CN107001271A - Hydroxyamidines analog derivative, its preparation method and its in application pharmaceutically - Google Patents

Hydroxyamidines analog derivative, its preparation method and its in application pharmaceutically Download PDF

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CN107001271A
CN107001271A CN201680003843.4A CN201680003843A CN107001271A CN 107001271 A CN107001271 A CN 107001271A CN 201680003843 A CN201680003843 A CN 201680003843A CN 107001271 A CN107001271 A CN 107001271A
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amino
reaction
cycloalkyl
alkyl
bromo
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CN107001271B (en
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杨方龙
桂斌
胡齐悦
金芳芳
贺峰
孙飘扬
陶维康
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/14—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

There is provided a kind of hydroxyamidines analog derivative, its preparation method and its in application pharmaceutically.Especially, pharmaceutical composition there is provided the hydroxyamidines analog derivative shown in a kind of logical formula (I), its preparation method and containing the derivative, and the purposes of disease of its treatment with the IDO tryptophan metabolic pathway pathological characteristicses mediated, each substituent that described disease is included in cancer, Alzheimer disease, autoimmune disease, depression, anxiety disorder, cataract, mental handicape and AIDS, its formula of (I) is identical with the definition in specification.

Description

Hydroxyamidines analog derivative, its preparation method and its in application pharmaceutically Technical field
The invention belongs to field of medicaments, it is related to hydroxyamidines analog derivative, its preparation method and its application on medical research, IDO inhibitor is used as the invention discloses it, for treating the disease with the IDO tryptophan metabolic pathway pathological characteristicses mediated, described disease includes cancer, Alzheimer disease, autoimmune disease, depression, anxiety disorder, cataract, mental handicape and AIDS.
Background technology
Tumor biotherapy is the new treatment that treatment and prevention of tumour is carried out using modern biotechnology and its Related product, because of it safely, effectively, the low feature of adverse reaction, the 4th kind of pattern (Clin Cancer Res, 1997 as the oncotherapy after operation, radiotherapy, chemotherapy；3:2623-2629), its natural immunology defense by transferring host, such as suppress the tumor immune escape mechanism of IDO mediations, or gives naturally-produced targeting very strong material to obtain antineoplastic effect.
Indoleamine 2,3- dioxygenases (Indoleamine-pyrrole-2,3-dioxygenase, IDO) it is a kind of iron content ferroheme monomeric protein, it is made up of 403 amino acid residues, include the α-helixstructure domain of two foldings, big structure domain includes catalytic pocket, and substrate can occur hydrophobic wait with IDO in catalytic pocket and act on (Int J Biochem Cell Biol.2007；39(12):2167-72).In mammal, the irrelevant enzyme containing ferroheme for having two kinds of gene codes can be catalyzed the oxidative degradation of tryptophan：IDO and tryptophan 2,3- dioxygenases (TDO).Every kind of enzymatic identical reaction：Promote the oxidation Decomposition of the 2,3- double bonds of indole ring in first rate-limiting step tryptophan catabolism in kynurenin path.TDO expression is limited primarily to liver, it appears that be used as a homeostasis or " house keeper " gene, it is impossible to induce or reconcile (Nat Rev Immunol.2004 by the signal of immune system；4(10):762-74).IDO is to be catalyzed the enzyme that tryptophan transfer turns to formylkynurenine, it is widely distributed in people and other tissues of mammal (rabbit, mouse) in addition to liver, it is that the rate-limiting enzyme of tryptophan catabolism can be uniquely catalyzed beyond liver, it is also to constitute the indispensable important component of protein (Adv Exp Med Biol.2003 and tryptophan is cell maintenance activation and the necessary amino acid of propagation；527:455-63、Biochim Biophys Acta.2001；1527(3):167-75).IDO and interferon (interferon, IFN), interleukins (interleukin, IL), the cytokine profiles such as TNF are in close relations, and they can activate IDO (J Psychiatry Neurosci.2004 under certain condition；29(1):11–17、Med Hypotheses.2003；61(5-6):519-25).And there is the very sensitive point of adjustment of a tryptophan level in the cell cycle of T- cells, on the one hand, IDO makes local tryptophan depletion, causes T- cells arrests in the G1 interim phases, so as to inhibit the propagation of T cell；On the other hand, the primary product cynruin that IDO catalysis tryptophan metabolism is produced is caused Cellular Oxidation agent and antioxidant to change and is induced T- Apoptosis by Mediated by Free Radicals, and this is the intrinsic immunosuppression mechanism for being present in body.Current numerous studies show IDO higher expression in leukaemia, make local T cell propagation suppressed, suppress the cell-mediated immune responses of T-, the transduction of T- cell activation signals is obstructed, so that mediate tumor cell is escaped The attack for immune system of escaping.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).Therefore, IDO is the target of the cancer immunotherapy of a tool potentiality.
Disclosed selective depression IDO inhibitor patent application is including WO2004094409, WO2006122150, WO2007075598, WO200409387, WO2008147283, WO2013174947, WO2008075991, WO2004093871, WO2005051321, WO2006056304, WO2010005958 and WO2014066834 etc..
IDO inhibitor has a good application prospect as medicine in pharmaceuticals industry, can be as marketed drug but not yet find good IDO inhibitor at present, in order to reach the purpose of more preferable oncotherapy effect, the market demand is better met, 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 selective IDO inhibitor of new structure, and find that the compound with this class formation shows excellent effect and effect, and particularly excellent medicine generation absorbs activity.
The content of the invention
It is an object of the invention to provide the compound shown in a kind of logical formula (I) or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its pharmaceutically useful salt：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt,
Wherein：
Mixture selected from cis-isomer, transisomer and cis-trans-isomer；
Ring A is selected from cycloalkyl or heterocyclic radical, wherein described cycloalkyl or heterocyclic radical are optionally selected from alkyl, halogen, amino, nitro, hydroxyl, alkoxy, hydroxyalkyl, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR independently of one another4、-C(O)R4、-C(O)OR4、-S(O)mR4、-S(O)mNR5R6、-NR5R6、-C(O)NR5R6、-NR5C(O)R6With-NR5S(O)mR6One or more of substituent replaced；
R1It is identical or different, and it is each independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano group, cycloalkyl, heterocyclic radical, 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 described alkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amino, nitro, cyano group, hydroxyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-R independently of one another3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-S(O)mNR7R8、-NR7R8、-C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8One or more of Substituent is replaced；
R2It is identical or different, and it is each independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano group, cycloalkyl, heterocyclic radical, aryl and heteroaryl；
R3Selected from alkyl, haloalkyl, cycloalkyl, cycloalkyl alkoxy, heterocyclic radical, aryl and heteroaryl, wherein described alkyl, haloalkyl, cycloalkyl, cycloalkyl alkoxy, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, halogen, haloalkyl, amino, nitro, hydroxyl, alkoxy, hydroxyalkyl, cyano group, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) NR independently of one another7R8、-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)mR6One or more of substituent replaced；Wherein described cycloalkyl-alkyl is optionally selected from one or more of alkyl, halogen, haloalkyl, amino, hydroxyl, alkoxy, hydroxyalkyl substituent and replaced；
R4Selected from hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, alkoxy, halogenated alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR7R8、-NR7C(O)R8With-NR7S(O)mR8, wherein described alkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, halogen, amino, nitro, cyano group, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-R independently of one another3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8One or more of substituent replaced；
R5And R6It is identical or different, and it is each independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, hydroxyalkyl, hydroxyl, amino, cycloalkyl, heterocyclic radical, 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 described alkyl, haloalkyl, amino, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, hydroxyl, amino, nitro, cyano group, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl ,-R independently of one another3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8One or more of substituent replaced；
R7And R8It is identical or different, and it is each independently selected from hydrogen atom, alkyl, alkoxy, hydroxyalkyl, hydroxyl, amino, carboxylic acid ester groups ,-S (O)mNR9C(O)OR10、-C(O)OR10、-S(O)mNR9R10, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical, aryl and heteroaryl, replaced wherein described alkyl, amino, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from one or more of alkyl, halogen, hydroxyl, amino, carboxylic acid ester groups, nitro, cyano group, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl substituent independently of one another；
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 yet other embodiments, lead to the compound shown in formula (I), its middle ring A is selected from cycloalkyl or heterocyclic radical, preferably C3-8Cycloalkyl or 3-8 members containing 1 N atom monocyclic heterocycles base or the bridge heterocyclic radical of 7-10 members, more preferably cyclohexyl, cyclobutyl, nafoxidine, piperidyl, cycloheximide, most preferably piperidyl, cyclohexyl.
In yet other embodiments, lead to the compound shown in formula (I), wherein n is 1.
In yet other embodiments, lead to the compound shown in formula (I), wherein p is 1 or 2.
In yet other embodiments, lead to the compound shown in formula (I), 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；Wherein described alkyl, amino, aryl and heteroaryl is optionally selected from nitro, cyano group ,-R independently of one another3、-C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8One or more of substituent replaced；R3~R8, x and m be as defined in logical formula (I).
In yet other embodiments, lead to the compound shown in formula (I), wherein R2For halogen, haloalkyl or alkenyl.
In yet other embodiments, lead to the compound shown in formula (I), wherein R4Selected from hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, alkoxy, halogenated alkoxy, cycloalkyl, heterocyclic radical.
In yet other embodiments, lead to the compound shown in formula (I), it is the compound shown in logical formula (II)：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt,
Wherein：R1、R2With p as defined in logical formula (I).
In yet other embodiments, lead to the compound shown in formula (II), it is the compound shown in logical formula (III)：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt,
Wherein：R1、R2With p as defined in logical formula (I).
In yet other embodiments, lead to the compound shown in formula (I), it is the compound shown in logical formula (IV)：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt,
Wherein：
Ring B is selected from aryl or heteroaryl；
RaSelected from hydrogen atom, alkyl, haloalkyl, halogen, amino, nitro, cyano group, hydroxyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, 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 yet other embodiments, lead to the compound shown in formula (I), it is the compound shown in logical formula (V)：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt,
Wherein：
G is selected from C or N；
RaSelected from hydrogen atom, alkyl, haloalkyl, halogen, amino, nitro, cyano group, hydroxyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, 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 the compound shown in yet other embodiments formula of (I), it is the compound shown in logical formula (VI)：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt,
Wherein：
RaSelected from hydrogen atom, alkyl, haloalkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano group, cycloalkyl, heterocyclic radical, 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 described alkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amino, nitro, cyano group, hydroxyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-R independently of one another3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8One or more of substituent replaced；
R2~R8, m, x and p be as defined in logical formula (I)；And
Y is 0,1,2,3,4 or 5 integer.
In yet other embodiments, lead to the compound shown in formula (I), it is the compound shown in formula (V-A)：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt,
Wherein：
RbSelected from hydrogen atom, alkyl, haloalkyl, amino, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein described wherein described alkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independent Ground is optionally selected from alkyl, halogen, amino, nitro, hydroxyl, alkoxy, hydroxyalkyl, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR4、-C(O)R4、-C(O)OR4、-S(O)mR4、-S(O)mNR5R6、-NR5R6、-C(O)NR5R6、-NR5C(O)R6With-NR5S(O)mR6One or more of substituent replaced；
R4~R6With m as defined in logical formula (I).
Present invention also offers a kind of method for preparing the compound shown in logical formula (I), this method includes：
Formula (I-A) compound at ambient temperature, with R1NCO react or at low temperature under alkalescence condition with R1Halide reaction, be optionally deprotected in acid condition, obtain logical formula (I) compound；
Wherein, R1、R2, A, p and n be as defined in logical formula (I).
In yet other embodiments, compound shown in a kind of formula (I-B)：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt, compound shown in formula (I) can be led to as preparing；
Wherein, R1With n as right is led to defined in formula (I).
Present invention also offers a kind of method for preparing compound shown in logical formula (I), this method includes：
The derivatives reaction of formula (I-B) compound at ambient temperature with aniline, obtains logical formula (I) compound；
Wherein, R1、R2, A, p and n be as defined in logical formula (I).
The typical compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures of logical formula (I), or its officinal salt, include but is not limited to：
The typical compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures of logical formula (V), or its officinal salt, include but is not limited to：
Another aspect of the present invention is related to a kind of pharmaceutical composition, its logical formula (I) for containing treatment effective dose, (II), (III), (IV), (IV-A) and compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures or pharmaceutically useful salt shown in (VI), and one or more pharmaceutically acceptable carriers, diluent or excipient.The invention further relates to a kind of method for preparing above-mentioned composition, it includes mixing logical formula (I), (II), (III), (IV), (IV-A) and compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its pharmaceutically useful salt and pharmaceutically acceptable carrier, diluent or excipient shown in (VI).
The invention further relates to lead to compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (I), or its officinal salt, or purposes of the pharmaceutical composition comprising it in the medicine of the disease of pathological characteristicses for the tryptophan metabolic pathway that for prevention and/or Prevention there is IDO to mediate is prepared.IDO inhibitor can be used for the suppression of cardiac disorder and treat the disease of the pathological characteristicses of other tryptophan metabolic pathways that there is IDO to mediate, the infection of these diseases virus such as including AIDS, the cell infection such as Lyme disease and streptococcal infection, Neurodegenerative conditions (such as Alzheimer disease, Huntington disease and the golden gloomy disease of bat), autoimmune disease, depression, anxiety disorder, cataract, mental handicape, AIDS, cancer (including T cell leukaemia and colon cancer), ocular disease state (example Such as cataract and age-related yellow) and autoimmune disease, wherein described cancer can be selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, stomach cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, carcinoma of urinary bladder, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phases melanoma, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process kidney knurl, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer.
The invention further relates to lead to compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (I), or its officinal salt, or the pharmaceutical composition comprising it, it is used for the disease of the pathological characteristicses for the tryptophan metabolic pathway that there is IDO to mediate for prevention and/or Prevention.The infection of these diseases virus such as including AIDS, the cell infection such as Lyme disease and streptococcal infection, Neurodegenerative conditions (such as Alzheimer disease, Huntington disease and the golden gloomy disease of bat), 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 described cancer can be selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, stomach cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, carcinoma of urinary bladder, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phase melanomas, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process kidney knurl, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer.
There is the method for the disease of the pathological characteristicses of the tryptophan metabolic pathway of IDO mediations the invention further relates to a kind of Prevention and/or Prevention, it includes compound or its dynamic isomer shown in the logical formula (I) of patient therapeuticallv's effective dose, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt, or the pharmaceutical composition comprising it.The infection of these diseases virus such as including AIDS, the cell infection such as Lyme disease and streptococcal infection, Neurodegenerative conditions (such as Alzheimer disease, Huntington disease and the golden gloomy disease of bat), 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 described cancer can be selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, stomach cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, carcinoma of urinary bladder, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phase melanomas, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process kidney knurl, 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, this method includes the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures described in the logical formula (I) of the invention of patient therapeuticallv's effective dose, or its officinal salt.This method shows prominent curative effect and less side effect, wherein described cancer can selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, Stomach cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, carcinoma of urinary bladder, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phases melanoma, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process kidney knurl, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer, preferably fallopian tube cneoplasms, peritoneal tumor, IV phases melanoma, myeloma and breast cancer, more preferably breast cancer.
Pharmaceutical composition containing active component can apply to oral form, such as tablet, dragee, lozenge, water or oil suspension, dispersible powder or particle, emulsion, hard or soft capsule, or syrup or elixir.Orally administered composition can be prepared according to any known method for preparing Pharmaceutical composition in this area, such composition can be selected from following composition containing one or more：Sweetener, flavouring, colouring agent and preservative, to provide pleasing and tasty pharmaceutical formulation.Tablet contains active component and the suitable nontoxic pharmaceutically useful excipient for preparing tablet for mixing.These excipient can be inert excipient, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate；Granulating agent and disintegrant, such as microcrystalline cellulose, Ac-Di-Sol, cornstarch or alginic acid；Adhesive, such as starch, gelatin, polyvinylpyrrolidone or Arabic gum；And lubricant, such as magnesium stearate, stearic acid or talcum powder.These tablets can not be coated or can be coated by covering the taste of medicine or delay disintegration and absorption in the gastrointestinal tract, thus providing the known technology of slow releasing function in a long time.For example, water soluble taste can be used to shelter material, such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or extension time material such as ethyl cellulose, acetylbutyrylcellulose.
Also wherein active component and the inert solid diluent hard gelatin capsule that for example calcium carbonate, calcium phosphate or kaolin are mixed are can use, or wherein active component provides oral formulations with water-solubility carrier such as polyethylene glycol or the oily solvent Perle that for example peanut oil, atoleine or olive oil are mixed.
Water slurry contains active material and the suitable excipient for preparing water slurry for mixing.Such excipient is suspending agent, for example sodium carboxy methyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, mosanom, polyvinylpyrrolidone and Arabic gum；Dispersant or wetting agent can be naturally-produced phosphatide such as lecithin, or the condensation product of alkylene oxide and aliphatic acid such as Myrj 45, or the condensation product of oxirane and long-chain fatty alcohol, such as 17 carbon ethyleneoxy group cetanols (heptadecaethyleneoxy cetanol), or the condensation product of oxirane and the part ester as derived from aliphatic acid and hexitol, such as polyoxyethylene sorbitol monoleate, or the condensation product of oxirane and the partial ester as derived from aliphatic acid and hexitan, such as PEO Arlacel-80.Aqueous suspension can also contain one or more preservatives such as ethylparaben or nipalgin n-propyl, one or more colouring agents, one or more flavourings and one or more sweeteners, such as sucrose, saccharin or aspartame.
Oil suspension can be formulated by making active component be suspended in vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as atoleine.Oil suspension can contain thickener, such as beeswax, hard paraffin or cetanol.Above-mentioned sweetener and flavouring can be added, to provide tasty preparation.These compositions can be preserved by adding antioxidant such as Butylated Hydroxyanisole or alpha-tocopherol.
It can make to be applied to prepare dispersible powder and particle offer active component and use that water is suspended also by adding water In the dispersant or wetting agent of mixing, suspending agent or one or more preservatives.Above-mentioned example can be explained in suitable dispersant or wetting agent and suspending agent.Also other excipient such as sweetener, flavouring and colouring agent can be added.These compositions are preserved by adding antioxidant such as ascorbic acid.
The pharmaceutical composition of the present invention can also be the form of oil in water emulsion.Oil phase can be vegetable oil such as olive oil or peanut oil, or mineral oil such as atoleine or its mixture.Suitable emulsifying agent can be naturally-produced phosphatide, such as soybean lecithin and ester or partial ester such as sorbitan monooleate as derived from aliphatic acid and hexitan, and the partial ester and oxirane condensation product, such as polyoxyethylene sorbitol monoleate.Emulsion can also contain sweetener, flavouring, preservative and antioxidant.Syrup and elixir can be prepared with Sweetening agents such as glycerine, propane diols, sorbierite or sucrose.Such preparation can also contain moderator, preservative, colouring agent and antioxidant.
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 oil-in-water microemulsion that wherein active component is dissolved in oil phase.For example active component is dissolved in the mixture of soybean oil and lecithin.Then oil solution is added to processing in the mixture of water and glycerine and forms micro emulsion.Parenteral solution or micro emulsion can be injected in the blood flow of patient by local a large amount of injections.Or, preferably give solution and micro emulsion 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 Deltec CADD-PLUS.TM.5400 type Iv pumps.
Pharmaceutical composition can be aseptic injection water or the form of oil suspension for intramuscular and subcutaneous administration.By known technology the suspension can be prepared with the suitable dispersant of those described above or wetting agent and suspending agent.Aseptic injection preparation can also be the solution prepared in the aseptic injectable solution or suspension prepared in the acceptable non-toxic diluent of parenteral or solvent, such as 1,3-BDO.In addition, it is convenient to be used as solvent or suspension media with sterile fixed oil.For this purpose, any mediation fixing oil including synthetic glycerine list or diester can be used.In addition, aliphatic acid such as oleic acid can also prepare injection.
The compounds of this invention can be given by the suppository form for rectally.Can be by the way that by medicine, with being at normal temperatures solid but being liquid in the rectum, thus the suitable nonirritant excipient that can be dissolved in the rectum and discharge medicine mixes to prepare these pharmaceutical compositions.Such material includes the mixture of the fatty acid ester of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, the polyethylene glycol of various molecular weight and polyethylene glycol.
As it is well known to the skilled in the art, the dosage of medicine depends on many factors, including but it is not limited to following factor：The activity of particular compound used, the age of patient, the body weight of patient, the health status of patient, the row quilt of patient, the diet of patient, administration time, administering mode, speed, the combination of medicine of excretion etc.；In addition, optimal therapeutic modality can be verified such as the species of the pattern treated, the consumption per day of general formula compound (I) or pharmaceutically useful salt according to traditional therapeutic scheme.
Detailed description of the invention
Unless stated to the contrary, the term used in the specification and in the claims has following implications.
Term " alkyl " refers to saturated aliphatic hydrocarbons group, and it is the straight or branched for including 1 to 20 carbon atom Group, preferably comprises the alkyl of 1 to 12 carbon atom, the alkyl of further preferably 1 to 6 carbon atom.Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyl propyl group, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls, n-heptyl, 2- methylhexyls, 3- methylhexyls, 4- methylhexyls, 5- methylhexyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl amyl groups, 3,3- dimethyl amyl groups, 2- ethyl pentyl groups, 3- ethyl pentyl groups, n-octyl, 2,3- dimethylhexanyls, 2,4- dimethylhexanyls, 2,5- dimethylhexanyls, 2,2- dimethylhexanyls, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls, 2- ethylhexyls, 3- ethylhexyls, 4- ethylhexyls, 2- methyl -2- ethyl pentyl groups, 2- methyl -3- ethyl pentyl groups, n-nonyl, 2- methyl -2- ethylhexyls, 2- methyl -3- ethylhexyls, 2,2- diethyl amyl groups, positive decyl, 3,3- diethylhexyls, 2,2- diethylhexyls, and its various branched chain isomers etc..Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting example includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1, 1- dimethyl propyls, 1, 2- dimethyl propyls, 2, 2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyl propyl group, 1, 1, 2- thmethylpropyls, 1, 1- dimethylbutyls, 1, 2- dimethylbutyls, 2, 2- dimethylbutyls, 1, 3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2, 3- dimethylbutyls etc..Alkyl can be substitution or non-substituted, when substituted, substituent can be substituted on any workable tie point, the substituent is preferably one or more following groups, and it is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl or carboxylic acid ester groups.
Term " alkylidene " refers to that a hydrogen atom of alkyl is further substituted, for example：" methylene " refers to-CH2-, " ethylidene " refer to-(CH2)2-, " propylidene " refer to-(CH2)3-, " butylidene " refer to-(CH2)4- etc..Term " alkenyl " refers to the alkyl as defined above by being at least made up of two carbon atoms and at least one carbon-to-carbon double bond, such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl.Alkenyl can be substitution or non-substituted, when substituted, substituent is preferably one or more following groups, and it is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
Term " cycloalkyl " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and cycloalkyl ring includes 3 to 20 carbon atoms, 3 to 12 carbon atoms preferably comprised, more preferably comprising 3 to 8 carbon atoms, more preferably comprising 4 to 7 carbon atoms.The non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc.；Polycyclic naphthene base includes the cycloalkyl of loop coil, condensed ring and bridged ring.
Term " spiro cycloalkyl group " refers to the polycyclic moiety that a carbon atom (title spiro-atom) is shared between 5 to 20 yuan monocyclic, and it can contain one or more double bonds, but neither one 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 by single spiro cycloalkyl group, double spiro cycloalkyl groups or many spiro cycloalkyl groups according to the number of shared spiro-atom between ring and ring, is 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 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl groups.The non-limiting examples of spiro cycloalkyl group include：
Term " cycloalkyl " refers to 5 to 20 yuan, the full carbon polycyclic moiety of each ring and shared a pair of the carbon atoms adjoined of other rings in system in system, wherein one or more rings can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl can be divided into according to the number of composition ring.The non-limiting examples of cycloalkyl include：
Term " bridge ring alkyl " refers to 5 to 20 yuan, and any two ring shares the full carbon polycyclic moiety of two carbon atoms being not directly connected, and it can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge ring alkyl, preferably bicyclic, three rings or Fourth Ring can be divided into according to the number of composition ring, bicyclic or three rings are more elected as.The non-limiting examples of bridge ring alkyl include：
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being cycloalkyl with the ring that precursor structure links together, non-limiting examples include indanyl, tetralyl, benzocyclohepta alkyl etc..Cycloalkyl can be optionally substituted or non-substituted, when substituted, substituent is preferably one or more following groups, and it is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl or carboxylic acid ester groups.
Term " heterocyclic radical " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 annular atoms, and 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 include-O-O- ,-O-S- or-S-S- loop section, remaining annular atom is carbon.Preferably comprise 3 To 12 annular atoms, wherein 1~4 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 is hetero atom.The non-limiting examples of monocyclic heterocycles base include pyrrolidinyl, imidazolidinyl, tetrahydrofuran base, tetrahydro-thienyl, glyoxalidine base, dihydrofuran base, pyrazoline base, pyrrolin base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base, pyranose, THP trtrahydropyranyl etc., preferably piperidyl, pyrrolidinyl, pyranose, THP trtrahydropyranyl or morpholinyl.Multiring heterocyclic includes the heterocyclic radical of loop coil, condensed ring and bridged ring.
Term " spiro heterocyclic radical " refers to the polycyclic heterocyclic group that an atom (title spiro-atom) is shared between 5 to 20 yuan monocyclic, and 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 is carbon.It can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Spiro heterocyclic radical is divided into by single spiro heterocyclic radical, double spiro heterocyclic radicals or many spiro heterocyclic radicals according to the number of shared spiro-atom between ring and ring, is preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting examples of spiro heterocyclic radical include：
Term " condensed hetero ring base " refers to 5 to 20 yuan, the polycyclic heterocyclic group of each ring and shared a pair of the atoms adjoined of other rings in system in system, one or more rings can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, 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 is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic condensed hetero ring base, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero ring bases can be divided into according to the number of composition ring.The non-limiting examples of condensed hetero ring base include：
Term " bridge heterocyclic radical " refers to 5 to 14 yuan, any two ring shares the polycyclic heterocyclic group of two atoms being not directly connected, it can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, 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 is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to the number of composition ring Mesh can be divided into bicyclic, three rings, Fourth Ring or polycyclic bridge heterocyclic radical, preferably bicyclic, three rings or Fourth Ring, more elect bicyclic or three rings as.The non-limiting examples of bridge heterocyclic radical include：
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein the ring linked together with precursor structure is heterocyclic radical, its non-limiting examples includes：
Heterocyclic radical can be optionally substituted or non-substituted, when substituted, substituent is preferably one or more following groups, and it is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl or carboxylic acid ester groups.
Term " aryl ", which refers to, has 6 to 14 yuan of full carbon of the pi-electron system being conjugated monocyclic or fused polycycle (rings for namely sharing adjacent carbon atoms pair) group, preferably 6 to 10 yuan, such as phenyl and naphthyl.More preferably phenyl.The aryl rings can be condensed on heteroaryl, heterocyclic radical or cycloalkyl ring, wherein the ring linked together with precursor structure is aryl rings, its non-limiting examples includes：
Aryl can be substitution or non-substituted, when substituted, substituent is preferably one or more following groups, and it is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl or carboxylic acid ester groups.
Term " heteroaryl " refers to the heteroaromatic system comprising 1 to 4 hetero atom, 5 to 14 annular atoms, and wherein hetero atom is selected from oxygen, sulphur and nitrogen.Heteroaryl is preferably 5 to 10 yuan, containing 1 to 3 hetero atom；More preferably 5 yuan or 6 yuan, containing 1 to 2 hetero atom；It is preferred that such as imidazole radicals, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrole radicals, tetrazole radical, pyridine radicals, pyrimidine radicals, thiadiazoles, pyrazinyl, preferably imidazole radicals, tetrazole radical, tetrazole base, thienyl, pyrazolyl or pyrimidine radicals, thiazolyl；More select imidazoles Base, pyrazolyl or thiazolyl.The heteroaryl ring can be condensed on aryl, heterocyclic radical or cycloalkyl ring, wherein the ring linked together with precursor structure is heteroaryl ring, its non-limiting examples includes：
Heteroaryl can be optionally substituted or non-substituted, when substituted, substituent is preferably one or more following groups, and it is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl or carboxylic acid ester groups.
Term " alkoxy " refers to-O- (alkyl) and-O- (non-substituted cycloalkyl), and wherein alkyl is as defined above.The non-limiting examples of alkoxy include：Methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy.Alkoxy can be optionally substituted or non-substituted, when substituted, substituent is preferably one or more following groups, and it is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl or carboxylic acid ester groups.
Term " haloalkyl " refers to the alkyl replaced by one or more halogens, wherein alkyl as defined above.
Term " halogenated alkoxy " refers to the alkoxy replaced by one or more halogens, wherein alkoxy as defined above.
Term " cycloalkyl-alkyl " refers to the alkyl replaced by one or more cycloalkyl, wherein cycloalkyl, alkyl as defined above.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 cycloalkyl, wherein cycloalkyl, 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, wherein alkyl as defined above.
Term " hydroxyl " refers to-OH groups.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " amino " refers to-NH2。
Term " cyano group " 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 " carboxylic acid ester groups " refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl as defined above.
Term " carboxylic acid halides " refers to the compound of the group containing-C (O)-halogen.
" optional " or " optionally " mean event described later or environment can with but need not occur, the explanation includes the occasion that the event or environment occur or do not occurred.For example, " optionally by alkyl-substituted heterocyclic group " mean alkyl can with 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 of group hydrogen atom, and preferably at most 5, more preferably 1~3 hydrogen atom is replaced by the substituent of respective number independently of one another.Self-evident, substituent is only in their possible chemical position, and those skilled in the art can determine (by experiment or theoretical) possible or impossible substitution in the case where not paying excessively effort.For example, amino or hydroxyl with free hydrogen are probably unstable when being combined with the carbon atom with unsaturated (such as olefinic) key.
" pharmaceutical composition " is represented containing one or more compounds described herein or its physiologically/pharmaceutically useful salt or pro-drug and the mixture of other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.The purpose of pharmaceutical composition is to promote the administration to organism, the absorption beneficial to active component and then performance bioactivity.
" officinal salt " refers to the salt of the compounds of this invention, and this kind of salt has security and validity when being used in mammal body, and with due bioactivity.
