 3- (trifluoromethyl) aniline, Title product 69 (30mg, white solid), yield 31.3% is made.
MS m/z (ESI): 395.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.82 (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)
Embodiment 70
N- (the chloro- 5- ethenylphenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- amino-sulfonyl piperidin-4-yl) ethanamidine
The first step
The chloro- 3- nitro -5- vinyl benzene 70b of 1-
70a (450mg, 1.9mmol are prepared using method disclosed in patent application " CN102146022 ") is dissolved in The in the mixed solvent of 18mL Isosorbide-5-Nitrae-dioxane and water (V: V=6: 1), sequentially add vinyl boronic acids pinacol ester (293mg, 1.9mmoml), [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride (139mg, 0.19mmol), potassium carbonate (787mg, 5.7mmol), under argon atmospher, 80 DEG C are stirred to react 6 hours.After reaction, it is cooled to room temperature, 30mL water is added to reaction solution, Ethyl acetate extracts (20mL × 3), merges organic phase, saturated sodium-chloride water solution washing, and anhydrous sodium sulfate is dried, filtered, filtered Liquid be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 70b (250mg, Huang Color grease), yield 71.4%.
Second step
The chloro- 5- vinyl aniline 70c of 3-
70b (250mg, 1.36mmol) is dissolved in the in the mixed solvent of 12mL second alcohol and water (V: V=5: 1), Xiang Fanying It is sequentially added in liquid iron powder (152mg, 2.7mmol), ammonium chloride (294mg, 5.44mmol).Reaction solution is warming up to 80 DEG C, stirring Reaction 1 hour.After reaction, reaction solution is cooled to room temperature, 20mL water is added, ethyl acetate extracts (20mL × 3), merges Organic phase, saturated sodium-chloride water solution 50mL washing, anhydrous sodium sulfate dry, filter, filtrate decompression concentration.Use silica gel column chromatography Method purifies gained residue with eluant, eluent system B, obtains title product 70c (180mg, yellow oil), yield 86.1%.
Third step
N- (3- bromophenyl)-N '-hydroxyl -2- carbonyl -2- (1- amino-sulfonyl piperidin-4-yl) ethanamidine 70
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroaniline of raw material 3- is replaced with into 70c, title product is made 70 (2mg, white solids), yield 33.8%.
MS m/z (ESI): 387.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.78 (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)
Embodiment 71
N- benzyl -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- thioformamide 71
By benzyl isothiocyanate 71a (43mg, 0.291mmol, using well known method " Beilstein Journal of Organic Chemistry, 2012,8 (6), 61-70 " are prepared) it is dissolved in 2mL tetrahydrofuran, it is added dropwise to prefabricated 1f In the 8mL tetrahydrofuran solution of (100mg, 0.29mmol), it is stirred to react at 25 DEG C 1 hour.After reaction, it is concentrated, use is thin Layer chromatography purifies gained residue with solvent system A, obtains title product 71 (25mg, faint yellow solid), yield 17%.
MS m/z (ESI): 493.3 [M+1]
1H NMR (400MHz, CDCl3) δ 7.77 (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)
Embodiment 72
N- (the bromo- 4- fluorophenyl of 3-) -2- (1- (5- cyano thiazole -2- base) piperidin-4-yl)-N '-hydroxyl -2- carbonyl ethanamidine 72
By the chloro- 5- cyano thiazole 72a of 2- (42mg, 0.29mmol, using side disclosed in patent application " WO2002006276 " Method is prepared) it is dissolved in 5mL n,N-Dimethylformamide, it is added 1f (100mg, 0.29mmol), 150 DEG C to be stirred to react 1 small When.After reaction, it is cooled to room temperature, reaction solution is poured into water, ethyl acetate extraction, saturated sodium chloride solution washing, nothing Aqueous sodium persulfate dries, filters, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system B purify gained residue, obtain Title product 72 (20mg, white solid), yield 15.2%.
MS m/z (LC-MS): 452.3 [M+1]
1H NMR (400MHz, CD3OD) 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)
Embodiment 73
N- (the bromo- 4- fluorophenyl of 3-) -2- (1- (2- fluoro- 4- (mesyl) phenyl) piperidin-4-yl)-N '-hydroxyl -2- carbonyl Base ethanamidine 73
Using the synthetic route of embodiment 72, raw material 72a is replaced with into the fluoro- 4- methyl sulphonyl benzene of 1,2- bis-, mark is made It inscribes product 73 (20mg, yellow solid), yield 13.3%.
MS m/z (LC-MS): 516.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 74
N- (the bromo- 4- fluorophenyl of 3-) -2- (1- (4- cyanopyridine -2- base) piperidin-4-yl)-N '-hydroxyl -2- carbonyl ethanamidine 74
The chloro- 4- cyanopyridine 74a (60mg, 0.43mmol) of 2- is dissolved in 2mL n,N-Dimethylformamide, 1f is added (100mg, 0.29mmol), 65 DEG C are stirred to react 3 hours.After reaction, it is cooled to room temperature, reaction solution is poured into 20mL water In, ethyl acetate extracts (15mL × 3), merges organic phase, saturated sodium chloride solution 20mL washing, anhydrous sodium sulfate is dry, mistake Filter, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 74 (15mg, light yellow solid), yield 11.6%.
MS m/z (LC-MS): 446.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.69 (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)
Embodiment 75
N- (the bromo- 4- fluorophenyl of 3-) -2- (1- (5- cyanopyridine -2- base) piperidin-4-yl)-N '-hydroxyl -2- carbonyl ethanamidine 75
The chloro- nicotinonitrile 75a (61mg, 0.44mmol) of 6- is dissolved in 3mL N-Methyl pyrrolidone, 1f is added (100mg, 0.29mmol), n,N-diisopropylethylamine (170mg, 1.32mmol), 25 DEG C are stirred to react 18 hours.Reaction terminates Afterwards, reaction solution is poured into 30mL water, ethyl acetate extracts (30mL × 3), merges organic phase, saturated sodium-chloride water solution washing (30mL × 2), anhydrous sodium sulfate dries, filters, filtrate decompression concentration.Institute is purified with eluant, eluent system B with silica gel column chromatography Residue is obtained, title product 75 (55mg, white solid), yield 42.3% are obtained.
MS m/z (LC-MS): 446.3 [M+1]
Embodiment 76
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- (1- (4- (mesyl) phenyl) piperidin-4-yl) -2- carbonyl second Amidine 76
Using the synthetic route of embodiment 72, raw material 72a is replaced with into 4- methyl sulphonyl fluorobenzene, title product 76 is made (10mg, white solid), yield 13.8%.
MS m/z (LC-MS): 498.3 [M+1]
Embodiment 77
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- (pyridine -2- base) piperidin-4-yl) ethanamidine 77
Using the synthetic route of embodiment 72, raw material 72a is replaced with into 2- chloropyridine, title product 77 (4mg, palm fibre is made Color solid), yield 4%.
MS m/z (LC-MS): 421.3 [M+1]
Embodiment 78
4-4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) ethyl benzoate 78
Using the synthetic route of embodiment 72, raw material 72a is replaced with into 4- ethyl fluoro benzoate, title product 78 is made (5mg, yellow solid), yield 10.2%.
MS m/z (LC-MS): 492.3 [M+1]
1H NMR (400MHz, CD3OD) δ 7.85-7.87 (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)
Embodiment 79
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- (pyrimidine-4-yl) piperidin-4-yl) ethanamidine 79
Using the synthetic route of embodiment 72, raw material 72a is replaced with into 4- chlorine pyrimidine, be made title product 79 (20mg, it is white Color solid), yield 16.3%.
MS m/z (LC-MS): 422.3 [M+1]
1H NMR (400MHz, CDCl3) 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)
Embodiment 80
4- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) benzoic acid
The first step
4- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) t-butyl perbenzoate 80b
The fluoro- t-butyl perbenzoate 80a (410mg, 2.09mmol) of 4- is dissolved in 20mL n,N-Dimethylformamide, is added Enter 1f (650mg, 1.74mmol), n,N-diisopropylethylamine (561mg, 4.35mmol), 95 DEG C are stirred to react 72 hours.Reaction After, it is cooled to room temperature, reaction solution is poured into water, ethyl acetate extraction, saturated sodium chloride solution washing, anhydrous sodium sulfate Dry, filter, filtrate decompression concentration, obtain crude title product 80b (120mg, yellow solid), product without further purification directly into Row reacts in next step.
Second step
4- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) benzoic acid 80
80b (120mg, 0.23mmol) is dissolved in 6mL methylene chloride, 0.5mL trifluoracetic acid is added, 25 DEG C are stirred to react 18 hours.After reaction, be concentrated under reduced pressure reaction solution, with thin-layered chromatography with eluant, eluent system A purify obtained by residue, obtain Title product 80 (65mg, white solid), yield 60.7%.
MS m/z (LC-MS): 464.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 12.28 (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)
Embodiment 81
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- Phenylpiperidine -4- base)-ethanamidine
The first step
2- (1- (4- aminophenyl) piperidin-4-yl)-N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl ethanamidine 81a
28 (220mg, 0.47mmol) are dissolved in 30mL Isosorbide-5-Nitrae-dioxane and 10mL water, sodium dithionite is added (823mg, 4.7mmol), potassium carbonate (324.3mg, 2.35mmol), 25 DEG C are stirred to react 1 hour.After reaction, reaction solution 20mL water is added, ethyl acetate extracts (15mL × 3), merges organic phase, saturated sodium chloride solution washs (20mL × 1), anhydrous Sodium sulphate dries, filters, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system A purify gained residue, marked It inscribes product 81a (130mg, white solid), yield 63.5%.
Second step
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- Phenylpiperidine -4- base)-ethanamidine 81
81a (20mg, 0.46mmol) is dissolved in 4mL n,N-Dimethylformamide, is heated to 70 DEG C, is added dropwise to prefabricated 1mL nitrite tert-butyl (10mg, 0.92mmol) n,N-Dimethylformamide solution, be added dropwise and immediately treat reaction. 50mL water is added in reaction solution, and ethyl acetate extracts (40mL × 1), successively uses water (30mL × 3), saturated sodium chloride solution (30mL × 3) it washs, anhydrous sodium sulfate dries, filters, filtrate decompression concentration.With thin layer chromatography with solvent system A purify gained it is residual Excess obtains title product 81 (5mg, yellow solid), yield 26.3%.
MS m/z (LC-MS): 420.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 82
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- (1- (2- methoxyphenyl) piperidin-4-yl) -2- carbonyl ethanamidine
The first step
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- (1- (2- methoxyl group -4- nitrobenzene) piperidin-4-yl) -2- carbonyl second Amidine 82b
2- methoxyl group -4- fluoronitrobenzene 82a (206mg, 1.21mmol) is dissolved in 13mL n,N-Dimethylformamide, It is added 1f (378mg, 1.1mmol), n,N-diisopropylethylamine (213mg, 1.65mmol), 100 DEG C are stirred to react 12 hours.Instead After answering, 50mL water is added in reaction solution and 50mL ethyl acetate, liquid separation, organic phase wash (20mL with saturated sodium chloride solution × 2), anhydrous sodium sulfate dries, filters, filtrate decompression concentration.It is remaining that gained purified with solvent system B with thin-layered chromatography Object obtains title product 82b (200mg, yellow solid), yield 40.4%.