The synthetic method of the compounds of this invention
In order to complete the purpose of the present invention, the present invention is adopted the following technical scheme that：
Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in the logical formula (I) of the present invention, or its pharmaceutically useful salt preparation method, comprise the following steps：
Scheme one
Under the conditions of high-temperature acidic (reagent for providing acid condition is preferably acetic acid), formula (a) compound is oxidized agent and is oxidized to formula (b) compound, the preferred selenium dioxide of the oxidant；Formula (b) compound in the basic conditions (reagent for providing alkalescence condition is preferably potassium carbonate), is reacted, obtains formula (c) compound at room temperature with hydroxylamine hydrochloride；Obtained formula (c) compound is reacted with N- chlorosuccinimides in acid condition, Obtain formula (d) compound；The derivatives reaction of obtained formula (d) compound at ambient temperature with aniline, obtained formula (I-A) compound；Obtained formula (I-A) compound at ambient temperature with R1NCO react or at low temperature under alkalescence condition with R1Halide reaction, obtain logical formula (I) compound.
There is provided the reagent of alkalescence condition includes organic base and inorganic base, described organic bases include but is not limited to triethylamine, N, N- diisopropylethylamine, n-BuLi, lithium diisopropylamine, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, described inorganic base include 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), formula (e) compound is oxidized agent and is oxidized to formula (f) compound, the preferred selenium dioxide of the oxidant；Formula (f) compound in the basic conditions (reagent for providing alkalescence condition is preferably potassium carbonate), is reacted, obtains formula (g) compound at room temperature with hydroxylamine hydrochloride；Obtained formula (g) compound is reacted with N- chlorosuccinimides in acid condition, formula (I-B) compound is obtained；The derivatives reaction of obtained formula (I-B) compound at ambient temperature with aniline, obtains logical formula (I) compound.
There is provided the reagent of alkalescence condition includes organic base and inorganic base, described organic bases include but is not limited to triethylamine, N, N- diisopropylethylamine, n-BuLi, lithium diisopropylamine, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, described inorganic base include 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
At low temperature (being preferably 0 DEG C), (being preferably triethylamine), formula (III-a) compound and R under alkalescence condition1Halide reaction, obtain formula (III) compound.
There is provided the reagent of alkalescence condition includes organic base and inorganic base, described organic bases include but is not limited to triethylamine, N, N- diisopropylethylamine, n-BuLi, lithium diisopropylamine, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, described inorganic base include 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).
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 determined by nuclear magnetic resonance (NMR) or mass spectrum (MS).NMR measure is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometers, and measure solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3OD), tetramethylsilane (TMS) is inside designated as, chemical shift is with 10-6(ppm) provided as unit.
MS measure is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer：Thermo, model：Finnigan LCQ advantage MAX).
HPLC measure uses Agilent 1200DAD high pressure liquid chromatographs (Sunfire 150 × 4.6mm of C18 chromatographic columns) and Waters 2695-2996 high pressure liquid chromatographs (Gimini 150 × 4.6mm of C18 chromatographic columns).
Kinases average inhibition and IC50The measure of value is with NovoStar ELIASAs (German BMG companies).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, the specification that the silica gel plate that thin-layered chromatography (TLC) is used is used is 0.15mm~0.2mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm silica gel plates.
Column chromatography is carrier typically using the mesh silica gel of the Yantai Huanghai Sea 200~300.
The known initiation material of the present invention can be used or synthesized according to methods known in the art, or it is commercially available from ABCR GmbH ＆ Co.KG, Acros Organnics, Aldrich Chemical Company, splendid remote chemistry scientific and technological (Accela ChemBio Inc), up to companies such as auspicious chemicals.
In embodiment unless otherwise specified, reaction is carried out under argon atmospher or blanket of nitrogen.
Argon atmospher or blanket of nitrogen refer to that reaction bulb connects the argon gas or nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
Pressure hydration reaction uses Parr 3916EKX types hydrogenation instrument and clear indigo plant QL-500 types hydrogen generator or HC2-SS types hydrogenation instrument.
Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.
Microwave reaction uses the type microwave reactors of CEM Discover-S 908860.
In embodiment unless otherwise specified, the solution in reaction refers to the 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), there is the system of solvent used in reaction：A：Dichloromethane 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 adjusted according to the polarity difference of compound.
The system of the eluant, eluent for the column chromatography that purifying compound is used and the system of the solvent of thin-layered chromatography include：A：Dichloromethane 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：Ethyl acetate, the volume ratio of solvent is adjusted according to the polarity difference of compound, can also add a small amount of triethylamine and acid or alkaline reagent etc. and be adjusted.
Embodiment 1
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- Phenylpiperidine -1- formamides
The first step
4- (2- carbonyls acetyl group) piperidines -1- t-butyl formates
By selenium dioxide (1.37g; 0.012mol) it is placed in reaction bulb; add 15mL 1; 4- dioxane; acetic acid (0.24g; 0.004mL), 0.23mL water, is warming up to 90 DEG C; add prefabricated 3mL 4- Acetylpiperidin -1- t-butyl formate 1a (1.4g; 0.006mmol, using known method " Bioorganic ＆ Medicinal Chemistry Letters, 2011; 21 (5); 1299-1305 " is prepared) Isosorbide-5-Nitrae-dioxane solution, reacted 16 hours in 90 DEG C.After reaction terminates; add water 10mL; it is 8 with saturated sodium bicarbonate solution regulation pH; it is extracted with ethyl acetate (15mL × 3), merges organic phase, washed with saturated nacl aqueous solution (20mL); anhydrous sodium sulfate drying; filtering, filtrate decompression concentration, obtains crude title product 4- (2- carbonyls acetyl group) piperidines -1- formic acid Tert-butyl ester 1b (1.4g, yellow oil), product is not purified directly to carry out next step reaction.
Second step
4- (2- (oximido) acetyl group) piperidines -1- t-butyl formates
By crude product 4- (2- carbonyls acetyl group) piperidines -1- t-butyl formate 1b (1.4g; 0.0058mol) it is dissolved in 20mL methanol; add potassium carbonate (1.20g; 0.0087mol); add hydroxylamine hydrochloride (0.323g; 0.0046mol), in the lower reaction of 25 DEG C of stirrings 2 hours.After reaction terminates; 30mL ethyl acetate is added, filtering, filtrate decompression is concentrated to give crude title product 4- (2- (oximido) acetyl group) piperidines -1- t-butyl formate 1c (1.1g; buff grease), product is not purified directly to carry out next step reaction.
MS m/z(LC-MS):255.1[M-1]
3rd step
4- (2- chloro- 2- (oximido) acetyl group) piperidines -1- t-butyl formates
By crude product 4- (2- (oximido) acetyl group) piperidines -1- t-butyl formate 1c (1.1g; 4.29mmol) add 10mLN; in dinethylformamide; add N- chlorosuccinimides (573.1mg; 4.29mmol); 5 diethyl ether solutions for dripping hydrogen chloride are added, in stirring reaction 1 hour at 25 DEG C.After reaction terminates; add 20mL water; it is extracted with ethyl acetate (15mL × 3), merges organic phase, organic phase is washed (20mL × 3) with saturated nacl aqueous solution; anhydrous sodium sulfate drying; filtering, filtrate decompression concentration, obtains crude title product 4- (2- chloro- 2- (oximido) acetyl group) piperidines -1- t-butyl formate 1d (2.0g; pale yellow oil), product is not purified directly to carry out next step reaction.
4th step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- t-butyl formates
By crude product 4- (2- chloro- 2- (oximido) acetyl group) piperidines -1- t-butyl formate 1d (1.45g; 5mmol) with the bromo- 4- fluoroanilines (1.90g of 3-; 10mmol) add in 10mL ethanol, in stirring reaction 16 hours at 25 DEG C.After reaction terminates; reaction solution is concentrated under reduced pressure; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- t-butyl formate 1e (800mg; yellow solid), yield 36.0%.
5th step
N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidine
By 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- t-butyl formate 1e (700mg; 1.57mL) it is placed in reaction bulb; add 10mL 4M hydrogen chloride 1; 4- dioxane, in stirring reaction 1 hour at 25 DEG C.After reaction terminates, reaction solution is concentrated under reduced pressure, crude title product N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidines 1f (500mg, yellow solid) are obtained, product is not purified directly to carry out next step reaction.
MS m/z(LC-MS):346.0[M+1]
6th step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- Phenylpiperidine -1- formamides
Aniline (15mg, 0.16mmol) is dissolved in 10mL tetrahydrofurans, p-nitrophenyl chloroformate ester (32 is added Mg, 0.158mmol), triethylamine (0.1mL, 0.72mmol), in stirring reaction 30 minutes at 25 DEG C, add crude product N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidine 1f (55mg, 0.159mmol), in reaction 1 hour at 25 DEG C, after reaction terminates, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, it is beaten with 5mL dichloromethane, obtain (the 15mg of title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- Phenylpiperidine -1- formamides 1, hazel-color solid), yield 20%.
MS m/z(LC-MS):463.2[M+1]
1H NMR(400MHz,DMSO-d6):δ11.69(s,1H),8.52(s,1H),8.40(s,1H),7.45(d,2H),7.16-7.24(m,3H),6.98-7.00(dd,1H),6.92(t,1H),6.70-6.73(m,1H),4.17-4.20(m,2H),3.52-3.57(m,1H),2.84-2.90(m,2H),1.85-1.87(m,2H),1.42-1.50(m,2H).
Embodiment 2
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyanophenyls) piperidines -1- formamides
By N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidine 1f (30mg, 0.208mmol) it is dissolved in 2mL tetrahydrofurans, add 4- isocyanic acid benzonitrile 2a (30mg, 0.20mmol, using known method " Chemical ＆ Pharmaceutical Bulletin, 2012,60 (8); 1046-1054 " is prepared), in stirring reaction 2 hours at 25 DEG C.After reaction terminates; reaction solution is concentrated under reduced pressure; with thin-layered chromatography with solvent system A purify gained residue; obtain (the 16mg of title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyanophenyls) piperidines -1- formamides 2; white solid), yield 36%.
MS m/z(ESI):488.2[M+1]
1H NMR(400MHz,DMSO-d6):δ11.67(s,1H),9.01(s,1H),8.38(s,1H),7.67(s,4H),7.17(t,1H),6.98(dd,1H),6.70-6.73(m,1H),4.17-4.20(m,2H),3.53-3.59(m,1H),2.89-2.95(m,2H),1.86-1.89(m,2H),1.46-1.52(m,2H).
Embodiment 3
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- methyl isophthalic acid H- pyrazoles -4- bases) phenyl) piperidines -1- formamides
The first step
4- (4- isocyanatophenyls) -1- methyl isophthalic acid H- pyrazoles
By 4- (1- methyl isophthalic acid H- pyrazoles -4- bases) aniline 3a (24mg, 0.14mmol, it is prepared using method disclosed in patent application " WO2010132015 ") it is dissolved in 10mL dichloromethane, add triethylamine (42mg, 0.42mmol), reaction system is cooled to 0 DEG C, triphosgene (14mg is added in 0 DEG C, 0.05mmol), in 0 DEG C of stirring reaction 30 minutes.After reaction terminates, crude title product 4- (4- isocyanatophenyls) -1- methyl isophthalic acid H- pyrazoles 3b (28mg, 0.14mmol), the not purified direct carry out next step of product are obtained.
Second step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- methyl isophthalic acid H- pyrazoles -4- bases) phenyl) piperidines -1- formamides
By crude product 4- (4- isocyanatophenyls) -1- methyl isophthalic acid H- pyrazoles 3b (28mg, 0.14mmol) it is dissolved in 10mL dichloromethane, add N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidine 1f (40mg, 0.12mmol), in 25 DEG C of stirring reactions 1 hour.After reaction terminates; reaction solution is concentrated under reduced pressure; with thin-layered chromatography with solvent system A purify gained residue; obtain (the 15mg of title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- methyl isophthalic acid H- pyrazoles -4- bases) phenyl) piperidines -1- formamides 3; white solid), yield 24%.
MS m/z(LC-MS):543.3[M-1]
1H NMR(400MHz,CD3OD):δ7.89(s,1H),7.76(s,1H),7.46(d,2H),7.36(d,2H),7.06-7.00(m,2H),6.80-6.76(m,1H),4.25-4.21(m,2H),3.92(s,3H),3.69-3.63(m,1H),3.05-2.99(m,2H),1.96-1.93(m,2H),1.70-1.60(m,2H).
Embodiment 4
N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (1- sulfamoyls piperidin-4-yl) ethanamidine
The first step
(4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) sulfonylcarbamic acid tert-butyl ester
By N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidine 1f (50mg; 0.145mmol) it is dissolved in 10mL dichloromethane; add triethylamine (44mg; 0.44mmol); reaction system is cooled to 0 DEG C; prefabricated 1mL chlorosulfonyl t-butyl carbamate 4a (22mg are added dropwise; 0.1mmol; be prepared using method disclosed in patent application " WO2010149684 ") dichloromethane solution, in 0 DEG C of stirring reaction 1 hour.After reaction terminates; add 5mL water; extracted with dichloromethane (10mL × 3); merge organic phase; washed with saturated nacl aqueous solution (5mL); with anhydrous sodium sulfate drying; filtering; filtrate decompression is concentrated; with thin-layered chromatography with solvent system A purify gained residue; obtain title product (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) sulfonylcarbamic acid tert-butyl ester 4b (60mg, colorless oil), yield 78%.
MS m/z(LC-MS):469.3[M-56+1]
Second step
N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (1- sulfamoyls piperidin-4-yl) ethanamidine
By (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) sulfonylcarbamic acid tert-butyl ester 4b (60mg; 0.11mmol) it is dissolved in 2mL methanol; add 2mL 4M hydrogen chloride 1; 4- dioxane, reaction system was in 25 DEG C of stirring reactions 1 hour.After reaction terminates; it is concentrated under reduced pressure after adding 5mL methanol; it is repeated twice; gained residue ammoniacal liquor regulation pH is 10; it is extracted with ethyl acetate (10mL × 2); organic phase anhydrous sodium sulfate drying; filtering; filtrate decompression is concentrated; with thin-layered chromatography with solvent system A purify gained residue; obtain title product N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (1- sulfamoyls piperidin-4-yl) ethanamidine 4 (10mg, faint yellow solid), yield 21%.
MS m/z(LC-MS):425.3[M+1]
1H NMR(400MHz,CD3OD):δ7.06-6.99(m,2H),6.79-6.76(m,1H),3.71-3.68(m,2H),3.50-3.44(m,1H),2.74-2.68(m,2H),2.00-1.98(m,2H),1.78-1.71(m,2H).
Embodiment 5
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (3- (methyl sulphonyl) phenyl) piperidines -1- formamides
The first step
1- isocyanate groups -3- (methyl sulphonyl) benzene
By 3- (methyl sulphonyl) anilinechlorides 5a (488mg, 2.35mmol, using known method " Helvetica Chimica Acta; 1981; 64 (6), 1849-53 " is prepared) add in 30mL dichloromethane, add triphosgene (220mg; 0.74mmol); triethylamine (0.37mL, 2.66mmol), reaction system was in 25 DEG C of stirring reactions 30 minutes; back flow reaction 45 minutes, react 30 minutes then at 25 DEG C again.Title product 1- isocyanate groups -3- (methyl sulphonyl) benzene 5b reaction solution is obtained, product is not purified directly to carry out next step reaction.
Second step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (3- (methyl sulphonyl) phenyl) piperidines -1- formamides
1mL is taken to add prefabricated 2mLN- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidine 1f (26mg above-mentioned 1- isocyanate groups -3- (methyl sulphonyl) benzene 5b reaction solution; 0.0755) in tetrahydrofuran solution, in 25 DEG C of stirring reactions 12 hours.After reaction terminates; reaction solution is concentrated under reduced pressure; with thin-layered chromatography with solvent system A purify gained residue; (the 9mg of title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (3- (methyl sulphonyl) phenyl) piperidines -1- formamides 5 is beaten to obtain with 5mL dichloromethane afterwards; white solid), yield 22%.
MS m/z(ESI):541.3[M+1]
1H NMR(400MHz,DMSO-d6):δ11.68(s,1H),8.95(s,1H),8.39(s,1H),8.09(t,1H),7.82(d,1H),7.51(t,1H),7.46-7.49(m,1H),7.18(t,1H),6.98(dd,1H),6.72(ddd,1H),4.19-4.22(m,2H),3.54-3.59(m,1H),2.89-2.95(m,2H),1.86-1.89(m,2H),1.43-1.51(m,2H).
Embodiment 6
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (3- cyano-phenyls) piperidines -1- formamides
The first step
3- isocyanate group benzonitriles
By triphosgene (187mg, 0.63mmol) it is dissolved in 20mL tetrahydrofurans, adds 3- anthranilo nitriles 6a (223mg, 1.887mmol) and triethylamine (0.52mL, 0.0876mmol), reaction system was in 25 DEG C of stirring reactions 1 hour.Title product 3- isocyanate group benzonitriles 6b suspension is obtained, product is not purified directly to carry out next step reaction.
Second step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyano-phenyls) piperidines -1- formamides
1mL is taken to add prefabricated 2mL N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidine 1f (30mg above-mentioned 3- isocyanate groups benzonitrile 6b suspension, in tetrahydrofuran solution 0.0876mmol), in 25 DEG C of stirring reactions 2 hours.After reaction terminates; reaction solution is concentrated under reduced pressure; with thin-layered chromatography with solvent system A purify gained residue; obtain (the 26mg of title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (3- cyano-phenyls) piperidines -1- formamides 6; white solid), yield 61.0%.
MS m/z(ESI):488.2[M+1]
1H NMR(400MHz,DMSO-d6):δ11.69(s,1H),8.88(s,1H),8.41(s,1H),7.94(s,1H),7.75(d,1H),7.45(t,1H),7.38(d,1H),7.18(t,1H),6.98(dd,1H),6.69-6.73(m,1H),4.17-4.20(m,2H),3.53-3.59(m,1H),2.88-2.94(m,2H),1.86-1.89(m,2H),1.43-1.51(m,2H).
Embodiment 7
N- benzyls -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides
By (isocyanatometyl) benzene 7a (20mg, 0.15mmol, using known method " Bioorganic ＆ Medicinal Chemistry; 2013; 21 (11); 2960-2967 " is prepared) add in prefabricated 2mL N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidines 1f (30mg, 0.0876) tetrahydrofuran solution, in 25 DEG C of stirring reactions 2 hours.After reaction terminates; reaction solution is concentrated under reduced pressure; with thin-layered chromatography with solvent system A purify gained residue; it is beaten with 5mL dichloromethane; obtain (the 6mg of title product N- benzyls -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides 7; white solid), yield 14%.
MS m/z(ESI):477.4[M+1]
1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.37(s,1H),7.15-7.32(m,6H),7.09(t,1H),6.98(dd,1H),6.69-6.73(m,1H),4.24(d,2H),4.05-4.08(m,2H),3.47-3.53(m,1H), 2.74-2.80(m,2H),1.78-1.80(m,2H),1.35-1.43(m,2H).
Embodiment 8
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (mesyl) phenyl) piperidines -1- formamides
By 1- isocyanate groups -4- (mesyl) benzene (20mg; 0.15mmol; using known method " Bioorganic ＆ Medicinal Chemistry Letters; 2010; 20 (4); 7397-7400 " is prepared) add in prefabricated 2mLN- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidines 1f (30mg, 0.0876) tetrahydrofuran solution, in 25 DEG C of stirring reactions 12 hours.After reaction terminates; reaction solution is concentrated under reduced pressure; with thin-layered chromatography with solvent system A purify gained residue; it is beaten with 5mL dichloromethane; obtain (the 13mg of title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (mesyl) phenyl) piperidines -1- formamides 8; white solid), yield 27.7%.
MS m/z(ESI):541.4[M+1]
1H NMR(400MHz,DMSO-d6):δ11.68(s,1H),9.04(s,1H),8.39(s,1H),7.77(d,2H),7.71(d,2H),7.17(t,1H),6.98(dd,1H),6.71(ddd,1H),4.18-4.21(m,2H),3.53-3.59(m,1H),3.14(s,3H),2.90-2.96(m,2H),1.87-1.90(m,2H),1.44-1.52(m,2H).
Embodiment 9
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- morpholino phenyls) piperidines -1- formamides
By 4- morpholinyl phenylamines (22mg, 0.123mmol) it is dissolved in 5mL tetrahydrofurans, add p-nitrophenyl chloroformate ester (25mg, 0.124mmol), triethylamine (0.04mL, 0.288mmol), reacted 30 minutes in 25 DEG C, N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidine 1f (40mg, 0.116mmol) are added, in 25 DEG C of stirring reactions 4 hours.After reaction terminates; reaction solution is concentrated under reduced pressure; with thin-layered chromatography with solvent system A purify gained residue; obtain (the 45mg of title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- morpholino phenyls) piperidines -1- formamides 9; white solid), yield 70%.
MS m/z(ESI):548.4[M+1]
1H NMR(400MHz,DMSO-d6):δ11.68(s,1H),8.39(s,1H),8.31(s,1H),7.29(d,2H),7.18(t,1H),6.99(dd,1H),6.84(d,2H),6.71(ddd,1H),4.15-4.18(m,2H),3.72(t,4H),3.50-3.56(m,1H),3.01(t,4H),2.81-2.87(m,2H),1.83-1.86(m,2H),1.41-1.49(m,2H).
Embodiment 10
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (sulfamoylamino group) phenyl) piperidines -1- formamides
The first step
N- (4- nitrobenzophenones) sulfamoylamino group carboxylate
Chlorine sulfonamido t-butyl formate 4a (1.6mg, 7.52mmol) is dissolved in 50mL dichloromethane, 4- nitroanilines (988mg, 7.5mmol) are added, triethylamine (1.5mL, 10.8mmol) is added, reacted 48 hours in 25 DEG C.After reaction terminates, reactant is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify gained residue, it is beaten again with 15mL dichloromethane, obtain title product N- (4- nitrobenzophenones) sulfamoylamino group carboxylate 10b (1.4g, white solid), yield 62%.
Second step
N- (4- aminophenyls) sulfamoylamino group t-butyl formate
N- (4- nitrobenzophenones) sulfamoylamino group carboxylate 10b (1.4g, 4.41mmol) are dissolved in 40mL methanol, 280mg 10% palladium carbon is added, reaction system is replaced three times with hydrogen, is reacted 3 hours in 25 DEG C.After reaction terminates, filtering, filtrate decompression concentration obtains crude title product N- (4- aminophenyls) sulfamoylamino group t-butyl formate 10c (1.4g, hazel-color solid), and product is not purified directly to carry out next step reaction.
3rd step
N- (4- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides) phenyl) sulfamoylamino group t-butyl formate
By crude product N- (4- aminophenyls) sulfamoylamino group t-butyl formate 10c (44mg, 0.153mmol) it is dissolved in 5mL tetrahydrofurans, add 4- nitrobenzoic acids (31mg, 0.153mmol, Adamas), triethylamine (0.03mL, 0.216mmol), reacted 30 minutes in 25 DEG C, add N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidine 1f (50mg, 0.145mmol), in 25 DEG C of stirring reactions 1 hour.After reaction terminates; reaction solution is concentrated under reduced pressure; with thin-layered chromatography with solvent system A purify gained residue, obtain title product N- (4- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides) 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- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (sulfamoylamino group) phenyl) piperidines -1- formamides
By N- (4- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides) phenyl) sulfamoylamino group t-butyl formate 10d (41mg; 0.0623mmol) it is placed in reaction bulb; add 4mL 4M hydrogen chloride 1; 4- dioxane solutions, react 1 hour in 25 DEG C.After reaction terminates; reaction solution is concentrated under reduced pressure; with saturated sodium bicarbonate solution regulation pH ＞ 7; it is extracted with ethyl acetate (25mL × 3); merge organic phase; anhydrous sodium sulfate drying; filtering; filtrate decompression is concentrated; with thin-layered chromatography with solvent system A purify gained residue; obtain title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (sulfamoylamino group) phenyl) piperidines -1- formamides 10 (25mg, white solid), yield 71%.
MS m/z(LC-MS):557.3[M+1]
1H NMR(400MHz,DMSO-d6):δ11.68(s,1H),9.14(s,1H),8.42(s,1H),8.39(s,1H),7.33(d,2H),7.18(t,1H),7.04(d,2H),6.98(dd,1H),6.94(s,2H),6.72(ddd,1H),4.15-4.19(m,2H),3.51-3.56(m,1H),2.83-2.88(m,2H),1.84-1.86(m,2H),1.41-1.49(m,2H).
Embodiment 11
N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- ((1r, 4r) -4- ((sulfamoylamino group) methyl) cyclohexyl) ethanamidine
The first step
(((1r, 4r) -4- (2- carbonyls 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 known method " Bioorganic ＆ Medicinal Chemistry; 2003; 11 (7), 1319-1341 " is prepared) add in 200mL Isosorbide-5-Nitraes-dioxane and 993 μ L water, add selenium dioxide (5.756g, 0.052mol), 993 μ L acetic acid, in 80 DEG C of stirring reactions 17 hours.After reaction terminates; 300mL water is added, is extracted with dichloromethane (150mL × 3), merges organic phase; anhydrous sodium sulfate drying; filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue; obtain title product (((1r; 4r) -4- (2- carbonyls acetyl group) cyclohexyl) methyl) t-butyl carbamate 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- carbonyls acetyl group) cyclohexyl) methyl) t-butyl carbamate 11b (2.4g; 8.911mmol) add in 10mL methanol; add hydroxylamine hydrochloride (619mg; 8.911mmol); potassium carbonate (1.847g, 13.366mmol) was added in reaction bulb, in 25 DEG C of stirring reactions 1 hour.After reaction terminates; add 200mL ethyl acetate; filtering; filtrate decompression is concentrated to give crude title product (((1r; 4r) -4- (2- (oximido) acetyl group) cyclohexyl) methyl) t-butyl carbamate 11c (2.132g; pale yellowish brown solid), product is not purified directly to carry out next step reaction.
MS m/z(LC-MS):283[M-1]
3rd 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; 7.385mmol) add 80mL N; in dinethylformamide; add N- chlorosuccinimides (986mg; 7.385mmol), in 25 DEG C of stirring reactions 2 hours.After reaction terminates; add 200mL ethyl acetate; organic phase is washed with water (100mL × 3); saturated nacl aqueous solution washs (100mL × 2); anhydrous sodium sulfate drying; filtering; filtrate decompression is concentrated; obtain crude title product (((1r; 4r) -4- (2- chloro- 2- (oximido) acetyl group) cyclohexyl) methyl) t-butyl carbamate 11d (1.788g; yellow oil), product is not purified directly to carry out next step reaction.
4th step
(((1r, 4r) -4 (- 2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclohexyl) methyl) t-butyl carbamate
By crude product (((1r; 4r) -4- (2- chloro- 2- (oximido) acetyl group) cyclohexyl) methyl) t-butyl carbamate 11d (1.788g; 5.608mmol) with the bromo- 4- fluoroanilines (2.131g of 3-; 11.217mol) add in 80mL ethanol, in stirring reaction 17 hours at 25 DEG C.After reaction terminates; reaction solution is concentrated under reduced pressure; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product (((1r; 4r) -4 (- 2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclohexyl) 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- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyl ethanamidines
By (((1r; 4r) -4 (- 2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclohexyl) methyl) t-butyl carbamate 11e (140mg; 0.296mL) it is placed in reaction bulb; add 2mL methanol; add 2.5mL 4M hydrogen chloride 1; 4- dioxane, in stirring reaction 30 minutes at 25 DEG C.After reaction terminates, reaction solution is concentrated under reduced pressure, obtain crude title product 2- ((1r, 4r) -4- (amino methyl) cyclohexyl)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyl ethanamidine 11f (130mg, yellow oil), product is not purified directly to carry out next step reaction.
MS m/z(LC-MS):372[M+1]
6th step
N- (((1r, 4r) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclohexyl) methyl) sulfamoylamino group t-butyl formate
Chloro sulfonyl isocyanate (42mg, 0.296mmol) is dissolved in 2mL dichloromethane, 0 DEG C is cooled to, the tert-butyl alcohol (22mg, 0.296mmol) is added, in standby after 0 DEG C of stirring reaction 15 minutes.By crude product 2- ((1r, 4r) -4- (amino methyl) cyclohexyl)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyl ethanamidine 11f (110mg, 0.296mmol), 2mL dichloromethane and triethylamine (124 μ L, 0.886mmol) add in reaction bulb, above-mentioned reserve liquid is added, in 25 DEG C of stirring reactions 1 hour.After reaction terminates; add 50mL dichloromethane; washed successively with saturated sodium bicarbonate solution (30mL × 2), water (30mL × 2), saturated nacl aqueous solution (30mL × 2); organic phase anhydrous sodium sulfate drying; filtering; filtrate decompression is concentrated; obtain crude title product N- (((1r; 4r) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclohexyl) methyl) sulfamoylamino group t-butyl formate 11g (132mg; yellow solid), product is not purified directly to carry out next step reaction.
MS m/z(LC-MS):551.0[M+1]
7th step
N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- ((1r, 4r) -4- ((sulfamoylamino group) methyl) cyclohexyl) ethanamidine
By crude product N- (((1r; 4r) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclohexyl) methyl) sulfamoylamino group t-butyl formate 11g (132mg; 0.239mmol) it is dissolved in 2mL methanol; add 2mL 4M hydrogen chloride 1; 4- dioxane solutions, reaction system was in 25 DEG C of stirring reactions 3 hours.After reaction terminates, reaction solution is concentrated under reduced pressure, add 50mL dichloromethane, washed successively with saturated sodium bicarbonate solution (50mL × 3), organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyl -2- ((1r, 4r) -4- ((sulfamoylamino group) methyl) cyclohexyl) ethanamidine 11 (45mg, faint yellow solid), yield 41.7%
MS m/z(LC-MS):451[M+1]
1H NMR(400MHz,DMSO-d6):δ11.60(s,1H),8.32(s,1H),7.18-7.14(m,1H),6.97-6.95(m,1H),6.71-6.67(m,1H),6.49-6.44(m,3H),3.28-3.22(m,1H),2.74-2.67(m,2H),1.88-1.85(m,4H),1.45-1.28(m,3H),0.98-0.87(m,2H).
Embodiment 12
2- (3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-phenyl acetanilide,Phenacetylaniline
The first step
2- (3- (methoxyl group (methyl) carbamoyl) ring fourth subunit) ethyl acetate
50mL tetrahydrofurans are placed in reaction bulb, ice bath is cooled to 0 DEG C, sodium hydride solid (60% is carefully added into batches, 1.76g, 0.044mol), phosphonoacetate (9.86g is added after 10 minutes, tetrahydrofuran solution 0.044mol), and persistently stirred 30 minutes in 0 DEG C, then prefabricated N- methoxy-. N-methyl -3- carbonyl ring fourth formamide 12a (6.28g are added, 0.04mol, be prepared using method disclosed in patent application " WO2009114512 ") tetrahydrofuran solution, and progressively rise to 25 DEG C react 30 minutes, the progress of TLC monitoring reactions.After reaction terminates; 10mL water quenchings are added to go out reaction; add water and each 200mL extractions point liquid of ethyl acetate; organic phase water; saturated nacl aqueous solution washs (30 × 3mL); collect organic phase; anhydrous sodium sulfate drying; filtering; filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 2- (3- (methoxyl group (methyl) carbamoyl) ring fourth subunit) 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
By 2- (3- (methoxyl group (methyl) carbamoyl) ring fourth subunit) ethyl acetate 12b (8.0g; 0.035mol) it is dissolved in 80mL ethyl acetate; 10% palladium carbon (800mg) is added, hydrogen is replaced 3 times, and is held under a hydrogen atmosphere Continuous stirring 3 days, the progress of TLC monitoring reactions.After question response terminates; it is filtered to remove palladium carbon; filtrate decompression is concentrated to give crude title product 2- (3- (methoxyl group (methyl) carbamoyl) cyclobutyl) ethyl acetate 12c (7.4g; yellow liquid); product is not purified directly to carry out next step reaction, yield 91.8%.
MS m/z(LC-MS):230.2[M+1]
3rd step
2- (3- acetyl cyclobutyl) ethyl acetate
By crude product 2- (3- (methoxyl group (methyl) carbamoyl) cyclobutyl) ethyl acetate 12c (7.4g; 32.3mmol) add in 50mL tetrahydrofurans; ice bath is cooled to 0 DEG C; 1.0M methyl magnesium bromide solutions (65mL is added dropwise; 64.6mmol), and at 0 DEG C stir 30 minutes.After reaction terminates; add 100mL saturated ammonium chloride solutions and reaction is quenched; then water and each 100mL of ethyl acetate are added; reaction mixture point liquid; organic phase water; saturated nacl aqueous solution washs (50mL × 3); collect organic phase; anhydrous sodium sulfate drying, filtering, filtrate decompression concentration; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain title product 2- (3- acetyl cyclobutyl) ethyl acetate 12d (4.5g, colourless liquid), yield 88.0%.
4th step
2- (3- (2- carbonyls acetyl group) cyclobutyl) ethyl acetate
2- (3- acetyl cyclobutyl) ethyl acetate 12d (2.0g, 10.85mmol) and selenium dioxide (2.4g, 21.7mmol) are added in 20mL dioxane, 80 DEG C is heated to and reacts 12 hours.Next day, filtering, filtrate decompression is concentrated to give the not purified directly progress next step reaction of crude title product 2- (3- (2- carbonyls acetyl group) cyclobutyl) ethyl acetate 12e (2.0g, red liquid) product, yield 93.0%.
5th step
2- (3- (2- (oximido) acetyl group) cyclobutyl) ethyl acetate
By crude product 2- (3- (2- carbonyls acetyl group) cyclobutyl) ethyl acetate 12e (2.0g; 10.1mmol) it is placed in reaction bulb; add 20mL methanol; it is separately added into potassium carbonate (2.1g; 15mmol); hydroxylamine hydrochloride (702mg, 10.1mmol), and stirring reaction 1 hour at 25 DEG C.After reaction terminates; pad silica gel filtering; filtrate decompression is concentrated to give crude title product 2- (3- (2- (oximido) acetyl group) cyclobutyl) ethyl acetate 12f (2.0g; red liquid); product is not purified directly to carry out next step reaction, yield 95.2%.
MS m/z(LC-MS):214.3[M+1]
6th step
2- (3- (2- chloro- 2- (oximido) acetyl group) cyclobutyl) ethyl acetate
By crude product 2- (3- (2- (oximido) acetyl group) cyclobutyl) ethyl acetate 12f (2.0g; 9.38mmol) it is dissolved in 20mL N; in dinethylformamide; add 4 and drip ether solution of hydrogen chloride; then N-chlorosuccinimide (1.25g is added; 9.38mmol), stirring reaction 1 hour and at 25 DEG C.After reaction terminates; water and each 50mL of ethyl acetate are added, point liquid, organic phase water; saturated nacl aqueous solution washs (30mL × 3); collect organic phase, anhydrous sodium sulfate drying, filtering; filtrate decompression is concentrated to give crude title product 2- (3- (2- chloro- 2- (oximido) acetyl group) cyclobutyl) ethyl acetate 12g (2.0g; yellow liquid), product is not purified directly to carry out next step reaction, yield 86.9%.
7th step
2- (3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) ethyl acetate
By crude product 2- (3- (2- chloro- 2- (oximido) acetyl group) cyclobutyl) ethyl acetate 12g (2.0g; 8.07mmol) it is dissolved in 20mL ethanol; add the bromo- 4- fluoroanilines 12h (2.3g of 3-; 12.1mmol), stirring reaction 3 days and at 25 DEG C.After reaction terminates; 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- fluorophenyls 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- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) acetic acid
2- (3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) ethyl acetate 12i (1.5g, 3.74mmol) is dissolved in the mixed solution (V of 23mL tetrahydrofurans and water:V=15:8) in, lithium hydroxide monohydrate (314mg, 7.48mmol) is added, 50 DEG C is heated to and persistently stirs 2 hours.After reaction terminates, reaction solution is concentrated under reduced pressure and removes most of organic solvent, residue adds water and each 100mL of dichloromethane, divide liquid, aqueous phase 6N salt acid for adjusting pH to 3~4, aqueous phase is extracted (50mL × 3) with dichloromethane, the organic phase water of collection, saturated nacl aqueous solution washs (30 × 3mL), collect organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give crude title product 2- (3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) acetic acid 12j (900mg, yellow solid), product is not purified directly to carry out next step reaction, yield 64.7%.
MS m/z(LC-MS):373.3[M+1]
9th step
2- (3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-phenyl acetanilide,Phenacetylaniline
By crude product 2- (3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) acetic acid 12j (30mg; 0.08mmol) it is dissolved in 10mL dichloromethane; argon gas is replaced three times; oxalyl chloride (51mg is added under an argon; 0.40mmol); stirred 2 hours in 0 DEG C, reaction solution is concentrated under reduced pressure, standby.10mL dichloromethane is added in residue, aniline (15mg, 0.16mmol), DIPEA (31mg, 0.24mmol) stirs, and reacted 30 minutes under the conditions of 25 DEG C, the progress of TLC monitoring reactions.After reaction terminates; add water and each 30mL of dichloromethane; divide liquid; organic phase water; saturated nacl aqueous solution washs (30 × 3mL); collect organic phase; anhydrous sodium sulfate drying; filtering; filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain (the 10mg of title product 2- (3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-phenyl acetanilide,Phenacetylaniline 12; white solid), yield 27.8%.
MS m/z(LC-MS):448.3[M+1]
1H NMR(400MHz,DMSO-d6):δ11.58(s,1H),9.84(s,1H),8.31(s,1H),7.55-7.57(m,2H),7.25-7.29(m,2H),7.13-7.18(m,1H),6.97-7.01(m,2H),6.71(m,1H),3.84-3.89(m,1H),2.65-2.69(m,1H),2.37-2.39(m,2H),2.26-2.29(m,2H),1.93-2.01(m,2H).
Embodiment 13
2- (3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-N- (4- methoxyphenyls) acetamide
By 2- (3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) acetic acid 12j (30mg; 0.08mmol) it is dissolved in 5mL dichloromethane; and with and in being cooled to 0 DEG C; half drop DMF is added, oxalyl chloride (51mg is added; 0.40mmol); stirred 2 hours in 0 DEG C, reaction solution is concentrated to dryness, standby.Residue is dissolved in 10mL dichloromethane, P-nethoxyaniline (19.8mg, 0.16mmol) is added, DIPEA (31mg, 0.24mmol) stirs, and is reacted 5 minutes at 25 DEG C, the progress of TLC monitoring reactions.After reaction terminates; reaction solution is concentrated to dryness; add a small amount of dichloromethane dissolving; with thin-layered chromatography respectively with solvent system A and B purify gained residue; obtain (the 6mg of title product 2- (3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-N- (4- methoxyphenyls) acetamide 13; yellow solid), yield 15.6%.
MS m/z(LC-MS):478.3[M+1]
1H NMR(400MHz,CD3OD):δ7.39-7.43(m,2H),6.97-7.03(m,2H),6.85-6.88(m,2H),6.74-6.77(m,1H),4.08-4.14(m,1H),3.77(s,3H),2.71-2.77(m,1H),2.38-2.42(m,2H),2.36-2.47(m,2H),2.01-2.07(m,2H).
Embodiment 14
2- (3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-N- (4- (1- methyl isophthalic acid H- pyrazoles -4- bases) phenyl) acetamide
By 2- (3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) acetic acid 12j (90mg; 0.24mmol) it is dissolved in 5mL dichloromethane; and be cooled with an ice bath to 0 DEG C; add 1 and drip DMF, add oxalyl chloride (152mg; 1.2mmol); stirred 2 hours in 0 DEG C, reaction solution is concentrated under reduced pressure, standby.Residue is dissolved in 10mL dichloromethane, 4- (1- methyl isophthalic acid H- pyrazoles -4- bases) aniline 3a (68mg, 0.36 is added Mmol, is prepared using method disclosed in patent application " WO2010132015 "), DIPEA (93mg, 0.72mmol) stirs, and reacts and stay overnight under the conditions of 25 DEG C, the progress of TLC monitoring reactions.After reaction terminates, saturated sodium bicarbonate solution and each 50mL of dichloromethane are added into reaction solution, divide liquid, organic phase water, saturated nacl aqueous solution washs (30 × 3mL), collect organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography respectively with solvent system A and B purify gained residue, obtain (the 3mg of title product 2- (3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-N- (4- (1- methyl isophthalic acid H- pyrazoles -4- bases) phenyl) acetamide 14, white solid), yield 2.4%.
MS m/z(LC-MS):528.4[M+1]
1H NMR(400MHz,CD3OD):δ7.91(s,1H),7.78(s,1H),7.47-7.54(m,4H),6.97-7.04(m,2H),6.75-6.77(m,1H),3.94-3.98(m,1H),3.91(s,3H),2.75-2.79(m,1H),2.44-2.46(m,2H),2.37-2.40(m,2H),2.02-2.05(m,2H).
Embodiment 15
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formic acid 3- pyridine esters 15
By 4- nitrobenzene pyridin-3-yl carbonic ester 15a (181mg, 0.697mmol, using applying for a patent " method disclosed in EP1849773A1 " is prepared) be dissolved in 30mL tetrahydrofurans, add 1f (200mg, 0.58mmol), triethylamine (0.243mL, 1.743mmol), stirring reaction 1 hour at 25 DEG C.After reaction terminates, reaction solution is concentrated under reduced pressure, and title product 15 (64mg, faint yellow solid), yield 23.7% are prepared using high performance liquid chromatography.
MS m/z(ESI):465.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.43-8.40(m,3H),7.64-7.62(m,1H),7.46-7.43(m,1H),7.20-7.15(m,1H),7.00-6.99(m,1H),6.73-6.71(m,1H),4.26-4.06(m,2H),3.57-3.55(m,1H),3.16-2.99(m,2H),1.94-1.91(m,2H),1.60-1.53(m,2H).
Embodiment 16
N- (4- (1H- pyrazoles -4- bases) phenyl) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides
The first step
4- (1- (tetrahydrochysene -2H- pyrans -2- bases) -1H- pyrazoles -4- bases) aniline
By 1- (tetrahydrochysene -2H- pyrans -2- bases) -4- (4,4,5,5- tetramethyls -1,3,2- dioxy boron pentane -2- bases) -1H- pyrazoles 16a (1.9g, 6.8mmol, using known method " Zeitschrift fuer Naturforschung, B:A Journal of Chemical Sciences, 2014,69 (1), 83-97 " is prepared); 4- bromanilines (1.17g, 6.8mmol), [1; double (diphenylphosphine) ferrocene of 1'-] palladium chloride (249mg; 0.34mmol), potassium carbonate (1.89g, 13.7mmol) was added in 30mL dioxane and 6mL water; under argon atmospher, in 100 DEG C of stirring reactions 4 hours.After reaction terminates, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- (1- (tetrahydrochysene -2H- pyrans -2- bases) -1H- pyrazoles -4- bases) aniline 16b (849mg, Tan solid), yield 51%.
Second step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (tetrahydrochysene -2H- pyrans -2- bases) -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides
By triphosgene (20mg, 0.067mmol) it is dissolved in 5mL tetrahydrofurans, add 4- (1- (tetrahydrochysene -2H- pyrans -2- bases) -1H- pyrazoles -4- bases) aniline 16b (42mg, 0.172mmol), 0.06mL triethylamines, react 30 minutes in 25 DEG C, add (N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidine 1f (50mg, 0.45mmol), reacted 1 hour in 25 DEG C.Reaction terminate after, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with eluant, eluent system A purify obtained by residue, obtain title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) Acetyl group)-N- (4- (1- (tetrahydrochysene -2H- pyrans -2- bases) -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides 16c (74mg, white solid), yield 83%.
3rd step
N- (4- (1H- pyrazoles -4- bases) phenyl) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides
By 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (tetrahydrochysene -2H- pyrans -2- bases) -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamide 16c (74mg; 0.12mmol) add in 10mL methanol; add p-methyl benzenesulfonic acid (27mg; 0.156mol), in stirring reaction 12 hours at 25 DEG C.After reaction terminates; add 0.1mL triethylamines; reaction solution is concentrated under reduced pressure; with thin-layered chromatography with eluant, eluent system A purify gained residue; obtain (the 30mg of title product N- (4- (1H- pyrazoles -4- bases) phenyl) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides 16; white solid), yield 47%.
MS m/z(LC-MS):531.4[M+1]
1H NMR(400MHz,DMSO-d6)δ12.83(s,1H),11.68(s,1H),8.51(s,1H),8.39(s,1H),8.04(s,1H),7.88(s,1H),7.43-7.48(m,4H),7.18(t,1H),6.99(dd,1H),6.71-6.74(m,1H),4.18-4.21(m,2H),3.52-3.58(m,1H),2.88-2.91(m,2H),1.85-1.88(m,2H),1.43-1.52(m,2H).
Embodiment 17
N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -2- ((1r, 4r) -4- (sulfonyloxy methyl amino methyl) cyclohexyl) -2- carbonyls ethanamidine 17
By 11f (79mg, 0.212mmol), 1.5mL dichloromethane and triethylamine (89 μ L, 0.637mmol) were added in reaction bulb, add methane sulfonyl chloride (24mg, 0.212mmol), in 25 DEG C of stirring reactions 1 hour.After reaction terminates, add 50mL dichloromethane, washed successively with saturated sodium bicarbonate solution (50mL × 3), water (50mL × 3), saturated nacl aqueous solution (50mL × 2), organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 17 (25mg, faint yellow solid), yield 26.3%.
MS m/z(ESI):452.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.32(s,1H),7.18-7.14(m,1H),6.99-6.95(m,2H),6.71-6.67(m,1H),3.28-3.22(m,1H),2.85(s,3H),2.81-2.78(m,2H),1.90-1.83(m,4H),1.39-1.33(m,3H),1.00-0.92(m,2H),
Embodiment 18
N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- ((1r, 4r) -4- (sulphamoylamino) cyclohexyl) ethanamidine 18
Using the synthetic route of embodiment 11; first step raw material is replaced with into ((1r; 4r) -4- acetyl butylcyclohexyl) t-butyl carbamate (being prepared using method disclosed in patent application " WO2012018668 "); title product 18 (14mg, yellow solid) is made.
MS m/z(ESI):437.3[M+1]
1HNMR(400MHz,DMSO-d6)δ11.64(s,1H),8.33(s,1H),7.18-7.14(m,1H),6.96-6.94(m,1H),6.71-6.68(m,1H),6.52-6.47(m,3H),3.13-3.17(m,1H),3.03-3.01(m,1H),2.05-2.01(m,2H),1.89-1.86(m,2H),1.38-1.31(m,4H).
Embodiment 19
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (2- cyanopyridine -4- bases) piperidines -1- formamides 19
By triphosgene (34mg, 0.116mmol) it is dissolved in 1.5mL tetrahydrofurans, 0 DEG C adds 4- amino 2- cyanopyridine 19a (14mg, 0.116mmol, it is prepared using method disclosed in patent application " WO2001302639 "), triethylamine (48 μ L, 0.349mmol, reacted 30 minutes in 0 DEG C, it is stand-by that the reaction solution that is concentrated under reduced pressure obtains residue faint yellow solid.1f (40mg, 0.116mmol) is dissolved in 1.5mL tetrahydrofurans, above-mentioned residue is added at 25 DEG C, is reacted 2 hours in 25 DEG C.Reaction terminate after, add 2mL methanol reaction is quenched, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 19 (8mg, white solid), yield 14%.
MS m/z(ESI):491.3[M+1]
1H NMR(400 MHz,DMSO-d6)δ11.69(s,1H),9.39(s,1H),8.46-8.45(m,1H),8.38(s,1H),8.04-8.03(m,1H),7.72-7.70(m,1H),7.19-7.14(m,1H),6.99-6.97(m,1H),6.73-6.69(m,1H),4.19-4.16(m,2H),3.59-3.53(m,1H),2.98-2.93(m,2H),1.90-1.87(m,2H),1.52-1.43(m,2H).
Embodiment 20
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- cyclopropyl -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides
The first step
1- cyclopropyl -4- (4- nitrobenzophenones) -1H- pyrazoles
By 4- (4- nitrobenzene) -1H- pyrazoles 20a (1.0g, 5.3mmol, using known method " Medicinal Chemistry Research; 2013; 22 (11); 5610-5616 " is prepared) be dissolved in 50mL 1,2- dichloroethanes, add cyclopropylboronic acid (1.02g, 11.9mmol), copper acetate (1.11g, 5.57mmol), bipyridyl (869mg, 5.57mmol), sodium carbonate (1.69g, 15.9mmol), reaction system is reacted 3 hours in 70 DEG C.After reaction terminates, it is cooled to room temperature, it is filtered to remove insoluble matter, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- cyclopropyl -4- (4- nitrobenzophenones) -1H- pyrazoles 20b (612mg, yellow solid), yield 52.1%.
Second step
4- (1- cyclopropyl -1H- pyrazoles -4- bases) aniline
By 1- cyclopropyl -4- (4- nitrobenzophenones) -1H- pyrazoles 20b (1.6g, 7.0mmol) add in 30mL ethanol and 10mL water, add iron powder (784mg, 14.0mmol) and ammonium chloride (1.5g, 28.0mmol), back flow reaction 2 hours.After reaction terminates, reaction solution is concentrated under reduced pressure removing ethanol, add dichloromethane 50mL, it is filtered to remove insoluble matter, filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 4- (1- cyclopropyl -1H- pyrazoles -4- bases) aniline 20c (1.33g, yellow solid), yield 95.6%.
3rd step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- cyclopropyl -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides
By triphosgene (18mg, 0.06mmol) it is dissolved in 10mL tetrahydrofurans, it is disposable to add 4- (1- cyclopropyl -1H- pyrazoles -4- bases) aniline 20c (35mg, 0.17mmol), add triethylamine (53mg, 0.32mmol), stirring reaction 30 minutes at room temperature.(N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyl -2- (piperazines are added into reaction solution Pyridine -4- bases) ethanamidine 1f (50mg, 0.145mmol), at room temperature stirring reaction 1 hour.After reaction terminates; reaction solution is concentrated under reduced pressure; with thin-layered chromatography with eluant, eluent system A purify gained residue; obtain (the 30mg of title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- cyclopropyl -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides 20; white solid), yield 36.5%.
MS m/z(LC-MS):569.4[M+1]
1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.52(s,1H),8.39(s,1H),8.12(s,1H),7.77(s,1H),7.44(s,4H),7.18(t,1H),6.99(dd,1H),6.71-6.74(m,1H),4.18-4.21(m,2H),3.69-3.74(m,1H),3.52-3.58(m,1H),2.85-2.91(m,2H),1.85-1.88(m,2H),1.43-1.51(m,2H),1.04-1.06(m,2H),0.96-0.99(m,2H).
Embodiment 21
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (difluoromethyl) -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides
The first step
1- (difluoromethyl) -4- (4- nitrobenzophenones) -1H- pyrazoles
By 4- (4- nitrobenzene) -1H- pyrazoles 20a (1.0g, 5.28mmo), ether (the 279mg of 18- crown-s 6,1.05mmol) it is dissolved in 40mL acetonitriles, added into reaction solution under difluoro sodium chloroacetate (0.967g, 6.34mmol), argon atmospher, reaction solution is warming up to backflow, stirring reaction 18 hours.Reaction solution is cooled to room temperature, filtering, filter cake is washed with ethyl acetate, collect filtrate, filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 1- (difluoromethyl) -4- (4- nitrobenzophenones) -1H- pyrazoles 21a (680mg, faint yellow solid), yield 54%.
Second step
4- (1- (difluoromethyl) -1H- pyrazoles -4- bases) aniline
1- (difluoromethyl) -4- (4- nitrobenzophenones) -1H- pyrazoles 21a (3g, 12.54mmol) are dissolved in 130mL second alcohol and waters (V:V=10:3) in the mixed solvent.Iron powder (1.4g, 25.08mmol), ammonium chloride (2.68g, 50.17mmol) are sequentially added into reaction solution.Reaction solution is warming up to 80 DEG C, stirring reaction 2 hours.After reaction terminates, reaction solution is cooled to room temperature, is concentrated under reduced pressure, ethyl acetate and a small amount of methanol are added in residue, pad diatomite filtering, filter cake is washed with ethyl acetate, collects filtrate, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- (1- (difluoromethyl) -1H- pyrazoles -4- bases) aniline 21b (2.35g, faint yellow solid), yield 89.7%.
3rd step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (difluoromethyl) -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides
By triphosgene (207mg, 0.7mmol) it is dissolved in 100mL tetrahydrofurans, gradually add 4- (1- (difluoromethyl) -1H- pyrazoles -4- bases) aniline 21b (382mg, 1.83mmol) with triethylamine (528mg, 5.23mmol), stirring reaction 30 minutes at room temperature.(N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (piperidin-4-yl) ethanamidine 1f (600g, 1.74mmol), at room temperature stirring reaction 1 hour are added into reaction solution.After reaction terminates; 20mL methanol is added to be quenched; it is concentrated under reduced pressure; with thin-layered chromatography with eluant, eluent system A purify gained residue; obtain (the 160mg of title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (difluoromethyl) -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides 21; white solid), yield 15.8%.
MS m/z(LC-MS):579.4[M+1]
1H NMR(400MHz,DMSO-d6):δ11.69(s,1H),8.60(s,1H),8.39(s,1H),8.20(s,1H),7.67(t,1H),7.57(d,2H),7.50(d,2H),7.18(t,1H),7.00(dd,1H),6.71-6.74(m,1H),4.18-4.21(m,2H),3.53-3.58(m,1H),2.86-2.92(m,2H),1.86-1.89(m,2H),1.43-1.52(m,2H).
Embodiment 22
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) fluoro- N- Phenylpiperidines -1- formamides of -4-
The first step
1- (tertbutyloxycarbonyl) -4- fluorine resources -4- formic acid 22b
22a (2g, 7.63mmol) is dissolved in 30mL ethanol, 9.5mL 2M sodium hydroxide solution is added, 60 DEG C of stirring reactions 2 hours.After reaction terminates, reaction solution is concentrated under reduced pressure, and adds 1M salt acid for adjusting pH and is less than 7, ethyl acetate is extracted three times, merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give crude title product 22b (1.78g, white solid), yield 94%.
Second step
Tert-butyl 4-fluoro-4- (methoxy (methyl) carbamoyl) the fluoro- 4- of piperidine-1-carboxylate4- (methoxyl group (methyl) carbamoyl) piperidines -1- t-butyl formates 22c
Crude product 22b (1.78g, 7.2mmol) is dissolved in 40mL dichloromethane, catalytic amount DMF and 0.9mL oxalyl chlorides is added, at room temperature stirring reaction 0.5 hour, reaction solution is concentrated under reduced pressure standby.40mL dichloromethane is added in residue, N, O- dimethyl hydroxylamine hydrochlorides (0.843g, 8.64mmol) and 3mL triethylamines is added, at room temperature stirring reaction 1 hour.Reaction terminate after, reaction solution is 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%.
3rd step
4- acetyl group -4- fluorine resources -1- t-butyl formates 22d
22c (1.3g, 4.48mmol) is dissolved in 15mL tetrahydrofurans, ice bath, adds stirring reaction 1 hour at 1.8mL 3M methyl magnesium bromide solution, 0 DEG C, add stirring reaction 0.5 hour at 0.45mL methyl magnesium bromide solutions, 0 DEG C.After reaction terminates, add saturated ammonium chloride solution and reaction is quenched, point liquid, aqueous phase is extracted with ethyl acetate three times, merge organic phase.Anhydrous sodium sulfate drying, filtering, filtrate decompression concentration purify gained residue, obtained title product 22d (930mg, colourless liquid), yield 84% with silica gel column chromatography with eluant, eluent system B.
4th step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) fluoro- N- Phenylpiperidines -1- formamides 22 of -4-
Using the synthetic route of embodiment 1, first step raw material 4- Acetylpiperidin -1- t-butyl formates are replaced with into 22d, title product 22 (40mg, white solid), yield 48% is made by number step reaction.
MS m/z(LC-MS):481.3[M+1]
Embodiment 23
2- ((1r, 3r) -3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl)-N- (4- (1- methyl isophthalic acid H- pyrazoles -4- bases) acetamides 23
12j (30mg, 0.08mmol) is dissolved in 8mL dichloromethane, 0 DEG C is cooled to, 1 is added and drips DMF, add oxalyl chloride (51mg, 0.40mmol), stirred 2 hours in 0 DEG C, reaction solution is concentrated to dryness, standby.Residue is dissolved in 8mL dichloromethane, 1- methyl isophthalic acid H- pyrazoles -4- amine (16mg, 0.16mmol) is added, DIPEA (31mg, 0.24mmol) stirs, and is reacted 5 minutes at 25 DEG C.After reaction terminates, add saturated sodium bicarbonate solution, water, saturated nacl aqueous solution, each 30mL of dichloromethane, divide liquid, washed successively with water (30mL × 3), saturated nacl aqueous solution (30mL × 3), organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, institute's residue is purified with solvent system A with thin-layered chromatography, faint yellow solid is obtained, with solid obtained by high performance liquid chromatography preparative separation, (the 5mg of title product 23 is obtained, white solid), yield 13.9%.
MS m/z(LC-MS):452.3[M+1]
1H NMR(400MHz,CD3OD)δ7.42-7.43(m,1H),6.98-7.04(m,2H),6.75-6.77(m,1H),6.44-6.46(m,1H),4.05-4.09(m,1H),3.78(s,3H),2.70-2.72(m,1H),2.43-2.58(m,4H),2.01-2.08(m,2H).
Embodiment 24
N- (the bromo- 4- fluorophenyls of 3-) -2- (1- (3,4- difluorophenyls) piperidin-4-yl)-N'- hydroxyl -2- carbonyls ethanamidine 24
1f (200mg, 0.58mmol) is dissolved in 20mL dichloromethane, 3,4- difluoro phenyl boric acids (270mg is added, 2.32mmol), copper acetate (140mg, 1.16mmol), triethylamine (230mg, 2.32mmol), reacts 16 hours in 25 DEG C.After reaction terminates, be filtered to remove insoluble matter, filtrate decompression concentration, with high performance liquid chromatography purify obtained by residue, obtain title product 24 (3mg, yellow liquid), yield 1.91%.
MS m/z(LC-MS):456.3[M+1]
1H NMR(400MHz,CD3OD)δ6.99-7.10(m,3H),6.78-6.79(m,1H),6.75-6.76(m,2H),3.65-3.68(m,2H),3.48-3.54(m,1H),2.73-2.78(m,2H),1.98-2.04(m,2H),1.75-1.81(m,2H).
Embodiment 25
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cycloheximide -1- t-butyl formates
The first step
4- (methoxyl group (methyl) carbamoyl) cycloheximide -1- t-butyl formates 25b
By 1- (tertbutyloxycarbonyl) cycloheximide -4- formic acid 25a (360mg, 1.48mmol, using known method " Angewandte Chemie, International Edition, 2013, 52 (23), 6072-6075 " is prepared) add in reaction bulb, add I-hydroxybenzotriazole (240mg, 1.78mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (341mg, 1.78mmol), triethylamine (448mg, 4.44mmol), N, O- dimethyl hydroxylamine hydrochlorides (216mg, 2.22mmol), add 10mL dichloromethane, react 16 hours at room temperature.After reaction terminates, 30mL water is added, point liquid, water layer is extracted with dichloromethane, saturated nacl aqueous solution is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 25b (356mg, colorless oil), yield 84.1%
Second step
4- acetyl group cycloheximide -1- t-butyl formates 25c
25b (350mg, 1.22mmol) is added in reaction bulb, 10mL tetrahydrofurans are added, frozen water is cooled down, dropwise addition methylmagnesium-bromide (0.6mol, 1.83mmol), completion of dropping, 0 DEG C is reacted 1 hour.After reaction terminates, add 50mL water, ethyl acetate is extracted, and organic phase washs (50mL × 3), anhydrous sodium sulfate drying with saturated nacl aqueous solution, filtering, filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 25c (220mg, light yellow oil), yield 74.5%
3rd step
4- (2- carbonyls acetyl group) cycloheximide -1- t-butyl formates 25d
Selenium dioxide (203mg, 1.82mol) is placed in reaction bulb, 10mL Isosorbide-5-Nitraes-dioxane is added, 25c (220mg, 0.91mmol) reacts 6 hours in 80 DEG C.After reaction terminates, insoluble matter is filtered to remove, the mL of water 30, ethyl acetate extraction is added, washed with saturated nacl aqueous solution, merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, crude title product 25d (300mg, red oil) is obtained, product is not purified directly to carry out next step reaction.
4th step
4- (2- (oximido) acetyl group) cycloheximide -1- t-butyl formates 25e
Crude product 25d (233mg, 0.91mol) is dissolved in 20mL methanol, potassium carbonate (189mg is added, 1.37mmol), in 0 DEG C of stirring reaction 10 minutes, hydroxylamine hydrochloride (32mg is added portionwise, 0.46mmol), in stirring reaction 1 hour at 0 DEG C.After reaction terminates, be 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 formates 25f
25e (120mg, 0.44mmol) is added in 5mL DMFs, N- chlorosuccinimides (62mg, 0.47mmol) are added, in stirring reaction 1.5 hours at 25 DEG C.After reaction terminates, add 20mL water, it is extracted with ethyl acetate (20mL × 3), merges organic phase, organic phase is washed (50mL × 3) with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude title product 25f (103mg, yellow oil), product is not purified directly to carry out next step reaction.