Second step
2- (1- (4- amino -2- methoxyphenyl) piperidin-4-yl)-N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl Ethanamidine 82c
82b (150mg, 0.3mmol) is dissolved in 8mL Isosorbide-5-Nitrae-dioxane and 4mL water, sodium dithionite is added (261mg, 1.5mmol), potassium carbonate (81mg, 0.6mmol), 25 DEG C are stirred to react 0.5 hour.After reaction, reaction solution adds Entering 50mL water, 50mL ethyl acetate, liquid separation, organic phase washed with water and saturated sodium chloride solution washing, anhydrous sodium sulfate is dry, Filtering, filtrate decompression concentration.With thin-layered chromatography with solvent system A purify gained residue, obtain title product 82c (40mg, gray solid), yield 28.6%.
Third step
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- (1- (2- methoxyphenyl) piperidin-4-yl) -2- carbonyl ethanamidine 82
82c (40mg, 0.086mmol) is dissolved in 4mL n,N-Dimethylformamide, is heated to 70 DEG C, is added dropwise to prefabricated 1mL nitrite tert-butyl (18mg, 0.172mmol) n,N-Dimethylformamide solution, be added dropwise and immediately treat reaction. 50mL water, 50mL ethyl acetate, liquid separation, organic phase washed with water and saturated sodium chloride solution washing, anhydrous sulphur is added in reaction solution Sour sodium dries, filters, filtrate decompression concentration.With thin layer chromatography with solvent system A purify gained residue, obtain title production Object 82 (4mg, white solid), yield 10.5%.
MS m/z (LC-MS): 450.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.14 (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)
Embodiment 83
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- (1- (5- nitrothiazole -2- base) piperidin-4-yl) -2- carbonyl ethanamidine 83
The bromo- 5- nitrothiazole 83a (1.0g, 4.78mmol) of 2- is dissolved in 15mL n,N-Dimethylformamide, 1f is added (1.65g, 4.78mmol), n,N-diisopropylethylamine (1.54g, 12mmol), 80 DEG C are stirred to react 2 hours.After reaction, It is cooled to room temperature, reaction solution is poured into water, ethyl acetate extraction, saturated sodium chloride solution washing, anhydrous sodium sulfate is dry, mistake Filter, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 83 (300mg, yellow solid), yield 13.6%.
MS m/z (LC-MS): 472.2 [M+1]
Embodiment 84
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- (4- pyridine -2- base) thiazol-2-yl) piperidines -4- Base) ethanamidine 84
By the bromo- 4- of 2- (pyridine -2- base) thiazole 84a (48mg, 0.2mmol, using patent application " WO2012170845 " public affairs The method opened is prepared) it is dissolved in 5mL n,N-Dimethylformamide, it is added 1f (68mg, 0.2mmol), N, N- diisopropyl Ethamine (52mg, 0.4mmol), 100 DEG C are stirred to react 5 hours.After reaction, it is cooled to room temperature, reaction solution is poured into 50mL In water, the extraction of 50mL ethyl acetate, organic phase water washing (30mL × 3), saturated sodium-chloride water solution washing (30mL × 3), nothing Aqueous sodium persulfate dries, filters, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system B purify gained residue, obtain Title product 84 (5mg, yellow solid), yield 4.5%.
MS m/z (LC-MS): 504.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.72 (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)
Embodiment 85
N- (the bromo- 4- fluorophenyl of 3-) -2- (1- (5- bromo thiazole -2- base) piperidin-4-yl)-N '-hydroxyl -- 2- carbonyl ethanamidine 85
Using the synthetic route of embodiment 84, raw material 84a is replaced with into 2,5-, bis- bromo thiazole, title product 85 is made (5mg, faint yellow solid), yield 10%.
MS m/z (LC-MS): 507.1 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.70 (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)
Embodiment 86
N- (the bromo- 4- fluorophenyl of 3-) -2- (1- (4- cyano thiazole -2- base) piperidin-4-yl)-N '-hydroxyl -2- carbonyl ethanamidine 86
Using the synthetic route of embodiment 84, raw material 84a is replaced with into the bromo- 4- cyano thiazole of 2-, title product 86 is made (13mg, faint yellow solid), yield 25%.
MS m/z (LC-MS): 452.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.71 (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)
Embodiment 87
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- (thiazol-2-yl) piperidin-4-yl)-ethanamidine 87
Using the synthetic route of embodiment 84, raw material 84a is replaced with into 2- bromo thiazole, be made title product 87 (10mg, it is light Yellow solid), yield 8%.
MS m/z (LC-MS): 427.3 [M+1]
Embodiment 88
2- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) thiazole-5-carboxylic acid first Ester 88
Using the synthetic route of embodiment 84, raw material 84a is replaced with into 2- bromo thiazole -5- carboxylate methyl ester (well known to use Method " Journal of Organic Chemistry, 2011,76 (16), 6972-6978 " are prepared), title is made and produces Object 88 (20mg, white solid), yield 41.7%.
MS m/z (LC-MS): 485.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.71 (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)
Embodiment 89
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- (4- (trifluoromethyl) thiazol-2-yl) piperidines -4- Base) ethanamidine 89
Using the synthetic route of embodiment 84, raw material 84a is replaced with into the bromo- 4- trifluoromethyl thiazole of 2-, title is made and produces Object 89 (100mg, white solid), yield 20.4%.
MS m/z (LC-MS): 495.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.71 (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)
Embodiment 90
2- (1- (5- amido-1,3,4-thiadiazoles -2- base) piperidin-4-yl)-N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl - 2- carbonyl ethanamidine 90
Using the synthetic route of embodiment 84, raw material 84a is replaced with into 2- amino -5- bromo- 1,3,4- thiadiazoles are (using special Method disclosed in benefit application " WO2013163244 " is prepared), title product 90 (45mg, pink solid), yield is made 69.8%.
MS m/z (LC-MS): 443.2 [M+1]
Embodiment 91
2- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl)-N- methylthiazol -5- Formamide
The first step
The bromo- N- methylthiazol -5- formamide 91b of 2-
2- bromo thiazole -5- carboxylic acid 91a (206mg, 1.0mmol) is dissolved in 5mL n,N-Dimethylformamide, 2M is added Methylamine (2mL, 4mmol), n,N-diisopropylethylamine (516mg, 4mmol), 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (456mg, 1.2mmol), 25 DEG C are stirred to react 16 hours.After reaction, it is concentrated under reduced pressure anti- Liquid is answered, gained residue is purified with eluant, eluent system B with silica gel column chromatography, obtaining title product 91b, (45mg, white are solid Body), yield 20.3%.
Second step
2- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl)-N- methylthiazol -5- Formamide 91
91b (45mg, 0.2mmol) is dissolved in 5mL dimethyl sulfoxide, is added 1f (69mg, 0.2mmol), N, N- bis- is different Propylethylamine (52mg, 0.4mmol), 90 DEG C are stirred to react 12 hours.After reaction, it is cooled to room temperature, reaction solution is poured into In 30mL water, the extraction of 30mL ethyl acetate, organic phase water washing (30mL × 3), saturated sodium-chloride water solution washing (30mL × 3), anhydrous sodium sulfate dries, filters, filtrate decompression concentration.With thin-layered chromatography with solvent system A purify gained residue, Obtain title product 91 (8mg, brown solid), yield 8.1%.
MS m/z (LC-MS): 484.2 [M+1]
1H NMR (400MHz, DMSO-d6): δ 11.69 (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)
Embodiment 92
2- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl)-N- methylthiazol -4- Formamide 92
Using the synthetic route of embodiment 91, raw material 91a is replaced with into the bromo- thiazole -4-carboxylic acid of 2-, title product 92 is made (10mg, brown solid), yield 10.1%.
MS m/z (LC-MS): 484.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.71 (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)
Embodiment 93
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (1- (2- ethoxy) -1H- pyrazoles -4- Base) piperidines -1- formamide
The first step
4- nitro -1- (2- ((tetrahydro -2H- pyrans -2- base) oxygroup) ethyl) -1H- pyrazoles 93b
By 2- (4- nitro -1H- pyrazol-1-yl) -1- ethyl alcohol 93a (1.878g, 11.9mmol, using patent application Method disclosed in " WO2013017479 " is prepared) it is dissolved in 70mL methylene chloride, addition 3,4- dihydropyran (1.65mL, 18.0mmol), para-methylbenzenepyridinsulfonate sulfonate (604mg, 2.4mmol), 25 DEG C are stirred to react 18 hours.After reaction, it depressurizes Dry reaction liquid is concentrated, 60 DEG C are stirred to react 18 hours.After reaction, it filters, filtrate decompression concentration obtains crude title product 93b (2.92g, colorless oil), product directly carry out next step reaction without further purification.
Second step
1- (2- ((tetrahydro -2H- pyrans -2- base) oxygroup) ethyl -1H- pyrazoles -4- amine 93c
Crude product 93b (2.92g, 12.1mmol) is dissolved in 40mL methanol, 10% palladium carbon of 590mg, hydrogen displacement three is added Secondary, 25 DEG C are stirred to react 3 hours.After reaction, diatomite filters, and filtrate decompression is concentrated to give crude title product 93c (2.6g, brown-red oil), product directly react in next step without further purification.
Third step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (1- (2- ((tetrahydro -2H- pyrans -2- Base) oxygroup) ethyl) -1H- pyrazoles -4- base) piperidines -1- formamide 93d
Triphosgene (350mg, 1.18mmol) is dissolved in 20mL tetrahydrofuran, prefabricated 20mL crude product 93c is added The tetrahydrofuran solution of (368mg, 1.74mmol), triethylamine (1.5mL, 10.8mmol) react 30 minutes in 25 DEG C, are added pre- The tetrahydrofuran solution of the 20mL 1f (500mg, 1.45mmol) of system reacts 1 hour in 25 DEG C.After reaction, methanol is added Quenching reaction, reaction solution be concentrated under reduced pressure, with thin-layered chromatography with eluant, eluent system A purify obtained by residue, obtain title product 93d (430mg, Tan solid), yield 51%.
4th step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (1- (2- ethoxy) -1H- pyrazoles -4- Base) piperidines -1- formamide 93
93d (430mg, 0.739mmol) is dissolved in 30mL methanol, one hydration p-methyl benzenesulfonic acid of addition (141mg, 0.738mmol), it is stirred to react 18 hours for 25 DEG C.After reaction, saturated sodium bicarbonate solution is added, is concentrated under reduced pressure, uses thin layer Chromatography purifies gained residue with eluant, eluent system A and obtains title product 93 (135mg, white solid), yield 36.7%.
MS m/z (ESI): 497.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.66 (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)
Embodiment 94
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (1- (2- methoxyethyl) -1H- pyrazoles - 4- yl) piperidines -1- formamide
The first step
- 4 nitro -1H- pyrazoles 94b of 1- (2- methoxy ethyl)
4- nitro -1H- pyrazoles 94a (2g, 17.7mmol) is dissolved in 20mL acetonitrile, bromoethanol methyl ether is sequentially added (2.7g, 19.4mmol), potassium carbonate (3.66g, 26.5mmol), 60 DEG C are stirred to react 18 hours.After reaction, it filters, filter Cake is washed with ethyl acetate and methylene chloride, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by it is residual Excess obtains title product 94b (3g, light yellow oil), yield 100%.
Second step
1- (2- methoxy ethyl) -1H- pyrazoles -4- amine 94c
94b (3.0g, 17.5mmol) is dissolved in 20mL methanol, 10% palladium carbon of 600mg is added, hydrogen is replaced three times, and 25 It DEG C is stirred to react 2 hours.After reaction, diatomite filters, and filtrate decompression is concentrated to give crude title product 94c (2.1g, purple Grease), product directly reacts in next step without further purification.
Third step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (1- (2- methoxyethyl) -1H- pyrazoles - 4- yl) piperidines -1- formamide 94
Triphosgene (43mg, 0.145mmol) is dissolved in 20mL tetrahydrofuran, addition crude product 94c (43mg, Tetrahydrofuran solution 0.305mmol), triethylamine (88mg, 0.87mmol) react 30 minutes in 25 DEG C, and prefabricated 5mL is added The tetrahydrofuran solution of 1f (100mg, 0.29mmol) reacts 1 hour in 25 DEG C.After reaction, methanol quenching reaction is added, Reaction solution be concentrated under reduced pressure, with thin-layered chromatography with eluant, eluent system A purify obtained by residue obtain title product 94 (142mg, it is white Color solid), yield 28%.
MS m/z (ESI): 511.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.67 (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)
Embodiment 95
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (the fluoro- 1- of 5- (2- ethoxy) -1H- pyrrole Azoles -4- base) piperidines -1- formamide
The first step
(1- (2- ((tetrahydro -2H- pyrans -2- base) oxygroup) ethyl) -1H- pyrazoles -4- base) t-butyl carbamate 95a
93c (3.5g, 16.6mmol) is dissolved in 100mL methylene chloride, 3.45mL triethylamine, 4- dimethylamino pyrrole is added Pyridine (202mg, 1.65mmol) and di-tert-butyl dicarbonate (4.34g, 19.9mmol), 25 DEG C are stirred to react 16 hours.Reaction knot Shu Hou, reaction solution be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 95a (4.62g, sepia grease), yield 90%.
Second step
N- [(tert-butoxy) carbonyl]-N- { 1- [2- (pyrans -2- base oxygroup) ethyl] -1H- pyrazoles -4- base } carbamic acid Tert-butyl ester 95b
95a (4.62g, 14.8mmol) is dissolved in 70mL tetrahydrofuran, ice bath is cooling, addition sodium hydride (713mg, 17.8mmol), it is stirred to react 0.5 hour for 0 DEG C, adds di-tert-butyl dicarbonate (4.53g, 20.8mmol), 0 DEG C is stirred to react 5 minutes, 25 DEG C were stirred to react 0.5 hour.After reaction, sodium hydrate aqueous solution quenching reaction, ethyl acetate extraction 3 is added It is secondary, merge organic phase, saturated sodium chloride solution is washed 1 time, and anhydrous sodium sulfate dries, filters, and silicagel column is used in filtrate decompression concentration Chromatography purifies gained residue with eluant, eluent system B, obtains title product 95b (5.3g, reddish tan liquid), yield 87%.
Third step
N- [(tert-butoxy) carbonyl]-N- { the fluoro- 1- of 5- [2- (pyrans -2- base oxygroup) ethyl] -1H- pyrazoles -4- base } ammonia Base t-butyl formate 95c
95b (3g, 7.29mmol) is dissolved in 80mL tetrahydrofuran, -78 DEG C is cooled to, the lithium diisopropylamine of 2M is added dropwise (4.4mL, 8.8mmol), -78 DEG C are stirred to react 1 hour, then be added dropwise prefabricated 30mL N- fluoro bis benzene sulfonamide (3.45g, Tetrahydrofuran solution 10.9mmol), -78 DEG C are stirred to react 1 hour.After reaction, sodium hydroxide solution is added to be quenched instead It answers, ethyl acetate extracts 3 times, merges organic phase, and saturated sodium chloride solution is washed 1 time, and anhydrous sodium sulfate dries, filters, filtrate Be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 95c (2.3g, yellow liquid Body), yield 73%.
4th step
N- [(tert-butoxy) carbonyl]-N- [the fluoro- 1- of 5- (2- ethoxy) -1H- pyrazoles -4- base] t-butyl carbamate 95d
95c (1.025g, 2.39mmol) is dissolved in 30mL methanol, one hydration p-methyl benzenesulfonic acid of addition (227mg, 1.19mmol), it is stirred to react 18 hours for 25 DEG C.After reaction, 1mL triethylamine is added, is concentrated under reduced pressure, obtains crude title production Object 95d (1.2g, yellow oil), product directly react in next step without further purification.
5th step
Acetic acid 2- (4- { two [(tert-butoxy) carbonyl] amino } the fluoro- 1H- pyrazol-1-yl of -5-) ethyl ester 95e
Crude product 95d (1.2g, 3.47mmol) is dissolved in 30mL methylene chloride, is cooled to 0 DEG C, tri- second of 0.75mL is added Amine is added dropwise to chloroacetic chloride (0.25mL, 3.5mmol), and 0 DEG C is stirred to react 1 hour.After reaction, sodium bicarbonate solution is added Quenching reaction, liquid separation, organic phase washed with water, saturated sodium chloride solution washing, anhydrous sodium sulfate dry, filter, filtrate decompression Concentration, obtains crude title product 95e (960mg, yellow oil), and product directly reacts in next step without further purification.
6th step
Acetic acid 2- (4- amino-5-fluorine -1H- pyrazol-1-yl) ethyl ester 95f
Crude product 95e (960mg, 2.48mmol) is dissolved in 20mL methylene chloride, 20mL trifluoracetic acid, 25 DEG C of stirrings are added Reaction 1 hour.After reaction, reaction solution is concentrated under reduced pressure, and methylene chloride is added, and saturated sodium bicarbonate solution washs 2 times, saturation Sodium chloride solution washs 1 time, and anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with thin-layered chromatography with solvent system B Purifying gained residue, obtains title product 95f (90mg, brown viscous object), yield 19%.
7th step
Acetic acid 2- (4- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamide) -5- Fluoro- 1H- pyrazol-1-yl) ethyl ester 95g
Triphosgene (139mg, 0.468mmol) is dissolved in 10mL tetrahydrofuran, is added 95f (88mg, 0.47mmol), three Ethamine (0.78mL, 5.6mmol), in 25 DEG C react 30 minutes, above-mentioned reaction solution is added prefabricated 15mL 1f (100mg, In tetrahydrofuran liquid 0.29mmol), it is stirred to react in 25 DEG C 1 hour.After reaction, methanol is added, reaction solution is depressurized Concentration, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 95g (50mg, brown solid), receipts Rate 19%.
8th step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (the fluoro- 1- of 5- (2- ethoxy) -1H- pyrrole Azoles -4- base) piperidines -1- formamide 95
95g (50mg, 0.0897mmol) is dissolved in 10mL methanol, is added potassium carbonate (25mg, 0.181mmol), 25 DEG C It is stirred to react 1 hour.After reaction, reaction solution be concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained remnants Object obtains title product 95 (10mg, white solid), yield 21.6%.
MS m/z (ESI): 515.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 96
(R) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (2,3- dihydroxy third Base) -1H- pyrazoles -4- base) phenyl) piperidines -1- formamide
The first step
(R) -1- (2,2- dimethyl -1,3-dioxolane -4- base) methyl) -4- (4- nitrobenzophenone) -1H- pyrazoles 98a
By 4- (4- nitrobenzene) -1H- pyrazoles 1g (500mg, 2.64mmol, using well known method " Medicinal Chemistry Research, 2013,22 (11), 5610-5616 " are prepared) it is dissolved in 20ml n,N-Dimethylformamide In, it is added cesium carbonate (1.29g, 3.95mmol), (S)-(-) -4- chloromethyl -2,2- dimethyl -1,3-dioxolane (478mg, 3.7mmol), it is reacted 18 hours in 100 DEG C.After reaction, ethyl acetate, pad diatomite filtering, filter cake acetic acid second is added Filtrate is collected in ester washing, and filtrate water washs three times, and saturated sodium chloride solution washed once, and anhydrous sodium sulfate dries, filters, Filtrate decompression concentration, obtains crude title product 96a (710mg, weak yellow liquid), and product is directly anti-in next step without further purification It answers.
Second step
(R) -4- (1- (2,2- dimethyl -1,3-dioxolane -4- base) methyl) -1H- pyrazoles -4- base) aniline 96b
Crude product 96a (710mg, 2.31mmol) is dissolved in the in the mixed solvent of 30mL second alcohol and water (V: V=5: 1).To It is sequentially added in reaction solution iron powder (306mg, 5.46mmol), ammonium chloride (584mg, 10.9mmol).Reaction solution is warming up to 80 DEG C, It is stirred to react 2 hours.After reaction, reaction solution is cooled to room temperature, is concentrated under reduced pressure, ethyl acetate is added in residue and lacked Measure methanol, pad diatomite filtering, filter cake washs with ethyl acetate, collect filtrate, filtrate decompression concentration, with silica gel column chromatography with Eluant, eluent system A purifying gained residue, obtains title product 96b (550mg, brown liquid), yield 87%.
Third step
(R) -4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- ((2,2- dimethyl -1, 3- dioxolanes -4- base) methyl) -1H- pyrazoles -4- base) phenyl) piperidines -1- formamide 96c
Triphosgene (34mg, 0.114mmol) is dissolved in 10mL tetrahydrofuran, be added prefabricated 10mL 96b (82mg, In 0.3mmol) tetrahydrofuran solution, 0.2mL triethylamine, in 25 DEG C react 30 minutes, prefabricated 10mL 1f is added The tetrahydrofuran solution of (100mg, 0.29mmol) reacts 1 hour in 25 DEG C.After reaction, reaction solution is concentrated under reduced pressure, is used Thin-layered chromatography purifies gained residue with eluant, eluent system A, obtains title product 96c (110mg, khaki solid), yield 59%.
4th step
(R) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (2,3- dihydroxy third Base) -1H- pyrazoles -4- base) phenyl) piperidines -1- formamide 96
96c (110mg, 0.193mmol) is dissolved in 15ml methanol, is added Loprazolam (25mg, 0.26mmol), in 25 DEG C reaction 18 hours.After reaction, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained it is residual Excess obtains title product 96 (40mg, khaki solid), yield 39%.