6th step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cycloheximide -1- t-butyl formates 25
The bromo- 4- fluoroanilines (125mg, 0.66mmol) of crude product 25f (100mg, 0.33mmol) and 3- are added in 5mL ethanol, in stirring reaction 16 hours at 25 DEG C.Reaction terminate after, reaction solution is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 25 (32mg, white solid), yield 21.2%.
MS m/z(ESI):458.3[M+1]
1H NMR(400MHz,DMSO-d6)δ7.27-7.00(m,2H),6.85-6.79(m,2H),3.74-3.60(m,2H),3.46-3.43(m,2H),3.27-3.20(m,1H),2.11-1.96(m,2H),1.72-1.66(m,4H),1.60(s,9H).
Embodiment 26
N- (the bromo- 4- fluorophenyls of 3-) -2- (3- (4- cyano-benzene oxygens) cyclobutyl)-N'- hydroxyl -2- carbonyl ethanamidines
The first step
3- hydroxy-ns-methoxy-. N-methyl cyclobutane -1- formamides 26a
N- methoxy-. N-methyl -3- carbonyl ring fourth formamide 12a (2.0g, 12.7mmol) are dissolved in 40mL methanol, sodium borohydride (0.97g, 25.5mmol) is added, reacted 1 hour at room temperature.After reaction terminates, add a small amount of water quenching and go out reaction, be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 26a (1.9g, colorless oil), yield 70%.
Second step
3- (4- cyano-benzene oxygens)-N- methoxy-. N-methyl cyclobutane -1- formamides 26b
By 26a (251mg, 2.11mmol) it is dissolved in dichloromethane, add 4-hydroxybenzonitrile (337mg, 2.11mmol), triphenylphosphine (663mg, 2.53mmol), ice bath, adds diisopropyl azodiformate (511mg, 2.53mmol), it is warmed to room temperature, stirring reaction 1 hour.Reaction terminate after, reaction solution is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 26b (140mg, white solid), yield 25.5%.
3rd step
4- ((3- acetyl tetramethylcyclobutyl) methyl) benzonitrile 26c
26b (140mg, 0.538mmol) is added in 2mL tetrahydrofurans, ice bath is cooled to 0 DEG C, 3.0M methyl magnesium bromide solutions (0.4mL, 1.076mmol) are added dropwise, 25 DEG C are stirred 2 hours, there is white solid precipitation.After reaction terminates, water is added, ethyl acetate extraction merges organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 26c (60mg, white solid), yield 52%.
4th step
N- (the bromo- 4- fluorophenyls of 3-) -2- (3- (4- cyano-benzene oxygens) cyclobutyl)-N'- hydroxyl -2- carbonyls ethanamidine 26
Using the synthetic route of the step of embodiment 25 the three to six, raw material 25c is replaced with into 26c, title product 26 (15mg, clear yellow viscous thing), yield 15% is made by number step reaction.
MS m/z(LC-MS):432.2[M+1]
Embodiment 27
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- benzyl formates 27
1f (103mg, 0.3mmol) is dissolved in 30mL tetrahydrofurans, triethylamine (59mg is added, 0.58mmol), frozen water is cooled down, and prefabricated 10mL benzyl chloroformates (54mg is added dropwise, tetrahydrofuran solution 0.32mmol), stirring reaction 2 hours at 0 DEG C.After reaction terminates, reaction solution adds 20mL water, and ethyl acetate extraction (10mL × 4), saturated nacl aqueous solution (50mL × 1) washing, anhydrous magnesium sulfate is dried, filtering, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system A purify gained residue, be made title product 27 (21mg, white solid), yield 15.2%.
MS m/z(LC-MS):478.2[M+1]
Embodiment 28
N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -2- (1- (4- nitrobenzophenones) piperidin-4-yl) -2- carbonyls ethanamidine 28
P-fluoronitrobenzene 28a (81.9mg, 0.58mmol) is dissolved in 2mL DMFs, add 1f (200mg, 0.58mmol), N, N- diisopropylethylamine (149.9mg, 1.16mmol), 60 DEG C of stirring reactions 1 hour.After reaction terminates, reaction solution adds 40mL water, and ethyl acetate extraction (15mL × 3) merges organic phase, saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 28 (100mg, yellow solid), yield 37.1%.
MS m/z(LC-MS):465.3[M+1]
1HNMR(400MHz,CDCl3)δ8.12-8.15(m,2H),7.02-7.10(m,2H),6.83-6.85(m,3H),4.01-4.03(m,2H),3.62-3.64(m,1H),3.10-3.13(m,2H),2.01-2.04(m,2H),1.81-1.84(m,2H).
Embodiment 29
N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -2- (1- (4- (1- methyl isophthalic acid H- pyrazoles -4- bases) -2- nitrobenzophenones) piperidin-4-yl) -2- carbonyls ethanamidine 29
Using the synthetic route of embodiment 28, raw material is replaced with into 4- (the fluoro- 3- nitrobenzene of 4-) -1- methyl isophthalic acid H- pyrazoles (being prepared using method disclosed in patent application " WO2013053983 "), (the 13mg of title product 29 is made, red solid), yield 15.9%.
MS m/z(LC-MS):545.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.39(s,1H),8.20(s,1H),7.97-7.98(m,1H),7.91(s,1H),7.76-7.78(m,1H),7.34-7.36(m,1H),7.18-7.20(m,1H),6.99-7.00(m,1H),6.73-6.74(m,1H),3.85(s,3H),3.43-3.49(m,1H),3.21-3.24(m,2H),2.85-2.88(m,2H),1.89-1.99(m,2H),1.64-1.69(m,2H).
Embodiment 30
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- ethyl -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides
The first step
1- ethyls -4- (4- nitrobenzophenones) -1H- pyrazoles 30a
20a (100mg, 0.53mmo) is dissolved in 5mL DMFs, 60% sodium hydride (25mg, 0.63mmol) is added, 25 DEG C are stirred 1 hour, iodoethane (99mg, 0.63mmol) is added into reaction solution, reaction continues stirring reaction 1 hour.After reaction terminates, water is added, is extracted with ethyl acetate 3 times, merge organic phase, water washing 3 times, saturated nacl aqueous solution is washed 1 time, and anhydrous sodium sulfate drying, filtering, filtrate subtracts Pressure concentration, with thin-layered chromatography with eluant, eluent system B purify obtained by residue, obtain title product 30a (90mg, yellow oil), yield 79%.
Second step
4- (1- ethyl -1H- pyrazoles -4- bases) aniline 30b
30a (90mg, 0.4mmol) is added in 12mL ethanol and 3mL water, iron powder (93mg, 1.66mmol) and ammonium chloride (177mg, 3.3mmol) is added, in 75 DEG C of stirring reactions 2 hours.After reaction terminates, reaction solution is concentrated under reduced pressure, ethyl acetate is added, is washed with water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying obtains crude title product 30b (60mg, red brown solid), yield 78%.
3rd step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- ethyl -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides 30
By triphosgene (32mg, 0.174mmol) it is dissolved in 50mL tetrahydrofurans, add prefabricated 1mL 30b (32mg, tetrahydrofuran solution 0.174mmol), adds triethylamine (18mg, 0.06mmol), stirring reaction 1 minute at room temperature, 1f (50mg, 0.145mmol) is added, at room temperature stirring reaction 1 hour.Reaction terminate after, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with eluant, eluent system A purify obtained by residue, obtain title product 30 (35mg, white solid), yield 43%.
MS m/z(ESI):557.4[M+1]
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.52(s,1H),8.39(s,1H),8.07(s,1H),7.78(s,1H),7.44-7.46(m,4H),7.16-7.20(t,1H),6.98-7.00(m,1H),6.71-6.73(m,1H),4.10-4.21(m,4H),3.53-3.57(m,1H),2.85-2.91(m,2H),1.85-1.88(m,2H),1.38-1.48(m,5H).
Embodiment 31
N- (6- (1H- tetrazole -1- bases) pyridin-3-yl) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides
The first step
5- nitros -2- (1H-TETRAZOLE -1- bases) piperidines 31c
1H- tetrazoles 31a (700mg, 10mmol) is dissolved in 100mL acetonitriles, 2- chloro-5-nitropyridines 31b (1.74g, 11mmol) and potassium carbonate (1.38g, 10mmol) is added, 90 DEG C are stirred 5 hours.Reaction terminate after, be cooled to room temperature, 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- bases) pyridine -3- amine 31d
31c (600mg, 3.1mmol) is dissolved in 20mL ethyl acetate, 120mg 10% palladium carbon is added, hydrogen is replaced three times, in 25 DEG C of stirring reactions 2 hours.After reaction terminates, filtering, filtrate decompression concentration obtains crude title product 31d (460mg, faint yellow solid), and product is not purified directly to carry out next step reaction.
3rd step
N- (6- (1H-TETRAZOLE -1- bases) pyridin-3-yl) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides 31
Triphosgene (30mg, 0.185mmol) is dissolved in 10mL tetrahydrofurans, crude product 31d (30mg, 0.185mmol) is added, adds triethylamine (0.15mL, 1.08mmol), at room temperature stirring reaction 30 minutes.1f (50mg, 0.145mmol) is added into reaction solution, at room temperature stirring reaction 1 hour.Reaction terminate after, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 31 (25mg, white solid), yield 32%.
MS m/z(ESI):532.4[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),10.09(s,1H),9.10(s,1H),8.72(d,1H),8.39(s,1H),8.24(dd,1H),7.96(s,1H),7.18(t,1H),6.98-7.00(m,1H),6.71-6.73(m,1H),4.20-4.24(m,2H),3.55-3.61(m,1H),2.93-2.99(m,2H),1.89-1.92(m,2H),1.46-1.54(m,2H).
Embodiment 32
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (2- picoline -4- bases) phenyl) piperidines -1- first Acid amides
The first step
2- methyl -4- (4- nitrobenzophenones) pyridine 32c
By 4- bromine-2-methylpyridine 32a (260mg, 1.5mmol), 4- nitrobenzene boronic acids 32b (250mg, 1.5mmol), [1, double (diphenylphosphine) ferrocene of 1'-] palladium chloride (55mg, 0.075mmol), potassium carbonate (414mg, 3mmol) is added in 10mL dioxane and 1mL water, under argon atmospher, in 105 DEG C of stirring reactions 4 hours.After reaction terminates, room temperature is cooled to, is filtered, filtrate decompression concentration purify gained residue, obtained title product 32c (260mg, white solid), yield 81% with thin-layered chromatography with solvent system B.
Second step
4- (2- picoline -4- bases) amine 32d
32c (260mg, 1.2mmol) is dissolved in 20mL ethyl acetate, the palladium carbons of 52mg 10% are added, hydrogen is replaced three times, in 25 DEG C of stirring reactions 2 hours.After reaction terminates, filtering, filtrate decompression concentration obtains crude title product 32d (220mg, faint yellow solid), and crude product is not purified directly to carry out next step reaction.
3rd step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (2- picoline -4- bases) phenyl) piperidines -1- formamides 32
Triphosgene (20mg, 0.07mmol) is dissolved in 10mL tetrahydrofurans, crude product 32d (32mg, 0.174mmol) is added, adds triethylamine (53mg, 0.52mmol), at room temperature stirring reaction 1 hour.1f (53mg, 0.52mmol) is added into reaction solution, at room temperature stirring reaction 1 hour.Reaction terminate after, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 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- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- (4- methyl-1 H-imidazole-1-groups) pyridin-3-yl) piperidines -1- formamides
The first step
2- (4- methyl-1 H-imidazole-1-groups) -5- nitropyridines 33c
The bromo- 5- nitropyridines 33a (500mg, 2.46mmol) of 2- are dissolved in 5mL DMFs, add 4- methyl isophthalic acid H- imidazoles 33b (0.81g, 9.86mmol), potassium carbonate (1.02g, 7.39mmol), react 16 hours at room temperature.After reaction terminates, reaction solution is poured into 200mL water, and filtering, filter cake is washed with water, ethyl acetate dissolving filter cake is added, anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure, obtain crude title product 33c (478mg, white solid), the not purified direct next step reaction of product.
Second step
6- (4- methyl-1 H-imidazole-1-groups) pyridine -3- amine 33d
Crude product 33c (478mg, 2.34mmol) is dissolved in 20mL methanol, the water of stannous chloride two (1.8g, 7.97mmol) is added, in 70 DEG C of stirring reactions 5 hours.After reaction terminates, filtering, filtrate decompression concentration adds the methanol solution of 1N sodium hydroxides to pH>7, it is concentrated under reduced pressure, adds 100mL dichloromethane and methanol (V:V=10:1) mixed solvent, filtering, filter cake dichloromethane and methanol (V:V=10:1) mixed solvent washing, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 33d (310mg, faint yellow solid), yield 76%.
3rd step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- (4- methyl-1 H-imidazole-1-groups) pyridin-3-yl) piperidines -1- formamides 33
Triphosgene (21mg, 0.07mmol) is dissolved in 10mL tetrahydrofurans, prefabricated 1mL 33d are added The tetrahydrofuran solution of (30mg, 0.172mmol), adds triethylamine (0.1mL, 0.72mmol), at room temperature stirring reaction 30 minutes.1f (50mg, 0.145mmol) is added into reaction solution, at room temperature stirring reaction 1 hour.Reaction terminate after, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 33 (40mg, white yellow solid), yield 52%.
MS m/z(LC-MS):544.5[M+1]
Embodiment 34
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -2- (1-N- (tetrahydrochysene -2H- pyrans -4- bases) amino-sulfonyl) piperidin-4-yl) ethanamidine 34
Using the synthetic route of embodiment 4, first step raw material is replaced with into (tetrahydrochysene -2H- pyrans -4- bases) sulfamic acid chloride, title product 34 (9mg, yellow solid), yield 15.2% is made.
MS m/z(ESI):507.4[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.34(s,1H),7.35-7.33(m,1H),7.19-7.14(m,1H),6.98-6.86(m,1H),6.73-6.69(m,1H),3.82-3.79(m,2H),3.59-3.56(m,2H),3.40-3.37(m,2H),3.24-3.16(m,2H),2.70-2.65(m,2H),1.93-1.90(m,2H),1.78-1.75(m,2H),1.57-1.43(m,4H).
Embodiment 35
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- morpholines pyridin-3-yl) piperidines -1- formamides 35
Using the synthetic route of embodiment 31, first step raw material is replaced with into morpholine, title product 35 (27mg, white solid), yield 34% is made.
MS m/z(ESI):549.5[M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.38(s,2H),8.16(s,1H),7.63(d,1H),7.18(t,1H),6.98-7.00(m,1H),6.77(d,1H),6.68-6.70(m,1H),4.14-4.18(m,2H),3.68-3.71(m,4H),3.50-3.56(m,1H),3.32(s,4H),2.83-2.89(m,2H),1.84-1.87(m,2H),1.41-1.50(m,2H).
Embodiment 36
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (1- phenyl -1H- pyrazoles -4- bases) piperidines -1- formamides 36
Using the synthetic route of embodiment 19, raw material 19a is replaced with into 1- phenyl -1H- pyrazoles -4- amine, title product 36 (10mg, white solid), yield 10% is made.
MS m/z(LC-MS):529.4[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.78(s,1H),8.39(s,1H),8.35(s,1H),7.74(d,2H),7.70(s,1H),7.47(t,2H),7.26(t,1H),7.17(t,1H),6.98-7.00(m,1H),6.70-6.72(m,1H),4.15-4.18(m,2H),3.52-3.58(m,1H),2.86-2.92(m,2H),1.85-1.88(m,2H),1.41-1.49(m,2H).
Embodiment 37
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (2- ethoxys) -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides
The first step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (2- ((tetrahydrochysene -2H- pyrans -2- bases) epoxide) ethyl) -1H- pyrazole-3-yls) phenyl) piperidines -1- formamides 37a
Using the synthetic route of embodiment 30, first step raw material is replaced with into (2- bromine oxethyls)-t-butyldimethyl silane (being prepared using method disclosed in patent application " WO2012084683 "), title product 37a (70mg are made by number step reaction, white solid), yield 64%.
Second step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (2- ethoxys) -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides 37
37a (70mg, 0.1mmol) is dissolved in 10mL tetrahydrofurans, tetrabutyl ammonium fluoride solution (0.15mL, 0.15mmol), 25 DEG C of stirring reactions 1 hour is added.Reaction terminate after, be concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue obtain title product 37 (20mg, off-white powder), yield 34%.
MS m/z(ESI):573.4[M+1]
1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.56(s,1H),8.39(s,1H),8.04(s,1H),7.79(s,1H),7.42-7.47(m,4H),7.16-7.20(t,1H),6.98-7.00(m,1H),6.71-6.73(m,1H),4.93-4.96(m,1H),4.12-4.22(m,4H),3.73-3.77(m,2H),3.51-3.60(m,1H),2.85-2.91(m,2H),1.85-1.88(m,2H),1.46-1.48(m,2H).
Embodiment 38
2- (1- (benzo [d] thiazol-2-yl) piperidin-4-yl)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls ethanamidine 38
Using the synthetic route of embodiment 28, raw material is replaced with into 2- chloro benzothiazoles, title product 38 (16mg, yellow solid), yield 38.1% is made.
MS m/z(ESI):477.3[M+1]
1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.76-7.75(m,1H),7.46-7.44(m,1H),7.29-7.25(m,2H),7.18-7.14(m,1H),7.08-7.04(m,1H),7.00-6.98(m,1H),6.71-6.69(m,1H),4.12-4.08(m,2H),3.64-3.61(m,1H),3.27-3.23(m,2H),2.02-1.99(m,2H),1.64-1.59(m,2H).
Embodiment 39
N- ((3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) methyl) benzamide
The first step
2- (3- acetyl tetramethylcyclobutyl) acetic acid 39a
Raw material 12d (5g, 0.027mol) is added in 50mL tetrahydrofurans, 10mL methanol, 5mL water, a hydronium(ion) lithia (2.28g .054mol) is added, at room temperature stirring reaction 16 hours.After reaction terminates, reaction solution is concentrated under reduced pressure, and adds water, with 1M salt acid for adjusting pH to 3, ethyl acetate is extracted three times, merges organic phase, and saturated nacl aqueous solution washed once, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude title product 39a (4.1g, weak yellow liquid), the not purified direct next step reaction of product.
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 alcohols are added, 15.5mL triethylamines and 6.8mL diphenyl phosphate azides, 90 DEG C of stirring reactions 16 hours.After reaction terminates, reaction solution is concentrated under reduced pressure, and gained residue, obtained title product 39b (2g, weak yellow liquid), yield 34% purify with eluant, eluent system B with silica gel column chromatography.
3rd step
((3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- oximidos) 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) t-butyl carbamate 39b; crude title product 39c (280mg are made by three-step reaction; brown-red oil), product is not purified directly to carry out next step reaction.
4th step
2- (3- (aminomethyl) cyclobutyl)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyl ethanamidines 39d
Crude product 39c (100mg, 0.22mmol) is placed in reaction bulb, 10mL methanol is added, 1mL4M hydrogen chloride Isosorbide-5-Nitrae-dioxane is added, in stirring reaction 1 hour at 25 DEG C.After reaction terminates, reaction solution is concentrated under reduced pressure, crude title product 39d (70mg, red brown solid) is obtained, product is not purified directly to carry out next step reaction.
5th step
N- ((3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cyclobutyl) methyl) benzamide 39
Crude product 39d (70mg, 0.2mmol) is dissolved in 10mL dichloromethane, triethylamine (62mg, 0.6mmol) is added, stirring reaction 1 hour at chlorobenzoyl chloride (14mg, 0.1mmol), 25 DEG C is added dropwise.After reaction terminates, reaction solution adds 5mL water, and dichloromethane extraction (10mL × 3) merges organic phase, saturated nacl aqueous solution washed once, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify gained residue, title product 39 (10mg, yellow solid), yield 11% is made.
MS m/z(LC-MS):448.3[M+1]
Embodiment 40
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (methylcarbamoyl) phenyl) piperidines -1- first Acid amides
The first step
4- Amino-N-methyl benzamides 40b
Raw material 40a (1.1g, 7.07mmol) is dissolved in 10mL tetrahydrofurans, 14.1mL 2M methylamine tetrahydrofuran solutions are added, at room temperature stirring reaction 1 hour.After reaction terminates, reaction solution is concentrated under reduced pressure, and gained residue, obtained title product 40b (672mg, pale yellow oil), yield 63% purify with solvent system B with thin-layered chromatography.
Second step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (methylcarbamoyl) phenyl) piperidines -1- formamides 40
Using the synthetic route of embodiment 19, raw material is replaced with into 40b, title product 40 (25mg, yellow solid), yield 32.9% is made.
MS m/z(ESI):520.4[M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.76(s,1H),8.38(s,1H),8.23-8.22(m,1H),7.73-7.70(m,2H),7.54-7.51(m,2H),7.19-7.15(m,1H),6.99-6.97(m,1H),6.53-6.50(m,1H),4.20-4.17(m,2H),3.55-3.52(m,1H),2.93-2.87(m,3H),2.76-2.73(m,2H),1.88-1.85(m,2H),1.51-1.46(m,2H).
Embodiment 41
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (tetrahydrochysene -2H- pyrans -4- bases) piperidines -1- formamides 41
Using the synthetic route of embodiment 19, raw material is replaced with into tetrahydrochysene -2H- pyrans -4- amine, title product 41 (44mg, yellow solid), yield 64% is made.
MS m/z(LC-MS):471.1[M+1]
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.36(s,1H),7.17(t,1H),6.96-6.98(m,1H),6.69-6.71(m,1H),6.26-6.28(m,1H),4.01-4.05(m,2H),3.81-3.84(m,2H),3.61-3.64(m,1H),3.46-3.48(m,1H),3.27-3.30(m,2H),2.70(t,2H),1.76-1.78(m,2H),1.65-1.68(m,2H),1.35-1.44(m,4H).
Embodiment 42
(2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (pyridine -2- bases) piperidines -1- formamides 42
Using the synthetic route of embodiment 19, raw material is replaced with into PA, title product 42 (5mg, yellow solid), yield 9.2% is made.
MS m/z(LC-MS):464.0[M+1]
Embodiment 43
N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- ((1r, 3r) -3- ((sulphamoylamino) methyl) cyclobutyl) ethanamidine 43
Using the synthetic route of embodiment 4, raw material 1f is replaced with into 39d, title product 43 (2.1mg, white solid), yield 6% is made.
MS m/z(ESI):423.2[M+1]
Embodiment 44
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -2- (1- amino-sulfonyl cycloheximide -4- bases) ethanamidine
The first step
2- (cycloheximide -4- bases)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyl ethanamidines 44a
In hydrochloric acid Isosorbide-5-Nitrae-dioxane that 25 (28mg, 0.061mmol) are added to 5mL 4N, react 2 hours at room temperature.After reaction terminates, it is concentrated under reduced pressure, obtains crude title product 44a (30mg, yellow solid), product is not purified directly carries out next step reaction.
Second step
(4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) cycloheximide -1- bases) sulfonylcarbamic acid tert-butyl ester 44b
Isocyanic acid chlorosulfonic acid ester (10mg, 0.073mmol) is dissolved in 5mL dichloromethane, at 0 DEG C, the dichloromethane solution of the prefabricated 1mL tert-butyl alcohols (6mg, 0.073mmol) is added dropwise, stirring reaction obtains reserve liquid a in 30 minutes.Prefabricated 2mL crude products 44a (21mg, 0.061mmol) dichloromethane solution is added in reaction bulb, above-mentioned reserve liquid a is added dropwise, reaction 1 hour is stirred at room temperature.After reaction terminates, water 20mL is added, is extracted with dichloromethane, saturated nacl aqueous solution washing, anhydrous magnesium sulfate 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%.
3rd step
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -2- (1- amino-sulfonyl cycloheximide -4- bases) ethanamidine 44
44b (15mg, 0.03mmol) is dissolved in 5mL dichloromethane, 5mL trifluoroacetic acids are added, reaction system was in 25 DEG C of stirring reactions 2 hours.Reaction terminate after, 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)δ6.98-7.04(m,2H),6.75-6.78(m,1H),3.65-3.50(m,1H),3.44-3.48(m,1H),3.31-3.35(m,1H),3.15-3.31(m,1H),2.02-2.16(m,3H),1.62-1.81(m,3H).
Embodiment 45
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- ((2- ethoxys) amino) pyridin-3-yl) piperidines -1- formamides
The first step
N- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -5- nitropyridine -2- amine 45b
By 2- ((5- nitropyridine -2- bases) amino) ethanol 45a (0.5g, 2.732mmol, it is prepared using method disclosed in patent application " WO2013013815 ") it is dissolved in 10mL tetrahydrofurans, add imidazoles (0.28g, 4.098mmol) with tert-butyl chloro-silicane (0.49g, 3.279mmol), react 24 hours at 25 DEG C.After reaction terminates, 40mL water is added, is extracted with ethyl acetate (80mL × 3), merge organic phase, organic phase washed once with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give title product 45b (590mg, yellow solid), yield 72.7%.The not purified direct next step reaction of product.
Second step
(2- ((t-Butyldimethylsilyl) epoxide) ethyl)-(5- nitropyridine -2- bases) t-butyl carbamate 45c
Crude product 45b (0.5g, 1.68mmol) is dissolved in 20mL acetonitriles, adds at DMAP (0.02g, 0.168mmol) and di-tert-butyl dicarbonate (0.4g, 1.85mmol), 25 DEG C and reacts 16 hours.After reaction terminates, reaction solution is concentrated under reduced pressure, and silica gel column chromatography purifies gained residue with eluant, eluent system A, obtains title product 45c (600mg, colorless oil), yield 89%.
3rd step
(5- aminopyridine -2- bases) (2- ((t-Butyldimethylsilyl) epoxide) ethyl) t-butyl carbamate 45d
45c (50mg, 0.126mmol) is dissolved in 12mL first alcohol and waters (V:V=5:1) in the mixed solvent.Iron powder (21mg, 0.377mmol), ammonium chloride (40mg, 0.755mmol) are sequentially added into reaction solution.Reaction solution is warming up to 70 DEG C, stirring reaction 1 hour.After reaction terminates, reaction solution is cooled to room temperature, is concentrated under reduced pressure, 20mL ethyl acetate and 15mL water are added in residue, point liquid, aqueous phase is extracted with ethyl acetate (20mL × 2), merge organic phase, organic phase washed once with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, crude title product 45d (45mg, yellow oil) is obtained, product is not purified directly to carry out next step reaction.
4th step
(5- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamidos) pyridine -2- bases) (2- ((t-Butyldimethylsilyl) epoxide) ethyl) t-butyl carbamate 45e
By triphosgene (14mg, 0.0466mmol) it is dissolved in 10mL tetrahydrofurans, add crude product 45d (45mg, 0.122mmol), triethylamine (36mg, 0.352mmol), reacted 30 minutes in 25 DEG C, 1f (40mg, 0.117mmol) is added, is reacted 1 hour in 25 DEG C.After reaction terminates, add 2mL methanol and reaction is quenched, reaction solution is concentrated under reduced pressure, obtain crude title product 45e (60mg, yellow oil), product is not purified directly to carry out next step reaction
5th step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- ((2- ethoxys) amino) pyridin-3-yl) piperidines -1- formamides 45
Crude product 45e (60mg, 0.0813mmol) is dissolved in 2mL methanol, stirring reaction 18 hours at 2mL 2M hydrochloric acid solution, 25 DEG C are added.After reaction terminates, pH to 7 is adjusted with saturated sodium bicarbonate solution, ethyl acetate extracts (30mL × 3), merges organic phase, and organic phase washed once with saturated nacl aqueous solution 30mL, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue obtain the (3mg of title product 45, white solid), yield 7.05%.
MS m/z(ESI):523.3[M+1]
1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.52-7.55(m,1H),7.30(t,1H),7.01(t,1H),6.73-6.77(m,1H),6.63(d,1H),5.34(t,2H),4.59(s,1H),4.18(d,2H),3.71(t,2H),3.63(s,1H),3.60(s,1H),3.00(t,2H),2.19(t,2H),1.95-2.05(m,4H).
Embodiment 46
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (1- (mesyl) -1H- pyrazoles -4- bases) piperidines -1- formamides
The first step
4- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamidos) -1H- pyrazoles -1- t-butyl formates 46b
At 0 DEG C, by triphosgene (129mg, 0.436mmol) it is dissolved in 3mL tetrahydrofurans, add 4- amino -1H- pyrazoles -1- t-butyl formate 46a (80mg, 0.436mmol, it is prepared using method disclosed in applying for a patent " " WO2014128465 " "), triethylamine (0.304mL, 2.179mmol), reacted 20 minutes in 0 DEG C, reaction solution is concentrated under reduced pressure to obtain residue, adds 3mL tetrahydrofurans, 1f (150mg, 0.436mmol), triethylamine (0.304mL, 2.179mmol) is added, is reacted 1 hour in 25 DEG C.After reaction terminates, reaction is quenched in 2mL methanol, and reaction solution is concentrated under reduced pressure, with silica gel chromatography with eluant, eluent system A purify obtained by residue, obtained title product 46b (182mg, yellow solid), yield 44%.
Second step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (1H- pyrazoles -4- bases) piperidines -1- formamides 46c
46b (182mg, 0.329mmol) is dissolved in 4mL dichloromethane, 4mL trifluoracetic acids, 25 DEG C of stirring reactions 1 hour is added.After reaction terminates, reaction solution is concentrated under reduced pressure, 50mL ethyl acetate and 50mL sodium bicarbonate solutions are added, point liquid, aqueous phase is extracted with ethyl acetate (50mL × 2), merge organic phase, be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 46c (143mg, yellow solid), yield 96%.
3rd step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (1- (mesyl) -1H- pyrazoles -4- bases) piperidines -1- formamides 46
46c (100mg, 0.221mmol) is dissolved in 4mL dichloromethane, 0.092mL triethylamines is added, is cooled to 0 DEG C, be added dropwise to methane sulfonyl chloride (25mg, 0.221mmol), 0 DEG C of stirring reaction 1 hour.Reaction terminate after, add 2mL methanol reaction is quenched, reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify obtained by residue, obtain title product 46 (7mg, white solid), yield 6.0%.
MS m/z(ESI):531.2[M+1]
1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),10.59(s,1H),8.98(s,1H),8.13(s,1H),8.02-7.91(m,2H),7.50(s,1H),7.34(s,1H),4.12-4.09(m,2H),3.44(s,3H),2.86-2.80(m,2H),2.66(s,1H),1.85-1.83(m,2H),1.51-1.48(m,2H).
Embodiment 47
N- (6- (((1- amino cyclopropyl) methyl) amino) pyridin-3-yl) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides
The first step
4- toluene sulfonic acides (1- ((tertbutyloxycarbonyl) amino) cyclopropyl) methyl ester 47b
By (1- methylols) cyclopropyl) t-butyl carbamate 47a (2g, 10.68mmol) it is dissolved in 50mL dichloromethane, add DMAP (1.566g, 12.818mmol), add paratoluensulfonyl chloride (2.24g, 11.75mmol), 25 DEG C of stirring reactions 3 hours.After reaction terminates, 150mL water is added, is extracted with dichloromethane (100mL × 3), merge organic phase, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains thick Product title product 47b (3.5g, yellow solid), product is not purified directly to carry out next step reaction.
Second step
(1- ((1,3- dicarbapentaborane isoindoline -2- bases) methyl) cyclopropyl) t-butyl carbamate 47c
Crude product 47b (3.5g, 10.25mmol) is dissolved in 120mL DMFs, 18- crown-s 6 (2.71g, 10.25mmol) are added, potassium phthalimide (2.848g is added, 15.376mmol), 50 DEG C of stirring reactions 18 hours.After reaction terminates, add 100mL water, it is extracted with ethyl acetate (100mL × 3), merges organic phase, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 47c (3.19g, yellow solid), yield 98.5%.
3rd step
(1- (aminomethyl) cyclopropyl) t-butyl carbamate 47d
47c (3.19g, 10.1mmol) is dissolved in 60mL methanol, 85% hydrazine hydrate (773mg, 13.125mmol) is added, return stirring reacts 18 hours.After reaction terminates, reaction solution is concentrated under reduced pressure, and adds 500mL dichloromethane, stirs 30 minutes, filtering, filtrate anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, crude title product 47d (1.8g, yellow oil) is obtained, product is not purified directly to carry out next step reaction.
4th step
(1- (((5- nitropyridine -2- bases) amino) methyl) cyclopropyl) t-butyl carbamate 47e
Crude product 47d (1.8g, 9.644mmol) is dissolved in 60mL DMFs, 2- chloro-5-nitropyridines (1.685g, 10.63mmol) are added, potassium carbonate (4.001g is added, 28.992mmol), 80 DEG C of stirring reactions 18 hours.After reaction terminates, add 300mL water, it is extracted with ethyl acetate (200mL × 3), merge organic phase, organic phase washed with water (300mL × 3), saturated nacl aqueous solution (300mL × 2) washing, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated to give crude title product 47e (952mg, sepia solid), and product is not purified directly to carry out next step reaction.
5th step
((1- ((tertbutyloxycarbonyl) amino) cyclopropyl) methyl) (5- nitropyridine -2- bases) t-butyl carbamate 47f
By 47e (0.5g, 1.68mmol) it is dissolved in 20mL tetrahydrofurans, add triethylamine (0.542mL, 3.892mmol), DMAP (16mg, 0.130mmol) with di-tert-butyl dicarbonate (0.566g, 2.594mmol), reacted 17 hours at 25 DEG C.After reaction terminates, 100mL water is added, is extracted with ethyl acetate (100mL × 3), merge organic phase, be concentrated under reduced pressure, silica gel column chromatography purifies gained residue with eluant, eluent system B, obtain title product 47f (305mg, yellow oil), yield 57.5%.
6th step
(5- aminopyridine -2- bases) ((1- ((tert-butyl carbonyl) amino) cyclopropyl) methyl) t-butyl carbamate 47g
47f (305mg, 0.747mmol) is dissolved in 25mL second alcohol and waters (V:V=4:1) in the mixed solvent.Iron powder (167mg, 2.987mmol), ammonium chloride (920mg, 5.974mmol) are sequentially added into reaction solution.Reaction solution return stirring reacts 1 hour.After reaction terminates, reaction solution is added into 100mL water, it is extracted with ethyl acetate (100mL × 3), merges organic phase, organic phase is washed (200mL × 3) with saturated nacl aqueous solution, anhydrous magnesium sulfate is dried, filtering, filtrate decompression concentration, obtain crude title product 47g (280mg, brown color oil Shape thing), the not purified direct next step of product.
7th step
(5- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides) pyridine -2- bases) ((1- ((tertbutyloxycarbonyl) amino) cyclopropyl) methyl) t-butyl carbamate 47h
At 0 DEG C, triphosgene (73mg, 0.245mmol) is placed in 50mL single port bottles, add prefabricated 3mL and contain 47g (92mg, 0.245mmol) and triethylamine (0.171mL, 1.224mmol) tetrahydrofuran solution, reacted 30 minutes in 0 DEG C, reaction solution is concentrated under reduced pressure to obtain residue, adds 3mL tetrahydrofurans, 1f (84mg, 0.245mmol), triethylamine (0.171mL, 1.224mmol) is added, is reacted 1 hour in 25 DEG C.After reaction terminates, reaction is quenched in 2mL methanol, and reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtained 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- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides 47
47h (60mg, 0.08mmol) is dissolved in 2mL methanol, stirring reaction 4 hours at 2mL 4M hydrogen chloride Isosorbide-5-Nitrae-dioxane solution, 25 DEG C are added.After reaction terminates, 50mL ethyl acetate is added, is washed with saturated sodium bicarbonate solution (30mL × 3), organic phase is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue be made title product 47 (30mg, faint yellow solid), yield 68.2%.
MS m/z(ESI):548.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(brs,2H),8.37(s,1H),8.28(s,1H),7.98-7.97(m,1H),7.46-7.43(m,1H),7.19-7.15(m,2H),6.99-6.97(m,1H),6.72-6.69(m,1H),6.54-6.53(m,1H),6.50-6.48(m,1H),4.17-4.13(m,2H),3.53-5.51(m,1H),3.43-3.42(m,2H),2.87-2.81(m,2H),1.85-1.82(m,2H),1.46-1.43(m,2H),0.79-0.73(m,4H).
Embodiment 48
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- methoxy piperide -1- formamides
The first step
Methoxy carbamate 4- amino phenyl esters 48b
Methoxy amine hydrochlorate (456mg, 5.46mmol) is dissolved in 16mL dichloromethane and water (V:V=3:5) in the mixed solvent, adds sodium acid carbonate (767mg, 9.13mmol), is cooled to 0 DEG C.At 0 DEG C, drip thereto Plus prefabricated 4mL 4- amino phenyl chloroformate 48a (1g, 4.96mmol) dichloromethane solution, stirring reaction 20min at 0 DEG C.After reaction terminates, filter cake is dissolved in ether, anhydrous sodium sulfate drying by filtering, filter cake washing, pressurization concentration, obtains crude title product 48b (700mg, white solid), and product is not purified directly to carry out next step reaction.
Second step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- methoxy piperide -1- formamides 48
1f (306mg, 0.889mmol) is dissolved in tetrahydrofuran, 0 DEG C is cooled to, 136b (198mg, 0.933mmol) is added, adds stirring reaction 2 hours at trifluoracetic acid (0.5mL, 3.6mmol), 0 DEG C.Reaction terminate after, add methanol, be concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 48 (230mg, white solid), yield 62%.
MS m/z(ESI):417.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),9.70(s,1H),8.37(s,1H),7.17(t,1H),6.96-6.98(m,1H),6.71-6.72(m,1H),3.87-3.91(m,2H),3.52(s,3H),3.45-3.52(m,1H),2.72-2.78(m,2H),1.77-1.80(m,2H),1.33-1.42(m,2H).
Embodiment 49
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides 49
1f (400mg, 1.16mmol) is dissolved in 30mL tetrahydrofuran solutions, 1mL triethylamines is added, is added dropwise to trimethyl silicane based isocyanate (0.19ml, 1.41mmol), in 25 DEG C of stirring reactions 18 hours.Reaction terminate after, reaction is quenched in methanol, and reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 49 (170mg, faint yellow solid), yield 38%.
MS m/z(ESI):387.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.37(s,1H),7.15-7.19(m,1H),6.96-6.98(m,1H),6.69-6.71(m,1H),5.94(s,2H),3.97-4.00(m,2H),3.44-3.50(m,1H),2.69-2.75(m,2H),1.74-1.77(m,2H),1.32-1.40(m,2H).
Embodiment 50
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- methyl piperidine -1- formamides 50
By acetic acid (68mg, 1.13mmol) with triethylamine (0.26mL, 1.87mmol) it is dissolved in 2mL toluene, adds diphenyl phosphate azide 50a (312mg, 1.13mmol), stirring reaction is sealed at 100 DEG C 1 hour, it is cooled to after room temperature, ice bath, reaction solution is added dropwise to prefabricated 15mL 1f (409mg, in tetrahydrofuran solution 1.18mmol), stirring reaction 1 hour at 0 DEG C.Reaction terminate after, 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)δ11.66(s,1H),8.37(s,1H),7.17(t,1H),6.96-6.98(m,1H),6.68-6.71(m,1H),6.41-6.43(m,1H),3.97-4.00(m,2H),3.44-3.49(m,1H),2.68-2.74(m,2H),2.55(d,3H),1.75-1.78(m,2H),1.31-1.40(m,2H).
Embodiment 51
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- carbonamidines 51
1- pyrazoles amitraz hydrochloride 51a (140mg, 0.955mmol) are dissolved in 10mL DMFs, add 1f (300mg, 0.87mmol), N, N- diisopropylethylamine (0.3mL, 1.69mmol), 25 DEG C of stirring reactions 60 hours.Reaction terminate after, reaction solution is concentrated under reduced pressure, with high performance liquid chromatography purify obtained by residue, obtain title product 51 (133mg, beige solid), yield 39.6%.
MS m/z(LC-MS):386.3[M+1]
Embodiment 52
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- (methane sulfonylamino) pyridin-3-yl) piperidines -1- formamides
The first step
(5- nitropyridine -2- bases) t-butyl carbamate 52b
By 5- nitropyridine -2- amine 52a (2g, 0.014mol) it is dissolved in 80mL dichloromethane, add dicarbapentaborane di tert butyl carbonate (3.452g, 0.016mol), triethylamine (3.0mL, 0.022mol), DMAP (878mg, 7.188mmol) add in reaction bulb, reacted 17 hours in 25 DEG C.Reaction terminate after, add 100mL dichloromethane, be washed with water, organic phase is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 52b (793mg, yellow solid), yield 23.0%.
Second step
(5- aminopyridine -2- bases) t-butyl carbamate 52c
52b (794mg, 3.319mmol) is dissolved in 30mL methanol and 10mL water, 744mg iron is added, ammonium chloride (1.422g, 26.552mmol) reacts 1 hour in 70 DEG C.After reaction terminates, 100mL is added Water, ethyl acetate extraction, organic phase is washed with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude title product 52c (550mg, light brown red solid), and product is not purified directly to carry out next step reaction.
3rd step
(5- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides) pyridine -2- bases) t-butyl carbamate 52d
4mL tetrahydrofurans are added in reaction bulb, at 0 DEG C, triphosgene (129mg are added, 0.436mmol), crude product 52c (91mg, 0.436mmol), triethylamine (304 μ L, 2.179mmol), in 0 DEG C of stirring reaction 30 minutes, it is concentrated under reduced pressure standby, it is added dropwise to prefabricated 4mL 1f (150mg, tetrahydrofuran solution and triethylamine (304 μ L, 2.179mmol) 0.436mmol), in 25 DEG C of stirring reactions 2 hours.Reaction terminate after, add 2 mL methanol reaction is quenched, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 52d (154mg, yellow solid), yield 61.1%.
4th step
N- (6- aminopyridine -3- bases) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides 52e
Crude product 52d (154mg, 3.319mmol) is dissolved in 10mL dichloromethane, 10mL trifluoroacetic acids are added, reacted 3 hours in 25 DEG C.After reaction terminates, reaction solution is concentrated under reduced pressure, add 100mL ethyl acetate, organic phase is washed with saturated sodium bicarbonate solution and saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, crude title product 52e (120mg, yellow oil) is obtained, product is not purified directly to carry out next step reaction.
5th step
N- (5- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides) pyridine -2- bases) sulfamoylamino group t-butyl formate 52f
2mL tetrahydrofurans are added in reaction bulb, at 0 DEG C, chloro sulfonyl isocyanate (42mg, 0.300mmol) is added, adds the tert-butyl alcohol (22mg, 0.300mmol), in standby after 0 DEG C of stirring reaction 20 minutes.By prefabricated 2ml crude products 52e (120mg, 0.250mmol) tetrahydrofuran solution, triethylamine (174 μ L, 1.252mmol) was added in reaction bulb, adds above-mentioned reserve liquid, in 25 DEG C of stirring reactions 1 hour.Reaction terminate after, add 3mL methanol reaction is quenched, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 52f (135mg, yellow solid), yield 81.8%.
6th step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- (methane sulfonylamino) pyridin-3-yl) piperidines -1- formamides 52
52f (135mg, 0.205mmol) is placed in reaction bulb, 10mL dichloromethane and 10mL trifluoroacetic acids is added, reacted 1 hour in 25 DEG C.After reaction terminates, reaction solution is concentrated under reduced pressure, high performance liquid chromatography purifying gained residue obtains title product 52 (13mg, faint yellow solid), yield 11.4%.
MS m/z(ESI):558.2[M+1]
1H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.88(s,1H),7.30-7.27(m,1H),7.21-7.11(m,2H),8.89(s,1H),8.66(s,1H),8.29-8.27(m,1H),5.33-5.31(m,3H),4.16-4.13(m,2H),3.61(s,1H),2.85-2.79(m,2H),2.02-1.97(m,2H),1.81-1.78(m,2H).
Embodiment 53
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -2- (1- amino-sulfonyl pyrrolidines -4- bases) ethanamidine 53
Using the synthetic route of embodiment 44; raw material is replaced with into 3- acetyl-pyrrolidine -1- t-butyl carbamates (being prepared using method disclosed in patent application " WO2012126901 "); obtain title product 53 (20mg, yellow solid), yield 41.6%.
MS m/z(LC-MS):409.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),8.40(s,1H),7.14-7.19(t,1H),7.00-7.02(m,1H),6.84(s,2H),6.72-6.74(m,1H),3.98-4.01(m,1H),3.41-3.43(m,1H),3.23-3.25(m,1H),3.15-3.19(m,2H),1.99-2.02(m,2H).
Embodiment 54
(S)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (1- sulfamoyl piperidines -3- bases) ethanamidine 54
Using the synthetic route of embodiment 44; raw material is replaced with into (S) -3- Acetylpiperidin -1- t-butyl formates (being prepared using method disclosed in patent application " WO2011117254 "); (the 40mg of title product 54 is made; yellow solid), yield 70.2%.
MS m/z(ESI):423.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),8.38(s,1H),7.17-7.13(m,1H),7.02-7.00(m,1H),8.79(s,2H),8.74-8.70(m,1H),3.58-3.49(m,2H),3.39(s,2H),2.68-2.63(m,1H),1.95-1.93(m,1H),1.83-1.80(m,1H),1.56-1.52(m,1H),1.41-1.33(m,1H).
Embodiment 55
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- carboxylate methyl esters 55
1f (103mg, 0.3mmol) is dissolved in 10mL dichloromethane, triethylamine (60mg is added, 0.6mmol), frozen water is cooled down, and methylchloroformate (28mg is added dropwise, 0.3mmol, is dissolved in 5mL dichloromethane) dichloromethane solution, stirring reaction 1 hour at 0 DEG C.After reaction terminates, reaction solution adds 30mL water, and dichloromethane extraction (20mL × 3), saturated nacl aqueous solution (50mL × 1) washing, anhydrous magnesium sulfate is dried, filtering, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 55 (75mg, white solid), yield 62.5%.
MS m/z(ESI):402.2[M+1]
1H NMR(400MHz,CDCl3)δ9.12(s,1H),7.00-7.07(m,2H),6.88(s,1H),6.79-6.81(m,1H),4.21-4.29(m,2H),3.75(s,3H),3.48-3.53(m,1H),2.88-2.94(m,2H),1.85-1.95(m,2H),1.65(s,2H).
Embodiment 56
(1R, 5S) -3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) -8- azabicyclos [3.2.1] octane -8- t-butyl formates
The first step
(1R, 5S) -3- (1- ethoxys) -8- azabicyclos [3.2.1] octane -8- carboxylic acid tert-butyl esters 56b
By raw material (1R; 5S) -3- formoxyls -8- azabicyclos [3.2.1] octane -8- carboxylic acid tert-butyl ester 56a (1g; 4.18mmol; it is prepared using method disclosed in patent application " WO2011059021 ") it is dissolved in 15mL tetrahydrofurans; it is cooled to 0 DEG C; add stirring reaction 1 hour at 1.7mL 3M methyl magnesium bromide solution, 0 DEG C.After reaction terminates, reaction is quenched in the hydrochloric acid solution for adding 1M.Divide liquid, aqueous phase is extracted with ethyl acetate three times, merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains crude title product 56b (1.06g, nothing Color liquid), the not purified direct next step reaction of product.
Second step
(1R, 5S) -3- acetyl group -8- azabicyclos [3.2.1] octane -8- carboxylic acid tert-butyl esters 56c
Crude product 56b (1.06g, 4.18mmol) is dissolved in 30mL dichloromethane, stirring reaction 1.5 hours at Dai Si-Martin's oxidant (1.8g, 4.17mmol), 25 DEG C are added.After reaction terminates, saturated sodium bicarbonate solution and saturated sodium thiosulfate solution are added, is stirred 5 minutes.Divide liquid, aqueous phase is extracted three times with dichloromethane, merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.Silica gel column chromatography purifies gained residue with eluant, eluent system A, obtains title product 56c (807mg, colourless liquid), yield 77%.
3rd step
(1R, 5S) -3- (2- carbonyls acetyl group) -8- azabicyclos [3.2.1] octane -8- t-butyl formates 56d
Selenium dioxide (700mg, 6.3mmol) is placed in reaction bulb, 30mL Isosorbide-5-Nitraes-dioxane is added, 56c (800mg, 3.19mmol) reacts 12 hours in 90 DEG C.After reaction terminates, insoluble matter, filtrate decompression concentration are filtered to remove, gained residue is dissolved in ethyl acetate, filtering, filtrate water washing, merges organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude title product 56d (670mg, pale brown oil thing), product is not purified directly to carry out next step reaction.
4th step
(1R, 5S) -3- (2- (oximido) acetyl group) -8- azabicyclos [3.2.1] octane -8- t-butyl formates 56e
By crude product 56d (67mg, 2.53mmol) it is dissolved in 20mL methanol, add potassium carbonate (524mg, 3.79mmol), in 0 DEG C of stirring reaction 10 minutes, the methanol solution of prefabricated 2.5mL hydroxylamine hydrochlorides (88mg, 1.266mmol) is added portionwise, in the lower reaction of 0 DEG C of stirring 0.5 hour.After reaction terminates, be filtered to remove insoluble matter, filtrate decompression concentration, with thin-layered chromatography with solvent system B purify obtained by residue, obtain title product 56e (166mg, pale brown oil thing), yield 23%.
5th step
(1R, 5S) -3- (2- chloro- 2- (oximido) acetyl group) -8- azabicyclos [3.2.1] octane -8- t-butyl formates 56f
56e (2.52g, 8.9mmol) is added in 30mL DMFs, N- chlorosuccinimides (1.25g, 9.36mmol) are added, in stirring reaction 1 hour at 25 DEG C.After reaction terminates, add water and ethyl acetate point liquid, organic phase is extracted with ethyl acetate (50mL × 3), merges organic phase, organic phase washed with water and saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude title product 56f (3.167g, pale yellow oil), product is not purified directly to carry out next step reaction.
6th step
(1R, 5S) -3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) -8- azabicyclos [3.2.1] octane -8- t-butyl formates 56
The bromo- 4- fluoroanilines (3.8g, 19.9mmol) of crude product 56f (3.15g, 9.9mmol) and 3- are added in 30mL ethanol, in stirring reaction 12 hours at 25 DEG C.Reaction terminate after, reaction solution is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 56 (1.8g, brown viscous thing), yield 38%.
MS m/z(ESI):470.2[M+1]
1H NMR(400MHz,CDCl3)δ7.61(s,1H),7.08-7.10(m,1H),7.03(t,1H),6.83-6.86(m,2H),4.28-4.38(m,2H),3.85-3.91(m,1H),2.04-2.06(m,2H),1.89-1.92(m,2H),1.73-1.78(m,4H),1.50-1.54(m,9H).
Embodiment 57
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyano group -3- isopropyl phenyls) piperidines -1- formamides
The first step
4- amino -2- cumene formonitrile HCNs 57b
By 4- amino -2- bromobenzylcyanide 57a (150mg, 0.76mmol) it is dissolved in 20mL1, in 4- dioxane, add [1, the double Diphenyl phosphino ferrocenes of 1'-] palladium chloride (56mg, 0.076mmol) and 0.25M diisopropyls zinc (6mL, 1.5mmol), under argon atmospher, in 100 DEG C of stirring reactions 2 hours.Reaction terminate after, diatomite filtering reacting liquid, filtrate decompression concentration, with thin-layered chromatography with solvent system B purify obtained by residue, obtain title product 57b (80mg, brown oil), yield 66%.
Second step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyano group -3- isopropyl phenyls) piperidines -1- formamides 57
By triphosgene (86mg, 0.29mmol) it is dissolved in 30mL tetrahydrofurans, add 57b (49mg, 0.305mmol), triethylamine (88mg, 0.87mmol), reacted 30 minutes in 25 DEG C, 1f (100mg, 0.29mmol) is added, in 25 DEG C of stirring reactions 1 hour.Reaction terminate after, add methanol, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 57 (10mg, white solid), yield 6.5%.
MS m/z(ESI):530.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),9.00(s,1H),8.39(s,1H),756-7.62(m,3H),7.15-7.20(m,1H),6.98-7.00(m,1H),6.70-6.73(m,1H),4.19-4.22(m,2H),3.53-3.61(m,1H),3.15-3.18(m,1H),2.89-2.95(m,2H),1.87-1.90(m,2H),1.43-1.51(m,2H),0.93-0.94(d,6H).
Embodiment 58
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -2- ((1R, 5S) -8- sulfamoyl -8- azabicyclos [3.2.1] octane -3- bases) ethanamidine
The first step
2- ((1R, 5S) -8- azabicyclos [3.2.1] octane -3- bases)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyl ethanamidines 58a
56 (600mg, 1.28mmol) are dissolved in 3mL dichloromethane, 3mL trifluoroacetic acids are added, reaction system was in 25 DEG C of stirring reactions 1 hour.After reaction terminates, it is concentrated under reduced pressure, obtains crude title product 58a (1.2g, tan solid), product is not purified directly carries out next step reaction.
Second step
((1R, 5S) -3- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) -8- azabicyclos [3.2.1] octane -8- bases) sulfonylcarbamic acid tert-butyl ester 58b
Chloro sulfonyl isocyanate (9.17mg, 6.48mmol) is dissolved in 10mL dichloromethane, 0 DEG C is cooled to, the tert-butyl alcohol (480mg, 6.47mmol) is added, 0 DEG C of stirring reaction obtains reserve liquid in 5 minutes.By 58a (1.2g, 3.24mmol), triethylamine (2.25mL, 16.2mmol) and 30mL dichloromethane enter in reaction bulb, add at 4mL reserve liquids, 0 DEG C and stir 1 hour.Reaction terminate after, add methanol reaction is quenched, be concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 58b (180mg, brown solid), yield 10%.
3rd step
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -2- ((1R, 5S) -8- sulfamoyl -8- azabicyclos [3.2.1] octane -3- bases) ethanamidine 58
58b (180mg, 0.327mmol) is dissolved in 3mL dichloromethane, 3mL trifluoroacetic acids are added, reaction system was in 25 DEG C of stirring reactions 1 hour.Reaction terminate after, be concentrated under reduced pressure with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 58 (86mg, pale solid), yield 58%.
MS m/z(ESI):449.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.38(s,1H),7.17(t,1H),6.95-6.97 (m,1H),6.83(s,2H),6.67-6.69(m,1H),4.12(s,2H),3.73-3.78(m,1H),2.13-2.15(m,2H),1.72-1.78(m,2H),1.62-1.66(m,2H).
Embodiment 59
N- (the bromo- 4- fluorophenyls of 3-) -2- (1- formyl piperidine -4- bases)-N '-hydroxyl -2- carbonyls ethanamidine 59
By formic acid (88mg, 1.91mmol) it is dissolved in acetic anhydride (100mg, in 0.97mmol), 60 DEG C of stirring reactions 2 hours, above-mentioned reaction solution is dissolved in 1mL tetrahydrofurans, under ice bath, prefabricated 30mL mixing 1f (300mg are added to, 0.87mmol) and in the tetrahydrofuran solution of 1mL triethylamines, 0 DEG C of stirring reaction 1 hour.Reaction terminate after, add methanol, be concentrated under reduced pressure dry reaction liquid, with thin-layered chromatography with eluant, eluent system A purify obtained by residue, obtain title product 59 (90mg, faint yellow solid), yield 25%.
MS m/z(ESI):372.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.39(s,1H),7.99(s,1H),7.17(t,1H),6.97-6.98(m,1H),6.69-6.71(m,1H),4.20-4.23(m,1H),3.72-3.75(m,1H),3.57-3.61
(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- (the bromo- 2,4 difluorobenzene bases of 3-)-N '-hydroxyl -2- carbonyls -2- (1- amino-sulfonyls piperidin-4-yl) ethanamidine
The first step
4- (2- ((the bromo- 2,4 difluorobenzene bases of 3-) amino) -2- (oximido) acetyl group) piperidines -1- t-butyl formates 60a
Bromo- 2, the 4- difluoroanilines (572mg, 2.752mmol) of crude product 1d (400mg, 1.376mmol) and 3- are added in 10mL ethanol, in stirring reaction 16 hours at 25 DEG C.After reaction terminates, reaction solution is concentrated under reduced pressure, With thin-layered chromatography with solvent system A purify gained residue, obtain title product 60a (210mg, yellow oil), yield 33.0%.
Second step
N- (the bromo- 2,4 difluorobenzene bases of 3-)-N '-hydroxyl -2- carbonyls -2- (1- amino-sulfonyls 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), yield is made：37%.
MS m/z(ESI):441.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),8.28(s,1H),7.07-7.16(m,2H),6.77(s,2H),3.52(d,2H),3.26-3.30(m,1H),2.53-2.58(m,2H),1.88(d,2H),1.47-1.57(m,2H)
Embodiment 61
N '-hydroxy-n-(3- iodophenyls) -2- carbonyls -2- (1- amino-sulfonyls piperidin-4-yl) ethanamidine 61
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroanilines of raw material 3- are replaced with into 3- Iodoanilines, title product 61 (45mg, white solid), yield 27.6% is made.
MS m/z(ESI):453.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.35(s,1H),7.18(d,1H),7.06(s,1H),6.92-6.98(m,1H),6.78(s,2H),6.68(d,1H),3.53(d,2H),3.23-3.29(m,1H),2.57(t,2H),1.94(d,2H),1.55-1.58(m,2H).
Embodiment 62
N- (the bromo- 2- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -2- (1- amino-sulfonyls piperidin-4-yl) ethanamidine 62
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroanilines of raw material 3- are replaced with into the bromo- 2- fluoroanilines of 3-, title product 62 (30mg, white solid), yield 80.8% is made.
MS m/z(ESI)423.2[M+1]
1H NMR(400MHz,CDCl3)δ11.50(s,1H),8.31(s,1H),7.23-7.27(m,1H),7.00(m,2H),6.77(m,2H),3.52(d,2H),3.26-3.30(m,1H),2.52-2.58(m,2H),1.89(d,2H),1.49-1.55(m,2H).
Embodiment 63
N- (the bromo- 2- fluorophenyls of 5-)-N '-hydroxyl -2- carbonyls -2- (1- amino-sulfonyls piperidin-4-yl) ethanamidine 63
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroanilines of raw material 3- are replaced with into the bromo- 2- fluoroanilines of 5-, title product 63 (13mg, white solid), yield 30.9% is made.
MS m/z(ESI):423.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),8.29(s,1H),7.20(d,1H),7.11-7.18(m,1H),7.05(t,1H),6.76(s,2H),3.52(d,2H),3.23-3.29(m,1H),2.52-2.58(m,2H),1.88(d,2H),1.50-1.55(m,2H).
Embodiment 64
N- (3- bromophenyls)-N '-hydroxyl -2- carbonyls -2- (1- amino-sulfonyls piperidin-4-yl) ethanamidine 64
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroanilines of raw material 3- are replaced with into 3- bromanilines, title product 64 (26mg, white solid), yield 29.4% is made.
MS m/z(ESI):405.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.42(s,1H),7.05-7.15(m,1H),6.95-7.02(m,1H),6.87(s,1H),6.78(s,2H),6.66(d,1H),3.52(d,2H),3.26-3.31(m,1H),2.57(t,2H),1.94(d,2H),1.49-1.62(m,2H).
Embodiment 65
N- (3- chlorphenyls)-N '-hydroxyl -2- carbonyls -2- (1- amino-sulfonyls piperidin-4-yl) ethanamidine 65
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroanilines of raw material 3- are replaced with into 3- chloroanilines, title product 65 (30mg, white solid), yield 31.9% is made.
MS m/z(ESI):361.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.42(s,1H),7.16(t,1H),6.87(d,1H),6.73-6.77(m,3H),6.62(d,1H),3.53(d,2H),3.26-3.31(m,1H),2.57(t,2H),1.94(d,2H),1.53-1.59(m,2H).
Embodiment 66
N- (4- fluoro- 3- (trifluoromethyl) phenyl)-N'- hydroxyl -2- carbonyls -2- (1- sulfamoyls piperidin-4-yl) ethanamidine 66
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroanilines of raw material 3- are replaced with into the fluoro- 3- 5-trifluoromethylanilines of 4-, title product 66 (30mg, white solid), yield 32.3% is made.
MS m/z(ESI):413.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),8.55(s,1H),7.28(d,1H),6.95-7.01(m,2H),6.78(s,2H),3.53(d,2H),3.32-3.40(m,1H),2.57(t,2H),1.94(d,2H),1.53-1.59(m,2H).