MS m/z (ESI): 603.4 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.69 (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)
Embodiment 97
(S) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (2,3- dihydroxy third Base) -1H- pyrazoles -4- base) phenyl) piperidines -1- formamide 97
Using the synthetic route of embodiment 96, by raw material (S)-(-) -4- chloromethyl -2,2- dimethyl -1,3-dioxolane Replace with (R)-(-) -4- chloromethyl -2,2- dimethyl -1,3-dioxolane (using well known method " Pharma Chemica, Title product 97 (45mg, Tan solid), yield 48% is made in 2011,3 (4), 219-226 ".
MS m/z (ESI): 603.4 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.69 (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)
Embodiment 98
N- (4- (1- ((1- amino cyclopropyl) methyl) -1H- pyrazoles -4- base) phenyl) -4- (2- ((the bromo- 4- fluorophenyl of 3-) Amino) -2- (oximido) acetyl group) piperidines -1- formamide
The first step
Methanesulfonic acid (1- ((tertbutyloxycarbonyl) amino) cyclopropyl) methyl ester 98b
By (1- methylol) cyclopropyl) t-butyl carbamate 98a (3.74g, 20mmol) is dissolved in 40mL methylene chloride, It is added triethylamine (3g, 30mmol), ice bath is added dropwise to methane sulfonyl chloride (2.75g, 24mmol), and 0 DEG C is stirred to react 2 hours.Instead After answering, 50mL saturated sodium bicarbonate solution, liquid separation is added, organic phase washed once with saturated sodium chloride solution 50mL, nothing Aqueous sodium persulfate dries, filters, filtrate decompression concentration, obtain crude title product 98b (4.8g, faint yellow solid), product without Purifying is directly in next step.
Second step
(1- ((4 iodo- 1H- pyrazol-1-yl) methyl) cyclopropyl) t-butyl carbamate 98c
Crude product 98b (4.53g, 17mmol) is dissolved in 40mL dimethyl acetamide, addition cesium carbonate (11.1g, 34.2mmol), the iodo- 1H- pyrazoles (2.2g, 11.4mmol) of 4- is added, under argon atmospher, 70 DEG C are stirred to react 16 hours.Reaction knot Shu Hou, reaction solution are concentrated under reduced pressure, and 100mL water is added in residue, and ethyl acetate extracts (100mL × 3), merge organic phase, organic It mutually washed once with saturated sodium chloride solution 100mL, anhydrous sodium sulfate dries, filters, and silica gel column chromatography is used in filtrate decompression concentration Method purifies gained residue with eluant, eluent system B, obtains title product 98c (3g, off-white powder), yield 73%.
Third step
(1- ((4- (4- nitrobenzophenone) -1H- pyrazol-1-yl) methyl) cyclopropyl) t-butyl carbamate 98e
By 98c (600mg, 1.65mmol), 4- nitrobenzene boronic acid 98d (276mg, 1.65mmol), [1,1 '-bis- (diphenyl Phosphorus) ferrocene] palladium chloride (121mg, 0.16mmol), potassium carbonate (456mg, 3.3mmol) addition 30mL dioxane and 6mL In water, under argon atmospher, it is stirred to react in 100 DEG C 16 hours.After reaction, ethyl acetate and anhydrous sodium sulfate, diatom is added Soil filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 98e (320mg, hazel-color solid), yield 54%.
4th step
(1- ((4- (4- aminophenyl) -1H- pyrazol-1-yl) methyl) cyclopropyl) t-butyl carbamate 98f
98e (320mg, 0.89mmol) is dissolved in the in the mixed solvent of 25mL second alcohol and water (V: V=5: 1).To reaction It is sequentially added in liquid iron powder (100mg, 1.78mmol), ammonium chloride (191mg, 3.57mmol).Reaction solution is warming up to 80 DEG C, stirring Reaction 3 hours.After reaction, reaction solution is cooled to room temperature, is concentrated under reduced pressure, ethyl acetate is added in residue, pad diatom Soil filtering, filter cake are washed with ethyl acetate, collect filtrate, and filtrate decompression concentration is pure with eluant, eluent system A with silica gel column chromatography Change gained residue, obtains title product 98f (160mg, brown liquid), yield 54%.
5th step
(1- ((4- (4- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamide) benzene Base) -1H- pyrazol-1-yl) methyl) cyclopropyl) t-butyl carbamate 98g
Triphosgene (34mg, 0.114mmol) is dissolved in 10mL tetrahydrofuran, prefabricated 10mL 98f is added (100mg, 0.3mmol) tetrahydrofuran solution, 0.12mL triethylamine react 30 minutes in 25 DEG C, prefabricated 10mL 1f are added The tetrahydrofuran solution of (100mg, 0.29mmol) reacts 1 hour in 25 DEG C.After reaction, methanol quenching reaction will react Liquid be concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 98g (70mg, white consolidate Body), yield 34%.
6th step
N- (4- (1- ((1- amino cyclopropyl) methyl) -1H- pyrazoles -4- base) phenyl) -4- (2- ((the bromo- 4- fluorophenyl of 3-) Amino) -2- (oximido) Acetylpiperidin -1- formamide 98
98g (70mg, 0.112mmol) is dissolved in hydrogen chloride Isosorbide-5-Nitrae-dioxane solution of 15mL 4M, reacts 1 in 25 DEG C Hour.After reaction, reaction solution being concentrated under reduced pressure, title product 98 (40mg, white solid) is made in high performance liquid chromatography, Yield 63.5%.
MS m/z (ESI): 598.4 [M+1]
1H NMR (400MHz, CD3OD) 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)
Embodiment 99
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- cyano -5- methoxypyridine -3- Base) piperidines -1- formamide 99
Triphosgene (181mg, 0.114mmol) is dissolved in 20mL tetrahydrofuran, prefabricated 20mL 2- cyano -3- is added Methoxyl group -5- aminopyridine 99a (136mg, 0.91mmol, using apply for a patent method disclosed in WO2003062241 " preparation and ) tetrahydrofuran solution, triethylamine (264mg, 2.6mmol), in 25 DEG C react 30 minutes, be added prefabricated 1f (100mg, 20mL tetrahydrofuran solution 0.29mmol) reacts 1 hour in 25 DEG C.After reaction, methanol quenching reaction, by reaction solution It is concentrated under reduced pressure, gained residue purify with solvent system A with thin-layered chromatography, title product 99 is made, and (200mg, white is admittedly Body), yield 44%.
MS m/z (ESI): 519.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.69 (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)
Embodiment 100
4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- luorobenzyl) piperidines -1- formamide 100
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- fluorin benzyl amine, obtain title product 100 (50mg, it is white Color solid), yield 34.9%.
MS m/z (ESI): 495.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.65 (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)
Embodiment 101
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- cyano -5- picoline -3- base) Piperidines -1- formamide 101
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 2- cyano -3- first -5- aminopyridine (using patent Method disclosed in application " WO2015155626 " is prepared, title product 4- (2- ((the bromo- 4- fluorophenyl of 3-) amino)-is made 2- (oximido) acetyl group)-N- (6- cyano -5- picoline -3- base) piperidines -1- formamide 101 (13mg, white solid), it receives Rate 10%.
MS m/z (ESI): 503.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.69 (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)
Embodiment 102
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyano -3- methoxyphenyl) piperazine Pyridine -1- formamide 102
Using 99 synthetic route of embodiment, raw material 99a is replaced with into 4- amino -2- methoxy cyanophenyl, mark is made It inscribes product 102 (70mg, white solid), yield 46%.
MS m/z (ESI): 518.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 103
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- methoxy-benzyl) piperidines -1- first Amide 103
Using 99 synthetic route of embodiment, raw material 99a is replaced with into 4- methoxybenzylamine, title product 103 is made (60mg, white solid), yield 40.5%.
MS m/z (ESI): 507.3 [M+1]
1H NMR (400MHz, CDCl3) δ 9.07 (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)
Embodiment 104
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- piperidine -1- formamide 104
Using the synthetic route of embodiment 99, raw material 99a is replaced with into phenyl ethylamine, be made title product 104 (35mg, it is white Color solid), yield 24.6%.
MS m/z (ESI): 491.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.66 (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)
Embodiment 105
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (5- cyanopyridine -3- base) piperidines -1- Formamide 105
Using 99 synthetic route of embodiment, raw material 99a is replaced with into 5- Amino 3 cyano pyridine, title product 105 is made (130mg, white solid), yield 45.8%.
MS m/z (ESI): 489.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 106
4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (the fluoro- 4- mesyl of 2-) piperidines -1- Formamide 106
Using embodiment 99 at route, raw material 99a is replaced with into the fluoro- 4- methanesulfonylaniline of 2-, title product 106 is made (100mg, faint yellow solid), yield 62%.
MS m/z (ESI): 559.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 107
4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (5- cyanopyridine -3- base) piperidines -1- Formamide 107
Using 99 synthetic route of embodiment, raw material 99a is replaced with into 5- Amino 3 cyano pyridine, title product 107 is made (60mg, faint yellow solid), yield 42%.
MS m/z (ESI): 489.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 108
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (pyridin-3-yl) piperidines -1- formamide 108
Using 99 synthetic route of embodiment, raw material 99a is replaced with into 3- aminopyridine, be made title product 108 (50mg, Khaki solid), yield 37%.
MS m/z (ESI): 464.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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).
Embodiment 109
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (3- cyanobenzyls) piperidines -1- formyl Amine 109
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 3- cyano benzylamine, title product 109 is made (23mg, white solid), yield 15.7%.
MS m/z (ESI): 502.3 [M+1]
1H NMR (400MHz, CDCl3) δ 7.55-7.59 (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)
Embodiment 110
4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (3- cyano -4- methoxy-benzyl) piperazine Pyridine -1- formamide 110
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 5- (aminomethyl) -2- methoxy cyanophenyl (using special Method disclosed in benefit application " WO2001030745 " is prepared), obtain title product 110 (45mg, pale solid), yield 29%.
MS m/z (ESI): 532.4 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.66 (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)
Embodiment 111
(S) -4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (1- phenethyl) piperidines -1- formyl Amine 111
Using 99 synthetic route of embodiment, raw material 99a is replaced with into (S) -1- phenyl ethylamine, title product 111 is made (55mg, white solid), yield 38.7%.
MS m/z (ESI): 491.3 [M+1]
1H NMR (400MHz, CDCl3) 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)
Embodiment 112
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- fluorobenzene ethyl) piperidines -1- formyl Amine 112
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- fluorophenethylamine, title product 112 is made (62mg, faint yellow solid), yield 42%.
MS m/z (ESI): 509.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.65 (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).
Embodiment 113
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- carbamoyl benzyl) piperidines - 1- formamide 113
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- (aminomethyl) benzamide (using patent application Method disclosed in " WO2003097579 " is prepared), obtain title product 113 (10mg, white solid), yield 6.6%.