Embodiment 67
N- (the chloro- 4- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -2- (1- amino-sulfonyls piperidin-4-yl) ethanamidine 67
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroanilines of raw material 3- are replaced with into the chloro- 4- fluoroanilines of 3-, title product 67 (35mg, white solid), yield 40.1% is made.
MS m/z(ESI):379.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.39(s,1H),7.19(t,1H),6.85(dd,1H),6.77(s,2H),6.65-6.68(s,1H),3.52(d,2H),3.26-3.31(m,1H),2.57(t,2H),1.93(d,2H),1.53-1.59(m,2H).
Embodiment 68
N- (the bromo- 5- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -2- (1- amino-sulfonyls piperidin-4-yl) ethanamidine 68
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroanilines of raw material 3- are replaced with into the bromo- 5- fluoroanilines of 3-, title product 68 (50mg, Tan solid), yield 15% is made.
MS m/z(ESI):423.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.64(s,1H),6.94(d,1H),6.78(s,1H),6.71(s,1H),6.48(d,1H),3.52-3.55(m,2H),2.54-2.60(m,1H),1.94-1.99(m,2H),1.23-1.30(m,2H).
Embodiment 69
N'- hydroxyl -2- carbonyls -2- (1- sulfamoyls piperidin-4-yl)-N- (3- (trifluoromethyl) phenyl) ethanamidine 69
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroanilines of raw material 3- are 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)δ11.82(s,1H),8.58(s,1H),7.37(t,1H),7.16(d,1H),6.99(s,1H),6.94(d,1H),6.78(d,2H),3.58(d,2H),3.26-3.31(m,1H),2.58(t,2H),1.95(d,2H),1.53-1.59(m,2H).
Embodiment 70
N- (the chloro- 5- ethenylphenyls of 3-)-N '-hydroxyl -2- carbonyls -2- (1- amino-sulfonyls piperidin-4-yl) ethanamidine
The first step
The chloro- 3- nitros -5- vinyl benzenes 70b of 1-
70a (450mg, 1.9mmol are prepared using method disclosed in patent application " CN102146022 ") is dissolved in 18mL Isosorbide-5-Nitraes-dioxane and water (V:V=6:1) in the mixed solvent, sequentially add vinyl boronic acids pinacol ester (293mg, 1.9mmoml), [1,1'- double (diphenylphosphine) ferrocene] palladium chloride (139mg, 0.19mmol), potassium carbonate (787mg, 5.7mmol), under argon atmospher, 80 DEG C of stirring reactions 6 hours.After reaction terminates, room temperature is cooled to, 30mL water is added to reaction solution, ethyl acetate extracts (20mL × 3), merge organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 70b (250mg, yellow oil), yield 71.4%.
Second step
The chloro- 5- vinyl aniline 70c of 3-
70b (250mg, 1.36mmol) is dissolved in 12mL second alcohol and waters (V:V=5:1) in the mixed solvent, iron powder (152mg, 2.7mmol), ammonium chloride (294mg, 5.44mmol) are sequentially added into reaction solution.Reaction solution is warming up to 80 DEG C, stirring reaction 1 hour.After reaction terminates, reaction solution is cooled to room temperature, 20mL is added Water, ethyl acetate extraction (20mL × 3) merges organic phase, saturated sodium-chloride water solution 50mL washings, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 70c (180mg, yellow oil), yield 86.1%.
3rd step
N- (3- bromophenyls)-N '-hydroxyl -2- carbonyls -2- (1- amino-sulfonyls piperidin-4-yl) ethanamidine 70
Using the synthetic route of embodiment 60, bromo- 2, the 4- difluoroanilines of raw material 3- are replaced with into 70c, title product 70 (2mg, white solid), yield 33.8% is made.
MS m/z(ESI):387.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),8.43(s,1H),7.04(s,1H),6.79(s,2H),6.99-6.60(m,3H),5.80-5.75(d,1H),5.30-5.27(d,1H),5.55-5.52(m,2H),3.17-3.16(m,1H),2.60-2.55(m,2H),1.97-1.94(m,2H),1.61-1.55(m,2H).
Embodiment 71
N- benzyls -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- thioformamides 71
By benzyl isothiocyanate 71a (43mg, 0.291mmol, using known method " Beilstein Journal of Organic Chemistry; 2012; 8 (6), 61-70 " is prepared) be dissolved in 2mL tetrahydrofurans, be added dropwise to prefabricated 1f (100mg, in 8mL tetrahydrofuran solutions 0.29mmol), stirring reaction 1 hour at 25 DEG C.Reaction terminate after, concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 71 (25mg, faint yellow solid), yield 17%.
MS m/z(ESI):493.3[M+1]
1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.35(m,5H),7.07(s,1H),7.00(t,1H),6.78-6.83(m,2H),5.67(s,1H),4.87(d,1H),4.59(d,2H),3.55-3.65(m,1H),3.20(t,2H),1.95(d,2H),1.73-1.78(m,2H).
Embodiment 72
N- (the bromo- 4- fluorophenyls of 3-) -2- (1- (5- cyano thiazole -2- bases) piperidin-4-yl)-N '-hydroxyl -2- carbonyls ethanamidine 72
The chloro- 5- cyano thiazoles 72a of 2- (42mg, 0.29mmol are prepared using method disclosed in patent application " WO2002006276 ") are dissolved in 5mL N, in dinethylformamide, add 1f (100mg, 0.29mmol), 150 DEG C of stirring reactions 1 hour.After reaction terminates, room temperature is cooled to, reaction solution is poured into water, ethyl acetate extraction, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filtering, 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)δ11.71(s,1H),8.38(s,1H),8.02(s,1H),7.14-7.18(s,1H),6.98-7.00(m,1H),6.70-6.72(m,1H),3.99-4.03(d,2H),3.60-3.62(m,1H),3.26-3.29(d,2H),1.96-1.99(d,2H),1.57-1.61(m,2H).
Embodiment 73
N- (the bromo- 4- fluorophenyls of 3-) -2- (1- (2- fluoro- 4- (mesyl) phenyl) piperidin-4-yl)-N '-hydroxyl -2- carbonyls ethanamidine 73
Using the synthetic route of embodiment 72, raw material 72a is replaced with into the fluoro- 4- methyl sulphonyls benzene of 1,2- bis-, title product 73 (20mg, yellow solid), yield 13.3% is made.
MS m/z(LC-MS):516.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.39(s,1H),7.62-7.66(t,2H),7.15-7.24(m,2H),6.98-7.01(m,1H),6.71-6.73(d,1H),3.61-3.64(d,2H),3.48-3.53(m,1H),3.18(s,3H),2.88-2.94(t,2H),1.94-1.99(t,2H),1.68-1.73(t,2H).
Embodiment 74
N- (the bromo- 4- fluorophenyls of 3-) -2- (1- (4- cyanopyridine -2- bases) piperidin-4-yl)-N '-hydroxyl -2- carbonyls ethanamidine 74
The chloro- 4- cyanopyridines 74a (60mg, 0.43mmol) of 2- are dissolved in 2mL DMFs, 1f (100mg, 0.29mmol), 65 DEG C of stirring reactions 3 hours is added.After reaction terminates, room temperature is cooled to, reaction solution is poured into 20mL water, ethyl acetate extraction (15mL × 3) merges organic phase, saturated nacl aqueous solution 20mL washings, anhydrous sodium sulfate drying, filtering, 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)δ11.69(s,1H),8.37(s,1H),8.27-8.29(m,1H),7.34(s,1H),7.16-7.18(m,1H),6.91-6.99(m,2H),6.69-6.71(m,1H),4.40-4.44(m,2H),3.61-3.64(m,1H),2.94-3.00(m,2H),1.87-1.91(m,2H),1.47-1.52(m,2H).
Embodiment 75
N- (the bromo- 4- fluorophenyls of 3-) -2- (1- (5- cyanopyridine -2- bases) piperidin-4-yl)-N '-hydroxyl -2- carbonyls ethanamidine 75
The chloro- nicotinonitrile 75a (61mg, 0.44mmol) of 6- are dissolved in 3mL 1-METHYLPYRROLIDONEs, 1f (100mg are added, 0.29mmol), DIPEA (170mg, 1.32mmol), 25 DEG C of stirring reactions 18 hours.After reaction terminates, reaction solution is poured into 30mL water, ethyl acetate extraction (30mL × 3), merge organic phase, saturated sodium-chloride water solution washing (30mL × 2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 75 (55mg, white solid), yield 42.3%.
MS m/z(LC-MS):446.3[M+1]
Embodiment 76
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- (1- (4- (mesyl) phenyl) piperidin-4-yl) -2- carbonyls ethanamidine 76
Using the synthetic route of embodiment 72, raw material 72a is replaced with into 4- methyl sulphonyl fluorobenzene, title product 76 (10mg, white solid), yield 13.8% is made.
MS m/z(LC-MS):498.3[M+1]
Embodiment 77
N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -2- (1- (pyridine -2- bases) piperidin-4-yl) ethanamidine 77
Using the synthetic route of embodiment 72, raw material 72a is replaced with into 2- chloropyridines, title product 77 (4mg, brown solid), yield 4% is made.
MS m/z(LC-MS):421.3[M+1]
Embodiment 78
4-4- (2- ((the bromo- 4- fluorophenyls 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 benzoates, title product 78 (5mg, yellow solid), yield 10.2% is made.
MS m/z(LC-MS):492.3[M+1]
1H NMR(400MHz,CD3OD)δ7.85-7.87(m,2H),6.96-7.05(m,4H),6.75-6.78(m,1H),4.27-4.32(m,2H),3.97-4.01(m,2H),3.59-3.65(m,1H),2.92-3.01(m,2H),1.96-1.98(m,2H),1.72-1.77(m,2H),1.29-1.38(m,3H).
Embodiment 79
N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls -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 pyrimidines, title product 79 (20mg, white solid), yield 16.3% is made.
MS m/z(LC-MS):422.3[M+1]
1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.19-8.21(m,1H),7.01-7.08(m,2H),6.84-6.89(m,2H),6.54-6.56(m,1H),4.45-4.48(m,2H),3.66-3.68(m,1H),3.03-3.10(m,2H),1.99-2.04(m,2H),1.69-1.73(m,2H).
Embodiment 80
4- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) benzoic acid
The first step
4- (4- (2- ((the bromo- 4- fluorophenyls 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- are dissolved in 20mL DMFs, add 1f (650mg, 1.74mmol), N, N- diisopropylethylamine (561mg, 4.35mmol), 95 DEG C of stirring reactions 72 hours.After reaction terminates, room temperature is cooled to, reaction solution is poured into water, ethyl acetate extraction, saturated nacl aqueous solution is washed, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, crude title product 80b (120mg, yellow solid) is obtained, product is not purified directly to carry out next step reaction.
Second step
4- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) benzoic acid 80
80b (120mg, 0.23mmol) is dissolved in 6mL dichloromethane, 0.5mL trifluoracetic acids, 25 DEG C of stirring reactions 18 hours is added.Reaction terminate after, 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)δ12.28(s,1H),11.70(s,1H),8.40(s,1H),7.70-7.77(m,2H),7.14-7.19(m,1H),6.96-6.99(m,3H),6.69-6.72(m,1H),3.96-4.01(m,2H),3.53-3.59(m,1H),2.88-2.94(m,2H),1.88-1.91(m,2H),1.55-1.61(m,2H).
Embodiment 81
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -2- (1- Phenylpiperidine -4- bases)-ethanamidine
The first step
2- (1- (4- aminophenyls) piperidin-4-yl)-N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyl ethanamidines 81a
28 (220mg, 0.47mmol) are dissolved in 30mL Isosorbide-5-Nitraes-dioxane and 10mL water, sodium dithionite (823mg, 4.7mmol), potassium carbonate (324.3mg, 2.35mmol), 25 DEG C of stirring reactions 1 hour is added.After reaction terminates, reaction solution adds 20mL water, and ethyl acetate extraction (15mL × 3) merges organic phase, saturated nacl aqueous solution washing (20mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 81a (130mg, white solid), yield 63.5%.
Second step
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -2- (1- Phenylpiperidine -4- bases)-ethanamidine 81
81a (20mg, 0.46mmol) is dissolved in 4mL DMFs, 70 DEG C are heated to, the N of prefabricated 1mL nitrite tert-butyls (10mg, 0.92mmol) is added dropwise to, dinethylformamide solution, completion of dropping immediately treats reaction.Reaction solution adds 50mL water, and ethyl acetate extraction (40mL × 1) is washed, anhydrous sodium sulfate drying with water (30mL × 3), saturated nacl aqueous solution (30mL × 3), filtered successively, filtrate decompression concentration.With TLC with solvent system A purify gained residue, obtain title product 81 (5mg, yellow solid), yield 26.3%.
MS m/z(LC-MS):420.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.38(s,1H),7.17-7.22(m,3H),6.94-6.98(m,3H),6.72-6.76(m,2H),3.75-3.78(m,2H),3.42-3.49(m,1H),2.69-2.75(m,2H),1.89-2.01(m,2H),1.61-1.67(m,2H).
Embodiment 82
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- (1- (2- methoxyphenyls) piperidin-4-yl) -2- carbonyl ethanamidines
The first step
N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyls -2- (1- (2- methoxyl group -4- nitrobenzene) piperidin-4-yl) -2- carbonyl ethanamidines 82b
2- methoxyl group -4- fluoronitrobenzenes 82a (206mg, 1.21mmol) are dissolved in 13mL DMFs, add 1f (378mg, 1.1mmol), N, N- diisopropylethylamine (213mg, 1.65mmol), 100 DEG C of stirring reactions 12 hours.After reaction terminates, reaction solution adds 50mL water and 50mL ethyl acetate, and point liquid, organic phase is washed (20mL × 2) with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.With thin-layered chromatography with solvent system B purify gained residue, obtain title product 82b (200mg, yellow solid), yield 40.4%.
Second step
2- (1- (4- amino -2- methoxyphenyls) piperidin-4-yl)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyl ethanamidines 82c
82b (150mg, 0.3mmol) is dissolved in 8mL Isosorbide-5-Nitraes-dioxane and 4mL water, sodium dithionite (261mg, 1.5mmol), potassium carbonate (81mg, 0.6mmol), 25 DEG C of stirring reactions 0.5 hour is added.After reaction terminates, reaction solution adds 50mL water, 50mL ethyl acetate, point liquid, organic phase washed with water and saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, 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%.
3rd step
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- (1- (2- methoxyphenyls) piperidin-4-yl) -2- carbonyls ethanamidine 82
82c (40mg, 0.086mmol) is dissolved in 4mL DMFs, 70 DEG C are heated to, the N of prefabricated 1mL nitrite tert-butyls (18mg, 0.172mmol) is added dropwise to, dinethylformamide solution, completion of dropping immediately treats reaction.Reaction solution adds 50mL water, 50mL ethyl acetate, point liquid, organic phase washed with water and saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.With TLC with solvent system A purify gained residue, obtain title product 82 (4mg, white solid), Yield 10.5%.
MS m/z(LC-MS):450.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.14(s,1H),7.58-7.61(m,2H),7.32-7.39(m,5H),4.28(s,3H),3.91-3.97(m,2H),3.27-3.28(m,1H),3.08-3.13(m,2H),2.39-2.41(m,2H),2.27-2.29(m,2H).
Embodiment 83
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- (1- (5- nitrothiazole -2- bases) piperidin-4-yl) -2- carbonyls ethanamidine 83
The bromo- 5- nitrothiazoles 83a (1.0g, 4.78mmol) of 2- are dissolved in 15mL DMFs, add 1f (1.65g, 4.78mmol), N, N- diisopropylethylamine (1.54g, 12mmol), 80 DEG C of stirring reactions 2 hours.After reaction terminates, room temperature is cooled to, reaction solution is poured into water, ethyl acetate extraction, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filtering, 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- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -2- (1- (4- pyridine -2- bases) thiazol-2-yl) piperidin-4-yl) ethanamidine 84
The bromo- 4- of 2- (pyridine -2- bases) thiazole 84a (48mg, 0.2mmol are prepared using method disclosed in patent application " WO2012170845 ") is dissolved in 5mL DMFs, 1f is added (68mg, 0.2mmol), DIPEA (52mg, 0.4mmol), 100 DEG C of stirring reactions 5 hours.After reaction terminates, room temperature is cooled to, reaction solution is poured into 50mL water, 50mL ethyl acetate is extracted, organic phase water washing (30mL × 3), saturated sodium-chloride water solution washing (30mL × 3), anhydrous sodium sulfate drying, filtering, 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)δ11.72(s,1H),8.55-8.56(m,1H),8.39(s,1H),7.92-7.94(m,1H),7.83-7.85(m,1H),7.47(s,1H),7.28-7.30(m,1H),7.15-7.19(m,1H),6.99-7.01(m,1H),6.71-6.74(m,1H),4.04-4.07(m,2H),3.57-3.63(m,1H),3.13-3.19(m,2H),1.96-2.01(m,2H),1.62-1.65(m,2H).
Embodiment 85
N- (the bromo- 4- fluorophenyls of 3-) -2- (1- (5- bromo thiazole -2- bases) piperidin-4-yl)-N '-hydroxyl -- 2- carbonyls ethanamidine 85
Using the synthetic route of embodiment 84, raw material 84a is replaced with into the bromo thiazoles of 2,5- bis-, title product 85 (5mg, faint yellow solid), yield 10% is made.
MS m/z(LC-MS):507.1[M+1]
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.37(s,1H),7.14-7.20(m,2H),6.98-7.00(m,1H),6.69-6.72(m,1H),3.86-2.89(m,2H),3.54-3.60(m,1H),3.07-3.13(m,2H),1.91-1.94(m,2H),1.51-1.61(m,2H).
Embodiment 86
N- (the bromo- 4- fluorophenyls of 3-) -2- (1- (4- cyano thiazole -2- bases) piperidin-4-yl)-N '-hydroxyl -2- carbonyls ethanamidine 86
Using the synthetic route of embodiment 84, raw material 84a is replaced with into the bromo- 4- cyano thiazoles of 2-, title product 86 (13mg, faint yellow solid), yield 25% is made.
MS m/z(LC-MS):452.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.38(s,1H),7.96(m,1H),7.14-7.19(m,1H),6.98-7.00(m,1H),6.70-6.72(m,1H),3.93-3.96(m,2H),3.55-3.61(m,1H),3.15-3.21(m,2H),1.94-1.96(m,2H),1.58-1.60(m,2H).
Embodiment 87
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -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 thiazoles, title product 87 (10mg, faint yellow solid), yield 8% is made.
MS m/z(LC-MS):427.3[M+1]
Embodiment 88
2- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl) thiazole-5-carboxylic acid methyl esters 88
Using the synthetic route of embodiment 84, raw material 84a is replaced with into 2- bromo thiazole -5- carboxylate methyl esters (using known method " Journal of Organic Chemistry; 2011; 76 (16); 6972-6978 " is prepared), title product 88 (20mg, white solid), yield 41.7% is made.
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- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -2- (1- (4- (trifluoromethyl) thiazol-2-yl) piperidin-4-yl) ethanamidine 89
Using the synthetic route of embodiment 84, raw material 84a is replaced with into the bromo- 4- trifluoromethyl thiazoles of 2-, title product 89 (100 mg, white solid), yield 20.4% is made.
MS m/z(LC-MS):495.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.38(s,1H),7.54(s,1H),7.14-7.19(m,1H),6.99-7.00(m,1H),6.70-6.72(m,1H),3.93-3.96(m,2H),3.54-3.60(m,1H),3.13-3.19(m,2H),1.94-1.97(m,2H),1.54-1.64(m,2H).
Embodiment 90
2- (1- (5- amino -1,3,4- thiadiazoles -2- bases) piperidin-4-yl)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls ethanamidine 90
Using the synthetic route of embodiment 84, raw material 84a is replaced with into 2- amino -5- bromo- 1,3,4- thiadiazoles (is prepared) using method disclosed in patent application " WO2013163244 ", title product 90 (45mg, pink solid), yield 69.8% is made.
MS m/z(LC-MS):443.2[M+1]
Embodiment 91
2- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl)-N- methylthiazol -5- formamides
The first step
The bromo- N- methylthiazols -5- formamides 91b of 2-
2- bromo thiazole -5- carboxylic acids 91a (206mg, 1.0mmol) are dissolved in 5mL DMFs, add 2M methylamine (2mL, 4mmol), N, N- diisopropylethylamine (516mg, 4mmol), 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (456mg, 1.2mmol), 25 DEG C of stirring reactions 16 hours.Reaction terminate after, be concentrated under reduced pressure reaction solution, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 91b (45mg, white solid), yield 20.3%.
Second step
2- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl)-N- methylthiazol -5- formamides 91
91b (45mg, 0.2mmol) is dissolved in 5mL dimethyl sulfoxide (DMSO)s, 1f (69mg, 0.2mmol), DIPEA (52mg, 0.4mmol), 90 DEG C of stirring reactions 12 hours is added.After reaction terminates, room temperature is cooled to, reaction solution is poured into 30mL water, 30mL ethyl acetate is extracted, organic phase water washing (30mL × 3), saturated sodium-chloride water solution washing (30mL × 3), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.With thin Layer chromatography purifies gained residue with solvent system A, obtains title product 91 (8mg, brown solid), yield 8.1%.
MS m/z(LC-MS):484.2[M+1]
1H NMR(400MHz,DMSO-d6):δ11.69(s,1H),8.37(s,1H),8.14-8.15(m,1H),7.72(s,1H),7.13-7.17(m,1H),6.97-6.99(m,1H),6.69-6.72(m,1H),3.96-3.99(m,2H),3.56-3.60(m,1H),3.12-3.17(m,2H),2.69-2.70(m,3H),1.54-1.60(m,2H),1.22-1.32(m,2H).
Embodiment 92
2- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidin-1-yl)-N- methylthiazol -4- formamides 92
Using the synthetic route of embodiment 91, raw material 91a is replaced with into the bromo- thiazole -4-carboxylic acids of 2-, title product 92 (10mg, brown solid), yield 10.1% is made.
MS m/z(LC-MS):484.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.38(s,1H),8.02-8.03(m,1H),7.36(s,1H),7.14-7.19(m,1H),6.98-7.00(m,1H),6.71-6.74(m,1H),4.01-4.04(m,2H),3.55-3.61(m,1H),3.09-3.17(m,2H),2.73-2.74(m,3H),1.93-1.96(m,2H),1.55-1.64(m,2H).
Embodiment 93
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (1- (2- ethoxys) -1H- pyrazoles -4- bases) piperidines -1- formamides
The first step
4- nitros -1- (2- ((tetrahydrochysene -2H- pyrans -2- bases) epoxide) ethyl) -1H- pyrazoles 93b
By 2- (4- nitro -1H- pyrazol-1-yls) -1- ethanol 93a (1.878g, 11.9mmol, it is prepared using method disclosed in patent application " WO2013017479 ") it is dissolved in 70mL dichloromethane, add 3,4- dihydropyran (1.65mL, 18.0mmol), para-methylbenzenepyridinsulfonate sulfonate (604mg, 2.4mmol), 25 DEG C of stirring reactions 18 hours.After reaction terminates, be concentrated under reduced pressure dry reaction liquid, 60 DEG C of stirring reactions 18 hours.After reaction terminates, filtering, filtrate decompression concentration obtains crude title product 93b (2.92g, colorless oil), and product is not purified directly to carry out next step reaction.
Second step
1- (2- ((tetrahydrochysene -2H- pyrans -2- bases) epoxide) ethyl -1H- pyrazoles -4- amine 93c
Crude product 93b (2.92g, 12.1mmol) is dissolved in 40mL methanol, the palladium carbons of 590mg 10% are added, hydrogen is replaced three times, 25 DEG C of stirring reactions 3 hours.After reaction terminates, diatomite filtering, filtrate decompression is concentrated to give crude title product 93c (2.6g, brown-red oil), the not purified direct next step reaction of product.
3rd step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (1- (2- ((tetrahydrochysene -2H- pyrans -2- bases) epoxide) ethyl) -1H- pyrazoles -4- bases) piperidines -1- formamides 93d
By triphosgene (350mg, 1.18mmol) it is dissolved in 20mL tetrahydrofurans, add prefabricated 20mL crude product 93c (368mg, tetrahydrofuran solution 1.74mmol), triethylamine (1.5mL, 10.8mmol) reacts 30 minutes in 25 DEG C, adds prefabricated 20mL 1f (500mg, tetrahydrofuran solution 1.45mmol), reacts 1 hour in 25 DEG C.Reaction terminate after, add methanol reaction is quenched, reaction solution is 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- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (1- (2- ethoxys) -1H- pyrazoles -4- bases) piperidines -1- formamides 93
93d (430mg, 0.739mmol) is dissolved in 30mL methanol, one is added and is hydrated p-methyl benzenesulfonic acid (141mg, 0.738mmol), 25 DEG C of stirring reactions 18 hours.After reaction terminates, saturated sodium bicarbonate solution is added, Be concentrated under reduced pressure, with thin-layered chromatography with eluant, eluent system A purify gained residue obtain title product 93 (135mg, white solid), yield 36.7%.
MS m/z(ESI):497.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.51(s,1H),8.37(s,1H),7.70(s,1H),7.35(s,1H),7.17(t,1H),6.97-6.99(m,1H),6.69-6.73(m,1H),4.83(t,1H),4.05-4.13(m,2H),4.02-4.04(m,2H),3.65-3.69(m,2H),3.49-3.52(m,1H),2.81-2.86(m,2H),1.81-1.84(m,2H),1.37-1.46(m,2H).
Embodiment 94
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (1- (2- methoxyethyls) -1H- pyrazoles -4- bases) piperidines -1- formamides
The first step
Nitro -1H- pyrazoles the 94b of 1- (2- methoxy ethyls) -4
4- nitro -1H- pyrazoles 94a (2g, 17.7mmol) are dissolved in 20mL acetonitriles, bromoethanol methyl ether (2.7g, 19.4mmol) is sequentially added, potassium carbonate (3.66g, 26.5mmol), 60 DEG C of stirring reactions 18 hours.After reaction terminates, filtering, filter cake wash with ethyl acetate and dichloromethane, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 94b (3g, pale yellow oil), yield 100%.
Second step
1- (2- methoxy ethyls) -1H- pyrazoles -4- amine 94c
94b (3.0g, 17.5mmol) is dissolved in 20mL methanol, the palladium carbons of 600mg 10% are added, hydrogen is replaced three times, 25 DEG C of stirring reactions 2 hours.After reaction terminates, diatomite filtering, filtrate decompression is concentrated to give crude title product 94c (2.1g, purple grease), the not purified direct next step reaction of product.
3rd step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (1- (2- methoxyethyls) -1H- pyrazoles -4- bases) piperidines -1- formamides 94
Triphosgene (43mg, 0.145mmol) is dissolved in 20mL tetrahydrofurans, addition crude product 94c (43mg, Tetrahydrofuran solution 0.305mmol), triethylamine (88mg, 0.87mmol) reacts 30 minutes in 25 DEG C, adds prefabricated 5mL 1f (100mg, 0.29mmol) tetrahydrofuran solution, is reacted 1 hour in 25 DEG C.Reaction terminate after, add methanol reaction is quenched, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with eluant, eluent system A purify obtained by residue obtain title product 94 (142mg, white solid), yield 28%.
MS m/z(ESI):511.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.51(s,1H),8.38(s,1H),7.68(s,1H),7.36(s,1H),7.15-7.19(d,1H),6.97-6.99(m,1H),6.70-6.72(m,1H),4.10-4.17(m,4H),3.61-3.63(m,2H),3.51-3.53(m,1H),3.22(s,3H),2.81-2.87(m,2H),1.82-1.84(m,2H),1.38-1.44(m,2H).
Embodiment 95
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (the fluoro- 1- of 5- (2- ethoxys) -1H- pyrazoles -4- bases) piperidines -1- formamides
The first step
(1- (2- ((tetrahydrochysene -2H- pyrans -2- bases) epoxide) ethyl) -1H- pyrazoles -4- bases) t-butyl carbamate 95a
93c (3.5g, 16.6mmol) is dissolved in 100mL dichloromethane, 3.45mL triethylamines are added, DMAP (202mg, 1.65mmol) and di-tert-butyl dicarbonate (4.34g, 19.9mmol), 25 DEG C of stirring reactions 16 hours.Reaction terminate after, reaction solution is 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- bases epoxide) ethyl] -1H- pyrazoles -4- bases } t-butyl carbamate 95b
By 95a (4.62g, 14.8mmol) it is dissolved in 70mL tetrahydrofurans, ice bath is cooled down, add sodium hydride (713mg, 17.8mmol), 0 DEG C of stirring reaction 0.5 hour, add di-tert-butyl dicarbonate (4.53g, 20.8mmol), 0 DEG C of stirring reaction 5 minutes, 25 DEG C of stirring reactions 0.5 hour.After reaction terminates, add sodium hydrate aqueous solution and reaction is quenched, ethyl acetate is extracted 3 times, merges organic phase, saturated nacl aqueous solution is washed 1 time, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 95b (5.3g, reddish tan liquid), yield 87%.
3rd step
N- [(tert-butoxy) carbonyl]-N- { the fluoro- 1- of 5- [2- (pyrans -2- bases epoxide) ethyl] -1H- pyrazoles -4- bases } t-butyl carbamate 95c
By 95b (3g, 7.29mmol) it is dissolved in 80mL tetrahydrofurans, it is cooled to -78 DEG C, 2M lithium diisopropylamine (4.4mL is added dropwise, 8.8mmol), -78 DEG C of stirring reactions 1 hour, then the double benzsulfamide (3.45g of prefabricated 30mL N- fluoro are added dropwise, tetrahydrofuran solution 10.9mmol), -78 DEG C of stirring reactions 1 hour.After reaction terminates, add sodium hydroxide solution and reaction is quenched, ethyl acetate is extracted 3 times, merges organic phase, saturated nacl aqueous solution is washed 1 time, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 95c (2.3g, yellow liquid), yield 73%.
4th step
N- [(tert-butoxy) carbonyl]-N- [the fluoro- 1- of 5- (2- ethoxys) -1H- pyrazoles -4- bases] t-butyl carbamate 95d
95c (1.025g, 2.39mmol) is dissolved in 30mL methanol, one is added and is hydrated p-methyl benzenesulfonic acid (227mg, 1.19mmol), 25 DEG C of stirring reactions 18 hours.After reaction terminates, 1mL triethylamines are added, are concentrated under reduced pressure, obtain crude title product 95d (1.2g, yellow oil), the not purified direct next step reaction of product.