MS m/z (ESI): 520.3 [M+1]
1H NMR (400MHz, CDCl3) δ 8.00 (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)
Embodiment 114
(R) -4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (1- phenethyl) piperidines -1- formyl Amine 114
Using the synthetic route of embodiment 99, raw material 99a is replaced with into (R) -1- phenyl ethylamine, title product 114 is made (69mg, faint yellow solid), yield 48%.
MS m/z (ESI): 491.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.67 (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)
Embodiment 115
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (2- cyanopyridine -4- base) methyl) piperazine Pyridine -1- formamide 115
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- aminomethyl -2- cyanopyridine (well known to use Method " Bioorganic&Medicinal Chemistry, 2005,13 (12), 4022-4036 " are prepared), title is made Product 115 (40mg, hazel-color solid), yield 27%.
MS m/z (ESI): 503.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.67 (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)
Embodiment 116
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- picoline -3- base) piperidines -1- Formamide 116
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 3- amino -6- picoline, title product is made 116 (45mg, faint yellow solids), yield 32.4%.
MS m/z (ESI): 478.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.67 (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)
Embodiment 117
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (3- methoxy-benzyl) piperidines -1- first Amide 117
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 3- methoxybenzylamine, title product 4- (2- is made ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (3- methoxy-benzyl) piperidines -1- formamide 117 (30mg, White solid), yield 20.4%.
MS m/z (ESI): 507.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.67 (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)
Embodiment 118
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (pyridine -2- ylmethyl) piperidines -1- first Amide 118
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 2- pyridyl-methanamine, title product 118 is made (15mg, light yellow solid), yield 11%.
MS m/z (ESI): 478.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 119
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (cyclohexyl methyl) piperidines -1- formyl Amine 119
Using the synthetic route of embodiment 99, raw material 99a is replaced with into cyclohexylmethylamine, title product 119 is made (25mg, white solid), yield 16.8%.
MS m/z (ESI): 483.3 [M+1]
1H NMR (400MHz, CDCl3) 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)
Embodiment 120
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- methoxyphenethyl) piperidines -1- Formamide 120
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- methoxyphenethylamine, title product 120 is made (45mg, white solid), yield 29.8%.
MS m/z (ESI): 521.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.67 (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)
Embodiment 121
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- methyl sulphonyl) benzyl) piperidines - 1- formamide 121
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- mesyl benzylamine, title product 121 is made (35mg, white solid), yield 21.7%.
MS m/z (ESI): 555.3 [M+1]
Embodiment 122
4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (2- methoxy-benzyl) piperidines -1- formyl Amine 122
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 2- methoxybenzylamine, title product 122 is made (40mg, faint yellow solid), yield 27%.
MS m/z (ESI): 507.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.66 (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)
Embodiment 123
4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (pyridin-4-yl methyl) piperidines -1- first Amide 123
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- dimethylaminopyridine, title product 123 is made (33mg, faint yellow solid), yield 23.9%.
MS m/z (ESI): 478.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 124
4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (pyridin-3-yl methyl) piperidines -1- first Amide 124
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 3- dimethylaminopyridine, title product 124 is made (25mg, faint yellow solid), yield 18%.
MS m/z (ESI): 478.3 [M+1]
Embodiment 125
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- (1- cyclopropyl -1H- pyrazoles -4- Base) pyridin-3-yl) piperidines -1- formamide
The first step
6- (1- cyclopropyl -1H- pyrazoles -4- base) pyridine -3- amine 125b
By 1- cyclopropyl -4- (4,4,5,5- tetramethyls -1,3,2- dioxy boron pentane -2- base) -1H- pyrazoles 125a (304mg, 1.3mmol are prepared using method disclosed in patent application " CN103122000 "), the bromo- 3- aminopyridine of 6- (150mg, 0.867mmol), [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride (28mg, 0.043mmol), potassium carbonate (180mg, 1.3mmol) is added in 16mL dioxane and 2mL water, under argon atmospher, is stirred to react in 85 DEG C 18 hours.Reaction knot 100mL water is added in reaction solution, is extracted with ethyl acetate (60mL × 3) by Shu Hou, merges organic phase, and silica gel column chromatography is used in concentration Method purifies gained residue with eluant, eluent system A, obtains title product 125b (154mg, Tan solid), yield 89%.
Second step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- (1- cyclopropyl -1H- pyrazoles -4- Base) pyridin-3-yl) piperidines -1- formamide 125
Triphosgene (172mg, 0.579mmol) is dissolved in 50mL tetrahydrofuran, addition 125b (290mg, 1.448mmol), 0.6mL triethylamine reacts 30 minutes in 0 DEG C, is added 1f (498mg, 1.448mmol), small in 25 DEG C of reactions 1 When.After reaction, 10mL methanol is added, reaction solution is concentrated under reduced pressure, purify with thin-layered chromatography with solvent system A obtained by Residue obtains title product 125 (135mg, white solid), yield 16.3%.
MS m/z (ESI): 570.4 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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).
Embodiment 126
4- ((4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamido) methyl) benzene Formic acid
The first step
4- ((4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamido) methyl) benzene Ethyl formate 126b
Triphosgene (34mg, 0.116mmol) is dissolved in 20mL tetrahydrofuran, Aminomethylbenzoic Acid ethyl ester 126a is added (54mg, 0.307mmol), triethylamine (0.12mL, 0.86mmol) react 30 minutes in 25 DEG C, addition 1f (100mg, 0.29mmol), it is stirred to react in 25 DEG C 1 hour.After reaction, methanol is added, reaction solution is concentrated under reduced pressure, thin-layer chromatography is used Method purifies gained residue with solvent system A, obtains title product 126b (40mg, white solid), yield 25%.
Second step
4- ((4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamido) methyl) benzene Formic acid 126
126b (20mg, 0.0364mmol) is dissolved in 1mL ethyl alcohol, be added 1mL sodium hydroxide (3mg, 0.0728mmol) solution, 25 DEG C are stirred to react 16 hours.After reaction, with 1M salt acid for adjusting pH to 5, ethyl acetate extraction (20mL × 3) merge organic phase, and saturated sodium chloride solution is washed 1 time, and anhydrous sodium sulfate dries, filters, filtrate decompression concentration, With thin-layered chromatography with solvent system A purify gained residue, obtain title product 126 (5mg, white solid), yield 26%.
MS m/z (ESI): 521.3 [M+1]
1H NMR (400MHz, CD3OD) δ 7.96 (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)
Embodiment 127
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- (2- hydroxy ethoxy) pyridine -3- Base) piperidines -1- formamide
The first step
2- (2- ((t-Butyldimethylsilyl) oxygroup) ethyoxyl) -5- nitropyridine 127b
By 2- (5- nitro -2- pyridine oxygroup) ethyl alcohol 127a (0.5g, 2.732mmol, using patent application Method disclosed in " WO2008084873 " is prepared) it is dissolved in 10mL tetrahydrofuran, it is added imidazoles (0.28g, 4.098mmol) With tert-butyl chloro-silicane (0.49g, 3.279mmol), react 24 hours at 25 DEG C.After reaction, 40mL water is added, It is extracted with ethyl acetate (80mL × 3), merges organic phase, organic phase washed once with saturated sodium chloride solution, anhydrous sodium sulfate It dries, filters, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system B purify gained residue obtain title product 127b (350mg, yellow oil), yield 43%.
Second step
6- (2- ((t-Butyldimethylsilyl) oxygroup) ethyoxyl) pyridine -3- amine 127c
127b (360mg, 1.204mmol) is dissolved in the in the mixed solvent of 20mL second alcohol and water (V: V=5: 1).To anti- It answers and is sequentially added in liquid iron powder (202mg, 3.612mmol), ammonium chloride (384mg, 7.224mmol).Reaction solution is warming up to 70 DEG C, It is stirred to react 1 hour.After reaction, reaction solution is cooled to room temperature, is concentrated under reduced pressure, 50mL ethyl acetate is added in residue With 40mL water, liquid separation, water phase is extracted with ethyl acetate (50mL × 2), merges organic phase, and organic phase is washed with saturated sodium chloride solution It washs once, anhydrous sodium sulfate dries, filters, and filtrate decompression concentration, obtaining crude title product 127c, (330mg, yellow green are solid Body), product directly carries out next step reaction without further purification.
Third step
4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- (2- ((t-Butyldimethylsilyl) Oxygroup) ethyoxyl) pyridine) -3- base) piperidines -1- formamide 127d
Triphosgene (17mg, 0.058mmol) is dissolved in 10mL tetrahydrofuran, addition crude product 127c (41mg, 0.153mmol), 0.06mL triethylamine reacts 30 minutes in 25 DEG C, is added 1f (50mg, 0.146mmol), small in 25 DEG C of reactions 1 When.After reaction, 2mL methanol quenching reaction is added, reaction solution is concentrated under reduced pressure.In residue be added 50mL ethyl acetate and 30mL water, liquid separation, water phase are extracted with ethyl acetate (40mL × 2), merge organic phase, and organic phase is washed with saturated sodium chloride solution Once, anhydrous sodium sulfate dries, filters, and filtrate decompression concentration obtains crude title product 127d (60mg, yellow oil), Product directly carries out next step reaction without further purification
4th step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- (2- hydroxy ethoxy) pyridine -3- Base) piperidines -1- formamide 127
Crude product 127d (60mg, 0.0942mmol) is dissolved in 5mL methanol, the hydrochloric acid solution that addition 1mL concentration is 2M, 25 It is stirred to react at DEG C 18 hours.After reaction, reaction solution saturated solution of sodium bicarbonate adjusts pH to 7, ethyl acetate extraction (30mL × 3) merge organic phase, and organic phase washed once with saturated sodium chloride solution 30mL, and anhydrous sodium sulfate dries, filters, Filtrate decompression concentration, with thin-layered chromatography with solvent system A purify gained residue obtain title product 127 (12mg, white consolidate Body), yield 24%.
MS m/z (ESI): 524.3 [M+1]
1H NMR (400MHz, CD3OD) δ 8.07 (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)
Embodiment 128
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyano -3- methoxy-benzyl) piperazine Pyridine -1- formamide
The first step
4- (azido-methyl) -2- methoxy cyanophenyl 128b
4- chloromethyl -2- methoxy cyanophenyl 128a (400mg, 2.2mmol) is dissolved in 10mL n,N-Dimethylformamide In, prefabricated 2mL sodium azide (170mg, 2.62mmol) solution is added dropwise, is stirred to react 2 hours at 25 DEG C.After reaction, Ethyl acetate is added, water washing 2 times, saturated sodium chloride solution is washed 1 time, and anhydrous sodium sulfate dries, filters, and filtrate decompression is dense Contracting, obtain crude title product 128b (400mg, colorless oil), product without further purification directly in next step.