5th step
Acetic acid 2- (4- { two [(tert-butoxy) carbonyl] amino } the fluoro- 1H- pyrazol-1-yls of -5-) ethyl ester 95e
Crude product 95d (1.2g, 3.47mmol) is dissolved in 30mL dichloromethane, 0 DEG C is cooled to, 0.75mL triethylamines are added, chloroacetic chloride (0.25mL, 3.5mmol) is added dropwise to, 0 DEG C of stirring reaction 1 hour.After reaction terminates, add sodium bicarbonate solution and reaction is quenched, divide liquid, organic phase washed with water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain crude title product 95e (960mg, yellow oil), the not purified direct next step reaction of product.
6th step
Acetic acid 2- (4- amino-5-fluorine -1H- pyrazol-1-yls) ethyl ester 95f
Crude product 95e (960mg, 2.48mmol) is dissolved in 20mL dichloromethane, 20mL trifluoracetic acids, 25 DEG C of stirring reactions 1 hour is added.After reaction terminates, reaction solution is concentrated under reduced pressure, and adds dichloromethane, and saturated sodium bicarbonate solution is washed 2 times, saturated nacl aqueous solution is washed 1 time, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system B purify gained residue, obtain title product 95f (90mg, brown viscous thing), yield 19%.
7th step
Acetic acid 2- (4- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides) the fluoro- 1H- pyrazol-1-yls of -5-) ethyl ester 95g
By triphosgene (139mg, 0.468mmol) it is dissolved in 10mL tetrahydrofurans, add 95f (88mg, 0.47mmol), triethylamine (0.78mL, 5.6mmol), reacted 30 minutes in 25 DEG C, in the tetrahydrofuran liquid for the 1f (100mg, 0.29mmol) that above-mentioned reaction solution is added to prefabricated 15mL, in 25 DEG C of stirring reactions 1 hour.Reaction terminate after, add methanol, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 95g (50mg, brown solid), yield 19%.
8th step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (the fluoro- 1- of 5- (2- ethoxys) -1H- pyrazoles -4- bases) piperidines -1- formamides 95
95g (50mg, 0.0897mmol) is dissolved in 10mL methanol, potassium carbonate (25mg, 0.181mmol), 25 DEG C of stirring reactions 1 hour is added.Reaction terminate after, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 95 (10mg, white solid), yield 21.6%.
MS m/z(ESI):515.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.38(s,1H),8.01(s,1H),7.32(s,1H),7.17(t,1H),6.98-6.99(m,1H),6.70-6.73(m,1H),4.08-4.12(m,2H),3.98(t,2H),3.67(t,2H),3.49-3.52(m,1H),2.81-2.87(m,2H),1.81-1.84(m,2H),1.38-1.46(m,2H).
Embodiment 96
(R) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (2,3- dihydroxypropyls) -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides
The first step
(R) -1- (2,2- dimethyl -1,3- dioxolanes -4- bases) methyl) -4- (4- nitrobenzophenones) -1H- pyrazoles 98a
By 4- (4- nitrobenzene) -1H- pyrazoles 1g (500mg, 2.64mmol, using known method " Medicinal Chemistry Research; 2013; 22 (11); 5610-5616 " is prepared) be dissolved in 20ml N, in dinethylformamide, add cesium carbonate (1.29g, 3.95mmol), (S)-(-) -4- chloromethyls -2,2- dimethyl -1,3- dioxolanes (478mg, 3.7mmol), reacts 18 hours in 100 DEG C.After reaction terminates, ethyl acetate, pad diatomite filtering are added, filter cake is washed with ethyl acetate, filtrate is collected, filtrate water is washed three times, and saturated nacl aqueous solution washed once, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude title product 96a (710mg, weak yellow liquid), the not purified direct next step reaction of product.
Second step
(R) -4- (1- (2,2- dimethyl -1,3- dioxolanes -4- bases) methyl) -1H- pyrazoles -4- bases) aniline 96b
Crude product 96a (710mg, 2.31mmol) is dissolved in 30mL second alcohol and waters (V:V=5:1) in the mixed solvent.Iron powder (306mg, 5.46mmol), ammonium chloride (584mg, 10.9mmol) are sequentially added into reaction solution.Reaction solution is warming up to 80 DEG C, stirring reaction 2 hours.After reaction terminates, reaction solution is cooled to room temperature, is concentrated under reduced pressure, ethyl acetate and a small amount of methanol are added in residue, pad diatomite filtering, filter cake is washed with ethyl acetate, collects filtrate, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 96b (550mg, brown liquid), yield 87%.
3rd step
(R) -4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- ((2; 2- dimethyl -1,3- dioxolanes -4- bases) methyl) -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides 96c
By triphosgene (34mg, 0.114mmol) it is dissolved in 10mL tetrahydrofurans, add prefabricated 10mL 96b (82mg, in 0.3mmol) tetrahydrofuran solution, 0.2mL triethylamines, react 30 minutes in 25 DEG C, add prefabricated 10mL 1f (100mg, tetrahydrofuran solution 0.29mmol), reacts 1 hour in 25 DEG C.Reaction terminate after, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with eluant, eluent system A purify obtained by residue, obtain title product 96c (110mg, khaki solid), yield 59%.
4th step
(R) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (2,3- dihydroxypropyls) -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides 96
96c (110mg, 0.193mmol) is dissolved in 15ml methanol, Loprazolam (25mg, 0.26mmol) is added, reacted 18 hours in 25 DEG C.Reaction terminate after, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 96 (40mg, khaki solid), yield 39%.
MS m/z(ESI):603.4[M+1]
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.52(s,1H),8.39(s,1H),8.00(s,1H),7.79(s,1H),7.44-7.46(m,4H),7.18(t,1H),6.98-7.00(m,1H),6.73-6.74(m,1H),5.00(d,1H),4.75(t,1H),4.18-4.24(m,3H),3.95-4.00(m,1H),3.81-3.84(m,1H),3.54-3.56(m,1H),3.30-3.38(m,2H),2.85-2.91(m,2H),1.85-1.89(m,2H),1.45-1.49(m,2H).
Embodiment 97
(S) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- (1- (2,3- dihydroxypropyls) -1H- pyrazoles -4- bases) phenyl) piperidines -1- formamides 97
Using the synthetic route of embodiment 96, raw material (S)-(-) -4- chloromethyls -2,2- dimethyl-DOX is replaced with into (R)-(-) -4- chloromethyls -2,2- dimethyl -1,3- dioxolanes is (using known method " Pharma Chemica, 2011,3 (4); 219-226 ", title product 97 (45mg, Tan solid), yield 48% is made.
MS m/z(ESI):603.4[M+1]
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.52(s,1H),8.39(s,1H),8.00(s,1H),7.79(s,1H),7.44-7.46(m,4H),7.18(t,1H),6.98-7.00(m,1H),6.73-6.74(m,1H),5.00(d,1H),4.75(t,1H),4.18-4.24(m,3H),3.95-4.00(m,1H),3.81-3.84(m,1H),3.54-3.56(m,1H),3.30-3.38(m,2H),2.85-2.91(m,2H),1.85-1.89(m,2H),1.45-1.49(m,2H).
Embodiment 98
N- (4- (1- ((1- amino cyclopropyl) methyl) -1H- pyrazoles -4- bases) phenyl) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides
The first step
Methanesulfonic acid (1- ((tertbutyloxycarbonyl) amino) cyclopropyl) methyl ester 98b
By (1- methylols) cyclopropyl) t-butyl carbamate 98a (3.74g, 20mmol) it is dissolved in 40mL dichloromethane, add triethylamine (3g, 30mmol), ice bath, it is added dropwise to methane sulfonyl chloride (2.75g, 24mmol), 0 DEG C of stirring reaction 2 hours.After reaction terminates, 50mL saturated sodium bicarbonate solutions are added, point liquid, organic phase washed once with saturated nacl aqueous solution 50mL, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain crude title product 98b (4.8g, faint yellow solid), the not purified direct next step of product.
Second step
(1- ((4 iodo- 1H- pyrazol-1-yls) methyl) cyclopropyl) t-butyl carbamate 98c
Crude product 98b (4.53g, 17mmol) is dissolved in 40mL dimethyl acetamides, cesium carbonate (11.1g, 34.2mmol) is added, the iodo- 1H- pyrazoles (2.2g, 11.4mmol) of 4- are added, under argon atmospher, 70 DEG C of stirring reactions 16 hours.After reaction terminates, reaction solution is concentrated under reduced pressure, and residue adds 100mL water, ethyl acetate extracts (100mL × 3), merge organic phase, organic phase washed once with saturated nacl aqueous solution 100mL, anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 98c (3g, off-white powder), yield 73%.
3rd step
(1- ((4- (4- nitrobenzophenones) -1H- pyrazol-1-yls) methyl) cyclopropyl) t-butyl carbamate 98e
By 98c (600mg, 1.65mmol), 4- nitrobenzene boronic acids 98d (276mg, 1.65mmol), [1,1'- Double (diphenylphosphine) ferrocene] palladium chloride (121mg, 0.16mmol), potassium carbonate (456mg, 3.3mmol) was added in 30mL dioxane and 6mL water, under argon atmospher, in 100 DEG C of stirring reactions 16 hours.After reaction terminates, add ethyl acetate and anhydrous sodium sulfate, diatomite 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- aminophenyls) -1H- pyrazol-1-yls) methyl) cyclopropyl) t-butyl carbamate 98f
98e (320mg, 0.89mmol) is dissolved in 25mL second alcohol and waters (V:V=5:1) in the mixed solvent.Iron powder (100mg, 1.78mmol), ammonium chloride (191mg, 3.57mmol) are sequentially added into reaction solution.Reaction solution is warming up to 80 DEG C, stirring reaction 3 hours.After reaction terminates, reaction solution is cooled to room temperature, is concentrated under reduced pressure, ethyl acetate is added in residue, pad diatomite filtering, filter cake is washed with ethyl acetate, collects filtrate, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 98f (160mg, brown liquid), yield 54%.
5th step
(1- ((4- (4- (4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides) phenyl) -1H- pyrazol-1-yls) methyl) cyclopropyl) t-butyl carbamate 98g
By triphosgene (34mg, 0.114mmol) it is dissolved in 10mL tetrahydrofurans, add prefabricated 10mL 98f (100mg, 0.3mmol) tetrahydrofuran solution, 0.12mL triethylamines, react 30 minutes in 25 DEG C, add prefabricated 10mL 1f (100mg, tetrahydrofuran solution 0.29mmol), reacts 1 hour in 25 DEG C.Reaction terminate after, reaction is quenched in methanol, and reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 98g (70mg, white solid), yield 34%.
6th step
N- (4- (1- ((1- amino cyclopropyl) methyl) -1H- pyrazoles -4- bases) phenyl) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) Acetylpiperidin -1- formamides 98
98g (70mg, 0.112mmol) is dissolved in 15mL 4M hydrogen chloride Isosorbide-5-Nitrae-dioxane solution, reacted 1 hour in 25 DEG C.After reaction terminates, reaction solution is concentrated under reduced pressure, title product 98 (40mg, white solid), yield 63.5% is made in high performance liquid chromatography.
MS m/z(ESI):598.4[M+1]
1H NMR(400MHz,CD3OD)δ7.98(s,1H),7.91(s,1H),7..49-7.52(m,2H),7.37-7.40(m,2H),7.01-7.07(m,2H),6.78-6.81(m,1H),4.41(s,2H),4.22-4.26(m,2H),3.64-3.70(m,1H),3.00-3.06(m,2H),1.94-1.97(m,2H),1.64-1.69(m,2H),1.15-1.21(m,2H),1.08-1.19(m,2H).
Embodiment 99
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- cyano group -5- methoxypyridine -3- bases) piperidines -1- formamides 99
By triphosgene (181mg, 0.114mmol) it is dissolved in 20mL tetrahydrofurans, add prefabricated 20mL 2- cyano group -3- methoxyl group -5- aminopyridine 99a (136mg, 0.91mmol, be prepared using method disclosed in WO2003062241 " of applying for a patent) tetrahydrofuran solution; triethylamine (264mg; 2.6mmol); reacted 30 minutes in 25 DEG C; add prefabricated 1f (100mg; 0.29mmol) 20mL tetrahydrofuran solutions, reacted 1 hour in 25 DEG C.After reaction terminates, reaction is quenched in methanol, and reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtained title product 99 (200mg, white solid), yield 44%.
MS m/z(ESI):519.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),9.27(s,1H),8.40(s,2H),7.93(s,1H),7.15-7.19(t,1H),6.98-7.00(m,1H),6.70-6.71(m,1H),4.18-4.22(m,2H),3.91(s,3H),3.50-3.51(m,1H),2.94-2.98(m,2H),1.88-1.91(m,2H),1.48-1.50(m,2H).
Embodiment 100
4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- luorobenzyls) piperidines -1- formamides 100
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- fluorin benzyl amines, title product 100 (50mg, white solid), yield 34.9% is obtained.
MS m/z(ESI):495.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.36(s,1H),7.26-7.28(m,2H)7.10-7.17(m,4H),6.98-7.10(m,1H),6.71-6.72(m,1H),4.20-4.21(s,2H),4.03-4.07(m,2H),3.46-3.52(m,1H),2.74-2.80(m,2H),1.77-1.80(m,2H),1.34-1.43(m,2H).
Embodiment 101
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- cyano group -5- picoline -3- bases) piperidines -1- formamides 101
Using the synthetic route of embodiment 99; raw material 99a is replaced with into 2- cyano group -3- first -5- aminopyridines (being prepared using method disclosed in patent application " WO2015155626 "); (the 13mg of title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- cyano group -5- picoline -3- bases) piperidines -1- formamides 101 is made; white solid), yield 10%.
MS m/z(ESI):503.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),9.18(s,1H),8.62(s,1H),8.40(s,1H),8.02(s,1H),7.15-7.20(m,1H),6.99-6.70(m,1H),6.71-6.73(m,1H),4.18-4.21(m,2H),3.55-3.60(m,1H),2.92-2.99(m,2H),2.30(s,3H),1.88-1.91(m,2H),1.44-1.52(m,2H).
Embodiment 102
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyano group -3- methoxyphenyls) piperidines -1- formamides 102
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- amino -2- methoxy cyanophenyls, title product 102 (70mg, white solid), yield 46% is made.
MS m/z(ESI):518.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),9.01(s,1H),8.39(s,1H),7.53(d,1H),7.45(s,1H),7.23(d,1H),7.17(t,1H),6.98-7.00(m,1H),6.71-6.73(m,1H),4.17-4.20(m,2H),3.53-3.59(m,1H),2.90-2.96(m,2H),1.87-1.90(m,2H),1.43-1.51(m,2H).
Embodiment 103
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- methoxy-benzyls) piperidines -1- formamides 103
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- methoxybenzylamines, title product 103 (60mg, white solid), yield 40.5% is made.
MS m/z(ESI):507.3[M+1]
1H NMR(400MHz,CDCl3)δ9.07(s,1H),7.24(d,2H),7.04-7.06(m,1H),6.97-7.00(m,1H),6.87(d,2H),6.80(s,1H),4.69-4.75(m,1H),4.37(d,2H),4.05(d,2H),3.81(s,3H),3.50(s,2H),2.92(t,2H),1.93(d,2H),1.57-1.69(m,2H)
Embodiment 104
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- piperidine -1- formamides 104
Using the synthetic route of embodiment 99, raw material 99a is replaced with into phenyl ethylamine, title product 104 (35mg, white solid), yield 24.6% is made.
MS m/z(ESI):491.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.37(s,1H),7.26-7.28(m,5H),7.10-7.17(m,2H),6.98-7.10(m,1H),6.71-6.72(m,1H),4.20-4.21(s,2H),4.03-4.07(m,3H),2.74-2.80(m,4H),1.77-1.80(m,2H),1.34-1.43(m,2H)
Embodiment 105
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (5- cyanopyridine -3- bases) piperidines -1- formamides 105
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 5- Amino 3 cyano pyridines, title product 105 (130mg, white solid), yield 45.8% is made.
MS m/z(ESI):489.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),9.09(s,1H),8.88(s,1H),8.57(s,1H),8.39(s,1H),8.33(s,1H),7.17(t,1H),6.98-7.00(m,1H),6.71-6.73(m,1H),4.18-4.20(m,2H),3.55-3.60(m,1H),2.92-2.98(m,2H),1.88-1.91(m,2H),1.45-1.54(m,2H).
Embodiment 106
4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (the fluoro- 4- mesyls of 2-) piperidines -1- formamides 106
Using embodiment 99 into route, raw material 99a is replaced with into the fluoro- 4- methanesulfonylanilines of 2-, title product 106 (100mg, faint yellow solid), yield 62% is made.
MS m/z(ESI):559.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.76(s,1H),8.39(s,1H),7.78(t,1H),7.73(d,1H),7.68(d,1H),7.18(d,1H),6.98-7.00(m,1H),6.70-6.73(m,1H),4.18-4.20(d,2H),3.53-3.59(m,1H),2.91-2.97(m,2H),1.86-1.89(m,2H),1.45-1.54(m,2H).
Embodiment 107
4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (5- cyanopyridine -3- bases) piperidines -1- formamides 107
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 5- Amino 3 cyano pyridines, title product 107 (60mg, faint yellow solid), yield 42% is made.
MS m/z(ESI):489.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),9.09(s,1H),8.88(s,1H),8.57(s,1H),8.39(s,1H),8.33(s,1H),7.17(m,1H),6.98-7.00(m,1H),6.71-6.74(m,1H),4.17-4.21(m,2H),3.54-3.60(m,1H),2.92-2.98(m,2H),1.88-1.91(m,2H),1.44-1.53(m,2H).
Embodiment 108
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (pyridin-3-yl) piperidines -1- formamides 108
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 3- aminopyridines, title product 108 (50mg, khaki solid), yield 37% is made.
MS m/z(ESI):464.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.74(s,1H),8.65(s,1H),8.38(s,1H),8.15(s,1H),7.89(d,1H),7.27-7.28(m,1H),7.17(t,1H),6.99(m,1H),6.70-6.73(m, 1H),4.17-4.21(m,2H),3.55-3.56(m,1H),2.88-2.94(m,2H),1.86-1.89(m,2H),1.45-1.49(m,2H).
Embodiment 109
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (3- cyanobenzyls) piperidines -1- formamides 109
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 3- cyano group benzylamines, title product 109 (23mg, white solid), yield 15.7% is made.
MS m/z(ESI):502.3[M+1]
1H NMR(400MHz,CDCl3)δ7.55-7.59(m,4H),7.43-7.46(m,1H),6.98-7.05(m,1H),6.78-6.84(m,1H),4.82-4.90(s,1H),4.42-4.49(m,3H),3.98-4.04(m,1H),3.50(s,1H),2.84-2.96(m,2H),2.03-2.18(m,2H),1.80-1.95(m,2H).
Embodiment 110
4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (3- cyano group -4- methoxy-benzyls) piperidines -1- formamides 110
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 5- (aminomethyl) -2- methoxy cyanophenyls (being prepared using method disclosed in patent application " WO2001030745 "), obtain title product 110 (45mg, pale solid), yield 29%.
MS m/z(ESI):532.4[M+1]
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.37(s,1H),7.54-7.55(m,2H),7.15-7.20(m,2H),7.09-7.11(m,1H),6.98-6.99(m,1H),6.70-6.72(m,1H),4.18(s,2H),4.02-4.05(m,2H),3.89(s,3H),3.49-3.51(m,1H),2.74-2.77(m,2H),1.78-1.81(m,2H),1.35-1.39(m,2H).
Embodiment 111
(S) -4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (1- phenethyls) piperidines -1- formamides 111
Using the synthetic route of embodiment 99, raw material 99a is replaced with into (S) -1- phenyl ethylamines, title product 111 (55mg, white solid), yield 38.7% is made.
MS m/z(ESI):491.3[M+1]
1H NMR(400MHz,CDCl3)δ9.65(s,1H),8.65(s,1H),7.32-7.36(m,4H),6.96-7.04(m,2H),6.63-6.79(m,2H),4.99-5.06(m,1H),4.75(d,1H),4.00-4.06(m,2H),3.94-3.99(m,1H),2.91(t,2H),1.87-1.94(m,2H),1.63-1.70(m,2H),1.50(d,3H).
Embodiment 112
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- fluorobenzene ethyl) piperidines -1- formamides 112
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- fluorophenethylamines, title product 112 (62mg, faint yellow solid), yield 42% is made.
MS m/z(ESI):509.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.36(s,1H),7.17-7.23(m,3H),7.07-7.11(m,2H),6.98-6.99(m,1H),6.71-6.73(m,1H),6.57-6.59(m,1H),3.98-4.00(m,2H),3.45-3.51(m,1H),3.19-3.23(m,2H),2.69-2.75(m,4H),1.74-1.77(m,2H),1.31-1.39(m,2H).
Embodiment 113
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- carbamoyls benzyl) piperidines -1- formamides 113
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- (aminomethyl) benzamide (being prepared using method disclosed in patent application " WO2003097579 "), obtain title product 113 (10mg, white solid), yield 6.6%.
MS m/z(ESI):520.3[M+1]
1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.80(s,1H),7.68(d,1H),7.50(t,1H),7.42(t,1H),7.04-7.07(m,1H),7.01(t,1H),6.82-6.98(m,1H),5.35(s,1H),4.87-4.93(m,1H),4.50(d,2H),4.04(d,2H),3.46(t,1H),2.94(t,2H),2.23(t,1H),2.01-2.06(m,1H),1.87-1.94(m,2H).
Embodiment 114
(R) -4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (1- phenethyls) piperidines -1- formamides 114
Using the synthetic route of embodiment 99, raw material 99a is replaced with into (R) -1- phenyl ethylamines, title product 114 (69mg, faint yellow solid), yield 48% is made.
MS m/z(ESI):491.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.38(s,1H),7.25-7.28(m,5H),7.10-7.17(m,2H),6.98-7.10(m,1H),6.71-6.72(m,1H),4.83-4.85(m,1H),3.68-3.70(m,4H),2.53-2.55(m,1H),2.03-2.05(m,2H),1.78-1.81(m,2H),1.64(s,3H)
Embodiment 115
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (2- cyanopyridine -4- bases) methyl) piperidines -1- formamides 115
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- aminomethyl -2- cyanopyridines (using known method " Bioorganic ＆ Medicinal Chemistry; 2005; 13 (12); 4022-4036 " is prepared), title product 115 (40mg, hazel-color solid), yield 27% is made.
MS m/z(ESI):503.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.66-8.69(m,1H),8.38(s,1H),7.87(m,1H),7.57-7.59(m,1H),7.26-7.28(m,1H),7.17(t,1H),6.97-6.99(m,1H),6.70-6.72(m,1H),4.30(d,2H),4.03-4.07(m,2H),3.48-3.51(m,1H),2.79-2.85(m,2H),1.77-1.83(m,2H),1.39-1.45(m,2H).
Embodiment 116
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- picoline -3- bases) piperidines -1- formamides 116
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 3- amino -6- picolines, title product 116 (45mg, faint yellow solid), yield 32.4% is made.
MS m/z(ESI):478.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.60(s,1H),8.48-8.47(m,1H),8.38(s,1H),7.76-7.73(m,1H),7.19-7.15(m,1H),7.11-7.10(m,1H),6.99-6.98(m,1H),6.72-6.70(m,1H),4.19-4.16(m,2H),3.57-3.51(m,1H),2.91-2.86(m,2H),2.37(s,3H),1.88-1.85(m,2H),1.51-1.42(m,2H).
Embodiment 117
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (3- methoxy-benzyls) piperidines -1- formamides 117
Using the synthetic route of embodiment 99; raw material 99a is replaced with into 3- methoxybenzylamines; (the 30mg of title product 4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (3- methoxy-benzyls) piperidines -1- formamides 117 is made; white solid), yield 20.4%.
MS m/z(ESI):507.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.38(s,1H),7.17-7.21(m,2H),7.08-7.10(m,1H),6.97-6.98(m,1H),6.72-6.83(m,4H),4.22(s,2H),4.05-4.09(m,2H),3.73(s,3H),3.49-3.51(m,1H),2.75-2.81(m,2H),1.78-1.81(m,2H),1.38-1.40(m,2H).
Embodiment 118
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (pyridine -2- ylmethyls) piperidines -1- formamides 118
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 2- pyridyl-methanamines, title product 118 (15mg, light yellow solid), yield 11% is made.
MS m/z(ESI):478.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.48(s,1H),8.38(s,1H),7.72-7.76(m,1H),7.18-7.26(m,4H),6.98-6.99(m,1H),6.71-6.73(m,1H),4.33(s,2H),4.06-4.10(m,2H),3.51-3.57(m,1H),2.77-2.84(m,2H),1.79-1.82(m,2H),1.40-1.43(m,2H).
Embodiment 119
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (cyclohexyl methyl) piperidines -1- formamides 119
Using the synthetic route of embodiment 99, raw material 99a is replaced with into cyclohexylmethylamine, title product 119 (25mg, white solid), yield 16.8% is made.
MS m/z(ESI):483.3[M+1]
1H NMR(400MHz,CDCl3)δ7.08-7.15(m,1H),7.00(t,1H),6.55-6.67(m,1H),5.52-5.60(m,1H),5.30-5.35(m,1H),4.52(s,1H),4.32-4.36(m,1H),3.95-4.05(m,3H),3.83-3.87(m,1H),3.50(s,3H),3.09(t,2H),2.91(t,2H),2.82(s,1H),2.45-2.50(t,1H),2.20-2.29(m,1H),1.71-1.90(m,3H),1.58-1.68(m,4H).
Embodiment 120
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- methoxyphenethyls) piperidines -1- formamides 120
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- methoxyphenethylamines, title product 120 (45mg, white solid), yield 29.8% is made.
MS m/z(ESI):521.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.40(s,1H),7.13-7.17(t,1H),7.08-7.10(d,2H),6.97-6.98(m,1H),6.85-6.86(d,2H),6.71-6.83(m,1H),6.57-6.58(m,1H),3.98-4.01(m,2H),3.47-3.49(m,1H),3.15-3.18(m,2H),2.62-2.74(m,4H),1.74-1.77(m,2H),1.34-1.36(m,2H).
Embodiment 121
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- methyl sulphonyls) benzyl) piperidines -1- formamides 121
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- mesyl benzylamines, title product 121 (35mg, white solid), yield 21.7% is made.
MS m/z(ESI):555.3[M+1]
Embodiment 122
4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (2- methoxy-benzyls) piperidines -1- formamides 122
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 2- methoxybenzylamines, title product 122 (40mg, faint yellow solid), yield 27% is made.
MS m/z(ESI):507.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.37(s,1H),7.15-7.19(m,3H),6.88-6.98(m,4H),6.71-6.72(m,1H),4.22(s,2H),4.06-4.10(m,2H),3.75(s,3H),3.49-3.51(m,1H),2.76-2.81(m,2H),1.78-1.81(m,2H),1.39-1.43(m,2H).
Embodiment 123
4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (pyridin-4-yl methyl) piperidines -1- formamides 123
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 4- dimethylaminopyridines, title product 123 (33mg, faint yellow solid), yield 23.9% is made.
MS m/z(ESI):478.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.48(s,1H),8.35-8.42(m,2H),7.82-7.85(m,2H),7.18-7.26(m,2H),6.98-6.99(m,1H),6.71-6.73(m,1H),4.33(s,2H),4.06-4.10(m,2H),3.51-3.57(m,1H),2.77-2.84(m,2H),1.79-1.82(m,2H),1.40-1.43(m,2H).
Embodiment 124
4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (pyridin-3-yl methyl) piperidines -1- formamides 124
Using the synthetic route of embodiment 99, raw material 99a is replaced with into 3- dimethylaminopyridines, title product 124 (25mg, faint yellow solid), yield 18% is made.
MS m/z(ESI):478.3[M+1]
Embodiment 125
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- (1- cyclopropyl -1H- pyrazoles -4- bases) pyridin-3-yl) piperidines -1- formamides
The first step
6- (1- cyclopropyl -1H- pyrazoles -4- bases) pyridine -3- amine 125b
By 1- cyclopropyl -4- (4,4,5,5- tetramethyls -1,3,2- dioxy boron pentane -2- bases) -1H- pyrazoles 125a (304mg, 1.3mmol, it is prepared using method disclosed in patent application " CN103122000 "), the bromo- 3- aminopyridines (150mg, 0.867mmol) of 6-, [1, double (diphenylphosphine) ferrocene of 1'-] palladium chloride (28mg, 0.043mmol), potassium carbonate (180mg, 1.3mmol) is added in 16mL dioxane and 2mL water, under argon atmospher, in 85 DEG C of stirring reactions 18 hours.After reaction terminates, 100mL water is added in reaction solution, is extracted with ethyl acetate (60mL × 3), merge organic phase, concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 125b (154mg, Tan solid), yield 89%.
Second step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- (1- cyclopropyl -1H- pyrazoles -4- bases) pyridin-3-yl) piperidines -1- formamides 125
Triphosgene (172mg, 0.579mmol) is dissolved in 50mL tetrahydrofurans, 125b (290mg are added, 1.448mmol), 0.6mL triethylamines, react 30 minutes in 0 DEG C, 1f (498mg, 1.448mmol) is added, is reacted 1 hour in 25 DEG C.Reaction terminate after, add 10mL methanol, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 125 (135mg, white solid), yield 16.3%.
MS m/z(ESI):570.4[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.70(s,1H),8.55(s,1H),8.38(s,1H),8.24(s,1H),7.88(s,1H),7.86-7.83(m,1H),7.54-7.52(m,1H),7.19-7.15(m,1H),7.00-6.98(m,1H),6.73-6.70(m,1H),4.21-4.17(m,2H),3.77-3.72(m,1H),3.58-3.52(m,1H),2.93-2.87(m,2H),1.89-1.86(m,2H),1.51-1.43(m,2H),1.10-1.06(m,2H), 0.99-0.94(m,2H).
Embodiment 126
4- ((4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamidos) methyl) benzoic acid
The first step
4- ((4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamidos) methyl) ethyl benzoate 126b
By triphosgene (34mg, 0.116mmol) it is dissolved in 20mL tetrahydrofurans, add Aminomethylbenzoic Acid ethyl ester 126a (54mg, 0.307mmol), triethylamine (0.12mL, 0.86mmol), reacted 30 minutes in 25 DEG C, 1f (100mg, 0.29mmol) is added, in 25 DEG C of stirring reactions 1 hour.Reaction terminate after, add methanol, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 126b (40mg, white solid), yield 25%.
Second step
4- ((4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamidos) methyl) benzoic acid 126
126b (20mg, 0.0364mmol) is dissolved in 1mL ethanol, 1mL sodium hydroxide (3mg, 0.0728mmol) solution, 25 DEG C of stirring reactions 16 hours is added.After reaction terminates, with 1M salt acid for adjusting pH to 5, ethyl acetate extraction (20mL × 3) merges organic phase, saturated nacl aqueous solution is washed 1 time, anhydrous sodium sulfate drying, filtering, 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)δ7.96(d,2H),7.38(d,2H),6.95-7.04(m,2H),6.74-6.76(m,1H),4.42(s,2H),4.10(d,2H),3.62(t,1H),2.94(t,2H),1.89-1.98(m,2H), 1.53-1.62(m,2H).
Embodiment 127
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- (2- hydroxy ethoxies) pyridin-3-yl) piperidines -1- formamides
The first step
2- (2- ((t-Butyldimethylsilyl) epoxide) ethyoxyl) -5- nitropyridines 127b
By 2- (5- nitro -2- pyridines epoxide) ethanol 127a (0.5g, 2.732mmol, it is prepared using method disclosed in patent application " WO2008084873 ") it is dissolved in 10mL tetrahydrofurans, add imidazoles (0.28g, 4.098mmol) with tert-butyl chloro-silicane (0.49g, 3.279mmol), react 24 hours at 25 DEG C.After reaction terminates, 40mL water is added, is extracted with ethyl acetate (80mL × 3), merge organic phase, organic phase washed once with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, 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) epoxide) ethyoxyl) pyridine -3- amine 127c
127b (360mg, 1.204mmol) is dissolved in 20mL second alcohol and waters (V:V=5:1) in the mixed solvent. Iron powder (202mg, 3.612mmol), ammonium chloride (384mg, 7.224mmol) are sequentially added into reaction solution.Reaction solution is warming up to 70 DEG C, stirring reaction 1 hour.After reaction terminates, reaction solution is cooled to room temperature, is concentrated under reduced pressure, 50mL ethyl acetate and 40mL water are added in residue, point liquid, aqueous phase is extracted with ethyl acetate (50mL × 2), merge organic phase, organic phase washed once with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, crude title product 127c (330mg, greenish yellow solid) is obtained, product is not purified directly to carry out next step reaction.
3rd step
4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- (2- ((t-Butyldimethylsilyl) epoxide) ethyoxyl) pyridine) -3- bases) piperidines -1- formamides 127d
Triphosgene (17mg, 0.058mmol) is dissolved in 10mL tetrahydrofurans, crude product 127c (41mg are added, 0.153mmol), 0.06mL triethylamines, react 30 minutes in 25 DEG C, 1f (50mg, 0.146mmol) is added, is reacted 1 hour in 25 DEG C.After reaction terminates, add 2mL methanol and reaction is quenched, reaction solution is concentrated under reduced pressure.50mL ethyl acetate and 30mL water are added in residue, divide liquid, aqueous phase is extracted with ethyl acetate (40mL × 2), merges organic phase, and organic phase washed once with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude title product 127d (60mg, yellow oil), product is not purified directly to carry out next step reaction
4th step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- (2- hydroxy ethoxies) pyridin-3-yl) piperidines -1- formamides 127
Crude product 127d (60mg, 0.0942mmol) is dissolved in 5mL methanol, stirring reaction 18 hours at the hydrochloric acid solution that 1mL concentration is 2M, 25 DEG C are added.After reaction terminates, reaction solution adjusts pH to 7 with saturated solution of sodium bicarbonate, ethyl acetate extracts (30mL × 3), merges organic phase, and organic phase washed once with saturated nacl aqueous solution 30mL, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue obtain the (12mg of title product 127, white solid), yield 24%.
MS m/z(ESI):524.3[M+1]
1H NMR(400MHz,CD3OD)δ8.07(d,2H),7.70(dd,1H),6.98-7.05(m,2H),6.75-6.80(m,2H),4.30(t,2H),4.20(d,2H),3.86(t,2H),3.60-3.70(m,1H),3.35(s,1H),3.01(t,2H),1.93(d,2H),1.60-1.67(m,2H).
Embodiment 128
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyano group -3- methoxy-benzyls) piperidines -1- formamides
The first step
4- (azido-methyl) -2- methoxy cyanophenyls 128b
4- chloromethyl -2- methoxy cyanophenyls 128a (400mg, 2.2mmol) are dissolved in 10mL DMFs, stirring reaction 2 hours at prefabricated 2mL sodium azide (170mg, 2.62mmol) solution, 25 DEG C are added dropwise.After reaction terminates, ethyl acetate is added, water washing 2 times, saturated nacl aqueous solution is washed 1 time, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains crude title product 128b (400mg, colorless oil), the not purified direct next step of product.
Second step
4- (aminomethyl) -2- methoxy cyanophenyls 128c
Crude product 128b (400mg, 2.12mmol) is dissolved in 20mL tetrahydrofurans, addition 3mL water, triphenylphosphine (669mg, 2.55mmol), stirring reaction 18 hours at 45 DEG C.After reaction terminates, ethyl acetate is added, saturated nacl aqueous solution is washed 1 time, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 128c (130mg, white solid), yield 31.8%.
3rd step
4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (4- cyano group -3- methoxybenzyls) piperidines -1- formamides 128
By triphosgene (43mg, 0.15mmol) it is dissolved in 20mL tetrahydrofurans, add prefabricated 5mL 128c (49mg, 0.305mmol) with triethylamine (88mg, tetrahydrofuran solution 0.87mmol), reacts 30 minutes in 25 DEG C, adds 1f (100mg, 0.29mmol), reacted 1 hour in 25 DEG C.Reaction terminate after, add methanol reaction is quenched, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue obtain title product 128 (60mg, pale solid), yield 38.9%.
MS m/z(ESI):532.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.37(s,1H),7.64-7.66(d,1H),717-7.22(m,2H),7.10(s,1H),6.96-6.98(m,2H),6.69-6.71(m,1H),4.30(s,2H),4.05-4.08(m,2H),3.88(s,3H),3.49-3.51(m,1H),2.79-2.81(m,2H),1.79-1.82(m,2H),1.39-1.42(m,2H).
Embodiment 129
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- (1- difluoromethyls) -1H- pyrazoles -4- bases) pyridin-3-yl) piperidines -1- formamides
The first step
6- (1- (difluoromethyl) -1H- pyrazoles -4- bases) pyridine -3- amine 129b
By 1- (difluoromethyl) -4- (4,4,5,5- tetramethyls -1,3,2- dioxy boron pentane -2- bases) -1H- pyrazoles 129a (150mg, 0.615mmol, it is prepared using method disclosed in patent application " WO2014159224 "), the bromo- 3- aminopyridines (106mg, 0.615mmol) of 6-, [1, double (diphenylphosphine) ferrocene of 1'-] palladium chloride (45mg, 0.062mmol), potassium carbonate (255mg, 1.845mmol) is added in 10mL dioxane and 2mL water, under argon atmospher, in 85 DEG C of stirring reactions 3 hours.After reaction terminates, 50mL water is added in reaction solution, it is extracted with ethyl acetate (80mL × 3), merges organic phase, organic phase is washed 1 time with 50mL saturated sodium-chloride water solutions, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 129b (150mg, brown oil).
Second step
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (6- (1- difluoromethyls) -1H- pyrazoles -4- bases) pyridin-3-yl) piperidines -1- formamides 129
Triphosgene (40mg, 0.135mmol) is dissolved in 10mL tetrahydrofurans, 129b (34mg are added, 0.161mmol), 0.3mL triethylamines, react 30 minutes in 25 DEG C, 1f (50mg, 0.145mmol) is added, is reacted 1 hour in 25 DEG C.Reaction terminate after, add methanol, reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 129 (9mg, yellow solid), yield 10.7%.
MS m/z(ESI):580.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.79(s,1H),8.70(s,1H),8.64(s,1H),8.39(s,1H),8.28(s,1H),7.92(d,1H),7.84(t,1H),7.70(d,1H),7.16(t,1H),6.98-7.00(m,1H),6.71-6.73(m,1H),4.19-4.22(m,2H),3.53-3.59(m,1H),2.89-2.95 (m,2H),1.87-1.90(m,2H),1.45-1.53(m,2H).
Embodiment 130
N- (6- ((1- amino cyclopropyl) methoxyl group) pyridin-3-yl) -4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides
The first step
(1- (((5- nitropyridine -2- bases) epoxide) methyl) cyclopropyl) amino tert-butyl ester 130b
By (1- (methylol) cyclopropyl) t-butyl carbamate (0.709g, 3.784mmol) it is dissolved in 20mL N, in dinethylformamide, ice bath, adds 60% sodium hydride (0.15g, 3.784mmol), reacted 0.5 hour at 25 DEG C, add at 2- chloro-5-nitropyridines 130a (0.5g, 3.154mmol), 25 DEG C and react 2.5 hours.After reaction terminates, 60mL water is added, is extracted with ethyl acetate (50mL × 3), merge organic phase, organic phase is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 130b (455mg, yellow solid), yield 46.6%.
Second step
(1- (((5- aminopyridine -2- bases) epoxide) methyl) cyclopropyl) t-butyl carbamate 130c
130b (455mg, 1.471mmol) is dissolved in 25mL second alcohol and waters (V:V=4:1) in the mixed solvent.Iron powder (329mg, 5.884mmol), ammonium chloride (1.812g, 11.768mmol) are sequentially added into reaction solution.Reaction solution is warming up to 70 DEG C, stirring reaction 1.5 hours.After reaction terminates, reaction solution is added into 50mL water, It is extracted with ethyl acetate (30mL × 3), merges organic phase, organic phase is washed (100mL × 2) with saturated nacl aqueous solution, is concentrated under reduced pressure, and obtains crude title product 130c (410mg), the not purified direct next step of product.
3rd step
(1- (((5-4- (2- (the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides) pyridine -2- bases) epoxide) methyl) cyclopropyl) t-butyl carbamate 130d
At 0 DEG C, by triphosgene (86mg, 0.29mmol) it is dissolved in 5mL tetrahydrofurans, the prefabricated 1mL crude products 130c (81mg, 0.290mmol) of addition and the tetrahydrofuran solution of triethylamine (0.163mL, 1.162mmol) mixing, 0 DEG C is reacted 30 minutes, 25 DEG C add 1f (100mg, 0.29mmol) and 5mL tetrahydrofurans, are reacted 2 hours in 25 DEG C.After reaction terminates, add 5mL methanol and reaction be quenched, reaction solution is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify obtained by residue obtain title product and 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- fluorophenyls of 3-) amino) -2- (oximido) acetyl group) piperidines -1- formamides 130
130d (122mg, 0.188mmol) is dissolved in 3mL methanol, stirring reaction 2 hours at hydrogen chloride Isosorbide-5-Nitrae-dioxane solution that 3mL concentration is 4M, 25 DEG C are added.After reaction terminates, reaction solution is concentrated under reduced pressure.Residue adds 100mL ethyl acetate, with 100mL saturated solution of sodium bicarbonate, ethyl acetate extracts (100mL × 3), merge organic phase, it is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify gained residue be made title product 130 (50mg, white solid), yield 48.5%.
MS m/z(ESI):549.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(brs,2H),8.50(s,1H),8.38(s,1H),8.13-8.12(m,1H),7.76-7.73(m,1H),7.19-7.15(m,1H),6.99-6.97(m,1H),6.77-6.72(m,3H),4.18-4.15(m,2H),4.08(s,2H),3.57-3.51(m,1H),2.90-2.84(m,2H),1.87-1.84(m,2H),1.50-1.41(m,2H),0.57-0.50(m,4H).
Embodiment 131
2- (1- (4- (1H- tetrazole -1- bases) phenyl) piperidin-4-yl)-N- (the bromo- 4- fluorophenyls of 3-)-N'- hydroxyl -2- carbonyls ethanamidine 131
Raw material 81a (43.3mg, 0.1mmol) is dissolved in 1mL acetic acid, 0.1mL triethyl orthoformates are added, 25 DEG C are reacted 0.5 hour, are added under sodium azide (9.75mg, 0.15mmol), argon atmospher, and 80 DEG C are reacted 3 hours.After reaction terminates, 20mL water is added, saturated sodium bicarbonate solution regulation pH to 8, dichloromethane extraction (20mL × 3) merges organic phase, saturated nacl aqueous solution washing (20mL × 1), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.Title product 131 (12mg, light tan solid), yield 24.6% is made with eluant, eluent system A purifying institute residue in thin-layered chromatography.
MS m/z(LC-MS):488.3[M+1]
1H NMR(400MHz,CDCl3)δ8.68(s,1H),7.53-7.55(m,2H),7.02-7.06(m,3H),6.87-7.00(m,2H),3.85-3.88(m,2H),3.51-3.54(m,1H),2.93-2.96(m,2H),2.01-2.04(m,2H),1.86-1.89(m,2H).
Embodiment 132
4- (2- ((the bromo- 4- fluorophenyls of 3-) amino) -2- (oximido) acetyl group)-N- (3,4- dicyanos benzyl) piperidines -1- formamides 132
Using the synthetic route of embodiment 128, raw material 4- chloromethyl -2- methoxy cyanophenyls are replaced with 3,4- dicyano benzyls bromine (method known to using " Chem.Eur.T; 2012; 18,1727-1736 " are prepared), (50mg of title product 132 is made, khaki solid), yield 33%.
MS m/z(ESI):527.3[M+1]
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.37(s,1H),8.09(d,1H),7.97(s,1H),7.75(dd,1H),7.27(t,1H),7.17(t,1H),6.96-6.99(m,1H),6.72-6.73(m,1H),4.33(d,2H),4.02-4.05(m,2H),3.49-3.51(m,1H),2.78-2.83(m,2H),1.80-1.82(m,2H),1.38-1.44(m,2H).
Embodiment 133
2- (4- (2- ((the bromo- 4- fluorophenyls 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- bases) thiazole is replaced with into 2- bromo thiazole -5- formic acid, title product 133 (10mg, white solid), yield 7.4% is made.
MS m/z(LC-MS):471.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),8.37(s,1H),7.57(s,1H),7.14-7.19(m,1H),6.98-7.00(m,1H),6.70-6.73(m,1H),3.98-4.01(m,2H),3.56-3.62(m,1H),3.12-3.18(m,2H),1.92-1.99(m,2H),1.54-1.62(m,2H).
Embodiment 134
N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl -2- carbonyls -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 134 (5mg, yellow solid), yield 5% is made.
MS m/z(LC-MS):499.3[M+1]
Biological assessment
The explanation present invention is further described below in conjunction with test case, but these embodiments are in no way meant to be limiting for the scope of the invention.
The measure of test case 1, the compounds of this invention to people source IDO1 protease inhibiting activities
External people source IDO1 proteinase activities are tested by following method.
This method is used for determining inhibitory action of the compound in the present invention to people source IDO1 proteinase activities.
First, experiment material and instrument
1st, ELIASA (Synergy HT, BIOTEK)
2nd, tryptophan (T0254-5G, Sigma-Aldrich)
3rd, catalase derives from cattle liver (C1345-1G, Sigma-Aldrich)
4th, methylenum careuleum (M9140-25G, Sigma-Aldrich)
5th, L-AA sodium (A7631-25G, Sigma-Aldrich)
6th, 4- (dimethylamino) benzaldehyde (D2004-25G, Sigma-Aldrich)
7th, trichloroacetic acid (T9159-100G, Sigma-Aldrich)
8th, people source IDO1 genes (SC126221, Origene)
2nd, experimental procedure
The self-control of IDO1 protease
People source IDO1 genes are transferred in PET-30 (a) plasmids (Millipore, article No. 69909) by gene clone technology, the Escherichia coli rosseta of competence is then transferred to；Liquid LB (Luria-Bertani) culture medium [according to《Molecular Cloning:A Laboratory guide》(J. Pehanorm Brooker D.W. Russells work) prepares every liter of culture medium] middle amplification culture, thalline is collected, ultrasonication, by hanging nickel post, affords the IDO1 protease of purifying.
Compound test experiments：
24 μ l 100 times of enzyme (IDO1) is diluted to 2400 μ l with 50mM KPB, obtain the enzyme solutions that concentration is 2.6ng/ μ l, 24 μ l enzyme solutions are added per hole in 96 hole reaction plates (AXYGEN, PCR-96-FLT-C) (hereinafter referred to as reaction plate).Blank control wells add the 24 μ l KPB [preparations (50mM) of KPB buffer solutions： KH is weighed with assay balance2PO46.805g is put into 1000ml beaker, adds deionized water to 900ml with graduated cylinder, adjusts PH to 6.5 with 1M KOH, be conducted into 1L graduated cylinder, moisturizing to 1L.4 DEG C of storages].1 μ l compound or DMSO are added into corresponding reacting hole in reaction plate.Prepare A liquid：200 μ l 500mM L-AAs sodium plus 1050 μ l KPB are taken, are mixed.B liquid：The acid of 100 μ l 10mM color ammonia adds 100 μ l 100000unit/ml catalase, plus 5 μ l 10mM methylenum careuleum, finally plus 1050 μ lKPB, mix.1200 μ l A liquid and 1200 μ l B liquid are taken, are mixed.Then this mixed liquor is added in reaction plate with every μ l of hole 24.Reaction plate is put into constant-temperature incubation case, 37 DEG C, is incubated 1h.In reaction plate, 10 μ l 30% (W/V) trichloroacetic acids are added per hole, 65 DEG C are incubated 15 minutes in incubator.By reaction plate, 4700RPM is centrifuged on centrifuge, room temperature, 5 minutes.40 μ l supernatants are shifted into 96 hole test boards (Corning, #3599) of correspondence from reaction plate with the volley of rifle fire.40 μ l 2% (W/V) 4- (dimethylamino) benzaldehyde/glacial acetic acid solution is added per hole, 1 is mixed.After incubation at room temperature 2 minutes, the light absorption value at 480nm is read on Synergy HT (BIOTEK).
Compound is measured to experiment of the people source IDO1 protease inhibiting activities more than in the present invention, the IC measured50Value is shown in Table 1.
Compound suppresses IC to people source IDO1 proteinase activities in the present invention of table 150
Conclusion：The compounds of this invention has obvious inhibitory action to people source IDO1 proteinase activities.
The measure of test case 2, the compounds of this invention IDO protease inhibiting activities intracellular to HeLa
The intracellular IDO proteinase activities of HeLa are tested by following method.
This method is used for determining the inhibitory action of the compound IDO proteinase activities intracellular to HeLa in the present invention.(note：HeLa cell lines express indole amine 2,3-dioxygenase (IDO) under interferon gamma (INF- γ) induction)
First, experiment material and instrument
1st, ELIASA (Synergy HT, BIOTEK)
2nd, tryptophan (T0254-5G, Sigma-Aldrich)
3rd, 4- (dimethylamino) benzaldehyde (D2004-25G, Sigma-Aldrich)
4th, trichloroacetic acid (T9159-100G, Sigma-Aldrich)
5th, HeLa cell lines (CCL-2, ATCC)
2nd, experimental procedure
HeLa cell suspensions are produced with Fresh cell culture medium, with 10000 cells/wells, 100 μ l cell suspensions are added into 96 porocyte culture plates, 5% carbon dioxide, 37 DEG C are cultivated 24 hours.Supernatant is removed, 90 μ l serum-free DMEM high glucose mediums are first added per hole；Then the compounds of 10 μ l gradient dilutions is separately added into per hole, and (dilution is γ containing INF- and tryptophan and 20%FBS culture medium, and its final concentration is followed successively by：100000,10000,1000,100,10,1nM), 5% carbon dioxide, 37 DEG C are cultivated 48 hours, take 96 hole cell trainings Support the μ l of supernatant 80 in plate and, into 96 hole round bottom plates, 16 μ l 30% (W/V) trichloroacetic acids are added per hole, 65 DEG C are incubated 25 minutes in incubator.By reaction plate, 4700RPM is centrifuged on centrifuge, 5 minutes.50 μ l supernatants are shifted into 96 hole flat bottom clear plates from reaction plate with the volley of rifle fire, 50 μ l 2% (W/V) 4- (dimethylamino) benzaldehyde/glacial acetic acid solution is then added per hole, are mixed 1 minute on the oscillator.After incubation at room temperature 2 minutes, the light absorption value at 480nm is read on Synergy HT Reader.
Experiment of the compound IDO protease inhibiting activities intracellular to HeLa more than is measured in the present invention, the IC measured50Value is shown in Table 2.
Compound IDO proteinase activities intracellular to HeLa suppress IC in the present invention of table 250
Conclusion：The compounds of this invention IDO proteinase activities intracellular to HeLa have obvious inhibitory action.
Pharmacokinetic Evaluation
The pharmacokinetics test of test case 3, compound of the embodiment of the present invention
1st, make a summary
Using SD rats as animal subject, determine rat oral gavage using LC/MS/MS methods and give after embodiment 2,3,4,20,21,30,50,105,106,107 and 125 compounds not drug concentration in blood plasma in the same time.Pharmacokinetics behavior of the compounds of this invention in rat body is studied, its characteristics of pharmacokinetics is evaluated.
2nd, 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, male and female half and half, purchased from the western pul-Bi Kai experimental animals Co., Ltd in Shanghai, animal productiong licensing number：SCXK (Shanghai) 2008-0016.
2.3 medicines are prepared
Appropriate amount of drug is weighed, adding 0.3ml dimethyl acetamides makes after dissolving, add 10%2- hydroxypropyl-β-cyclodextrins to final volume, 0.3mg/ml suspensions are made in ultrasound.0.2mg/mL suspensions are made in the wherein ultrasound of embodiment 50.
2.4 administration
SD rats 44, male and female half and half are divided into 11 groups；Gastric infusion, gastric infusion volume 10ml/kg are distinguished after the night of fasting one.
3rd, operate
Gastric infusion group 0.5,1.0,2.0,4.0,6.0,8.0,11.0,24.0h blood sampling 0.2ml before being administered and after administration, are placed in heparinised tubes, 3500rpm centrifugation 10min separated plasmas, are preserved in -20 DEG C.
The testing compound content after different compound gastric infusions in rat plasma is determined with LC/MS/MS methods.
4th, 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 is as follows：
Conclusion：In the medicine generation of the compounds of this invention, absorbs good, with obvious medicine for assimilation effect.

Claims (21)

  1. A kind of compound shown in logical formula (I)：
    Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt,
    Wherein：
    Mixture selected from cis-isomer, transisomer and cis-trans-isomer；
    Ring A is selected from cycloalkyl or heterocyclic radical, wherein described cycloalkyl or heterocyclic radical are optionally selected from alkyl, halogen, amino, nitro, hydroxyl, alkoxy, hydroxyalkyl, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR independently of one another4、-C(O)R4、-C(O)OR4、-S(O)mR4、-S(O)mNR5R6、-NR5R6、-C(O)NR5R6、-NR5C(O)R6With-NR5S(O)mR6One or more of substituent replaced；
    R1It is identical or different, and it is each independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano group, cycloalkyl, heterocyclic radical, 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 described alkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amino, nitro, cyano group, hydroxyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-R independently of one another3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-S(O)mNR7R8、-NR7R8、-C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8One or more of substituent replaced；
    R2It is identical or different, and it is each independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano group, cycloalkyl, heterocyclic radical, aryl and heteroaryl；
    R3Selected from alkyl, haloalkyl, cycloalkyl, cycloalkyl alkoxy, heterocyclic radical, aryl and heteroaryl, wherein described alkyl, haloalkyl, cycloalkyl, cycloalkyl alkoxy, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, halogen, haloalkyl, amino, nitro, hydroxyl, alkoxy, hydroxyalkyl, cyano group, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) NR independently of one another7R8、-S(O)mR7、-C(O)OR7With-OR7One or more of substituent replaced；Wherein described cycloalkyl-alkyl is optionally selected from one or more of alkyl, halogen, haloalkyl, amino, hydroxyl, alkoxy, hydroxyalkyl substituent and replaced；
    R4Selected from hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, alkoxy, halogenated alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR7R8、-NR7C(O)R8With-NR7S(O)mR8, wherein described alkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, halogen independently of one another Element, amino, nitro, cyano group, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, 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 substituent replaced；
    R5And R6It is identical or different, and it is each independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, hydroxyalkyl, hydroxyl, amino, cycloalkyl, heterocyclic radical, 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 described alkyl, haloalkyl, amino, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, hydroxyl, amino, nitro, cyano group, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl ,-R independently of one another3、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR7R8、-C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8One or more of substituent replaced；
    R7And R8It is identical or different, and it is each independently selected from hydrogen atom, alkyl, alkoxy, hydroxyalkyl, hydroxyl, amino, carboxylic acid ester groups ,-S (O)mNR9C(O)OR10、-C(O)OR10、-S(O)mNR9R10, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical, aryl and heteroaryl, replaced wherein described alkyl, amino, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical, aryl and heteroaryl are optionally selected from one or more of alkyl, halogen, hydroxyl, amino, carboxylic acid ester groups, nitro, cyano group, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl substituent independently of one another；
    R9And R10It is identical or different, and it is 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.
  2. Compound shown in logical formula (I) according to claim 1, wherein：A is selected from cycloalkyl or heterocyclic radical.
  3. Compound according to logical formula (I) according to any one of claims 1 to 2, wherein n is 1.
  4. Compound according to logical formula (I) according to any one of claims 1 to 3, wherein p is 1,2 or 3.
  5. Compound according to logical formula (I) according to any one of claims 1 to 4, 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, wherein described alkyl, amino, aryl and heteroaryl are optionally selected from nitro, cyano group ,-R independently of one another3、-C(O)NR7R8、-NR7C(O)R8With-NR7S(O)mR8 One or more of substituent replaced；R3~R8, x and m it is as defined in claim 1.
  6. According to logical formula (I) according to any one of claims 1 to 5, wherein R2For halogen, haloalkyl or alkenyl.
  7. Compound shown in logical formula (I) according to claim 1, it is the compound shown in logical formula (II)：
    Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt,
    Wherein：R1、R2And p is as defined in claim 1.
  8. Compound shown in logical formula (II) according to claim 7, it is the compound shown in logical formula (III)：
    Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt,
    Wherein：R1、R2It is as defined in claim 1 with p.
  9. Compound shown in logical formula (I) according to claim 1, it is the compound shown in logical formula (IV)：
    Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt,
    Wherein：
    Ring B is selected from aryl or heteroaryl；
    RaSelected from hydrogen atom, alkyl, haloalkyl, halogen, amino, nitro, cyano group, hydroxyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, 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 it is as defined in claim 1；And
    Y is 0,1,2,3,4 or 5.
  10. Compound shown in logical formula (I) according to claim 1, it is the compound shown in logical formula (V)：
    Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt,
    Wherein：
    G is selected from C or N；
    RaSelected from hydrogen atom, alkyl, haloalkyl, halogen, amino, nitro, cyano group, hydroxyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, 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 it is as defined in claim 1；And
    Y is 0,1,2,3,4 or 5.
  11. Compound shown in logical formula (V) according to claim 10, it is the compound shown in formula (V-A)：
    Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt,
    Wherein：
    RbSelected from hydrogen atom, alkyl, haloalkyl, amino, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein described wherein described alkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl is optionally selected from alkyl, halogen, amino, nitro, hydroxyl, alkoxy, hydroxyalkyl, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR independently of one another4、-C(O)R4、-C(O)OR4、-S(O)mR4、-S(O)mNR5R6、-NR5R6、-C(O)NR5R6、-NR5C(O)R6With-NR5S(O)mR6One or more of substituent replaced；
    R4~R6It is as defined in claim 1 with m.
  12. The compound shown in logical formula (I) according to any one of claim 1~11, it is selected from：
  13. A kind of method for preparing logical formula (I) compound according to claim 1, this method includes：
    Formula (I-A) compound at ambient temperature, with R1- NCO react or at low temperature under alkalescence condition with R1Halide reaction, be optionally deprotected in acid condition, obtain 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 includes：
    The derivatives reaction of formula (I-B) compound at ambient temperature with aniline, obtains logical formula (I) compound；
    Wherein, R1、R2, A, p and n it is as defined in claim 1.
  15. Compound shown in a kind of formula (I-B)：
    Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt,
    Wherein, R1It is as defined in claim 1 with n.
  16. The compound shown in formula (I-B) according to claim 15, it is selected from：
  17. A kind of pharmaceutical composition, it contains the compound shown in the logical formula (I) according to any one of claim 1~12 of therapeutically effective amount, and one or more pharmaceutically acceptable carriers, diluent or excipient.
  18. The purposes of compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt or pharmaceutical composition according to claim 17 in the medicine for preparing the disease for preventing and/or treating the pathological characteristicses with the IDO tryptophan metabolic pathways mediated shown in logical formula (I) according to any one of claim 1~12.
  19. Purposes according to claim 18, the wherein described disease with the IDO tryptophan metabolic pathway pathological characteristicses mediated is selected from cancer, myelodysplastic syndrome, Alzheimer disease, autoimmune disease, depression, anxiety disorder, cataract, mental handicape and AIDS, wherein described cancer is preferably selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, stomach cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, carcinoma of urinary bladder, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phase melanomas, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, breast Prominent kidney knurl, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer.
  20. The method that a kind of Prevention and/or Prevention have the disease of the pathological characteristicses of the tryptophan metabolic pathway of IDO mediations, it includes the compound or its dynamic isomer shown in the logical formula (I) according to any one of claim 1~12 of patient therapeuticallv's effective dose, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt or pharmaceutical composition according to claim 17, the wherein described disease with the IDO tryptophan metabolic pathway pathological characteristicses mediated is selected from cancer, myelodysplastic syndrome, Alzheimer disease, autoimmune disease, depression, anxiety disorder, cataract, mental handicape and AIDS.
  21. The method that a kind of Prevention and/or Prevention have the disease of the pathological characteristicses of the tryptophan metabolic pathway of IDO mediations, it includes the compound or its dynamic isomer shown in the logical formula (I) according to any one of claim 1~12 of patient therapeuticallv's effective dose, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures or its officinal salt or pharmaceutical composition according to claim 17, wherein the disease with the IDO tryptophan metabolic pathway pathological characteristicses mediated is selected from cancer, wherein described cancer is selected from breast cancer, cervical carcinoma, colon cancer, lung cancer, stomach cancer, the carcinoma of the rectum, cancer of pancreas, the cancer of the brain, cutaneum carcinoma, carcinoma of mouth, prostate cancer, osteocarcinoma, kidney, oophoroma, carcinoma of urinary bladder, liver cancer, fallopian tube cneoplasms, ovarioncus, peritoneal tumor, IV phase melanomas, solid tumor, glioma, spongioblastoma, hepatocellular carcinoma, mastoid process kidney knurl, head and neck neoplasm, leukaemia, lymthoma, myeloma and non-small cell lung cancer.
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