Second step
4- (aminomethyl) -2- methoxy cyanophenyl 128c
Crude product 128b (400mg, 2.12mmol) is dissolved in 20mL tetrahydrofuran, 3mL water, triphenylphosphine is added (669mg, 2.55mmol) is stirred to react 18 hours at 45 DEG C.After reaction, ethyl acetate, saturated sodium chloride solution is added Washing 1 time, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by it is residual Excess obtains title product 128c (130mg, white solid), yield 31.8%.
Third step
4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyano -3- methoxybenzyl) piperidines - 1- formamide 128
Triphosgene (43mg, 0.15mmol) is dissolved in 20mL tetrahydrofuran, be added prefabricated 5mL 128c (49mg, It 0.305mmol) with the tetrahydrofuran solution of triethylamine (88mg, 0.87mmol), is reacted 30 minutes in 25 DEG C, 1f is added (100mg, 0.29mmol) reacts 1 hour in 25 DEG C.After reaction, methanol quenching reaction is added, reaction solution is concentrated under reduced pressure, With thin-layered chromatography with solvent system A purify gained residue obtain title product 128 (60mg, pale solid), yield 38.9%.
MS m/z (ESI): 532.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.67 (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)
Embodiment 129
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- (1- difluoromethyl) -1H- pyrazoles - 4- yl) pyridin-3-yl) piperidines -1- formamide
The first step
6- (1- (difluoromethyl) -1H- pyrazoles -4- base) pyridine -3- amine 129b
By 1- (difluoromethyl) -4- (4,4,5,5- tetramethyls -1,3,2- dioxy boron pentane -2- base) -1H- pyrazoles 129a (150mg, 0.615mmol are prepared using method disclosed in patent application " WO2014159224 "), the bromo- 3- amino pyrrole of 6- Pyridine (106mg, 0.615mmol), [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride (45mg, 0.062mmol), potassium carbonate (255mg, 1.845mmol) is added in 10mL dioxane and 2mL water, under argon atmospher, is stirred to react in 85 DEG C 3 hours.Reaction After, 50mL water is added in reaction solution, is extracted with ethyl acetate (80mL × 3), merges organic phase, organic phase is saturated with 50mL Sodium-chloride water solution washs 1 time, and anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent body It is A purifying gained residue, obtains title product 129b (150mg, brown oil).
Second step
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (6- (1- difluoromethyl) -1H- pyrazoles - 4- yl) pyridin-3-yl) piperidines -1- formamide 129
Triphosgene (40mg, 0.135mmol) is dissolved in 10mL tetrahydrofuran, is added 129b (34mg, 0.161mmol), 0.3mL triethylamine reacts 30 minutes in 25 DEG C, is added 1f (50mg, 0.145mmol), reacts 1 hour in 25 DEG C.Reaction terminates Afterwards, be added methanol, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain title produce Object 129 (9mg, yellow solid), yield 10.7%.
MS m/z (ESI): 580.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (s, 1H), 8.79 (s, 1H), 8.70 (s, 1H), 8.64 (s, 1H), 8.39 (s, 1H), 8.38 (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)
Embodiment 130
N- (6- ((1- amino cyclopropyl) methoxyl group) pyridin-3-yl) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamide
The first step
(1- (((5- nitropyridine -2- base) oxygroup) methyl) cyclopropyl) amino tert-butyl ester 130b
(1- (methylol) cyclopropyl) t-butyl carbamate (0.709g, 3.784mmol) is dissolved in 20mL N, N- diformazan In base formamide, ice bath is added 60% sodium hydride (0.15g, 3.784mmol), reacts 0.5 hour at 25 DEG C, and the chloro- 5- of 2- is added Nitropyridine 130a (0.5g, 3.154mmol) reacts 2.5 hours at 25 DEG C.After reaction, 60mL water is added, with acetic acid second Ester extracts (50mL × 3), merges organic phase, and organic phase is concentrated under reduced pressure, purify with silica gel column chromatography with eluant, eluent system B obtained by Residue obtains title product 130b (455mg, yellow solid), yield 46.6%.
Second step
(1- (((5- aminopyridine -2- base) oxygroup) methyl) cyclopropyl) t-butyl carbamate 130c
130b (455mg, 1.471mmol) is dissolved in the in the mixed solvent of 25mL second alcohol and water (V: V=4: 1).To anti- It answers and is sequentially added in liquid iron powder (329mg, 5.884mmol), ammonium chloride (1.812g, 11.768mmol).Reaction solution is warming up to 70 DEG C, it is stirred to react 1.5 hours.After reaction, 50mL water is added in reaction solution, be extracted with ethyl acetate (30mL × 3), merged Organic phase, organic phase are washed (100mL × 2) with saturated sodium chloride solution, are concentrated under reduced pressure, are obtained crude title product 130c (410mg), product without further purification directly in next step.
Third step
(1- (((5-4- (2- (the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamide) pyridine - 2- yl) oxygroup) methyl) cyclopropyl) t-butyl carbamate 130d
At 0 DEG C, triphosgene (86mg, 0.29mmol) is dissolved in 5mL tetrahydrofuran, prefabricated 1mL crude product 130c is added The tetrahydrofuran solution of (81mg, 0.290mmol) and triethylamine (0.163mL, 1.162mmol) mixing, 0 DEG C is reacted 30 minutes, 25 DEG C of addition 1f (100mg, 0.29mmol) and 5mL tetrahydrofuran react 2 hours in 25 DEG C.After reaction, 5mL first is added Alcohol quenching reaction, reaction solution be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue obtain title product Obtain title product 130d (122mg, yellow oil), yield 64.9%.
4th step
N- (6- ((1- amino cyclopropyl) methoxyl group) pyridin-3-yl) -4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamide 130
130d (122mg, 0.188mmol) is dissolved in 3mL methanol, hydrogen chloride Isosorbide-5-Nitrae-dioxy that 3mL concentration is 4M is added Six ring solution are stirred to react 2 hours at 25 DEG C.After reaction, reaction solution is concentrated under reduced pressure.100mL acetic acid second is added in residue Ester and 100mL saturated solution of sodium bicarbonate, ethyl acetate extract (100mL × 3), merge organic phase, are concentrated under reduced pressure, use silica gel Column chromatography purifies gained residue with eluant, eluent system A and title product 130 (50mg, white solid), yield 48.5% is made.
MS m/z (ESI): 549.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.68 (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)
Embodiment 131
2- (1- (4- (1H- tetrazole -1- base) phenyl) piperidin-4-yl)-N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- Carbonyl ethanamidine 131
Raw material 81a (43.3mg, 0.1mmol) is dissolved in 1mL acetic acid, 0.1mL triethyl orthoformate, 25 DEG C of reactions are added It 0.5 hour, is added sodium azide (9.75mg, 0.15mmol), under argon atmospher, 80 DEG C are reacted 3 hours.After reaction, it is added 20mL water, saturated sodium bicarbonate solution adjust pH to 8, and methylene chloride extracts (20mL × 3), merge organic phase, saturated sodium-chloride Solution washs (20mL × 1), and anhydrous sodium sulfate dries, filters, filtrate decompression concentration.Thin-layered chromatography is pure with eluant, eluent system A Change institute's residue and title product 131 (12mg, light tan solid), yield 24.6% is made.
MS m/z (LC-MS): 488.3 [M+1]
1H NMR (400MHz, CDCl3) 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)
Embodiment 132
4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group)-N- (3,4- dicyano benzyl) piperidines -1- Formamide 132
Using the synthetic route of embodiment 128, raw material 4- chloromethyl -2- methoxy cyanophenyl is replaced with into 3,4- dicyano benzyl Bromine (the well known method of use " Chem.Eur.T, 2012,18,1727-1736 " is prepared), title product 132 is made (50mg, khaki solid), yield 33%.
MS m/z (ESI): 527.3 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.66 (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).
Embodiment 133
2- (4- (2- ((the bromo- 4- fluorophenyl of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) thiazole -5- formic acid 133
Using the synthetic route of embodiment 84, the bromo- 4- of raw material 2- (pyridine -2- base) thiazole is replaced with into 2- bromo thiazole -5- Title product 133 (10mg, white solid), yield 7.4% is made in formic acid.
MS m/z (LC-MS): 471.2 [M+1]
1H NMR (400MHz, DMSO-d6) δ 11.80 (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)
Embodiment 134
N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -2- carbonyl -2- (1- (4- (amino-sulfonyl) phenyl) piperidin-4-yl) Ethanamidine 134
Using the synthetic route of embodiment 72, raw material 72a is replaced with into 4- amino-sulfonyl fluorobenzene, title product is made 134 (5mg, yellow solids), yield 5%.
MS m/z (LC-MS): 499.3 [M+1]
Biological assessment
Below in conjunction with test case further describe explanation the present invention, but these embodiments be not meant as limiting it is of the invention Range.
The measurement of test case 1, the compounds of this invention to source of people IDO1 protease inhibiting activity
External source of people IDO1 proteinase activity is tested by the following method.
This method is used to measure the compound in the present invention to the inhibiting effect of source of people IDO1 proteinase activity.
One, experimental material and instrument
1, microplate reader (Synergy HT, BIOTEK)
2, tryptophan (T0254-5G, Sigma-Aldrich)
3, catalase derives from cattle liver (C1345-1G, Sigma-Aldrich)
4, methylenum careuleum (M9140-25G, Sigma-Aldrich)
5, L-AA sodium (A7631-25G, Sigma-Aldrich)
6,4- (dimethylamino) benzaldehyde (D2004-25G, Sigma-Aldrich)
7, trichloroacetic acid (T9159-100G, Sigma-Aldrich)
8, source of people IDO1 gene (SC126221, Origene)
Two, experimental procedure
The self-control of IDO1 protease
Source of people IDO1 gene is transferred to PET-30 (a) plasmid (Millipore, article No. by gene clone technology 69909) in, then it is transferred to the Escherichia coli rosseta of competence；Liquid LB (Luria-Bertani) culture medium [according to " Molecular Cloning:A Laboratory guide " (J. Pehanorm Brooker D.W. Russell work) prepare every liter of culture medium] in amplification culture, collect bacterium Body, ultrasonication afford the IDO1 protease of purifying by hanging nickel column.
Compound test experiments:
100 times of the enzyme (IDO1) of 24 μ l is diluted to 2400 μ l with the KPB of 50mM, it is molten to obtain the enzyme that concentration is 2.6ng/ μ l 24 μ l enzyme solutions are added in the every hole of 96 hole reaction plates (AXYGEN, PCR-96-FLT-C) (hereinafter referred to as reaction plate) in liquid.Blank pair 24 μ l KPB are added according to hole and [preparation (50mM) of KPB buffer: weigh KH with assay balance2PO46.805g being put into 1000ml's Beaker is added deionized water to 900ml with graduated cylinder, adjusts PH to 6.5 with the KOH of 1M, be conducted into the graduated cylinder of 1L, moisturizing is extremely 1L.4 DEG C of storages].Reaction plate be added 1 μ l compound or DMSO into corresponding reacting hole.Prepare A liquid: taking 200 μ l 500mM L-AA sodium adds 1050 μ l KPB, mixes.B liquid: the acid of 100 μ l 10mM color ammonia adds 100 μ l 100000unit/ The catalase of ml adds the methylenum careuleum of 5 μ l 10mM, finally plus 1050 μ l KPB, mixes.Take 1200 μ l A liquid and 1200 μ l B liquid mixes.Then this mixed liquor is added in reaction plate with every 24 μ l of hole.Reaction plate is put into constant-temperature incubation case, 37 DEG C, It is incubated for 1h.In reaction plate, 10 μ l 30% (W/V) trichloroacetic acids are added in every hole, are incubated for 15 minutes for 65 DEG C in incubator.It will Reaction plate 4700RPM on centrifuge is centrifuged, room temperature, and 5 minutes.40 μ l supernatants are shifted from reaction plate with the volley of rifle fire to corresponding 96 In hole test board (Corning, #3599).4- (dimethylamino) benzaldehyde/glacial acetic acid of 40 μ l 2% (W/V) is added in every hole Solution mixes 1.After incubation at room temperature 2 minutes, the light absorption value at 480nm is read on Synergy HT (BIOTEK).
Compound is measured source of people IDO1 protease inhibiting activity by above test in the present invention, measures IC50Value is shown in Table 1.
Compound inhibits IC to source of people IDO1 proteinase activity in 1 present invention of table50
Conclusion: the compounds of this invention significantly inhibits source of people IDO1 proteinase activity.
The measurement of test case 2, the compounds of this invention IDO protease inhibiting activity intracellular to HeLa
The intracellular IDO proteinase activity of HeLa is tested by the following method.
This method is used to measure the inhibiting effect of the compound IDO proteinase activity intracellular to HeLa in the present invention. (note: HeLa cell strain expresses indoleamine 2,3-dioxygenase (IDO) under the induction of interferon gamma (INF- γ))
One, experimental material and instrument
1, microplate reader (Synergy HT, BIOTEK)
2, tryptophan (T0254-5G, Sigma-Aldrich)
3,4- (dimethylamino) benzaldehyde (D2004-25G, Sigma-Aldrich)
4, trichloroacetic acid (T9159-100G, Sigma-Aldrich)
5, HeLa cell strain (CCL-2, ATCC)
Two, experimental procedure
HeLa cell suspension is produced with Fresh cell culture medium, with 10000 cells/wells, 100 μ l cell suspensions is added and arrive In 96 porocyte culture plates, 5% carbon dioxide, 37 DEG C are cultivated 24 hours.Supernatant is removed, first 90 μ l serum-free DMEM are added in every hole High glucose medium；Then every hole be separately added into 10 μ l gradient dilutions compound (dilution be γ containing INF- and tryptophan and The culture medium of 20%FBS, final concentration is successively are as follows: 100000,10000,1000,100,10,1nM), 5% carbon dioxide, 37 DEG C Culture 48 hours takes in 96 porocyte culture plates 80 μ l of supernatant into 96 hole round bottom plates, and 16 μ l, 30% (W/V) three is added in every hole Monoxone is incubated for 25 minutes for 65 DEG C in incubator.By reaction plate, 4700RPM is centrifuged on centrifuge, and 5 minutes.With the volley of rifle fire from 50 μ l supernatants are shifted in reaction plate into 96 hole flat bottom clear plates, then 4- (the dimethyl of 50 μ l 2% (W/V) is added in every hole Amino) benzaldehyde/glacial acetic acid solution, it mixes 1 minute on the oscillator.After incubation at room temperature 2 minutes, in Synergy HT The light absorption value at 480nm is read on Reader.
Compound IDO protease inhibiting activity intracellular to HeLa is measured by above test in the present invention, is surveyed The IC obtained50Value is shown in Table 2.
Compound IDO proteinase activity intracellular to HeLa inhibits IC in 2 present invention of table50
Conclusion: the compounds of this invention IDO proteinase activity intracellular to HeLa significantly inhibits.
Pharmacokinetic Evaluation
The pharmacokinetics test of test case 3, compound of the embodiment of the present invention
1, it makes a summary
Using SD rat as animal subject, using LC/MS/MS method determine rat oral gavage give embodiment 2,3,4,20,21, 30, the drug concentration after 50,105,106,107 and 125 compounds in different moments blood plasma.The compounds of this invention is studied in rat Intracorporal pharmacokinetics behavior, evaluates its characteristics of pharmacokinetics.
2, testing program
2.1 test drug
Embodiment 2,3,4,20,21,30,50,105,106,107 and 125 compounds
2.2 experimental animal
Healthy adult SD rat 44, half male and half female is purchased from the western Poole-Bi Kai experimental animal in Shanghai Co., Ltd, animal Production licence number: SCXK (Shanghai) 2008-0016.
2.3 drugs are prepared
It weighs appropriate amount of drug and 10%2- hydroxypropyl-β-cyclodextrin is added after addition 0.3ml dimethyl acetamide makes dissolution To final volume, 0.3mg/ml suspension is made in ultrasound.Wherein 0.2mg/mL suspension is made in 50 ultrasound of embodiment.
2.4 administration
SD rat 44, half male and half female is divided into 11 groups；Gastric infusion, gastric infusion volume are distinguished after one night of fasting 10ml/kg。
3, it operates
0.5,1.0,2.0,4.0,6.0,8.0,11.0, the 24.0h blood sampling before administration and after administration of gastric infusion group 0.2ml is placed in heparinised tubes, and 3500rpm is centrifuged 10min separated plasma, is saved in -20 DEG C.
Untested compound content after measuring different compound gastric infusions with LC/MS/MS method in rat plasma.
4, pharmacokinetic parameter result
The pharmacokinetic parameter of the embodiment of the present invention 2,3,4,20,21,30,50,105,106,107 and 125 compounds It is as follows:
Conclusion: in the medicine generation of the compounds of this invention, absorbs well, has apparent medicine for assimilation effect.

Claims (22)

1. a kind of logical formula (I) compound represented:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form, or Its pharmaceutical salt,
Wherein:
Mixture selected from cis-isomer, transisomer and cis-trans-isomer；
Ring A is selected from C3-8Naphthenic base or heterocycle, wherein the C3-8Naphthenic base or heterocycle are optionally selected from each independently C1-6Replaced one or more substituent groups in alkyl and halogen；
R1It is identical or different, and it is each independently selected from hydrogen atom, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6 Alkoxy, halogen, amino, nitro, hydroxyl, cyano, C3-8Naphthenic base, heterocycle, C6-10Aryl, heteroaryl ,-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)R6With-(CH2)xNR5S(O)mR6, wherein the C1-6Alkyl, halogenated C1-6Alkyl, C3-8Ring Alkyl, 3 to 8 element heterocycle bases, C6-10Aryl and heteroaryl are optionally selected from C each independently1-6Alkyl, halogenated C1-6Alkyl, halogen Element, amino, nitro, cyano, hydroxyl, C1-6Alkoxy, halogenated C1-6Alkoxy, C1-6Hydroxyalkyl, C3-8Naphthenic base, heterocycle, C6-10Aryl, heteroaryl ,-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-S(O)mNR7R8、-NR7R8、-C(O)NR7R8、- NR7C(O)R8With-NR7S(O)mR8In one or more substituent groups replaced；
R2It is identical or different, and it is each independently selected from hydrogen atom, C1-6Alkyl, halogenated C1-6Alkyl, alkenyl and halogen；
R3Selected from C1-6Alkyl, halogenated C1-6Alkyl, C3-8Naphthenic base, C3-8Naphthenic base C1-6Alkoxy, heterocycle, C6-10Aryl and miscellaneous Aryl, wherein the C1-6Alkyl, halogenated C1-6Alkyl, C3-8Naphthenic base, C3-8Naphthenic base C1-6Alkoxy, heterocycle, C6-10Virtue Base and heteroaryl are optionally selected from C each independently1-6Alkyl, halogen, halogenated C1-6Alkyl, amino, nitro, hydroxyl, C1-6Alcoxyl Base, C1-6Hydroxyalkyl, cyano, C3-8Naphthenic base, C3-8Naphthenic base C1-6Alkyl, heterocycle, C6-10Aryl, heteroaryl ,-C (O) NR7R8、-S(O)mR7、-C(O)OR7With-OR7In one or more substituent groups replaced；The wherein C3-8Naphthenic base C1-6 Alkyl is optionally selected from C1-6Alkyl, halogen, halogenated C1-6Alkyl, amino, hydroxyl, C1-6Alkoxy, C1-6One in hydroxyalkyl Or replaced multiple substituent groups；
R4Selected from hydrogen atom, C1-6Alkyl, halogenated C1-6Alkyl, hydroxyl, amino, C1-6Alkoxy, halogenated C1-6Alkoxy, C3-8Cycloalkanes Base, heterocycle, C6-10Aryl, heteroaryl, wherein the C1-6Alkyl, halogenated C1-6Alkyl, C3-8Naphthenic base, heterocycle, aryl Optionally C is selected from each independently with heteroaryl1-6Alkyl, halogen, amino, nitro, cyano, hydroxyl, C1-6Hydroxyalkyl, C1-6Alkane Oxygroup, C3-8Naphthenic base, heterocycle, C6-10Replaced one or more substituent groups in aryl and heteroaryl；
R5And R6It is identical or different, and it is each independently selected from hydrogen atom, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, C1-6 Hydroxyalkyl, hydroxyl, amino, C3-8Naphthenic base, heterocycle, C6-10Aryl, heteroaryl ,-(CH2)xR3、-OR7、-C(O)R7、-C(O) OR7、-S(O)mR7、-S(O)mNR7R8、-NR7R8、-(CH2)xC(O)NR7R8、-(CH2)xNR7C(O)R8With-(CH2)xNR7S(O)mR8, wherein the C1-6Alkyl, halogenated C1-6Alkyl, amino, C3-8Naphthenic base, heterocycle, C6-10Aryl and heteroaryl are respectively only On the spot optionally it is selected from C1-6Alkyl, halogenated C1-6Alkyl, halogen, hydroxyl, amino, nitro, cyano, C1-6Alkoxy, C1-6Hydroxyl alkane Base, C3-8Naphthenic base, heterocycle, C6-10Aryl and heteroaryl ,-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、- C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8In one or more substituent groups replaced；
R7And R8It is identical or different, and it is each independently selected from hydrogen atom, C1-6Alkyl, C1-6Alkoxy, C1-6Hydroxyalkyl, hydroxyl, Amino, carboxylate ,-S (O)mNR9C(O)OR10、-C(O)OR10、-S(O)mNR9R10、C3-8Naphthenic base, C3-8Naphthenic base C1-6Alkane Base, heterocycle, C6-10Aryl and heteroaryl；
R9And R10It is identical or different, and it is each independently selected from hydrogen atom, C1-6Alkyl, amino, C1-6Alkoxy or C1-6Hydroxyl alkane Base；
M is 0,1 or 2；
N is 0,1,2,3,4 or 5；
P is 0,1,2,3,4 or 5；And
X is 0,1,2 or 3；
The heterocycle is the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, includes 3 to 8 annular atoms, wherein 1 It is the hetero atom selected from nitrogen, oxygen or sulphur to 3；
The heteroaryl is 5- or 6-membered heteroaryl, contains 5 or 6 annular atoms, wherein 1 to 4 is selected from oxygen, sulphur and nitrogen Hetero atom.
2. logical formula (I) compound represented according to claim 1, in which: A is selected from C3-8Naphthenic base or heterocycle, it is described Heterocycle it is as defined in claim 1.
3. logical formula (I) compound represented according to claim 1, wherein n is 1.
4. logical formula (I) compound represented according to claim 1, wherein p is 1,2 or 3.
5. logical formula (I) compound represented according to claim 1, wherein R1It is identical or different, and be each independently selected from Hydrogen atom, C1-6Alkyl, amino, hydroxyl, C6-10Aryl, heteroaryl ,-C (O) R4、-(CH2)xC(O)OR4、-S(O)mR4、-S(O)mNR5R6、-(CH2)xNR5R6、-(CH2)xC(O)NR5R6、-(CH2)xNR5C(O)R6With-(CH2)xNR5S(O)mR6, wherein described C1-6Alkyl, C6-10Aryl and heteroaryl are optionally selected from nitro, cyano ,-R each independently3、-C(O)NR7R8、-NR7C(O)R8 With-NR7S(O)mR8In one or more substituent groups replaced；R3~R8, x and m, heteroaryl it is as defined in claim 1.
6. logical formula (I) compound represented according to claim 1, wherein R2For halogen, halogenated C1-6Alkyl or alkenyl.
7. logical formula (I) compound represented according to claim 1, to lead to formula (II) compound represented:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form, or Its officinal salt,
Wherein: R1、R2And p is as defined in claim 1.
8. logical formula (II) compound represented according to claim 7, to lead to formula (III) compound represented:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form, or Its officinal salt,
Wherein: R1、R2It is as defined in claim 1 with p.
9. logical formula (I) compound represented according to claim 1, to lead to formula (IV) compound represented:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form, or Its officinal salt,
Wherein:
Ring B is selected from C6-10Aryl or heteroaryl；
RaSelected from hydrogen atom, C1-6Alkyl, halogenated C1-6Alkyl, halogen, amino, nitro, cyano, hydroxyl, C1-6Alkoxy, C1-6Hydroxyl Alkyl, C3-8Naphthenic base, heterocycle, C6-10Aryl, heteroaryl ,-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、- NR7R8、-C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8；
R2、R3、R7、R8, m, p, heterocycle and heteroaryl are as defined in claim 1；And
Y is 0,1,2,3,4 or 5.
10. logical formula (I) compound represented according to claim 1, to lead to formula (V) compound represented:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form, or Its officinal salt,
Wherein:
G is selected from C or N；
RaSelected from hydrogen atom, C1-6Alkyl, halogenated C1-6Alkyl, halogen, amino, nitro, cyano, hydroxyl, C1-6Alkoxy, C1-6Hydroxyl Alkyl, C3-8Naphthenic base, heterocycle, C6-10Aryl, heteroaryl ,-R3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、- NR7R8、-C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8；
R2、R3、R7、R8, m, p, heterocycle and heteroaryl are as defined in claim 1；And
Y is 0,1,2,3,4 or 5.
11. logical formula (V) compound represented according to claim 10 is general formula (V-A) compound represented:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form, or Its officinal salt,
Wherein:
RbSelected from hydrogen atom, C1-6Alkyl, halogenated C1-6Alkyl, amino, C3-8Naphthenic base, C3-8Naphthenic base C1-6Alkyl, C1-6Hydroxyl alkane Base, heterocycle, C6-10Aryl and heteroaryl；Heterocycle and heteroaryl are as defined in claim 1.
12. logical formula (I) compound represented described according to claim 1~any one of 11, is selected from:
13. a kind of method for preparing logical formula (I) compound according to claim 1, this method comprises:
General formula (I-A) compound at room temperature, with R1- NCO reaction or at low temperature under alkaline condition with R1Halide Reaction, is optionally deprotected in acid condition, obtains logical formula (I) compound；
Wherein:
R1、R2, A, p and n it is as defined in claim 1.
14. a kind of method for preparing logical formula (I) compound according to claim 1, this method comprises:
General formula (I-B) compound with the derivatives reaction of aniline, obtains logical formula (I) compound at room temperature；
Wherein, R1、R2, A, p and n it is as defined in claim 1.
15. compound shown in a kind of general formula (I-B):
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form, or Its officinal salt,
Wherein, R1, A and n it is as defined in claim 1.
16. general formula (I-B) compound represented according to claim 15, is selected from:
17. a kind of pharmaceutical composition, containing therapeutically effective amount according to claim 1~any one of 12 described in general formula (I) compound represented and one or more pharmaceutically acceptable carriers, diluent or excipient.
18. logical formula (I) compound represented or its tautomer described according to claim 1~any one of 12 interior disappear Revolve or mixtures thereof body, racemic modification, enantiomter, diastereoisomer form or its officinal salt or according to claim Pharmaceutical composition described in 17 is in preparation for preventing and/or treating the pathology with the IDO tryptophan metabolic pathway mediated Purposes in the drug of the disease of feature.
19. purposes according to claim 18, wherein the tryptophan metabolic pathway pathological characteristics mediated with IDO Disease be selected from cancer, myelodysplastic syndrome, Alzheimer disease, autoimmune disease, depression, anxiety disorder, Cataract, mental handicape and AIDS.
20. purposes according to claim 19, wherein the cancer be selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, Gastric cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, bladder cancer, liver cancer, Fallopian tube cneoplasms, peritoneal tumor, IV phase melanoma, solid tumor, glioma, the renal tumor of mastoid process, head and neck neoplasm, white blood Disease, lymthoma and myeloma.
21. purposes according to claim 19, wherein the cancer is ovarioncus.
22. purposes according to claim 20, wherein the cancer is selected from spongioblastoma, hepatocellular carcinoma and non- Small Cell Lung Cancer.
CN201680003843.4A 2015-08-07 2016-08-05 Hydroxyamidine derivatives, their preparation method and their application in medicine Active CN107001271B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
CN201510481127 2015-08-07
CN2015104811274 2015-08-07
CN201510673998 2015-10-13
CN2015106739986 2015-10-13
PCT/CN2016/093584 WO2017024996A1 (en) 2015-08-07 2016-08-05 Hydroxy amidine derivative, preparation method and use in medicine thereof

Publications (2)

Publication Number Publication Date
CN107001271A CN107001271A (en) 2017-08-01
CN107001271B true CN107001271B (en) 2019-05-10

Family

ID=57983949

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201680003843.4A Active CN107001271B (en) 2015-08-07 2016-08-05 Hydroxyamidine derivatives, their preparation method and their application in medicine

Country Status (2)

Country Link
CN (1) CN107001271B (en)
WO (1) WO2017024996A1 (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106967005B (en) * 2017-04-07 2019-07-16 上海肇钰医药科技有限公司 A kind of compound that can inhibit IDO, Its Preparation Method And Use
US11266640B2 (en) 2017-09-20 2022-03-08 Hangzhou Innogate Pharma Co., Ltd. Polycyclic compound acting as IDO inhibitor and/or IDO-HDAC dual inhibitor
CN117185987A (en) * 2018-03-19 2023-12-08 四川科伦博泰生物医药股份有限公司 Amidine and guanidine derivatives, their preparation methods and their applications in medicine
EP4052705A1 (en) 2021-03-05 2022-09-07 Universität Basel Vizerektorat Forschung Compositions for the treatment of ebv associated diseases or conditions
MX2023010371A (en) 2021-03-05 2024-02-12 Univ Basel Compositions for the treatment of ebv associated diseases or conditions.
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
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

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007095050A2 (en) * 2006-02-09 2007-08-23 Incyte Corporation N-hydroxyguanidines as modulators of indoleamine 2,3-dioxygenase
JP5465720B2 (en) * 2008-07-08 2014-04-09 インサイト・コーポレイション 1,2,5-oxadiazole as an inhibitor of indoleamine 2,3-dioxygenase
CN102164092B (en) * 2011-05-23 2013-12-18 北京交通大学 Method and system for guaranteeing service quality of integrated identification network
CN104725276B (en) * 2013-12-18 2017-05-10 浙江省化工研究院有限公司 Heptafluoroisopropyl-containing carbonyl oxime ether compound, preparation method and applications thereof
RU2016149812A (en) * 2014-06-06 2018-07-17 Флексус Байосайенсиз, Инк. IMMUNO REGULATORY MEANS

Also Published As

Publication number Publication date
CN107001271A (en) 2017-08-01
WO2017024996A1 (en) 2017-02-16

Similar Documents

Publication Publication Date Title
CN107001271B (en) Hydroxyamidine derivatives, their preparation method and their application in medicine
CN111377917B (en) Heterocyclic compounds, intermediates, preparation methods and applications thereof
CN106715440B (en) Imidazoisoindole derivatives, their preparation method and their application in medicine
CA2356263C (en) Aminopyrazole derivatives
CN102325753B (en) Carbazole carboxamide compounds useful as kinase inhibitors
TWI746562B (en) Sulfonamide compound or its salt
CN112638373A (en) Cyclin-dependent kinase inhibitors
KR20140049026A (en) Substituted heteroaromatic pyrazole-containing carboxamide and urea derivatives as vanilloid receptor ligands
CN106458982A (en) Indazole compounds as irak4 inhibitors
JP2007514690A (en) Benzazepine derivatives as histamine H3 antagonists
CN111434655A (en) Lysophosphatidic acid receptor antagonists and process for their preparation
CN121013839A (en) 1-(([1,1',-biphenyl]-2-yl)sulfonyl)-4-fluoro-N-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide derivatives used as RAS-PI3K modulators in the treatment of cancer, for example.
CN102753522A (en) Substituted pyrrolidine-2-carboxamides
CN114409656B (en) PIM kinase inhibitors
TW201427952A (en) Novel pyridine derivatives
TW201043603A (en) Substituted phenylureas and phenylamides as vanilloid receptor ligands
CA2938198A1 (en) Heterocyclic sulfonamide derivative and medicine comprising same
WO2020103817A1 (en) TGF-βR1 INHIBITOR AND USE THEREOF
AU2011345969B2 (en) Novel substituted isoquinoline derivative
CN109897011B (en) IDO inhibitor and application thereof
KR20230043103A (en) sulfonamide compounds
JP6906449B2 (en) Heterocyclic sulfonamide derivative and pharmaceuticals containing it
CN107849029A (en) Cyclopropane derivatives and medicines containing them
CN116870016B (en) Heteroaromatic compound and medical application thereof
HK40048952A (en) Heterocyclic compound, intermediate, preparation method therefor and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant